GENEMEDICS APP

GENEMEDICS NUTRITION

HEALTH LIBRARY

Human Growth Hormone/IGF-1

Free Consultation

Health Library Single Page
Sending

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. [1] 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. [2]

Overall Health Benefits of GH and IGF-1

  • Improves Symptoms of Diabetes [61-89]
  • Lowers Blood Pressure [90-105]
  • Boosts Sexual Vitality and Improves Sexual Health [106-114]
  • Accelerates Recovery from Injury [115-122]
  • Speeds Up Wound Healing [123-139]
  • Prevents and Treats Nerve Damage [140-162]
  • Lowers Risk for Stroke [163-179]
  • Improves Kidney Function and Treats Chronic Kidney Disease (CKD) [180-191]
  • Lowers Risk for Cardiovascular Diseases [192-216]
  • Prevents Muscle Wasting [217-231]
  • Prevents Alzheimer’s Disease (AD) and Boosts Cognitive Health [232-268]
  • Prevents Cancer [269-288]
  • Improves Sleep Quality [289-299]
  • Decreases Organ Atrophy and Dysfunction of Organs [300-316]
  • Wards off Depression and Improves Mood [317-325]
  • Improves Energy Levels [329-350]
  • Lowers Risk for Cardiovascular Diseases and Related Deaths [351-366]
  • Improves Body Composition and Metabolic Abnormalities [367-380]
  • Treats Muscular Abnormalities [381-387]
  • Prevents Bone Abnormalities and Lowers Risk for Fractures [388-399]
  • Improves Blood Sugar Levels [400]

GH and IGF-1 Production

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. [3] Different external stimulatory and inhibitory factors may affect the release of GH including: [4]

  • Fasting, low blood sugar and vigorous exercise
  • Ghrelin (an enzyme that stimulates appetite)
  • Growth hormone-releasing hormone (somatocrinin)
  • Sex hormones such as androgens and estrogen

Some inhibitors of growth hormone secretion include: [5]

  • Circulating concentrations of GH and IGF-1 (Insulin-like growth factor 1)
  • Dihydrotestosterone (active form of testosterone)
  • Growth hormone-inhibiting hormone (somatostatin)
  • Glucocorticoids (powerful anti-inflammatory compounds)
  • Hyperglycemia (high blood sugar)

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. [6] 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. [7]
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. [8] 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. [9]
Measurements of IGF-1 are adjusted for age because its levels tend to decline over time. Normal ranges of IGF-1 by age are: [10]

  • 16 to 24 years old: 182 to 780 ng/mL
  • 25 to 39 years old: 114 to 492 ng/mL
  • 40 to 54 years old: 90 to 360 ng/mL
  • 55 years old and above: 71 to 290 ng/mL

Relationship between HGH and IGF-1

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. [11] When the levels of GH rise or fall below the normal, the same thing will happen to IGF-1. [12] The GH/IGF1 system is dynamic and its activity is greatly influenced by age, sexual maturation, body composition and other factors.

Growth Hormone Deficiency

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. [13] 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:

  • Binding protein levels (IGF-I and IGFBP-3): This is used to show whether GHD is caused by a problem in the pituitary gland. [14]
  • GH stimulation test: This test is used to diagnose GHD and hypopituitarism (diminished hormone secretion by the pituitary gland). The test makes use of an intravenous solution to stimulate GH release from the pituitary gland and check whether GH release is at normal levels. [15]
  • GH suppression test: This test helps to diagnose GH excess. The patient is given a standard dose of glucose to drink and blood is drawn at timed intervals to check if the pituitary gland is sufficiently suppressed. [16]
  • Insulin tolerance test: This test involves injection of insulin into a patient’s vein to assess pituitary function. [17]

In addition to blood tests, the doctor can also perform additional exams and tests such as X-rays and MRI to help diagnose GHD.

Causes

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:

    • Brain tumors
    • Abnormal pituitary gland
    • Cleft lips or cleft palates (children with these conditions often have poorly developed pituitary glands) [18]
    • Gene mutations (e.g. Growth-hormone-releasing hormone receptor, GH1)
    • Congenital diseases such as Prader-Willi syndrome, Turner syndrome, [19] or short stature homeobox gene (SHOX) deficiency [20]
    • Chronic kidney disease (CKD) [21]

Acquired causes of GHD include the following:

  • Serious head injuries or trauma
  • Infections
  • Surgery
  • Radiation

Symptoms

In children, symptoms of GHD include the following: [22]

  • Children with GHD are shorter than their peers
  • Delayed puberty
  • Increased fat around the face and stomach
  • Slow tooth development
  • Sluggish hair growth
  • Younger, rounder faces
  • Small penis

In adults, the symptoms can vary, and most of them can experience the following: [23]

  • Baldness
  • Decrease in sexual function and interest
  • Decreased muscle mass and strength
  • Difficulty concentrating
  • Dry, thin skin
  • Fatigue related to low energy levels
  • Cardiovascular problems
  • High levels of bad cholesterol
  • Insulin resistance
  • Memory problems
  • Mood changes
  • Reduced bone density
  • Sensitivity to heat and cold
  • Weight gain

IGF-1 Deficiency

This medical condition happens when there is insufficient conversion of GH to IGF-1 by the liver. [24] 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. [25] 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. [26]

Causes

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, [27] 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. [28] Also, caloric or protein restriction in the diet can decrease the levels of IGF-1 by decreasing the liver cells’ sensitivity to GH stimulation. [29]

Symptoms

In children, the following may indicate IGF-1 deficiency: [30]

  • Slowed growth rate in early childhood relative to group norms
  • Shorter stature than others of the same chronological age
  • Delayed puberty
  • X-rays showing delayed bone development

In adults, abnormally low levels of IGF-1 may cause subtle, nonspecific symptoms such as: [31]

  • Adverse lipid changes
  • Decreased bone density
  • Fatigue
  • Reduced exercise tolerance

Anti-Aging Research

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. [32] 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.

Anti-Aging Effect of Growth Hormone

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. [35] 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. [36] 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, [37] and with the ability of GH therapy to improve age-related changes in metabolic characteristics, brain vascularity and cognitive function. [38] The actions of GH have already been related to longevity in other mammals such as carnivores, rodents and ungulates. [39]

Anti-Aging Effect of IGF-1

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. [40] In mammals, the natural decline in circulating IGF-1 levels due to aging has been associated with neuronal aging and symptoms of neurodegeneration. [41]
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. [44] Aging is associated with increased vascular oxidative stress and vascular disease. [45] One of the mechanisms in which IGF-1 can slow the process of aging is that IGF-1 can reduce oxidative stress. [46]

IGF-1 Supplementation

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, [47] increasing nerve regeneration, and ramping up sexual power.

Route of Administration

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. [48] 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.

Variants

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, [49] 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

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. [50] 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. [51] 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

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. [52] The half-life for IGF-1 DES is about 20-30 minutes. [53] 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. [54] 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.

IGF-1 versus GH/HGH

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. [55] 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. [56] 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. [57] 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. [58] 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. [59]
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). [60] 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.

Benefits of IGF-1 in Specific Medical Conditions

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:

  • Improves Symptoms of Diabetes

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. [61] 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. [62] 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. [63] 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.

  • Lowers Blood Pressure

Low levels of IGF-1 are associated with hypertension. [90] Several clinical trials have suggested that IGF-1 may have a role in preventing the development of hypertension. [91] 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. [94] 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. [95] 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. [96] 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]

  • Boosts Sexual Vitality and Improves Sexual Health

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. [106] 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. [113] Other studies even reported that restoring IGF-1 levels through IGF-1 supplementation may help treat erectile dysfunction and increase libido. [114]

  • Accelerates Recovery from Injury

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. [115] 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. [116] 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. [117] In another study, Emel et al. investigated the effects of local administration of IGF-1 on the functional recovery of paralyzed muscles. [118] 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]

  • Speeds Up Wound Healing

Wound healing is a complex process which is affected by IGF-1 bound to insulin-like growth factor-binding protein (IGFBP). [123] This growth factor has receptors which stimulate local collagen formation necessary for wound healing. [124] In addition, IGF-1 and other growth factors modulate skin cell survival and regeneration. [125] 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. [126] 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. [127] 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]

  • Prevents and Treats Nerve Damage

Neuropathy is the term used to describe a problem with the nerves, typically causing numbness and problems with mobility. [140] 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. [141] 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.[142] 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. [143] 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]

  • Lowers Risk for Stroke

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. [173] 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). [174] Moreover, IGF-1 appears to be linked with repair processes following brain damage by controlling the regeneration of injured peripheral nerves. [175] In one study, Sohrabji et al. reported that estrogen-mediated neuroprotection in neural injury models is critically dependent on IGF-1 signaling. [176] 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. [179]

  • Improves Kidney Function and Treats Chronic Kidney Disease (CKD)

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). [180] 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. [181] 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. [182] 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]

  • Lowers Risk for Cardiovascular Diseases

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. [192] 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. [193]
2. By promoting insulin sensitivity [194]
3. By promoting potassium-channel opening [195]
4. By improving lipid profiles [196]
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. [204] 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. [205] 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. [206] 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.

  • Prevents Muscle Wasting

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. [217] 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). [218] 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. [219] Similarly, Nystom et al. found that IGF-1 attenuates sepsis-induced muscle wasting apparently by increasing muscle protein synthesis and potentially decreasing protein breakdown. [220] 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]

  • Prevents Alzheimer’s Disease (AD) and Boosts Cognitive Health

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). [232] 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. [268]

  • Prevents Cancer

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. [269] 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. [270] 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. [271] 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. [272] 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. [273] 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. [274] Also, IGF-1 reduces inflammation [275] 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]

  • Improves Sleep Quality

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. [299]

  • Decreases Organ Atrophy and Dysfunction of Organs

With advancing age, all cells in the body are less able to divide and multiply. [300] 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.

  • Wards off Depression and Improves Mood

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. [323] A study by Malberg et al. even found that IGF-1 also has anti-anxiety effect aside from its anti-depressant effect. [324] 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. [325]

Growth Hormone Supplementation

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.

Route of Administration

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. [326]

Today, subcutaneous injection is the route of choice for GH administration. [327] In addition to this, trials for alternative less invasive modes of GH administration such as the nasal, pulmonary and transdermal routes are under way. [328] Oral route of GH administration is ineffective because they are typically destroyed in the gastrointestinal tract during the process of digestion.

Benefits of HGH Supplementation

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:

  • Improves Cognition and Energy Levels

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. [334] 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. [335] 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]

  • Lowers Risk for Cardiovascular Diseases and Related Deaths

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. [361] 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. [364] 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. [365] 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. [366]

  • Improves Body Composition and Metabolic Abnormalities

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. [375] 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. [376] 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. [377] 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]

  • Treats Muscular Abnormalities

There is a significant association between reduced lean muscle mass and impaired neuromuscular function. [381] In one study, a significant improvement in lean mass and neuromuscular function was observed after more than 10 years of GH replacement therapy. [382] 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. [383] In states of GH deficiency, Weber et al. reported that reduced muscle mass and strength can be reversed successfully with supplementation of GH. [384] 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. [387]

  • Prevents Bone Abnormalities and Lowers Risk for Fractures

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. [397] 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. [398] 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. [399]

  • Improves Blood Sugar Levels

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. [400]

Growth Hormone and IGF-1 in Athletics

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. [401] 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.

Anabolic Effect in Athletes

GH and IGF-1 compounds bind to specific receptors, initiating cell division, which in turn causes muscle growth and an increase in muscle mass. [402] 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: [403]

  • Boosts protein synthesis, leading to improved muscle mass and strength
  • Causes significant fat reduction
  • Inhibits the catabolic effects (breakdown phase) of athletic training
  • Causes significant height increase
  • Causes a synergistic anabolic effect when used with anabolic steroids

Controversy and History of HGH in Athletics

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. [404] 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. [405] 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. [406] 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. [407]

Current Status of IGF-1 in Athletics

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). [408] 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: [409]
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.

