Growth hormone (GH), also known as somatotropin or human growth hormone (hGH or HGH), is a peptide hormone (substances made of amino acids) that stimulates muscle and bone growth, cell reproduction, and cell regeneration in humans and other animals.  GH also plays a major role in increasing muscle mass and bone density, sugar and fat metabolism, regulating body fluids, and maintaining the health of all human tissues, including vital organs such as the heart and brain. 
The release of GH in the pituitary gland, a pea-sized gland located below the brain, is governed by two hormones: growth hormone-releasing hormone and growth hormone-inhibiting hormone.  Different external stimulatory and inhibitory factors may affect the release of GH including: 
Some inhibitors of growth hormone secretion include: 
Young adolescents especially those in the puberty period, secrete GH at the rate of about 700 μg/day, while healthy adults secrete GH at a lower rate of about 400 μg/day – these surges of GH secretion occur during the day every 3 to 5 hours.  When secreted into the bloodstream, GH remains active for only a few minutes, but this is enough time for the liver to convert it into growth factors, which are necessary for the stimulation of growth in living cells. 
The most essential of all growth factors is the insulin-like growth factor 1 (IGF-1), also called somatomedin C, which boasts a host of anabolic properties. IGF-1 is a hormone that resembles the molecular structure of insulin. It supports cellular division, growth of muscles and organs, helps repair nerve damage in different vital organs, reduces body fat by using fat as a source of energy instead of glucose, and it helps increase the number and size of cells in the body.  IGF-1 is produced primarily by the liver as an endocrine hormone. Its production is stimulated by GH and can be retarded by a number of factors such as malnutrition, growth hormone insensitivity and lack of growth hormone receptors. 
Measurements of IGF-1 are adjusted for age because its levels tend to decline over time. Normal ranges of IGF-1 by age are: 
GH stimulates the production of IGF-1. GH is broken down in the liver and is converted to IGF-1. Additional IGF-1 is also generated within target tissues. IGF-1 by itself and in combination with other growth factors play an important role in healing, muscle and bone growth, repair processes, and other essential functions in the body. Most of the effects of GH are mediated through IGF-1.  When the levels of GH rise or fall below the normal, the same thing will happen to IGF-1.  The GH/IGF1 system is dynamic and its activity is greatly influenced by age, sexual maturation, body composition and other factors.
Growth hormone deficiency (GHD) is a disorder characterized by an absent or insufficient secretion of growth hormone from the pituitary gland, resulting in slower growth and development.  Both children and adults can be diagnosed with GHD, and the exams and tests used are the same for all age groups. Diagnosing GHD typically starts with a physical exam to assess signs and symptoms of slowed growth. The doctor will check the patient’s weight, height, and body proportions as individuals with GHD are much shorter than normal persons. Other than a physical exam, there are a wide range of tests and exams required in order to come up with a GHD diagnosis.
Blood tests for GHD include the following:
In addition to blood tests, the doctor can also perform additional exams and tests such as X-rays and MRI to help diagnose GHD.
It is normal for the pituitary gland to produce lesser amounts of GH, sex hormones, and other essential hormones in the body as a person ages. Physicians therefore distinguish between age-related GHD and those with identifiable causes which can be present at birth (congenital), or acquired at some point in life.
Congenital causes of GHD are:
Acquired causes of GHD include the following:
In children, symptoms of GHD include the following: 
In adults, the symptoms can vary, and most of them can experience the following: 
This medical condition happens when there is insufficient conversion of GH to IGF-1 by the liver.  To determine IGF-1-deficiency, your doctor will order an IGF-1 blood test, or also known as SM-C/IGF-1, Somatomedin-C, and Sulfation factor. IGF-1 blood test is primarily ordered to check for pituitary gland disorders and to assess abnormalities in growth hormone production.  An IGF-1 blood test is commonly ordered for patients with symptoms of insufficient or excess production of GH and IGF-1. Unlike GH, the levels of IGF-1 are stable throughout the day, making it a significant indicator of average GH levels. 
Several factors can affect the conversion of GH to IGF-1 by the liver, leading to deficient IGF-1 levels. First and foremost, if there is an existing problem in the principal site of GH to IGF-1 conversion which is the liver,  then such conversion may not happen or the liver can only produce little amounts of IGF-1. Also, if there is insufficient amount of GH in the blood, the levels of IGF-1 can fall below the normal. Other factors which can affect IGF-1 levels are pituitary tumors, gene mutations, head injuries or trauma, infections, radiation and surgery.  Also, caloric or protein restriction in the diet can decrease the levels of IGF-1 by decreasing the liver cells’ sensitivity to GH stimulation. 
In children, the following may indicate IGF-1 deficiency: 
In adults, abnormally low levels of IGF-1 may cause subtle, nonspecific symptoms such as: 
The billion-dollar anti-aging hormone-therapy industry is based on a simple principle: As people age, levels of various hormones in the body decrease significantly; so replenishing youthful levels of those hormones is the key to slowing down the process of aging. The anti-aging hormone-therapy began as an industry in 1990, in New England, when 12 men over age 60 were injected with growth hormones.  All of the subjects experienced an increase in muscle mass and bone density, and had a significant reduction in body fat. Entrepreneurs quickly took on the study and repackaged it as a form of “anti-aging” and began offering it in cosmetic clinics and other pharmaceutical companies. Since then, thousands of research studies have been conducted on GH and IGF-1, linking it to an ever-expanding list of health-related benefits.
Among its many biological effects, GH injection promotes an increase in muscle mass, bone density, exercise capacity, and a decrease in body fat. [33-34] Studies show that people with significant GH deficiency secondary to pituitary disease, have increased body fat and decreased muscle mass and bone density.  These body changes in GH-deficient patients mimic aging.
The landmark study of Rudman and colleagues in 1990 reported that 6 months GH injections in men over 65 years of age who have low levels of plasma IGF-1, showed increased muscle mass and bone mineral density in some of the examined sites of the skeleton and showed improved general well-being.  These promising results elicited enormous general interest in large pharmaceutical companies and wellness clinics, and raised the possibility of using GH replacement therapy to slow down, or perhaps reverse the process of aging, or at least some symptoms related to it. These exciting possibilities were consistent with well-documented and beneficial effects of GH supplementation in GH-deficient patients,  and with the ability of GH therapy to improve age-related changes in metabolic characteristics, brain vascularity and cognitive function.  The actions of GH have already been related to longevity in other mammals such as carnivores, rodents and ungulates. 
The major role of IGF-1, insulin and other homologous molecules in the control of longevity has been conclusively documented in a wide variety of organisms such as worms, insects, and mammals.  In mammals, the natural decline in circulating IGF-1 levels due to aging has been associated with neuronal aging and symptoms of neurodegeneration. 
Signaling through the insulin/IGF-1 pro-survival pathway is known to demonstrate protective effects in nerve cells (neurons) and it plays an important role in neuronal growth and physiology. [42-43] Suspected mechanisms of IGF-1 action in aging include reduced insulin signaling and enhanced sensitivity to insulin, thus, slowing the aging process.  Aging is associated with increased vascular oxidative stress and vascular disease.  One of the mechanisms in which IGF-1 can slow the process of aging is that IGF-1 can reduce oxidative stress. 
As people age, there are a wide array of health issues they face. These include loss of muscle and bone mass, slow recovery from injury, decreased sexual function and desire, mood changes and other symptoms related with aging. Fortunately, recent advances in the anti-aging industry showed that an effective IGF-1 supplement can address all of these concerns by supporting muscle and bone growth,  increasing nerve regeneration, and ramping up sexual power.
No matter what value and how potent an IGF-1 supplement has, it is useless if the method of delivery is not viable. IGF-1, like all growth factor hormones, is difficult to supplement due to the fragility of the compounds. Oral supplementation of IGF-1 is ineffective because they are typically destroyed in the gastrointestinal tract due to their extreme sensitivity to decomposition during digestion.  IGF-1, whether artificial or natural, must be administered via subcutaneous (between the skin and muscle) or intramuscular injections to avoid stomach acids and for it to be effective.
IGF-1 variants are classified into two groups: IGF-1 LR3 and DES IGF-1. Base IGF-1 has a very short half-life which only lasts about 10 to 20 minutes,  as a result, it is quickly destroyed by the body. To solve this issue, IGF-1 was modified leading to the creation of the amino acid analog IGF-1 LR3 (Long). The other variant of IGF-1 is known as DES IGF-1, which is a truncated version that is 10 times more potent than IGF-1. These variants have different actions which allow them to function in specific ways.
IGF-1 LR3 is also known as Insulin-Like Growth Factor-I Long Arg3 or Long R3 IGF-1. The IGF-1 LR3 is a long-term analog of human IGF-1 which has a half-life of about 20 to 30 hours and is much more potent than base IGF-1.  The enhanced potency of IGF-1 LR3 is due to its decreased binding action to all known IGF binding proteins – these binding proteins normally inhibit the biological actions of IGF. Since the half-life of IGF-1 LR3 is about a day, it will circulate in the body for longer periods of time and will bind to receptors and activate cell communication that improves muscle growth and fat reduction.
IGF-1 LR3 helps build new muscle tissue in the body by promoting nitrogen retention and protein synthesis.  This in turn causes muscle growth through both hyperplasia (increase in muscle cells) and mitogenesis (actual growth of new muscle fibers). Thus, IGF-1 LR3 does not only make muscle fibers grow bigger, but it also makes more of them.
When IGF-1 LR3 is active, it plays multiple roles on the tissues in muscle cells. IGF-1 LR3 increases the activity of satellite cells (precursors to skeletal muscle cells), muscle protein content, muscle DNA, muscle weight and muscle cross sectional area – all of these induce muscle growth and their effects are enhanced when combined with weight training.
IGF-1 DES is the shorter version of the IGF-1 chain, which is 5 times more potent than IGF-LR3 and 10 times more potent than regular base IGF-1.  The half-life for IGF-1 DES is about 20-30 minutes.  It has the ability to stimulate muscle hyperplasia better than IGF-1 LR3 so it is best used for site injections where you want to see muscle growth rather than overall growth. In addition, IGF-1 DES is known to bind to receptors that have been deformed by lactic acid, which occurs during workouts.  This allows IGF-1 DES to bind itself to a mutated receptor and signal growth of tissues during training. IGF-1 DES can be used for longer periods of time and more frequently than IGF-1 LR3.
GH actually is a precursor to IGF-1. GH does not directly cause muscle growth, but indirectly causes muscle growth by signaling the release of IGF-1.  There are several theories as to how GH affects muscle growth. One is called the Dual Effectory Theory, which states that GH has direct anabolic effects on different tissues of the body.  In one study involving genetically altered mice, GH has been shown to have more growth potential than 1GF-1, but when an element that destroys IGF-1 was administered together with GH, the anabolic effects weren’t present.  This shows that IGF-1 is involved somewhere between the pituitary gland and the target tissue.
A second theory is the Somatomedin theory. This states that GH exerts its anabolic effects through IGF-1.  When GH is first released into the bloodstream, it travels to the liver and other surrounding tissues where it begins the synthesis and release of IGF-1. A study performed to support this theory showed that GH-deficient animals were able to reach normal growth levels after IGF-1 administration. 
It is a well-known fact that the levels of IGF-1 are significantly raised after GH administration. It would seem logical that one could skip GH administration and take IGF-1 instead as IGF-1 is considered as a potential promoter of growth and lipolysis (lipid breakdown).  Due to the lower cost of IGF-1, many have opted to replace GH supplementation with IGF-1. Skipping the sequences involved with synthesizing IGF-1 from GH will yield results that are equal or greater than GH administration.
IGF-1 may be implicated in various pathological conditions. IGF-1 and synthetic IGF-1 analogues have therapeutic medical applications aside from its benefits in bodybuilding, growth and development, and other essential biochemical processes. An overwhelming body of research supports the following benefits of IGF-1:
IGF-1 has significant structural homology with insulin. It has been shown to bind to insulin receptors to stimulate the transport of blood sugar (glucose) into fat and muscle, inhibit excessive glucose production by the liver and lower blood glucose while simultaneously suppressing the secretion of insulin.  Studies in diabetic patients who are in insulin-deficient states have shown that their IGF-1 concentrations in the blood were also low and were increased with insulin therapy.  Similarly, administration of insulin via the portal vein (a vessel that moves blood from the spleen and gastrointestinal tract to the liver) results in optimization of plasma IGF-1 concentrations. In one study involving a patient with a partial gene deletion (a mutation in which a chromosome or a sequence of DNA is lost) of the insulin-like growth factor-1 (IGF-1) gene, Woods et al. reported that the lack of IGF-1 gene results in IGF-1 deficiency, severe insulin resistance, and short stature, and that IGF-1 therapy resulted in beneficial effects on insulin sensitivity, body composition, bone size, and linear growth.  Administration of IGF-1 in diabetic patients has also been shown to result in an improvement not only in insulin sensitivity and quality of life, but it significantly reduced the dose of the required insulin to maintain balance in glucose levels. [64-89] Taken together, these findings support that IGF-1 administration is necessary to maintain normal insulin sensitivity, and impairment in the synthesis of IGF-1 results in a worsening state of insulin resistance.
Low levels of IGF-1 are associated with hypertension.  Several clinical trials have suggested that IGF-1 may have a role in preventing the development of hypertension.  In vitro and in vivo experiments have shown that IGF-1 has vasodilatory properties. [92-93] Normally, blood pressure increases if blood cannot flow freely inside the blood vessels due to narrowing of the opening, fat deposits, plaques and other causes.  Vasodilatory action of IGF-1 causes the blood vessels to relax or widen, thereby allowing more blood to flow freely inside it. This in turn leads to a reduction in the blood pressure. IGF-1 also attenuates the contractile action of the powerful vasoconstrictor known as endothelin-1 by altering the signaling activity of its receptors in smooth muscle cells.  Moreover, the role of IGF-1 in improving blood glucose levels can also help lower blood pressure. High blood glucose causes the blood to become thick and sticky, thus affecting its normal flow.  This in turn increases the pressure within the blood vessels and can lead to rupture if not treated. Because of these powerful mechanisms, numerous high-quality studies have shown that IGF-1 replacement therapy in patients with hypertension may help normalize blood pressure, thereby reducing their risk of developing serious medical conditions. [97-105]
IGF-1 levels, like testosterone, decline in an age-dependent manner. This progressive decline leads to various symptoms including erectile dysfunction (ED). Interestingly, IGF-1 is known to mediate endothelial nitric oxide production. Nitric oxide is considered to be a principal mediator of penile erection by causing relaxation of vascular smooth muscle which leads to engorgement of the penis with blood, thereby developing an erection.  The relationship of IGF-1 and penile erection has been described in otherwise healthy male subjects, and recent in vitro studies suggest that IGF-1 increases nitric oxide and may help maintain erectile function. [107-112] In one study, Pastuszak et al. reported that IGF-1 levels correlate significantly with sexual function scores in 65 men who completed the Sexual Health Inventory for Men (SHIM) and Expanded Prostate Cancer Index Composite (EPIC) questionnaires.  Other studies even reported that restoring IGF-1 levels through IGF-1 supplementation may help treat erectile dysfunction and increase libido. 
In recent years, there have been rapid developments in the use of growth factors such as IGF-1 for accelerated healing of injury. The crucial role of IGF-1 in wound healing and tissue repair has been successfully used in plastic surgery and the technology is now being developed for orthopedics and sports medicine applications.  Growth factors mediate the biological processes necessary for repair of muscles, tendons and ligaments following acute traumatic or overuse injury. In one study, Provenzano et al. reported that systemic administration of IGF-1 improved healing in collagenous connective tissue, such as ligament.  In a similar study, Kurtz et al. found out that IGF-1 has an anti-inflammatory mechanism which reduces maximum functional deficit and accelerates recovery after Achilles tendon injury.  In another study, Emel et al. investigated the effects of local administration of IGF-1 on the functional recovery of paralyzed muscles.  The results of the study showed that IGF-1 administration increased the rate of axon (nerve fiber) regeneration in crush-injured and freeze-injured sciatic nerves of the lower spine, buttocks and back of the thigh. Furthermore, numerous studies even show that IGF-1 can accelerate the regeneration of damaged body structures. [119-122]
Wound healing is a complex process which is affected by IGF-1 bound to insulin-like growth factor-binding protein (IGFBP).  This growth factor has receptors which stimulate local collagen formation necessary for wound healing.  In addition, IGF-1 and other growth factors modulate skin cell survival and regeneration.  A study performed to support the wound healing effects of IGF-1 showed that patients receiving 0.2 mg/kg/day recombinant human growth hormone (rHGH) demonstrated significantly higher IGF-1 blood levels and a significant decrease in donor-site healing times and length of hospital stay.  In another study, Aydin et al. reported that diabetic patients who had higher levels of IGF-1 had improved wound healing rate compared to those with lower levels.  Other studies assessing the therapeutic benefits of IGF-1 in patients with chronic wound have shown that the treatment speeds up the repair of damaged tissues by increasing the number of cells necessary for the wound healing process. [128-139]
Neuropathy is the term used to describe a problem with the nerves, typically causing numbness and problems with mobility.  Preclinical studies suggest that IGF-1 can be useful for the treatment of mixed motor and sensory neuropathies. The successful use of IGF-1 in the treatment of peripheral neuropathies may provide the first true therapy for this previously untreatable group of neurological disorders. In one study, Schmidt et al. reported that IGF-1 treatment for a period of 2 months resulted in nearly complete normalization of diabetic neuropathy without altering the severity of diabetes.  In another study, therapeutic administration of IGF-1 slowed the degeneration of spinal cord motor neuron axons by reducing the incidence of programmed cell death. Several recent studies involving IGF-1 treatment for Duchenne Muscular Dystrophy (DMD), one of the most prevalent muscle disorders, have also shown significant improvements in muscle functional recovery after the treatment.  Similarly, other studies assessing the therapeutic benefits of IGF-1 therapy in a wide array of medical conditions related to nerve damage have shown that the treatment may help restore nerve function and sensation. [144-162]
Recent studies have shown that patients who suffered from acute stroke and those who are at increased risk for stroke have depressed blood levels of IGF-1. [163-172] It seems also that post-stroke IGF-1 blood levels are correlated with the outcome from ischemic brain injury (insufficient blood flow to the brain), with higher IGF-1 levels reducing lethality.  Many studies have shown the benefits of IGF-1 administration in post-stroke patients by reducing loss of neurons, infarct volume (extent of ischemic brain injury), while increasing glial proliferation (glial cells supply essential nutrients and protect the neurons).  Moreover, IGF-1 appears to be linked with repair processes following brain damage by controlling the regeneration of injured peripheral nerves.  In one study, Sohrabji et al. reported that estrogen-mediated neuroprotection in neural injury models is critically dependent on IGF-1 signaling.  The results of the study showed that estrogen and IGF-1 act cooperatively to influence cell survival. When given alone, posttraumatic administration of IGF-1 may be efficacious in ameliorating neurobehavioral dysfunction in traumatic brain injury. [177-178] A study by Lioutas et al. even found that intranasal IGF-1 administration has demonstrated a benefit for prevention of cognitive decline in older people, and has shown to improve functional outcomes in patients who suffered from stroke. 
IGF-1 and IGFBP (Insulin-like Growth Factor Binding Protein) axis plays a critical role in the maintenance of normal kidney function and progression of chronic kidney disease (CKD).  In fact, the levels of IGF-1 and IGFBPs are altered in different stages of CKD. One study revealed that short-term administration of recombinant IGF-1 (rhIGF-1) in patients with end-stage renal disease (ESRD) and in healthy subjects has been shown to increase glomerular filtration rate (GFR) and blood flow to the kidneys.  In another study, Vijayan et al. reported that IGF-1 supplementation in 15 patients with advanced CKD at a dose of 100 micrograms per kilogram twice daily for 31 days improved the kidney’s ability to filter waste products and toxins as evidenced by an increase in GFR.  Other clinical trials assessing the therapeutic benefits of IGF-1 supplementation in patients with kidney disorders have also shown that the treatment may help improve symptoms and overall kidney function. [183-191]
Recent advances in the field of cardiology have focused on proliferation and regeneration as potential cardiovascular defense mechanisms. Endothelial dysfunction (malfunctioning of the inner lining of blood vessels known as endothelium) is considered an initial step in the development of atherosclerotic lesions (plaque build-up), through activation of a suicidal pathway that leads to programmed cell death of endothelial cells known as apoptosis.  IGF-1 can directly oppose endothelial dysfunction in several ways:
1. By increasing the production of nitric oxide, thereby improving blood flow to the heart. 
2. By promoting insulin sensitivity 
3. By promoting potassium-channel opening 
4. By improving lipid profiles 
5. Through IGF-1’s anti-apoptotic and anti-inflammatory properties. [197-201]
A large body of research has linked IGF-1 levels and prevalence of cardiovascular diseases. For instance, a cross-sectional study of 122 young subjects revealed that low level of IGF-1 is associated with coronary artery disease (CAD). [202-203] A prospective, nested, case-control study involving more than 600 healthy individuals with 15 years follow-up period showed that lower circulating IGF-1 levels are associated with increased risk of ischemic heart disease.  In patients with acute myocardial infarction (AMI), IGF-1 levels on hospital admission were markedly reduced and were significantly lower in those with a worse prognosis.  These observations uniformly support the possibility that IGF-1 deficiency may increase one’s risk for cardiovascular diseases. Interestingly, several research groups have studied the effects of IGF-1 in patients with impaired cardiac function. IGF-1 is known to induce vasodilation, thereby contributing to regulation of vascular tone and arterial blood pressure, as well as preservation of coronary blood flow.  Other studies also support that IGF-1 supplementation in patients with heart disease may help improve heart function by boosting the heart’s pumping power, thus improving blood circulation. [207-216] These beneficial effects of IGF-1 supplementation can help prevent the development of cardiovascular diseases and help treat its related symptoms.
Most muscle pathologies are characterized by the progressive loss of muscle tissue due to a chronic illness combined with the inability to regenerate the damaged muscle. These pathological changes, known as muscle wasting, can be attributed to alteration in muscle growth factors, specifically IGF-1. The administration of IGF-1 has been considered as a promising therapeutic intervention for advanced muscle weakness and wasting because of IGF-1’s role in skeletal muscle growth, survival, and regeneration.  Muscle wasting results primarily from accelerated protein degradation and is associated with increased synthesis of two muscle-specific ubiquitin ligases (a type of protein) known as atrogin-1 and muscle ring finger 1 (MuRF1).  Sacheck et al. reported that IGF-1 administration can prevent muscle wasting by stimulating muscle growth through suppression of protein breakdown and atrophy-related ubiquitin ligases, atrogin-1 and MuRF1.  Similarly, Nystom et al. found that IGF-1 attenuates sepsis-induced muscle wasting apparently by increasing muscle protein synthesis and potentially decreasing protein breakdown.  Numerous high-quality studies assessing the therapeutic benefits of IGF-1 in patients with muscle wasting have also proved that the treatment may stimulate muscle repair, increase muscle mass, and improve muscle strength. [221-231]
The search for a cure for AD is restless. Researchers suggest that in order to prevent or slow the progression of AD, medical interventions should be focused on treating the root cause of the disease. Normally, the brains of people with AD have an abundance of abnormal structure called amyloid plaques (sticky buildup of abnormal proteins outside nerve cells or neurons).  Recent advances in medicine have shown that brain amyloid clearance is modulated by IGF-1. [233-234] An overwhelming body of clinical research even found that patients with low IGF-1 levels in the blood are at higher risk for AD. [235-243] Interestingly, numerous studies found that higher levels of IGF-1 may help protect against degeneration of brain cells and can lower one’s risk for AD. [244-248] According to other studies assessing the therapeutic benefits of IGF-1 on brain health, the specific mechanisms by which IGF-1 may help protect against AD and other neurological disorder is that IGF-1 promotes nerve cell regeneration and prevents programmed cell death of brain cells. [249-267] These neuroprotective effects may be the reason why IGF-1 administration in patients with AD resulted in significant improvement in memory and thinking skills. 
A large body of clinical trials suggests that IGF-1 has anti-cancer properties. In one of the largest studies ever conducted on IGF-1 and cancer, a long-term follow-up surveillance data involving 13,581 patients diagnosed with common cancers who are treated with IGF-1, did not show any increase in the risk of disease recurrence or death in cancer survivors.  In another large study by Swerdlow et al., GH and IGF-1 treatment in patients with brain tumors did not increase the risk of recurrence.  Data from the Childhood Cancer Survivor Study (CCSS) are also consistent with the finding that IGF-1 and GH administration do not increase risk of disease recurrence in patients with primary brain tumors and acute leukemia.  Furthermore, data from the two largest international databases and surveillance studies involving 86,000 patients on GH and IGF-1 therapy have shown no significant increase in cancer incidence.  In another study, researchers revealed that GH and IGF-1 levels approximately 10% that of normal showed almost complete growth suppression of transplanted human breast cancer cells.  Finally, there is compelling evidence that IGF-1 regulates hematopoiesis, a process that gives rise to all the other blood cells including neutrophils, macrophages, cytotoxic natural killer cells, and granulocytes – all of which helps protect the body against disease-causing microorganisms such as cancer cells.  Also, IGF-1 reduces inflammation  and blood sugar. It is a well-known fact that long-term inflammation [276-285] and elevated blood sugar levels [286-294] are risk factors that feed cancer growth or development. In addition, studies show that the anti-tumor properties of IGF-1 can be attributed to its ability to enhance natural killer cell activity of the immune system. [286-288]
During sleep, the body releases a cascade of hormones that are necessary for recovery and growth. One of the most important hormones released during this process is IGF-1. The age-related decline in IGF-1 leads to the development of sleep problems and poor sleep quality in both men and women. In fact, studies have shown that low levels of IGF-1 were associated with poor sleep quality and prevalence of sleeping difficulties. [289-293] On the other hand, studies show that higher levels of IGF-1 were associated with improved sleeping pattern and sleep quality. [294-298] This may be the reason why restoring IGF-1 levels in older patients through hormone replacement therapy has been shown to improve energy levels, emotions and sleep quality. 
With advancing age, all cells in the body are less able to divide and multiply.  In addition to this, many cells lose their ability to function, or they function abnormally. Aside from these changes, many tissues and organs lose mass and fail to function normally. This process is medically known as organ atrophy. When an organ loses mass and is worked harder than usual, it may lead to sudden failure or other life-threatening problems. There is increasing body of evidence that aside from aging, a process known as endothelial dysfunction can potentially contribute to organ atrophy and dysfunction. [301-306] Of note, studies show that IGF-1 can directly oppose endothelial dysfunction by increasing the production of nitric oxide, promoting insulin sensitivity, promoting potassium-channel opening, improving lipid profiles, and through IGF-1’s anti-apoptotic and anti-inflammatory properties. [307-311] Other studies assessing the therapeutic benefits of IGF-1 have also shown that this hormone may help prevent atrophy of the gut and brain. [312-316] These findings suggest that IGF-1 does have the ability to fight internal signs of aging.
Depression and low mood are related to dysregulation of many physiological processes including changes in the levels of brain chemicals and a disturbance in the endocrine system. Recent studies indicate that impairment and changes in specific structures of the brain, particularly the hippocampus, may be an important factor in the development of depression and low mood. [317-318] The abnormal changes in the brain structures may be related to alterations in the levels of IGF-1, with a number of high-quality studies supporting that low level of IGF-1 is a major risk factor for these medical conditions. [319-322] There is increasing evidence that IGF-1 does have an anti-depressant effect, possibly due to its ability to increase the levels of certain brain chemicals including serotonin, which helps regulate mood.  A study by Malberg et al. even found that IGF-1 also has anti-anxiety effect aside from its anti-depressant effect.  These mechanisms may be the reason why IGF-1 administration in patients with major depressive disorder resulted in improved mood, cognitive abilities, and quality of life. 
Human growth hormone can turn back your body’s internal clock by helping you build muscle fast, slash fat, and restore sexual vitality to increase your self-confidence and improve your quality of life. GH plays numerous roles in the body that are critical for survival including regulation of body composition, body fluids, sugar and fat metabolism, heart function, and growth of muscles and bones. Produced synthetically, GH is the active ingredient in several prescription drugs and in other health products.
Approved indications for GH therapy include treatment of growth hormone deficiency, chronic renal insufficiency, idiopathic short stature, AIDS-related muscle wasting and fat accumulation. GH therapy usually begins at a low dose and is gradually adjusted to obtain optimal efficacy. 
Today, subcutaneous injection is the route of choice for GH administration.  In addition to this, trials for alternative less invasive modes of GH administration such as the nasal, pulmonary and transdermal routes are under way.  Oral route of GH administration is ineffective because they are typically destroyed in the gastrointestinal tract during the process of digestion.
GH plays a major role in muscle growth, increasing bone density, regulating body fluids, sugar and fat metabolism, and maintaining the health of all human tissues, including vital organs such as the heart and brain. The effects of HGH supplementation depend on the dosage and start gradually. First ones are usually noticeable within days or weeks of starting the daily injections.
An extensive body of high-quality research shows the benefits of GH in a wide array of diseases and abnormalities:
Patients with Growth Hormone Deficiency (GHD) often suffer from low energy levels, mood changes, mental fatigue, and cognitive impairment. [329-333] Interestingly, a study by Wallymahmed et al. have shown that GH replacement therapy in GHD patients for 6 to 12 months led to significant improvements in body composition, muscle strength, energy levels, emotional reactions, and self-esteem scores.  In another study, Sathiavageeswaran et al. demonstrated that up to 70% of patients with the fibromyalgia syndrome (long-term condition that causes pain all over the body) who received GH replacement therapy had significant improvements in perceived energy levels, body image, pain level and cognition.  Other studies have also shown that GH replacement therapy in GH-deficient individuals resulted in significant improvements in various parameters of cognitive health such as memory, language function, attentional performance, thinking skills, and quality of life. [336-341] Numerous studies even found that GH replacement therapy in patients with traumatic brain injury induced reduction of depression, social dysfunction, and certain cognitive domains. [342-350]
Numerous studies have shown that lower GH levels are strongly linked with a higher risk of cardiovascular disease and related deaths. [351-360] The degree of GHD is directly related to elevated levels of total cholesterol and low-density lipoprotein (bad cholesterol), increased truncal fat, abnormal waist–hip ratio, and risk of hypertension – all of these factors can increase one’s risk for death related to heart diseases.  Interestingly, a meta-analysis of clinical studies assessing various cardiovascular parameters were investigated in patients treated with GH and the results of the study showed significant improvements in lean body mass, total cholesterol, LDL cholesterol, and diastolic blood pressure. [362-363] Similarly, a study by Agarwal et al. has shown that treatment of GH deficiency through GH replacement therapy may help improve outcomes in heart failure.  In another study, Tritos et al. reported that patients with congestive heart failure (CHF) who received recombinant human growth hormone (rhGH) therapy had improved exercise duration and increased cardiac output.  Finally, in a meta-analysis of several clinical trials assessing the therapeutic benefits of GH therapy on cardiac function, Volterrani et al. reported that patients with CHF who received the treatment experienced a significant improvement in their symptoms without any adverse side effects. 
In adults with GHD, there is a reduction in lean body mass and an increase in abdominal adiposity, which ultimately lead to obesity. [367-373] In a study of 15 healthy adult women, Miller et al. showed that the secretion of GH was much lesser in patients with high truncal fat compared to those with low truncal fat.  In another study, researchers found that GH deficiency is associated with high triglyceride levels, hypertension, and low levels of high-density lipoprotein (good cholesterol), and that recombinant GH replacement may help improve these body parameters.  In a meta-analysis of 37 blinded, randomized, placebo-controlled trials, Maison et al. found that GH replacement therapy has an overall beneficial effect on LDL cholesterol and total cholesterol profiles.  Other studies have also shown that GH therapy in patients with GHD resulted in significant reduction in body fat percentage as well as LDL cholesterol levels. [378-380]
There is a significant association between reduced lean muscle mass and impaired neuromuscular function.  In one study, a significant improvement in lean mass and neuromuscular function was observed after more than 10 years of GH replacement therapy.  In a very interesting study of patients with the fibromyalgia syndrome, 70% of patients with GHD showed a marked improvement in symptoms following GH replacement therapy.  In states of GH deficiency, Weber et al. reported that reduced muscle mass and strength can be reversed successfully with supplementation of GH.  In men over 50 years old, GH supplementation is associated with a statistically significant increase in muscle strength in the lower body part, suggesting that GH may help prevent the age-related decline in muscle function. [385-386] In patients with adult-onset and childhood-onset adult GH deficiency, GH therapy can significantly improve symptoms of neuromuscular dysfunction. 
Adult Growth Hormone Deficiency (AGHD) causes osteoporosis, which increases one’s risk for various fractures and low bone mass. [388-394] In order to preserve bone mass and decrease the prevalence of fractures especially in the older population, GH supplementation may be considered as a therapeutic option. In one study, Giustina et al. reported that GH replacement may help reverse bone abnormalities by increasing markers of bone formation and bone resorption [395-396] (process by which osteoclasts break down bone and release minerals, resulting in a transfer of calcium from bone fluid to the blood). In another study, Gillberg et al. found that two years of treatment with recombinant human growth hormone increased bone mineral density in men with osteoporosis of unknown cause.  In a meta-analysis of several clinical trials assessing the therapeutic benefits of GH, Barake et al. found that GH treatment resulted in significant increase in osteocalcin (a cell that helps build bones) and in bone resorption markers.  Moreover, patients who received GH had a significant decrease in fracture risk. In patients with GHD, Wuster et al. found that GH treatment significantly increased bone metabolism and improved bone geometry. 
There is strong scientific evidence supporting the beneficial effects of GH on blood sugar levels. Studies show that GH deficiency is highly associated with impaired insulin sensitivity, indicating that GH has a role in the regulation of insulin as well as blood sugar levels. 
IGF-1 has a growth stimulating effect, independent of and in conjunction with GH. According to researchers, IGF-1 achieves this effect by suppressing the breakdown of protein and preserving skeletal muscle.  Such effect can lead to increased muscle mass, strength and performance. Even though it is tightly controlled by law, GH and IGF-1 supplements are wildly attractive to both pro and amateur weightlifters and athletes. The reasons are simple. These supplements build lean muscle faster, increase recovery rate and makes you train harder. Taking GH and IGF-1 supplements can give athletes an edge over other competitors by boosting their performance in their field of sports.
GH and IGF-1 compounds bind to specific receptors, initiating cell division, which in turn causes muscle growth and an increase in muscle mass.  IGF-1 has a specific role in protein synthesis which leads to bone formation, and has a major role in muscle and bone repair. Both GH and IGF-1 exert the following anabolic effects which can benefit pros and amateur athletes alike: 
HGH is a prescription medication, meaning that its distribution and use without the prescription of a certified doctor is illegal. Use of exogenous GH, via injection, was originally used for medical purposes such as GH deficiency until athletes began abusing GH with the goal of enhancing their abilities and performance. Before recombinant human growth hormone (rHGH) was developed in 1981, cadavers are the only source of HGH. In 1982, the first description of GH use as a doping agent was Dan Duchaine’s “Underground Steroid handbook”; it is not known where and when GH was first used this way.  In 1989, the use of anabolic steroids became increasingly popular among Olympic athletes and professional sports players that’s why the International Olympic Committee banned the use of HGH.  Although abuse of HGH for athletic purposes is illegal in the U.S., over the past decade it appears that such abuse is present in all levels of sport.  This is fueled at least in part by the fact that the use of GH is more difficult to detect than most other performance-enhancing drugs.
