Human Growth Hormone/IGF-1

Growth hormone (GH), also known as somatotropin, or as 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 tissue, including vital organs such as the heart and brain.[2]

The release of GH in the pituitary gland, which is 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. Some of the factors that can stimulate GH release are the following:[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 levels tend to decline with age. 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 plays 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 falls 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 to make 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 of a substance 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 makes use of insulin to be injected 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 primary hormones administered through anti-aging clinics are human growth hormone which prompts the liver to produce IGF-1. 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 their muscle mass and bone density, and they had a decline 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.


Growth Hormone

Clinical data indicate that the risks far outweigh any minimal potential benefits if GH injections are misused. For this reason, the US Food and Drug Administration (FDA) has approved GH for children and adults who have true growth hormone deficiency – not the natural decline in GH due to aging.[33] Among its many biological effects, GH injection promotes an increase in muscle mass, bone density, exercise capacity, and a decrease in body fat.[34] People who have a significant deficiency in GH 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 in old rats.[38]

The actions of GH and control of cell or somatic growth have already been related to aging and longevity in other mammals such as carnivores, rodents and ungulates.[39] Although much of the currently available information concerning the role of GH in anti-aging is limited in scope and uncertain, and some are conflicting, there is every reason to believe that the outcome of ongoing and future studies will yield to a paradigm shift.


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] However, signaling through the insulin/IGF-1-like receptor pathway contributes to biological aging in many organisms.[43] Suspected mechanisms of IGF-I 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] 


Benefits of 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, increasing nerve regeneration, and ramping up sexual power.

In a recent study posted in the New Zealand Medical Journal, natural IGF-1 supplements improved bone density in patients with osteoarthritis.[47] In another study conducted by CNBC, the researchers reported that weightlifters who received IGF-1 supplements over a 10-week period had significant muscle gains and improvement in strength over those who hadn’t.[48]

In addition to its anabolic effects on skeletal muscle, IGF-1 has been shown to stimulate lipoprotein lipase (LPL) activity – that is, fat breakdown for energy – and it may also inhibit insulin activity in fat cells.[49] The combination of an increase in LPL activity and a reduction in insulin activity may help improve fat metabolism. This explains how IGF-1 booster supplements help users lose body fat, while maintaining lean muscle mass.   

IGF-1 has also been shown to increase the body’s ability to recover from injury. Whether you have an injured ligament, tendon, or muscle, an increase in the levels of IGF-1 has been shown to dramatically improve this injury.[50] Higher levels of IGF-1 has also been shown to have positive effects on physical and sexual endurance.[51]  


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.[52] 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;[53] 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.[54] 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.[55] 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.[55] 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[55] – 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.[56] The half-life for IGF-1 DES is about 20-30 minutes.[57] It has the ability to stimulate muscle hyperplasia better than IGF-1 LR3 so it is best used for site injections where you want 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.[56] 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.[58] 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.[59] 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.[60] 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.[61] 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.[62]

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).[63] 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.


In specific diseases

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 in the body.


Diabetes and high blood glucose

IGF-I has significant structural homology with insulin. It has been shown to bind to insulin receptors to stimulate the transport of blood sugar or also known as glucose in fat and muscle, to inhibit excessive glucose production by the liver and to lower blood glucose while   simultaneously suppressing the secretion of insulin.[64] Studies in diabetic patients who are in insulin-deficient states have shown that serum IGF-I concentrations are also low and increase with insulin therapy.[65] 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-I concentrations.[65]

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-I (IGF-I) gene, Woods et al reported that the lack of IGF-1 gene results in IGF-I deficiency, severe insulin resistance, and short stature, and that IGF-I therapy resulted in beneficial effects on insulin sensitivity, body composition, bone size, and linear growth.[66]

Administration of IGF-I in diabetic patients has been shown to result in an improvement not only in insulin sensitivity, but it significantly reduces the dose of the required administered insulin to maintain balance in glucose levels.[65] Taken together, these findings support that IGF-I administration is necessary to maintain normal insulin sensitivity, and impairment of the synthesis of IGF-1 results in a worsening state of insulin resistance.