References:

  1. Firdos Alam Khan (8 May 2014). Biotechnology in Medical Sciences. CRC Press. pp. 389–. ISBN 978-1-4822-2368-2.
  2. Suzanne C. O’Connell Smeltzer; Brenda G. Bare; Janice L. Hinkle; Kerry H. Cheever (2010). Brunner & Suddarth’s Textbook of Medical-surgical Nursing. Lippincott Williams & Wilkins. pp. 1788–. ISBN 978-0-7817-8589-1.
  3. APH Publishing. pp. 127–. ISBN 978-81-313-0305-4.
  4. Shlomo Melmed; Kenneth S. Polonsky; P. Reed Larsen; Henry M. Kronenberg (30 November 2015). Williams Textbook of Endocrinology. Elsevier Health Sciences. pp. 188–. ISBN 978-0-323-29738-7.
  5. Kenneth B. Storey (25 February 2005). Functional Metabolism: Regulation and Adaptation. John Wiley & Sons. pp. 280–. ISBN 978-0-471-67557-0.
  6. Gardner DG, Shoback D (2007). Greenspan’s Basic and Clinical Endocrinology (8th ed.). New York: McGraw-Hill Medical. pp. 193–201. ISBN 0-07-144011-9.
  7. Ridha Arem (8 January 2013). The Protein Boost Diet: Improve Your Hormone Efficiency for a Fast Metabolism and Weight Loss. Simon and Schuster. pp. 66–. ISBN 978-1-4516-9954-8.
  8. Leslie J. DeGroot; J. Larry Jameson (2006). Endocrinology. Elsevier Saunders. ISBN 978-0-7216-0376-6.
  9. Max Corradi (3 February 2014). Low dose medicine: Healing without side effects using low dose homeopathic cytokines, interleukins, hormones, and neurotrophines. Jaborandi Publishing. pp. 56–. ISBN 978-0-9927304-3-7.
  10. Normal Ranges for Insulin-Like Growth Factor. (n.d.). Retrieved February 04, 2016, from https://www.urmc.rochester.edu/encyclopedia/content.aspx?ContentTypeID=167.
  11. Donald G. Barceloux (3 February 2012). Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants. John Wiley & Sons. pp. 344–. ISBN 978-1-118-10605-1.
  12. Michael B. Ranke; P.-E. Mullis (2011). Diagnostics of Endocrine Function in Children and Adolescents. Karger Medical and Scientific Publishers. pp. 178–. ISBN 978-3-8055-9414-1.
  13. Frank J. Domino; Robert A. Baldor; Jill A. Grimes; Jeremy Golding (6 May 2014). The 5-Minute Clinical Consult Premium 2015. Lippincott Williams & Wilkins. pp. 500–. ISBN 978-1-4511-9215-5.
  14. Thomas H. Ollendick; Carolyn S. Schroeder (6 December 2012). Encyclopedia of Clinical Child and Pediatric Psychology. Springer Science & Business Media. pp. 267–. ISBN 978-1-4615-0107-7.
  15. Michael B. Ranke; David Anthony Price; Edward O. Reiter (1 January 2007). Growth Hormone Therapy in Pediatrics: 20 Years of KIGS. Karger Medical and Scientific Publishers. pp. 40–. ISBN 978-3-8055-8256-8.
  16. David Capewell; Saran Shantikumar (5 August 2008). Get ahead! MEDICINE 150 EMQs for Finals. CRC Press. pp. 342–. ISBN 978-1-85315-887-2.
  17. Barbara A Gylys; Mary Ellen Wedding (5 December 2012). Medical Terminology Systems: A Body Systems Approach. F.A. Davis. pp. 482–. ISBN 978-0-8036-3913-3.
  18. Margaret R Colyar (4 April 2011). Assessment Of The School-Age Child and Adolescent. F.A. Davis. pp. 129–. ISBN 978-0-8036-2643-0.
  19. Growth failure (in children) – human growth hormone (HGH)” (pdf). National Institute for Clinical Excellence. 2008-09-25. Retrieved 2016-02-05.
  20. Rappold GA, Fukami M, Niesler B, et al. (March 2002). “Deletions of the homeobox gene SHOX (short stature homeobox) are an important cause of growth failure in children with short stature”. J. Clin. Endocrinol. Metab. 87 (3): 1402–6. doi:10.1210/jc.87.3.1402. PMID 11889216.
  21. R A P Ped. Endocrinology Spl Vol. 13. Jaypee Brothers Publishers. pp. 59–. ISBN 978-81-8061-208-4.
  22. Stanley T. Diagnosis of growth hormone deficiency in childhood. Curr Opin Endocrinol Diabetes Obes. 2012;19(1):47–52. doi:10.1097/MED.0b013e32834ec952.
  23. Nessar Ahmed (25 November 2010). Clinical Biochemistry. OUP Oxford. pp. 315–. ISBN 978-0-19-953393-0.
  24. Debasis Bagchi; Sreejayan Nair; Chandan K. Sen (26 July 2013). Nutrition and Enhanced Sports Performance: Muscle Building, Endurance, and Strength. Academic Press. pp. 76–. ISBN 978-0-12-396477-9.
  25. William A. Petit; William A. Jr Petit; Christine A. Adamec (2005). The Encyclopedia of Endocrine Diseases and Disorders. Infobase Publishing. pp. 3–. ISBN 978-0-8160-6638-4.
  26. Yeung (March 2007). Internal Medical Care of Cancer Patients. PMPH-USA. pp. 671–. ISBN 978-1-55009-312-4.
  27. Marschall S. Runge; Cam Patterson (18 November 2007). Principles of Molecular Medicine. Springer Science & Business Media. pp. 454–. ISBN 978-1-59259-963-9.
  28. Shlomo Melmed; P.Michael Conn (5 November 2007). Endocrinology: Basic and Clinical Principles. Springer Science & Business Media. pp. 203–. ISBN 978-1-59259-829-8.
  29. Philip E. Harris; Pierre-Marc G. Bouloux (24 March 2014). Endocrinology in Clinical Practice, Second Edition. CRC Press. pp. 125–. ISBN 978-1-84184-952-2.
  30. Bertram Katzung (5 January 2004). Basic & Clinical Pharmacology. McGraw Hill Professional. ISBN 978-0-07-154378-1.
  31. David B. Arciniegas, MD; M. Ross Bullock, MD, PHD; Douglas I. Katz, MD; Jeffrey S. Kreutzer, PHD, ABPP, Ross D. Zafonte, DO, Nathan D. Zasler, MD (27 August 2012). Brain Injury Medicine, 2nd Edition: Principles and Practice. Demos Medical Publishing. pp. 893–. ISBN 978-1-61705-057-2.
  32. George H. Miller, Jr. (2 October 2001). Optimum Fitness: How to Use Your Muscles As Peripheral Hearts to Achieve Optimum Muscular and Aerobic Fitness. Xlibris Corporation. pp. 139–. ISBN 978-1-4628-1725-2.
  33. Ivor J. Benjamin; Robert C. Griggs; Edward J. Wing; J. Gregory Fitz (17 April 2015). Andreoli and Carpenter’s Cecil Essentials of Medicine. Elsevier Health Sciences. pp. 627–. ISBN 978-1-4377-1899-7.
  34. Joseph DiPiro; Robert L. Talbert; Gary Yee; Barbara Wells, L. Michael Posey (22 March 2014). Pharmacotherapy A Pathophysiologic Approach 9/E. McGraw Hill Professional. ISBN 978-0-07-180054-9.
  35. A4m American Academy (10 January 2012). Anti-Aging Therapeutics. eBookIt.com. pp. 190–. ISBN 978-1-934715-08-6.
  36. Rudman D, Feller AG, Nagraj HS, et al. Effects of human growth hormone in men over 60 years old. N Engl J Med. 1990;323(1):1-6.
  37. Baum HB, Katznelson L, Sherman JC, et al. Effects of physiological growth hormone (GH) therapy on cognition and quality of life in patients with adult-onset GH deficiency. J Clin Endocrinol Metab. 1998;83(9):3184-9.
  38. Ramsey MM, Weiner JL, Moore TP, Carter CS, Sonntag WE. Growth hormone treatment attenuates age-related changes in hippocampal short-term plasticity and spatial learning. Neuroscience. 2004;129(1):119-27.
  39. Chanson; Jacques Epelbaum; S.W.J. Lamberts (9 March 2013). Endocrine Aspects of Successful Aging: Genes, Hormones and Lifestyles. Springer Science & Business Media. pp. 36–. ISBN 978-3-662-07019-2.
  40. Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R (1993). “A C. elegans mutant that lives twice as long as wild type”. Nature 366 (6454): 461–464. doi:10.1038/366461a0. PMID 8247153.
  41. Tang BL. SIRT1, neuronal cell survival and the insulin/IGF-1 aging paradox. Neurobiol Aging. 2006;27(3):501-5.
  42. Yung Hou Wong; J. T. Y. Wong (2005). Neuro-Signals. Karger.
  43. Chanson; Jacques Epelbaum; S.W.J. Lamberts (9 March 2013). Endocrine Aspects of Successful Aging: Genes, Hormones and Lifestyles. Springer Science & Business Media. pp. 23. ISBN 978-3-662-07019-2.
  44. Leon V. Clark (2006). New Research on Atherosclerosis. Nova Publishers. pp. 23–. ISBN 978-1-59454-942-7.
  45. Higashi Y, Sukhanov S, Anwar A, Shai SY, Delafontaine P. IGF-1, oxidative stress and atheroprotection. Trends Endocrinol Metab. 2010;21(4):245-54.
  46. Tahira Farooqui; Akhlaq A. Farooqui (24 October 2011). Oxidative Stress in Vertebrates and Invertebrates: Molecular Aspects of Cell Signaling. John Wiley & Sons. pp. 354–. ISBN 978-1-118-14811-2.
  47. Johansson AG, Lindh E, Blum WF, Kollerup G, Sørensen OH, Ljunghall S. Effects of growth hormone and insulin-like growth factor I in men with idiopathic osteoporosis. J Clin Endocrinol Metab. 1996;81(1):44-8.
    1. United States. Executive Office of the President (1994). Use of bovine somatotropin (BST) in the United States: its potential effects.
    2. Puri (1 January 2005). Textbook Of Biochemistry. Elsevier India. pp. 771–. ISBN 978-81-8147-844-3.
    3. Shayne Cox Gad (25 May 2007). Handbook of Pharmaceutical Biotechnology. John Wiley & Sons. pp. 256–. ISBN 978-0-470-11710-1.
    4. James Squires (2010). Applied Animal Endocrinology. CABI. pp. 113–. ISBN 978-1-84593-755-3.
    5. Insulin-like growth factor-1 (IGF-1). Available at: http://www.evolutionary.org/insulin-like-growth-factor-1. Accessed February 11, 2016.
    6. George Greeley (31 December 1998). Gastrointestinal Endocrinology. Springer Science & Business Media. pp. 481–. ISBN 978-1-59259-695-9.
    7. Insulin-like growth factor-1 (IGF-1). Available at: http://www.evolutionary.org/insulin-like-growth-factor-1. Accessed February 11, 2016.
    8. Carel; Z. Hochberg (2011). Yearbook of Pediatric Endocrinology 2011. Karger Medical and Scientific Publishers. pp. 54–. ISBN 978-3-8055-9859-0.
    9. Danish Medical Bulletin. Danish Medical Association. 1993.
    10. Brown-borg HM, Rakoczy SG, Romanick MA, Kennedy MA. Effects of growth hormone and insulin-like growth factor-1 on hepatocyte antioxidative enzymes. Exp Biol Med (Maywood). 2002;227(2):94-104.
    11. Arie Altman (6 November 1997). Agricultural Biotechnology. CRC Press. pp. 559–. ISBN 978-1-4200-4927-5.
    12. Carter CS, Ramsey MM, Ingram RL, et al. Models of growth hormone and IGF-1 deficiency: applications to studies of aging processes and life-span determination. J Gerontol A Biol Sci Med Sci. 2002;57(5):B177-88.
    13. Eric C.R. Reeve (14 January 2014). Encyclopedia of Genetics. Routledge. pp. 364–. ISBN 978-1-134-26350-9. Eric C.R. Reeve (14 January 2014). Encyclopedia of Genetics. Routledge. pp. 364–. ISBN 978-1-134-26350-9.
    14. Elliott Proctor Joslin; C. Ronald Kahn (2005). Joslin’s Diabetes Mellitus: Edited by C. Ronald Kahn … [et Al.]. Lippincott Williams & Wilkins. pp. 172–. ISBN 978-0-7817-2796-9.
    15. Clemmons DR. Role of insulin-like growth factor in maintaining normal glucose homeostasis. Horm Res. 2004;62 Suppl 1:77-82.
    16. Woods KA, Camacho-hübner C, Bergman RN, Barter D, Clark AJ, Savage MO. Effects of insulin-like growth factor I (IGF-I) therapy on body composition and insulin resistance in IGF-I gene deletion. J Clin Endocrinol Metab. 2000;85(4):1407-11.
    17. Mohamed-Ali V, Pinkney J. Therapeutic potential of insulin-like growth factor-1 in patients with diabetes mellitus. Treatments in endocrinology. 2002; 1(6):399-410.
    18. Carroll PV, Christ ER, Umpleby AM. IGF-I treatment in adults with type 1 diabetes: effects on glucose and protein metabolism in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp. Diabetes. 2000; 49(5):789-96.
    19. Simpson HL, Umpleby AM, Russell-Jones DL. Insulin-like growth factor-I and diabetes. A review. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. 1998; 8(2):83-95.
    20. Kolaczynski JW, Caro JF. Insulin-like growth factor-1 therapy in diabetes: physiologic basis, clinical benefits, and risks. Annals of internal medicine. 1994; 120(1):47-55.
    21. Sádaba MC, Martín-Estal I, Puche JE, Castilla-Cortázar I. Insulin-like growth factor 1 (IGF-1) therapy: Mitochondrial dysfunction and diseases. Biochimica et biophysica acta. 2016; 1862(7):1267-78.
    22. Gatenby VK, Kearney MT. The role of IGF-1 resistance in obesity and type 2 diabetes-mellitus-related insulin resistance and vascular disease. Expert opinion on therapeutic targets. 2010; 14(12):1333-42.
    23. Shiva S, Behbod H, Ghergherechi R. Effect of insulin therapy on IGF-1 level in children with new-onset type 1 diabetes mellitus: a comparison between DKA and non-DKA. Journal of pediatric endocrinology & metabolism: JPEM. 2013; 26(9-10):883-6.
    24. Moses AC. Insulin resistance and type 2 diabetes mellitus: is there a therapeutic role for IGF-1? Endocrine development. 2005; 9:121-34.
    25. Available from https://link.springer.com/chapter/10.1007/978-1-59259-712-3_30.
    26. Drogan D, Schulze MB, Boeing H, Pischon T. Insulin-Like Growth Factor 1 and Insulin-Like Growth Factor-Binding Protein 3 in Relation to the Risk of Type 2 Diabetes Mellitus: Results From the EPIC-Potsdam Study. American journal of epidemiology. 2016; 183(6):553-60.
    27. van Dijk PR, Logtenberg SJ, Groenier KH, Kleefstra N, Bilo HJ, Arnqvist HJ. Effect of i.p. insulin administration on IGF1 and IGFBP1 in type 1 diabetes. Endocrine connections. 2014; 3(1):17-23.
    28. Dunger DB, Cheetham TD, Crowne EC. Insulin-like growth factors (IGFs) and IGF-I treatment in the adolescent with insulin-dependent diabetes mellitus. Metabolism: clinical and experimental. 1995; 44(10 Suppl 4):119-23.
    29. Weber DR, Stanescu DE, Semple R, Holland C, Magge SN. Continuous subcutaneous IGF-1 therapy via insulin pump in a patient with Donohue syndrome. Journal of pediatric endocrinology & metabolism : JPEM. 2014; 27(11-12):1237-41.
      1. Thrailkill K, Quattrin T, Baker L. Dual hormonal replacement therapy with insulin and recombinant human insulin-like growth factor (IGF)-I in insulin-dependent diabetes mellitus: effects on the growth hormone/IGF/IGF-binding protein system. The Journal of clinical endocrinology and metabolism. 1997; 82(4):1181-7.
      2. Clemmons DR. The relative roles of growth hormone and IGF-1 in controlling insulin sensitivity. The Journal of Clinical Investigation. 2004;113(1):25-27. doi:10.1172/JCI200420660.
      3. Friedrich N, Thuesen B, Jørgensen T, et al. The Association Between IGF-I and Insulin Resistance: A general population study in Danish adults. Diabetes Care. 2012;35(4):768-773. doi:10.2337/dc11-1833.
      4. Clemmons DR. Metabolic Actions of IGF-I in Normal Physiology and Diabetes. Endocrinology and Metabolism Clinics of North America. 2012;41(2):425-443. doi:10.1016/j.ecl.2012.04.017.
      5. Vaessen N, Heutink P, Janssen JA, et al. A polymorphism in the gene for IGF-I: functional properties and risk for type 2 diabetes and myocardial infarction. Diabetes. 2001;50(3):637-42.
      1. Simpson HL, Umpleby AM, Russell-jones DL. Insulin-like growth factor-I and diabetes. A review. Growth Horm IGF Res. 1998;8(2):83-95.
      1. Aguirre GA, De Ita JR, de la Garza RG, Castilla-Cortazar I. Insulin-like growth factor-1 deficiency and metabolic syndrome. J Transl Med. 2016;14:3. Published 2016 Jan 6. doi:10.1186/s12967-015-0762-z.
        1. Zenobi PD, Jaeggi-groisman SE, Riesen WF, Røder ME, Froesch ER. Insulin-like growth factor-I improves glucose and lipid metabolism in type 2 diabetes mellitus. J Clin Invest. 1992;90(6):2234-41.
        1. Regan FM, Williams RM, Mcdonald A, et al. Treatment with recombinant human insulin-like growth factor (rhIGF)-I/rhIGF binding protein-3 complex improves metabolic control in subjects with severe insulin resistance. J Clin Endocrinol Metab. 2010;95(5):2113-22.
        1. Cheetham TD, Holly JM, Clayton K, Cwyfan-hughes S, Dunger DB. The effects of repeated daily recombinant human insulin-like growth factor I administration in adolescents with type 1 diabetes. Diabet Med. 1995;12(10):885-92.