According to a report from the United States House Committee on Oversight and Government Reform on steroid and GH use, it was found out that the inappropriate use of HGH and other performance-enhancing drugs by professional athletes and entertainers was fuelling the industry peddling these banned substances to the general public for medically inappropriate uses. 
For the time being, public opinion seems to believe that the use of IGF-1 is comparable to anabolic steroids. IGF-1 is a prohibited substance on the list of World Anti-Doping Agency (WADA).  The WADA Prohibited List bans the use of exogenous IGF-1 and any substance containing IGF-1 in any competition and even out-of-competition. According to the ban, IGF-1 violates the following criteria: 
1. It enhances sport performance.
2. It violates the spirit of sport.
For the general public, any form of IGF-1 may be used legally, provided there is a prescription from a qualified medical doctor.
Effects of Growth Hormone and Insulin-like Growth Factor 1 in Men with Idiopathic Osteoporosis
Idiopathic osteoporosis is a rare type of osteoporosis which occurs in children and young adults who have normal levels of hormones and vitamins with no obvious reason to have weak bones. It is so called “idiopathic” because its cause is of unknown origin. At first, this type of osteoporosis causes no symptoms because the rate at which bone density decline occurs very gradually. Some people with idiopathic osteoporosis never develop symptoms. Eventually, however, the gradual decrease in bone density may cause bones to collapse or develop fracture, resulting in severe sudden pain and bone deformities.
Effect of GH/IGF-1 on Bones
In vitro studies using cultured chondrocytes (cells of healthy cartilage) have shown that GH stimulated the formation of young chrondocytes while IGF-1 stimulated cells at later stage of maturation. Both GH and IGF-1 are known to have a direct action on osteoblasts (cells that make bone) by increasing its production and enhancing its activity. Both of these hormones play major roles in bone mass acquisition and maintenance. Although GH and IGF-1 have different effects on the bones, they exert a synergistic effect when administered together.
GH and IGF-1 Administration in Patients with Idiopathic Osteoporosis
Injections with GH or IGF-1 have been proposed for anabolic therapy in osteoporosis. In a cross-over study, Johansson and colleagues treated 12 men with idiopathic osteoporosis using daily subcutaneous injections of GH (2 IU/m2) or IGF-1 (80 micrograms/kg) for 7 days with 12 weeks wash-out period. The aim of the study is to elucidate the effects of GH and IGF-1 in this type of osteoporosis. Following administration, the researchers observed that the blood levels of procollagen type 1 (soluble precursor of collagen) increased by 29% with GH treatment and by 43% with IGF-1, whereas both GH and IGF-1 treatments increased the levels of osteocalcin (noncollagenous protein that helps build bones) by 20%, indicating enhanced bone formation in these patients. In addition to this, the urinary levels of deoxypyridinoline, which is a marker of bone resorption (transfer of calcium from bone tissue to the blood), increased by 44% following GH injections and by 29% following IGF-1, and there were 28% increase in the blood levels of IGF-1 after GH than after IGF-1 injections. Although the markers of bone metabolism increased following both GH and IGF-1 injections in these patients, comparison of the treatments suggests that IGF-1 enhanced formation of collagen type 1 more than did GH. Moreover, the increase in the urinary levels of deoxypyridinoline, which is a marker of bone resorption, was detected 4 days after the start of GH injections. Some of the differences in the results of the study might be dose-dependent, but could also indicate separate mechanisms at the cellular level.
These results clearly suggest that both GH and IGF-1 administration can be beneficial in patients with idiopathic osteoporosis. In addition to osteoporosis medications, diet rich in calcium and vitamin D, and lifestyle modifications aimed at slowing bone breakdown in these patients, administration of GH combined with IGF-1 can exert a synergistic effect in preventing further bone breakdown and restoring normal bone density.
Continuous Subcutaneous IGF-1 Therapy via Insulin Pump in a Patient with Donohue Syndrome
Donohue syndrome (also known as Leprechaunism) is a rare disorder characterized by severe insulin resistance, a condition in which the body does not respond properly to the effects of insulin. The hormone insulin normally helps lower blood sugar levels by controlling how much sugar enters into the cells to be used as energy. This condition is caused by mutations in the INSR gene, which provides instructions for making a protein called insulin receptor. People with Donohue syndrome are unusually small and affected infants do not grow and gain weight at the expected rate. Additional features include lack of fatty tissue under the skin, muscle wasting, excessive body hair, ovarian cysts, and enlargement of nipples, genitals, heart, kidneys, and other organs. Most people with Donohue syndrome have a skin condition called acanthosis nigricans, in which the skin in body folds and creases becomes thick and brown to black in color. Most children with Donohue syndrome do not survive beyond age 2.
Treatment options for Donohue syndrome are limited. The first line therapy for high blood sugar and accumulation of waste products in the blood related to severe insulin resistance is high-dose insulin. However, prolonged use of high doses of insulin can lead to adverse side effects such as low blood sugar and allergic reactions. Because of this, recombinant human IGF-1 (rhIGF-1) has become a treatment alternative for disorders with severe insulin resistance because of its safety and efficacy. rhIGF-1 has been shown to improve blood sugar control in patients with severe insulin resistance due to INSR mutations. To further elucidate the effects of rhIGF-1 on Donohue syndrome, Weber and colleagues treated a female infant with this medical condition. The patient weighs 1595 grams and has gestational diabetes with episodes of severe insulin resistance and high blood sugar. For the first year of life, her only treatment was frequent feedings, and she showed consistent growth with no episodes of high blood sugar. By 13 months of age, HbA1c (Hemoglobin A1c is a measure of blood sugar over 3 months) increased to 7.1%. By 19 months, HbA1c increased to 9.5% and rhIGF-1 was started at 80 micrograms per kilogram per day divided twice daily via subcutaneous injections and steadily increased to 640 micrograms per kilogram per day over the next year. At 30 months, rhIGF-1 was increased to 560 micrograms per kilogram per day and given every 6 hours, yet high blood sugar persisted. Continuous subcutaneous rhIGF-1 infusion at 800 micrograms per kilogram divided evenly over 24 hours was started via insulin pump. Infusion set and site were changed on a daily basis. Over 5 months, rhIGF-1 dose was increased for high blood sugar to a maximum of 1200 micrograms per kilogram per day. Three months after initiation of continuous rhIGF-1 via insulin pump, HbA1c was 8.8% and weight gain reached an average of 202 grams per month. Within the succeeding months, the patient’s blood sugar levels stayed within the normal range. Notably, the patient’s acanthosis nigricans improved with rhIGF-1 treatment.
In conclusion, this study demonstrate that the use of an insulin pump for continuous rhIGF-1 infusion in patients with Donohue syndrome seemed to improve blood sugar control, weight and core symptoms including acanthosis nigricans in these patients.
A Polymorphism in the Gene for IGF-1 Functional Properties and Risk for Type 2 Diabetes and Myocardial Infarction
Insulin-like growth factor 1 (IGF-1) plays a pivotal role in bone growth, cell production and survival, and metabolism. Its structural and functional resemblance with insulin as well as its blood sugar-lowering effects observed after recombinant IGF-1 administration, suggest that this hormone is involved in the regulation of normal blood sugar levels. In patients with type 2 diabetes, low levels of IGF-1 in the blood are common. Evidence is accumulating that low levels of IGF-1 can eventually lead to complications of diabetes. Since IGF-1 may also play a role in the regulation of the heart function, various studies have also linked low IGF-1 levels and heart disease.
Studies of the role of IGF-1 in the development of heart disease and diabetes have been hampered by the fact that circulating IGF-1 levels in the body do not necessarily reflect the local production of IGF-1 in specific tissues, such as the heart muscle and pancreas. A genetic polymorphism (presence of genetic variation within a population) in the IGF-1 gene promoter region has been identified, which may influence the production of IGF-1. This may open new opportunity to characterize, on a genetic basis, patients who experience low levels of IGF-1 throughout the body. Until now, studies focusing on this polymorphism in relation to the levels of IGF-1 in the body have been limited to osteoporosis and related disorders.
Vaessen and colleagues studied the role of a genetic polymorphism in the promoter region of the IGF-1 gene in relation to circulating IGF-1 levels and growth measured as body height, as well as the relationship of this polymorphism with type 2 diabetes and myocardial infarction. The aim of the study was to investigate determinants of chronic and disabling diseases of the heart, nerves, and eyes. The relation between the IGF-1 polymorphism and body height was assessed in a population-based sample of 900 subjects, where 50 subjects were randomly selected. To assess the risk for type 2 diabetes, the researchers studied 220 patients and 596 control subjects with normal blood sugar levels. For myocardial infarction, 477 patients with evidence of the disease on electrocardiogram and 808 control subjects were studied. In this population-based study, the researchers found out that the absence of the wild-type (192-bp) allele (one of a pair of genes) of a genetic polymorphism in the regulatory region of the IGF-1 gene is significantly linked with short stature and low levels of IGF-1 in the body.
Interestingly, the absence of this allele is also significantly associated with an increased risk for type 2 diabetes and myocardial infarction. Moreover, the relative risk for myocardial infarction is strongly increased in subjects without the 192-bp allele. This is the first study focusing on the role of IGF-1 promoter polymorphism in the development of type 2 diabetes and myocardial infarction. This study suggests that a lifetime exposure to moderate alterations in levels of IGF-1 in the body may also be relevant in terms of the risk for these diseases. In short, this study may present an opportunity to identify diabetic patients who are at high risk for heart disease and who are potential candidates for IGF- 1 therapy.
Insulin-like Growth Factor (IGF-1) and Diabetes
The underlying rationale for using IGF-1 as a therapeutic option in diabetic patients has a strong physiological basis. IGF-1 is the same as insulin both in structure and function, specifically, stimulation of blood sugar transport into skeletal muscle cells, that’s why it is being used as a blood sugar-lowering agent in diabetes. Studies in humans have shown that post-prandial glucose test result which determines the level of blood sugar, is partly dependent upon IGF-1 concentrations and that IGF-1 administration in patients with either severe insulin resistance or type 2 diabetes led to an improved blood sugar test result. This occurs primarily at the level of skeletal muscle as IGF-1 receptor deletion in skeletal muscle of mice models resulted in elevated blood sugar levels and impaired insulin action.
IGF-1 Enhances Insulin Action
Several observations suggest that IGF-1 can enhance the action of insulin in different body tissues by stimulating PI3K activation, which is a key enzyme for regulating normal blood sugar transport within the cells. Other studies suggest that IGF-1 can improve the body’s response to insulin action by inhibiting growth hormone (GH) secretion, which can function as an insulin antagonist. The same mechanism was seen in patients with type 2 diabetes who received IGF-1 treatment because GH is known to be a direct antagonist of insulin in the liver.
IGF-1 Improves Haemoglobin A1C
Haemoglobin A1C or also known as glycosylated hemoglobin or glycohemoglobin is a blood test used to measure the average level of blood sugar in the past 2 to 3 months. This test can check how well a diabetic person controls blood sugar levels and can also be used in diagnosing diabetes. Larger clinical trials of IGF-1 administration to patients with type 1 diabetes have shown a consistent maintenance of reduced insulin requirements over 4–8-week periods and significant reductions in haemoglobin A1C. However, the empiric fact remains that some diabetic patients experienced long-term control of blood sugar levels with co-administration of IGF1 and insulin.
Several large trials conducted in patients with type 2 diabetes using IGF-1 alone, significantly reduced haemoglobin A1C by 1.2%. However, administration of both IGF-1 and IGFBP3 appears to be equally effective in terms of improving elevated blood sugar levels and the body’s response to insulin. Administration of this combination to 52 diabetic patients for 2 weeks significantly reduced fasting blood glucose result by 35-40% with a marked reduction in insulin requirements averaging 66%. Notably different from previous studies with IGF-1 alone, this was achieved with minimal side effects.
With these findings, it is plausible that IGF-1 can be considered as a potent blood sugar-lowering agent, even when it’s given with its binding protein IGFBP3, or with insulin. In relation to this, IGF-1 levels in diabetic patients can be a predictive marker whether the patient is responding well to treatments. Moreover, consistent IGF-1 and blood sugar monitoring while diabetic patients are under IGF-1 therapy, can help healthcare providers determine the outcome of the intervention.
Insulin-like Growth Factor-1 (IGF-1) and Metabolic Syndrome
Metabolic syndrome (MetS) is a cluster of conditions including high blood pressure and blood sugar level, abnormal cholesterol levels, and excess body fat around the waist. Having just one of these conditions doesn’t mean you have the disease. However, any of these conditions increase your risk of having diabetes and other heart problems. If more than one of these conditions occur, your risk is even greater. Most of the disorders associated with metabolic syndrome usually have no symptoms, although a large waist circumference is a visible sign. However, in case your blood sugar shoots up, you might experience signs and symptoms of diabetes such as increased thirst and urination, dizziness, blurred vision, fatigue, and other debilitating symptoms.
Metabolic syndrome is linked to a medical condition called insulin resistance. Normally, the food that you eat is broken down into sugar (also known as glucose) by the digestive system. This sugar is needed by your cells as a source of energy for many biological processes within the body. In order for the sugar to enter the cells, they need a hormone called insulin. In people with insulin resistance, the body cannot utilize insulin effectively. This may be due to impairment in the pancreas’ ability to produce insulin, or the body simply doesn’t respond to the effects of insulin. As a result, blood sugar levels become elevated. This can eventually lead to diabetes and trigger various symptoms. Aside from insulin resistance, obesity, genetics, and hormonal decline related to aging may play a role in the development of metabolic syndrome.
IGF-1 Levels and Metabolic Syndrome
Consistent evidence associates IGF-1 deficiency and metabolic syndrome. The anti-inflammatory actions of IGF-1 can be regarded as a crucial factor in protecting tissues from the deleterious effects of inflammatory substances in chronic disorders such as obesity. In addition to this, inflammatory substances produced by fat cells in obese patients affect normal nutrition-related signaling, establishing the progression to metabolic syndrome and to type 2 diabetes. Ultimately, these effects result in a blockade of IGF-1 beneficial actions. Under this scenario, a correlation between lower IGF-1 levels and metabolic syndrome can be established.
IGF-1 can Improve Insulin Resistance in Metabolic Syndrome
IGF-1 is known to promote normal blood sugar transport in certain tissues. In addition to this, IGF-1 administration has been shown to reduce blood sugar levels not only in healthy individuals but also in patients with insulin resistance and type 2 diabetes. The specific mechanism by which IGF-1 lower blood sugar levels is by suppressing the process of synthesizing blood sugar in the body from non-carbohydrate sources by the liver as well as improving insulin in this organ. Interestingly, additional performed studies suggested that the several mechanisms involved in blood sugar and lipid balance as well as cholesterol transport are altered in metabolic syndrome, and that IGF-1 administration can help normalize these compounds. These results suggest that IGF-1 can be a therapeutic option in reversing metabolic syndrome in parallel with diet and exercise before it onsets to type 2 diabetes.
Insulin-like growth factor-I Improves Glucose and Lipid Metabolism in Type 2 Diabetes Mellitus
Aside from growth stimulation, growth hormone (GH) and insulin-like growth factor 1 (IGF-1) have many different functions in the body. In the liver, GH functions to antagonize the ability of insulin by inhibiting the synthesis of glucose from non-carbohydrate sources (gluconeogenesis) and enhancing the breakdown of lipids (lipolysis), which functions to increase blood sugar or glucose levels. IGF1 can directly lower blood sugar levels by inhibiting gluconeogenesis in the kidney. Moreover, IGF-1 can also act indirectly through its receptors in the skeletal muscle, to enhance the action of insulin on blood sugar transport. In order to maintain normal blood sugar levels in the body, IGF-1 indirectly bocks the ability of GH to antagonize insulin action. IGF-1 is the same in both structure and function as insulin, and is implicated in the development of insulin resistance as well as heart disease.
Low IGF-1 Levels and Diabetes Mellitus
Low levels of IGF-1 in the body have been proposed to have a role in diabetes. In a recent study, Teppala and colleagues examined the blood IGF-1 levels of 5,511 participants, 387 of whom had diabetes, in order to determine the association between serum IGF-1 and diabetes in a representative sample of U.S. adults. The results of the study showed that lower blood IGF-1 levels were positively associated with diabetes in younger subjects after adjusting for several factors such as age, gender, race/ethnicity, education, lifestyle, BMI, hypertension, glomerular filtration rate, and cholesterol levels. These results indicate that low IGF-1 levels can be a predictor of diabetes in younger individuals.
IGF-1 Administration in Diabetic Patients
High blood sugar levels, excess levels of insulin circulating in the blood, and poor response to the action of insulin cause vascular disease (abnormal condition of the blood vessels) in type 2 diabetes mellitus. Dietary modification alone often is ineffective and oral drugs or insulin enhances the excess levels of insulin in the blood. In previous studies, recombinant human IGF-1 (rhIGF-I) has been used in Type 2 diabetes to improve the body’s response to insulin and aid in controlling the normal blood sugar levels in the body. RhIGF-I administration through the vein resulted in normalization of blood sugar levels in insulin-resistant diabetics whereas rhIGF-I infusions lowered insulin and lipid levels in healthy humans. This suggests that rhIGF-I is an effective therapeutic option in insulin-resistant states.
To further assess the safety and efficacy of rhIGF-I, Zenobi and colleagues treated 8 type 2 diabetics on a diet received on five treatment days of subcutaneous rhIGF-I. Interestingly, rhIGF-I administration significantly increased the total IGF-I levels in the blood 5.3-fold. Also, rhIGF-I administration improved lipid levels in the blood. The magnitude of the effects of rhIGF-I administration in all the subjects correlated with the respective control levels.
The availability of rhIGF-I used either alone or in combination with insulin, has led to various human clinical trials testing these hypotheses. In one study, Mohamed-ali and colleagues treated patients with type 1 and 2 diabetes mellitus with rhIGF-I, which resulted in significant improvement in insulin requirements and blood sugar levels. In addition to this, IGF-1 was found to have a protective effect on nerve problems, which is one of the complications of diabetes.
Long-term Recombinant Human Insulin-like Growth Factor-1 (rhIGF-1) for Severe Insulin Resistance Syndrome
Severe insulin resistance syndrome is a condition wherein the body doesn’t respond to the effects of the hormone insulin. Normally, insulin serves a key in order for the blood sugar to enter the cells to be used as energy. In case of severe insulin resistance, the body doesn’t utilize insulin effectively, resulting in elevated blood sugar levels. Prolonged elevation of blood sugar can cause debilitating symptoms and can be life-threatening.
Management of severe insulin resistance is a major clinical challenge in obese patients as well as those with genetic defects in the insulin receptor. Initially, excess levels of insulin circulating in the blood produces ovarian enlargement and increased male sex hormones in women, and often low blood sugar levels. However, low blood sugar gradually evolves into insulin-resistant high blood sugar when the function of the beta cells of the pancreas decline. Medical management of these complex disorders depends on early recognition of the problem and appropriate targeting of both high and low blood sugar levels.
Long Term rhIGF-1 Administration in Severe Insulin-Resistant States
Several studies have shown that recombinant human insulin-like growth factor 1 (rhIGF-1) can help improve survival in infants with the most severe defects in insulin receptor and also improve the function of the insulin-producing beta cells. In the past, the first line therapy for high blood sugar and accumulation of waste products in the blood related to severe insulin resistance is the administration of high-dose insulin. However, rhIGF-1 has been used as a treatment alternative to high dose insulin because prolonged use of insulin is linked with episodes of low blood sugar levels.
Clinical trials were conducted to study patients with severe insulin-resistant states. In most of these investigations, the administration of IGF-1 was given for less than 3 months at a dose of 50-100-160 micrograms per kilogram of body weight, injected via subcutaneous route once or twice a day. However, the results of a trial of patients with severe insulin resistance who received rhIGF-1 for 1 year suggested that IGF-1 treatment may be a safe and effective long-term therapy. In children and adults with type 1 diabetes, long term administration of IGF-1 has also shown improvement in blood sugar control.
To further elucidate the ability of treatment with rhIGF1 to improve metabolic and clinical parameters in the long-term, De kerdanet and colleagues studied the case of a four-month-old female baby with leprechaunism, a rare genetic disease resulting from mutations in the insulin receptor gene, and is characterized by severe insulin resistance, growth failure and, usually, premature death. The diagnosis of leprechaunism was confirmed based on mutations in the insulin receptor gene of the patient. The researchers analyzed the patient’s skin fibroblasts (cells in connective tissue) for response to insulin and IGF1. Cultured fibroblasts from the patient’s skin showed a decreased number of insulin receptors and were insulin-resistant. Interestingly, the results of the study showed that treatment with IGF-1/IGFBP3 (Insulin-like Growth Factor Binding Protein-3) for 8.7 years, then IGF-1 for 2 years, resulted in normalization of circulating levels of IGF-1 and IGFBP3. In addition to this, improvements in the blood sugar levels of the patient were observed. Regarding growth, the patient’s body mass index (BMI) normalized and length/height score improved. Moreover, the patient presented normal neurological development and academic achievement. In the entire duration of the study, no adverse side effects were observed.
These results provide evidence that long term rhIGF-1 administration (more than 10 years) with and without rhIGFBP3 can help prevent fatal outcomes in patients with severe insulin resistance syndrome, and can improve growth and metabolic parameters in a safe and effective manner.
The Effects of Repeated Daily Recombinant Human Insulin-like Growth Factor 1 Administration in Adolescents with Type 1 Diabetes
Several studies have shown that the levels of insulin are higher during puberty than they are during adulthood or the years preceding puberty. A decrease in insulin-stimulated blood sugar uptake in healthy adolescents compared with pre-pubertal children was demonstrated for the first time in the 1980s. Healthcare professionals should be aware of the evolution of insulin insensitivity (inability of the body to respond the effects of insulin) during puberty in children and adolescents with type 1 diabetes and appropriately adjust the dose of insulin in order to prevent any deterioration in blood sugar control.
Recently, a large cross-sectional study of children without diabetes has shown that insulin sensitivity is lowest at age 12 to 14 years in both genders, and across ethnic groups, returning to almost pre-pubertal levels in young people above 16 years of age. Experts believe that the major hormonal changes that are associated with the onset of puberty such as the two-fold increase in the production of growth hormone and sex steroids are likely hormonal candidates for inducing insulin sensitivity in adolescents. However, while insulin sensitivity during puberty is transient, the increasing levels of sex steroids remain elevated and insulin sensitivity subsides during adulthood. Once the pubertal growth spurt is completed, the levels of growth hormone decline.
Behavioral and Psychosocial changes during Adolescence
In addition to the hormonal and metabolic changes during the puberty period, adolescents experience rapid behavioral changes that may impact diabetes control. Behavioral changes include being rebellious, heightened awareness of self-image and peer pressure, challenging of authority figures, establishing independence, seeking privacy and the emergence of eating disorders – all of these may be affected by the presence of a chronic illness like diabetes. Adolescents with a chronic disease are at increased risk for major depression, anxiety, and low self-esteem. The combination of depression and diabetes in adolescents has serious consequences including increased rates of suicide or suicidal tendencies, making diabetes management and self-care extremely difficult.
Insulin-like Growth Factor 1 Administration in Adolescents with Type 1 Diabetes
Good blood sugar control in type 1 diabetes to prevent complications may be difficult to achieve during adolescence, because of hormonal fluctuations in the production of growth hormone or insulin-like growth-factor-l (IGF-1) which can lead to lower insulin sensitivity. Recombinant human IGF-1 (rhlGF-l) given in addition to insulin therapy in type 1 diabetes, might improve blood sugar control in adolescents.
Reduced IGF-1 has been liked to poor metabolic control and increased production of growth hormone in adolescents with type 1 diabetes. To evaluate the safety and efficacy of rhIGF-1 in these patients, Cheetham and colleagues studied a group of 6 adolescent male subjects with type 1 diabetes who were given rhIGF-1 at a dose of 40 micrograms per kilogram for 28 days via subcutaneous injections. Glycated hemoglobin (HbA1c) levels were measured throughout the study to determine blood sugar concentrations and overnight profiles were undertaken to study levels of IGF-1, insulin-like growth factor binding protein-3 (IGFBP-3), and growth hormone concentrations. Interestingly, rhIGF-1 administration was well tolerated and low blood sugar was not problematic at any stage of the study. In addition to this, rhIGF-1 led to a sustained increase in IGF-1, IGFBP-3 and mean overnight growth hormone decreased during the study. Furthermore, rhIGF-1 administration improved the levels of glycated hemoglobin in these patients, suggesting an improvement in blood sugar levels.
The restoration of IGF-1 levels in these patients may indeed have a beneficial impact on blood sugar control. In addition to rhIGF-1 administration, a multifaceted approach that includes lifestyle and diet modifications as well as proper counseling can help adolescents with type 1 diabetes achieve good blood sugar control.
The Relative Roles of Insulin-like Growth Factor (IGF-1) in Controlling Insulin Sensitivity
To understand insulin sensitivity, it is important to understand the role of insulin in the body first. Insulin is a hormone that helps transport blood sugar or glucose, into the cells as a source of energy. Since the body makes use of blood sugar for energy, insulin plays a vital role. Just think of insulin as a ”key” required by blood sugar to enter the cells. Without sufficient insulin, blood sugar cannot be transported inside the cells and remains in the bloodstream. As a result, the levels of blood sugar shoot up, which if prolonged, can lead to debilitating symptoms such as:
Insulin sensitivity describes how sensitive the body is to the effects of insulin. If a person is insulin sensitive, he or she will require smaller amounts of insulin to achieve a lower blood sugar level. Insulin sensitivity varies from person to person. People with low insulin sensitivity, also known as insulin resistance, will require larger amounts of insulin either from their own body or from injections to achieve a normal blood sugar level.
Role of IGF-1 in Modulating Insulin Sensitivity
IGF-1, which has the same structure and function as insulin, improves insulin sensitivity in both experimental animals and human subjects. The underlying mechanism in which IGF-1 exerts this action is by binding to insulin receptors with very low affinity. IGF-1 administration in healthy humans results in glucose lowering that is approximately one-twelfth as potent as that induced by insulin, and in patients with extreme insulin resistance, it improves insulin sensitivity and normalizes carbohydrate levels.
Almost all human studies of IGF-1 show that, in addition to enhancing the action of insulin, IGF-1 also suppresses the secretion of growth hormone (GH). One exception is the group of subjects with GH receptor mutations who develop insulin resistance as adults. IGF-1 administration to these patients, who are unresponsive to the effects of GH, results in improvement in insulin sensitivity. Although GH counters the action of insulin the skeletal muscle, experts believe that the role of IGF-1 may still be predominant in that tissue. Inhibiting the action of GH to attain a relatively normal physiologic level rather than a GH-deficient level will be vital to further understand the role of IGF-1 in the maintenance of normal blood sugar levels. Even though IGF-1 suppresses GH section in order to improve insulin sensitivity, it is still clear how IGF-1 can be of great use in lowering elevated blood sugar levels.
In larger clinical trials of IGF-1 administration to patients with type 1 diabetes, the results showed a consistent maintenance of reduced insulin requirements over 4–8-week periods and significant reductions in blood sugar levels. Surprisingly, the administration of both IGF-1 and IGFBP3 appears to be equally effective in terms of improving elevated blood sugar levels and insulin sensitivity. Administration of this combination to 52 diabetic patients for 2 weeks significantly reduced fasting blood glucose result by 35-40% with a marked reduction in insulin requirements averaging 66% with minimal side effects. This large body of clinical trials clearly suggests that IGF-1 can be a potent treatment in the maintenance of normal blood sugar levels especially in patients with diabetes.
Growth Hormone: A Potential Treatment Option in Diabetes?
Under normal conditions, insulin is the major regulator of blood glucose levels. However, human growth hormone (HGH) and insulin-like growth factor-1 (IGF-1) also play an important contributory role. Both of these hormones have potent effects on the metabolism of glucose which may be utilized in the management of diabetes. HGH has major effects on glucose metabolism. It increases the concentrations of glucose in the blood and decreases the body’s sensitivity to insulin, thus opposing the normal action of insulin. In people with diabetes, the concentrations of glucose are up to 2-3 times higher. Excessive GH secretion may be partly responsible for the ‘dawn phenomenon’ – a rise of blood glucose concentrations in the early morning before waking up.
Insulin-like Growth Factor-1 (IGF-1) and Diabetes
Although GH has many actions of its own, most of its actions are mediated through the generation of IGF-1. This hormone resembles the structure and function of insulin, including a rapid reduction in blood glucose levels. In people with Type 1 diabetes, the amount of insulin reaching their liver is reduced even in situations where there is intensive subcutaneous insulin treatment. As a consequence, their concentrations of IGF-1 in the blood are also reduced. Interestingly, when insulin therapy is given directly into the abdominal cavity by an implantable pump, the levels of insulin increase and there is near-normalization of IGF-1 concentrations.
Clinical Trials of IGF-1
When IGF-1 is given to people with Type 1 diabetes, significant improvement in blood glucose levels and a reduction in the insulin dose required to maintain normal glucose levels are observed. Similar results, together with a fat mass reduction, are seen in people with Type 2 diabetes who receive larger doses of IGF-1. Promising early clinical trials have been performed with the combination of IGF-1 and IGFBP-3, the major circulating IGF-1 binding protein. Over a 2-week period, there was a reduction in the doses of insulin and fasting blood glucose levels in patients with Type 1 and Type 2 diabetes. Notably different from previous studies with IGF-1 alone, this was achieved with minimal side effects. Low doses of IGF-1 have also been used in different rare conditions to prevent ketoacidosis (accumulation of ketones in the blood) and maintain normal blood glucose levels. Unfortunately, as IGF-1 doses increases, so is the rate of side effects.
Diabetic patients appear to have abnormalities in both HGH and IGF-1 and this contributes to both the metabolic disturbance and the susceptibility to complications. HGH may be beneficial for people with abdominal obesity who are at high risk for Type 2 diabetes. IGF-1 treatments in diabetic patients result in improved blood glucose control but its use has been limited by side effects. More recently, the combination of IGF-1 and IGFBP-3 has been shown to lower blood glucose levels without any side effects. However, further research will be needed to confirm the safety and efficacy of this compound.
Insulin-like Growth Factor (IGF-1) and Age-related Diseases
Aging is a universal, inevitable, irreversible and multidimensional process characterized by a gradual loss of physiological functions that increases the probability of death. Although related, longevity is different from aging, since longevity is simply considered as the length of the life span independent of the biological aging process. Circulating levels of GH and IGF-1 are at their peak during puberty and early adulthood; however, they gradually decline with age. This age-related decline is known as somatopause, in analogy with menopause and andropause. Reduced secretion of GH and IGF-1 hormones in the elderly is associated with unpleasant symptoms including mood changes, decline in energy levels, loss of muscle mass, increased fat mass, reduced bone mineral density, as well as alterations in the quality of life.
There are diverse theories of aging that basically point out to complex physiological essential for longevity: genetic stability, telomere shortening, stress resistance and metabolic control. Interestingly, IGF-I is somehow related to all of them. Firstly, assuming that the “powerhouse of the cells” called mitochondria are the main source of internal free radicals, it has been previously reported that species with increased metabolism have shorter lifespan due to accumulation of free radicals that lead to cell damage, thereby accelerating the aging process. IGF-I has been shown to restore mitochondrial dysfunction during aging by increasing mitochondrial membrane potential, reducing oxygen consumption, and increasing the synthesis of adenosine triphosphate (transports chemical energy within cells for metabolism) and subsequently promote survival of neurons by decreasing programmed cell death. By improving mitochondrial function and decreasing damage induced by free radicals, IGF-I may protect DNA, proteins and lipids. Furthermore, IGF-I’s antioxidant capability protects neurons in specific brain regions.
Secondly, IGF-I has been proposed as an index of healthy aging, due to the finding that it directly correlates with the leukocyte telomere length, a biomarker of human aging associated with a wide array of diseases. And thirdly, another aspect where IGF-I may play a role in delaying the symptoms of aging is by controlling metabolism and insulin. In addition, the body’s ability to respond normally to the effect of insulin decreases with age, and insulin resistance is a well-established human risk factor for a variety of illnesses such as diabetes, hypertension, heart disease, stroke and other disorders. Interestingly, low doses of IGF-1 improve insulin resistance and lipid metabolism in aging rats, thus becoming a potential beneficial agent to prevent insulin resistance-related pathologies.
Insulin and Insulin‐like Growth Factor‐1 Cause Vasorelaxation in Human Vessels In vitro
Vasorelaxation or vasodilation is the physiological mechanism of the widening of the blood vessels in the body due to the relaxation of smooth muscle tissue that they are connected to. Different stimulus in the environment such as weather and changes in physical exertion can stimulate these muscles to control both vasoconstriction (narrowing of blood vessels) and vasodilation. Widening of blood vessels actually has a number of benefits in the body. The vasodilation process allows a higher volume of blood, oxygen and other essential nutrients to flow through the vessels that have widened. More oxygen and nutrients benefit the muscles by increasing its capability of being stressed for longer periods of time and more intensively. Moreover, essential substances such as amino acids, testosterone, growth hormone (GH) and insulin-like growth factor 1 (IGF-1) are delivered to your starving muscles, resulting in increased muscle mass, strength and regeneration. Therefore, by feeding your system more blood, oxygen and nutrients, you transport elevated amounts of important substances into your muscles necessary for various biological processes in the body.
Nitric Oxide is the Key in Vasodilation
Nitric oxide (NO) initiates and maintains vasodilation by:
Insulin and Insulin‐like Growth Factor‐1 (IGF-1) Increases Nitric Oxide
Several studies have demonstrated IGF-1’s action in increasing NO. To evaluate the vasodilatory effects of insulin and IGF‐1 and to elucidate their mechanisms of action on human vessels, Izhar and colleagues studied blood vessels taken from patients with and without noninsulin‐dependent diabetes mellitus (NIDDM). The researchers harvested vascular rings of human internal mammary artery (IMA) and saphenous vein from 54 diabetic patients undergoing coronary bypass surgery and treated it with insulin and IGF-1, and were studied in vitro. Interestingly, the IMA rings from patients without NIDDM displayed greater relaxation than in saphenous vein rings treated with both insulin and IGF-1. Similar results were obtained with vessels from patients with NIDDM. Of note, vasodilation was not affected by the removal of the endothelium (produces NO) and by inhibition of the production of NO. Both insulin and IGF‐1 induced vasodilation of rings from human IMA and saphenous veins, through a mechanism involving activation of potassium channels. This mechanism remained intact in the blood vessels of patients with NIDDM.
These results further support the role of IGF-1 in triggering vasodilation in human blood vessels. This vasodilatory effect of IGF-1 can be of great therapeutic value in managing a wide array of diseases that impairs blood circulation such as stroke, heart diseases, blood vessel diseases, high blood pressure, high blood sugar, and other fatal diseases. By restoring normal blood flow to vital organs, IGF-1 can indeed be beneficial in patients with blood circulation problems.
