Is growth hormone a sound anti-aging therapy?

The marketing of human growth hormone (HGH) has only increased since this commentary was published in JAMA (the Journal of the American Medical Association) several years ago:

"The distribution and marketing of human growth hormone (HGH or GH) via Web sites and antiaging clinics has grown into a multimillion-dollar antiaging industry. Despite congressional hearings warning of deceptive marketing claims and the potential health and economic dangers associated with the antiaging industry, and statements issued by the National Institute on Aging and the Federal Trade Commission, the distribution and use of GH for antiaging is now common. For example, entering the terms "HGH" and "anti-aging" into the Google search engine generated 3 410 000 hits as of September 26, 2005, many representing Web sites and clinics marketing and selling GH."

Is the marketing of GH to people without an objective test demonstrating growth hormone deficiency a safe and effective practice? A number of studies indicate that using supraphysiological (abnormally high) levels of growth hormone as a 'shortcut' to improve body composition (lose fat) is neither necessary nor safe. A perspective published in The New England Journal of Medicine recalls the single study that launched the GH anti-aging industry:

"An article by Rudman et al. that appeared in the Journal in 1990 reported the effect on body composition of administering human growth hormone for six months to 12 older men. This article incited a proliferation of “antiaging” clinics and lay publications, such as “Grow Young with HGH,” extolling the benefits of growth hormone in reversing or preventing aging...First, it is necessary to recall exactly what the study...demonstrated. Twelve healthy men...received growth hormone for six months...The weekly dose of growth hormone was approximately twice as high as the dose used in adult men with a growth hormone deficiency...The administration of growth hormone in older men resulted in a 4.7-kg increase in lean body mass, a 3.5-kg decrease in adipose mass, and an increase of 0.02 g per square centimeter in lumbar-spine density; systolic blood pressure and the fasting glucose concentration increased significantly. The study was not double-blind (there was a control group consisting of nine men who received no treatment); there were no assessments of muscle strength, exercise endurance, or quality of life. This study is the basis for claims that growth hormone reverses aging...A recent...study...confirmed the effects of growth hormone on body composition; there was no change in muscle strength or maximal oxygen uptake during exercise in either group..."

Is this improvement in body composition, without any increase in strength or oxygen efficiency, anything that can't be accomplished with simple lifestyle measures?

"Not mentioned on the “antiaging” Web sites is a study of 18 healthy men, 65 to 82 years of age, who underwent progressive strength training for 14 weeks, followed by an additional 10 weeks of strength training plus either growth hormone or placebo. In that study, resistance exercise training increased muscle strength significantly; the addition of growth hormone did not result in any further improvement. Going to the gym is beneficial and certainly cheaper than growth hormone."

But what about safety, especially the increased risk of developing cancer?

"In 152 healthy men, the relative risk of the subsequent development of prostate cancer was increased by a factor of 4.3 among men who had serum concentrations of insulin-like growth factor I in the highest quartile, as compared with those whose concentrations were in the lowest quartile (Insulin-like growth factor I mediates the action of growth hormone, and its concentration reflects the circulating concentration of growth hormone)."

The author concludes by stating:

"Studies that have followed the 1990 report by Rudman et al. confirm the effects of growth hormone on body composition but do not show improvement in function. In contrast, resistance training improves muscle strength and function, indicating that real effort is beneficial. There is no current “magic-bullet” medication that retards or reverses aging."

Several years later a review of the matter was published in the Annals of Internal Medicine. The authors first note:

"Human growth hormone (GH) is widely used as an antiaging therapy, although its use for this purpose has not been approved by the U.S. Food and Drug Administration and its distribution as an antiaging agent is illegal in the United States."

Their data synthesis encompassed 31 papers and 18 study populations with an average treatment duration of 27 weeks. The picture that emerged from their data was very interesting:

"In participants treated with GH compared with those not treated with GH, overall fat mass decreased and overall lean body mass increased, and their weight did not change significantly. Total cholesterol levels decreased although not significantly after adjustment for body composition changes. Other outcomes, including bone density and other serum lipid levels, did not change. Persons treated with GH were significantly more likely to experience soft tissue edema, arthralgias, carpal tunnel syndrome, and gynecomastia [breast enlargement] and were somewhat more likely to experience the onset of diabetes mellitus and impaired fasting glucose."

The authors conclude:"The literature published on randomized, controlled trials evaluating GH therapy in the healthy elderly is limited but suggests that it is associated with small changes in body composition and increased rates of adverse events. On the basis of this evidence, GH cannot be recommended as an antiaging therapy."The authors of the first paper cited above published in JAMA state in a subsequent reply that while there are legitimate therapeutic uses of GH:

"We are concerned that patients are led to believe that they have adult growth hormone deficiency (AGHD) and then are provided with GH inappropriately, when the clinical requirements for this diagnosis have not been met. The package inserts for GH state unambiguously that to make a diagnosis of AGHD that satisfies FDA criteria, both a specific pathology involving the anterior pituitary gland and a defined lack of a response to a stimulation test are required."

