Growth hormone (GH or somatotropin) is a 191-amino acid, single chain polypeptide hormone which is synthesised, stored and secreted by the somatotroph cells within the lateral wings of the anterior pituitary gland, which stimulates growth and cell reproduction in humans and other animals.

Terminology

Growth hormone (GH) is also called “somatropin” and “somatotropin” (British: “somatotrophin”).

“hGH” refers to human growth hormone and is an abbreviation for human GH measured in the extracts from human pituitary glands.

In 1985, biosynthetic human growth hormone replaced pituitary-derived human growth hormone for therapeutic use in the U.S. and elsewhere. Biosynthetic human growth hormone, also referred to as recombinant human growth hormone, is also called somatropin and abbreviated as “rhGH”.

Since the mid-1990s the abbreviation HGH has begun to carry paradoxical connotations, and now rarely refers to real GH used for indicated purposes.

Physiologic Effects of Growth Hormone

A critical concept in understanding growth hormone activity is that it has two distinct types of effects:

  • Direct effects are the result of growth hormone binding its receptor on target cells. Fat cells (adipocytes), for example, have growth hormone receptors, and growth hormone stimulates them to break down triglyceride and supresses their ability to take up and accumulate circulating lipids.
  • Indirect effects are mediated primarily by a insulin-like growth factor-I (IGF-I), a hormone that is secreted from the liver and other tissues in response to growth hormone. A majority of the growth promoting effects of growth hormone is actually due to IGF-I acting on its target cells.

Keeping this distinction in mind, we can discuss two major roles of growth hormone and its minion IGF-I in physiology.

Effects on Growth

Growth is a very complex process, and requires the coordinated action of several hormones. The major role of growth hormone in stimulating body growth is to stimulate the liver and other tissues to secrete IGF-I. IGF-I stimulates proliferation of chondrocytes (cartilage cells), resulting in bone growth. Growth hormone does seem to have a direct effect on bone growth in stimulating differentiation of chondrocytes.

IGF-I also appears to be the key player in muscle growth. It stimulates both the differentiation and proliferation of myoblasts. It also stimulates amino acid uptake and protein synthesis in muscle and other tissues.

Other functions

Although height growth is the best known effect of GH, it serves many other metabolic functions as well.

  • It increases calcium retention, and strengthens and increases the mineralization of bone.
  • It increases muscle mass through the creation of new muscle cells (which differs from hypertrophy)
  • It promotes lipolysis, which results in the reduction of adipose tissue (body fat).
  • It increases protein synthesis and stimulates the growth of all internal organs excluding the brain.
  • It plays a role in fuel homeostasis.
  • It reduces liver uptake of glucose, an effect that opposes that of insulin.
  • It promotes liver gluconeogenesis.
  • It contributes to the maintenance and function of pancreatic islets.
  • It stimulates the immune system.

Secretion of Growth Hormone

Several molecular forms of GH circulate. Much of the growth hormone in the circulation is bound to a protein (growth hormone binding protein, GHBP) which is derived from the growth hormone receptor.

GH is secreted into the blood by the somatotrope cells of the anterior pituitary gland, in larger amounts than any other pituitary hormone. Secretion levels are highest during puberty. The transcription factor PIT-1 stimulates both the development of these cells and their production of GH. Failure of development of these cells, as well as destruction of the anterior pituitary gland, results in GH deficiency.

Regulation of Growth Hormone

Peptides released by neurosecretory nuclei of the hypothalamus into the portal venous blood surrounding the pituitary are the major controllers of GH secretion by the somatotropes. However, although the balance of these stimulating and inhibiting peptides determines GH release, this balance is affected by many physiological stimulators and inhibitors of GH secretion.


Stimulators of GH secretion include:

  • growth hormone releasing hormone (GHRH) from the arcuate nucleus
  • ghrelin
  • sleep
  • exercise
  • low levels of blood sugar (hypoglycemia)
  • dietary protein
  • estradiol
  • arginine

Inhibitors of GH secretion include:

  • somatostatin from the periventricular nucleus inhibits it.
  • circulating concentrations of GH and IGF-1 (negative feedback)
  • dietary carbohydrate
  • glucocorticoids

In addition to control by endogenous processes, a number of foreign compounds (xenobiotics) are now known to influence GH secretion and function, highlighting the fact that the GH-IGF axis is an emerging target for certain endocrine disrupting chemicals.