IGF-1 Levels are Significantly Correlated With Patient-reported Measures of Sexual Function
The male sexual cycle is regulated by a complex interplay between neuroendocrine, vascular and genital systems. Any dysfunction in these systems can lead to erectile dysfunction (ED). ED or also known as impotence is the inability to get and maintain an erection firm enough for sexual intercourse. Multiple studies have shown links between ED, growth hormone (GH) and insulin-like growth factor-1 (IGF-1). GH stimulates IGF-1 production while IGF-1 is known to be the main intermediary of GH action. There is a relationship between all of these hormones that has been shown to affect a man’s ability to maintain an erection.
IGF-1 and Penile Erection
In recent studies, it has been shown that in healthy male patients, the levels of GH increase during penile erection. In patients with ED, GH levels are decreased approximately sevenfold. It has been postulated that the effects of GH in ED may be determined by IGF-1’s action in increasing nitric oxide levels. Nitric oxide is considered to be a principal mediator of penile erection by increasing cGMP formation, which in turn causes relaxation of vascular smooth muscle. This leads to engorgement of the penis with blood, thereby developing an erection.
The relationship of IGF-1 and penile erection has been described in otherwise healthy male subjects. Pastuszak and colleagues reported that IGF-1 levels correlate significantly with sexual function scores in 65 men who completed the Sexual Health Inventory for Men (SHIM) and Expanded Prostate Cancer Index Composite (EPIC) questionnaires. This study was able to show a relationship between IGF-1 and validated measures of patient-reported sexual function. All subjects in this study provided a preoperative blood sample of IGF-1 and testosterone between 1 week and 2 months before scheduled surgical removal of the prostate (prostatectomy). Subjects were asked to complete the SHIM and EPIC questionnaires (questions regarding sexual function) before prostatectomy. The results of the study showed that the subjects’ IGF-1 levels were correlated with self-reported sexual function as assessed using the questionnaires.
It is conceivable that supplementation with GH or IGF-1 can have a positive impact in ED after surgical removal of the prostate. However, there are controversies regarding IGF-1’s link to prostate cancer. In the same study, the researchers found no correlation between Gleason score (used to help evaluate the prognosis of men with prostate cancer) and IGF-1 levels. These data suggests that IGF-1 and the GH axis do not stimulate development of cancer and other aggressive tumors.
Low IGF-1 Levels and ED
IGF-1’s action in increasing nitric oxide levels is vital in maintaining penile erection and improving sexual function. With increasing age comes the decline in the levels of IGF-1 which is linked to the development of ED. This condition is a common public health problem that significantly impairs the quality of life and psychological well-being of the affected individual and his partner.
To determine the association between IGF-1 levels and ED, Otunctemur and colleagues evaluated the presence of ED in two groups: 80 patients suffering from ED for more than 1 year and 80 subjects without ED. Surprisingly, the results of the study showed that the blood IGF-1 levels were significantly lower in patients with ED, suggesting that IGF-1 level might be used in early prediction of ED in the future.
Benefits of Topical Insulin-like Growth Factor-1 Therapy for Sudden Deafness
Sudden sensorineural hearing loss (SSHL), commonly known as sudden deafness, is a medical condition that occurs as an unexplained, rapid loss of hearing usually in one ear. Hearing loss has an onset of less than 72 hours and reportedly affects 5 to 20 patients per 100,000 persons per year. In most cases of SSHL, physicians prescribe systemic corticosteroid as the standard treatment for this condition. Hearing improvement after taking systemic corticosteroids occurs in 50% of the patients, but approximately 20% of the patients do not respond to this treatment. It has been reported that systemic corticosteroid causes adverse side effects that can occasionally be life-threatening. As an alternative for systemic corticosteroids, physicians prescribe intratympanic corticosteroid treatment which is administered via direct injection into the middle ear because of its low risk for adverse side effects. This mode of corticosteroid injection is commonly used for the treatment of SSHL, after the administration of systemic corticosteroid has failed.
A major difficulty in treating SSHL is the poor regeneration of the cochlea (inner ear structure). Therefore, protecting this structure from irreversible degeneration is the main focus of the treatment. Several growth factors including insulin-like growth factor 1 (IGF-1) have been investigated for their protective effects on the sensory hair cells of the cochlea. IGF-1 is known to play a major role in the development and maintenance of the cochlea, thus, the administration of this growth factor can be beneficial in SSHL.
To further investigate the efficacy and safety of topical IGF-1 therapy as a novel therapeutic option for SSHL, Nakagawa and colleagues conducted a multicenter, randomized clinical trial from November 2010 through October 2013 at 9 tertiary referral hospitals in Japan to compare topical IGF-1 therapy and intratympanic corticosteroid therapy for treating SSHL. The participants were all adults, 20 years or older, who had SSHL. This is the first randomized controlled clinical trial to test the efficacy of IGF-1 for the treatment of SSHL. The researchers randomly assigned patients with SSHL to receive either gelatin hydrogels impregnated with IGF-1 in the middle ear (62 patients) or four intratympanic injections with dexamethasone (58 patients).
Interestingly, in the IGF-1 group, 66.7% of the patients showed hearing improvement compared to 53.6% of the patients who received intratympanic injections with dexamethasone. The difference in changes in pure-tone average hearing thresholds (a test for hearing) over time between the two treatments was statistically significant. Also, no serious adverse side effects were observed in the IGF-1 group. In addition, a trend that the proportion of patients treated with IGF-1 who showed complete or marked recovery was higher than those treated with dexamethasone injections.
These findings strongly suggest the superior efficacy of topical IGF-1 therapy over intratympanic dexamethasone injections. On the other hand, the high incidence of tympanic membrane perforation in patients treated with intratympanic dexamethasone injections might affect hearing recovery outcomes. The positive effect of topical IGF-1 application on hearing levels and its favorable safety profile suggest that IGF-1 administration might be of great therapeutic value in patients with SSHL as well as other hearing problems.
Biological Repair of the Degenerated Intervertebral Disc by the Injection of Growth Factors
Degenerative disc disease is caused by the repeated daily stresses on the spine and occasional minor, unnoticed injuries, as well as major ones. For most people the gradual degeneration of the discs is not a problem. However, in severe cases, it can cause chronic and debilitating pain. To better understand the disease, it is important to understand how the intervertebral discs work. Normally, the intervertebral discs of a healthy young adult are consist of 90% fluid. Over time, the fluid content in the discs decreases, making it thinner. Think of your intervertebral discs as the cushion or shock-absorber between each vertebra. With increasing age, it starts to degenerate and become less effective. This degeneration of the disc occurs more rapidly in obese people, those who do strenuous physical work regularly, and people who smoke regularly. When the vertebrae have less padding between them because of decreased fluid content, the whole spine becomes less stable. The body tries to compensate by building osteophytes or also known as bone spurs or bony outgrowth. Osteophytes are small bony projections along the edge of the bones which can press against the spinal cord or spinal nerve roots, resulting in severe pain and alteration of the nerve function.
Effects of Insulin-like Growth Factor-1 IGF-1) on Intervertebral Disc Cells
Recent therapeutic strategies for disc degeneration have included attempts to increase the production of key matrix proteins such as aggrecan, or to decrease the levels of pro-inflammatory cytokines. One of the most advanced treatment options to regenerate or repair a degenerated disc is the injection of a recombinant growth factor. IGF-1 has been shown to stimulate intervertebral disc cell proliferation and matrix synthesis in vitro. In another study, Gruber and colleagues reported that IGF-1 and platelet-derived growth factor (PDGF) were both able to significantly reduce the percentage of cell death in intervertebral disc cells induced by serum depletion in culture.
Although the clinical application of IGF-1 and other growth factors to treat degenerative disc disease has been initiated and has shown positive results, several important considerations need to be taken into account. First, the target population of IGF-1 administration is mainly an aged population, which has decreased intervertebral disc cells especially those with advanced stage of degeneration. Without functional cells, the injection of IGF-1 and other growth factors will not achieve a therapeutic effect. Therefore, for this type of treatment option to be effective, healthcare providers must determine the appropriate stage of disc degeneration and age of the patients.
Abundant evidence for the efficacy of growth factor injection therapy for the treatment of degenerative disc disease can be found in preclinical animal studies. Recent data obtained from animal studies following growth factor injection illustrate the great potential for patients with chronic low back pain. Considering the difficulty of repairing or regenerating disc tissues in the advanced stages of disc degeneration, the use of IGF-1 and other growth factors such as its application to discs adjacent to a fusion level, may be an alternative approach. With regards to pain management in degenerative disc disease, growth factor-targeted interventions would need to either supply the disc with the lacking growth factor (such as IGF-1) or would target the resulting pain by inhibiting the actions of nerve growth factor (NGF).
Therefore, IGF-1 administration in degenerative disc disease might have the ability to reverse the progressing tissue destruction which occurs with ageing, thereby greatly improving the quality of life of the affected patients.
The Role of Insulin-like growth factor 1 (IGF-1) therapy in Mitochondrial dysfunction and Diseases
Mitochondrial dysfunction is linked to a wide range of illnesses and conditions. The mitochondria or also known as the “powerhouse of the cell” generate chemical energy called adenosine triphosphate (ATP), which is the energy source of every single cell in the body. Because the mitochondria are responsible for producing energy, any illness that has an energy problem could be related to it. Mitochondrial dysfunction has been implicated in the following diseases:
Mitochondrial diseases are the result of either inherited or spontaneous mutations or alterations in a person’s DNA. Because the mitochondria have so many different bodily functions, there are hundreds of different diseases linked with dysregulation in the mitochondria. Each disorder can yield a spectrum of abnormalities that can be confusing to both healthcare providers and patients in early stages of diagnosis and in planning the best medical intervention.
IGF-1 as a Mitochondrial Protector
A decrease in IGF-1 levels has been widely documented and it may be involved in the development of abnormal brain structures, cognitive loss, neural inflammation, oxidative stress and mitochondrial dysfunction. Although research is ongoing, treatment options for mitochondrial dysfunction are currently limited. In order to treat this condition, physicians prescribe vitamins, antioxidants, and spindle transfer, where the DNA is transferred to another healthy egg cell leaving the defective mitochondrial DNA behind.
In several experimental models, IGF-1 has been found to play a pivotal role in protecting the mitochondria. Normally, mitochondria are a major source of reactive oxygen species (ROS) under physiologic conditions. ROS are chemically reactive chemical species containing oxygen. The mitochondria are particularly sensitive to ROS-induced injury because oxidative stress exerts deleterious effects on the function of the mitochondria by directly impairing oxidative phosphorylation (a process by which most ATPs are produced in cellular respiration) through direct attack of proteins or membrane lipids. Moreover, ROS can also delete the mitochondrial DNA and induce mitochondrial membrane permeability transition, which leads to cell death.
In order to give a better insight into the mechanisms by which IGF-1 exerts its protective function in the liver, Pérez and colleagues treated Wistar rats with low doses of IGF-1. Interestingly, untreated rats with liver cirrhosis showed a mitochondrial dysfunction characterized by a significant reduction of mitochondrial membrane potential, an increase in ROS and a significant reduction in the activity of ATPase (necessary for ATP production). On the contrary, IGF-1 treated rats showed increased mitochondrial membrane potential and ATPase activity and reduced ROS levels. These results suggest that IGF-1 therapy can normalize mitochondrial function by increasing the membrane potential and ATPase activity while reducing ROS production.
In another study, Hao and colleagues assessed the effects of IGF-1 addition in human umbilical vein endothelial cells (HUVECs) following exposure to hydrogen peroxide. Exposing cells to hydrogen peroxide can trigger cell death in a time dependent manner. Surprisingly, the addition of IGF-1 blocked this oxidative-stress effect in HUVECs by reducing mitochondrial dysfunction. Specifically, the protective mechanism of IGF-1 involves preserving the integrity of the mitochondrial membrane and reducing the activity of caspase-3 (helps trigger programmed cell death or apoptosis).
Potential Utility of rhIGF-1 in Neuromuscular and/or Degenerative Disease
Neuromuscular or neurodegenerative disorders, such as the death of spinal cord motor neurons in amyotrophic lateral sclerosis (ALS) or the degeneration of spinal cord motor neuron axons in certain peripheral neuropathies, present a unique opportunity for therapeutic intervention with neurotrophic proteins (family of proteins that induce the survival, development, and function of neurons).
Vaught et al found that in mixed rat embryonic spinal cord cultures or in purified motor neuron preparations, recombinant human insulin-like growth factor 1 (rhIGF-1) displays neuroprotective effects by enhancing the survival of motor neurons. In a model of programmed cell death in the embryo, rhIGF-1 administration produces a marked survival of motor neurons. In a variety of models of predominantly motor neuron or nerve injury in rodents, rhIGF-1 administration prevents the death of motor neurons in neonatal facial nerve lesions and hastens recovery from sciatic nerve crush in mice. In a genetic model of motor neuron compromise, the wobbler mouse, rhIGF-1 administration at a dose of 1 mg/kg per day given subcutaneously delayed the deterioration of grip strength and provided for a more normal distribution of fiber types. In addition, rhIGF-1 administration at a dose of 0.3-1.0 mg/kg per day given subcutaneously prevents the motor and/or sensory neuropathy in rodents caused by chemotherapeutic drugs such as vincristine, cisplatinum or Taxol.
These combined data indicate that rhIGF-1 has marked effects on the survival of compromised motor neurons and the maintenance of their axons (long threadlike part of a nerve cell) and functional connections. They also suggest the potential utility of rhIGF-1 for the treatment of diseases such as ALS and certain neuropathies.
Administration of Human Recombinant Insulin-like Growth Factor-I (IGF-1) to Patients following Major Gastrointestinal Surgery
Patients undergoing major gastrointestinal surgery have increased protein breakdown as well as metabolism known as “catabolic state” which if prolonged delays recovery and increases the risk for complications and death. To manage catabolic states and help improve the clinical outcome of critically ill or post-operative patients, healthcare providers make use of adjunctive anabolic therapy which focuses on increasing bone mass and strength, and parenteral nutrition (feeding through the veins). However, parenteral nutrition alone is unable to prevent catabolic state but with adjunctive growth hormone (GH) therapy, positive balance of nitrogen within the body which is necessary for muscle growth and maintenance of muscle mass, may be achieved. The anabolic actions of GH at target tissues are mediated by the hormone known as insulin like growth factor-I (IGF-1). It is possible, therefore, that IGF-1 itself may prove to be a potent anabolic agent.
Recombinant IGF-1 (rhIGF-1) has been administered to patients with Laron type dwarfism, GH-deficient patients and healthy volunteers. As IGF-1’s actions are modulated by its binding proteins whose levels vary in different disease states, healthcare providers find it difficult to determine the effects of IGF-1 administration on post-surgical patients. To provide answers to this, Miell and colleagues assessed the effects of IGF-1 administration in patients who have undergone major abdominal surgery. Thirty patients (aged between 45 and 75 years) undergoing major abdominal surgery were enrolled in the study. All of them had no history of endocrine disorder, diabetes, and had no major liver or kidney problem. Twenty-four hours following surgery, the researchers collected baseline blood samples from the venous catheter at 2-hour intervals for 10 hours. Forty-eight hours after the surgery, the researchers administered subcutaneous injection of rhIGF-1. All blood samples were allowed to clot at 4°C for approximately 1 hour. During the study, subjects remained fasted, and for the 8 hours following injection of IGF-1, all patients received 5% dextrose or normal saline. Interestingly, the results of the study showed that the administration of a single dose of rhIGF-1 to 19 patients following major abdominal surgery normalized total circulating levels of IGF-1 and increased its availability in the blood circulation by 50%. Moreover, the treatment proved to be safe and well-tolerated by all patients. However, four patients complained of slight stinging at the site of IGF-1 injection which was short lived. Also, IGF-1 administration did not affect the GH levels of all the patients. Fasting and major abdominal surgeries are associated with an increase the baseline GH levels and a decrease in IGF-1 levels. These changes were able to positively influence the levels of potassium, cholesterol and creatinine in these patients.
Malnourished, severely ill or post-operative patients seem to have low levels of IGF-1 and are relatively insensitive to the effects of GH. In severe illness, parenteral feeding alone is not enough to reverse the process of muscle wasting, weight loss, and protein breakdown. Thus, rhIGF-I administration must be added to these patients’ medical management because of its potential as an anticatabolic therapy. Moreover, its added benefits on influencing the levels of potassium, cholesterol and creatinine in post-operative patients may have beneficial effect in the recovery process.
Effect of Growth Factors on Wound Healing
The failure of chronic wounds to heal remains a major medical problem. The majority of investigations on wound healing have concentrated on the inner layer of the skin and wound bed remodeling, with little emphasis on the regeneration of the upper skin layer (epidermal wound healing). Epidermal wound healing is a complex process involving migration and proliferation of skin cells into the wound under the influence and direction of growth factors.
In vitro experiments have shown that IGF-1 increases the production of collagen and inhibits the production of matrix metalloproteinase (MMP-1), which breaks down the collagen matrix in the inner layer of the skin called dermis. Collagen maintains skin firmness, suppleness and is responsible for constant renewal of skin cells to keep the skin healthy and radiant. Aside from these effects, IGF-1 and other growth factors such as fibroblast growth factor (FGF) and epidermal growth factor (EGF) are released at the site of injury and presumed to be an essential part of the wound healing process. Moreover, each of these growth factors has been shown to improve healing when added exogenously to healing wounds.
To further assess the effects of growth factors on wound healing and to study the temporal relationship of FGF, IGF-1, and EGF on DNA synthesis, Bhora and colleagues developed an in vitro model of epidermal wound healing using harvested tissues from human skin. This model is one of the most useful experimental models to study wound healing and tissue repair because it is very similar to the wound environment. The researchers made use full thickness skin obtained from the amputated lower extremities of human subjects after voluntary consent and in accordance with institutional guidelines. The skin model were trimmed of excess fat cells and incubated prior to the study. The aim of the study is to explore two features of growth factor effect: cellular proliferation and epithelial outgrowth (growth of cells on the skin surface).
The results of the study showed that proliferation of cells in human skin model occurs at a constant rate over 7 days and is accelerated by administration of growth factors. FGF, IGF-1, and EGF each induced cell division in the human skin model as early as 24 hours after organ culture, which persisted on days 3 and 7. Furthermore, each growth factor exhibits different effect on the skin. EGF has been shown to induce cell division in the skin’s outer layer. FGF induce cell division in collagen-producing cells, keratin-producing cells and cells of the blood vessels, while IGF-1 primarily stimulates collagen-producing cells and smooth muscle cells. In addition to this, treatment with FGF and IGF-1 was able to increase epidermal outgrowth when compared to baseline.
It is increasingly apparent that growth factors such as FGF, IGF-1, and EGF play pivotal roles in impaired tissue healing as well as normal skin development. Thus, it may be advantageous to augment growth factor levels to achieve accelerated normal wound healing. Furthermore, combining multiple growth factors may potentiate wound healing benefits.
IGF-1 Increases with Hyperbaric Oxygen Therapy and Promotes Wound Healing in Diabetic Foot Ulcers
Nerve and blood vessel problems, as well as poor blood sugar control in diabetic patients increase the likelihood that they will develop foot ulcers. Hyperbaric oxygen therapy (HBOT), which delivers 100% oxygen at pressures above one atmosphere, has been promoted as an effective mode of treatment in patients with diabetic foot wounds. Experts believe that HBOT can improve wound tissue hypoxia (inadequate oxygen in the wound tissue), enhance blood circulation, reduce edema or swelling, and increase the production of cells necessary for wound repair, thus, making HBOT as a useful adjunct in clinical practice for wound problems including diabetic foot ulcers. Moreover, HBOT is also touted for eradicating difficult to treat soft tissue and bone infections by enhancing the function of immune system cells such as white blood cells. In a 2004 Cochrane database systematic review, the researchers concluded that HBOT significantly reduced the risk of major amputation and may improve wound healing in diabetic patients at 1 year.
IGF-1 and Wound Healing
Insulin-like growth factor (IGF) has been shown to stimulate keratin production in vitro. Keratin is the protein that protects epithelial cells (barrier between the inside and outside of the body) from damage or stress and is the key structural material comprising the outer layer of skin. Existing evidence indicates that IGF- regulates tissue growth and repair, as well as normalization of blood sugar levels in diabetic patients. A lack of IGF-1 production within the skin may contribute to delayed wound healing in diabetic patients. Moreover, IGF-1 plays a role in improving blood circulation to damaged tissues by decreasing the blood vessel constricting actions of angiotensin II, norepinephrine, and vasopressin. This in turn leads to adequate amount of blood as well as oxygen and essential nutrients going to the damaged tissues which aid in faster wound healing.
There is little information on the link between IGF-1 and wound healing in diabetic foot ulcers treated with HBOT. To determine whether IGF-1 levels change in response to HBOT and whether IGF-1 is a predictive indicator of wound healing in diabetic patients with foot ulcers, Aydin and colleagues treated 48 consecutive diabetic patients. The patients were classified into two groups: the healed group and the non-healed group. Interestingly, the results of the study showed no significant difference in initial IGF-1 levels between the healed and non-healed group. In the healed group, the mean IGF-1 levels increased significantly and the final values were significantly higher than the non-healed group. The researchers concluded that HBOT is a safe and effective treatment modality in diabetic patients with foot ulcers, with an elevation of IGF-1. The significant increase in IGF-1 levels following HBOT seems to be a predictive factor for wound healing.
If realized clinically, the beneficial effects of HBOT and IGF-1 elevation in diabetic foot ulcers might powerfully reduce the risk of lower-extremity amputation by accelerating the wound healing process. Thus, rigorously assessing the clinical effectiveness of HBOT as well as changes in IGF-1 levels during the treatment in patients with diabetic foot wounds can help healthcare providers determine the outcome of the medical intervention.
Insulin-Like Growth Factor 1 (IGF-1) Enhances the Wound Healing Process
Wound healing is a dynamic process that involves the integrated action of several types of cells and inflammatory substances known as cytokines. In recent years, advances in technology have been made, focusing on growth factors’ ability to regenerate and repair various tissues and organs in the body. Growth factors are proteins that enhance the communication of cells. Their function depends on the receptor site they attach to. Recently, growth factors have been shown to regulate many of the activities involved in wound healing, which is a critical component of the successful resolution of a wound. Growth factors released in the traumatized or injured area promote cell migration into the wound, stimulate the growth of cells, initiate the formation of new blood vessels, and stimulate formation and remodeling of the affected area. Animal studies have shown that administration of growth factors into the injured area can accelerate the normal wound healing process. In humans, growth factors have been used successfully in treating incurable wounds related to chronic illnesses. The most intensively studied growth factors are insulin-like growth factor 1 (IGF-1), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), transforming growth factor (TGF)-α, and TGF-β.
Keratinocyte Migration: A Critical Phase of the Wound Healing Process
An essential feature of a healed wound is the restoration of an intact outer skin layer through wound epithelialization (formation of granulation tissue into an open wound). The directed migration of keratinocytes (cells of the outermost layer of the skin) is critical to wound epithelialization and defects in this function are associated with delayed wound healing or non-healing wounds. In order to better understand the wound healing process, you must first know the different phases of wound healing:
IGF-1 Enhances Keratinocyte Migration
Keratinocyte migration and proliferation are required for epithelialization. A number of evidence has shown that these processes are regulated by one or more growth factors. To further elucidate the effects of IGF-1 and other growth factors in wound healing, Ando and colleagues performed a direct observation of the migration path of growth factors using the phagokinetic assay on human keratinocytes. Interestingly, addition of EGF to human keratinocytes in the absence of any other growth factor induced an increase in migration of 2.5-4.5 fold after overnight incubation. Moreover, the addition of an antibody completely prevented the EGF-induced migration; however, the enhancement of migration of human keratinocytes by using insulin or IGF-1 was not blocked. These results suggest that IGF-1 and insulin enhance human keratinocyte migration by a mechanism distinct from that of EGF. IGF-1’s ability to enhance this critical phase of the wound healing process can be of great therapeutic value in delayed wounds or non-healing wounds related to chronic illnesses.
The Role of Growth Factors in Intestinal Regeneration and Repair in Necrotizing Enterocolitis
Necrotizing enterocolitis (NEC) is characterized by death of the inner lining of the small or large intestine. This causes the intestine to become inflamed. Over time, this may cause a hole in the wall of the intestine, resulting in the leakage of the intestinal bacteria into the abdomen and cause widespread infection. NEC can develop in any newborn within two weeks. However, the disease is more likely to occur in premature infants, accounting for 60 to 80 percent of cases. This disease can progress very quickly and is life-threatening that’s why it is important to get treatment right away.
What are the Symptoms of Necrotizing Enterocolitis?
The symptoms of NEC often include the following:
What Causes Necrotizing Enterocolitis?
Although the exact cause of NEC is unknown, experts believe that insufficient amounts of oxygen during a difficult delivery can contribute to its development. When there’s inadequate oxygen or blood flow to the intestine, it can become weak. As a result, the bacteria from the food can easily damage the intestinal tissues.
Insulin-Like Growth Factor-1 (IGF-1) Stimulates Cellular Proliferation
IGF-1 is synthesized primarily in the liver but also in the gastrointestinal tract. This hormone is also found in the intestine of the fetus as well as in human milk, suggesting a role in the development of the intestine. IGF-1 is known to increase intestinal cell proliferation and growth. In animal models and in human studies of short bowel syndrome (malabsorption disorder), enlargement of the intestine, or inflammatory bowel disease, IGF-1 is more potent in stimulating intestinal growth than growth hormone (GH), suggesting a role in intestinal repair in NEC.
In vivo evidence for the proliferative effects of IGF-1 on the intestines is derived from experimental models using both oral and parenteral route. Oral feeding of IGF-1 to neonatal pigs led to an increase in the height and weight of small intestine
IGF-1 is Pro-Survival
IGF-1 increases intestinal growth, in part, by inhibition of cell death or destruction. In vitro and in vivo studies demonstrate that IGF-1 administration promotes survival in smooth muscle cells of the muscularis propria (thick muscle deep in the bladder wall) of humans and mice.
IGF-1 and Gastric Ulceration
Recently, decreased IGF-1 level in chronically ulcerated gastric tissue has been described. When IGF-1 is administered in rat models with thermally-induced gastric injury, accelerated healing of the intestines is observed. The potential applicability of IGF-1 treatment to gastric injury is further supported by its ability to inhibit gastric acid secretion, which is an important mechanism in preventing further ulcerations in NEC.
IGF-1 Promotes Wound Healing and Repair in the Intestinal Tract
IGF-1 does not only stimulate proliferation and inhibition of cell death of intestinal cells, it also increases the production of collagen in these cells. Collagen plays a key role in each phase of wound healing, suggesting that IGF-1 can help repair ulcerations in NEC.
Application of Insulin-like Growth Factor-1 in the Treatment of Inner Ear Disorders
Sensorineural hearing loss (SNHL) is a common disability. It occurs when there is damage or injury to the inner ear known as cochlea, or to the nerve pathways from the cochlea to the brain. Usually, SNHL cannot be corrected even through surgery that’s why it is the most common type of permanent hearing loss. SNHL is caused by several factors such as certain underlying illnesses, drugs that are toxic to the ears, genetics, aging, head trauma, malformation of the inner ear acquired at birth or some point in life, and exposure to loud noises. In the United States, about 63% of people age 70 years and above have hearing loss. Despite the high prevalence, no effective treatment has been established for SNHL. In most of the cases of SNHL, the loss or functional impairment of hair cells in the inner ear is the main culprit. Consequently, hair cells never regenerate that’s why experts have difficulties in developing the most effective methods of treating SNHL.
Insulin-like Growth Factor-1 (IGF-1) and the Inner Ear
As regenerative medicine emerged in the 21st century, several researchers have attempted to regenerate hair cells in the inner ear using stem cell transplantation, alteration of specific genes, and treatment with growth factors. Among these techniques, the use of growth factors has shown promising results in regenerating hair cells in the inner ear because of their healing abilities.
Since Leon and colleagues reported that IGF-1 promotes the growth of chicken otocysts (inner ear structure) by inducing cell proliferation, many studies have shown the effectiveness of IGF-1 and its signaling system in the development and maintenance of the inner ear. In human beings, several studies have shown that SNHL occurs in patients with mutations in IGF-1 gene, primary IGF-1 deficiency or low blood levels of IGF-1 due to other genetic defects, indicating the importance of IGF-1 in hearing.
IGF-1’s Regenerative Role in the Hair Cells of the Inner Ear
The SNHL in Laron syndrome patients is attributed to dysfunction in the inner ear. Replacement therapy using recombinant IGF-1 in these patients was able to correct hearing dysfunction. In line with this finding, another clinical trial was performed to study the efficacy of IGF-1 in the treatment of SNHL. In this clinical trial, Nakagawa and colleagues treated 25 patients with sudden sensorineural hearing loss (SSHL) using IGF-1 gelatin hydrogel which was applied onto the opening of the inner ear. Surprisingly, at 12 and 24 weeks after IGF-1 treatment, the patients showed hearing improvement without any serious side effects.
There are two possible mechanisms by which IGF-1 maintain the numbers of hair cells in the inner ear: 1. inhibition of cell death, and 2. increasing the production of hair cells. In addition to this, IGF-1 activates both its downstream signaling pathways, the MEK/ERK and PI3K/Akt pathways in the inner ear, which has a protective role in the hair cells. Moreover, IGF-1 protects hair cells from various injuries to the inner ear such as reduced blood flow, noise exposure, and from side effects of medications which are toxic to the ears. With these mechanisms, IGF-1 can be considered as a promising medication for SNHL.
Continuous Subcutaneous IGF-1 Therapy via Insulin Pump in a Patient with Donohue Syndrome
Amyotrophic lateral sclerosis (ALS) or also known as Lou Gehrig’s disease, is a disease of the nervous system that causes muscle weakness leading to impairment in physical function. ALS often begins with muscle twitching and weakness in an arm or leg. Eventually, the disease can affect your ability to control the muscles needed to move, eat, speak and breathe. This type of motor neuron disease has gradual onset and affected individuals experience worsening of symptoms over time.
The exact cause of ALS is unknown. However, there are several factors that may lead to ALS such as:
Gene mutation: Gene mutations from parents can be passed down to their siblings and cause ALS.
Chemical imbalance: Affected individuals generally have higher levels of glutamate, a chemical messenger in the brain. Higher levels of glutamate are known to be toxic to some nerve cells.
Altered immune function: The immune system of persons with ALS attacks his or her own normal cells, which kills the nerve cells.
Protein mishandling: This lead to gradual build-up of abnormal proteins in the nerve cells, eventually causing these cells to die.
Distribution of IGF and Insulin Binding Sites in the Body
The respective role of environmental toxins, viral infections, and other toxic substances in the development of ALS remains to be fully established. Since the etiology of ALS is still unclear, recent studies on ALS have focused on potential therapeutic approaches that may alter the course of the disease or at least prevent worsening of the symptoms and prolong the patient’s life.
Recent studies reported that IGF-1 was effective in altering the progression of ALS in a large cohort of patients. IGF-1, IGF-11 and insulin are structurally related peptides with a wide array of functions. For example, IGFs have the ability to repair lesioned peripheral nerves, induce marked collateral sprouting of intramuscular nerve fibers, promote survival of motor neurons (nerve cells which stimulate muscle movement) in vitro, and induce brain growth and formation of the protective covering of nerve cells called myelin sheath.
Specific IGF-1 and insulin binding sites are discretely and differentially distributed in the human thoracic spinal cord. Interestingly, the levels of IGF-1 and insulin binding sites were found to be significantly increased in the spinal cord of ALS patients. The increases in IGF-1 and IGF-11 binding sites were not restricted to markedly pathologically affected areas such as motor neurons but also in sensory areas, suggesting that both motor neurons and sensory areas are altered in ALS.
IGF-1 Administration in ALS Patients
The peripheral injection of IGFs, especially IGF-1, has shown to have beneficial effects on the motor neurons in the spinal cord with minimal side effects. In a double-blind, placebo-controlled, randomized study of 266 ALS patients, Lai et al. reported that the progression of functional impairment in ALS patients receiving high-dose (0.10 mg/kg/day) recombinant human insulin-like growth factor 1 (rhIGF-1) was 26% slower than in patients receiving placebo. Moreover, ALS patients treated with rhIGF-1 exhibited a slower decline in quality of life with no medically important adverse effects. These encouraging results point to the potential clinical usefulness of IGF-1 in the treatment of ALS and other neurodegenerative disorders.
The Therapeutic Potential of Insulin-like Growth Factor-1 in Central Nervous System Disorders
The nervous system is a complex, sophisticated system that plays many different roles in the body. It is made up of two major divisions:
In addition to this, principal organs of the nervous system include the eyes, ears, tongue, nose, and sensory receptors located in all parts of the body. Disorders of the nervous system may involve the following:
IGF-1 Administration in Different Central Nervous System Disorders
Neurotrophic factors are family of small proteins that support the growth and survival of both developing and mature neurons (nerve cells), and are critical for the proper development of the central nervous system (CNS). Any disruption in these important developmental processes can lead to a wide array of CNS disorders. Neurotrophic factors have been the focus of recent research aimed at understanding the development and possible therapeutic option for several CNS disorders. One such factor is insulin-like growth factor-1 (IGF-1), a hormone that is similar to insulin both in structure and function.
Clinical trials with recombinant IGF-1 (rhIGF-1) in amyotrophic lateral sclerosis, Alzheimer’s disease, multiple sclerosis, and Rett syndrome have led to positive results. One study involving rhIGF-1 use in amyotrophic lateral sclerosis led to a significant retardation of disease progression, increased muscle strength, improved respiratory functioning and an increase in quality of life. In Alzheimer’s disease, IGF-1 has the ability to regulate amyloid beta levels by increasing the permeability (ability to allow substances to pass) of blood brain barrier to the amyloid beta carrying proteins. In multiple sclerosis, systemic delivery of IGF-1 stimulates regulatory immune cells known as T cells and suppresses autoimmune disease. In patients with Rett syndrome, IGF-1 administration led to an improvement in cognitive abilities and in the interactions with the surrounding environment.
Finally, Costales and colleagues summarized the results of completed and ongoing pre-clinical and clinical trials using IGF-1 as a pharmacologic intervention in various CNS disorders. The researchers included all randomized controlled clinical trials, prospective and retrospective cohort studies, and cross-sectional studies in this review. Interestingly, the therapeutic potential of IGF-1 was found to be relevant to the treatment of several CNS disorders, most notably amyotrophic lateral sclerosis, multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, and autism spectrum disorder.
The effects of IGF-1 during development and its administration in many different CNS disorders clearly demonstrate its many potential therapeutic roles in a wide array of diseases. Although the specific mechanisms responsible for proper development of the CNS is not yet fully understood, there are several pathways in the brain that have consistently been implicated in neurodevelopmental disorders. Of note, IGF-1 not only has significant interactions with pathways that trigger the development of several CNS disorders, but its administration is also effective in reversing these disorders and slowing its progression.