        1. Clemmons DR. The relative roles of growth hormone and IGF-1 in controlling insulin sensitivity. J Clin Invest. 2004;113(1):25-7.
        1. Balasubramanian P, Longo VD. Growth factors, aging and age-related diseases. Growth Horm IGF Res. 2016;28:66-8.
        1. Cathy Soto (1 January 2016). ECG: Essentials of Electrocardiography. Cengage Learning. pp. 31–. ISBN 978-1-305-68775-2.
        2. Hasdai D, Holmes DR, Jr, Richardson DM, Izhar U, Lerman A. Insulin and Igf-I Attenuate the Coronary Vasoconstrictor Effects of Endothelin-1 but Not of Sarafotoxin 6c. Cardiovasc Res. 1998;39:644–650.
        3. Bruce Miller. 7 Keys To Bring Your Diabetes Under Control: Add Years and Quality To Life By Keeping Your Sugar Level Under Control. Oak Publication Sdn Bhd. pp. 10–. ISBN 978-983-3735-47-1.
        4. Schutte AE, Volpe M, Tocci G, Conti E. Revisiting the relationship between blood pressure and insulin-like growth factor-1. Hypertension (Dallas, Tex.: 1979). 2014; 63(5):1070-7.
        5. Watanabe T, Miyazaki A, Katagiri T, Yamamoto H, Idei T, Iguchi T. Relationship between serum insulin-like growth factor-1 levels and Alzheimer’s disease and vascular dementia. Journal of the American Geriatrics Society. 2005; 53(10):1748-53.
        6. Poehlman ET, Toth MJ, Ades PA, Rosen CJ. Menopause-associated changes in plasma lipids, insulin-like growth factor I and blood pressure: a longitudinal study. European journal of clinical investigation. 1997; 27(4):322-6.
        7. Landin-Wilhelmsen K, Wilhelmsen L, Lappas G. Serum insulin-like growth factor I in a random population sample of men and women: relation to age, sex, smoking habits, coffee consumption and physical activity, blood pressure and concentrations of plasma lipids, fibrinogen, parathyroid hormone and osteocalcin. Clinical endocrinology. 1994; 41(3):351-7.
        8. Nolan BP, Senechal P, Waqar S, Myers J, Standley CA, Standley PR. Altered insulin-like growth factor-1 and nitric oxide sensitivities in hypertension contribute to vascular hyperplasia. American journal of hypertension. 2003; 16(5 Pt 1):393-400.
        9. Schut AF, Janssen JA, Deinum J. Polymorphism in the promoter region of the insulin-like growth factor I gene is related to carotid intima-media thickness and aortic pulse wave velocity in subjects with hypertension. Stroke. 2003; 34(7):1623-7.
        10. Cooley SM, Donnelly JC, Geary MP, Rodeck CH, Hindmarsh PC. Maternal insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and IGF BP-3 and the hypertensive disorders of pregnancy. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 2010; 23(7):658-61.
        11. Available from http://erj.ersjournals.com/content/44/Suppl_58/P316.
        12. Epithelial Cells—Advances in Research and Application: 2013 Edition. ScholarlyEditions. 21 June 2013. pp. 331–. ISBN 978-1-4816-8761-4.
        13. Hemat (2004). Principles of Orthomolecularism. Urotext. pp. 408–. ISBN 978-1-903737-05-7.
        14. Otunctemur A, Ozbek E, Sahin S, et al. Low serum insulin-like growth factor-1 in patients with erectile dysfunction. Basic and Clinical Andrology. 2016;26:1. doi:10.1186/s12610-015-0028-x.
        15. Rajfer J. Growth Factors and Gene Therapy for Erectile Dysfunction. Reviews in Urology. 2000;2(1):34.
        16. Sullivan ME, Thompson CS, Dashwood MR. Nitric oxide and penile erection: is erectile dysfunction another manifestation of vascular disease? Cardiovascular research. 1999; 43(3):658-65.
        17. Khorram O, Laughlin GA, Yen SS. Endocrine and metabolic effects of long-term administration of [Nle27]growth hormone-releasing hormone-(1-29)-NH2 in age-advanced men and women. The Journal of clinical endocrinology and metabolism. 1997; 82(5):1472-9.
        18. Musicki B, Palese MA, Crone JK, Burnett AL. Phosphorylated endothelial nitric oxide synthase mediates vascular endothelial growth factor-induced penile erection. Biology of reproduction. 2004; 70(2):282-9.
        19. Morales AJ, Nolan JJ, Nelson JC, Yen SS. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. The Journal of clinical endocrinology and metabolism. 1994; 78(6):1360-7.
        20. Pastuszak AW, Liu JS, Vij A. IGF-1 levels are significantly correlated with patient-reported measures of sexual function. International journal of impotence research. 2011; 23(5):220-6

</ol

          1. Tokish JM, Derosa DC. Pharmacologic approaches to the aging athlete. Sports health. 2014; 6(1):49-55.
          2. Creaney L, Hamilton B. Growth factor delivery methods in the management of sports injuries: the state of play. Br J Sports Med. 2008;42(5):314-20.
          3. Provenzano PP, Alejandro-osorio AL, Grorud KW, et al. Systemic administration of IGF-I enhances healing in collagenous extracellular matrices: evaluation of loaded and unloaded ligaments. BMC Physiol. 2007;7:2.
          4. Kurtz CA, Loebig TG, Anderson DD, Demeo PJ, Campbell PG. Insulin-like growth factor I accelerates functional recovery from Achilles tendon injury in a rat model. Am J Sports Med. 1999;27(3):363-9.
          5. Emel E, Ergün SS, Kotan D, et al. Effects of insulin-like growth factor-I and platelet-rich plasma on sciatic nerve crush injury in a rat model. J Neurosurg. 2011;114(2):522-8.
          6. Nakagawa T, Kumakawa K, Usami S, et al. A randomized controlled clinical trial of topical insulin-like growth factor-1 therapy for sudden deafness refractory to systemic corticosteroid treatment. BMC Med. 2014;12:219. Published 2014 Nov 19. doi:10.1186/s12916-014-0219-x.
          1. Masuda K. Biological repair of the degenerated intervertebral disc by the injection of growth factors. Eur Spine J. 2008;17 Suppl 4(Suppl 4):441-51.
          1. Sádaba MC, Martín-estal I, Puche JE, Castilla-cortázar I. Insulin-like growth factor 1 (IGF-1) therapy: Mitochondrial dysfunction and diseases. Biochim Biophys Acta. 2016;1862(7):1267-78.