Hypertension

Low levels of IGF-1 are associated with hypertension in subjects without pituitary and cardiovascular diseases.[67] Several trials have suggested that IGF-1 may have a pathophysiological role in the development of arterial essential hypertension.[68] In vitro and in vivo experiments showed that IGF-1 has vasodilator properties.[69]. 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.[70] 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.[71]

The role of IGF-1 in improving blood glucose levels can also significantly improve blood pressure. High blood glucose causes the blood to become thick and sticky, thus affecting its normal flow.[72] This in turn increases the pressure within the blood vessels and can lead to rupture if not treated. This shows that IGF-1 can reduce high blood pressure in hypertensive individuals by normalizing blood glucose levels.


Sexual health in men

IGF-1 levels, like testosterone, decline in an age-dependent manner. This progressive decline leads to various symptoms including erectile dysfunction (ED). IGF-1 is known to mediate endothelial nitric oxide production.[73] 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.[74]

The relationship of IGF-1 and penile erection has been described in otherwise healthy male subjects, and recent in vitro and animal studies suggest that IGF-1 upregulates nitric oxide and may thus help to maintain erectile function.[75] 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.[75]

In another study, gene transfer of IGF-1 to the penis of streptozotocin (STZ)-induced diabetic rats significantly increased erectile function via restoration of the integrity of smooth muscle of corpus cavernosum (a pair of sponge-like regions of erectile tissue) and modulation of NO-cGMP pathways (responsible for maintaining penile erection).[76] These results suggest that in vivo gene transfer of IGF-1 might be considered as a new therapeutic intervention for the treatment of erectile dysfunction (ED).


Injury recovery

In recent years there have been rapid developments in the use of growth factors such as IGF-I 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.[77] Growth factors mediate the biological processes necessary for repair of muscles, tendons and ligaments following acute traumatic or overuse injury, and animal studies have demonstrated clear benefits in terms of accelerated healing.

In one study, Provenzano et al reported that systemic administration of IGF-I in male rats improved healing in collagenous connective tissue, such as ligament.[78] In a similar study, Kurtz et al found out that IGF-1 has an anti-inflammatory mechanism which reduces maximum functional deficit and accelerates recovery after Achilles tendon injury in rats.[79] In another rat study, Emel et al investigated the effects of local administration of IGF-1 on the functional recovery of paralyzed muscles.[80] The results of the study showed that IGF-1 administration increased the rate of axon (nerve fiber) regeneration in crush-injured and freeze-injured rat sciatic nerves (extends from the lower end of the spinal cord down the back of the thigh).

Wound healing is a complex process which is affected by IGF-1 bound to Insulin-like growth factor-binding protein (IGFBP).[81] This growth factor has receptors which stimulate local collagen formation necessary for wound healing.[82] In addition, IGF-1 and other growth factors modulate skin cell survival and regeneration.[83] 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 serum IGF-1 levels and a significant decrease in donor-site healing times and length of hospital stay.[84] 


Neuropathy

Neuropathy is the term used to describe a problem with the nerves, typically causing numbness and problems with mobility.[85] 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.

Recent studies have suggested a role for neurotrophic substances (family of proteins that induce the survival, development, and function of neurons) in the pathogenesis and treatment of diabetic neuropathy. In one study, Schmidt et al reported that IGF-1 treatment in streptozotocin-induced diabetic rat model with established neuroaxonal dystrophy (rare inherited neurological disorder) for a period of 2 months resulted in nearly complete normalization of the condition without altering the severity of diabetes.[86]