Role and Importance of IGF-1 in Traumatic Brain Injuries
The somatotropic axis (GH and IGF-1) seems to be the most affected in traumatic brain injuries (TBI). IGF-1 plays an important role in the growth and development of the brain, and is related to repair responses to damage for both the central and peripheral nervous system. The levels of IGF-1 in the blood are prone to decrease during both the early and late phases after TBI. During the last two decades, several evidences have shown a hormonal crucial role in influencing the damage after TBI. Therefore several studies focused their attention on posttraumatic endocrine dysfunction, attempting to correlate it with the outcome of TBI. In this contest, blood modifications of growth hormone (GH) and IGF-1 concentration appear to be the most affected. Various researchers had increasingly assigned a greater value to IGF-1 because it seems to play important roles in the development and secondary response to brain damage.
IGF-1 in the CNS
IGF-1 stimulates the proliferation and differentiation of oligodendrocytes (glial cells that support myelin production). It can increase levels of neurotransmitters (brain chemicals), neurotransmitter receptors, and proteins of the cytoskeleton; it can inhibit cell death in nerve cells; it stimulates dendrite growth, development of new blood vessels, and amyloid clearance. Moreover IGF-1 gene disruption, leading to loss of function, induces neuronal loss in brain regions such as the hippocampus and striatum. Thus, it can be assumed that the age-dependent decline in the levels of IGF-1 and IGF-1 receptor could be a possible contributing factor to the development of cognitive impairments in the elderly.
IGF-1 in the CNS Pathologies
IGF neurotrophic activity which is responsible for growth, survival and maintenance of neurons, is suggested to be fundamental in the recovery of neural tissue from injury. In this sense, various studies involving the central nervous system have revealed an impressive IGF-1 induction after different brain injury such as ischemia and cortical injuries as well as spinal cord injury. The major role of IGF-1 in hypoxic/ischemic damage, through its stimulation of the repair mechanisms in the body, is increasingly being recognized. The levels of IGF-1 in the blood have been proved to be depressed following acute stroke in humans, while in rodent models, IGF-1 blood levels in the brain resulted in increase in the perilesional stroke area, thus likely revealing a neuroprotective role. It seems also that higher level of IGF-1 following a stroke is related with reduced lethality. Several studies have shown the beneficial effect of IGF-1 administration in post-stroke patients, reducing neuronal loss and infarct volume, while increasing glial proliferation.
A recent study demonstrates that depressed levels of IGF-1 in the blood are associated with increased risk of developing Alzheimer’s disease dementia, while higher IGF-1 levels are related to greater brain volumes and may help protect against degeneration of nerve cells. Moreover, IGF-1 appears to be linked with repair processes after brain damage, controlling the regeneration of injured peripheral nerves.
Role of IGF-1 in TBI: Experimental Studies
The activity of IGF-1 in the central nervous system seems to be essential even in TBI with a number of recent findings supporting IGF-1’s role in wound healing in the brain. IGF-1 is a potent mitogen (substance that triggers cell division) and can induce differentiation of neural cells in vitro. It may also influence similar functions in vivo, exerting its mitogenic and trophic effects (induces growth) on a variety of cell types, after brain injury.
Several evidences suggest that IGF-1 may play a role in the regulation of reactive astrogliosis, which is one of the most prominent manifestations of the repair response in the mature CNS. IGF-1 has also been proved to stimulate in vitro the astrocyte migration in response to axonal injury. Walter et al. showed an increased expression of IGF-R protein in the early stage (1–7 days) of penetrant cerebral wounds model. In another study, Rubovitch et al. confirmed the activation of the Akt pathway (promotes survival and growth) and also showed the activation of ERK1/2 (promotes cell proliferation and cell death) following mild-TBI. IGF-1 may even exert its neuroprotective activity after mild-TBI in mice through the PERK/CHOP pathway.
Role of GH and IGF-1 in TBI: Clinical Studies
IGF-1 plasma concentrations in patients with TBI are typically below the normal range. However, plasma IGF-1 concentrations do not seem to be a reliable reflection of GH secretion or action in the setting of acute illness. Other studies instead show that the levels of GH remain relatively normal or slightly elevated throughout the acute setting in mild, moderate, and severe TBI. In a recent study, a transient decrease in IGF-1 levels in the blood has been recognized with low levels on day 1 and then restored towards normal on day 4 after severe TBI. In another study, Agha et al. and Dimopoulou et al. showed no statistical differences in plasma IGF-1 concentrations between the GH-sufficient and GH-deficient groups, after severe TBI.
The detection of a peripheral resistance to GH action, manifested by elevated plasma GH concentrations, with low plasma IGF-1 concentrations, underlines the influence on plasma IGF-1 levels even by factors other than GH secretion and action. In this sense, there are evidences supporting injuries as factors able to influence the brain expression of IGF-1 as much as GH and nutrition do. The role of the trauma-induced elevation in IGF-1 is unclear, but it is feasible that IGF-1 upregulation in surviving neurons may act to limit the progression of cell death, induce progenitor cell (stem cell) differentiation, or promote neurite (refers to any projection from the cell body of a neuron) outgrowth.
Strategies to either increase the endogenous upregulation of IGF-1 after TBI or supplement it with exogenous IGF-1 may improve neuronal survival after TBI. Along with more recent data linking brain insulin/IGF-1 function to the etiology of a number of neurodegenerative diseases will, undoubtedly, translate into more clinically oriented avenues of research in the near future. Depending on each personal genetic background, antidiabetic drugs and other molecules potentially interacting with the IGF-1 system may probably play a role in the next future when facing TBI and other nervous system pathologies. The identification of IGF-1 as a biomarker of posttraumatic injury could help healthcare providers in the future to understand whether and how to plan the hormone replacement therapy to prevent secondary damage of trauma and to improve patient outcome.
The Insulin-like Growth Factor System in Chronic Kidney Disease
Chronic kidney disease (CKD) is a medical condition wherein the kidneys gradually lose its function. Normally, the kidneys filter wastes and excess fluids from the blood and then excrete it in the form of urine. During advanced stage of CKD, dangerous levels of body fluids and wastes build up in the blood. Some of these wastes are toxic and they may damage vital organs in the body, which can eventually lead to death.
CKD results from several medical conditions such as diabetes, high blood pressure, glomerulonephritis (inflammation of the kidney’s filtering units), polycystic kidney disease (formation of large cysts in the kidney), repeated urinary infections, lupus, tumors, kidney stones, enlarged prostate gland and other diseases that affect the body’s immune system. CKD is recognized as a major risk factor for heart diseases and end-stage renal disease (ESRD). Moreover, CKD is fast becoming a worldwide epidemic affecting 26 million Americans that’s why it is recognized as a major public health problem.
Association between IGF-1 and CKD
CKD results in complex metabolic and hormonal disturbances. Alterations in these hormones are responsible for many CKD complications such as catabolism and growth retardation as well as progression of the disease. Insulin-like growth factor (IGF-1) has been associated with heart disease, high blood pressure and diabetes. However, the link between IGF-1 and CKD has not been previously studied. Therefore, Teppala and colleagues examined the association between serum IGF-1 and CKD in a representative sample of US adults. Interestingly, the results of study showed that higher blood levels of IGF-1 were positively associated with CKD after adjusting for several factors such as age, gender, lifestyle, race/ethnicity, body mass index, existing medical conditions, and cholesterol levels. These results suggest that IGF-1 levels in the blood might be a predictor of CKD in Western populations.
Potential Therapeutic Role of IGF-1 in CKD
In CKD, decreased IGF-1 activity may partially explain why CKD patients are malnourished. In addition to this, in children with CKD, GH resistance may play a pivotal role for stunted growth. The GH resistance associated with CKD may be amenable to recombinant human IGF-1 (rhIGF-1) treatment. To support this, rhIGF-1 treatment in children with GH-receptor deficiency or GH-inactivating antibodies led to an increase in growth velocity and height standard deviation score. Moreover, short-term administration of rhIGF-1 has been shown to increase glomerular filtration rate (a test used to check how well the kidneys are working) and blood flow to the kidneys in patients with ESRD and in healthy subjects.
In another study, Vijayan and colleagues demonstrated sustained improvement in the function of the kidneys in 15 patients with advanced CKD, who had received intermittent doses of rhIGF-1. One reason for the use of IGF-1 in CKD patients is that while patients are GH sufficient, they are GH resistant. Therefore, rhIGF-1 may be more effective than GH therapy in terms of treating short stature and kidney dysfunction in CKD. However, IGF-1 and GH therapy may be combined in order to achieve better results.
Effects of IGF-1 on Renal Function in Patients with Chronic Renal Failure
Chronic kidney disease, also known as chronic renal failure, chronic renal disease, or chronic kidney failure, is a medical condition wherein the kidneys gradually lose its function. Eventually, the affected individual has permanent kidney failure. This disease often goes undetected and undiagnosed until it is well advanced and kidney failure is fairly imminent. As the severity of chronic kidney disease advances, dangerous levels of waste and fluid build up. Some of these wastes are toxic and they may damage vital organs in the body, which can be life threatening. Treatment is focused on stopping or slowing down the progression of the disease by controlling its underlying cause. If chronic kidney disease ends in end-stage kidney disease (occurs when the kidneys stopped working), the patient will not survive without dialysis or a kidney transplant.
The most common signs and symptoms of chronic kidney disease include:
Insulin-like Growth Factor 1 (IGF-1) Administration in Patients with Chronic Renal Failure
Insulin-like growth factor 1 (IGF-1) has been shown to increase glomerular filtration rate (GFR) and renal plasma flow (RPF) in rats and humans with normal renal function. GFR refers to the kidney’s ability to filter waste products from the blood while RPF refers to the amount of blood going to the kidneys. In rats with reduced kidney function, IGF-1 administration doesn’t affect GFR and RPF. To determine whether IGF-1 affects GFR and RPF in humans with reduced kidney function, O’shea and colleagues administered recombinant human IGF-1 (rhIGF-1) to patients with moderate chronic renal failure. The researchers placed four patients on a 1 g.kg-1.day-1 protein diet and studied over a 10-day period. On days 4-7, 100 micrograms per kg of rhIGF-1 was subcutaneously administered twice daily to the patients. After rhIGF-1 administration, IGF-1 levels, inulin clearance (a measure of GFR), p-aminohippurate clearance (a measure of RPF), kidney volume, blood sugar, urine calcium, phosphate, sodium and protein were determined.
Of note, the results of the study showed that administration of rhIGF-1 increased the levels of circulating IGF-1, inulin clearances, p-aminohippurate clearances, and kidney size in each of the four patients. Furthermore, rhIGF-1 administration in these patients did not cause weight gain, excretion of sodium and protein in the urine, or low blood sugar. In addition to this, tubular reabsorption, which refers to your kidneys’ ability to return the water and solutes that you need back into your system, was increased in these patients.
In conclusion, administration of rhIGF-1 in patients with chronic kidney disease or chronic renal failure can help enhance GFR and RPF. The enhancement is associated with an increase in kidney volume. These results clearly suggest that rhIGF-1 administration can be a potential therapeutic option in treating patients with failing kidneys and can help eliminate the need for dialysis or kidney transplant in these patients.
Effects of Insulin-like Growth Factor 1 on Kidney Function in Normal Men
Insulin-like growth factor 1 (IGF-1) is a hormone that is present in the blood and most tissues. It is synthesized in the kidney and released from the glomerulus (a network of capillaries that serves as the first stage in the filtering process). Previous studies have shown that in normal human subjects injected with recombinant human growth hormone (rhGH), IGF-1 may mediate the GH-induced rise in renal plasma flow (RPF) and glomerular filtration rate (GFR). This relationship was therefore examined in further detail in animal models where the results showed that short-term infusion of recombinant insulin-like growth factor (rhIGF-1) increases RPF and GFR. Guler and colleagues reported, in preliminary studies, that rhIGF-1 administration via subcutaneous injections for 3 days raised the kidney clearances of iothalamate and iodohippurate, which are measures of effective blood flow to the kidney. This study has also shown that rhIGF-1 administration in human subjects increases the creatinine clearance, which is the kidney’s ability to remove creatinine, a waste product of normal muscle tissue breakdown. However, their studies were only conducted in two normal men, and the measures of kidney function were done before treatment, after 3 days of rhIGF-1 treatment and after cessation of treatment.
Tubular reabsorption mechanisms in the nephrons (tiny filtering structure) of your kidneys return the water and solutes that you need back into your system. Aside from reabsorbing the essential substances, your nephrons secrete waste products and other unwanted substances from your bloodstream so that it will be excreted out of the body in the form of urine. No studies of the effects of rhIGF-1 on the kidney’s tubular reabsorption of phosphorus or calcium have been reported in humans. Hirschberg and colleagues, therefore, decided to examine the effects of rhIGF-1 on kidney function in humans in a more systematic manner. Specifically, this study was carried out in a larger group of subjects: 8 men. The aim of the study is to determine the following:
Participants were studied for 5.5 consecutive days in a clinical research center while they ate a constant diet. From the 2nd to the 4th day, subjects received rhIGF-1 at a dose of 60 micrograms per kilogram via subcutaneous injections three times a day. After commencing the rhIGF-1 injections, the researchers observed that the levels IGF-1 rose quickly and remained at about 3 to 4 times that of baseline throughout the period of rhIGF-1 injections. Of note, all the subjects had an increase in RPF and GFR, suggesting an improvement in kidney function. Also, the fractional excretion of phosphate decreased markedly during rhIGF-1 treatment, but the value of calcium and sodium remains the same.
These findings demonstrate that in normal men, subcutaneous injections of rhIGF-1 is beneficial in increasing blood flow to the kidneys, enhancing the filtration rate of the glomerulus as well as the tubular phosphorus reabsorption in the kidneys.
Insulin-like Growth Factor-1 (IGF-1) and Mortality in Hemodialysis Patients
In hemodialysis (HD), a machine does the job of your failing kidneys by filtering wastes, salts and fluid from your blood. HD is one way to treat kidney failure and can help you live longer despite failing kidneys. Protein-energy wasting (PEW) which is characterized by protein breakdown, is highly prevalent in patients with end-stage renal disease (ESRD) undergoing HD. Several surrogate markers of PEW are associated with increased risk of death and heart disease, especially when inflammation is present. Hypoalbuminemia (abnormally low albumin) has been viewed as a marker of PEW, but is confounded by inflammation and urinary losses.
IGF-1 mediates the effects of growth hormone (GH) on lipid, blood sugar and protein metabolism, and heart function. Reduced levels of IGF-1 have been associated with cardiovascular disease and increase risk of death in the general population. Dysfunction in the GH/IGF-1 axis may lead to PEW in ESRD and its activity is reduced in inflammatory states. Therefore, disturbances in the GH/IGF-1 axis could have an impact on survival in patients with ESRD through increased PEW and increased risk for cardiovascular disease. Moreover, low levels of IGF-1 might be a predictor of the severity of kidney disease in patients undergoing HD.
IGF-1 as a Predictor of Mortality in HD Patients
Nilsson and colleagues investigated IGF-1 as a predictor of mortality and its relation to inflammation and albuminin in HD patients. The researchers studied a cohort of incident HD patients recruited from a single HD centre at Örebro University Hospital, Sweden during 1991–2009 and followed for up to 3 years. They included patients starting HD without a previous history of dialysis treatment or kidney transplantation.
The definition of low IGF-1 used in the study population corresponded to 75 ng/mL. During a follow-up of up to 36 months, 134 patients died, 49 were tr ansplanted and 7 regained kidney function. The causes of death are heart diseases, withdrawal from dialysis, infection and malignancy while the other causes were unknown. On the other hand, diabetes, collagen vascular disease (disease of connective tissue) and female gender were not associated with increased risk of death. Among laboratory variables, blood levels of albumin, creatinine, IGF-1, IGFBP-3 and C-reactive protein correlated to outcome.
Low IGF-1 levels in HD patients were associated with increased risk of death, independent of biomarkers of inflammation (C-reactive protein) and PEW. Serum albumin modulates the relationship between IGF-1 levels and increased incidence of death, indicating shared pathophysiological pathways with IGF-1. Therefore, it is clear that patients with various kidney diseases who are undergoing HD might have lower levels of IGF-1, suggesting that IGF-1 can be considered as a diagnostic marker of the severity of kidney diseases as well as increased mortality in HD patients.
Recombinant Insulin-like Growth Factor-1 as a Therapy for IGF-1 Deficiency in Kidney Failure
To understand how growth is inhibited in kidney failure, it is necessary to understand the normal process of growth and development. Growth hormone (GH) via the generation of insulin-like growth factor 1 (IGF-1) in the liver regulates the majority of body growth. Together, GH and IGF-1 signals the bones, muscles, organs, and tissues to grow by adding more cells. Kidney disease in children disrupts the GH/IGF-1 axis and causes growth failure. Although several studies have shown that GH therapy stimulates growth in these children, short stature related to kidney failure is likely due to IGF-1 deficiency (IGFD) rather than GH deficiency. Moreover, children with kidney failure have very high concentrations of insulin-like growth factor binding proteins (IGFBPs), which likely impair the activity of IGF-1. Despite normal or even elevated secretion of GH and normal IGF-1 levels in the blood, these patients have short stature and functional IGF-1 deficiency as well as GH insensitivity.
The evaluation of children with short stature has centered primarily on IGFD as a diagnosis for these patients. One reason for this is that large databases of short children treated with rhGH such as the National Cooperative Growth Study (NCGS) have shown that IGFD is relatively common among children with short stature. For example, Attie and colleagues studied 511 children with idiopathic short stature. (3) These patients had very low IGF-1 concentrations despite GH sufficiency. In another NCGS study, pre-pubertal children with idiopathic growth failure were diagnosed as either GH-deficient or with idiopathic short stature. The GH-deficient children had similarly low levels of IGF-1 as those with idiopathic short stature. Therefore, a large proportion of patients with growth failure appear to be IGF-1 deficient despite being GH sufficient. Clearly, any abnormality in the GH/IGF-1 system leading to IGF-1 deficiency might contribute to short stature in non-deficient patients.
The administration of recombinant IGF-1 (rhIGF-1) to IGF-1-deficient children with no functional GH receptors has produced surprisingly large growth responses, suggesting that rhIGF-1 might be useful as a systemic treatment for short stature related to kidney failure. Also, IGF-1 may have some advantages over GH as a therapeutic option for kidney failure because of the following reasons:
There are therefore sufficient animal and human studies to support the beneficial effects of rhIGF-1, alone or in conjunction with GH, for the treatment of short stature and kidney failure in children with IGF-1deficiency. In addition to this, augmenting the levels of IGF-1 in IGF-1 deficient patients especially those with growth failure and kidney problems, may help alleviate symptoms related to these conditions as well as treat the root cause of these problems. Restoring IGF-1 levels to normal can help these patients achieve optimal kidney function and growth acceleration as well as improvement in the quality of life.
IGF-1 and Kidney Diseases
The IGF system is involved in the normal development and maintenance of the kidney by preserving kidney cells that help filter out substances and protecting the glomerular basement membrane from damage. Age-related dysregulation of this system may lead to the development of kidney and blood vessel diseases, including hypertension. In addition, under kidney dysfunction conditions, there are profound changes in kidney responses to GH/IGF-I system as well as in the circulating levels of these hormones, despite the limited role of the kidney for removing IGF-I from the circulation.
In humans, IGF-I increases blood flow to the kidneys as well as glomelular filtration rate (process by which the kidneys filter the blood, removing excess wastes and fluids) by 25%. IGF-I administered to GH-deficient patients normalizes the low glomelular filtration rate as does GH replacement in GH deficiency. Interestingly, the effects of GH on kidney function are similar to those observed with IGF-I, except that the functional response to GH is delayed several days, correlating with the secondary increase in serum IGF-I levels, and thus indicating that the GH effects are mediated by IGF-I. However, it is noteworthy that GH receptors are present in the proximal tubule, a site where IGF-I mRNA is not normally expressed, suggesting that GH also may have direct actions on tubular function.
While most reports appear to implicate IGF-I as a potential mediator of pathological changes in the diabetic kidney, IGF-I is also protective against oxidative stress and programmed cell death caused by high levels of blood sugar in cultured mesangial cells (specialized cells around blood vessels in the kidney). This protection appears to be mediated by Akt/PKB and MAPK signalling pathways and it has been suggested that stimulation of this survival pathways may be turned to therapeutic advantage for protection against cell death and progression of kidney diseases.
Insulin-Like Growth Factor-1 Regulates Glutathione Peroxidase Expression and Activity in Vascular Endothelial Cells
Heart disease is the leading cause of death worldwide. The underlying etiology responsible for the development of heart disease is atherosclerosis. This condition is characterized by the deposition of plaques of fatty material on the inner walls of the artery, resulting in impairment in blood circulation. Atherosclerosis has a complicated pathogenesis in which increased inflammatory responses and oxidative stress play a major role. Over time, oxidative stress promotes blood vessel dysfunction and premature ageing. Such dysfunction can impair blood circulation in different vital organs and can lead to heart attack, stroke, or death.
In previous studies, systemic elevation of insulin-like growth factor-1 (IGF-1) was shown to suppress oxidative stress in the blood vessels, thereby preventing atherosclerosis in mice. In order to determine the potential antioxidant effects of IGF-1 humans, Higashi et al. treated human aortic endothelial cells with 0–100 ng/mL IGF-1 prior to exposure to native or oxidized low-density lipoprotein. The researchers found out that IGF-1 enhances the antioxidant activity within the linings of the blood vessels, primarily via increasing the cellular components of glutathione peroxidase -1 (GPX1), whose main biological role is to protect the organism from oxidative damage. To determine mechanisms whereby IGF-1 exerted its antioxidant effects, the researchers assessed activities of major antioxidant systems in human aortic endothelial cells after exposure to IGF-1. After 24 hours of exposure, the activity of glutathione peroxidase (GPX) was increased in a dose-dependent and time-dependent manner. Moreover, it has been reported that IGF-1 potentially regulates glutathione levels in the heart, kidney and brain. Interestingly, glutathione is known to be an essential substrate (material on which a process is conducted) for glutathione peroxidase to exert its antioxidant activity.
One of the consequences of oxidative stress in the lining of blood vessels is the premature decline in the cell’s ability to divide or reproduce, known as cell senescence. To gain insights into the biological significance of increasing glutathione peroxidase by IGF-1, the same researchers exposed human aortic endothelial cells to hydrogen peroxide for an hour, followed by in situ staining for senescence associated β-galactosidase activity. Incubation with 100 ng/mL IGF-1 for 24 hours prior to hydrogen peroxide exposure significantly reduced the activity of β-galactosidase (this enzyme causes cell senescence), indicating that IGF-1 can counteract oxidative stress.
In summary, IGF-1 was found to have a potent antioxidant effects in the linings of blood vessels, which at least in part mediated by increasing the activity of glutathione peroxidase (GPX) in a dose-dependent and time-dependent manner. These findings demonstrated that IGF-1 prevents oxidative stress and they provide novel insights into mechanisms whereby IGF-1 reduces complications related to oxidative damage. IGF-1 may indeed contribute to maintaining blood vessel integrity by counteracting oxidative stress, thereby limiting atherosclerosis development and preventing a wide array of fatal illnesses such as heart disease and stroke. Also, this study suggests the significance of consistently monitoring IGF-1 levels in patients with potential risk for heart attack or stroke to reduce the incidence of death.
The Superior Therapeutic Potential of Insulin-like Growth Factor 1 (IGF-1) and its Receptors for Heart Muscle Regeneration
Following the recognition that hematopoietic stem cells (give rise to all the other blood cells) may help improve the outcome of myocardial infarction in animal models, bone marrow cells, CD34-positive cells (routinely used in stem cell transplantation and gene therapy) and mesenchymal stromal cells (adult stem cells in the bone marrow) have been introduced clinically with rather consistent results. The injection of these cells into the coronary artery and heart muscle has been shown to be safe and effective in improving heart function. The identification of resident heart stem cells in the human heart as well as the isolation of a complex pool of heart cells called the cardiospheres, has shown positive results for the management of heart diseases. Preclinical studies have been completed and two phase 1 clinical trials are currently in progress in patients with acute and chronic heart ailments who are treated with human cardiac stem cells (hCSCs).
IGF-1 in hCSCs
Multiple variables can interfere with the growth behavior of stem cells in the aging heart. To define the in vitro properties of hCSCs and its regenerative effects within the damaged heart muscle, D’Amario and colleagues studied 24 human heart muscle samples. These samples were used to isolate and expand hCSCs and define their role in heart muscle regeneration. Distinct classes of hCSCs with low and high level of cell growth were then injected in the damaged heart to assess their differences in repairing the heart muscle and tissues. The researchers also assessed the presence of three growth factor-receptor systems in hCSCs: IGF-1, IGF-1 receptor (IGF-1R), IGF-2, IGF-2 receptor (IGF-2R) and Renin Angiotensin System, all of which has an effect on hCSC division, maturation and survival. Interestingly, IGF-1, IGF-1R, IGF-2, IGF-2R were present in hCSCs, suggesting that IGF-1 and its receptors play an important role in the regeneration of the heart muscle and tissues.
IGF-1 and hCSC Growth
To define the role of IGF-1R and IGF-2R in hCSCs, heart muscle cells from 6-10 patients were randomly selected and studied. Of note, addition of phosphate to the IGF-1 receptor led to recruitment of the insulin receptor substrate protein that triggers the PI3K and Akt pathways – both of these pathways are necessary in preventing the incidence of programmed cell death (apoptosis) in various cell types, as well as stimulating metabolism, growth and proliferation in these cells.
The growth of stem cells in the body is regulated by the length of their telomeres and the level of the activity of the enzyme known as telomerase. When the telomere becomes too short, the chromosome reaches a “critical length” which triggers cell death and ends the process of cell division. Variables of stem cell expansion were measured in 12 patients (48 to 86 years old). Interestingly, in all 12 cases, hCSCs containing the IGF-1 receptor had longer telomeres than hCSCs containing IGF-2 receptor, suggesting that IGF-1 and its receptors play an essential role in the growth of hCSCs.
In conclusion, hCSCs containing IGF-1 and its receptor are potent modulators of stem cell replication, growth and regeneration, making it the ideal candidate cell for the management of human heart failure.
IGF-1 and Cardiovascular diseases (CVD)
Cardiovascular diseases remain the biggest cause of deaths worldwide. Over the last years, low levels of IGF-1 have been correlated with an increased risk for CVD in humans. In cross-sectional studies, low levels of IGF-1 were found to be associated with coronary artery disease (CAD) and may predict fatal ischemic heart disease, a significantly increased risk of ischemic stroke and congestive heart failure in elderly patients, as well as a worse prognosis of recovery after an acute myocardial infarction. Additionally, a positive correlation between IGF-1 levels and both coronary flow reserve as well as successful cardiovascular aging in healthy centenarians has been documented.
It was recently demonstrated that the IGF-I system confers the ability to protect the blood vessels and the heart, and contribute to the maintenance of microvasculature structural and functional integrity. However, the IGF-I system cannot compensate for deficiency of circulating IGF-I. Beneficial effects of the IGF-I/IGF-IR system in cardiac progenitor cells are also starting to be documented. Progenitor cells are early descendants of stem cells that can differentiate to form one or more kinds of cells, but cannot divide and reproduce indefinitely. The recent identification of a subpopulation of human cardiac stem cells expressing IGF-IR and secreting IGF-I with a secondary therapeutic potential for regeneration of heart muscle, may be an important step toward global recognition of the therapeutic effect of IGF-1 in cardiovascular diseases.
Aging is associated with functional and physical or biochemical alterations in the circulation of blood vessels including endothelial dysfunction, oxidative stress, chronic low-grade inflammation, and microvascular rarefaction (reduced number and combined length of small vessels in a given volume of tissue), all of which increases a person’s risk for cardiovascular diseases. IGF-1 is known to contribute to the maintenance of microcirculation functional and structural integrity, increasing nitric oxide bioavailability to improve blood circulation, and decreasing the production of harmful reactive oxygen species. IGF-1 has also the ability to reduce inflammation, prevent programmed cell death, and stimulate the formation of new blood vessels (angiogenesis). The mechanisms by which IGF-I reverses and/or prevents microvascular rarefaction and improves tissue blood supply include the following:
It has been postulated that the majority of cardiovascular events related to low levels of IGF-1 may be due to inability of the body to respond to the effects of insulin (insulin sensitivity) and accelerated accumulation of fatty materials or plaque inside the walls of the arteries (atherosclerosis). The antioxidant and anti-inflammatory effects of IGF-I have been documented to reduce the incidence of atherosclerosis and improve insulin sensitivity.
The Emerging Role of IGF-1 Deficiency in Cardiovascular Aging: Recent Advances
Disruption of the insulin/insulin-like growth factor (IGF)-1 pathway increases life span in invertebrates. However, the loss of insulin signaling in mammals can be lethal. The role of growth hormone (GH) and IGF-1 in the aging process in humans remains controversial. The cardiovascular system is an important target organ for both GH and IGF-1. There is evidence that cardiac muscle cells, vascular endothelial and smooth muscle cells abundantly express IGF1R and that they are more sensitive to IGF-1 than to insulin.
The effects of the GH/IGF-1 axis on the cardiovascular system are considered in terms of potential mechanisms involved in blood vessels protection and cardiac protection in aging. Secretion of GH and, consequently, the production of IGF-1 by the liver decline in an age-dependent manner. Several evidences obtained in human patients with endocrine IGF-1 deficiencies support the concept that IGF-1 exerts protective effects in the cardiovascular system.
Cardiovascular Dysfunction in Patients with IGF-1 Deficiency
It is well documented that in human patients, GH deficiency and low circulating levels of IGF-1 significantly increase the risk for diseases of the heart, brain, and blood vessels. In cross-sectional studies, low level of IGF-1 was found to be associated with angiographically documented coronary artery disease. A prospective nested case–control study of over 600 initially healthy participants who were followed for 15 years demonstrated that lower than normal circulating IGF-1 levels increase the risk of coronary heart disease. This conclusion is supported by another prospective study of 1,185 men and women who were followed up for over a decade, showing that circulating IGF-1 levels predict fatal ischemic heart disease. Moreover, in patients, in the early phase of acute myocardial infarction, low circulating IGF-1 levels predict a worse prognosis. A cross-sectional study of 400 elderly men also documented an inverse correlation between circulating IGF-1 levels and carotid arterial intima–media thickness, a measure used to diagnose the extent of carotid atherosclerotic vascular disease.
Most human data also support the concept that normal levels of GH and IGF-1 are important for the maintenance of a healthy endothelial function. In patients with GH-deficiency, there is impairment in the flow-mediated endothelium-dependent dilation of peripheral arteries, which is use to assess the effectiveness of various interventions that may affect vascular health. There is also a positive correlation between circulating IGF-1 levels and the maximum increase in blood flow through the coronary arteries above the normal resting volume known as coronary flow reserve.
A significantly increased risk of ischemic stroke was also demonstrated in patients with low circulating IGF-1 levels. Studies on patients with ischemic stroke suggest that high circulating IGF-1 levels are associated with neurological recovery and a better functional outcome. These findings are significant as IGF-1 is known to exert nerve cell protective effects when given shortly after the incidence of stroke.
Acute Cardiovascular Effects of Insulin-Like Growth Factor 1 in Patients with Chronic Heart Failure
Experimental evidence has accumulated that insulin-like growth factor 1 (IGF-1) has specific actions on the heart in addition to its role in growth and development as well as metabolism. IGF-1, but not growth hormone (GH), enhances the development and contractility of long-term cultured heart muscle cells in rats. Further investigations demonstrated that IGF-1 exerts its cardioprotective effect in doxorubicin-treated rats and that IGF-1 administration was able to improve the function of the heart muscle. Furthermore, IGF-I was able to prevent tissue injury in rats by inhibiting cell death and white blood cell-induced heart tissue death.
The ability of IGF-1 to dilate the blood vessels has been described in men. Normally, if blood vessels remain dilated, more blood will be able to flow through it, thus, different body parts especially the vital organs will receive adequate amount of oxygen as well as essential nutrients. Recently, it has been shown that IGF-1 increases the amount of blood pumped by the heart per minute in healthy human volunteers. Furthermore, IGF-1 has the ability to lower insulin and blood sugar levels, and improve lipid profile. Taken together, IGF-I can be an effective treatment option for various heart diseases including heart failure.
Donath and colleagues examined the effects of recombinant human (rh) IGF-1 in eight patients (one woman and seven men) with congestive heart failure of more than 3-month duration. Of the eight patients, five had idiopathic dilated cardiomyopathy (a disease of the heart muscle), and three had ischemic cardiomyopathy (narrowing of the coronary arteries). No patient experience chest pain, but all had difficulty of breathing. All patients have normal heart rhythm and are clinically stable on regimens of diuretics (helps excrete unneeded water and salt through the urine), anti-hypertensives, anti-coagulants and anti-arrhythmic drugs. The researchers also obtained written informed consent from each patient prior to the study. Interestingly, patients treated with IGF-1 did not report any adverse symptoms or reactions to IGF-1 infusion. However, three of eight patients experienced a feeling of warmth 40–60 min after IGF-1 administration which disappeared within 10–20 min. The results of the study showed that IGF-1 increased the amount of blood pumped by the heart per minute in patients with chronic heart failure, as previously shown in healthy human volunteers. Moreover, IGF-1 reduced the pressure within the left and right chambers of the heart, suggesting that IGF-1 was able to improve blood flow in these patients. In addition to this, IGF-1 infusion was able to reduce insulin and C peptide (plays a role in insulin synthesis) levels, whereas blood sugar and electrolyte levels remain unchanged. Also, urinary levels of norepinephrine (substance that increases blood pressure) decreased significantly during IGF-1 infusion.
With these findings, it is plausible that acute administration of IGF-1 in patients with chronic heart failure is safe and can improve heart function by improving its pumping action and lowering the pressure within its chambers. Moreover, IGF-1’s ability in preventing cell death and tissue injury in the heart muscle makes IGF-1 of potential interest for the treatment of heart failure.
Effects of Insulin-Like Growth Factor 1 Administration in Patients with Chronic Heart Failure
A number of evidences has accumulated that insulin-like growth factor 1 (IGF-1) has specific effects on the heart in addition to its growth-promoting effects. It has been shown that IGF-1 induces dilation of blood vessels, resulting in good blood circulation. The ability of IGF-1 to dilate the blood vessels has been described in men. Recently, it has been shown that IGF-1 increases the amount of blood pumped by the heart per minute (cardiac output), the amount of blood ejected by the left ventricle in one contraction (stroke volume), and the amount of blood that is pumped out of the ventricles with each contraction (ejection fraction) in healthy human volunteers. Furthermore, IGF-1 has been shown to lower insulin levels, increase the body’s response to insulin, and improve lipid profile. Taken together, IGF-1 can indeed be considered as a therapeutic option for the treatment of heart problems such as heart failure.