We can also appreciate the paper published a year and a half ago in Clinical Interventions in Aging that undertakes an extensive and detailed review of the scientific evidence:

"Although advanced age or symptoms of aging are not among approved indications for growth hormone (GH) therapy, recombinant human GH (rhGH) and various GH-related products are aggressively promoted as anti-aging therapies. Well-controlled studies of the effects of rhGH treatment in endocrinologically normal elderly subjects report some improvements in body composition and a number of undesirable side effects in sharp contrast to major benefits of GH therapy in patients with [actual, as determined by tests] GH deficiency. Controversies surrounding the potential utility of GH in treatment of a geriatric patient are fueled by increasing evidence linking GH and cancer and by remarkably increased lifespan of GH-resistant and GH-deficient mice [lower GH = longer lifespan]."

Their massive accumulation of data led to this conclusion:

"We suggest that the normal, physiological functions of GH in promoting growth, sexual maturation and fecundity involve significant costs in terms of aging and life expectancy. Natural decline in GH levels during aging likely contributes to concomitant alterations in body composition and vigor but also may be offering important protection from cancer and other age-associated diseases."

What data is there for the dangers of a supraphysiological increase in GH (as measured through IGF-I levels because direct GH measurement is not practical)? A study published 10 years ago in the Journal of the National Cancer Institute considers this in relation to colorectal cancers in women:

"Leading a Western lifestyle, being overweight, and being sedentary are associated with an increased risk of colorectal cancer. Recent theories propose that the effects of these risk factors may be mediated by increases in circulating insulin levels and in the bioactivity of insulin-like growth factor (IGF)-I."

The authors investigated this association in a cohort of 14,275 women over a period of six years. What did the data show? Remember that GH works partly by increasing IGF-I.

"Chronically high levels of circulating insulin and IGFs associated with a Western lifestyle may increase colorectal cancer risk, possibly by decreasing IGFBP-1 and increasing the bioactivity of IGF-I."

Further evidence was reported in a paper published in the journal Cancer Research:

"It has been shown previously that slight elevations in serum levels of insulin-like growth factor-I (IGF-I) are correlated with an increased risk for developing prostate, breast, colon, and lung cancer. The aim of this study was to determine the role of serum IGF-I levels in the process of stimulating tumor growth and metastasis..."

When they compared injections of GH in 'normal' and GH-deficient mice to saline injections a disturbing picture emerged:

"Both control and LID mice treated with recombinant human IGF-I displayed significantly increased rates of tumor development on the cecum and metastasis to the liver, as compared with saline-injected mice. The number of metastatic nodules in the liver was significantly higher...vessel abundance in the cecum tumors was dependent on the levels of serum IGF-I. This study supports the hypothesis that circulating IGF-I levels play an important role in tumor development and metastasis."

Another study published around the same time in The Lancet discusses similar concerns even for patients with documented GH deficiency:

"Despite these limitations, the high incidence of cancer, and in particular of colon cancer, is worrying. That growth hormone might increase the risk of colorectal cancer is plausible for several reasons. Growth hormone causes raised serum IGF-I and to a lesser extent IGF binding protein-3 (IGFBP-3), and consequently causes a raised ratio of IGF-I to IGFBP-3, with this ratio being greater as growth hormone concentrations increase. IGF-I receptors have been identified on human colorectal cells, mRNAs for IGF-I have been detected in colorectal tumours, IGF-I is a potent stimulator of colorectal-cancer-cell proliferation in vitro, and blockade of IGF-I receptors inhibits growth of human colorectal cancer cells."

Note that their study cohort was young people (39% under 10 and 60% under 19 years of age) with proven GH deficiency. The risk of death from cancer overall was increased approximately 3-fold, from colorectal cancer and Hodgkin’s disease approximately 11-fold and incidence of colorectal cancer was increased approximately 8-fold.

"In conclusion, we found a significantly raised frequency of colon cancer mortality after growth hormone treatment which, although based on small numbers, is of concern because it concurs with raised risks found in patients with acromegaly and in individuals with previously increased concentrations of IGF-I...Our data...suggest the need for increased awareness of the possibility of cancer risks, and for surveillance of growth hormone-treated patients."

A different group of researchers reported high levels of IGF-I receptors in human colon cancers in a study published in the journal Cancer:

"High concentrations of insulin-like growth factor (IGF)-I and IGF-II have been demonstrated in human colonic adenocarcinomas and exert mitogenic effects through paracrine/autocrine interactions with the IGF-I receptor (IGF-IR)."

Their findings confirm the role of IGF-I (which mediates the effects of increases in GH) in human colon cancers:

"Our results demonstrate that, in addition to IGF-II, a strong overexpression of IGF-IR is found in the majority of colorectal carcinomas, supporting the hypothesis of an important role of the IGF system in the pathogenesis of colorectal carcinoma."

More evidence of the link between 'anti-aging therapy' with GH and cancer appeared in a paper published in Clinical Gastroenterology and Hepatology:

"Our findings of increased tumor tissue IGF1R expression as compared with normal colon lends support to an etiologic role for the GH/IGF1 axis in the development and progression of colon cancer, as has been previously described..."

They present a case report of colorectal cancer after administration of GH for 'anti-aging' purposes:

"That it occurred in an individual already at increased risk for colon cancer underscores the need for further investigation of the pro-neoplastic [pro-cancer] potential of growth hormone supplementation for anti-aging."

There is an important principle of functional endocrinology implicit here: it is mandatory that hormone replacement be used only to treat true deficiencies, administration must not exceed physiological levels, and it must be cautiously managed with pre and post testing to affirm safety and efficacy.