Secretion patterns

Most of the physiologically important secretion occurs as several large pulses or peaks of GH release each day. The plasma concentration of GH during these peaks may range from 5 to 35 ng/mL or more. Peaks typically last from 10 to 30 minutes before returning to basal levels. The largest and most predictable of these GH peaks occurs about an hour after onset of sleep. Otherwise there is wide variation between days and individuals. Between the peaks, basal GH levels are low, usually less than 3 ng/mL for most of the day and night.

The amount and pattern of GH secretion change throughout life. Basal levels are highest in early childhood. The amplitude and frequency of peaks is greatest during the pubertal growth spurt. Healthy children and adolescents average about 8 peaks per 24 hours. Adults average about 5 peaks. Basal levels and the frequency and amplitude of peaks decline throughout adult life.

Related diseases

States of both growth hormone deficiency and excess provide very visible testaments to the role of this hormone in normal physiology. Such disorders can reflect lesions in either the hypothalamus, the pituitary or in target cells. A deficiency state can result not only from a deficiency in production of the hormone, but in the target cell’s response to the hormone.

Growth hormone excess: (acromegaly and pituitary gigantism)

The most common disease of GH excess is a pituitary tumor comprised of somatotroph cells of the anterior pituitary. These somatotroph adenomas are benign and grow slowly, gradually producing more and more GH. For years, the principal clinical problems are those of GH excess. Eventually the adenoma may become large enough to cause headaches, impair vision by pressure on the optic nerves, or cause deficiency of other pituitary hormones by displacement.
Prolonged GH excess thickens the bones of the jaw, fingers and toes. Resulting heaviness of the jaw and increased thickness of digits is referred to as acromegaly. Accompanying problems can include pressure on nerves (e.g., carpal tunnel syndrome), muscle weakness, insulin resistance or even a rare form of type 2 diabetes, and reduced sexual function.
GH-secreting tumors are typically recognized in the 5th decade of life. It is extremely rare for such a tumor to occur in childhood, but when it does the excessive GH can cause excessive growth, traditionally referred to as pituitary gigantism.
Surgical removal is the usual treatment for GH-producing tumors. In some circumstances focused radiation or a GH antagonist such as bromocriptine or octreotide may be employed to shrink the tumor or block function.

Growth hormone deficiency (GHD)

Deficiency of GH produces significantly different problems at various ages. In children, growth failure and short stature are the major manifestations of GH deficiency. In adults the effects of deficiency are more subtle, and may include deficiencies of strength, energy, and bone mass, as well as increased cardiovascular risk.
There are many causes of GH deficiency, including mutations of specific genes, congenital malformations involving the hypothalamus and/or pituitary gland, and damage to the pituitary from injury, surgery or disease.
Diagnosis of GH deficiency involves a multiple step diagnostic process, usually culminating in GH stimulation test(s) to see if the patient’s pituitary gland will release a pulse of GH when provoked by various stimuli.
GH deficiency is treated by replacing GH. All GH in current use is a biosynthetic version of human GH, manufactured by recombinant DNA technology. As GH is a large protein molecule, it must be injected into subcutaneous tissue (or muscle) to get it into the blood. When the patient has had a long-standing deficiency of GH, benefits of treatment are often dramatic and gratifying and side effects of treatment are rare. Increased growth in childhood can result in dramatically improved adult height.
GH is used as replacement therapy in adults with GH deficiency of either childhood-onset (after completing growth phase) or adult-onset (usually as a result of an acquired pituitary tumor). In these patients, benefits have variably included reduced fat mass, increased lean mass, increased bone density, improved lipid profile, reduced cardiovascular risk factors, and improved psychosocial well-being.