Donath and colleagues examined the acute hemodynamic effects of recombinant human IGF-1 (IGF-1) in eight patients with chronic heart failure (1 woman and 7 men) of more than 3-month duration. No patient experienced chest pain, but all had difficulty of breathing. All patients are clinically stable on medication regimens. During the entire study period, the patients were put on complete bed rest. Systemic hemodynamics (dynamics of blood flow) was measured by standard techniques. The heart rate of all the patients was monitored throughout the entire study using electrocardiogram. Three of eight subjects experienced a feeling of warmth 40–60 minutes after initiating IGF-1 infusion, which disappeared within 10-20 minutes. No other symptoms were reported during the entire study. After the duration of the treatment, IGF-1 administration tended to increase heart rate and cardiac output compared to placebo. In addition, IGF-1 administration improved stroke volume. No abnormal changes were observed on the electrocardiogram. In response to the intravenous infusion of 60 micrograms per kilogram of rhIGF-1, there was a significant increase in the levels of IGF-1 in all patients. Moreover, IGF-1 treatment led to a decrease in insulin and C peptide levels at the end of the infusion, suggesting that IGF-1 was able to increase insulin sensitivity (body’s response to the effects of insulin) in these patients.
In conclusion, the results of the study showed that IGF-1 has the capacity to increase cardiac output and stroke volume in patients with chronic heart failure, suggesting that IGF-1 can improve the pumping action of the heart. The increase in cardiac output was due to dilation of the arteries and reduction in the pressure in the wall of the left ventricle during ejection (afterload). Moreover, the levels of norepinephrine significantly decreased during the IGF-1 infusion, which might indicate a beneficial effect on neurohumoral activation (increased activity of the sympathetic nervous system) in patients with chronic heart failure. Accordingly, IGF-1 appears to have a balanced vasodilatory effect on both arteries and veins. This effect can improve blood flow especially to vital organs in the body. Taken together, these results make IGF-1 of potential interest for the treatment of heart failure and other heart diseases.
Therapeutic Benefits of Insulin-like Growth Factor 1(IGF-1) in Atherothrombosis
Atherothrombosis (AT) is characterized by narrowing or obstruction of the arteries that supply blood flow to the different parts of the body. AT starts when cholesterol deposits in the wall of the arteries. Overtime, these deposits known as plaque restricts blood flow in the affected artery. As blood flows over the plaque, stress forces are exerted on the plaque surface which causes it to rupture and form blood clot. This clot can be life-threatening because it can limit or completely stop blood flow and oxygen to certain organs (ischemia) such as the heart or brain, giving rise to heart attack or stroke. If you are obese and have high blood pressure and high cholesterol, then you are at risk for developing AT.
IGF-1 contributes to regulate cellular growth, proliferation, specialization and survival against cell death, tissue remodeling, energy metabolism, regulation of brain network and networking, and protection of nerve cells, which ultimately influence one’s health. Among these effects, the metabolic function of IGF-1 appears more central in heart health and other related diseases. Owing to its crucial activities, there are several evidences showing a possible causative role of decreased IGF-1 levels in several heart diseases, including atherothrombosis, myocardial infarction, heart failure, diabetes, hypertension and kidney disease.
Role of IGF-1 in Ischemia
IGF-1 has been shown to play a critical role in the reduction of ischemia or reperfusion damage (caused when blood supply returns to the tissue after a period of ischemia), left ventricular dysfunction remodelling and in the recovery of ischemic cardiomyopathy (occurs when the heart doesn’t pump enough blood) through a reduction in cell death and inflammation. By optimizing the heart workload, improving the metabolism of glycolipid (lipids with a carbohydrate attached), and reducing blood clotting, IGF-1 can prevent or limit ischemia, reperfusion damage and dilatation of ventricles.
IGF-1 Administration in Patients with Ischemia-related Diseases
Acute IGF-1 administration in patients with chronic heart failure increased the amount of blood pumped by the left ventricle into the systemic circulation and decreased the pressure in the wall of the left ventricle during ejection, suggesting a possible therapeutic role in these patients. In line with these findings, subcutaneous administration of IGF-1 at a dose of 60 mircograms per kg of body weight in healthy volunteers also increased the amount of blood pumped by the left ventricle into the systemic circulation but the maximal exercise duration and peak oxygen consumption in these subjects were unchanged.
In another study, subcutaneous injections of low doses of recombinant IGF-1 at 20 micrograms per kg of body weight in healthy adults increased the strength of contraction of the heart muscle while maintaining normal circulating levels of IGF-1.
These evidences suggest that IGF-1 is a very important tool in the maintenance of heart and metabolic health, owing to its ability to counter the formation of blood clots and prevent ischemia while improving blood flow to certain body organs such as the heart. All of these mechanisms clearly demonstrate IGF-1’s therapeutic role in atherothrombosis and other ischemia-related diseases.
IGF-1 and Catabolic States
Clinical investigators have shown that the levels of IGF-1 are often significantly altered in catabolic states, including the acute postoperative period, burn patients and chronic catabolic illnesses, such as cystic fibrosis and HIV with wasting. All of these conditions result in low levels of IGF-1 in the body, and significant changes in IGF-I positively correlate with changes in lean body mass, as well as reversal of acute catabolic states.
In clinical use, children with extensive thermal burns who were treated with IGF-1 in combination with IGFBP-3, presented a reduction of inflammatory mediators such as IL-1β, TNF-α, C-reactive protein, α1-acid glycoprotein, and complement C-3 in the blood. In contrast, there is a significant increase in the blood levels of retinol-binding proteins, prealbumin, and transferrin, all of which play an important role in wound healing. From these results, researchers concluded that attenuating the pro-inflammatory acute phase with IGF-1/IGFBP-3 may prevent multiple organ failure and improve clinical outcomes after thermal injury without any detectable adverse side effects. Also, when IGF-1 was used to monitor total parenteral nutrition therapy in catabolic patients, the changes correlate with improvements in protein metabolism. Consistently, a close correlation between IGF-1 and protein synthesis in burn patients was reported. Similarly, extremely low IGF-I levels observed in severe malnutrition improved with caloric repletion.
Several catabolic states result in relative resistance to GH, which is mediated by increases in the production of tumour necrosis factor (TNF) and interleukin 1 (IL1), both of which inhibit the production of IGF-1 and block its actions in several tissues. GH resistance has also been demonstrated in several catabolic states such as HIV with muscle wasting, nutritional deficiency, cystic fibrosis, celiac disease, anorexia nervosa, and burns. Interestingly, these catabolic patients responded to IGF-1 treatment with increases in protein synthesis and a positive or overall anabolic response. When IGF-1 is co-administered with IGBP3, it led to an increase in the synthesis of proteins.
IGF1 is a potent growth factor for bone cells, and two studies, one in older patients with hip fracture and one in younger patients with anorexia nervosa, have been undertaken. Anorexic patients received IGF-1 alone while patients with hip fracture received IGF-1 and IGF binding protein-3 (IGBP3). Surprisingly, both studies showed improvements in bone mineral density (BMD).
Studies have also been conducted in catabolic patients with muscle wasting disease. One study showed that 4 months of IGF-1 administration in patients with myotonic dystrophy (affects both smooth and skeletal muscles) resulted in improvements in muscle mass and strength.
Normally, severely burned patients experience hypermetabolic phase wherein the body rapidly breaks down protein as a compensatory mechanism. The result is severe protein loss leading to muscle wasting. IGF-1 alone has been infused in burned patients with improvements in protein synthesis. However, co-administration of IGF-1 with IGBP3 in severely burned children significantly improved protein synthesis without any side effects. These findings suggest that IGF-1 and IGBP3 whether given alone or co-administered with each other can have a positive impact in reversing catabolic states.
Insulin-like Growth Factor -1 (IGF-1) and Sarcopenia
Sarcopenia is a syndrome that involves progressive generalized loss of skeletal muscle mass and strength. Affected individuals usually experience physical inactivity, decreased mobility, reduced physical endurance, and slow gait. It has been estimated that 15% of people 65 years old and above and as many as 50% of people 80 years old and above have sarcopenia. The cause of sarcopenia is not yet known. However, multiple factors appear to be involved in the development of sarcopenia such as genetics, underlying medical conditions, and environmental factors. It has been suggested that the renin–angiotensin system in the kidneys may play a role in modulating muscle function. Circulating angiotensin 2 (a chemical that raises blood pressure) is associated with muscle wasting, low IGF-1 levels, and poor response to the effects of insulin, and could therefore contribute to sarcopenia.
Growth Factors: Potential Intervention for Sarcopenia
Growth hormone (GH) is required for maintenance of muscle and bone. GH exerts most of its effects through IGF-1 which is synthesized in the liver for release in the bloodstream. IGF-1 is known to increase the production of muscle cells as well as muscle contractile proteins. The strongest evidence for the use of GH supplementation in increasing muscle mass and strength appears to be in states of reduced GH secretion. In younger GH deficient adults, 3 years of GH supplementation was able to improve thigh muscle mass, strength, as well as exercise capacity. However, in healthy non-GH deficient older people, some studies have shown an increase in muscle mass but no improvement in muscle strength, whereas some studies have shown an improvement in both.
With increasing age comes the decline in GH and IGF-1 levels. There is evidence that such decline contributes to the development of sarcopenia. IGF-1 is perhaps the most important mediator of muscle growth and repair in the body possibly by activating the Akt pathway. In one study, the administration of IGF-1 in patients with myotonic dystrophy (disease affecting both smooth and skeletal muscles) for 4 months resulted in improvements in muscle mass and strength. In line with this findings, co-administration of IGF-1 with insulin-like growth factor-binding protein 3 (IGBP3) in severely burned children significantly improved protein synthesis without any side effects, suggesting that IGF-1 can reverse muscle wasting.
It has been shown that treatment using low doses of recombinant IGF-1 produces significant, but transient, nitrogen retention, which helps reverse the process of muscle wasting in HIV/AIDS. In the case of marked weight loss in patients with cancer, it was found that administration of lGF-1 together with IGFBP-3 significantly increased muscle protein synthesis. Moreover, a high dosage level of this combination improved the patient’s food intake and blood sugar metabolism, and reduced weight loss.
With all of these studies, it can be concluded that the administration of IGF-1 in patients with sarcopenia might help inhibit or slow down the progressive generalized loss of skeletal muscle mass and strength related to this condition. Moreover, administration of IGF-1 together with GH and IGFBP-3 in patients with sarcopenia may have added beneficial effects on muscle mass and strength.
Insulin-like Growth Factor-1 (IGF-1) Lowers Protein Breakdown in Patients with Thermal Injury
Accelerated protein breakdown is a constant feature of hypermetabolic response to thermal injury or burns. Normally, severely burned patients experience hypermetabolic phase wherein the body rapidly breaks down protein as a compensatory mechanism. The result is severe protein loss leading to muscle wasting. Attempts to limit protein breakdown by experimental treatment with growth factors have been promising under certain conditions. The administration of growth hormone (GH) at pharmacologic doses in fasting adults resulted in protein sparring effect. Clinical trials using GH in a variety of catabolic conditions was effective in conserving protein levels in the body. However, in critically ill patients, GH has been shown to have reduced effectiveness in stimulating the release of IGF-1, thus, possibly explaining the failure of GH to reverse protein breakdown in some patients.
Data confirming the role of IGF-1 in the regulation of growth and metabolism have expanded remarkably during the last decade. The availability of recombinant IGF-1 has opened new opportunities to study its potential benefits in patients with burn injury. According to statistics, 75% of all deaths in burn cases are related to sepsis or infection. Following trauma, there is an immediate inflammatory response that quickly spreads throughout the body including the lungs, liver and intestines. Moreover, burn injury can impair blood circulation in the gut by causing constriction of blood vessels, thereby affecting oxygen levels.
Both in human and animal studies, muscle breakdown induced by diet and tumor necrosis factor (TNF) have been reversed by the administration of IGF-1. More importantly, IGF-1 has been shown to inhibit hypermetabolism and gut degeneration in burn patients. Furthermore, IGF-1 was able to reduce gut inflammation and bacterial translocation or clearance in burn patients.
To determine the effects of continuous administration of recombinant IGF-1 on the catabolic response to burn injury in adult patients, Cioffi et. al studied 8 subjects with burns of more than 25% of their body surfaces. Within 72 hours following injury, resting energy expenditure (REE) was measured. REE is the amount of energy required for a 24-hour period by the body during resting conditions. Enteral feedings (delivery of a nutritionally complete feed directly into the stomach) were initiated at a rate sufficient to meet the patient’s estimated calorie and protein needs. Oral intake was not allowed during the study period. Excision and grafting of the burn wounds were performed. After 3 days of nutritional intake, the researchers obtained body weight measurements, and blood levels of IGF-1, IGF-1 binding protein and glucose levels. After obtaining baseline measurements, each patient received an intravenous infusion of IGF-1 at a rate of 20 micrograms per kilogram per hour.
The results of the study showed a significant rise in the levels of REE, IGF-1 and IGF binding protein with a concomitant decrease in GH while receiving IGF-1. Furthermore, the short-term anabolic effects of IGF-1 are preserved after severe burn injury in patients who were receiving full nutritional support. Although IGF-1 inhibited the secretion of insulin in these patients, it was able to display its protein-sparing effect, suggesting that IGF-1 may indeed inhibit protein breakdown in severely burned patients.
Insulin-like Growth Factor-1 in the Treatment of Skeletal Muscle Injury
Skeletal muscle injuries are the most common injury in sports. Athletes sustain such injuries through a variety of mechanisms, including direct trauma or related to neurological dysfunctions. As muscle injuries heal, the complete recovery from the injury is now compromised because scar tissue develops in the affected area. Moreover, the formed scar tissue is always mechanically inferior and therefore much less able to perform the function of the injured muscle fiber, making it more susceptible to reinjury. To minimize the disability and enhance full functional recovery of patients suffering from muscle injuries, the current conservative treatment includes rest, ice, compression and elevation (RICE), anti-inflammatory drugs, and physical therapy.
Therapeutic Role of IGF-1 in Skeletal Muscle Injury
Recently, it has been suggested that growth factors such as insulin-like growth factor-1 (IGF-1) might have regenerative properties on the injured skeletal muscle. Since then, multiple research groups have attempted to find drugs that help regenerate injured skeletal muscle fibers. Several growth factors are capable of promoting muscle regeneration including basic fibroblast growth factor (bFGF), insulin growth factor (IGF), nerve growth factor (NGF), TGF-β1, and platelet-derived growth factor (PDGF).
Takahashi and colleagues reported that gene delivery of IGF-1 via electroporation (DNA introduction into cell membranes using electricity) led to an increase in the number of regenerating muscle cells. In line with this finding, Huard and colleagues injected IGF-1 in healthy old men. Surprisingly, IGF-1 administration prevented the loss of muscle mass that is related with aging. In a mice model of muscle strain, Kasemkijwattana and colleagues reported that bFGF, NGF and IGF-1 administration at 1 to 3 and 5 days after injury improved muscle performance and muscle strength. In the treated group, the number of regenerating muscle fibers was increased 3.5 times for bGF and IGF-1 and 1.5 times for NGF, suggesting that specific growth factors have the ability to improve regeneration of injured muscle by stimulating the production of muscle fibers at the site of injury.
When a skeletal muscle is injured, the body compensates by stimulating the growth factors to activate satellite cells within 18 hours of injury. At the same time, inflammatory cells migrate to the injury site. Regeneration of single muscle fibers or entire muscles can only occur upon the activation of satellite cells. Growth factors have been shown to regulate the production, specialization, and fusion of muscle cells and satellite cells in vivo and in vitro, which are important in the complete functional recovery after muscle injury. Among these growth factors, NGF and IGF-1 are known to promote muscle repair in peripheral and central nervous system injuries. NGF plays pivotal role in the muscle regeneration process while IGF-1 plays a role in increasing the number and size of regenerating muscle fibers after injury. Aside from NGF and IGF-1, injection of b-FGF following muscle injury showed that this growth factor is a potent stimulator of the production and fusion of muscle fibers in vivo and in vitro. With these findings, IGF-1 and other growth factors can be considered as a new therapeutic option for sports-related injuries in addition to RICE therapy, use of anti-inflammatory drugs, and physical therapy.
Recombinant Human Insulin-like Growth Factor-1 Induces an Anabolic Response in Malnourished CAPD Patients
The principal role of the kidneys is to filter and remove waste products and excess fluid from the blood. In people whose kidneys are not functioning normally, dialysis is a way of replacing kidney function. There are two main forms of dialysis:
Many adult patients undergoing either maintenance hemodialysis or CAPD show evidence for protein-energy malnutrition. The incidence of malnutrition in patients undergoing CAPD ranges from approximately 18 to 56%. Several factors may cause malnutrition in CAPD patients. Because malnutrition is an important risk factor for increased incidence of illness and deaths in both hemodialysis and CAPD patients, this issue appears to be of considerable clinical importance.
With the availability of growth factors, specifically recombinant human insulin-like growth factor-1 (rhIGF-1), a number of studies have examined the nutritional effects of this compound in malnourished patients. In the past years, the most commonly used anabolic agent has been recombinant growth hormone (rhGH). This hormone induces an anabolic response in patients with acute catabolic states but without kidney failure, and chronically malnourished patients in advanced kidney failure. However, the effectiveness of rhGH may be markedly reduced in both severe infection and in malnourished patients with a low protein and/or energy intake. Such impaired anabolic responsiveness is evident in malnourished patients undergoing dialysis who had sustained recurrent infections.
To evaluate whether insulin-like growth factor-1 (IGF-1), the hormone which mediates most of the anabolic effects of GH, would be effective in promoting an anabolic response in malnourished CAPD patients, Fouque and colleagues studied six CAPD patients with protein-energy malnutrition who underwent nitrogen balance studies in a clinical research center for 35 days each. Each patient had documented marginal or low protein intakes that is thought to be the main culprit of their malnutrition. Each patient received a constant protein and energy diet in order to exclude the possibility that dietary modification might affect the metabolic response during the study. After a 15-day baseline phase, the participants received human rhIGF-1 at a dose of 50 to 100 micrograms per kilogram body weight every 12 hours via subcutaneous injections for the next 20 days.
During the treatment with rhIGF-1, blood levels of IGF-1 increased by about 100% and nitrogen balance (marker of muscle and tissue growth) became strongly positive. This anabolic effect was observed within hours after starting rhIGF-1. In addition to this, the blood levels of phosphorus decreased significantly while calcium levels increased during the first several days of rhIGF-1 treatment. This is of important clinical significance since high phosphorus levels can cause damage to the body by pulling calcium out of the bones, making them weak. During the entire study, rhIGF-1 treatment was well tolerated by all patients.
In conclusion, injections of rhIGF-1 induce a strong and sustained anabolic effect, as evidenced by a positive nitrogen balance in CAPD patients with protein-energy malnutrition. These results indicate that rhIGF-1 administration may be a safe and effective method for treating malnutrition in maintenance dialysis patients.
Reversal of Diet-induced Catabolism by Infusion of Recombinant Insulin-like Growth Factor-1 (rhIGF-1) in Humans
The body faces a catabolic state during the process of normal metabolism. This idea, opposed to an anabolic state in which body builds biological molecules, actually defines the breakdown of foods and essential nutrients needed for muscle and tissue growth process.
The Process of Catabolism
When food enters the body, your body naturally digests larger sized molecules into smaller ones. The idea of digestion actually implies catabolism. Once the food you eat are broken down into smaller particles, these chemical strains release energy. The catabolic process releases energy to help maintain normal muscle activity. In short, the process of catabolism acts as the sole energy provider for the proper preservation and growth of all body cells. Aside from fueling the body with energy, catabolism sometimes can lead to adverse health conditions. High rate of catabolism causes the body to lose significant amounts of muscle tissue and essential fat deposits in an attempt to find a source of stored energy.
IGF-1’s Role in Catabolism
Clinical investigators have shown that the levels of IGF-1 are often significantly altered in a wide array of catabolic states, including the acute postoperative period, burns, cystic fibrosis, HIV-AIDS and other muscle wasting diseases. All of these conditions result in low levels of IGF-1 in the body, and normalization of IGF-1 positively correlate with changes in lean body mass, as well as reversal of acute catabolic states. Treatment of catabolic conditions with IGF-1, the hormone that mediates some of the anabolic growth-promoting actions of growth hormone (GH), offers potential advantages of preventing the low blood sugar phenomenon caused by GH administration.
To further assess the effects of recombinant insulin-like growth factor-1 (rhIGF-1) on healthy volunteers with diet-induced catabolism, Clemmons and colleagues studied six normal, young adult volunteers with induced state of moderate catabolism by restricting their daily dietary intake to 20 kilocalories per kilogram per day. During the last 6 days of the two 2-week diet-study periods, the volunteers received either IGF-1 (12 micrograms per kilogram per hour via intravenous infusion over 16 hours) or GH (0.05 mg per kilogram per day via subcutaneous injections). Interestingly, the results of the study showed an improvement in nitrogen balance (a measure of muscle growth) during the last 4 days of IGF-1 infusion. A similar effect was observed with GH administration. In addition to this, IGF-1 infusion decreased fasting blood sugar levels, while GH raised blood sugar values. Despite these differences in blood sugar levels, IGF-1 infusions decreased blood levels of insulin and the concentrations of connecting-peptide (a substance produced by the beta cells in the pancreas). On the other hand, GH raised insulin and connecting-peptide levels. At the dose of each hormone used, the reduction of nitrogen wasting produced by IGF-1 infusions in these patients was similar in magnitude and timing to that produced by GH administration. Moreover, the reduction in blood sugar levels produced by IGF-1 compared with the increase in blood sugar noted during GH administration could help benefit catabolic patients with high blood sugar levels.
These findings suggest that although IGF-1 and GH exerts the same effect in reversing diet-induced catabolism, IGF-1 doesn’t cause high blood sugar levels upon administration. Moreover, IGF-1 administration is indeed a safe and effective therapeutic option in treating and slowing the progression of muscle tissue breakdown in catabolic states.
The Potential Therapeutic Role of Insulin-like Growth Factor 1 in Steroid Myopathy
Steroid myopathy is a medical condition that causes weakness of the muscles of the upper and lower limbs and to the neck flexors. Excessive intake of corticosteroids is believed to be the cause of steroid myopathy. People who use steroid for the treatment of asthma, chronic obstructive pulmonary disease, polymyositis, rheumatoid arthritis, connective tissue disorders and other inflammatory processes are at increased risk for this condition. Although the exact mechanism of the muscle pathology is unclear, it may be associated with decrease protein production, alterations in carbohydrate metabolism, electrolyte disturbances, and impairment in the cell’s source of energy. In addition to this, sedentary lifestyle may increase the risk of muscle weakness in patients taking corticosteroids.
Long Term Steroid Use Depletes Glutamine
Glutamine is considered as an essential amino acid found in your muscles and plays a key role in protein synthesis. It is consists of 19% nitrogen, making it the primary transporter of nitrogen into your muscle cells. During strenuous activities, the levels of glutamine in your body decreases along with your strength, stamina and recovery, and it takes about a week for it to return to normal. Aside from vigorous training and activities, the levels of glutamine in the muscles fall with injury and disease in circumstances associated with increases in blood corticosteroids. Glutamine depletion increases your risk for steroid myopathy.
There are mechanisms proposed on inhibitory effects of glucocorticoids and other steroids on protein synthesis:
Insulin-like Growth Factor-1 (IGF-1) Inhibits Glucocorticoid-induced Glutamine Synthetase
The levels of IGF-1 are often significantly altered in catabolic states, including the acute postoperative period, burns, cystic fibrosis, HIV with wasting, and other chronic illnesses. Recently, glutamine synthetase has been reported to play a key role in the development of steroid myopathy. Glutamine synthetase is an enzyme that plays a major role in nitrogen metabolism and glutamine production. Recent studies have revealed that glutamine synthetase is induced by glucocorticoids and other steroids and may be related to the development of steroid myopathy. Although this enzyme is essential for protein synthesis and maintenance of muscles, steroid-induced glutamine synthetase may increase your risk for steroid myopathy. Several studies have shown the beneficial effects of IGF-1 in increasing muscle mass and strength. To determine the effects of IGF-1 in preventing steroid myopathy, Kimura and colleagues studied skeletal muscle cells treated with IGF-1. To increase the activity of glutamine synthetase in these muscle cells, dexamethosone (a type of steroid medication) was used. Interestingly, addition of IGF-1 at a dose of 750 milligrams per milliliters decreased glutamine synthetase to approximately 50%, suggesting that IGF-1 may indeed have a preventive effect in steroid myopathy.
These results suggest that IGF-1 administration in patients with steroid myopathy can be of great therapeutic value. By inhibiting steroid-induced glutamine synthetase activity, IGF-1 might have beneficial effects in slowing down the progression of muscle weakness in these patients.
Muscle-specific Expression of IGF-1 Blocks Angiotensin II–induced Skeletal Muscle Wasting
CHF is a leading cause of cardiovascular mortality and morbidity. It is associated with elevated levels of the potent vasoconstrictor angiotensin II and muscle wasting, which is an important predictor of poor outcome in patients with this disease. Recent studies using in vitro models of muscle atrophy have indicated that IGF-1 acts through Akt and Foxo to suppress atrogin-1/muscle ring finger–1 (atrogin-1/MuRF-1) transcription whose expression is elevated in various muscle atrophy models.
In vivo studies have indicated that apoptosis (cell death) is also involved in muscle wasting. Furthermore, Yao-Hua Song et al have recently shown that activation of caspase-3 (crucial mediators of programmed cell death or apoptosis) contributes to protein breakdown in catabolic conditions such as uremia or diabetes and leaves a characteristic 14-kDa actin fragment in muscle. In view of the potent anabolic and antiapoptotic effects of IGF-1, Yao-Hua Song et al demonstrated that reduced levels of IGF-1 signaling in response to angiotensin II would lead to a coordinated activation of both caspase-3–mediated apoptosis and activation of the ubiquitin-proteasome (Ub-P’some) pathway, resulting in loss of skeletal muscle. To demonstrate that caspase-3 activation is required in angiotensin II–induced muscle wasting, the researchers administered a caspase inhibitor Z-Asp-2,6-dichlorobenzoyloxymethylketone to mice. This inhibitor has been shown to inhibit caspase-3 activation and ameliorate apoptosis and cardiac remodeling in rats with myocardial infarction. The results of the study showed that the caspase inhibitor markedly blunted the wasting effect of angiotensin II. Thus, there was no statistically significant difference in body and muscle weight between angiotensin II–infused and pair-fed groups treated with caspase inhibitor after 5 days
In summary, angiotensin II–induced muscle wasting is mediated by reduced action of IGF-1 in skeletal muscle resulting from decreased IGF-1 expression and signaling, which lead to stimulation of the Ub-P’some pathway, activation of caspase-3, and apoptosis. Targeting the IGF-1 pathway in catabolic conditions, particularly those in which the renin-angiotensin system is activated, will likely provide therapeutic benefit. These findings have important implications for understanding mechanisms of weight loss in conditions such as heart failure, in which the renin-angiotensin system is activated, and provide a strong rationale for developing therapeutic strategies to activate the skeletal muscle IGF-1 system in wasting conditions.
The Role of IGF-1 on Muscle Wasting: a Therapeutic Approach
While much has been learned about skeletal muscle formation in the embryo, less is known about the molecular pathways controlling the survival and plasticity of muscle cells in the adult. The complex contractile properties of skeletal muscle depend upon several factors such as physical activity, diet, oxygen supply, and changes in hormone levels and motor-neuron activity. Fiber type is an essential determinant of muscle function and alteration, and is considered as a major component in muscle wasting associated with muscle diseases. In this context, the prolongation of skeletal muscle strength in aging and neuromuscular disease has been the objective of numerous studies employing a variety of approaches. Several studies have focused on the potential therapeutic role of insulin-like growth factor 1 (IGF-1) in treatment of muscle wasting associated with several muscle diseases.
Role of IGF-1 on Muscle Differentiation
IGF-1 has been implicated in many anabolic pathways in skeletal muscle and it plays a central role during muscle regeneration. Unlike other growth factors, IGF-1 also stimulates differentiation and enlargement of muscle cells in vivo and in vitro, suggesting that this growth factor can regulate both proliferative and differentiative responses in muscle cells. The effects of IGF-1 on proliferation and differentiation are temporally separated. IGF-1 plays its roles step by step, first acting upon the replication of myoblast (an embryonic cell that becomes a cell of muscle fiber) and subsequently promoting muscle cell differentiation. Several experimental evidences suggest that IGF-1 exerts its functions by activating two different intracellular signal transduction pathways, conveying proliferative and differentiative signals, respectively. The proliferative response is mediated by the MAP-kinase pathway, whereas the pathway leading to differentiation involves the activation of PI3-Kinase.
Role of IGF-1 on Muscle Homeostasis
IGF-1 plays a key role in muscle development in vivo, and IGF-1 secretion also facilitates muscle regeneration after injury and in denervated muscle. To test the possibility that enhanced IGF-1 expression could affect a similar muscle hypertrophic response in muscle tissue in vivo, Musaro et al recently generated a transgenic mouse in which the local isoform of IGF-1 (mIGF-1) is driven by myosin light chain promoter (MLC/mIGF-1), thus specifically restricted to skeletal muscle tissue. Transgenic mice exhibit marked skeletal muscle hypertrophy with dramatic reduction in body fat and no undesirable side effects such as tumor formation, as revealed in transgenic mice over-expressing the circulating IGF-1 isoform. Examination of older mice revealed that expression of the mIGF-1 transgene was protective against normal loss of muscle mass during senescence. Moreover mIGF-1 expression promotes and preserves the regeneration capacity of muscle tissues during aging, suggesting that IGF-1 expression preserves muscle integrity and the heterogeneity of myofibers, two fundamental parameters of muscle function. More recently, muscle-specific expression of mIGF-1 counters muscle wasting in mdx mouse which represent the animal model of human Duchenne and Becker muscular dystrophy. High levels of mIGF-1 transgene expression in the mdx mouse preserves muscle function in the absence of dystrophin, inducing significant muscle enlargement at all ages, and elevating signaling pathways associated with muscle survival and regeneration.
IGF-1 and Therapeutic Strategies
IGF-1 represents a good candidate to sustain muscle hypertrophy and to improve muscle regeneration. Gene therapy represents a promising tool to cure, when it is possible, or attenuate the genetic diseases leading to muscle wasting. Introduction of mIGF-1 somatically using an AdenoAssociated-Viral (AAV) vector was sufficient to rejuvenate the leg muscles of 27 month old mice, which exhibited the same mechanical force as legs of younger mice, and did not develop the pathological characteristics of senescent muscle. The dramatic muscle enlargement induced by expression of virally delivered IGF-1 is the consequence of a combination of satellite cell activation and an increase of protein synthesis. In addition, age-related reduction in force production and loss of fast fibers, all of which are typical of ageing skeletal muscle, were prevented both by virally delivered IGF-1 gene expression. Understanding the signal transduction pathways involved in muscle wasting will help to devise therapeutic strategies to combat muscle degeneration.
IGF-1 and Neurodegenerative Diseases
Neurodegenerative diseases are a diverse group of disorders from virtually unknown cause, which eventually lead to nerve degeneration and dysfunction. The GH/IGF-I axis is involved in many aspects of brain development, growth and function, their progressive decline with age could be related with a variety of diseases, including Alzheimer’s disease, vascular dementia, amyotrophic lateral sclerosis and stroke. Alzheimer’s disease (AD) and vascular dementia (VD) are the most common forms of dementia in the elderly. A decrease in IGF-1 levels in both of these diseases has been widely documented and it may be involved in the development of abnormal brain structures, cognitive loss, neural inflammation, oxidative stress or mitochondrial dysfunction.
The brains of people with AD have an abundance of abnormal structure called amyloid plaques, which are sticky buildup outside the nerve cells, or neurons. Recent advances in medicine have shown that brain amyloid clearance is modulated by serum IGF-I. In fact, blockade of systemic IGF-I action at the choroid plexus (network of blood vessels in each ventricle of the brain) was sufficient to induce amyloid build up on the walls of the arteries in the brain. Another well recognized finding in AD is the accumulation of abnormally hyperphosphorylated Tau (hallmark of neurodegenerative disorders) in degenerating neurons. IGF-I is known as inhibitors of Tau phosphorylation by inhibiting a major Tau kinase, such as glycogen synthase kinase-β. This inhibitory action of IGF-1 helps control the levels of hyperphosphorylated Tau in brain. Two other pathological processes underlying neuronal decline in AD are gaining attention: oxidative stress and inflammation. Again, the ability of IGF-1 to fight inflammation, protect cells from free radical-induced damage, and to reduce the incidence of programmed cell death, endorses IGF-I as a suitable candidate for the treatment of AD.
On the other hand, amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder in adults. Beneficial effects of IGF-I treatment in ALS have been demonstrated both in vivo and in vitro, from which IGF-I has been shown to be an important factor for the maintenance and survival of motor neurons in the spinal cord by activating clue pathways as PI3K/Akt and p44/42 MAPK.
Cerebrovascular accident (CVA) or also known as stroke is currently the second leading cause of death in the Western world, ranking after heart disease and before cancer. Studies on patients with ischemic stroke suggest that high circulating IGF-I levels are associated with neurological recovery and a better functional outcome, probably because IGF-1 has the ability to protect neurons and prevent programmed cell death.
Insulin and Insulin-like Growth Factor-1 Regulate Tau Phosphorylation in Cultured Human Neurons
Aggregation of insoluble proteins known as tau is most commonly known as a primary marker of Alzheimer’s disease. Hyperphosphorylation (biochemical process that involves the addition of excess phosphate to an organic compound) is thought to be a critical event in the development of this disease. Tau proteins help stabilize microtubules and are abundant in neurons (nerve cells) of the central nervous system. Microtubules play a major role in cell migration and cell division. Tau accumulates in neurofibrillary tangles in the brains of patients with Alzheimer’s disease. There is significant evidence that a disruption in the normal phosphorylation events results in tau dysfunction. Hyperphosphorylation impairs the microtubule binding function of tau. The predominant component of the tangle which is the major cause of Alzheimer’s disease is an abnormal fibrous assembly known as the paired helical filament (PHF), which is formed by a twisted double-helical ribbon. It has been hypothesized that the reduced binding ability of PHF-tau to microtubules along with a decline in the levels of normal tau, destabilizes microtubules in Alzheimer’s disease. This results in the disruption of chemical signals and degeneration of affected neurons.
Recently, glycogen-synthase kinase-3 (GSK-3) has been shown to phosphorylate tau in vitro and in non-neuronal cells introduced with tau. The activity of glycogen-synthase kinase-3 can be inhibited in response to insulin or insulin-like growth factor-1 (IGF-1) through the activation of the phosphatidylinositol 3-kinase (PI(3)K-PKB) pathway and affect tau phosphorylation in neuronal cells. To test this hypothesis, Hong and colleagues studied human NT2N neurons, which are derived from a human teratocarcinoma (type of testicular cancer) cell line after treatment with retinoic acid. These NT2N cells resemble embryonic central nervous system neurons as well as the characteristics of tau. Using this system, the researchers were able to demonstrate that insulin and IGF-1 has the ability to reduce tau phosphorylation and promote tau binding to microtubules through the inhibition of GSK-3 via the PI(3)K-PKB signaling pathway. They treated 2–4-week-old NT2 cells with retinoic acid for 5 weeks and kept it in a culture medium. To study the effects of insulin and IGF-1, NT2N cells were treated with 100 ng/ml of insulin or 10 ng/ml of IGF-1 for 5 min. The researchers also examined the effects of GSK-3 on tau binding to microtubules.
