Human Growth Hormone

Physiology and Clinical Use of hGH

Paul Savage MD, FACEP

CMO, BodyLogicMD

“Life without Growth Hormone is poor in both quantity and quality”

-- R. Savine

INTRODUCTION TO ANTI-AGING AND THE USE OF GROWTH HORMONE

Too often, as a physician, I have encountered patients and other physicians stating that growth hormone is unproven in its use, as well as potentially dangerous. Interesting as those comments are, we are seeing an increased use of growth hormone not only by anti-aging physicians, but as well pediatricians, cardiologists, orthopedics, and gerontologists. Pediatricians are using growth hormone with increasingly frequency in child of low stature, cardiologist are using growth hormone to treat patients with cardiomyopathies and congestive heart failure, orthopedics are using growth hormone in the elderly with hip fractures, and gerontologists are using growth hormone with increasing frequency in elderly patients with sarcopenia, osteoporosis, and metabolic syndrome. Growth hormone is like any other hormone in its potential use as well as its side-effects. When used appropriately with the proper patient in the indicated clinical setting, growth hormone can significantly improve the patient’s well-being and health when used at the proper dose.

THE HISTORY OF GROWTH HORMONE

Growth Hormone was first identified in 1920, at which time Dr. Maurice Ruben used growth hormone in the treatment of dwarfism in children. Noting the effects on longitudinal growth in his studies was some of the first clinical work done with Growth Hormone.

Growth Hormone at that time was derived from cadaver’s pituitaries, of which it took thousands of cadavers to treat just one child. In the 1980’s, 3 children developed Creutzfeldt-Jakob disease from the cadaver-derived Growth Hormone and subsequently, Growth Hormone from cadavers was pulled from the market.

This led to the US government passing a bill named “the orphan act”, which granted pharmaceutical companies a long patent period for any company developing the genetically derived human Growth Hormone. Genetech was the first company to produce and release Protropin, a Growth Hormone that had 190 out of the 191 amino acids in the correct order. Shortly thereafter Ely Lilly manufactured the first identical Growth Hormone named Humatrope. This was followed by two other companies eventually deriving their own technique in genetically manufacturing human growth hormone. After a long legal battle, all companies were allowed to produce and distribute the genetically derived human growth hormone.

In 1996, the FDA lifted the ban on the use of human growth hormone for the treatment of adults with Growth Hormone Deficiency Syndrome.

PHYSIOLOGY OF HUMAN GROWTH HORMONE

WHAT IS GROWTH HORMONE

Human Growth Hormone (hGH) is also known as Somatotropin. It is a 191 amino acid hormone produced by the anterior pituitary gland. Somatropes, the cells that produce human growth hormone, comprise the largest numbers of cells in the anterior pituitary gland. Growth Hormone peaks in adolescence, excreted in the early morning hours of sleep, but is also released during times of stress and with time of intense exercise.

The hypothalamus stimulates the pituitary to release hGH through Growth Hormone Releasing Hormone (GHRH). The average healthy adult pituitary releases about 400 micrograms of hGH per day. The Growth Hormone is transported through the blood on binding hormones known as Growth Hormone Binding Hormones. When free growth hormone binds to the cellular receptors (most notably the liver), it stimulates a signal transduction that leads to the production of Insulin-like Growth Hormone (IGF-1), the major growth factor related to hGH. IGF-1 is transported in the blood also bound to binding proteins. The major product of hGH stimulation (IGF-1) is related to many of the positive growth effects of hGH. IGF-1 itself binds to cellular receptors of its target cells (most notably muscle, bone, and glands) to produce a signal transduction and subsequent reactive growth of the target cell. It is due to the relatively short half life of hGH (about 20-50 minutes, occurring in the early morning hours) that we measure the serum levels of IGF-1, which has a much longer half life of 15 hours and remains quite steady throughout the day.

THE PHYSIOLOGIC EFFECT OF HUMAN GROWTH HORMONE

Growth hormone affects all the other hormones of our body, as well as stimulating all cells and organs. It has reparative and restorative powers that reverse cellular and tissue damage. It assists in maintaining size and health of other endocrine glands.

