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Growth Hormone in Aging
Posted on: April 15, 2005

Growth Hormone

Growth hormone, also known as somatotropin, is a protein hormone of about 190 amino acids that is synthesized and secreted by cells called somatotrophs in the anterior pituitary. It is a major participant in control of several complex physiologic processes, including growth and metabolism. Growth hormone is also of considerable interest as a drug used in both humans and animals.


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 suppresses their ability to take up and accumulate circulating lipids.
  • Indirect effects are mediated primarily by a insulin-like growth factor-1 (IGF-1), 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-1 acting on its target cells.

Keeping this distinction in mind, we can discuss two major roles of growth hormone and its minion IGF-1 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-1. IGF-1 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-1 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.

Metabolic Effects

Growth hormone has important effects on protein, lipid and carbohydrate metabolism. In some cases, a direct effect of growth hormone has been clearly demonstrated, in others, IGF-1 is thought to be the critical mediator, and some cases it appears that both direct and indirect effects are at play.

  • Protein metabolism: In general, growth hormone stimulates protein anabolism in many tissues. This effect reflects increased amino acid uptake, increased protein synthesis and decreased oxidation of proteins.
  • Fat metabolism: Growth hormone enhances the utilization of fat by stimulating triglyceride breakdown and oxidation in adipocytes.
  • Carbohydrate metabolism: Growth hormone is one of a battery of hormones that serves to maintain blood glucose within a normal range. Growth hormone is often said to have anti-insulin activity, because it supresses the abilities of insulin to stimulate uptake of glucose in peripheral tissues and enhance glucose synthesis in the liver. Somewhat paradoxically, administration of growth hormone stimulates insulin secretion, leading to hyperinsulinemia.

Control of Growth Hormone Secretion


Production of growth hormone is modulated by many factors, including stress, exercise, nutrition, sleep and growth hormone itself. However, its primary controllers are two hypothalamic hormones and one hormone from the stomach:

  • Growth hormone-releasing hormone (GHRH) is a hypothalamic peptide that stimulates both the synthesis and secretion of growth hormone.
  • Somatostatin (SS) is a peptide produced by several tissues in the body, including the hypothalamus. Somatostatin inhibits growth hormone release in response to GHRH and to other stimulatory factors such as low blood glucose concentration.
  • Ghrelin is a peptide hormone secreted from the stomach. Ghrelin binds to receptors on somatotrophs and potently stimulates secretion of growth hormone.

Growth hormone secretion is also part of a negative feedback loop involving IGF-1. High blood levels of IGF-1 lead to decreased secretion of growth hormone not only by directly suppressing the somatotroph, but also by stimulating release of somatostatin from the hypothalamus.
Growth hormone also feeds back to inhibit GHRH secretion and probably has a direct (autocrine) inhibitory effect on secretion from the somatotroph.
Integration of all the factors that affect growth hormone synthesis and secretion lead to a pulsatile pattern of release. Basal concentrations of growth hormone in blood are very low. In children and young adults, the most intense period of growth hormone release is shortly after the onset of deep sleep.

Disease States

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.
Clinically, deficiency in growth hormone or receptor defects is as growth retardation or dwarfism. The manifestation of growth hormone deficiency depends upon the age of onset of the disorder and can result from either heritable or acquired disease. The effect of excessive secretion of growth hormone is also very dependent on the age of onset and is seen as two distinctive disorders:

  • Giantism is the result of excessive growth hormone secretion that begins in young children or adolescents. It is a very rare disorder, usually resulting from a tumor of somatotropes. One of the most famous giants was a man named Robert Wadlow. He weighed 8.5 pounds at birth, but by 5 years of age was 105 pounds and 5 feet 4 inches tall. Robert reached an adult weight of 490 pounds and 8 feet 11 inches in height. He died at age 22.
  • Acromegaly results from excessive secretion of growth hormone in adults. The onset of this disorder is typically insideous. Clinically, an overgrowth of bone and connective tissue leads to a change in appearance that might be described as having "coarse features". The excessive growth hormone and IGF-1 also lead to metabolic derangements, including glucose intolerance.

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 recombinant growth hormone 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 athletic 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.
The role of growth hormone in normal aging remains poorly understood, but some of the cosmetic symptoms of aging appear to be amenable to growth hormone therapy. This is an active area of research, and additional information and recommendations about risks and benefits will undoubtedly surface in the near future.
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.