The results of the study showed that in NT2N cells treated with insulin and IGF-1, T1 immunoreactivity increased, indicating a reduction of tau phosphorylation. This effect is achieved by 100 ng/ml of insulin and 10 ng/ml of IGF-1. In addition to this, in cells treated with GSK-3, a significant amount of tau was bound to microtubules in cells, suggesting that GSK-3 phosphorylates tau at multiple sites and reduces the affinity of tau for microtubules. These findings suggest that the inhibition of GSK-3 by insulin or IGF-1 via the PI(3)K-PKB pathway can help regulate tau phosphorylation in human neurons, thereby preventing the development or progression of neurodegenerative diseases such as Alzheimer’s disease. The identification of these pathways brings new insights to the study of treatment options for Alzheimer’s disease. It raises the possibility that defects in this pathway may contribute to the development or progression of neurodegenerative diseases.
Aging, Synaptic Dysfunction, and Insulin-Like Growth Factor (IGF)-1
Aging has long been associated with a wide array of nervous system dysfunctions including impairment in the senses, changes in appetite, memory problems, and difficulty in finding adequate expressions and words. Studies on brains from a variety of mammals including humans conclude that a reduced number of synaptic connections (enhances the transmission of signals of nerve cells) among nerve cells or neurons, is the most consistent correlate with ageing and decline in cognitive function. In humans and other mammalian species, the complex role of IGF-1 in the body has been linked to improvements in cognitive function by affecting synaptic structure and activity.
IGF-1 and Synapses
To better understand the relationship between IGF-1 and the synapse, it is important to understand first how the synapse works. The synapse is a small gap at the end of a nerve cell that permits a signal to pass from one nerve cell to the other. Once a nerve impulse has triggered the release of brain chemicals, they will cross the synaptic gap until they reach the end of the nerve cell.
IGF-1 has multiple effects on the synaptic structure and brain plasticity (ability to change throughout life) that are beneficial in maintaining cognitive function. IGF-1 is known to increase the activity of N-methyl-D-aspartate receptor (NMDA receptor or NMDAR) and inhibits FOXO transcription factor. These changes are known to reduce programmed cell death in the brain, thereby, preventing cognitive decline.
Growth Hormone (GH), Insulin-like Growth Factor-1 (IGF-1), and Cognitive Function in Humans
In humans, growth hormone deficiency in children and adults has been linked with attention and memory problems as well as mood disorders. Moreover, impairments in short-term and long-term memory were reported in men with childhood-onset growth hormone deficiency compared with normal participants. In this study, replacement of growth hormone for 6 months at doses sufficient to increase blood levels of IGF-1 resulted in significant improvements in short- and long-term memory. In addition to this, restoration of IGF-1 to normal adult levels resulted in improvements in memory after 1 year.
Multiple studies have established that IGF-1 and its signaling pathway play a pivotal role in treating cognitive impairments in the elderly. These studies have similar results: that high levels of IGF-1 were associated with better information processing speed and better maintenance of cognition. Other studies showed a correlation between age, IGF-1 levels, and cognition status. Researchers found out that IGF-1 levels in the brain of middle age people are lower compared with younger ones, thus, suggesting that younger people with high levels of IGF-1 have better cognitive function.
Hormone replacement using IGF-1 is one of only a few therapeutic interventions that have consistently been reported to reverse cognitive decline associated with the process of ageing. Despite the well-recognized positive effects of IGF-1 on the synaptic structure and function, as well as cognitive function, further studies are needed to determine the complex role of IGF-1 in neurodegenerative diseases. Further research and advances in this field will identify targets for selective therapeutic interventions in the older population.
Insulin-like growth factor 1 Regulates Developing Brain Glucose Metabolism
The brains of mammals including humans depend upon blood sugar or commonly known as glucose as its main source of energy, and proper glucose metabolism is critical for brain physiology. Disruption in the normal glucose metabolism as well as its interdependence with cell death pathways are the main causes of many brain disorders. The largest proportion of brain energy is consumed for information processing. Additionally, glucose metabolism provides the energy and precursors for the production of brain chemicals. Dependence of the brain on glucose as its main source of energy derives mainly from the ability of the blood-brain barrier (BBB) to allow the entrance of glucose in the brain. Normally, glucose can’t be replaced as an energy source but it can be supplemented such as during vigorous activities or during prolonged starvation.
Murine and human brains consume over half of glucose for energy. When undernutrition, it may result in permanent intellectual deficit. Insulin preferentially enhances the energy source by peripheral tissues, but does not seem to play a role in the regulation of brain metabolism. However, insulin-like growth factor 1 (IGF-1) is abundant in the developing brain. Although the exact action of IGF-1 in brain development is not yet known, its importance seems clear because the deletion of the IGF-1 gene in humans results in mental retardation.
To determine how IGF-1 works in the brain, Cheng and colleagues investigated glucose utilization in IGF1-targeted gene deletion mice. The mice used in this study were from an IGF-1 deletion line which has been bred for several years. This study provided multiple lines of evidence indicating that IGF-1 can augment brain glucose utilization just like the action of insulin. Also, administration of IGF-1 through microinjections increases brain glucose utilization in these mouse models.
In vitro studies have suggested many potential roles for IGF-1 in the development and function of the human brain. The specific mechanisms exerted by IGF-1, however, are determined by the location and time of IGF-1 production. IGF-1 may promote process growth and synapse formation in mature and developing brains. Interestingly, the absence of IGF-1 during human brain development results in smaller cells with fewer processes and synapses, leading to mental retardation. These observations suggest that therapeutic augmentation of brain glucose metabolism by IGF-1 may enhance the potential for cognitive development.
Glucose Metabolism and the Regulation of Blood Flow to the Brain
Under resting conditions, the blood flow to the brain is highest in regions with the highest glucose metabolism. It is known that impairment in blood circulation to the brain may be an early cause of degeneration of brain cells, which can lead to vascular dementia and Alzheimer’s disease. Also, it is a known fact that when oxygen supply to the brain is cut off for about five minutes, brain death can occur immediately. Thus, fine-tuned glucose metabolism through the help of healthy levels of IGF-1 is necessary for the prevention of the progressive loss of structure or function of brain cells.
Insulin-like Growth Factor-1 Protects Human Dopaminergic SH-SY5Y Cells from Salsolinol-induced Toxicity
Parkinson’s disease (PD) is characterized by an extensive loss of dopaminergic neurons in the brain. Dopaminergic neurons or nerve cells are the main source of dopamine, which has major roles in memory, attention, cognition and other brain functions. Aside from aging, exposure to either pesticide or the neurotoxin salsolinol has been shown to mimic this dopaminergic cell loss. It has also been observed that the levels of salsolinol and its derivatives (e.g. norsalsolinol, N-methyl-norsalsolinol, N-methylsalsolinol) are increased in the cerebrospinal fluid and urine of patients with unknown cause of PD. Because norsalsolinol derivates are found in low or undetectable concentrations in healthy subjects, its role as a diagnostic marker for PD has been proposed. Salsolinol and its derivatives are synthesized in terminals of dopaminergic cells in the brain. During unfavorable conditions, salsolinol and/or one of its derivatives can participate in the subsequent development of PD. Therefore, researchers are now focusing on compounds that have the ability to protect dopaminergic neurons against cell death induced by salsolinol and its derivatives.
The Protective Role of Insulin-like Growth Factor 1 (IGF-1) in the Brain
IGF-1 induces survival, growth, development and function of nerve cells in the brain. Its role in cell survival by preventing cell death through activation of PI3K/Akt (signaling pathway) and inhibition of FOXO transcription factor, which regulates cell death, is one of the most important functions of IGF-1 in the brain. In addition to this, IGF-1 is known to counter the effects of oxidative stress, which is one of the main mechanisms proposed to contribute to brain aging and development of neurodegenerative disease. Furthermore, IGF-1 possesses the ability to lower the production of inflammatory substances such as prostaglandins and cytokines which are associated with various neurodegenerative diseases including PD.
The ability of IGF-1 to protect the nerve cells is of great therapeutic value in patients with PD as well as other neurodegenerative diseases. To further elucidate its protective effects, Shavali and colleagues created a model of salsolinol-induced toxicity using human dopaminergic SH-SY5Y cells. SH-SY5Y cells are human derived cell lines used in scientific research. The researchers treated these cells with salsolinol and a decrease in cell viability is observed 24 hours after exposure. To counter these effects, these cells were treated with IGF-1 and IGF-1 gene transfer was performed. Interestingly, IGF-1 administration as well as gene transfer prevented cell death induced by salsolinol. To further determine how IGF-1 exerts this effect, the researchers treated the cells with wortmannin, a specific phosphatidylinositol-3-kinase (PI-3 kinase) inhibitor. PI-3 kinase is a family of enzymes involved in cellular functions such as cell growth, proliferation and survival. The researchers observed that wortmannin administration completely blunted the IGF-1-induced nerve cell protection, suggesting that PI-3 kinase pathway is critical in mediating the protective effects of IGF-1 in various cell types including nerve cells.
These results confirm the protective effects of IGF-1 in the nerve cells of the brain, suggesting that IGF-1 can indeed be a therapeutic option in a wide array of neurodegenerative diseases such as PD.
Insulin-like Growth Factor-I Mediates Neuroprotection in Proteasome Inhibition-Induced Cytotoxicity in SH-SY5Y Cells
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects one’s movement that results from the death of dopaminergic neurons (main source of dopamine, which has major roles in memory, attention and cognition) in the brain. Several evidence shows that ubiquitin-proteasome system (UPS) dysfunction may activate intracellular stress responses that damage the powerhouse of the cell called mitochondria. The UPS system helps in eliminating unneeded or damaged proteins in the body by tagging or marking abnormal proteins with ubiquitin so that it can be easily identified by proteasome for degradation or break down. At present, this sequence of events triggers the development of PD. In patients with nonfamilial (sporadic) PD, abnormalities in the function and structure of proteasomes of neurons (nerve cells) can be found. More recent work has shown that systemic exposure of animal models to synthetic and naturally occurring proteasome inhibitors results in a syndrome that is very similar to PD.
Pharmacological inhibition of the proteasome is sufficient to induce cell death in neuron cultures and neuronal cell lines, suggesting that proteasome inhibition may play an essential role in PD and other neurodegenerative diseases. Proteasome inhibition in cultured dopaminergic neurons has been shown to cause mitochondrial dysfunction, decreased levels of glutathione, and increased generation of free radicals. Moreover, defects in the UPS participate in the development of various neurodegenerative disorders, thus, the UPS is an attractive target for treatment options in PD.
Insulin-like growth factor-1 (IGF-1) is a hormone that is essential for the development of the nervous system. IGF-1 receptors are distributed over most brain regions and regulate cell growth, specialization and survival of nerve cells. IGF-1 protects various cells against different kinds of stressors such as oxidative cell death related to treatment of cells with nitric oxide, hydrogen peroxide, high blood sugar concentrations, peroxynitrite, salsolinol and okadaic acid. Protection of several cell types from cell death by IGF-1 has been linked to the activation of the PI3/AKT pathway (intracellular signaling pathway). To further elucidate the protective effects of IGF-1, Cheng and colleagues treated SH-SY5Y cells with proteasome inhibitor Epoxomicin. The researchers chose to use SH-SY5Y cells as an experimental model because they secrete dopamine. In order to confirm that IGF-1 inhibits cell death caused by Epoxomycin, the SH-SY5Y cells were cultured for 18 hours in the presence or absence of IGF-1, followed by Epoxomicin treatment for 24 hours. Interestingly, proteasome inhibition by Epoxomicin treatment of these cells causes cell death, even at extremely low concentrations and pretreatment of these cells with IGF-1 prevented such occurrence. In these cells, IGF-1 treatment activated the PI3/AKT pathway in a time-dependent fashion.
These results indicate that IGF-1 blocks cell death induced by Epoxomicin treatment leading to decreased proteasome function. Clues as to the mechanism for this protective effect come from the following:
Together these findings suggest that IGF-1 can indeed protect cells from cell death following proteasome inhibition. This also shows that IGF-1 or other agents that activate the PI3/AKT pathway can prevent toxicity and cell death following abnormal accumulation of proteins due to proteasome inhibition, suggesting that these agents can be of great therapeutic value in PD and other neurodegenerative diseases.
Recombinant Human IGF-1 (rhIGF-1) for Patients with Schizophrenia
Schizophrenia is a long-term mental health condition that causes a wide array of psychological symptoms such as hallucinations, delusions, muddled thoughts, and changes in behavior. This mental condition is often described as a psychotic illness because affected individuals may not able to distinguish their own thoughts, beliefs and ideas from reality. The exact cause of schizophrenia is unknown. However, most experts believe that it is caused by genetic and environmental factors, substance abuse, and changes in the levels of brain chemicals. Currently, treatment for schizophrenia includes antipsychotic medicines and cognitive behavioral therapy (talking therapy focused on changing the way you think and behave). Affected individuals usually receive help from a community mental health team for daily support and treatment.
The Role of IGF-1 in Schizophrenia
There is increasing evidence that all types of glial cells (provide support and insulation between nerve cells), especially oligodendrocytes, are affected in schizophrenia. In addition to this, schizophrenia also affects the brain region called white matter, which regulates the electrical signals between nerve cells. When compared to healthy controls, patients suffering from schizophrenia usually have lower levels of IGF-1 in the blood. IGF-1 receptors are concentrated in the hippocampus (brain region associated with memory, emotion and spatial navigation) rendering this part of the brain likely to be more affected with IGF-1 deficits. Interestingly, hippocampal dysfunction has been proposed to be linked to auditory hallucinations (false perceptions of sound) experienced by patients with schizophrenia. Also, several factors such as low birth weight, loss of muscle mass and short stature, which are all linked to decreased levels of IGF-1, are shown to be associated with increased risk for developing schizophrenia.
Antipsychotic drugs (such as quetiapine) have been shown to promote the specialization of nerve cells into oligodendrocytes with the same importance that IGF-1 induces this effect. Aside from this effect, experimental and preclinical data support the fact that IGF-1 treatment can help improve the process of myelination, which protects the nerve cell or nerve fiber and help it conduct signals more efficiently. Because schizophrenia is a brain abnormality related to demyelination, which causes damage to the protective covering (myelin sheath) of nerve fibers in the brain and spinal cord, IGF-1 treatment can indeed provide beneficial effect in patients suffering from schizophrenia by enhancing the process of myelination.
In one study, Bou khalil and colleagues reported that subcutaneous recombinant human IGF-1 at a dose of 0.05 mg/kg given twice daily improved symptoms and is well-tolerated by patients with schizophrenia.
These findings suggest that IGF-1 administration can be a new therapeutic option for patients with schizophrenia in addition to antipsychotic medicines and cognitive behavioral therapy. The ability of IGF-1 to promote the specialization of nerve cells into oligodendrocytes and to enhance the myelination process in the central nervous system indicates that IGF-1 might be useful in treating schizophrenia. Moreover, this effect can also be used in a wide array of demyelinating diseases such as multiple sclerosis, Guillain-Barré syndrome, autoimmune encephalomyelitis and other diseases.
The IGF-1/Akt pathway is Neuroprotective in Huntington’s disease
Huntington’s disease (HD) is an incurable, hereditary brain disorder wherein nerve cells become damaged, causing various brain regions to deteriorate. Affected individuals suffer from problems with movement, behavior and cognition. Signs and symptoms can appear at any point in life and vary from person to person, but most commonly do so between 35 to 55 years old and start to worsen with increasing age. HD can have a negative impact on the lives of the patients as well as their families and healthcare providers.
Neuroprotective Role of Insulin and IGF-1
IGF-1 has a variety of effects on target organs and is necessary during nervous system development. With increasing age, IGF-1 levels decline in both plasma and brain. At cellular level, IGF-1 is best described as a prosurvival factor, generally acting through PI3K/Akt pathway to prevent programmed cell death. Moreover, IGF-1 also improves the metabolism of nerve cells and regulates neuronal excitability (firing of neurons to transmit electrical signals), two properties that, together with IGF-1’s actions in preventing cell death, may be crucial in protecting nerve cells against various injury or damage. At tissue level, IGF-1 stimulates vessel formation, regulates the clearance of plaques known as amyloid, and modulates the activity of nerve cell networks in the brain. Based on these biological activities, it is plausible that changes in the level of IGF-1 in the brain can contribute to the development of neurodegenerative diseases.
To date, there is no treatment available to prevent or delay the onset of HD. Medical management are more focused on alleviating the symptoms of HD and maintaining independence of the patient. Several studies have identified substances that might be used in the treatment of HD because of their ability to promote survival. It was reported that insulin may help protect from cell death induced by serum starvation and brain damage during low oxygen levels. In addition to this, Duarte and colleagues reported that insulin may help prevent cell death associated with oxidative damage. Also, the same researchers concluded that insulin can help restore adenosine triphosphate (energy source of cells) levels under oxidative stress.
Besides insulin, other studies demonstrated IGF-1’s ability to protect nerve cells during brain development. In 2004, Trejo and colleagues demonstrated IGF-1’s ability in controlling the growth and development of nervous tissue in adulthood. The specific mechanism underlying IGF-1’s nerve cell protective action is through the activation of IGF-1/Akt signaling pathway, which plays a key role in preventing cell death. Activation of this pathway is important especially for patients with HD, since Akt is altered in these patients. HD patients have reduced Akt levels, suggesting that the gradual deterioration of nerve cell damage in the brain may be related to this.
Impaired brain energy metabolism with increased levels of lactate in the brain may play a role in the deterioration of nerve cells in patients with HD, thus can worsen the condition. To determine IGF-1’s role in brain energy metabolism and interaction with lactate, Naia and colleagues studied the effect of IGF-1 on the lymphoblasts (immature white blood cells) of patients with HD. Interestingly, exposure of HD patients’ lymphoblasts to IGF-1 resulted in a significant reduction in lactate levels in HD cells compared to untreated cells. In addition to this, IGF-1 was able to normalize the generation of ATP in nerve cells. Based on these results, it is plausible that insulin and particularly IGF-1 may offer potential therapeutic protection against HD.
The Protective Effects of Insulin-like Growth Factor-1 (IGF-1) on BDE-209-induced Neurotoxicity in vitro
Polybrominated diphenyl ethers (PBDEs) are one of the most common types of brominated flame retardants (a key component in reducing the devastating impact of fires) applied to a wide array of industrial products including electronic devices, plastics, foams and textiles. Also, PBDEs exist extensively in various food stuffs such as meat, fish, potato, string beans, rice, and olive oil. PBDEs exhibit many negative biological effects especially potential toxic effects on the brain and nerve cells. It has been shown that chronic exposure to PBDEs may increase one’s risk for neurological disorders. Early-life exposures to this toxic substance lead to neuro-behavioral abnormalities later in life. It has been identified that intake of PBDEs through food is one of the main modes of exposure to humans. Decabrominated diphenyl ether (BDE-209) is the most abundant PBDE found in human samples, which affects target organs and overall health. Concerns have been raised with regard to the PBDE’s neurotoxicity in both prenatal and postnatal exposures because it readily crosses the placental barrier in pregnant women and is toxic in the developing fetus, particularly in the developing brain.
Dorsal root ganglion (DRG) is a structure of the peripheral nervous system (PNS) located on each spinal nerve. Given the growing evidence documenting the potential health hazards associated with PBDE exposure, it has presented a major public health challenge with rising levels in human tissues. Whether BDE-209 affects DRG is unclear. BDE-209 may exert its neurotoxic effects on primary sensory neurons (nerve cells) in vitro. The ability of IGF-1 to promote proliferation, cell survival and inhibition of cell death may help rescue specific DRG neurons with BDE-209-induced neurotoxicity. Aside from this, IGF-1 can help regenerate or repair cells of the spinal cord which are exposed to BDE-209 for prolonged periods of time. To determine the protective effects of IGF-1 on neurochemical phenotypes of DRG with BDE-209-induced neurotoxicity in vitro, Chen and colleagues studied DRG cell culture preparations of newborn rats (less than 24 hours after birth). The bilateral DRG were removed from each animal and placed in a culture medium. At 48 hours of culture age, primary cultured DRG neurons were exposed to BDE-209 and IGF-1 for additional 24 hours.
The results showed that IGF-1 promoted growth and viability of DRG cells with BDE-209-induced neurotoxicity. Interestingly, IGF-1 inhibited oxidative stress and cell death caused by exposure to BDE-209. In addition to this, IGF-1 helps reverse the decrease in growth-associated protein-43 and calcitonin gene-related peptide, both of which plays a role in the regeneration of nervous tissue after injury.
In conclusion, BDE-209-induced neurotoxicity could be reversed by the administration of IGF-1. The specific underlying mechanism in which IGF-1 exerts these effects is through combating oxidative stress and inhibiting nerve cell death. Simultaneously, IGF-1 may initiate growth-associated protein-43 expression to promote cell growth and viability of DRG neurons with BDE-209-induced neurotoxicity. Particularly, IGF-1 may have specific neuroprotective effect on calcitonin gene-related peptide of DRG neurons, which can help regenerate or repair damaged cells. With these findings, it is plausible that IGF-1 might be a potential option in preventing and treating BDE-209-induced neurotoxicity in humans.
Therapeutic Benefits of Insulin-like Growth Factor (IGF-1) in Alzheimer’s Disease (AD)
The synapse is a small gap at the end of a nerve cell that permits a signal to pass from one nerve cell to the other. Alterations in synaptic function are considered to be the main pathological features of decline in cognitive function in the older population. Moreover, recent results strongly support the concept that loss in synaptic function is linked with very early cognitive decline in Alzheimer’s disease (AD). IGF-1 appears to have multiple effects on the synapses and protects against toxic amyloid beta, which is the main component of plaques found in the brains of Alzheimer patients. Also, accumulation of amyloid beta is the main cause of disruption in the synaptic function. Interestingly, both insulin and IGF-1 reduce the formation of amyloid beta plaques, protecting the brain against possible synaptic dysfunction. Furthermore, insulin/IGF-1 receptor signaling may be a part of the neuroprotective effect of rosiglitazone (anti-diabetic drug), which can help reduce amyloid beta toxicity and improves memory test results in patients with AD. These results indicate that brain insulin resistance and IGF-1 receptors dysfunction are major contributors to toxic amyloid beta accumulation and subsequent synaptic loss.
IGF-1 and Amyloid Beta Production
IGF-1 appears to increase nerve cell network in cultured cells, and amyloid beta production is linked with nerve cell activity. Therefore, the possible beneficial effects of IGF-1 could be impaired in patients with Alzheimer’s disease through elevated amyloid beta secretion and accumulation. It is noteworthy that recent findings support a role of IGF-1 treatment in protecting the synaptic plasticity (ability of synapses to strengthen or weaken over time) from inflammatory agents. In addition to this, some reactions in the body including increased production of interleukin-6 (pro-inflammatory substance) clear amyloid from the brain, suggesting that inflammation is not a major driving force for the accumulation of amyloid.
Evidence is now emerging linking IGF-1 with central nervous system (CNS) development and repair, in particular, IGF-1 plays a pivotal role in protecting nerve cells and in its growth and development. In addition, the levels of IGF-1 in the brain and blood declines with increasing age and reduced levels of IGF-1 increases a person’s risk for AD. In 2002, Carro et al. were the first to demonstrate that IGF-1 has the ability to regulate amyloid beta levels by increasing the permeability (ability to allow substances to pass) of blood brain barrier to the amyloid beta carrying proteins. In this way, accumulation of amyloid beta in the brain can be prevented. Also, blockade of IGF-1 receptors in the choroid plexus (a network of blood vessels in each ventricle of the brain) induced accelerated AD-like pathology and cognitive impairment in mouse models. Conversely, IGF-1 administration to these mouse models improved cognitive performance and reduced AD-like pathology. Moreover, in human studies, increasing IGF-1 levels by supplementing with growth hormone releasing hormone significantly improved cognition in both healthy and cognitively impaired older populations. These beneficial effects support a possible therapeutic role of IGF-1 for AD.
Growth Factors for the Treatment of Ischemic Brain Injury (Growth Factor Treatment)
Hypoxic-ischemic injury, a condition characterized by impaired blood flow and reduced oxygen to the tissues, is a significant cause of mortality and morbidity in both adults and children. Brain injury like this progress over time through several different mechanisms that lead to cell damage and death. Following exposure to hypoxia-ischemia, body response mechanisms are activated including production of a number of inflammatory cytokines and growth factors. These growth factors play important roles in the normal function and development of the central nervous system, and they activate a number of signaling pathways that mediate changes in apoptosis (cell death), inflammation, angiogenesis (development of new blood vessels), cell differentiation and proliferation.
Insulin-Like Growth Factors
Insulin-like Growth Factor-1 (IGF-1) is responsible for a variety of pro-survival signaling mechanisms. It is produced by the growth hormone (GH) in the liver and is found in various types of cells. IGF-1 is used clinically as a treatment for GH resistance-related growth disorders but appears to have potential for treatment of ischemic brain injury. This may be due to the fact that IGF-1 is widely distributed in the brain in nerve cells and glia (connective tissue of the nervous system), and has major roles in neurodevelopment, protection, and survival.
In vitro, IGF-1 has been shown to inhibit glutamate, nitric oxide, and hydrogen peroxide-related apoptosis to protect both sensory and motor neurons against excitotoxicity (excessive stimulation of nerve cells) and oxidative stress.  Oxygen glucose deprivation-treated microvascular endothelial cells that form the blood brain barrier also increase secretion of IGF-1 after ischemia, resulting in decreased nerve cell injury. Drug induced inhibition of IGF-1 and inhibition of IGF receptors on astrocytes (a star-shaped glial cell of the central nervous system) shows that IGF-1 production is key to astrocyte survival after H2O2-induced oxidative stress, and is key to protecting nerve cells from oxidative stress through astrocyte-secreted Stem Cell Factor’s interactions with IGF-1.
In humans, IGF-1 has been studied in neurological disorders such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Alzheimer’s disease (AD). [2-4] Interestingly, these studies demonstrated a neuroprotective role of IGF-1. In case of ischemic brain injury, studies of the blood levels of IGF-1 after adult stroke and elderly stroke found that after ischemic injury, the levels of IGF-1 in the blood decrease significantly. All these studies found that lower levels of IGF-1 were associated with poor clinical outcome and increased risk of death associated with this condition.  This suggests that boosting IGF-1 levels through direct administration may have help protect against ischemic brain injury.
IGF-1 appears to exert protective effect against ischemic brain injury by stimulating pro-survival signaling mechanisms. Cell studies have shown that IGF-1 can inhibit programmed cell death induced by glutamate, nitric oxide, and hydrogen peroxide. In addition, this hormone can also decrease nerve cell injury after ischemia, with higher IGF-1 levels associated with increased rate of brain cell survival. Human studies have also shown that lower IGF-1 levels are strongly linked with poorer clinical outcome and can even increase risk of death related to ischemic brain injury. Therefore, IGF-1 administration as well as increased levels of this hormone may help protect against brain injury related to insufficient blood flow and may reduce mortality rates of patients with this debilitating medical condition.
Insulin-Like Growth Factor-I Regulation of Immune Function: A Potential Therapeutic Target in Autoimmune Diseases?
Insulin-like growth factors (IGF-I1 and IGF-II), their binding proteins (IGFBPs), and the receptors mediating their signaling (types I and II IGF-IR), is crucial in normal growth and development, metabolism and balance within the body. Detection of IGF-I and IGF-IR mRNAs (convey genetic information from DNA to the ribosome) and the proteins they encode suggests that they might play pivotal role in the immune function. In addition to this, IGF-I enhances diverse aspects of bone marrow function, including formation and maturation of white blood cells, and the production of red blood cells. Its effects are substantial in that they can reduce the myelosuppressive effects (condition in which bone marrow activity is decreased) of powerful chemotherapeutic agents such as azidothymidine. In animal models, administration of GH and IGF-1 promotes the development of immune system cells such as B and T cells. Thus, there is reason to explore the potential actions of these hormones as regulators of immunity. Moreover, targeting IGF-I and IGF-IR signaling in order to impair the natural course of chronic inflammation may become a strategy in managing and treating various autoimmune disease. Although the function of endocrine glands is intimately intertwined with growth and development, the potential relationship between immune function and IGF-1 has remained poorly understood until relatively recently. Interestingly, immune reactions and the inflammation with which they are often linked have been shown to affect normal tissue remodeling. These biological functions are somehow linked to the complex interplay between cytokines and IGF-1.
Hematopoiesis refers to the production, multiplication, and specialization of immune cells in the bone marrow. In mice, GH and IGF-I administration enhances reconstitution of the immune system by improving hematopoiesis after bone marrow transplantation. In one study, Alpdogan and colleagues demonstrated that the levels of white blood cells after bone marrow transplantation was enhanced by IGF-1. This hormone was able to increase the frequency of bone marrow cells with no effects on either morbidity or mortality among the animals.
Thymus Development and Function
The thymus gland produces T cells for the immune system. Certain factors seem to promote increased activity within the thymus. Among them, IGF-1 and GH target thymus cells, where they synergistically promote the action of anti-CD3 (one that binds to CD3 on the surface of T cells) in stimulating proliferation. In addition to this, IGF-I is known to directly stimulate DNA synthesis in thymus cells in a time-dependent manner.
IGF-I and IGF-II seem to modify several aspects of the inflammatory process by influencing the actions of cytokines. Cytokines are cell signaling molecules that are responsible for enhancing cell to cell communication in immune responses and stimulate the movement of cells towards sites of inflammation or infection. To support this, increased levels of IGF-1 was found in patients manifesting autoimmune diseases such as ulcerative colitis or Crohn’s diseases. On the contrary, these patients have lower levels of the inflammatory substance called C-reactive protein. This shows that IGF-1 levels are inversely correlated with those of C-reactive protein and can be a significant marker of autoimmune diseases.
Role of the Growth Hormone/Insulin-Like Growth Factor-1 Paracrine Axis in Rheumatic Diseases
Many studies have demonstrated altered hypothalamic-pituitary axis or HPA (a complex set of direct influences and feedback interactions among the hypothalamus, pituitary gland and adrenal glands) in patients with autoimmune inflammatory diseases such as rheumatic diseases. Rheumatoid arthritis (RA) is one of the most common and serious chronic inflammatory diseases. Although not yet fully understood, glucocorticoids clearly exert profound effect in the suppression of the body’s immune-inflammatory response and have been the cornerstone of treatment for RA for over 50 years. The concept that glucocorticoids produced by the adrenal glands, and regulated by the hypothalamus and pituitary, have a pivotal role in the regulation of inflammation has emerged more recently. It is now apparent that the occurrence of inflammation, through the release of inflammatory substances such as cytokines, provides a direct stimulus to pituitary and hypothalamus’ activity, resulting in adrenal glucocorticoids production under the influence of adrenocorticotrophic hormone (ACTH).
Circumstantial evidence suggests that failure of the HPA axis may lead to inadequate amounts of glucocorticoids within the body. Such failure has been associated with systemic disturbances in several rheumatic diseases. Longitudinal analysis of vital substances and hormones such as synovial fluid (thick, straw-colored liquid found in joints, tendons and sheaths), growth hormone (GH), insulin-like growth factor-1 (IGF-1), and somatostatin (secreted in the pancreas and pituitary gland) levels could provide significant surrogate measures of disease activity in RA. In order to determine their roles in RA, Denko and colleagues conducted a review of literature supporting the view that HPA axis dysfunction accompanies clinical symptoms in RA. In addition to this, the researchers analyzed the basal somatostatin levels in patients with hand, knee, hip and spine osteoarthritis (OA).
The results of the study showed elevation in blood GH levels in patients with OA, RA, fibromyalgia, and diffuse idiopathic skeletal hyperostosis (a form of degenerative arthritis) but not in patients with gout, pseudogout, or systemic lupus erythematosus (SLE). Many studies support an inverse relationship between age and IGF-1. In this study, increased GH levels in various rheumatic diseases were not coupled to changes in IGF-1 levels in the blood in diffuse idiopathic skeletal hyperostosis, RA, and fibromyalgia. In particular, the blood levels of IGF-1 in OA were lower or no different compared with age-matched normal subjects. In addition to this, blood levels of somatostatin were often lower in RA and SLE, but basal serum somatostatin levels were generally not altered in OA.
In conclusion, serum GH, IGF-1, and somatostatin levels must be monitored on a consistent basis during the course of medical therapy of rheumatic diseases. Doing so can help determine the extent to which changes in signs and symptoms (exemplified by pain reduction and decreased inflammation as well as improvement in range of motion of affected body part) are accompanied by changes in the levels of these hormones. Also, consistent and accurate monitoring of serum GH, IGF-1, and somatostatin levels can aid healthcare providers in making an accurate diagnosis especially in patients with suspected rheumatic disease.
IGF-1 in Inflammatory Bowel Disease (IBD)
Inflammatory bowel disease (IBD) involves chronic inflammation of all or part of the digestive tract. It primarily includes ulcerative colitis and Crohn’s disease, both of which involve abdominal pain, weight loss, extreme fatigue and severe diarrhea. If left untreated, IBD can lead to life-threatening complications. The etiology of IBD remains largely unknown, but it is considered to be caused by genetics and environmental factors. Surprisingly, the number of patients diagnosed with IBD in all age groups worldwide has dramatically increased over the past 50 years, with the highest annual incidence in North America and Europe. Noteworthy, the number of new cases of IBD is on the rise and mostly affects children.
The Role of Insulin growth factor-1 (IGF-1) as a Therapeutic Option for IBD
Several effective strategies for IBD treatment are currently available including glucocorticosteroids, immunosuppressive agents, 5-aminosalicylates and biological therapies. However, these treatments come with side effects such as high blood pressure, type 2 diabetes, short stature, increase risk for cancer, as well as economic costs. Therefore, it is urgent to bring forth a better understanding of IBD and new cost-effective therapeutic option for IBD.
IGF-1 is one of the most potent natural stimulators of cell growth and reproduction in various cell types. In addition to this, IGF-1 plays a pivotal role in the regulation of the metabolism of fats, proteins and carbohydrates, and in stimulating blood sugar transport into the muscle. Studies on IGF-1 administration in vivo revealed its anti-inflammatory effect and its ability to repair gastrointestinal organs. IGF-1 also plays a significant role in the physiology of the GI tract. Similarly to other body organs, the intestines produce its own IGF-1. Studies conducted to assess the GH/IGF-1 axis in adult patients with IBD reported a decreased level of IGF-1 in the blood. Chronic inflammation in adult IBD patients may cause long-term reductions in the level of IGF-1 and thus increase one’s risk for osteoporotic fractures. Patients with Crohn’s disease frequently experience osteoporotic bone fractures compared to patients with ulcerative colitis due to reductions in bone mineral density. In one study, Koutroubakis and colleagues concluded that there is a high prevalence of osteopenia (reduced bone mass) and osteoporosis in Greek patients with IBD, and that BMD was positively correlated with serum IGFBP-3 (insulin-like growth factor-binding protein 3). These findings suggest that IGF-1 and its binding proteins may be a predictive marker of complications related to IBD.