Pharmaceutical and Biotechnological Uses of Growth Hormone

In years past, growth hormone purified from human cadaver pituitaries was used to treat children with severe growth retardation. More recently, the virtually unlimited supply of growth hormone produced using recombinant DNA technology has lead to several other applications to human and animal populations.
Human growth hormone is commonly used to treat children of pathologically short stature. There is concern that this practice will be extended to treatment of essentially normal children - so called “enhancement therapy” or growth hormone on demand. Similarly, growth hormone has been used by some to enhance atheletic performance. Although growth hormone therapy is generally safe, it is not as safe as no therapy and does entail unpredictable health risks. Parents that request growth hormone therapy for children of essentially-normal stature are clearly misguided.
Growth hormone is currently approved and marketed for enhancing milk production in dairy cattle. There is no doubt that administration of bovine somatotropin to lactating cows results in increased milk yield, and, depending on the way the cows are managed, can be an economically-viable therapy. However, this treatment engenders abundant controversy, even among dairy farmers. One thing that appears clear is that drinking milk from cattle treated with bovine growth hormone does not pose a risk to human health.
Another application of growth hormone in animal agriculture is treatment of growing pigs with porcine growth hormone. Such treatment has been demonstrated to significantly stimulate muscle growth and reduce deposition of fat.

Anti-aging agent claims

Claims for GH as an anti-aging treatment date back to 1990 when the New England Journal of Medicine published a study where GH was used to treat 12 men over 60. At the conclusion of the study all the men showed statistically significant increases in lean body mass and bone mineral, while the control group did not. The authors of the study noted that these were the kind of changes that would occur naturally over a 10 to 20 year aging period. Despite the fact the authors at no time claimed that GH had reversed the aging process itself, their results were mis-interpreted as indicating GH was an effective anti-aging agent.
A Stanford University School of Medicine survey of clinical studies on the subject published in early 2007 showed that the application of GH on healthy elderly patients increased muscle by 2 kgs and decreased body fat by the same amount. However, these were the only positive effects from taking GH. No other critical factors were affected, such as bone density, cholesterol levels, lipid measurements, maximal oxygen consumption, or any other factor that would indicate increased fitness. Researchers also didn’t discover any gain in muscle strength, which led them to believe that GH merely let the body store more water in the muscles rather than increase muscle growth. This would explain the increase in lean body mass.
Regular application of GH did show several negative side effects such as joint swelling, joint pain, carpal tunnel syndrome, and an increased risk of diabetes. However, proponents of GH use as an anti-ageing substance claims that these side affects will not happen if injections are done in physiological amounts.

Risks and side effects of GH treatment

Risks and side effects of GH use in children are rare, principally headache due to pseudotumor cerebri and slipped capital femoral epiphysis. The most common minor side effects in adults include fluid retention, joint pain, and nerve compression symptoms. There is theoretical concern and weak evidence that GH treatment may increase the risks of diabetes or cancer, especially in those with other predispositions treated with higher doses. One survey of adults who had been treated with replacement cadaver GH during childhood showed a mildly increased incidence of colon cancer, but linkage with the GH treatment was not established.

Growth Hormone use Controversy

There are many controversies around the claims, products, and businesses related to the use of growth hormone as an anti-aging therapy. Most of this controversy falls into two categories:

  1. Claims of exaggerated, misleading, or unfounded assertions that real growth hormone treatment slows or reverses the effects of aging.
  2. The sale of products that fraudulently or misleadingly purport to be growth hormone or to increase the user’s own secretion of natural human growth hormone to a beneficial degree.

Following a study in 1990 by Rudman which showed fat loss, muscle mass increase and maintenance of healthy skin from the administration of growth hormone in elderly men, there has been a burgeoning industry surrounding the sale and administration of GH and its purported anti-aging effects.

As is common with such therapies, the literature is now dominated by advocacy from pharmaceutical companies. Solid medical evidence is harder to find, and appears to indicate mixed results. It is likely that there is some advantage, but it is also evident that benefits are being exaggerated by some for commercial gain.

Some of the side effects reportedly seen in previously healthy mature patients after taking HGH include:

  • Edema (retention of fluids) in extremities
  • Arthralgia (joint pain)
  • Carpal tunnel syndrome
  • Hypertension
  • Diabetes and other glucose metabolism imbalances
  • Gynecomastia (enlargement of male mammary glands)
  • Enlargement of Testicles

Chronic use of hGH is not well studied, except when used in children for acute growth deficiencies. A long term increase in colon cancer and Hodgkin’s Disease has been observed in these cases.

Sources: Wikipedia, colostate.edu

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