Human Growth Hormone has the physiologic effects of:

– Growth

– Healing

– Immune function

– Increased muscle mass

– Minimizing body fat

– Controlling cholesterol

– Maintaining levels of sexual energy

– Increasing bone strength

The effects of Human Growth Hormone can be divided into three categories.

• Protein Metabolism

• Lipid Metabolism

• Carbohydrate Metabolism

The effect on protein metabolism, most notably the increase in muscle mass, is mediated by Insulin-like Growth Factor (IGF-1). Its effects are to increase amino acid uptake, increase intracellular protein synthesis (thereby decreasing nitrogen excretion), as well as increasing bone synthesis.

Human Growth Hormone (hGH) has a direct effect on lipocytes to stimulate lipolysis and thereby increases ketone bodies in the blood.

Human Growth Hormone (hGH) also effects carbohydrate metabolism by decreasing glucose uptake in extrahepatic tissues yet increasing hepatic glycogen stores. The net effect for some patients is to increase (although transiently) their blood glucose levels.

Many factors affect Growth Hormone secretion. Physiologic factors that increase Growth Hormone levels include getting plenty of sleep, vigorous exercise, acute stress, as well as a nutritional plan that is higher in protein and lower in simple carbohydrates. The opposite effect is true as well, as patients who have less sleep, more chronic stress, a lack of exercise, as well as nutritional plan high in simple carbohydrates and lower in protein excrete lower levels of Growth Hormone.

Pathologic conditions that increase the release of Growth Hormone include acromegaly, anorexia nervosa, as well as acute starvation states. Contrary to that, obesity, hypothyroidism, hypogonadism, and hyperthyroidism may decrease endogenous excretion of hGH.

There are in addition, pharmaceutical medications given by physicians that may increase Growth Hormone secretion, including insulin, transdermal estrogens, Alpha Agonist agents (Clonidine), Beta Antagonist agents (Propranolol), Dopa Agonists (Levodopa), and Serotonin Agonists (SSRI).

Exogenous medications including hGH, glucocorticoids, progesterone, Alpha Antagonist agents (Phentolamine), Beta Agonists (Isoproterenol), Dopa Antagonist agents (Phenothiazines), and Serotonin Agonists (Methysergide) decrease endogenous production of hGH.

GROWTH HORMONE AND AGING

The production and release of Human Growth Hormone decline with age. In the years of 18-25, young adults produce over 700 micrograms per day, where as by the age of early adulthood, growth hormone declines to less than 400 micrograms per day. This steady decline continues with increasing age. The exact mechanism for the decline of growth hormone is not completely understood, but seems to be related to a decreasing release of Growth Hormone Releasing Hormone (GHRH) by the hypothalamus, a decreasing number of somatotropes in the anterior pituitary, as well as increasing negative feedback stimulation by the inhibitory hormone Somatostatin. What is known is that the adult human has a decrease in the production of hGH with advancing years at about a rate of 1-2% per years.

This decline in growth hormone leads to many detrimental effects on the human body including

• More fat

• Smaller muscles (sarcopenia)

• Thinner skin

• Weaker bones

• Worsening cholesterol

• More atherosclerosis

Sounds a lot like getting old, huh?

“And in the end, it's not the years in your life that count. It's the life in your years!”

Abraham Lincoln

CLINICAL STUDIES

MAJOR STUDIES

The first and most well reported study on hGH comes from Dr. Daniel Rudman, endocrinologist at University of Wisconsin. In this 1990 study, published in NEJM, he reported the effects of hGH on 12 elderly men, using 9 men as the control group. These men were given hGH 3 times a week, at what is now considered a high dosage-low frequency, and noted the following results:

– 14% decrease in body fat (average 3.5 kg loss)

– 8.8% increase in lean body mass (average 4.7 kg increase)

– Increased bone density (lumbar 0.02g/cm2 increase)

– Increased skin thickness

Often side-effects of swelling, edema, carpal tunnel, gynecomastia, and elevated fasting blood sugars were noted. These effects are not seen as commonly now, as the use of hGH is given in the “low dose-high frequency” method (noted below).