It is plausible that IGF-1 has the potential to become a new therapeutic option in IBD patients because of its anti-inflammatory effects. To support this, Howarth and colleagues demonstrated that IGF-1 administration for 7 days reduced inflammation in the mucous membrane in a model of experimental colitis. In line with this, a study by Yu and colleagues reported that IGF-1 treatment alleviates inflammation by reducing HMGB1, which a potent stimulator of tissue damage and inflammation. Finally, Johannesson and colleagues reported that IGF-1 suppresses allergic contact dermatitis by reducing the infiltration of immune cells in the affected area, thereby preventing inflammation. Moreover, IGF-1 administration directly stimulates the expansion of regulatory T cells, which may have therapeutic implication in other inflammatory conditions, such as IBD.
The Role of Insulin-like Growth Factor (IGF-1) in Neurodegenerative Diseases
Neurodegenerative diseases are defined as hereditary and sporadic conditions characterized by progressive alterations or dysfunction in the nervous system. Although neurodegeneration is extensively researched, the exact cause of neurodegenerative disease remains unclear. Studies suggest that neurodegeneration is a result of a complex interplay between oxidative damage, alteration in energy metabolism, nerve cell damage, and accumulation of cellular waste products.
IGF-1 is required for normal development of the brain. Neurodegenerative diseases show either high or low levels of circulating IGF-1. Several studies have shown a correlation between impaired IGF-1 signaling and decreased cognitive function in the elderly. Lower blood levels of IGF-1 are linked with impaired memory, orientation skills, and slow information processing speed.
IGF-1 – A Potent Neurotrophic Factor
IGF-1 is an important neurotrophin – a protein that induces survival, development and function of nerve cells. Its influence on energy metabolism, growth and repair of nervous tissues, learning and memory as well as cell survival encouraged some scientists to further study its role in the pathogenesis of neurodegenerative disease. IGF-1 seems to exert its effect on synaptic transmission (chemical signals between cells) through several important mechanisms. This in turn enhances the communication between nerve cells. Another important role of IGF-1 is its ability to prevent cell death through activation of PI3K/Akt (signaling pathway) and inhibition of FOXO transcription factor, which regulates cell death. This ability of IGF-1 can help slow down or completely stop the degeneration of nerve cells in a variety of neurodegenerative diseases.
Oxidative stress, IGF-1 and the Brain
Oxidative stress, which is the disturbance in the balance between the production of reactive oxygen species (free radicals) and antioxidant defenses, is one of the main mechanisms proposed to contribute to brain aging and development of neurodegenerative disease. Reactive oxygen species produced during excessive oxidative stress, exert damage to nerve cells by stimulating FOXO3, a pathway which triggers cell death. IGF-1 and insulin counters these processes by activating both insulin and IGF-1 receptors located in the brain tissue. As a result, the PI3K/Akt pathway is activated, which in turn inactivates FOXO3 and many other mediators participating in cell destruction. Not only do insulin and IGF-1 suppress these processes while fighting oxidative stress, but they also stimulate survival signals through induction of NF-κB. NF-κB suppresses the toxic effect of harmful substances on nerve cells.
IGF-1 and Inflammation Mediators
Prostangladins and pro-inflammatory cytokines are also associated with various neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, AIDS dementia complex, multiple sclerosis and other conditions caused by insufficient blood flow to the brain. These inflammatory substances are thought to increase free radicals, leading to severe oxidative stress and affecting IGF-1 signaling. In the brain, IGF-1 and prostangladins have opposing effects. IGF-1 lowers the production of prostaglandins as well as pro-inflammatory cytokines.
With IGF’s ability to promote cell proliferation, survival and metabolism, its effects in the context of neurodegenerative diseases are of great importance in today’s field of research. Using IGF-1 as a therapeutic option for various neurodegenerative diseases can help reverse brain damage and improve the quality of life of affected individuals.
IGF-1 Promotes the Development and Cytotoxic Activity of Human NK Cells
Within the ecosystem that is your body, natural killer cells or also known as NK cells are highly selective predators. They kill tumors, infected cells, or foreign bodies by releasing toxic substance while sparing healthy cells. NK cells work together with other cells of the innate immune system including neutrophils, macrophages, moncytes, dendritic cells and T-lymphocytes. By selectively killing their targets, NK cells play a pivotal role in protecting the body from a wide array of diseases, thus, amplifying the immune function.
IGF-1 Promotes the Development of Human NK Cells
IGF-1 has been demonstrated to promote the development of T-cells (lymphocytes produced by the thymus gland) and B lymphocytes in the bone marrow. To investigate the potential role of IGF-1 in human NK cell development, Fang and colleagues cultured umbilical cord blood cells, CD34 cells (give rise to all cell types in blood) and hematopoietic stem cells (responsible for formation of blood cellular components) with Flt3-L and stem cell factor (SCF) in the presence of either interleukin 15 (a type of immune system cell), IGF-1 or a combination of both cytokines for up to 4 weeks. The researchers found out that the combination of IL-15 and IGF-1 has a dramatic effect in activating the rapid reproduction of CD34 cells, suggesting that IGF-1 contributes to the development of NK subsets.
Exogenous IGF-1 Enhances NK Cell Cytotoxicity
IGF-1 may improve NK cell’s cytotoxic activity (the ability to kill abnormal cells). The presence of IGF-1 significantly increased CD107a release in human CD34+-derived CD56+ NK cells. This simply means that the higher the level of IGF-1 present in the body, the more CD107a is released, thus, enhancing the cytotoxic activity of NK cells and boosting the immune function.
NK Cell Cytotoxicity is dependent on Endogenous IGF-1
Human NK cells have the ability to produce IGF-1, which is important for NK cell cytotoxicity. To support this, Fang et al. administered an IGF-1-neutralizing antibody to a type of NK cell and resulted in a significant decrease in the cell’s ability to kill abnormal cells. These data suggest that the level of IGF-1 in the body is critical to the cytotoxic activity of human NK cells.
IGF-1’s Protective Effects
It has been indicated that IGF-1 has an important role in the promotion of cell division and protection from programmed cell death (apoptosis) in many cell types. This means that IGF-1 can increase the rapid reproduction of NK cells while preventing apoptosis. However, the effects of IGF-1 may simply vary depending on the doses or the experimental systems to which it is added.
In conclusion, IGF-1 has an expanded role in the positive regulation of human NK cell development and cytotoxicity. Moreover, the finding that adequate amounts of IGF-1 can enhance NK cell’s cytotoxic ability and protect it from programmed cell death, provides new mechanistic insights in terms of the importance of NK cells in immunotherapy. This new information might present new opportunities for boosting or limiting the effects of NK cells in the immune system to achieve a therapeutic effect.
Insulin-like Growth factor-1 Stimulates Regulatory T Cells and Suppresses Autoimmune Disease
Autoimmune diseases are increasingly widespread. Due to their prevalence, these diseases do not only affect the lives of affected individuals, but strain the economies of healthcare systems. Current treatment modalities for autoimmune diseases rely on suppressing the imbalanced immune system to avoid persistent inflammation and potential damage to organs and tissues. However, these immunosuppressive treatments inevitably lead to serious adverse long-term effects.
The immune system protects your body against various harmful foreign bodies while restricting those responses to avoid harm. Active suppression of inflammation and immune responses by regulatory T (Treg) cells is vital in maintaining this balance. T cells modulate the immune system to prevent autoimmune disease. Without T cells, your body’s immune system will attack itself leading to various diseases. T cell-based therapies have held great promise for restoring tolerance in autoimmune diseases. Yet efforts to develop effective strategies for boosting T cell numbers, have met with limited success.
Recombinant IGF-1 (rhIGF-1) Specifically Stimulates Proliferation of T cells
Previous studies have implicated IGF-1 as a powerful enhancer of regenerative responses in multiple tissue types. Cumulative evidence suggests that IGF-1 has a significant role in regulating the immune response, with a direct link found between IGF-1 signaling and the activation of T cells in vitro. RhIGF-1 treatment was able to affect human T cell activation along with its production, which is dependent on the activation of a canonical signalling pathway (proteins that pass signals into a cell through cell surface receptors) involving the PI3-kinase–Akt axis. Notably, rhIGF-1 doesn’t stimulate the pro-inflammatory immune cells such as CD4 cells and interferon gamma (IFNγ), underscoring its potential to alter the balance between suppression of inflammation and immune responses. Taken together, these data clearly supports IGF-1’s role in positively regulating T cell-mediated immunosuppression.
Systemic Delivery of IGF-1 Protects from Drug-induced and Genetic Diabetes
Type-1 diabetes is an autoimmune disease caused by T-cell-induced destruction of the insulin-producing beta cells of the pancreas. To test the therapeutic potential of systemic rhIGF-1 delivery in type-1 diabetes, Zdravkovic and colleagues implanted a subcutaneous osmotic minipump containing rhIGF-1 in female mice, and diabetes was induced by multiple low-dose streptozotocin injections. Notably, rhIGF-1 administration resulted in improved blood sugar levels, providing long-lasting protection of the beta cells of the pancreas with no reported adverse side effects. Increased T cells were also observed in the pancreas of the mice treated with rhIGF-1. Thus, relatively short but constant rhIGF-1 treatment prevents the development and progression of type-1 diabetes by increasing T cell numbers and stably recruiting them to damaged pancreatic tissue.
These findings provide the rationale and preclinical groundwork for the use of recombinant IGF-1 in a wide array of devastating autoimmune diseases such as type-1 diabetes by reestablishing tolerance to self-antigens by increasing T cell proliferation. Given that rhIGF-1 is already an approved therapeutic option for the treatment of severe primary IGF-1 deficiency and has already been tested in a variety of clinical settings with positive results, it is now apparent that human trials for its use in the treatment of autoimmune and inflammatory disorders can now be implemented.
Recombinant Insulin-like Growth Factor-1 (IGF-1) Improves T Cell Recovery in Patient with Omenn Syndrome
Omenn syndrome is an inherited form of severe combined immunodeficiency (SCID) characterized by skin redness, peeling of skin, hair loss, chronic diarrhea, enlarged lymph nodes, failure to thrive, increased white blood cells and immunoglobulin E (IgE ), and enlargement of the liver and spleen. Patients with omenn syndrome are highly susceptible to infection. In this condition, there is an elevated number of the immune cells known as T cells, but their function is impaired. Normally, the immune system protects your body against various harmful foreign bodies while restricting those responses to avoid harm. Active suppression of inflammation and immune responses by T cells is vital in maintaining this balance. T cells modulate the immune system to prevent autoimmune disease.
The standard treatment for Omenn syndrome is bone marrow transplantation to replace defective T cells. In addition to this, general care for any patient with SCID, including Omenn syndrome, includes isolation, meticulous hygienic practices and administration of broad-spectrum antibiotics to prevent further infection. Also, administration of intravenous nutrients and fluids is also done to treat diarrhea and weight loss. Without treatment, this medical condition is rapidly fatal in infants.
Therapeutic Role of IGF-1 in Omenn Syndrome
Enhancing immune reconstruction after a bone marrow transplant is necessary to improve survival rate in patients with Omenn syndrome. There is supporting evidence that IGF-1 helps improve T cell recovery in these patients. Kapoor and colleagues studied a clinical case of a 12-year-old Caucasian male who was diagnosed with Omenn syndrome at the age of 5 months. The subject has undergone bone marrow transplants but failed to show any recovery of T cells over next 20 months follow-up period. At age 5 years, the subject was referred to an endocrinologist for an evaluation of his short stature. The diagnosis of IGF-1 deficiency was made and Recombinant Human IGF-I (rhIGF-I) treatment was started. The researchers administered an initial dose of 0.04 mg/kg/dose twice daily via subcutaneous injections. The dose was later increased to 0.08 mg/kg twice daily via subcutaneous injections.
Of note, following rhIGF-1 treatment, the patient grew 7.6 cm and gained 3.4 kg during the first year of treatment. Moreover, his absolute CD3+ T cell significantly increased at 3, 6, and 15 months. Also, his CD45RA+ T cell count increased dramatically from a few to 135 cells/mm3 and continued to rise thereafter. Subsequently, he was healthy and gained weight and height. Interestingly, his T cell count continued to remain high and within the normal range and he has never been hospitalized again. These findings clearly suggest that rhIGF-1 treatment was able to enhance the immune function of the patient after bone marrow transplantation by increasing the T cells of the immune system.
In conclusion, the administration of IGF-1, in addition to promoting weight and height gain, can help stimulate and maintain the levels of T cell within the normal range after bone marrow transplant in patients diagnosed with Omenn syndrome. This case report supports the evidence that IGF-1 aids in the production of T cells, suggesting its potential role in enhancing the immune function. Such ability can be applied in combating a wide array of infectious and autoimmune diseases, which are hard to cure.
Higher IGF-1 Levels are Associated with Increased Delta Sleep in Healthy Older Men
Delta sleep or deep sleep is characterized by the presence of high-amplitude, low-frequency delta waves that are seen to occur in the electrocardiogram (EEG). Deep sleep is a time of nearly complete disengagement from the environment and it is very difficult for you to be awaken in this stage of sleep. Many important physiological processes occur during this stage. One of the most important processes that occur during deep sleep is the release of growth hormone (GH) which plays an important role in growth and development as well as other vital functions in the body, and interruption of this stage abruptly stops its release. In addition to this, other important benefits of deep sleep include:
Insulin-like Growth Factor 1 (IGF-1) Levels and Deep Sleep in Healthy Older Men
Sleep quality declines with age, with less time in deep sleep. Moreover, age-related declines also occur in lean body mass, GH and IGF-1. These changes in sleep quality and body parameters may be related as GH administration can enhance deep sleep and decrease awakenings in young men. However, the relationship between IGF-1 levels and deep sleep quality in older men has not yet been studied. Therefore, Prinz and colleagues studied the sleep EEG of 30 healthy elderly men for 2 consecutive nights. Blood samples were drawn within 3 weeks of EEG recording, and the levels of IGF-1 were measured. Interestingly, the researchers found out that higher levels of IGF-1 were associated with higher average delta energy. Although other measures of sleep quality were not correlated with IGF-1, this study clearly shows that higher levels of IGF-1 are associated with increased deep sleep in healthy older men, which may result in a wide array of beneficial effects. Furthermore, augmenting the levels of IGF-1 in patients with IGF-1 deficiency through hormone replacement therapy might help increase deep sleep and can be beneficial to these patients.
Beneficial Effect of IGF-1 in Depressive Disorder
Depression is a relatively common mental disorder which affects 15% of the population at least once in their lifetime. Depression is usually normal as a response to different life events such as death of a loved one, or other problems of daily living. However, if a person cannot move on with such problems, depression can become severe leading to sleeping difficulties, difficulty concentrating, short attention span, decreased energy levels, feelings of guilt, helplessness or worthlessness, loss of interest in activities, changes in appetite, and thoughts of suicides – all of these can impair one’s quality of life.
Over the years, many different directions have been explored to investigate the mechanisms of the onset of mental problems such as major depression. This condition has an unknown origin, but experts believe that it is related to genetic and environmental factors. Currently antidepressants are the mode of treatment for depression. However, clinical data show that patients with depression respond to this medication only after weeks or months of chronic treatment. The development of depression is complex, and apart from changes in the brain, dysregulation of the immune and endocrine systems also plays a pivotal role in the development of this mental disorder. Recent studies have indicated that impairment in synaptic plasticity (the ability of synapses to strengthen or weaken over time) in specific brain regions may be one of the causes of depression. On this basis, researchers came up with a theory linking the occurrence of depression with disturbances in insulin-like growth factor (IGF-1).
The Antidepressant-like Actions of IGF-1
To explore the antidepressant activity of IGF-1, many research groups administered IGF-1 to animal subjects. Different behavioral tests were used such as tail suspension and swimming test. Most of these data are very consistent and show that IGF-1 administration exerts antidepressant- like effect by normalization of behavioral disturbances in different animal models of depression. Furthermore, the antidepressant-like effects of IGF-1 were often linked with increase in cell production in specific brain regions.
There are various mechanisms in which IGF-1 exerts its antidepressant-like effect. One of which is may be related to the regulation of the levels of a brain chemical called serotonin. Hoshaw et al. found out that depletion of serotonin levels by an enzyme called tryptophan hydroxylase inhibitor p-chlorophenylalanine blocked the ability of IGF-1 to decrease immobility and increase swimming behavior in the forced swimming test in mice. In line with this finding, direct administration of IGF-1 in the brain was able to increase the levels of serotonin. Therefore, it may be concluded that IGF-1 exerts its antidepressant-like actions by increasing serotonin levels in the brain.
In human studies, Cassilhas et al. reported that 24 weeks of high resistance exercise was able to increase IGF-1 levels in patients with mood disorders, particularly anxiety and depression. Such increase was able to improve mood, anxiety, and concentration in these patients, indicating that augmentation of IGF-1 levels in patients with mood disorders can be beneficial.
In light of the wide variety of IGF-1 actions, including its role in the production, growth, and maturation of nerve cells in the brain, its modulation of behavioral disturbances, its ability to protect cells and prevent cell death, as well as its antidepressant and anti-inflammatory action, it may be a perfect subject for research aiming to further explore the role of growth factors in the brain and their potential therapeutic benefits in other mental disorders.
Growth Hormone and Memory
Numerous research support the beneficial effects of growth hormone (GH) replacement therapy on growth, body composition, bone and muscle development, cardiovascular risk factors and quality of life of GH-deficient human subjects. When properly administered and monitored, the effects of GH on all of these parameters are positive. However, the effects of GH replacement therapy on various aspects of learning and memory have received less attention but are clearly of the utmost importance.
What is Known Already and How can this be Applied to Humans?
One recent research paper by Nieves-Martinez and colleagues nicely addressed the effects of GH on memory of rats and has important implications for humans.  In this paper, rats, which are homozygous for the Dw-4 mutation (‘dwarf’) was used to mimic early onset or childhood GH deficiency (GHD). At 8 and 18 months, a water maze test is used to assess spatial learning ability of rats and it was shown that the early onset GH-deficient group had poor spatial learning compared to the other groups. The suggestion is made that GHD during adolescence has negative effects on learning and memory, and that this effect can be reversed in rats by GH supplementation.
In humans, there are clear deficiencies in cognitive functions in GHD patients. Impairment in the hippocampal/mesial temporal function has been shown in adulthood of patients with childhood onset GHD. In younger patients with GHD, GH replacement therapy has been shown to improve memory and attention. Such improvements depend on several factors such as the extent of cognitive impairment, the dose of GH administered and to some extent the age of onset of GHD.
In one study, Sathiavegeeswaran and colleagues have looked at the effects of GH on cognitive function in elderly patients with adult onset GHD.  They assessed cognition and mood using a battery of psychometric measures. After 6 months of GH replacement therapy, the patients showed improvements in cognition, but these differences between GH and the control group were in part due to a decline in performance in the placebo group, as well as improvement in the GH-treated group.
In younger patients with GHD, GH treatment has been linked with significant improvements in various tests assessing memory and attention. [3-4] There are also several factors associated with these improvements including the degree of cognitive dysfunction at baseline, dose of GH given, and the age at which GHD occurred.
Both animal and human studies support the beneficial effects of GH on memory. In rats, lower GH levels were associated with poor performance in the water maze test. In patients with GHD, this hormone can improve cognition especially memory, attention and mood when given for 6 months. However, these beneficial effects are evident depending on several factors such as the extent of cognitive impairment at baseline, dose of GH administered, and the age at which GHD started. These results suggest that GH administration may help treat cognitive dysfunction associated with GHD, while normal levels of this hormone may help prevent age-related cognitive decline and cognitive impairment related to brain disorders.
Safe, Effective Treatment Helps Restore Growth Hormone, Promotes Healthy Aging
Growth hormone (GH) is involved in a wide array of activities essential to health, including repair of damaged tissues, maintaining muscle mass, insulin sensitivity and burning fat, stimulating strong immune function, and supporting healthy blood vessels, blood pressure and cholesterol levels. Aging adults frequently report unpleasant symptoms related to GH decline including fatigue, mood changes, lethargy, decreased strength and exercise tolerance, and a decrease in the sense of well-being.
Over the last 15 years, a large body of clinical research has shown that Adult Growth Hormone Deficiency (AGHD) is quite common in the elderly, and that GH treatment to restore GH levels to mid-normal youthful ranges can successfully reverse symptoms of unhealthy aging, dramatically improving health and quality of life.
What are the Clinical Signs and Symptoms of AGHD?
An adult GH deficiency (AGHD) syndrome has been documented, consisting of increased abdominal fat, loss of muscle mass, decreased strength, bone mineral density (BMD) and exercise capacity, harmful changes in cholesterol levels, low energy, and poor quality of life.
GH Therapy Protects Brain Cells and Improves Cognition
A large body of clinical research has shown that GH therapy has the following benefits:
Interest in the use of GH to improve quality of life in the elderly has also increased due to several clinical research that support the protective effects of GH on brain cells, thereby improving cognition and memory in both gender. An evaluation of 460 U.S. male doctors (average age 57) participating in the Physicians’ Health Study II found that those with higher midlife levels of GH had significantly better late-life cognitive performance.
Similar results were found in a study involving 590 American women aged 60-68 years, and an Italian study of 353 elders 80 years or older, in whom lower than the normal level of GH were strongly linked with poor cognitive performance. In a placebo-controlled trial, healthy older (average age 68) adults who underwent daily growth hormone releasing hormone (GHRH) treatment for 6 months experienced significant improvements in cognition.
As we age, the number of blood vessels that supply the brain with oxygen and essential nutrients gradually decreases. This causes the cells responsible for repairing and maintaining these blood vessels (called endothelial progenitor cells) to malfunction. GH replacement therapy can help restore GH to youthful levels and reverse this process, thus improving blood flow to the brain and to other vital organs. GH’s renewing effects on the blood vessels is thought to be a key reason why GH replacement therapy enhances thinking abilities and memory.
Other recent studies also show that treatment with GH secretagogues (supplements that promote GH production) also causes improvement in the ability of brain cells to communicate with one another.
Could GH Therapy Increase Your Risk of Cancer or Diabetes?
Numerous studies have now shown that, when levels of GH are maintained in the low to normal range, no increase in cancer risk is seen. A recent meta-analysis that included 21 studies found no association between GH levels in the lower 3/4th of the normal range and any type of cancer. Extensive studies of two groups including childhood cancer survivors, and other children and adults treated with GH replacement have shown no evidence of an increase in cancer risk.
Although chronic elevation of GH has been found to produce insulin resistance (a condition in which the body produces insulin but does not use it effectively) in humans, which suggests daily dosing with GH should be avoided, less frequent dosing actually improves insulin sensitivity (describes how sensitive the body is to the effects of insulin) and is just as effective. It is well recognized that abdominal fat causes insulin resistance. Numerous clinical trials have demonstrated that GH therapy improves insulin sensitivity and lessens high blood sugar levels in patients suffering from not only severe insulin resistance, but type 1 and type 2 diabetes.
The Usefulness of Growth Hormone Treatment for Psychological Status in Young Adult Survivors of Childhood Leukaemia
In the last decades, the prognosis of childhood leukemia especially acute lymphoblastic leukaemia (ALL) has improved dramatically and long-term survival rates up to 80% have been reported. Along with this development, much research has been directed at determining the psychological effects of ALL treatment in children. Both intrathecal chemotherapy (ITC) and CNS radiation therapy (CRT) has negative effects on the brain. For instance, children with ALL who had received chemotherapy for 3 years manifested impairments on neurocognitive tasks. According to 33 reviewed studies on the long-term effects of CNS chemotherapy in ALL survivors, approximately two thirds document a decline in cognitive abilities. Thus, treatment for childhood ALL with chemotherapy may lead to brain abnormalities, such as decreased cerebral perfusion, slower resting electroencephalogram frequencies, white matter changes and enlargement of the ventricles and cortical sulci (a depression or groove in the cerebral cortex). From these studies, it may be concluded that cognitive impairment may be present in ALL patients especially children who have been treated with CRT or IT chemotherapy.
A number of pharmacological approaches to remediate these deficits have been proposed. One of which is the use of growth hormone (GH) treatment. In patients treated with CRT or IT chemotherapy, growth hormone deficiency (GHD) or impaired GH secretion are frequently found as late effects. Cognitive functioning and IQ appears subnormal in patients with GHD, as they frequently complain of difficulty in concentrating, memory problems, and lapses of attention. Moreover, their IQ score and educational level appear to be positively related to insulin-like growth factor I (IGF-I) concentration. IGF-1 concentration serves as a serum marker for GH status, suggesting that GHD is specifically related to impaired cognitive performance. The association between cognitive functions and GH may be explained by the presence of numerous binding sites of GH and IGF-I in the hippocampus, a brain structure that is important for learning and memory functions. Some studies suggest that GH therapy can have beneficial effects in GH deficient adults, in particular memory function and attention.
A study by Huisman and colleagues reported that GH therapy has positive effects on attention and visual-spatial memory in twenty young adult survivors of childhood ALL with reduced bone mineral density (BMD) and/or low IGF-1. A final group of 13 patients (9 males and 4 females) completed a 2-year treatment with GH. The IQ and neuropsychological performance of the patients were assessed at pre-treatment and after one and two years. These tests assess various parameters of cognitive function including neuropsychosocial function, intelligence, memory, attention, and executive function.
The result of the study showed normal cognitive tests scores in all of the subjects. Verbal short- and long-term memory performance increased between one to two years of GH therapy. Performance for sustained attention also improved. Visual-spatial memory was improved after one year of GH treatment. Also, IGF-I increases after one year of GH treatment and is associated with increase in cognitive-perceptual performance at month 12 and 24. The findings in this study suggest that GH treatment has positive effects on attention and visual-spatial memory.
The GH/IGF-1-Axis in Psychopathological Functions
Low levels of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) in humans may cause typical changes in brain function. On the other hand, alterations of brain function can affect GH and IGF-1 secretion. As aging advances, mood changes and anxiety may imply greater risk of mood disorders. Additionally, changes in the levels of GH and IGF-1 can lead to the prevalence of various psychiatric disorders and cognitive decline. It has been postulated that the pathologies of psychiatric disorders are complex, and apart from changes in brain chemicals, dysregulation or malfunction of the immune and endocrine systems also plays an important role in the progression of such disorders.
The GH/IGF-1 Axis and Psychopathology in Animal Models
Several studies investigating the function of the central nervous system have been focusing on IGF-1 instead of GH itself. In animal models, systemic administration of IGF-1 was found to enhance the activity of nerve cells, induce neuroplasticity (the brain’s capacity to change and adapt), and improve neurogenesis (growth and development of nervous tissues). Interestingly, the GH/IGF-1 system may have effects on the mood, not only by transient modifications but also by permanent changes in the environment of the brain. In one study, researchers found a positive correlation between trait anxiety and volume of the hippocampus (elongated ridges on the floor of each lateral ventricle of the brain). In line with these findings, researchers used mice models to determine the link between exercise, IGF-1, neurogenesis and anxiety-like behaviour. According to Trejo and colleagues, IGF-1-uptake to the brain is increased by strenuous activities in rat model. IGF-1 uptake is followed by an increase of brain-derived neurotrophic factor (promotes production of proteins essential for nerve cell survival) and the consecutive formation of new nerve cells in the brain. In addition to these findings, exercise was shown to induce anti-anxiety effects through the increased production of IGF-1 in the brain.
Psychopathological Function in Patients with GH Deficiency
GH stimulates the production of IGF-1. When GH is broken down in the liver, it is then converted to IGF-1. Most of the effects of GH are mediated through IGF-1. If a person has low levels of GH, he or she will most likely to have low levels of IGF-1 also, resulting to a wide array of medical conditions including psychiatric disorders.
In one study, Stabler and colleagues assessed the psychiatric status of 21 growth hormone deficient adults who had been treated with GH for short stature during childhood. The researchers found out that eight subjects have undiagnosed social phobia and that the scores of GHD subjects with social phobia corresponded closely to psychiatric patients with social phobia.
In another study, it has been found that patients with adult onset growth hormone deficiency have more difficulties in their job and reduced enjoyment from social occasions. Another study showed a high prevalence of depression in patients with adult onset growth hormone deficiency and that GH substitution in these patients resulted in less depressive symptoms.
Coronary Flow Reserve is Impaired in Patients with Adult Growth Hormone (GH) Deficiency
Relationship between adult growth hormone deficiency (AGHD) and an increased risk for cardiovascular disease is very well known in hypopituitary patients treated with conventional hormone replacement therapy other than growth hormone (GH) administration. Endothelial dysfunction, an early and reversible event in the development of atherosclerosis (characterized by the deposition of plaques of fatty material on arterial walls), is associated with increased vascular smooth muscle tone, arterial stiffening and intima-media thickness (IMT). Coronary flow reserve (CFR) measurement by transthoracic Doppler echocardiography (TTDE) reflects coronary microvascular and endothelial functions, as a cheaper and an easy screening test.
To evaluate endothelial function and coronary microvascular function in AGHD, Oflaz et al. used TTDE. A total of 10 GH-deficient adults on conventional replacement therapy other than GH (4 males, 6 females) and 15 healthy subjects (7 males, 8 females) were studied. All of the patients enrolled in the study were non-smokers, non-diabetic, and have normal blood pressure. Numerous parameters such as IGF-1, insulin, insulin resistance (IR), free T4, glucose, lipid profile, anthropometrical and physical parameters were recorded. CFR recordings and IMT measurements were performed using the Vivid 7 echocardiography device.
The results of the study showed that IMT were significantly higher in patients than controls and CFR was significantly lower in patients than in controls. CFR was positively correlated with IGF-1 levels and is significantly lower in adults with GH deficiency than in controls. Direct correlation between CFR and IGF-1 concentrations suggests GH replacement could improve blood vessel function and thereby could decrease the risk of heart disease and death in people with AGHD.
Impact of Growth Hormone (GH) Treatment on Cardiovascular Risk Factors in GH-Deficient Adults
Patients with hypopituitarism have an increased risk of death related to heart diseases. GH treatment could modify the cardiovascular risk in GH-deficient adults, but most published clinical trials involved few patients and the results are variable. In a systematic review of 37 blinded, randomized, placebo-controlled trials, a small but statistically significant beneficial effect of GH treatment on body composition (lean and fat body mass), LDL and total cholesterol, and diastolic blood pressure was seen in GH-deficient adults.
A major potential source of bias in systematic reviews is that trials with positive results are more likely to be published than trials with neutral or negative results. In a meta-analysis conducted by Maison et al., this bias seems unlikely with regard to blood pressure and total and LDL cholesterol (rare significant results) and blood glucose and insulin (negative results). Furthermore, the researchers gathered most GH trials that are published and selected only studies with protocols meeting strict methodological quality criteria.
Thirty-seven trials were identified. Maison et al combined the results for effects on lean and fat body mass, body mass index, triglyceride and cholesterol (high-density lipoprotein, low-density lipoprotein and total) levels, blood pressure, blood sugar, and insulin levels. GH treatment significantly reduced LDL cholesterol, total cholesterol, fat mass, and diastolic blood pressure, and significantly increased lean body mass, fasting plasma glucose and insulin. All effect sizes remained significant in trials with low doses and long-duration GH treatment.
In conclusion, this meta-analysis of blinded, placebo-controlled clinical trials shows that GH treatment has beneficial effects on several body parameters such as lean and fat body mass, cholesterol levels, and blood pressure but reduces insulin sensitivity in GH-deficient adults. GH may also have beneficial effects on other cardiovascular risk factors, such as fibrinogen, inflammatory parameters, heart function, and intima-media thickness (a measurement of the thickness of the inner walls of arteries). As expected, GH reduced insulin sensitivity, whatever the dose and duration of treatment. Overall, however, the global cardiovascular benefit of GH treatment in adults remains to be determined in large, long-term trials with appropriate clinical end points.
The GH/IGF-1 Axis and Heart Failure
The growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis plays a major role in regulation of heart growth, stimulation of heart contraction and influences the body’s network of blood vessels. The GH/IGF-1 axis controls intrinsic heart contractility by enhancing the availability of calcium within the cells and regulating expression of contractile proteins. It stimulates heart growth by increasing protein synthesis and enhances systemic vascular resistance by activating the nitric oxide system and regulating non-endothelial-dependent actions.
Several years ago, a clinical non-blinded study showed that recombinant GH plus standard therapy for heart failure in 7 patients for 3 months improved cardiac function and structure. More recent studies, including a small double-blind placebo-controlled study on GH effects on exercise tolerance and heart and lung performance, have shown that GH is beneficial in patients with congestive heart failure (CHF).
Growth hormone (GH) enhances the performance of the heart by increasing left ventricle mass and myocardial contractility, and decreasing wall stress and vascular resistance. The heart muscle and interior lining of blood vessels not only express receptors for both GH and IGF-1, but also produce IGF-1 locally. On vascular system, the GH/IGF-1 axis exerts its effects by activating the nitric oxide (NO) system which relaxes arterial smooth muscle cells, thereby reducing vascular tone. Furthermore, NO inhibits the production and migration of smooth muscle cells, decreases the activity of lipoxygenase (family of iron-containing enzymes) and oxidized LDL-cholesterol.Recently, NO has been shown to help cells maintain their shape and internal organization by altering the responsiveness of calcium myofilament (chain of protein molecules).In addition, IGF-1 induces vasodilation (relaxation of blood vessels) both by enhancing Na+/K+ ATPase activityand regulating gene expression of KATP channel in vascular smooth cells.
GH and Heart Failure
Patients with CHF have reduced heart contractility, decreased cardiac output, dilated left ventricle cavity, increased peripheral vascular resistance and enhanced wall stress. GH replacement may be beneficial in all steps of heart failure through the following:
Clinical Studies in Humans with Heart Failure
Several research groups have studied the effects of GH and IGF-1 in patients with heart failure. The first results were limited to case reports showing that the administration of GH considerably improved heart function. In 1996, the earliest open clinical trial in CHF was reported by Fazio and co-workers. They treated seven patients with idiopathic dilated cardiomyopathy, with moderate to severe heart failure, without GHD. After 3 months of recombinant human GH (rhGH) therapy, they found improvement in cardiac performance, exercise tolerance, hemodynamic profile and myocardial energetic metabolism. These encouraging preliminary findings prompted several larger and controlled clinical trials.
In one clinical trial, rhGH significantly increased exercise capacity and decreased left ventricle end-systolic and end-diastolic volumes in patients with post-ischemic CHF. The patients also had a 15% increase in posterior wall thickness and 16% increase in cardiac output. The administration of rhGH did not affect heart structure but greatly improved exercise performance and quality of life in ten post-ischemic CHF patients.
More recently, Adamopoulos and colleagues investigated the role of rhGH administration in the immune function of CHF patients. They found out that a three-month course of GH normalizes circulating levels of proinflammatory cytokines, which produce fever, inflammation, and tissue destruction.They subsequently reported that GH reduces molecules which generate free radicals and enhances cytokine production, and the macrophage chemoattractant protein-1 (MCP-1), which promotes the migration of mononuclear phagocytes (a type of cell within the body capable of engulfing and absorbing bacteria and other small cells and particles) into the injured myocardial tissue and endothelial cells.They also showed that GH induced a decrease in end systolic wall stress and an increase in contractile reserve.