Motor neuronal disorders, such as amyotrophic lateral sclerosis (degeneration of spinal cord motor neuron) present a unique opportunity for therapeutic intervention with neurotrophic proteins such as IGF-1. In one study, therapeutic administration of IGF-1 is associated with potential reversal of degeneration of spinal cord motor neuron axons by reducing the programmed cell death of motor neurons.[87]

Several recent studies involving IGF-1 treatment for Duchenne Muscular Dystrophy (DMD), which is one of the most prevalent types of muscular dystrophy, have shown very promising results. Secco et al showed that systemic delivery of human mesenchymal stromal cells (stem cells) combined with IGF-I enhances muscle functional recovery in mice with DMD.[88]


Stroke

Recent studies have shown that patients who suffered from acute stroke have depressed levels of serum iGF-1.[89] It seems also that post-stroke serum IGF-1 levels are correlated with the outcome from ischemic brain injury (insufficient blood flow to the brain), with its higher levels reducing lethality.[90] Many studies have shown the benefits of IGF-1 administration in post-stroke patients by reducing loss of neurons, infarct volume (one of the common indexes for assessing the extent of ischemic brain injury), while increasing glial proliferation[91] – glial cells supply essential nutrients and protect the neurons. Moreover, IGF-1 appears to be linked with repair processes following brain damage by controlling the regeneration of injured peripheral nerves.[92]

In animal models, IGF-I was able to exert its neuroprotective effects in both white and gray matter in the brain under different detrimental conditions.[93] Different routes of administration such as intravenous, intranasal and cerebroventricular were found to be effective. Furthermore, there are strong indications that IGF-I administration can also stimulate neural tissue regeneration.

In one study, Sohrabji et al reported that oestrogen-mediated neuroprotection in neural injury models is critically dependent on IGF-1 signalling.[94] The results of the study showed that oestrogen 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 male Sprague-Dawley rats with traumatic brain injury.[95]


Chronic kidney disease

Serum IGF-I and IGFBP (Insulin-like Growth Factor Binding Protein) axis plays a critical role in the maintenance of normal renal function and progression of chronic kidney disease (CKD).[96] The levels of IGF-1 and IGFBPs are altered with different stages of CKD. Recent studies demonstrate that growth failure in children with CKD is associated with functional IGF deficiency.[97]

The GH resistance in CKD is due to the increasing levels of IGFBPs. Such resistance may be amenable to treatment with recombinant human IGF-1 (rhIGF-1). In one study, Ranke et al investigated the effects of rhIGF-1 treatment in children with GH-receptor deficiency or GH-inactivating antibodies.[98] The results of the study showed a modest increase in growth velocity and height standard deviation score.

In addition, short-term administration of rhIGF-1 in patients with end-stage renal disease (ESRD) and in healthy subjects has been shown to increase glomerular filtration rate and renal plasma flow.[99] Vijayan et al. conducted a study to support the benefits of IGF-1 supplementation in 15 patients with advanced CKD for a period of 31 days.[100] The results of the study showed that administration of 100 microgram/kg of IGF-I twice a day to patients with ESRD improves renal function by increasing the glomerular filtration rate.


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, through activation of a suicidal pathway that leads to programmed cell death of endothelial cells known as apoptosis.[101] IGF-1 can directly oppose endothelial dysfunction in several ways:

  1. By interacting with high-affinity endothelial binding sites resulting to increased production of nitric oxide.[102]
  2. By promoting insulin sensitivity[103]
  3. By promoting potassium-channel opening[104]
  4. By preventing postprandial dyslipidemia[105] (occurs when the rapid absorption of dietary fat overwhelms the body’s ability to clear plasma triglyceride).
  5. Through IGF-1’s anti-apoptotic and anti-inflammatory properties.[106]

A cross-sectional study of 122 young subjects revealed that low level of IGF-1 is associated with coronary artery disease (CAD).[107] 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.[108] In patients with acute myocardial infarction (AMI), serum IGF-1 levels on hospital admission were markedly reduced and were significantly lower in those with a worse prognosis.[109] These observations uniformly support the possibility that IGF-1 deficiency may increase one’s risk for cardiovascular diseases.