          1. Vaught JL, Contreras PC, Glicksman MA, Neff NT. Potential utility of rhIGF-1 in neuromuscular and/or degenerative disease. Ciba Found Symp. 1996;196:18-27.
          1. Jeschke MG, et al. Interaction of exogenous liposomal insulin-like growth factor-I cDNA gene transfer with growth factors on collagen expression in acute wounds. Wound Repair Regen. 2005;13(3):269–277.
          2. Pierre EJ, et al. Insulin-like growth factor-I liposomal gene transfer and systemic growth hormone stimulate wound healing. J Burn Care Rehabil. 1997;18(4):287–291.
          3. Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med. 1999;341(10):738–746.
          4. Herndon DN, Barrow RE, Kunkel KR, Broemeling L, Rutan RL. Effects of recombinant human growth hormone on donor-site healing in severely burned children. Ann Surg. 1990;212(4):424-9.
          5. Joanne Zeis (September 2002). Essential Guide to Behcet’s Disease. Central Vision Press. pp. 144–. ISBN 978-0-9658403-3-0.
          6. Gartner MH, Benson JD, Caldwell MD. Insulin-like growth factors I and II expression in the healing wound. The Journal of surgical research. 1992; 52(4):389-94.
          7. Reckenbeil J, Kraus D, Stark H. Insulin-like growth factor 1 (IGF1) affects proliferation and differentiation and wound healing processes in an inflammatory environment with p38 controlling early osteoblast differentiation in periodontal ligament cells. Archives of oral biology. 2017; 73:142-150.
          8. Bitar MS. Insulin-like growth factor-1 reverses diabetes-induced wound healing impairment in rats. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 1997; 29(8):383-6.
          9. Brown DL, Kane CD, Chernausek SD, Greenhalgh DG. Differential expression and localization of insulin-like growth factors I and II in cutaneous wounds of diabetic and nondiabetic mice. The American Journal of Pathology. 1997;151(3):715-724.
          10. Sadagurski M, Yakar S, Weingarten G, et al. Insulin-Like Growth Factor 1 Receptor Signaling Regulates Skin Development and Inhibits Skin Keratinocyte Differentiation. Molecular and Cellular Biology. 2006;26(7):2675-2687. doi:10.1128/MCB.26.7.2675-2687.2006.
          11. Cioffi WG, Gore DC, Rue LW, et al. Insulin-like growth factor-1 lowers protein oxidation in patients with thermal injury. Annals of Surgery. 1994;220(3):310-319.
          12. Pierre EJ, Perez-Polo JR, Mitchell AT, Matin S, Foyt HL, Herndon DN. Insulin-like growth factor-I liposomal gene transfer and systemic growth hormone stimulate wound healing. The Journal of burn care & rehabilitation. 1997; 18(4):287-91.
          13. Miell JP, Taylor AM, Jones J, et al. Administration of human recombinant insulin-like growth factor-I to patients following major gastrointestinal surgery. Clin Endocrinol (Oxf). 1992;37(6):542-51.
          1. Steenfos HH. Growth factors and wound healing. Scand J Plast Reconstr Surg Hand Surg. 1994;28(2):95-105.

          1. Aydin F, Kaya A, Karapinar L, et al. IGF-1 Increases with Hyperbaric Oxygen Therapy and Promotes Wound Healing in Diabetic Foot Ulcers. J Diabetes Res. 2013;2013:567834.
          1. Provenzano PP, Alejandro-Osorio AL, Grorud KW, et al. Systemic administration of IGF-I enhances healing in collagenous extracellular matrices: evaluation of loaded and unloaded ligaments. BMC Physiol. 2007;7:2. Published 2007 Mar 26. doi:10.1186/1472-6793-7-2.

          1. Rowland KJ, Choi PM, Warner BW. The role of growth factors in intestinal regeneration and repair in necrotizing enterocolitis. Semin Pediatr Surg. 2013;22(2):101-11.
          1. Schmidt RE, Dorsey DA, Beaudet LN, Plurad SB, Parvin CA, Miller MS. Insulin-like growth factor I reverses experimental diabetic autonomic neuropathy. Am J Pathol. 1999;155(5):1651-60.
          2. Lewis ME, Neff NT, Contreras PC, et al. Insulin-like growth factor-I: potential for treatment of motor neuronal disorders. Exp Neurol. 1993;124(1):73-88.
          3. Secco M, Bueno C Jr, Vieira NM, Almeida C, Pelatti M, Zucconi E, Bartolini P, Vainzof M, Miyabara EH, Okamoto OK, Zatz M. Stem Cell Rev. 2013 Feb; 9(1):93-109.
          4. Schwab, M. Spranger, S. Krempien, W. Hacke, and M. Bettendorf, “Plasma insulin-like growth factor I and IGF binding protein 3 levels in patients with acute cerebral ischemic injury,” Stroke, vol. 28, no. 9, pp. 1744–1748, 1997.
          5. Benarroch EE. Insulin-like growth factors in the brain and their potential clinical implications. Neurology. 2012; 79(21):2148-53.
          6. Available from https://academic.oup.com/endo/article/149/12/5951/2455248.
          7. Lutz BS, Wei FC, Ma SF, Chuang DC. Effects of insulin-like growth factor-1 in motor nerve regeneration after nerve transection and repair vs. nerve crushing injury in the rat. Acta neurochirurgica. 1999; 141(10):1101-6.
          8. Bayrak AF, Olgun Y, Ozbakan A. The Effect of Insulin Like Growth Factor-1 on Recovery of Facial Nerve Crush Injury. Clinical and experimental otorhinolaryngology. 2017; 10(4):296-302.
          9. Gu J, Liu H, Zhang N, et al. Effect of transgenic human insulin-like growth factor-1 on spinal motor neurons following peripheral nerve injury. Experimental and Therapeutic Medicine. 2015;10(1):19-24. doi:10.3892/etm.2015.2472.
          10. Yamahara K, Yamamoto N, Nakagawa T, Ito J. Insulin-like growth factor 1: A novel treatment for the protection or regeneration of cochlear hair cells. Hearing research. 2015; 330(Pt A):2-9.
          11. Hammarberg H, Risling M, Hökfelt T, Cullheim S, Piehl F. Expression of insulin-like growth factors and corresponding binding proteins (IGFBP 1-6) in rat spinal cord and peripheral nerve after axonal injuries. The Journal of comparative neurology. 1998; 400(1):57-72.
          12. Oki K, Law TD, Loucks AB, Clark BC. The effects of testosterone and insulin-like growth factor 1 on motor system form and function. Experimental gerontology. 2015;64:81-86. doi:10.1016/j.exger.2015.02.005.
          13. Tuszynski MH. Growth-factor gene therapy for neurodegenerative disorders. The Lancet. Neurology. 2002; 1(1):51-7.
          14. Glat MJ, Benninger F, Barhum Y. Ectopic Muscle Expression of Neurotrophic Factors Improves Recovery After Nerve Injury. Journal of molecular neuroscience : MN. 2016; 58(1):39-45.
          15. LeRoith D. Insulin-like growth factor receptors and binding proteins. Bailliere’s clinical endocrinology and metabolism. 1996; 10(1):49-73.
          16. Yamamoto N, Nakagawa T, Ito J. Application of insulin-like growth factor-1 in the treatment of inner ear disorders. Front Pharmacol. 2014;5:208. Published 2014 Sep 10. doi:10.3389/fphar.2014.00208.
          1. Sakowski SA, Schuyler AD, Feldman EL. Insulin-like growth factor-I for the treatment of amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2009;10(2):63-73.

          1. Costales J, Kolevzon A. The therapeutic potential of insulin-like growth factor-1 in central nervous system disorders. Neurosci Biobehav Rev. 2016;63:207-22.

          1. Mitchell JD, Wokke JH, Borasio GD. Recombinant human insulin-like growth factor I (rhIGF-I) for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev. 2002;(3):CD002064.
          2. Borasio GD, Robberecht W, Leigh PN, et al. A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis. European ALS/IGF-I Study Group. Neurology. 1998;51(2):583-6.
          3. Steyn FJ, Ngo ST, Lee JD, et al. Impairments to the GH-IGF-I axis in hSOD1G93A mice give insight into possible mechanisms of GH dysregulation in patients with amyotrophic lateral sclerosis. Endocrinology. 2012;153(8):3735-46.
          4. Umehara H, Maekawa Y, Koizumi F, et al. Preclinical and phase I clinical studies of KW-2450, a dual IGF-1R/IR tyrosine kinase inhibitor, in combination with lapatinib and letrozole. Ther Adv Med Oncol. 2018;10:1758835918786858. Published 2018 Jul 30. doi:10.1177/1758835918786858.
          5. Available from https://clinicaltrials.gov/ct2/show/NCT00035815.
          6. Denti, V. Annoni, E. Cattadori et al., “Insulin-like growth factor 1 as a predictor of ischemic stroke outcome in the elderly,” American Journal of Medicine, vol. 117, no. 5, pp. 312–317, 2004.
          7. Saber H, Himali JJ, Beiser AS. Serum Insulin-Like Growth Factor 1 and the Risk of Ischemic Stroke: The Framingham Study. Stroke. 2017; 48(7):1760-1765.
          8. Zhang W, Wang W, Kuang L. The relation between insulin-like growth factor 1 levels and risk of depression in ischemic stroke. International journal of geriatric psychiatry. 2017.
          9. Bancu I, Navarro Díaz M, Serra A, et al. Low Insulin-Like Growth Factor-1 Level in Obesity Nephropathy: A New Risk Factor? Aguilera AI, ed. PLoS ONE. 2016;11(5):e0154451. doi:10.1371/journal.pone.0154451.
          10. Tang JH, Ma LL, Yu TX. Insulin-like growth factor-1 as a prognostic marker in patients with acute ischemic stroke. PloS one. 2014; 9(6):e99186.
          11. Dong X, Chang G, Ji XF, Tao DB, Wang YX. The relationship between serum insulin-like growth factor I levels and ischemic stroke risk. PloS one. 2014; 9(4):e94845.
          12. Bondanelli M, Ambrosio MR, Onofri A. Predictive value of circulating insulin-like growth factor I levels in ischemic stroke outcome. The Journal of clinical endocrinology and metabolism. 2006; 91(10):3928-34.
          13. Mehrpour M, Rahatlou H, Hamzehpur N, Kia S, Safdarian M. Association of insulin-like growth factor-I with the severity and outcomes of acute ischemic stroke. Iranian journal of neurology. 2016; 15(4):214-218.
          14. Armbrust M, Worthmann H, Dengler R. Circulating Insulin-like Growth Factor-1 and Insulin-like Growth Factor Binding Protein-3 predict Three-months Outcome after Ischemic Stroke. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. 2017; 125(7):485-491.
          15. Guan, L. Bennet, P. D. Gluckman, and A. J. Gunn, “Insulin-like growth factor-1 and post-ischemic brain injury,” Progress in Neurobiology, vol. 70, no. 6, pp. 443–462, 2003.
          16. Doré, K. Satyabrata, and R. Quirion, “Rediscovering an old friend, IFG-I: potential use in the treatment of neurodegenerative diseases,” Trends in Neurosciences, vol. 20, no. 8, pp. 326–331, 1997.
          17. Sohrabji F, Williams M. Stroke neuroprotection: oestrogen and insulin-like growth factor-1 interactions and the role of microglia. J Neuroendocrinol. 2013;25(11):1173-81.
          18. Saatman KE, Contreras PC, Smith DH, et al. Insulin-like growth factor-1 (IGF-1) improves both neurological motor and cognitive outcome following experimental brain injury. Exp Neurol. 1997;147(2):418-27.
          19. Victor R. Preedy (29 October 2013). Diabetes: Oxidative Stress and Dietary Antioxidants. Academic Press. pp. 142–. ISBN 978-0-12-405522-3.
          20. Mangiola A, Vigo V, Anile C, De bonis P, Marziali G, Lofrese G. Role and Importance of IGF-1 in Traumatic Brain Injuries. Biomed Res Int. 2015;2015:736104.

          1. Lioutas VA, Alfaro-Martinez F, Bedoya F, Chung CC, Pimentel DA, Novak V. Intranasal Insulin and Insulin-Like Growth Factor 1 as Neuroprotectants in Acute Ischemic Stroke. Translational stroke research. 2015; 6(4):264-75.
          2. Derek Leroith; Walter Zumkeller; Robert C. Baxter (31 July 2003). Insulin-like Growth Factor Receptor Signalling. Springer Science & Business Media. pp. 254–. ISBN 978-0-306-47846-8.
          3. Vijayan A, Franklin SC, Behrend T, Hammerman MR, Miller SB. Insulin-like growth factor I improves renal function in patients with end-stage chronic renal failure. Am J Physiol. 1999;276(4 Pt 2):R929-34.
          4. Hadi HA, Carr CS, Al suwaidi J. Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome. Vasc Health Risk Manag. 2005;1(3):183-98.
          5. Roelfsema V, Clark RG. The growth hormone and insulin-like growth factor axis: its manipulation for the benefit of growth disorders in renal failure. Journal of the American Society of Nephrology : JASN. 2001; 12(6):1297-306.
          6. Nesbitt T, Drezner MK. Insulin-like growth factor-I regulation of renal 25-hydroxyvitamin D-1-hydroxylase activity. Endocrinology. 1993; 132(1):133-8.
          7. Feldt-Rasmussen B, El Nahas M. Potential role of growth factors with particular focus on growth hormone and insulin-like growth factor-1 in the management of chronic kidney disease. Seminars in nephrology. 2009; 29(1):50-8.
          8. Oh Y. The insulin-like growth factor system in chronic kidney disease: Pathophysiology and therapeutic opportunities. Kidney Research and Clinical Practice. 2012;31(1):26-37. doi:10.1016/j.krcp.2011.12.005.