In an attempt to gain further understanding into the mechanisms by which GH may benefit patients with CHF, Fazio and colleagues have recently conducted a double-blind, placebo-controlled study of the effects of GH on exercise capacity and cardiopulmonary performance in twenty-two patients with moderate heart failure. After three months of treatment, the GH group showed improvement in exercise capacity, cardiopulmonary performance, and ventilatory efficiency, with a significant increase of VO2max and of chronotropic index. Moreover, at transthoracic echocardiography (a still or moving image of the internal parts of the heart using ultrasound), the GH group had an increase in left ventricular mass index, relative wall thickness and cardiac performance.
Although experimental models and preliminary human studies have demonstrated that the administration of GH may have beneficial cardiovascular effects in patients with CHF, more experimental and clinical studies are necessary to clarify the mechanisms that determine the variable sensitivity to GH and its positive effects in the failing heart.
Metabolic Profile in Growth Hormone-Deficient (GHD) Adults after Long-Term Recombinant Human Growth Hormone (rhGH) Therapy
The metabolic effects of recombinant human GH (rhGH) therapy in adults are well-documented in the short term. However, its long-term effects (beyond 5 years) on metabolic parameters are presently unknown. Since the 1990s, rhGH replacement therapy has been a regular treatment option for adults with growth hormone deficiency (GHD). Adult GHD is hypothesized to be a cardiovascular risk factor associated with increased deaths by inducing abdominal obesity, elevated cholesterol and triglyceride levels. In short-term studies, GH therapy in GH-deficient adults reduces some, but not all of these cardiovascular risk factors. Consistent “short-term” effects on body composition and lipid metabolism were documented, resulting in reduction of fat, total cholesterol and low-density lipoprotein cholesterol levels (bad cholesterol). In addition, favorable effects on bone mineral density (BMD) and quality of life have been reported.
A recent review addressing the effects of rhGH replacement in elderly patients (60 years and above) with GHD revealed that rhGH replacement decreases low-density lipoprotein cholesterol levels and improves quality of life, but the effects on other parameters were not unequivocal. However, sufficient data concerning the use of long-term rhGH therapy in elderly subjects are currently unavailable, as is the case in younger patients. To evaluate the long-term effects of rhGH treatment on biochemical and anthropometric parameters, Claessen et al. conducted a large cohort study of 99 GH-deficient adults treated with rhGH for at least 10 years. In this study, several parameters such as total cholesterol, high-density lipoprotein cholesterol (good cholesterol), low-density lipoprotein cholesterol, triglycerides, anthropometric parameters, IGF-I, and glucose were evaluated at baseline and after 5, 10, and 15 yr of treatment. In addition, the prevalence of the metabolic syndrome (MS) and the incidence of cardiovascular events were assessed.
Results of the study showed that fasting blood sugar levels increased by 6% at 5 year, thereafter remaining stable after 10 years of rhGH treatment. In addition, no significant changes were observed in triglycerides, waist-hip ratio, and systolic blood pressure. However, there is a reduction in diastolic blood pressure after 5 and 10 years of treatment. In the GH-deficient group who received rhGH treatment for 5 years, a decrease in total cholesterol and low-density lipoprotein and an increase in high-density lipoprotein (good cholesterol) were observed, improving further after 10 years of rhGH treatment. Among the subgroup of patients who completed the 15 years of rhGH treatment, notable beneficial effects were observed on fasting blood sugar and waist circumference. There were also a 20% decrease in total cholesterol and 32% decrease in low-density lipoprotein cholesterol, which are considered significant findings.
The present study showed beneficial effects of rhGH therapy in GH-deficient adults on lipids and body composition, whereas other cardiovascular risk factors continued to deteriorate after long-term rhGH treatment. These results indicate that long-term rhGH treatment may benefit overall cardiovascular risk, which can significantly lower mortality rate of GH-deficient individuals.
Recombinant Human GH Replacement Increases CD34+ Cells and Improves Endothelial Function in Adults with GH Deficiency
Growth hormone deficiency (GHD) is associated with an increased prevalence of cardiovascular risk factors, such as hypertension, obesity, elevated cholesterol, triglycerides and low density lipoprotein (LDL), a decrease in lean body mass, and an increase in insulin resistance. In addition, abnormalities in vascular function and structure have been described in patients with GHD. Recombinant human GH (rhGH) replacement in GHD is aimed at reversing these abnormalities.
For a decade, bone marrow-derived endothelial progenitor cells (biological cells that, like a stem cell, have a tendency to differentiate into a specific type of cell) have been proposed to play a major role in the repair and maintenance of the vascular system. Van der klaauw et al. have shown that the number of these cells is reduced in patients with type 1 diabetes, with other cardiovascular risk factors, and with established cardiovascular disease.
CD34+ cells are a bone marrow-derived biomarker for cardiovascular risk, but there is no information on the effects of rhGH replacement on these cells in adults with GHD. Therefore, Van der klaauw et al. studied the effects of rhGH replacement on the number of circulating CD34+ cells and vascular function and structure in GH-deficient adults. Fourteen patients with GHD were enrolled in this prospective open-label intervention study. They were treated with rhGH given subcutaneously every evening for 12 months. The initial dose of 0.2 mg/day rhGH was individually adjusted monthly in the first half year to achieve physiological serum insulin-like growth factor-I (IGF-I) concentrations, within the age-dependent laboratory reference range. The patients were studied at baseline, and 6 and 12 months after GH replacement. During the study, the researchers did not administer any anti-hypertensive or lipid-lowering drugs.
Effects of 1 Year rhGH Replacement
Within 6 months of rhGH replacement, IGF-I and IGFBP-3 concentrations increased and remained unchanged between 6 months and 1-year. Total, LDL, and HDL cholesterol remained unchanged as well as fasting glucose and triglycerides during 1 year of rhGH replacement. The novel finding in this study is the beneficial effect of rhGH treatment on the number of circulating CD34+ cells and on endothelial function, which was manifested within 6 months after the start of treatment and maintained 6 months thereafter. Since these outcome parameters are strong biomarkers for cardiovascular disease risk, these data indicate that GH replacement in GH-deficient adults may have beneficial effects on the vascular system.
Endothelial function was also measured in this study before and during rhGH replacement by assessing flow-mediated vasodilatation (assesses the relaxation of an artery). There was a decrease in flow-mediated vasodilatation observed at baseline. After 6 months of rhGH replacement, flow-mediated vasodilatation improved. These data are in agreement with earlier studies assessing the beneficial effects of rhGH replacement on endothelial function. In addition, these findings demonstrate that rhGH replacement improves vascular function through IGF-I-mediated stimulation of nitric oxide synthesis in the cells of the blood vessels. This is a significant finding since an increase in nitric oxide production causes the blood vessels to widen, thereby boosting blood circulation.
Advances in Recombinant Human Growth Hormone Replacement Therapy in Adults
Acquired growth hormone (GH) deficiency is caused by an abnormal or damaged pituitary gland and/or hypothalamus, usually from a tumor or secondary to surgical and/or radiation therapy. Although the diagnostic criteria and clinical sequelae GH deficiency are well established in children, there still unclear areas for investigation in adults. It is now apparent that acquired GH deficiency is related to significant changes in body composition, bone density, lipid metabolism, heart function and physical performance. Today, new information are available regarding the use of low doses of recombinant human growth hormone (rhGH) to reverse the symptoms of GH deficiency in adults.
What is Growth Hormone Deficiency Syndrome?
Acquired GH deficiency is characterized by increased fat mass, decreased lean body mass and weight gain. In one recent study, GH deficient patients displayed an increase in total body fat (about 7%) while lean body mass was decreased to a similar degree. The increased fat mass is displayed by an increase in the waist:hip ratio. In addition, the levels of triglycerides are increased while HDL levels (good cholesterol) are decreased. The increased lipid levels may explain the increase in blood vessel wall thickness, as measured by a medical procedure called carotid ultrasonography. These factors all likely contribute to the increased incidence of cardiovascular mortality seen in patients with GH deficiency.
GH-deficient patients display a decrease in muscle mass and strength. In the heart, these changes are manifested by a reduced left ventricular mass, decreased fractional shortening of cardiac muscle cells, and decreased cardiac output – all of these abnormalities contribute to decrease exercise capacity and physical activity. In one recent study, exercise capacity, as assessed by cycle ergometry (a stationary bicycle with an ergometer to measure the work done by the exerciser) was decreased by 20-25% compared to normal controls. Aside from exercise capacity, bone density is also known to be decreased in GH-deficient patients. In a recent study, cortical or compact bone density and spinal bone density were 2.8 and 1.5 standard deviations below the mean for age and sex matched controls.
Finally, GH-deficient patients appear to have psychological and neuropsychiatric impairments, such as lack of concentration, memory problems, reduced vitality, fatigue, depression and social isolation. However, it is unknown whether these impairments are associated specifically with GH deficiency or is due to another factor associated with hypopituitarism.
Recombinant Human Growth Hormone Therapy
Today, this therapy is considered as a therapeutic option for adults with acquired GH deficiency. Recent studies show that most of the metabolic and psychological abnormalities associated with GH deficiency can be reversed with low doses of GH replacement and with lesser side effects.
GH-deficient patients who received GH therapy at the relatively low dose of 0.003 mg/kg over 6 months showed significant reduction in fat mass and an increase in lean body mass. The improvement in lean body mass is associated with increased muscle mass, muscle function and protein synthesis. Fat mass reduction is most significant in visceral and trunk locations as compared to the arms, neck and legs.
In a recent study, short courses of GH replacement in adults reduced low density lipoprotein (LDL) cholesterol and this reduction correlated with increased mRNA expression of the LDL receptor in the liver.
GH is known to stimulate the reproduction of osteoblasts (cells that make bone). Furthermore, GH stimulates systemic and local production of Insulin Like Growth Factor I (IGF-1), a hormone that stimulates bone formation. In a recent study, GH replacement was shown to significantly increase bone Gla-protein, a sensitive indicator of osteoblast function. In another study, GH replacement over 12 months showed significant increases of 5% and 4% in spinal and cortical bone density.
Several recent studies in GH-deficient patients receiving GH therapy showed improvements in exercise capacity and cardiac function as evidenced by increased oxygen uptake and power output during cycle ergometry. Echocardiography has shown improvements in left ventricular mass index, fractional shortening and fiber shortening velocity after 6 months of low dose GH therapy.
Evidence from several studies indicates that GH therapy is beneficial in improving body composition, bone density, lipid metabolism, heart function and psychological well-being. Important issues remaining are the precise diagnosis between partial and complete GH deficiency. In addition, it is unclear whether some of the observed beneficial effects in several studies reflect pharmacological GH therapy rather than physiologic GH replacement. Nevertheless, it is clear that low doses of GH may suffice to achieve therapeutic results.
HGH – Anti-aging Breakthrough or Hype?
Recent advances in technology suggest that the legendary “Fountain of Youth” may be on the verge of being discovered in laboratories around the world. In spite of much hype claiming otherwise, the normal process of aging is inevitable and cannot be completely stooped or reversed. However, scientists around the world are showing certain aspects of aging can be slowed to improve one’s overall health.
The aging process is now known to be influenced by several factors, the two most well-studied being:
Recent research shows that oxidative breakdown can be slowed by taking nutritional supplements packed with antioxidants, minerals and phytonutirents. Likewise, hormone replacement therapy can slow, and in some cases even reverse the signs of aging. Of all the hormones that decline with age, Human Growth Hormone (HGH) is the one most commonly associated with premature aging. The anti-aging industry is becoming more and more convinced that supplementing vitamins, minerals, and phytonutrients along with hormone replacement therapy is the most effective way of slowing the process of aging.
Increased Resistance to Sports and Other Physically Related Injuries
As levels of HGH increase, your bone and ligament strength also increases. HGH regenerates different processes involved in building healthy tendons and ligaments, as well as increasing bone density. This can help you avoid common sports and exercise related injuries due to a weakness in any of these joint and bone related components.
Increases Immune System Function
Studies by Keith Kelley, M.D. and others, have shown that HGH replacement therapy can enhance immune system functions by:
HGH Reduces Fat Accumulation and Builds Lean Muscle Mass
In a placebo controlled study at Thomas Hospital in London involving 24 HGH-deficient adults, the hormone treated group lost 12.5 pounds of fat and gained an average of 12.1 pounds of lean body mass. In another study, Rudman and colleagues reported that HGH supplementation for 6 months among elderly men between age 60 and 81 resulted in 8.8% gain in lean body mass and 14.4% reduction in fat mass. The results of the study also showed an increase in the bone density of the lumbar spine by 1.6% and the liver and spleen grew by 19% and 17% respectively.
In a double blind, placebo controlled crossover study, overweight women receiving HGH therapy lost more than 4.6 pounds of body fat, most of this in the abdomen. In two double blind, placebo controlled studies by Dr. David Clemmons, HGH therapy combined with proper diet caused a 25% acceleration in the rate of fat loss. The HGH treated subjects lost 30 to 32 pounds, compared with 20 to 25 pounds in the controls.
Increases Bone Density
In a Swedish study involving severely GH-deficient patients, HGH treatment for two years caused significant increases in bone density of the hip joint and the vertebrae of the lower spine. Increases in calcium, osteocalcin (noncollagenous protein found in bone), and two types of collagen, were also noted in the study. Another study showed that HGH treatment helps build bone density and significantly reduces the risk of fractures in pre- and post-menopausal women, as well as GH-deficient patients.
Lowers Blood Pressure
HGH replacement therapy does improve heart and lung function, two benefits that can help lower blood pressure. In one study, HGH replacement therapy in HGH deficient adults reduced diastolic blood pressure by about 10%. Another way HGH replacement therapy helps reduce blood pressure is by enhancing one’s exercise capacity which will yield weight loss and overall fitness.
Improves Libido and Sexual Performance
Low levels of HGH are associated with decreased libido. HGH levels and sexual potency peak during puberty, and starts to decline with old age. 75% of men with HGH deficiency usually have difficulty in having or sustaining erections. A clinical study of 302 elderly patients showed that HGH replacement therapy was able to improve sexual potency and frequency in 75% of the men. Interviews with HGH users for anti-aging therapy indicate that almost everyone had improvement in libido and sexual function.
Improves Cardiac Function and Cholesterol Profiles
HGH replacement therapy also reversed heart failure in several studies. In a 1996 New England Journal of Medicine Article, seven patients treated with HGH (five men and two women) who had moderate-to-severe heart failure, showed an increase in heart contractility and blood supply, reduced the oxygen requirement of the heart, and improved exercise capacity.
HGH replacement therapy improves heart function and protects against several heart diseases in different ways. In studies of HGH deficient adults, HGH replacement therapy was able to significantly improve blood cholesterol profiles, raising high density lipoproteins (HDL) or “good cholesterol” and lowering low density lipoproteins (LDL) or “bad cholesterol”.
Reverses Skin Changes Related to Aging and Promotes Thicker Hair
In the world renowned study by Dr. Daniel Rudman, HGH replacement therapy was able to increase skin thickness (7.1% on average) in elderly men. A further self-evaluation of 202 people on HGH supplementation for 6 months showed improvement in skin texture, thickness and elasticity. Of this same group, 61% observed fewer wrinkles and 38% reported new hair growth within a few weeks of treatment.
Improves Mood and Sleep Patterns
In 1996, a team of Swedish scientists discovered the link between HGH and its antidepressant effect. They found out that it acts on the brain and raises the level of the brain chemical B-endorphin, which has been called the brain’s opiate. HGH also reduces dopamine, which is associated with feelings of agitation.
A 1998 report showed that depressed men have a marked decrease in the production of HGH during the first three hours of sleep as opposed to non-depressed controls. Three different studies in Sweden, Denmark, and England reported that HGH replacement therapy in depressed patients showed significant positive effects. Finally, a recent clinical study by Theirry Hertoghe, M. D. showed that HGH therapy decreased depression by 82% and anxiety and low self-esteem by over 70%.
May Be Helpful In Treating Crohn’s Disease
According to a study by Alfred E. Slonim, HGH may be a beneficial treatment for patients with chronically active Crohn’s Disease. In his study, 74% of those patients improved their scores and all those who were on prednisolone were able to discontinue it or reduce the dosage.
Muscle Strength in Elderly Adults with GH deficiency after 10 years of GH replacement
GH secretion declines in an age-dependent manner. Although elderly adults with GH deficiency (GHD) have significantly lower GH secretion than normal elderly subjects, both normal aging and GHD are associated with decreased muscle mass and strength. Because GH plays an important role in maintaining body composition, the progressive decline in GH levels may lead to the development of age-related impairments in muscle mass and function known as sarcopenia. In normal elderly subjects, sarcopenia is followed by adverse consequences such as disability and loss of independent way of living.
The results of several studies suggest that the reduced muscle strength in young GH-deficient adults can be reversed by GH replacement. However, absolute values of muscle strength returned towards baseline values between 5 and 10 years of GH replacement in GH-deficient adults of various ages in one study. Götherström et al. demonstrated that GHD adults above 60 years of age had decreased age- and sex-adjusted muscle strength. The 5 years of GH replacement therapy normalized age- and sex-adjusted values of knee flexor strength in the elderly GH-deficient patients.
To date, the long-term effects of GH replacement (more than 5 years) on muscle strength in elderly GH-deficient adults are unknown. Götherström et al. conducted a prospective, open-labeled, single-center study in 24 adults (13 women) with GHD above 60 years old with adult onset pituitary disease in order to evaluate the effect of 10-year GH replacement on muscle strength. In addition, superimposed single-twitch electrical stimulations were performed in GH-deficient subjects to estimate neuromuscular function and motor unit activation.
Ten years of GH replacement therapy in elderly GH-deficient adults resulted in a transient increase in isometric flexor strength and provided protection from most of the normal age-related decline in muscle performance and neuromuscular function. The researchers concluded that a possible mechanism underlying this protective effect of GH against age-related changes in the muscles is that GH replacement appeared to counteract the age-related reduction in voluntary motor unit activation. In both genders, after correction of the age-related decline in muscle strength, the GH replacement normalized knee flexor and extensor strength, and almost normalized handgrip strength.
Neuromuscular Dysfunction in Adult Growth Hormone Deficiency
Skeletal muscle comprises about 40% of your body. An adequate muscle mass is an integral part of health as it is involved in locomotion, breathing, regulation of body temperature, protection of vital organs, and control of blood sugar and fat metabolism. Therefore, healthy muscles are strongly associated with better physical activity and exercise performance.
Evidence suggests that growth hormone (GH) plays a key role in the regulation of muscle growth and function, making it an essential hormone with regards to maintenance of muscle health. In fact, GH use has been linked with improved physical capacity in patients without GH deficiency by boosting the production of collagen in the tendon and skeletal muscle. This in turn leads to better exercise training and increased muscle mass and strength.
Adult growth hormone deficiency (AGHD) is associated with fatigue, tiredness and muscle pain, which improves after initiating recombinant human GH (rhGH) therapy. In an attempt to explain the neuromuscular symptoms associated with adult-onset growth hormone deficiency (AGHD), Webb et al. conducted an extensive neuromuscular investigation of patients with AGHD.
Twenty adult patients (11 males) with untreated GHD of whom 10 were childhood-onset underwent a prospective neurological protocol, including physical examination and a neurophysiological study that comprised sensory and motor neurography (direct imaging of nerves in the body), repetitive stimulation, electromyogram (use to assess the health of muscles and nerve cells) and interference pattern analysis (IPA). In the first seven patients (four with childhood-onset GHD), the researchers performed biceps muscle biopsy, Western blot, and investigation of STAT-5a and -5b which are mediators of cellular immunity, reproduction, cell death and differentiation. Neuromuscular examination, sensory and motor neurography and repetitive stimulation were normal in 20/20 patients. Fourteen (seven child-onset and seven adult-onset) of the 20 patients had abnormal electromyogram and/or IPA suggestive of a neuromuscular dysfunction. In those seven patients with initially abnormal results, who also remained on regular rhGH for at least 1 year, repeated IPA was normal in six and improved in the remaining patient. The biceps muscle biopsy disclosed abnormal groupings in the seven cases tested, indicative of a neuromuscular abnormality. A marked increase in both STAT-5a and -5b (proteins that are essential in muscle growth) was observed in all seven patients.
The researchers concluded that the skeletal muscle of patients with both adult-onset and childhood-onset adult GH deficiency shows a neuromuscular dysfunction, as evidenced by abnormalities in the muscle biopsy and the neurophysiological study, which in the subgroup of treated patients responds positively to rhGH therapy. The results obtained suggest that the STAT-5 signal transduction pathway in muscle is abnormal in adult GH deficiency.
In conclusion, both adult-onset and childhood-onset adult GH deficiency can lead to neuromuscular dysfunction. In this group of patients, rhGH therapy can significantly improve the results of muscle biopsy and the neurophysiological study, suggesting that GH can help reverse neuromuscular dysfunction in patients with GH deficiency. This also suggests that GH can be of potential therapeutic option in patients suffering from various muscle abnormalities.
Bone Loss Is Correlated to the Severity of Growth Hormone Deficiency in Adult Patients with Hypopituitarism
Reduced bone mineral density (BMD) has been reported in patients with isolated GH deficiency (GHD) or with multiple pituitary hormone deficiencies (MPHD). To investigate whether the severity of GHD was correlated with the degree of bone mass and turnover impairment, Colao et al evaluated BMD at the lumbar spine and femoral neck, circulating levels of insulin-like growth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3), and osteocalcin levels, and urinary cross-linked N-telopeptides of type I collagen (Ntx) levels in 101 adult hypopituitary patients and 35 sex- and age-matched healthy subjects.
On the basis of the GH response to arginine plus GHRH (ARG+GHRH), patients were subdivided into 4 groups:
The results of study were as follows:
In conclusion, a significant BMD reduction associated with abnormalities of bone turnover parameters was found only in patients with very severe or severe GHD, whereas normal BMD values were found in non-GHD hypopituitary patients. These abnormalities were consistently present in all patients with GHD regardless of the presence of additional hormone deficits, suggesting that GHD plays a central role in the development of osteopenia in hypopituitary patients.
Effect of GH/IGF-1 on Bone Metabolism and Osteoporosis
Growth hormone (GH) and insulin-like growth factor (IGF-1) are fundamental in the growth of the skeleton during puberty and bone health throughout life. GH increases tissue formation by acting directly and indirectly on target cells; IGF-1 is a critical mediator of bone growth. GH deficiency in childhood decreases bone mineral density (BMD), while GH treatment increases bone growth and strength.
A positive correlation between IGF-1 level in the blood and BMD has been documented in women but not in men.Low levels of IGF-1 in women are reported to be associated with higher prevalence of fractures.
Recently, Ohlsson et al. demonstrated that low levels of IGF-1 were associated with an increased risk of fractures of about 40% and that the levels of IGF-1 in the blood could be clinically useful for assessing the risk of vertebral fractures. Osteoporosis in postmenopausal women is caused by a deficiency in the hormone estrogen and a high rate of bone remodeling with bone resorption exceeding bone formation. The estrogen deficiency is critical to the pathogenesis of osteoporosis in both men and women and the frequency of the secretion of GH is reduced in the amplitude with sex hormone reduction. It has been documented extensively that estrogen is one of the factors that regulates the expression of IGF-1 in maintaining healthy bones. IGF-1 plays a major role in cell growth, differentiation, survival, and cell cycle progression and is necessary for proper acquisition of peak bone mass. Furthermore, GH protects against bone loss induced by the removal of the ovaries.
The Effect of GH/IGF-1 on Bone
In vitro studies using cultured chondrocytes (cells that have secreted the matrix of cartilage and become embedded in it) have shown that GH stimulated the formation of colony of young precondrocytes directly while IGF-1 stimulated cells at later stage of maturation.  GH and IGF-1 stimulate the preadipocytes (precursor to fat cells) at different stages of development and they have a direct action on osteoblasts (cells that make bone).
Effect of GH Administration on Osteoporosis and Bone Metabolism
GH administration has been evaluated in various clinical trials in normal subjects and in women with osteoporosis and postmenopausal women. Studies have reported large age variance (from 22 to 81 years) and in the administered dose of GH (from 0.015 mg/kg/day to 0.75 mg/kg/day) in addition to the duration of the therapy ranging from 3 days to 3 years. In a large part of the studies, there was a significant increase in bone formation, bone mineral content (BMC), bone mineral density (BMD). In 1975, Kruse and Kuhlencordt reported that patients with primary and secondary osteoporosis treated with GH displayed an increase in periosteal new bone formation and an intracortical bone resorption with a significantly increased relative osteoblast activity. The effect of GH therapy has been evaluated in healthy subjects, in postmenopausal osteoporosis, and in men with idiopatic osteoporosis. In the most studies, a significant increase in bone resorption, bone formation and BMD were observed. In the longest double blind, randomized placebo-controlled trial, Landin-Wilhelmsen reported that GH treatment for 3 years increased bone mineral content by 14% in postmenopausal women with osteoporosis. GH administration at low doses was able to restore normal parathyroid hormone (PTH) secretory patterns in osteoporotic postmenopausal women, improves target organ sensitivity to PTH, and results in a net positive balance in bone mineral metabolism, all leading to an increase in BMD.
Effect of IGF-1 Administration on Osteoporosis and Bone Metabolism
Recombinant human IGF-1 (rhIGF-1) has been used for many years for the treatment of osteoporosis. Significant bone resorption and formation has been demonstrated in most studies and no significant side effects have been reported. An increase in circulating IGF-1, IGFBP-2 and IGFBP-3, and PINP (a bone formation marker) has also been reported. Previous studies have shown that IGF-1 treatment at low doses increased blood markers for bone formation without increased for resorption markers in osteoporosis of postmenopausal women and a dose response effect was described. Long-term studies demonstrated similar positive effects and a good safety record with low dosage rhIGF-1. In another study, Grinspoon et al. reported that rhIGF-1 administration selectively stimulated bone formation in osteopenic girls with anorexia nervosa.
Effect of GH/IGF-1 on Fracture Healing
In a fractured bone, the healing process is initiated by the formation of a thick periosteal callus (a membrane that covers the outer surface of all bones) of woven bone with a central area of cartilage. Endochondral ossification (bone tissue formation) of the cartilage occurs subsequently in the woven bone. Later a marked remodeling process is activated and the callus volume declines while the density is enhanced.
Many experimental and clinical studies have found that growth factors, such as morphogenetic proteins (MPs), the fibroblastic-like growth factors family (FGFs), transforming growth factors (TGFs), and plateled-derived growth factors (PDGF), stimulate bone formation during fracture healing. Evidence suggests that these hormones can also play a role in bone healing in patients who have sustained head injury with a more intensive callus formation than those without head injury. Various studies have investigated the effect of GH therapy in hip fracture all reporting a positive effect on bone healing and functional outcome. Only one study reported the effect of IGF-1 on bone healing. In this study, the researchers use a protein complex rhIGF-I/IGFBP-3 in the treatment of 20 women affected by hip fractures. The results of the study showed that a dose of 1 mg/kg/day stimulates bone metabolism in frail osteoporotic patients and the muscular efficiency increased. Also, placebo-treated subjects had an average bone mineral loss at the contralateral hip of about 6% during the first 6 months after the injury. The level of IGF-1 in the blood is significantly associated with the ability to function after hip fracture in women. GH therapy is also helpful in the prevention of risk of fracture in GH deficient subjects.
GH and IGF-1 have a great effect on bone resorption and bone anabolism and their administration has a positive effect on osteoporosis and fracture healing. The effect of GH and IGF-1 therapy on bone osteoporosis and fracture healing is mediated by several factors such as sex hormone levels, diet, inflammatory cytokines, and muscle mass and strength. More carefully designed, double-blind, and placebo-controlled randomized trials with large numbers of participants regarding GH plus sex hormone treatment of osteoporosis and bone healing after fractures are required.
Growth Hormone, Insulin-like Growth Factors, and the Skeleton
GH and IGF-I are important regulators of bone homeostasis throughout life. Before the period of puberty, GH and IGF-I are determinants of longitudinal bone growth, skeletal maturation, and acquisition of bone mass, whereas in adults they are important in the maintenance of bone mass. During embryonic development, IGF-I and IGF-II are key determinants of growth, acting independently of GH. After birth and throughout puberty, GH and IGF-I play a critical role in determining longitudinal skeletal growth, and children with GH deficiency (GHD) display short stature. In addition to the effects on longitudinal growth, GH and IGF-I have the potential to regulate bone modeling and remodeling. Bone remodeling is necessary to maintain the balance of calcium in the body and to remove potentially damaged bone. This process occurs mostly during growth. In contrast to bone remodeling, bone modeling is a process of uncoupled bone formation and bone breakdown.
Adult Growth Hormone Deficiency (AGHD)
AGHD is a recognized and treatable clinical entity. Severe GHD in adults is associated with adverse changes in body composition, insulin sensitivity, lipid metabolism, and exercise capacity. Adult patients with GHD suffer from low bone turnover osteoporosis leading to increased risk of fractures, which may contribute to increased risk of death observed in GHD.
Bone Turnover and Calcium Metabolism in Untreated GHD
Patients with GHD have a marked reduction in bone turnover (total volume of bone that is both resorbed and formed over a period of time). Bone biopsies from male adult patients with GHD reveal decreased bone minerals and bone formation rate. Serum levels of osteocalcin (special protein that plays a role in bone mineralization and calcium balance) and bone resorption markers are decreased, confirming the state of low bone turnover. GHD also is associated with abnormalities in the circadian rhythm of parathyroid hormone (PTH), which may affect bone remodeling.
Bone Mineral Density (BMD) and Fractures in Untreated GHD
Decreased BMD is reported in patients with GHD, either isolated or combined with other pituitary hormone deficiencies. Patients with GHD exhibit greater losses of cortical than trabecular bone. The degree of bone loss is related to the duration and age of onset of GHD, the severity of the disease, and the age of the patient. Patients with childhood-onset GHD are smaller and have a more pronounced decrease in muscle and bone mass and lower IGF-I and IGFBP-3 serum concentrations than patients with adult-onset GHD. The reason for the different degrees of bone loss may be because childhood-onset GHD occurs before the achievement of peak bone mass, and because the duration of the disease is longer. Patients with severe GHD or very severe GHD display significant reductions in BMD.
Skeletal Effects of Recombinant Human GH (rhGH) in Adult-onset GHD
rhGH replacement therapy leads to an increase in bone turnover, as determined by changes in biochemical markers of bone resorption and bone formation. rhGH causes a maximal effect on bone resorption after 3 months and on bone formation after 6 months. The effect of rhGH on bone formation is sustained for prolonged periods of time and is usually dose dependent, but not influenced by the route of administration. rhGH causes an increase in serum and urinary calcium after 3 to 6 months.
The effect of rhGH on BMD in adult-onset GHD is variable and depends on the duration of the treatment. It is well-documented that when bone formation is increased, bone mass increases, but an increase in BMD can be documented only after 6 to 12 months in children and after 18 to 24 months in adults receiving rhGH therapy. The increase in BMD is observed for periods of up to 10 years in patients receiving continuous rhGH therapy. Moreover, BMD may even continue to increase 18 months after rhGH discontinuation. rhGH increases bone mineral content to a greater extent than BMD because rhGH also increases bone area. This is supported by findings demonstrating an increase in periosteal bone formation during rhGH treatment.
Predictors of rhGH Response in Bone
Male and female patients with GHD may display different responses to rhGH in terms of changes in bone turnover and BMD. In men, bone formation and resorption are increased within 1 month of rhGH treatment, whereas in women the increase occurs after 3 months. The increase in markers of bone resorption precedes the change in bone formation markers by about 9 months.
In adult-onset GHD, bone formation increases after 6 months of treatment, with little change thereafter, whereas in childhood-onset GHD, there is a progressive increase in bone formation for up to 12 months after rhGH followed by a return to baseline values after 18 months of therapy. Patients with childhood-onset GHD generally display an increase in BMD after 6 to 12 months of rhGH therapy, whereas patients with adult-onset GHD require 18 to 24 months of rhGH to exhibit a change in BMD.
There is a linear correlation between the dose of rhGH and the increase in BMD in childhood-onset GHD, indicating a need for optimization of the dose of rhGH in children. In contrast, in adult-onset GHD, low of rhGH have an optimal effect on BMD, whereas at high doses rhGH may cause an initial decline in BMD, probably due to an increase in bone resorption.
Different pituitary disease may alter the effects of rhGH on bone mass. In patients with Cushing’s disease and in patients with hyperprolactinemia (increase levels of prolactin) and hypogonadism (reduction or absence of hormone secretion of the testes or ovaries), there is a delayed effect of rhGH replacement therapy on BMD.
GH and IGF-I are necessary to achieve and maintain bone mass throughout life. IGF-I mediates most of the effects of GH on skeletal metabolism, IGF-I increases bone formation by regulating the differentiated function of the osteoblast (cell that makes bones), and as a consequence GH and IGF-I increase bone remodeling. Diseases affecting the GH/IGF-I axis are frequently associated with significant alterations in bone metabolism that often lead to bone loss.
Insulin Sensitivity is Impaired in Adults with Varying Degrees of GH Deficiency
Severe growth hormone deficiency (GHD) is a condition defined by a peak GH (pGH) response to provocative tests of less than 3 µg/l. GHD occurs when your anterior pituitary gland does not produce sufficient amount of GH. This condition can occur in both children and adults and may display a multitude of signs and symptoms.
Most cases of adult onset growth hormone deficiency are caused by damage to the pituitary gland. The damage can be caused by pituitary tumor, surgical procedure, and/or radiotherapy. Other types of GHD are caused by genetic abnormalities such as Prader-Willi syndrome or Turner syndrome. In some cases, the cause is unknown or is said to be idiopathic.
The impact of lesser degrees of GHD in the adult is less well defined. Most adults with severe GHD are insulin resistant. To better understand this relationship, it is vital to know the functions of both growth hormone (GH) and insulin. Basically, GH causes the release of insulin-like growth factor 1 and other growth factors. Aside from this effect, GH counteracts in general the effects of insulin on blood sugar and metabolism of lipids while sharing protein anabolic properties with insulin. GH does not affect the total turnover of blood sugar directly. However, GH suppresses muscle uptake of blood sugar, indicating that GH plays a role in the redistribution of blood sugar.
Whether insulin action is impaired in the presence of GHD is not known. To determine whether insulin sensitivity is impaired in patients with GHD, Murray et al studied 30 GH-deficient patients. A short insulin tolerance test (ITT) was performed in a subset of 20 patients from each group and the rate constant for glucose disappearance (KITT) is calculated. The results of the study showed that GH-deficient adults were found to be insulin resistant from the KITT values compared with the control group. Insulin resistance increased in concert with percentage fat mass, age and male gender.
The researchers conclude that, although not detected under basal conditions, hypopituitary adults with GH deficiency are insulin resistant under conditions of insulin stimulation. This finding may be explained by the concomitant adverse changes in body composition observed in both these states of varying degrees of GHD. Insulin resistance is associated with numerous adverse risk factors such as heart diseases, hypertension, diabetes, and other diseases that may place GH-deficient patients at higher risks for fatal diseases.
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