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.[110] These beneficial effects of IGF-1 supplementation can help prevent the development of cardiovascular diseases and help treat its related symptoms by improving blood flow to the heart.


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 advance muscle weakness and wasting because of IGF-1’s role in skeletal muscle growth, differentiation, survival, and regeneration.[111]   

Muscle atrophy or also known as muscle wasting results primarily from accelerated protein degradation and is associated with increased expression of two muscle-specific ubiquitin ligases (a type of protein) known as atrogin-1 and muscle ring finger 1 (MuRF1).[112] Sacheck et al reported that IGF-I administration can prevent muscle wasting by stimulating muscle growth through suppression of protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1.[113]

Several chronic illnesses can lead to the development of muscle wasting. Advanced congestive heart failure is associated with activation of the renin-angiotensin system (hormone system that regulates blood pressure and fluid balance) and skeletal muscle wasting.[114] In one study, Song et al reported that the infusion of a potent vasoconstrictor angiotensin II in rats produces cachexia and also decreases levels of circulating and skeletal muscle IGF-1.[115] They also found out that muscle-specific expression of IGF-1 blocks skeletal muscle wasting in rats treated with angiotensin II.   


Alzheimer’s Disease (AD)

The search for a cure of Alzheimer’s dementia is restless. The brains of people with AD have an abundance of abnormal structure called amyloid plaques (sticky buildup which accumulates outside nerve cells, or neurons).[116] Recent advances in medicine have shown that  brain amyloid clearance is modulated by serum IGF-I.[117]  

In one study involving Dementia-free Framingham participants from generation 1 and generation 2 who had their serum IGF-1 measured in 1990-1994 and 1998-2001, respectively, and were followed prospectively for incident dementia and AD dementia, Westwood et al reported that those with lower serum levels of IGF-1 are at higher risk of developing AD dementia.[118] The results of the study showed that higher levels of IGF-1 may protect against neurodegeneration. To prove this, a study conducted by Freude et al revealed that neuronal IGF-1 resistance reduces beta-amyloid accumulation (hallmark feature of AD) and protects against premature death.[119]


Side effects of IGF-1 Supplementation

Hormone supplements such as IGF-1 are designed to treat people with measurable deficiencies. As such, safe and reliable formulas which are usually prescribed by doctors are recommended. Taking IGF-1 supplements can have the following side effects:[120]

  • Increase in muscle mass and strength
  • Increased recovery rate
  • Increased bone mineral density and bone growth
  • Short-term hypoglycemia (low blood sugar levels)


IGF-1 and its Role in Cancer

The link between the role of IGF-1 in cancer development remains controversial. Extensive study of cancer survivors treated with GH has failed to demonstrate an increase in tumor recurrence and de novo cancers (first occurrence of cancer in the body). One long-term follow-up surveillance data involving 13 581 children diagnosed with common cancers who are treated with IGF-1 does not appear to increase the risk of disease recurrence or death in survivors of childhood cancer.[121]

In another large study by Swerdlow and colleagues, GH treatment in children with brain tumors does not increase the risk of recurrence.[122] Data from the Childhood Cancer Survivor Study (CCSS) are also consistent with the finding that GH administration does not increase risk of disease recurrence in patients with primary brain tumors and acute leukemia.[123] Finally, data from the two largest international databases and surveillance studies involving 86 000 patients on GH and IGF-1 therapy has shown no significant increase in cancer incidence.[124]    

In animal studies, GH and IGF-1 levels approximately 10% that of normal showed almost complete growth suppression of transplanted human breast cancer cells, and more recent studies have demonstrated that introduction of growth hormone receptor antagonist in mice significantly reduced the incidence of mammary carcinogenesis.[125]

IGF-1 plays a major role in reducing the risk of cancer development. Increasing evidence suggests that IGF-1 regulates hematopoiesis, which is 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.[126] Also, IGF-1 reduces inflammation[126] and reduces blood sugar, all of which are risk factors that feed cancer growth or development.