          1. Mak RH, Cheung WW, Roberts CT. The growth hormone-insulin-like growth factor-I axis in chronic kidney disease. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. 2008;18(1):17-25. doi:10.1016/j.ghir.2007.07.009.
          2. Available at https://www.physiology.org/doi/abs/10.1152/ajprenal.1993.264.5.f917?journalCode=ajprenal.

            1. Hirschberg R, Brunori G, Kopple JD, Guler HP. Effects of insulin-like growth factor I on renal function in normal men. Kidney Int. 1993;43(2):387-97.
            1. Available at https://www.semanticscholar.org/paper/A-cohort-study-of-insulin-like-growth-factor-1-and-Nilsson-Carrero/950dec0e2d2e107139d2aa573e53722f80556893.
            1. Clark RG. Recombinant insulin-like growth factor-1 as a therapy for IGF-1 deficiency in renal failure. Pediatr Nephrol. 2005;20(3):290-4.

            1. Bach LA, Hale LJ. Insulin-like growth factors and kidney disease. Am J Kidney Dis. 2015;65(2):327-36.

            1. Schini-Kerth VB. Dual effects of insulin-like growth factor-1 on the constitutive and inducible nitric oxide (NO) synthase–dependent formation of NO in vascular cells. J Endocrinol Invest. 1999; 22: 82–88.
            2. Conti E, Andreotti F, Sestito A, et al. Reduced levels of insulin-like growth factor-1 in patients with angina pectoris, positive exercise stress test, and angiographically normal epicardial coronary arteries. Am J Cardiol. 2002; 89: 973–975.
            3. Oltman CL, Kane NL, Gutterman DD, et al. Mechanism of coronary vasodilation to insulin and insulin-like growth factor-1 is dependent on vessel size. Am J Physiol Endocrinol Metab. 2000; 279: E176–E181.
            4. Twickler MT, Cramer MJ, Koppeschaar HP. Unraveling Reaven’s Syndrome X: serum insulin-like growth factor-1 and cardiovascular disease. 2003; 107: e190–e192.
            5. Spies M, Nesic O, Barrow RE, et al. Liposomal IGF-1 gene transfer modulates pro- and anti-inflammatory cytokine mRNA expression in the burn wound. Gene Ther. 2001; 8: 1409–1415.
            6. Spallarossa P, Brunelli C, Minuto C, et al. Insulin-like growth factor-1 and angiographically documented coronary artery disease. Am J Cardiol. 1996; 77: 200–202.
            7. Higashi Y, Pandey A, Goodwin B, Delafontaine P. Insulin-like growth factor-1 regulates glutathione peroxidase expression and activity in vascular endothelial cells: Implications for atheroprotective actions of insulin-like growth factor-1. Biochim Biophys Acta. 2013;1832(3):391-9.

            1. D’Amario D, Cabral-Da-Silva MC, Zheng H, et al. Insulin-like growth factor-1 receptor identifies a pool of human cardiac stem cells with superior therapeutic potential for myocardial regeneration. Circ Res. 2011;108(12):1467-81.

            1. Available at https://www.ahajournals.org/doi/full/10.1161/01.CIR.0000030720.29247.9F
              1. Juul A, Scheike T, Davidsen M, et al. Low serum insulin-like growth factor-1 is associated with increased risk of ischemic heart disease: a population-based case-control study. 2002; 106: 939–944.
              2. Ungvari Z, Csiszar A. The emerging role of IGF-1 deficiency in cardiovascular aging: recent advances. J Gerontol A Biol Sci Med Sci. 2012;67(6):599-610.
              1. Conti E, Andreotti F, Sciahbasi A, et al. Markedly reduced insulin-like growth factor-1 in the acute phase of myocardial infarction. J Am Coll Cardiol. 2001; 38: 26–32.
              2. Gillespie CM, Merkel AL, Martin AA. Effects of insulin-like growth factor-1 and LR3IGF-1 on regional blood flow in normal rats. J Endocrinol. 1997; 155: 351–358.
              3. Annarosa Leri; Piero Anversa; William H. Frishman (15 April 2008). Cardiovascular Regeneration and Stem Cell Therapy. John Wiley & Sons. pp. 152–. ISBN 978-0-470-99430-6.
              4. Khan AS, Sane DC, Wannenburg T, Sonntag WE. Growth hormone, insulin-like growth factor-1 and the aging cardiovascular system. Cardiovascular research. 2002; 54(1):25-35.
              5. Conti E, Musumeci MB, Assenza GE, Quarta G, Autore C, Volpe M. Recombinant human insulin-like growth factor-1: a new cardiovascular disease treatment option? Cardiovascular & hematological agents in medicinal chemistry. 2008; 6(4):258-71.
              6. Castellano G, Affuso F, Conza PD, Fazio S. The GH/IGF-1 Axis and Heart Failure. Current Cardiology Reviews. 2009;5(3):203-215. doi:10.2174/157340309788970306.
              7. Arcopinto M, Bobbio E, Bossone E. The GH/IGF-1 axis in chronic heart failure. Endocrine, metabolic & immune disorders drug targets. 2013; 13(1):76-91.
              8. Duerr RL, Huang S, Miraliakbar HR, Clark R, Chien KR, Ross J. Insulin-like growth factor-1 enhances ventricular hypertrophy and function during the onset of experimental cardiac failure. The Journal of clinical investigation. 1995; 95(2):619-27.
              9. Aguirre GA, De Ita JR, de la Garza RG, Castilla-Cortazar I. Insulin-like growth factor-1 deficiency and metabolic syndrome. Journal of Translational Medicine. 2016;14:3. doi:10.1186/s12967-015-0762-z.
              10. Laron Z. Insulin-like growth factor 1 (IGF-1): a growth hormone. Molecular Pathology. 2001;54(5):311-316.
              11. Donath MY, Sütsch G, Yan XW, et al. Acute cardiovascular effects of insulin-like growth factor I in patients with chronic heart failure. J Clin Endocrinol Metab. 1998;83(9):3177-83.
              1. Perkel D, Naghi J, Agarwal M, et al. The potential effects of IGF-1 and GH on patients with chronic heart failure. J Cardiovasc Pharmacol Ther. 2012;17(1):72-8.

              1. Conti E, Musumeci MB, De giusti M, et al. IGF-1 and atherothrombosis: relevance to pathophysiology and therapy. Clin Sci. 2011;120(9):377-402.

              1. Mieczyslaw Pokorski (8 July 2013). Neurobiology of Respiration. Springer Science & Business Media. pp. 26–. ISBN 978-94-007-6627-3.
              2. Sacheck JM, Ohtsuka A, Mclary SC, Goldberg AL. IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1. Am J Physiol Endocrinol Metab. 2004;287(4):E591-601.
              3. Ben Atchison; Diane K. Dirette (2007). Conditions in Occupational Therapy: Effect on Occupational Performance. Lippincott Williams & Wilkins. pp. 145–. ISBN 978-0-7817-5487-3.
              4. Nystrom G, Pruznak A, Huber D, Frost RA, Lang CH. Local insulin-like growth factor I prevents sepsis-induced muscle atrophy. Metabolism: clinical and experimental. 2009; 58(6):787-97.
              5. Rosenbloom AL. Mecasermin (recombinant human insulin-like growth factor I). Advances in therapy. 2009; 26(1):40-54.
              6. Song YH, Song JL, Delafontaine P, Godard MP. The therapeutic potential of IGF-I in skeletal muscle repair. Trends in endocrinology and metabolism: TEM. 2013; 24(6):310-9.
              7. Velloso CP. Regulation of muscle mass by growth hormone and IGF-I. British Journal of Pharmacology. 2008;154(3):557-568. doi:10.1038/bjp.2008.153.
              8. Demling R. The use of anabolic agents in catabolic states. J Burns Wounds. 2007;6:e2. Published 2007 Feb 12.

              1. Hameed M, Harridge SD, Goldspink G. Sarcopenia and hypertrophy: a role for insulin-like growth factor-1 in aged muscle?. Exerc Sport Sci Rev. 2002;30(1):15-9.
              1. Cioffi WG, Gore DC, Rue LW, et al. Insulin-like growth factor-1 lowers protein oxidation in patients with thermal injury. Ann Surg. 1994;220(3):310-6; discussion 316-9.

              1. Song YH, Song JL, Delafontaine P, Godard MP. The therapeutic potential of IGF-I in skeletal muscle repair. Trends Endocrinol Metab. 2013;24(6):310-9.

              1. Fouque D, Peng SC, Shamir E, Kopple JD. Recombinant human insulin-like growth factor-1 induces an anabolic response in malnourished CAPD patients. Kidney Int. 2000;57(2):646-54.
              1. Clemmons DR, Smith-banks A, Underwood LE. Reversal of diet-induced catabolism by infusion of recombinant insulin-like growth factor-I in humans. J Clin Endocrinol Metab. 1992;75(1):234-8.
              1. Kanda F, Okuda S, Matsushita T, Takatani K, Kimura KI, Chihara K. Steroid myopathy: pathogenesis and effects of growth hormone and insulin-like growth factor-I administration. Horm Res. 2001;56 Suppl 1:24-8.

              1. Song YH, Li Y, Du J, Mitch WE, Rosenthal N, Delafontaine P. Muscle-specific expression of IGF-1 blocks angiotensin II-induced skeletal muscle wasting. J Clin Invest. 2005;115(2):451-8
              1. Isabel Varela-Nieto; Julie Ann Chowen (21 December 2005). The Growth Hormone/Insulin-Like Growth Factor Axis during Development. Springer Science & Business Media. pp. 250–. ISBN 978-0-387-26274-1.
              2. Marwarha G, Prasanthi JR, Schommer J, Dasari B, Ghribi O. Molecular interplay between leptin, insulin-like growth factor-1, and β-amyloid in organotypic slices from rabbit hippocampus. Molecular Neurodegeneration. 2011;6:41. doi:10.1186/1750-1326-6-41.
              3.  Available at https://www.researchgate.net/publication/281677239_The_role_of_IGF-1_in_neurodegenerative_diseases.
              1. Westwood AJ, Beiser A, Decarli C, et al. Insulin-like growth factor-1 and risk of Alzheimer dementia and brain atrophy. 2014;82(18):1613-9.
              2. Ostrowski PP, Barszczyk A, Forstenpointner J, Zheng W, Feng ZP. Meta-Analysis of Serum Insulin-Like Growth Factor 1 in Alzheimer’s Disease. PloS one. 2016; 11(5):e0155733.
              3. Available from https://www.researchgate.net/publication/304910663_Circulating_insulin-like_growth_factor_1_and_insulin-like_growth_factor_binding_protein-3_level_in_Alzheimer’s_disease_a_meta-analysis.
              4. Arai Y, Hirose N, Yamamura K. Serum insulin-like growth factor-1 in centenarians: implications of IGF-1 as a rapid turnover protein. The journals of gerontology. Series A, Biological sciences and medical sciences. 2001; 56(2):M79-82.
              5. Available from https://www.researchgate.net/publication/318677033_Risk_of_prevalent_and_incident_dementia_associated_with_insulin-like_growth_factor_and_insulin-like_growth_factor-binding_protein_3
              6. Watanabe K, Uemura K, Asada M. The participation of insulin-like growth factor-binding protein 3 released by astrocytes in the pathology of Alzheimer’s disease. Molecular brain. 2015; 8(1):82.
              7. Zhou Y-L, Liu S-Q, Yuan B, Lu N. The expression of insulin-like growth factor-1 in senior patients with diabetes and dementia. Experimental and Therapeutic Medicine. 2017;13(1):103-106. doi:10.3892/etm.2016.3961.
              8. Puglielli L. Aging of the brain, neurotrophin signaling, and Alzheimer’s disease: is IGF1-R the common culprit? Neurobiology of aging. 2008;29(6):795-811. doi:10.1016/j.neurobiolaging.2007.01.010.
              9. Bishop NA, Lu T, Yankner BA. Neural mechanisms of ageing and cognitive decline. Nature. 2010;464(7288):529-535. doi:10.1038/nature08983.
              10. Hong M, Lee VM. Insulin and insulin-like growth factor-1 regulate tau phosphorylation in cultured human neurons. J Biol Chem. 1997;272(31):19547-53.
              1. Marques F, Sousa JC, Sousa N, Palha JA. Blood–brain-barriers in aging and in Alzheimer’s disease. Molecular Neurodegeneration. 2013;8:38. doi:10.1186/1750-1326-8-38.
              2. Lunn JS, Sakowski SA, Hur J, Feldman EL. Stem Cell Technology for Neurodegenerative Diseases. Annals of neurology. 2011;70(3):353-361. doi:10.1002/ana.22487.
              3. De la Monte SM. Contributions of Brain Insulin Resistance and Deficiency in Amyloid-Related Neurodegeneration in Alzheimer’s Disease. Drugs. 2012;72(1):49-66. doi:10.2165/11597760-000000000-00000.
              4. George C, Gontier G, Lacube P, François JC, Holzenberger M, Aïd S. The Alzheimer’s disease transcriptome mimics the neuroprotective signature of IGF-1 receptor-deficient neurons. Brain : a journal of neurology. 2017; 140(7):2012-2027.
              5. Zheng WH, Kar S, Doré S, Quirion R. Insulin-like growth factor-1 (IGF-1): a neuroprotective trophic factor acting via the Akt kinase pathway. Journal of neural transmission. Supplementum. 2000.
              6. Correia SC, Santos RX, Cardoso S. Effects of estrogen in the brain: is it a neuroprotective agent in Alzheimer’s disease? Current aging science. 2010; 3(2):113-26.
              7. Gasparini L, Xu H. Potential roles of insulin and IGF-1 in Alzheimer’s disease. Trends in neurosciences. 2003; 26(8):404-6.
              8. Deak F, Sonntag WE. Aging, synaptic dysfunction, and insulin-like growth factor (IGF)-1. J Gerontol A Biol Sci Med Sci. 2012;67(6):611-25.
              1. Cheng CM, Reinhardt RR, Lee WH, Joncas G, Patel SC, Bondy CA. Insulin-like growth factor 1 regulates developing brain glucose metabolism. Proc Natl Acad Sci USA. 2000;97(18):10236-41.