Growth Hormone and Aging

The rate of GH secretion from the anterior pituitary is highest around puberty, and declines progressively thereafter. This age-related decline in GH secretion involves a number of changes in the GH axis, including decreased serum levels of insulin-like growth factor-1 (IGF-1) and decreased secretion of growth hormone-releasing hormone from the hypothalamus. The cause of the normal age-related decrease in GH secretion is not well understood, but is thought to result, in part, from increased secretion of somatostatin, the GH-inhibiting hormone.
Normal aging is accompanied by a number of catabolic effects, including a decrease in lean mass, increase in fat mass, and decrease in bone density. Associated with these physiologic changes is a clinical picture often referred to as the somatopause: frailty, muscle atrophy, relative obesity, increased frequency of fractures and disordered sleep. These clinical signs of aging are, without doubt, the manifestation of a very complex set of changes which involve, at least in part, the GH-axis. Naturally, this has spurred considerable interest in administering supplemental GH as a "treatment" for aging in humans, and the availability of recombinant human GH has made such studies feasible.
In contrast to the view that GH deficiency contributes to the aging phenomenon, there is information suggesting that normal or high levels of GH may accelerate aging. Mice with genetic dwarfism due to deficiency in GH, prolactin and thyroid-stimulating hormone live considerably longer than normal mice, and the increased levels of GH seen with acromegaly in humans are associated with reduced life expectancy. Both of these findings are likely due to metabolic effects of GH.

GH Replacement Therapy in GH-deficient Adults

Adult-onset GH deficiency in humans is usually due to pituitary disease, usually from a tumor or therapeutic efforts to treat a tumor. Such patients have increased risk of death from cardiovascular disease, and, relative to age-matched controls, show increased fat mass, reduced muscle mass and strength, lower bone density, and higher serum lipid concentrations. Additionally, they suffer from reduced vigor, sexual dysfunction and emotional problems.
More than a dozen clinical trials have sought to evaluate GH replacement in patients with adult-onset deficiency. The goal has usually been to normalize serum IGF-1 concentrations by daily injections of GH. In essentially all cases, several months of GH replacement therapy led to increased lean mass and decreased adiposity (especially in visceral fat). The effects of GH treatment on bone density and hyperlipidemia has been inconsistent or minor, as have been the effects on strength and mental abilities. Common side effects observed in these trials included edema and joint/muscle pain, which appeared related to dose of GH. Since the first of these trials was conducted in 1988, long-term risks are not yet known.

GH Therapy in the Elderly

Long before Ponce de Leon went in search of the legendary fountain of youth, people sought treatments to prevent or reverse the effects of aging. In 1990, considerable excitement was generated from a report by Rudman and colleagues that described wonderful effects of GH treatment in a small group of elderly men. These volunteers, who ranged in age from 61 to 81 years, showed increased lean body and bone mass, decreased fat mass and, perhaps most dramatically, restoration of skin thickness to that typical of a 50-year-old.
The study cited above and a handful of others have provided an initial understanding of the benefits, limitations and risks of sustained (6 to 12 month) GH supplementation in elderly men and women. A consistent finding in these investigations was a high incidence of adverse side effects – edema, fluid retention and carpal tunnel syndrome – which necessitated reductions in GH dose of cessation of treatment. GH treatment consistently induced an increase in serum IGF-1, a decrease in fat mass and increase in lean mass.
The effects on fat and lean masses may be viewed as positive effects, but, at the end of the day, it has to be asked whether GH treatment improved functioning in the elderly. In the studies in which function was objectively assessed, GH treatment did not improve cognitive function, and, despite the effects on lean body mass, was not any more effective than exercise alone in promoting strength. Long-term GH therapy in elderly postmenopausal women lead to significant increases in bone mineral density, but these increases were less than what is routinely achieved with estrogen replacement. While it must be acknowledged that a relatively small number of elderly patients have been treated for prolonged periods with GH, the controlled trials conducted thus far do not support is efficacy in aleviating age-related deficits in cognitive or somatic function.
Another indication of potentially serious side effects of GH therapy in adults, including the elderly, has been provided by controlled clinical trials that assessed the utility of human GH treatment in critical illness, where endogenous GH secretion is typically suppressed. GH therapy was anticipated to attenuate the catabolic effects of illness and thereby decrease duration of hospitalization. The results of several clinical trials involving hundreds of patients, demonstrated a significant increase in mortality associated with high doses of GH. Additionally, those patients treated with GH that survived had longer periods of intensive care and hospitalization than those receiving placebos.