Maureen Papadakis from UCSF repeated Dr. Rudman’s study in 1996 and noted similar results. In this study of 52 men, ranging in age from 70 to 85 years, she noted similar response in effects and side-effects to the men in the treatment group.

• Decrease in fat mass of 13.1%

• Increase in lean mass of 4.3%

• Increase in bone mineral content of 0.9%

• Increase in skin thickness of 13.4%

• Increase in muscle strength 10%

• Increase in maximum oxygen consumption 2.5%

In 1996 as well, Dr. Cass Terry compiled research on 202 patients treated by Dr. Edmund Chein. In this published report using low dose-high frequency hGH administration, they noted:

• 80% overall improved

• 73% reported increased resistance to illness

• 72% noted significant fat loss

• 60-70% had improved skin

• 55-71% healed faster

• 38% had increased hair growth

• Minimal side effects (edema, joint pain, carpel tunnel, gynecomastia)

One of the most remarkable and now often sighted studies was done by Dr. Mark Blackman at the National Institute of Health, in which they studied 131 men and women divide into group of:

• Control (received no medications)
• Treated only with hGH
• Treated only with sex steroids (testosterone to men, estradiol to women)
• Treated with hGH and sex steroids (testosterone to men, estradiol to women)

The results of this study showed Results:

• Growth hormone with or without sex steroids in healthy, aged women and men increased lean body mass and decreased fat mass.
• Sex steroid used with Growth hormone increased muscle strength marginally and cardiovascular endurance in men, but women had no significant change in strength or cardiovascular endurance.

GROWTH HORMONE AND HEART DISEASE

A number of studies have shown the beneficial effects of human growth hormone on heart disease. Not only on the effect hGH has on decreasing arteriosclerosis, but on the use of hGH on patients with congestive heart failure due to a cardiomyopathy or weakened heart musculature.

In the Rancho Bernardo Study 2004, it was shown that lower IGF-1 levels were associated with increased ischemic heart disease (IHD) among older community-dwelling men and women

• Ischemic Heart Disease increased 38% for every 40ng/ml decrease in IGF-1

• Ischemic Heart Disease is 3 times higher in population in the lowest 20th percentile of IGF-1

Ren et al showed in a study published in the Jour Mol Cell Cardiology that hGH

• Improves cardiac function after myocardial infarction by stimulating contractility and promoting tissue healing

• Improves contractility, cardiac output, stroke volume and ejection fraction

In a paper released in 1996 in the Journal of Clinical Endocrinology and Metabolism:

• Growth hormone normalizes intima-media thickness of carotid artery by 3 months
• Intima-media wall thickness negatively correlated with IGF-1

GROWTH HORMONE AND BODY COMPOSITION

In 1996, in the Journal of Clinical Endocrinology, Verhelst demonstrated:

• Benefit on body composition, effect weakened after two years

– Lean body mass gain at year one 2.7kg

– Lean body mass gain at year two 2.2kg

• Sick days consistently dropped and hospitalizations fell with patient on hGH

• Give hGH therapy individualized, monitoring IGF-1 levels and not related to weight nor sex

In 1999, Gibney demonstrated in an article published in the Journal of Clinical Endocrinology and Metabolism, with 21 growth hormone deficient adults, in a randomized, double blind, placebo-controlled trial of growth hormone treatment for 10 years

– 10 patients received continuous GH replacement, whereas 11 received placebo

– GH treatment for 10 years in GHD adults resulted in

• increased lean body and muscle mass

• less atherogenic lipid profile

• reduced carotid intima media thickness

• improved psychological well-being

GROWTH HORMONE AND COGNITIVE FUNCTION

In the publication Neuroendocrinology, a paper was published that showed that Growth hormone improves

• Cognitive abilities

• Memory

• Alertness

• Motivation, Work Capacity

In a study by Lamberts in the Archives of Neurology in 2002, he demonstrated that in healthy elderly men, serum IGF-1 levels demonstrated to be significantly associated with several aspects of cognition, specifically, and speed of information processing.