              1. Shavali S, Ren J, Ebadi M. Insulin-like growth factor-1 protects human dopaminergic SH-SY5Y cells from salsolinol-induced toxicity. Neurosci Lett. 2003;340(2):79-82.
              1. Cheng B, Maffi SK, Martinez AA, Acosta YP, Morales LD, Roberts JL. Insulin-like growth factor-I mediates neuroprotection in proteasome inhibition-induced cytotoxicity in SH-SY5Y cells. Mol Cell Neurosci. 2011;47(3):181-90.
              1. Bou khalil R. Recombinant human IGF-1 for patients with schizophrenia. Med Hypotheses. 2011;77(3):427-9.

              1. Humbert S, Bryson EA, Cordelières FP, et al. The IGF-1/Akt pathway is neuroprotective in Huntington’s disease and involves Huntingtin phosphorylation by Akt. Dev Cell. 2002;2(6):831-7.
              1. Bai X, Chen T, Gao Y, Li H, Li Z, Liu Z. The protective effects of insulin-like growth factor-1 on neurochemical phenotypes of dorsal root ganglion neurons with BDE-209-induced neurotoxicity in vitro. Toxicol Ind Health. 2017;33(3):250-264.

              1. Zemva J, Schubert M. The role of neuronal insulin/insulin-like growth factor-1 signaling for the pathogenesis of Alzheimer’s disease: possible therapeutic implications. CNS Neurol Disord Drug Targets. 2014;13(2):322-37.
              1. Larpthaveesarp A, Ferriero DM, Gonzalez FF. Growth factors for the treatment of ischemic brain injury (growth factor treatment). Brain Sci. 2015;5(2):165-77. Published 2015 Apr 30. doi:10.3390/brainsci5020165.
              1. Monson, J.P. (2003). Long-term experience with GH replacement therapy: efficacy and safety. European Journal of Endocrinology, 148 Suppl 2, S9–14.
              2. Pollak, M., Blouin, M.J., Zhang, J.C. & Kopchick, J.J. (2001). Reduced mammary gland carcinogenesis in transgenic mice expressing a growth hormone antagonist. British Journal of Cancer, 85, 428–430.
              3. Smith TJ. Insulin-like growth factor-I regulation of immune function: a potential therapeutic target in autoimmune diseases?. Pharmacol Rev. 2010;62(2):199-236.
              1. Jens O. L. Jørgensen; Jens Sandahl Christiansen (1 January 2005). Growth Hormone Deficiency in Adults. Karger Medical and Scientific Publishers. pp. 8–. ISBN 978-3-8055-7992-6.
              2. Russo and W. V. Moore, A comparison of subcutaneous and intramuscular administration of hGH in the therapy of growth hormone deficiency, J. Clin. Endocrinol. Metabol. 55:1003–1006, 1982.
              3. Russo L, Moore WV. A comparison of subcutaneous and intramuscular administration of human growth hormone in therapy of human growth hormone deficiency. J Clin Endocrinol Metab 1982; 55 : 1003-1006.
              4. Wallymahmed ME, Foy P, Shaw D, Hutcheon R, Edwards RH, MacFarlane IA. Quality of life, body composition and muscle strength in adult growth hormone deficiency: The influence of growth hormone replacement therapy for up to 3 years. Clin Endocrinol. 1997;47:439–46.
              5. Denko CW, Malemud CJ. Role of the growth hormone/insulin-like growth factor-1 paracrine axis in rheumatic diseases. Semin Arthritis Rheum. 2005;35(1):24-34.
              1. Shacter E, Weitzman SA. Chronic inflammation and cancer. Oncology (Williston Park, N.Y.). 2002; 16(2):217-26, 229; discussion 230-2.
              2. Multhoff G, Molls M, Radons J. Chronic Inflammation in Cancer Development. Frontiers in Immunology. 2011;2:98. doi:10.3389/fimmu.2011.00098.
              3. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860-867. doi:10.1038/nature01322.
              4. Crawford S. Anti-inflammatory/antioxidant use in long-term maintenance cancer therapy: a new therapeutic approach to disease progression and recurrence. Therapeutic Advances in Medical Oncology. 2014;6(2):52-68. doi:10.1177/1758834014521111.
              5. Franks AL, Slansky JE. Multiple Associations Between a Broad Spectrum of Autoimmune Diseases, Chronic Inflammatory Diseases and Cancer. Anticancer Research. 2012;32(4):1119-1136.
              6. Grivennikov SI, Greten FR, Karin M. Immunity, Inflammation, and Cancer. Cell. 2010;140(6):883-899. doi:10.1016/j.cell.2010.01.025.
              7. Rakoff-Nahoum S. Why Cancer and Inflammation? The Yale Journal of Biology and Medicine. 2006;79(3-4):123-130.
              8. Barahona-Garrido J, Hernández-Calleros J, García-Juárez I, Yamamoto-Furusho JK. Growth factors as treatment for inflammatory bowel disease: a concise review of the evidence toward their potential clinical utility. Saudi J Gastroenterol. 2009;15(3):208-12.
              1. Trejo JL, Carro E, Garcia-galloway E, Torres-aleman I. Role of insulin-like growth factor I signaling in neurodegenerative diseases. J Mol Med. 2004;82(3):156-62.
              1. Stattin P, Björ O, Ferrari P. Prospective study of hyperglycemia and cancer risk. Diabetes care. 2007; 30(3):561-7.
              2.  Ryu TY, Park J, Scherer PE. Hyperglycemia as a Risk Factor for Cancer Progression. Diabetes & Metabolism Journal. 2014;38(5):330-336. doi:10.4093/dmj.2014.38.5.330.
              3. Cui G, Zhang T, Ren F, et al. High Blood Glucose Levels Correlate with Tumor Malignancy in Colorectal Cancer Patients. Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2015;21:3825-3833. doi:10.12659/MSM.894783.
              4. Giovannucci E, Harlan DM, Archer MC, et al. Diabetes and Cancer: A consensus report. Diabetes Care. 2010;33(7):1674-1685. doi:10.2337/dc10-0666.
              5. Crawley DJ, Holmberg L, Melvin JC, et al. Serum glucose and risk of cancer: a meta-analysis. BMC Cancer. 2014;14:985. doi:10.1186/1471-2407-14-985.
              6. Johnson JA, Gale EAM. Diabetes, Insulin Use, and Cancer Risk: Are Observational Studies Part of the Solution–or Part of the Problem? Diabetes. 2010;59(5):1129-1131. doi:10.2337/db10-0334.
              7. Habib SL, Rojna M. Diabetes and Risk of Cancer. ISRN Oncology. 2013;2013:583786. doiIGF-1 Promotes the Development and Cytotoxic Activity of Human NK Cells:10.1155/2013/583786.
              8. Monzavi-Karbassi B, Gentry R, Kaur V, et al. Pre-diagnosis blood glucose and prognosis in women with breast cancer. Cancer & Metabolism. 2016;4:7. doi:10.1186/s40170-016-0147-7.
              9. Ni F, Sun R, Fu B, et al. IGF-1 promotes the development and cytotoxic activity of human NK cells. Nat Commun. 2013;4:1479.

</ol

                1. Bilbao D, Luciani L, Johannesson B, Piszczek A, Rosenthal N. Insulin-like growth factor-1 stimulates regulatory T cells and suppresses autoimmune disease. EMBO Mol Med. 2014;6(11):1423-35.

                1. Ma NS, Shah AJ, Geffner ME, Kapoor N. Igf-I stimulates in vivo thymopoiesis after stem cell transplantation in a child with Omenn syndrome. J Clin Immunol. 2010;30(1):114-20.

                1. Gianotti L, Pivetti S, Lanfranco F, Tassone F, Navone F, Vittori E,Ò et al. Concomitant impairment of growth hormone secretion and peripheral sensitivity in obese patients with obstructive sleep apnea syndrome. J Clin Endrocrinol Metab 2002;87:5052–7.
                2. Copinschi G, Nedeltcheva A, Leproult R, et al. Sleep Disturbances, Daytime Sleepiness, and Quality of Life in Adults with Growth Hormone Deficiency. The Journal of Clinical Endocrinology and Metabolism. 2010;95(5):2195-2202. doi:10.1210/jc.2009-2080.
                3. Schneider HJ, Oertel H, Murck H, Pollmächer T, Stalla GK, Steiger A. Night sleep EEG and daytime sleep propensity in adult hypopituitary patients with growth hormone deficiency before and after six months of growth hormone replacement. Psychoneuroendocrinology. 2005; 30(1):29-37.
                4. Deijen JB, Arwert LI. Impaired quality of life in hypopituitary adults with growth hormone deficiency : can somatropin replacement therapy help? Treatments in endocrinology. 2006; 5(4):243-50.
                5. Lanfranco F, Motta G, Minetto MA, Ghigo E, Maccario M. Growth hormone/insulin-like growth factor-I axis in obstructive sleep apnea syndrome: an update. Journal of endocrinological investigation. 2010; 33(3):192-6.
                6. Prinz PN, Moe KE, Dulberg EM, et al. Higher plasma IGF-1 levels are associated with increased delta sleep in healthy older men. J Gerontol A Biol Sci Med Sci. 1995;50(4):M222-6.