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 quality of life. GH plays a wide array of roles in the body 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 in children and in adults include treatment of growth hormone deficiency, chronic renal insufficiency, idiopathic short stature, AIDS-related wasting and fat accumulation. GH therapy usually begins at a low dose and is gradually adjusted to obtain optimal efficacy while minimizing side effects.[127]

Intramuscular route was initially recommended for GH. Subcutaneous injection of GH has been avoided owing to the effect that this route of administration might have on the development of antibodies to GH.[128] However, the efficacy, pharmacokinetic effects and the potential development of antibodies  in subcutaneous injection of GH are similar to intramuscular administration.[129] Today, subcutaneous injection is the route of choice for GH administration. In addition, trials for alternative less invasive modes of GH administration such as the nasal, pulmonary and transdermal routes are under way. Oral route of GH administration is ineffective because they are typically destroyed in the gastrointestinal tract during the process of digestion.


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 tissue, 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. Several studies have proved that HGH supplementation is beneficial in a wide array of diseases and abnormalities.


Neuropsychiatric-cognitive abnormalities

Patients with Growth Hormone Deficiency (GHD) often suffer from low energy levels, mood changes, and mental fatigue. In one study, GH replacement treatment for 6 to 12 months lead to significant improvements in body composition, muscle strength, energy levels, emotional reactions, and self-esteem scores.[130] Another study 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 treatment resulted in improvement in perceived energy levels, body image, pain level and cognition.[131]


Cardiovascular morbidity and mortality

The degree of GHD is directly related to elevated levels of total cholesterol, low-density lipoprotein (bad cholesterol), truncal fat, waist–hip ratio, and risk of hypertension – all of these factors can increase one’s risk for cardiovascular mortality.[132] A meta-analysis on the effects of different 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.[133]


Body composition and metabolic abnormalities

In adults with GHD, there is a reduction in lean body mass and an increase in abdominal adiposity. 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.[134] GH deficiency is associated with hypertriglyceridemia (high triglyceride levels), hypertension,[135] and low levels of high density lipoprotein (good cholesterol) has improved following recombinant GH replacement.[136]

In another study, a meta-analysis of 37 blinded, randomized, placebo-controlled trials found that GH replacement therapy has an overall beneficial effect on LDL cholesterol and total cholesterol profiles.[133] 


Muscular abnormalities

There is a significant association between reduced lean muscle mass and impaired neuromuscular function.[137] In one study, a significant improvement in lean mass and neuromuscular function was observed after more than 10 years of GH replacement therapy.[138]   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.[139]


Bone abnormalities

Adult Growth Hormone Deficiency (AGHD) causes osteoporosis which increases one’s risk for   vertebral and non-vertebral fractures, and low bone mass. In one study, GH replacement has shown to reverse this situation rapidly, resulting in increases in markers of bone formation and bone resorption[140] (process by which osteoclasts break down bone and release minerals, resulting in a transfer of calcium from bone fluid to the blood).


Growth Hormone and IGF-1 in Athletics

GF-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.[141] 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 athletics

GH and IGF-1 compounds bind to specific receptors, initiating cell division, which in turn causes muscle growth and an increase in muscle mass.[142] 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 exerts the following anabolic effects which can benefit athletes:[143]

  • Causes protein synthesis, muscle mass and strength
  • Causes significant fat reduction
  • Inhibits the catabolic effects (breakdown of complex molecules to form simpler ones, together with the release of energy) 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.[144] 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.[145] 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.[146] 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.[147]


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).[148] 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 three criteria:[149]   

  1. It enhances sport performance.
  2. It poses health risk to athletes.
  3. 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. IGF-1 is considered a Schedule III narcotic, even though it is naturally produced in the body.[150]  

 

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