In a study by Kalmijn in the Journal of Clinical Endocrinology in 2000, showed that in a prospective study in healthy elderly individuals, the decline in cognition function was inversely related to serum IGF-1 levels. In addition higher total IGF-1 were associated with less cognitive decline.

GROWTH HORMONE AND AGING

In the Journal of Clinical Endocrinology Metabolism in 2003, a study by A. Besson compared hereditary dwarfism with siblings who were not dwarfs. He showed that the median life span in Growth Hormone-deficient group (dwarves) was significantly shorter than that of unaffected brothers and sisters (males 56 vs. 75 yrs. and females 46 vs. 80 yrs.). His conclusion was that Growth Hormone treatment in adult patients suffering from either childhood- or adult-onset GHD is crucially important.

In a study published in Gerontoloy in 2002, Ruiz-Torres concluded that older males with higher IGF-1 levels do not show age related decreases in testosterone, lean body mass, nor increases in body fat. He concluded that Growth hormone determines life potential.

GROWTH HORMONE AND CANCER

Much concern proposed by physicians is that Growth Hormone promotes the growth of cancer and is related to an increase in cancer in patients treated with Growth Hormone. The medical literature does not support this conclusion.

In a long term study conducted by Dr. M. Vance, he concluded, as reported in the NEJM, that there was “no evidence that Growth Hormone replacement therapy affects the risk of cancer or cardiovascular disease.”

In 1999, in the Annals of Internal Medicine, Dr WL Isley reported that “There does not appear to be an increase in rates of cancer in adult patients who have received Growth Hormone Therapy”

And in yet a third major peer reviewed journal, Dr. ME Molitch reported in the Journal of Clinical Endocrinology and Metabolism that “Although there has been some concern about an increase risk of cancer, reviews of existing well-maintained databases of treated patients have shown this theoretical risk to be nonexistent.”

There are in fact established medical references to the fact that Growth Hormone may prevent the growth of cancer. In an article published in 2000 in the Journal of Perenteral and Enteralogic Nutrition, Dr. J Tacke states that Growth Hormone promotes protein synthesis, accelerates wound healing, and maintains immune function in the catabolic states. He further states that there no evidence for an increase risk of tumor recurrence with GH treatment.

Much of the concern regarding the treatment with Growth Hormone may be in fact that Insulin-like Growth Factor 1 has been associated with the increased growth of tumors. However, that does not translate to the therapeutic administration of Growth Hormone. It may be in fact that the administration of Growth Hormone not only increases the IGF-1 level, but as well, the level of binding proteins (IGFBP). Due to an increase of growth hormone binding proteins, the free level of IGF-1 is modified (lowered). It may be that the free level of IGF-1 is the factor associated with the increased growth of tumors.

As shown in a study by Dr. D.M. Cook, as published in the Annals of Internal Medicine in 2002, the epidemiologic studies suggest an increase in prostate, lung, and colon cancer in normal persons with high-normal serum IGF-1 concentrations and reduced levels of IGF binding proteins, resulting in elevated free IGF-1 concentrations. Appropriate Growth Hormone replacement therapy however is associated with normalization, not elevation, of serum IGF-I concentrations. In addition, levels of binding proteins are concomitantly increased with GH replacement, along with levels of IGF-1, resulting in normal, not elevated, free IGF-1 concentrations.

Melmed demonstrated that the increase in IGF-1 is offset by the associated increase in IGFBP-3 that occurs with Growth Hormone replacement. Elevated IGF-1 levels are potent inhibitors of apoptosis (cell death) and may be associated with an increased risk of cancer in the general population. However, higher IGFBP-3 levels have proapoptosis (increase cell death) effects, resulting in a concordant lower risk of cancer.

In one of the most effective studies showing the safety of Growth Hormone is the study done by Dr. Janssen of the Netherlands. The study showed that more than 100,000 patients worldwide have receiving hGH therapy and that the data to date does not suggest that hGH therapy of adults with Growth Hormone Deficiency increases the risk of cancer, provided that IGF-1 levels remain within the normal range.

“All would live long, but none would be old.” -- Benjamin Franklin