                1. Prinz PN, Moe KE, Dulberg EM. Higher plasma IGF-1 levels are associated with increased delta sleep in healthy older men. The journals of gerontology. Series A, Biological sciences and medical sciences. 1995; 50(4):M222-6.
                2. Rusch HL, Guardado P, Baxter T, Mysliwiec V, Gill JM. Improved Sleep Quality is Associated with Reductions in Depression and PTSD Arousal Symptoms and Increases in IGF-1 Concentrations. Journal of Clinical Sleep Medicine : JCSM : Official Publication of the American Academy of Sleep Medicine. 2015;11(6):615-623. doi:10.5664/jcsm.4770.
                3.  Damanti S, Bourron O, Doulazmi M, et al. Relationship between sleep parameters, insulin resistance and age-adjusted insulin like growth factor-1 score in non diabetic older patients. Blondeau B, ed. PLoS ONE. 2017;12(4):e0174876. doi:10.1371/journal.pone.0174876.
                4. Rusch HL, Gill JM. Effect of Acute Sleep Disturbance and Recovery on Insulin-Like Growth Factor-1 (IGF-1): Possible Connections and Clinical Implications. Journal of Clinical Sleep Medicine : JCSM : Official Publication of the American Academy of Sleep Medicine. 2015;11(10):1245-1246. doi:10.5664/jcsm.5108.
                5. Verhelst J, Abs R, Vandeweghe M. Two years of replacement therapy in adults with growth hormone deficiency. Clinical endocrinology. 1997; 47(4):485-94.
                6. Cooper GM. The Cell: A Molecular Approach. 2nd edition. Sunderland (MA): Sinauer Associates; 2000. Cell Proliferation in Development and Differentiation.
                7. Available from https://ccforum.biomedcentral.com/articles/10.1186/cc10359.
                8. Coletta C, Módis K, Oláh G, et al. Endothelial dysfunction is a potential contributor to multiple organ failure and mortality in aged mice subjected to septic shock: preclinical studies in a murine model of cecal ligation and puncture. Critical Care. 2014;18(5):511. doi:10.1186/s13054-014-0511-3.
                9. Boisramé-Helms J, Kremer H, Schini-Kerth V, Meziani F. Endothelial dysfunction in sepsis. Current vascular pharmacology. 2013; 11(2):150-60.
                10. Ince C, Mayeux PR, Nguyen T, et al. THE ENDOTHELIUM IN SEPSIS. Shock (Augusta, Ga). 2016;45(3):259-270. doi:10.1097/SHK.0000000000000473.
                11. Aird WC. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood. 2003; 101(10):3765-77.
                12. Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S. Endothelial Dysfunction as a Target for Prevention of Cardiovascular Disease. Diabetes Care. 2009;32(Suppl 2):S314-S321. doi:10.2337/dc09-S330.
                13. Conti E, Andreotti F, Sestito A, et al. Reduced levels of insulin-like growth factor-1 in patients with angina pectoris, positive exercise stress test, and angiographically normal epicardial coronary arteries. Am J Cardiol. 2002; 89: 973–975.
                14. Oltman CL, Kane NL, Gutterman DD, et al. Mechanism of coronary vasodilation to insulin and insulin-like growth factor-1 is dependent on vessel size. Am J Physiol Endocrinol Metab. 2000; 279: E176–E181.
                15. Twickler MT, Cramer MJ, Koppeschaar HP. Unraveling Reaven’s Syndrome X: serum insulin-like growth factor-1 and cardiovascular disease. 2003; 107: e190–e192.
                16. Spies M, Nesic O, Barrow RE, et al. Liposomal IGF-1 gene transfer modulates pro- and anti-inflammatory cytokine mRNA expression in the burn wound. Gene Ther. 2001; 8: 1409–1415.
                17. Spallarossa P, Brunelli C, Minuto C, et al. Insulin-like growth factor-1 and angiographically documented coronary artery disease. Am J Cardiol. 1996; 77: 200–202.
                18. Huang KF, Chung DH, Herndon DN. Insulinlike growth factor 1 (IGF-1) reduces gut atrophy and bacterial translocation after severe burn injury. Archives of surgery (Chicago, Ill. : 1960). 1993; 128(1):47-53; discussion 53-4.
                19. Latres E, Amini AR, Amini AA. Insulin-like growth factor-1 (IGF-1) inversely regulates atrophy-induced genes via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway. The Journal of biological chemistry. 2005; 280(4):2737-44.
                20. Šerbedžija P, Ishii DN. Insulin and insulin-like growth factor prevent brain atrophy and cognitive impairment in diabetic rats. Indian Journal of Endocrinology and Metabolism. 2012;16(Suppl 3):S601-S610. doi:10.4103/2230-8210.105578.
                21. Šerbedžija P, Madl JE, Ishii DN. Insulin and IGF-I prevent brain atrophy and DNA loss in diabetes. Brain research. 2009;1303:179-194. doi:10.1016/j.brainres.2009.09.063.
                22. Hitze B, Hubold C, van Dyken R. How the selfish brain organizes its supply and demand. Frontiers in neuroenergetics. 2010; 2:7.
                23. Gabbay V, Hess DA, Liu S, Babb JS, Klein RG, Gonen O (2007). Lateralized caudate metabolic abnormalities in adolescent major depressive disorder: a proton MR spectroscopy study. Am J Psychiatry 164: 1881–1889.
                24. Szczęsny E, Slusarczyk J, Głombik K. Possible contribution of IGF-1 to depressive disorder. Pharmacological reports : PR. 2013; 65(6):1622-31.

                1. Chigogora S, Zaninotto P, Kivimaki M, Steptoe A, Batty GD. Insulin-like growth factor 1 and risk of depression in older people: the English Longitudinal Study of Ageing. Translational Psychiatry. 2016;6(9):e898-. doi:10.1038/tp.2016.167.
                2. Mitschelen M, Yan H, Farley JA. Long-term deficiency of circulating and hippocampal insulin-like growth factor I induces depressive behavior in adult mice: a potential model of geriatric depression. Neuroscience. 2011; 185:50-60.
                3. Lin F, Suhr J, Diebold S, Heffner K. Associations between Depressive Symptoms and Memory Deficits Vary as a Function of Insulin-Like Growth Factor (IGF-1) Levels in Healthy Older Adults. Psychoneuroendocrinology. 2014;42:118-123. doi:10.1016/j.psyneuen.2014.01.006.
                4. Available from http://press.endocrine.org/doi/abs/10.1210/endo-meetings.2014.NP.10.SAT-0689.
                5. Hoshaw BA, Hill TI, Crowley JJ, et al. Antidepressant-like behavioral effects of IGF-I produced by enhanced serotonin transmission. European journal of pharmacology. 2008;594(1-3):109-116. doi:10.1016/j.ejphar.2008.07.023.
                6. Malberg JE, Platt B, Rizzo SJ. Increasing the levels of insulin-like growth factor-I by an IGF binding protein inhibitor produces anxiolytic and antidepressant-like effects. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology. 2007; 32(11):2360-8.
                7. Levada OA, Troyan AS. Insulin-like growth factor-1: a possible marker for emotional and cognitive disturbances, and treatment effectiveness in major depressive disorder. Annals of General Psychiatry. 2017;16:38. doi:10.1186/s12991-017-0161-3.
                8. Jens O. L. Jørgensen; Jens Sandahl Christiansen (1 January 2005). Growth Hormone Deficiency in Adults. Karger Medical and Scientific Publishers. pp. 8–. ISBN 978-3-8055-7992-6.
                9. Russo and W. V. Moore, A comparison of subcutaneous and intramuscular administration of hGH in the therapy of growth hormone deficiency, J. Clin. Endocrinol. Metabol. 55:1003–1006, 1982.
                10. Russo L, Moore WV. A comparison of subcutaneous and intramuscular administration of human growth hormone in therapy of human growth hormone deficiency. J Clin Endocrinol Metab 1982; 55 : 1003-1006.
                11. Deijen JB, de Boer H, Blok GJ, van der Veen EA. Cognitive impairments and mood disturbances in growth hormone deficient men. Psychoneuroendocrinology. 1996; 21(3):313-22.
                12. Rollero A, Murialdo G, Fonzi S. Relationship between cognitive function, growth hormone and insulin-like growth factor I plasma levels in aged subjects. Neuropsychobiology. 1998; 38(2):73-9.
                13. Sonntag WE, Ramsey M, Carter CS. Growth hormone and insulin-like growth factor-1 (IGF-1) and their influence on cognitive aging. Ageing research reviews. 2005; 4(2):195-212.
                14. van Dam PS, Aleman A, de Vries WR. Growth hormone, insulin-like growth factor I and cognitive function in adults. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. 2000; 10 Suppl B:S69-73.
                15. Aleman A, de Vries WR, de Haan EH, Verhaar HJ, Samson MM, Koppeschaar HP. Age-sensitive cognitive function, growth hormone and insulin-like growth factor 1 plasma levels in healthy older men. Neuropsychobiology. 2000; 41(2):73-8.
                16. Wallymahmed ME, Foy P, Shaw D, Hutcheon R, Edwards RH, MacFarlane IA. Quality of life, body composition and muscle strength in adult growth hormone deficiency: The influence of growth hormone replacement therapy for up to 3 years. Clin Endocrinol. 1997;47:439–46.
                17. Sathiavageeswaran M, Burman P, Lawrence D, Harris AG, Falleti MG, Maruff P, et al. Effects of GH on cognitive function in elderly patients with adult-onset GH deficiency: A placebo-controlled 12-month study. Eur J Endocrinol. 2007;156:439–47.
                18. Deijen JB, de Boer H, van der Veen EA. Cognitive changes during growth hormone replacement in adult men. Psychoneuroendocrinology. 1998; 23(1):45-55.
                19. Available from http://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.31468/abstract.
                20. Burman P, Broman JE, Hetta J. Quality of life in adults with growth hormone (GH) deficiency: response to treatment with recombinant human GH in a placebo-controlled 21-month trial. The Journal of clinical endocrinology and metabolism. 1995; 80(12):3585-90.
                21. Hoybye C, Thorén M, Böhm B. Cognitive, emotional, physical and social effects of growth hormone treatment in adults with Prader-Willi syndrome. Journal of intellectual disability research : JIDR. 2005; 49(Pt 4):245-52.
                22. Arwert LI, Veltman DJ, Deijen JB, van Dam PS, Drent ML. Effects of growth hormone substitution therapy on cognitive functioning in growth hormone deficient patients: a functional MRI study. Neuroendocrinology. 2006; 83(1):12-9.
                23. Oertel H, Schneider HJ, Stalla GK, Holsboer F, Zihl J. The effect of growth hormone substitution on cognitive performance in adult patients with hypopituitarism. Psychoneuroendocrinology. 2004; 29(7):839-50.
                24. Hull KL, Harvey S. Growth hormone therapy and Quality of Life: possibilities, pitfalls and mechanisms. The Journal of endocrinology. 2003; 179(3):311-33.
                25. Falleti MG, Maruff P, Burman P, Harris A. The effects of growth hormone (GH) deficiency and GH replacement on cognitive performance in adults: a meta-analysis of the current literature. Psychoneuroendocrinology. 2006; 31(6):681-91.
                26. Wass JA, Reddy R. Growth hormone and memory. J Endocrinol. 2010;207(2):125-6.

                1. Rinaldi A. Hormone therapy for the ageing. Despite the negative results of recent trials, hormone replacement therapy retains enticing promises for the elderly. EMBO Rep. 2004;5(10):938-41.

                1. Huisman J, Aukema EJ, Deijen JB, et al. The usefulness of growth hormone treatment for psychological status in young adult survivors of childhood leukaemia: an open-label study. BMC Pediatr. 2008;8:25.

                1. Maric NP, Doknic M, Pavlovic D. Psychiatric and neuropsychological changes in growth hormone-deficient patients after traumatic brain injury in response to growth hormone therapy. Journal of endocrinological investigation. 2010; 33(11):770-5.
                2. High WM, Briones-Galang M, Clark JA. Effect of growth hormone replacement therapy on cognition after traumatic brain injury. Journal of neurotrauma. 2010; 27(9):1565-75.
                3. Available at https://www.researchgate.net/publication/256103671_The_GHIGF-1-axis_in_psychopathological_functions.
                1. Isgaard J. Cardiovascular disease and risk factors: the role of growth hormone. Hormone research. 2004; 62 Suppl 4:31-8.
                2. Burger AG, Monson JP, Colao AM, Klibanski A. Cardiovascular risk in patients with growth hormone deficiency: effects of growth hormone substitution. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2007; 12(6):682-9.
                3. Volterrani M, Giustina A, Manelli F, Cicoira MA, Lorusso R, Giordano A. Role of growth hormone in chronic heart failure: therapeutic implications. Italian heart journal : official journal of the Italian Federation of Cardiology. 2000; 1(11):732-8.
                4. Arcopinto M, Salzano A, Giallauria F, et al. Growth Hormone Deficiency Is Associated with Worse Cardiac Function, Physical Performance, and Outcome in Chronic Heart Failure: Insights from the T.O.S.CA. GHD Study. Buchowski M, ed. PLoS ONE. 2017;12(1):e0170058. doi:10.1371/journal.pone.0170058.
                5. Rosén T, Edén S, Larson G, Wilhelmsen L, Bengtsson BA. Cardiovascular risk factors in adult patients with growth hormone deficiency. Acta endocrinologica. 1993; 129(3):195-200.
                6. De Leonibus C, De Marco S, Stevens A, Clayton P, Chiarelli F, Mohn A. Growth Hormone Deficiency in Prepubertal Children: Predictive Markers of Cardiovascular Disease. Hormone research in paediatrics. 2016; 85(6):363-71.
                7. Available from https://link.springer.com/article/10.1007/s12020-016-1206-0.
                8. Oflaz H, Sen F, Elitok A, et al. Coronary flow reserve is impaired in patients with adult growth hormone (GH) deficiency. Clin Endocrinol (Oxf). 2007;66(4):524-9.