Somatostatin

Somatostatin was first discovered in hypothalamic extracts and identified as a hormone that inhibited secretion of growth hormone. Subsequently, somatostatin is secreted by a broad range of tissues, including pancreas, intestinal tract and regions of the central nervous system outside the hypothalamus.

Structure and Synthesis

Two forms of somatostatin are synthesized. They are referred to as SS-14 and SS-28, reflecting their amino acid chain length. Both forms of somatostatin are generated by proteolytic cleavage of prosomatostatin, which itself is derived from preprosomatostatin. Two cysteine residules in SS-14 allow the peptide to form an internal disulfide bond.


The relative amount of SS-14 versus SS-28 secreted depends upon the tissue. For example, SS-14 is the predominant form produced in the nervous system and apparently the sole form secreted from pancreas, whereas the intestine secretes mostly SS-28.
In addition to tissue-specific differences in secretion of SS-14 and SS-28, the two forms of this hormone can have different biological potencies. SS-28 is roughly ten-fold more potent in inhibition of growth hormone secretion, but less potent that SS-14 in inhibiting glucagon release.

Receptors and Mechanism of Action

Five stomatostatin receptors have been identified and characterized, all of which are members of the G protein-coupled receptor super family. Each of the receptors activates distinct signaling mechanisms within cells, although all inhibit adenylyl cyclase. Four of the five receptors do not differentiate SS-14 from SS-28.

Physiologic Effects

Somatostatin acts by both endocrine and paracrine pathways to affect its target cells. A majority of the circulating somatostatin appears to come from the pancreas and gastrointestinal tract. If one had to summarize the effects of somatostatin in one phrase, it would be: "somatostatin inhibits the secretion of many other hormones".

Effects on the Pituitary Gland

Somatostatin was named for its effect of inhibiting secretion of growth hormone from the pituitary gland. Experimentally, all known stimuli for growth hormone secretion are suppressed by somatostatin administration. Additionally, animals treated with antisera to somatostatin show elevated blood concentrations of growth hormone, as do animals that are genetically engineered to disrupt their somatostatin gene.
Ultimately, growth hormone secretion is controlled by the interaction of somatostatin and growth hormone releasing hormone, both of which are secreted by hypothalamic neurons.

Effects on the Pancreas

Cells within pancreatic islets secrete insulin, glucagon and somatostatin. Somatostatin appears to act primarily in a paracrine manner to inhibit the secretion of both insulin and glucagon. It also has the effect in suppressing pancreatic exocrine secretions, by inhibiting cholecystokinin-stimulated enzyme secretion and secretin-stimulated bicarbonate secretion.

Effects on the Gastrointestinal Tract

Somatostatin is secreted by scattered cells in the GI epithelium, and by neurons in the enteric nervous system. It has been shown to inhibit secretion of many of the other GI hormones, including gastrin, cholecystokinin, secretin and vasoactive intestinal peptide.
In addition to the direct effects of inhibiting secretion of other GI hormones, somatostatin has a variety of other inhibitory effects on the GI tract, which may reflect its effects on other hormones, plus some additional direct effects. Somatostatin suppresses secretion of gastric acid and pepsin, lowers the rate of gastric emptying, and reduces smooth muscle contractions and blood flow within the intestine. Collectively, these activities seem to have the overall effect of decreasing the rate of nutrient absorption.

Effects on the Nervous System

Somatostatin is often referred to has having neuromodulatory activity within the central nervous system, and appears to have a variety of complex effects on neural transmission. Injection of somatostatin into the brain of rodents leads to such things as increased arousal and decreased sleep, and impairment of some motor responses.

Pharmacological Uses

Somatostatin and its synthetic analogs are used clinically to treat a variety of neoplasms. It is also used in to treat giantism and acromegaly, due to its ability to inhibit growth hormone secretion.

Source:Pathophysiology of the Endocrine System.
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