                1. Maison P, Griffin S, Nicoue-beglah M, et al. Impact of growth hormone (GH) treatment on cardiovascular risk factors in GH-deficient adults: a Metaanalysis of Blinded, Randomized, Placebo-Controlled Trials. J Clin Endocrinol Metab. 2004;89(5):2192-9.

                1. Castellano G, Affuso F, Conza PD, Fazio S. The GH/IGF-1 Axis and Heart Failure. Curr Cardiol Rev. 2009;5(3):203-15.

                1. Murray RD, Wieringa G, Lawrance JA, Adams JE, Shalet SM. Partial growth hormone deficiency is associated with an adverse cardiovascular risk factor profile and increased carotid intima-medial thickness. Clin Endocrinol (Oxf) 2010;73:508–15.
                2. Maison P, Griffin S, Nicoue-Beglah M, Haddad N, Balkau B, Chanson P. Impact of growth hormone (GH) treatment on cardiovascular risk factors in GH-deficient adults: A metaanalysis of blinded, randomized, placebo-controlled trials. J Clin Endocrinol Metab. 2004;89:2192–9.
                3. Available at https://academic.oup.com/jcem/article/98/1/352/2823298.

                1. Van der klaauw AA, Pereira AM, Rabelink TJ, et al. Recombinant human GH replacement increases CD34+ cells and improves endothelial function in adults with GH deficiency. Eur J Endocrinol. 2008;159(2):105-11.
                1. Agarwal M, Naghi J, Philip K, Phan A, Willix RD, Schwarz ER. Growth hormone and testosterone in heart failure therapy. Expert opinion on pharmacotherapy. 2010; 11(11):1835-44.
                2. Tritos NA, Danias PG. Growth hormone therapy in congestive heart failure due to left ventricular systolic dysfunction: a meta-analysis. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2008; 14(1):40-9.
                3. Volterrani M, Giustina A, Manelli F, Cicoira MA, Lorusso R, Giordano A. Role of growth hormone in chronic heart failure: therapeutic implications. Italian heart journal : official journal of the Italian Federation of Cardiology. 2000; 1(11):732-8.
                4. Langendonk JG, Meinders AE, Burggraaf J. Influence of obesity and body fat distribution on growth hormone kinetics in humans. The American journal of physiology. 1999; 277(5 Pt 1):E824-9.
                5. Germain-Lee EL. Short stature, obesity, and growth hormone deficiency in pseudohypoparathyroidism type 1a. Pediatric endocrinology reviews : PER. 2006; 3 Suppl 2:318-27.
                6. Scacchi M, Pincelli AI, Cavagnini F. Growth hormone in obesity. International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity. 1999; 23(3):260-71.
                7. Kelestimur F, Popovic V, Leal A. Effect of obesity and morbid obesity on the growth hormone (GH) secretion elicited by the combined GHRH + GHRP-6 test. Clinical endocrinology. 2006; 64(6):667-71.
                8. Available from https://link.springer.com/article/10.1007/s12020-015-0571-4.
                9. Luque RM, Kineman RD. Impact of obesity on the growth hormone axis: evidence for a direct inhibitory effect of hyperinsulinemia on pituitary function. Endocrinology. 2006; 147(6):2754-63.
                10. Available at https://pituitary.mgh.harvard.edu/E-F-944.htm.
                1. Miller KK, Biller BM, Lipman JG, Bradwin G, Rifai N, Klibanski A. Truncal adiposity, relative growth hormone deficiency and cardiovascular risk. J Clin Endocrinol Metab. 2005;90:768–74.
                2. Wallymahmed ME, Foy P, Shaw D, Hutcheon R, Edwards RH, MacFarlane IA. Quality of life, body composition and muscle strength in adult growth hormone deficiency: The influence of growth hormone replacement therapy for up to 3 years. Clin Endocrinol. 1997;47:439–46.
                3. Van der Klaauw AA, Biermasz NR, Feskens EJ, Bos MB, Smit JW, Roelfsema F, et al. The prevalence of the metabolic syndrome is increased in patients with GH deficiency, irrespective of long-term substitution with recombinant human GH. Eur J Endocrinol. 2007;156:455–62.
                4. Maison P, Griffin S, Nicoue-Beglah M, Haddad N, Balkau B, Chanson P. Impact of growth hormone (GH) treatment on cardiovascular risk factors in GH-deficient adults: A metaanalysis of blinded, randomized, placebo-controlled trials. J Clin Endocrinol Metab. 2004;89:2192–9.
                5. Shadid S, Jensen MD. Effects of growth hormone administration in human obesity. Obesity research. 2003; 11(2):170-5.
                6. Stewart C, Garcia-Filion P, Fink C, Ryabets-Lienhard A, Geffner ME, Borchert M. Efficacy of growth hormone replacement on anthropometric outcomes, obesity, and lipids in children with optic nerve hypoplasia and growth hormone deficiency. International Journal of Pediatric Endocrinology. 2016;2016:5. doi:10.1186/s13633-016-0023-9.
                7. Available at http://www.nhholistichealthnetwork.com/hgh-antiaging-breakthrough-hype/.

                1. Webb SM, de Andrés-Aguayo I, Rojas-García R, Ortega E, Gallardo E, Mestrón A, et al. Neuromuscular dysfunction in adult growth hormone deficiency. Clin Endocrinol (Oxf) 2003;59:450–8.
                2. Götherström G, Elbornsson M, Stibrant-Sunnerhagen K, Bengtsson BA, Johannsson G, Svensson J. Muscle strength in elderly adults with GH deficiency after 10 years of GH replacement. Eur J Endocrinol. 2010;163:207–15.
                3. Romano T. Adult growth hormone deficiency in fibromyalgia. PB89 Pain Practice Issue. 2009 Mar;9(Sup 1):118.
                4. Weber MM. Effects of growth hormone on skeletal muscle. Hormone research. 2002; 58 Suppl 3:43-8.
                5. Tavares ABW, Micmacher E, Biesek S, et al. Effects of Growth Hormone Administration on Muscle Strength in Men over 50 Years Old. International Journal of Endocrinology. 2013;2013:942030. doi:10.1155/2013/942030.
                6. Götherström G, Elbornsson M, Stibrant-sunnerhagen K, Bengtsson BA, Johannsson G, Svensson J. Muscle strength in elderly adults with GH deficiency after 10 years of GH replacement. Eur J Endocrinol. 2010;163(2):207-15.
                1. Webb SM, De andrés-aguayo I, Rojas-garcía R, et al. Neuromuscular dysfunction in adult growth hormone deficiency. Clin Endocrinol (Oxf). 2003;59(4):450-8.

                1. Available from https://link.springer.com/chapter/10.1007/978-1-59259-015-5_14.
                2. Kuzma M, Payer J. [Growth hormone deficiency, its influence on bone mineral density and risk of osteoporotic fractures]. Casopis lekaru ceskych. 2010; 149(5):211-6.
                3. Capozzi A, Casa SD, Altieri B, Pontecorvi A. Low bone mineral density in a growth hormone deficient (GHD) adolescent. Clinical Cases in Mineral and Bone Metabolism. 2013;10(3):203-205.
                4. Tanaka H. [Hormones and osteoporosis update. Growth hormone and bone]. Clinical calcium. 2009; 19(7):984-9.
                5. White HD, Ahmad AM, Vora JP. Effects of adult growth hormone deficiency and growth hormone replacement on circadian rhythmicity. Minerva Endocrinol. 2003;28(1):13-25.
                6. Colao A, Di somma C, Pivonello R, et al. Bone loss is correlated to the severity of growth hormone deficiency in adult patients with hypopituitarism. J Clin Endocrinol Metab. 1999;84(6):1919-24.

              1. Locatelli V, Bianchi VE. Effect of GH/IGF-1 on Bone Metabolism and Osteoporsosis. Int J Endocrinol. 2014;2014:235060.

              1. Giustina A, Mazziotti G, Canalis E. Growth hormone, insulin-like growth factors, and the skeleton. Endocr Rev. 2008;29(5):535-59.

              1. Giustina A, Mazziotti G, Canalis E. Growth hormone, insulin-like growth factors, and the skeleton. Endocr Rev. 2008;29:535–59.
              2. Gillberg P, Mallmin H, Petrén-Mallmin M, Ljunghall S, Nilsson AG. Two years of treatment with recombinant human growth hormone increases bone mineral density in men with idiopathic osteoporosis. The Journal of clinical endocrinology and metabolism. 2002; 87(11):4900-6.
              3. Barake M, Arabi A, Nakhoul N. Effects of growth hormone therapy on bone density and fracture risk in age-related osteoporosis in the absence of growth hormone deficiency: a systematic review and meta-analysis. Endocrine. 2017.
              4. Wuster C, Härle U, Rehn U. Benefits of growth hormone treatment on bone metabolism, bone density and bone strength in growth hormone deficiency and osteoporosis. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. 1998; 8 Suppl A:87-94.
              5. Murray RD, Shalet SM. Insulin sensitivity is impaired in adults with varying degrees of GH deficiency. Clin Endocrinol (Oxf). 2005;62(2):182-8.

              1. Jennifer M. Sacheck, Akira Ohtsuka, S. Christine McLary, and Alfred L. Goldberg. “IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1..” Published online before print April 20, 2004, doi: 10.1152/ajpendo.00073.2004.
              2. Shlomo Melmed; Kenneth S. Polonsky; P. Reed Larsen; Henry M. Kronenberg (30 November 2015). Williams Textbook of Endocrinology. Elsevier Health Sciences. pp. 191–. ISBN 978-0-323-29738-7.
              3. William N. Taylor, M.D. (16 January 2002). Anabolic Steroids and the Athlete, 2d ed. McFarland. pp. 138–. ISBN 978-0-7864-1128-3.
              4. Holt RI, et al. The history of doping and growth hormone abuse in sport. Growth Horm IGF Res. 2009 Aug;19(4):320-6. doi: 10.1016/j.ghir.2009.04.009. PMID 19467612.
              5. Saugy M, Robinson N, Saudan C, Baume N, Avois L, Mangin P (July 2006). “Human growth hormone doping in sport”. Br J Sports Med. 40 Suppl 1: i35–9. doi:10.1136/bjsm.2006.027573. PMC 2657499. PMID 16799101.
              6. Liu H, Bravata DM, Olkin I, Friedlander A, Liu V, Roberts B, Bendavid E, Saynina O, Salpeter SR, Garber AM, Hoffman AR (May 2008). “Systematic review: the effects of growth hormone on athletic performance”. Intern. Med. 148 (10): 747–58.
              7. Committee Holds Hearing on Myths and Facts about Human Growth Hormone, B12, and Other Substances (February 12, 2008)”. Committee on Oversight and Government Reform, United States House of Representatives. Retrieved 19 February 2016.
              8. Steven B. Karch, MD, FFFLM (21 December 2006). Drug Abuse Handbook, Second Edition. CRC Press. pp. 697–. ISBN 978-1-4200-0346-8.
              9. Christopher Madden; Margot Putukian; Eric McCarty; Craig Young (25 November 2013). Netter’s Sports Medicine. Elsevier Health Sciences. pp. 171–. ISBN 978-0-323-29615-1.
Share -

Other Peptides

BPC-157

KPV

Aminophylline

Mitochondrial ORF of the twelve S c (MOTS-c)

Valproic Acid

Success Stories

men testimonial before after

At the age of 60, I look and feel better than I ever have in my entire life! Switching my health program and hormone replacement therapy regimen over to Genemedics was one of the best decisions I’ve ever made in my life! Genemedics and Dr George have significantly improved my quality of life and also dramatically improved my overall health. I hav...
Nick Cassavetes ,60 yrs old Movie Director (“The Notebook”, “John Q”, “Alpha Dog”), Actor and Writer

See All Men’s Testimonials

Call 800-277-4041 for a Free Consultation

What to expect during your consultation:
  • Usually takes 15-30 minutes
  • Completely confidential
  • No obligation to purchase anything
  • We will discuss your symptoms along with your health and fitness goals
  • Free post-consult access for any additional questions you may have
Contact Us Page
Sending

About

Genemedics® Health Institute is a global premier institute dedicated to revolutionizing health and medicine through healthy lifestyle education, guidance and accountability in harmony with functional medicine. Our physician-supervised health programs are personally customized to help you reach your health and fitness goals while looking and feeling better than ever.

Our Services

 

genemedics logo

280 North Old Woodward Ave. Suite 210 Birmingham MI 48009,USA

800-277-4041

info@genemedics.com

© Copyright Genemedics Health Institute. All Rights Reserved. Privacy Policy.

Back to Top