Deficiency Of Growth Hormone And IGF-1 Reduces Cancer And Kidney Disease, But Creates Other Problems

Science Daily — April 7, 2007 WINSTON-SALEM, N.C. Deficiencies of growth hormone and similar compounds may reduce cancer and kidney disease late in life, but also may lead to cartilage degeneration and impaired memory and learning ability, according to research at Wake Forest University Baptist Medical Center and four other institutions.The researchers used a rat model to explore the effects of growth hormone and another compound, IGF-1 (insulin-like growth factor 1) on adult rats and found paradoxical effects, according to William E. Sonntag, Ph.D., professor of physiology and pharmacology at Wake Forest University Baptist Medical Center and the lead investigator.

"Things that happen when you are an adolescent may have an impact on how long you live and what you die of," he said.

"The presence of growth hormone and IGF-1 is necessary for maintenance of cognitive function and prevention of cartilage degeneration," Sonntag and his colleagues reported in an article in Endocrinology, published on-line today. But the hormones also increase cancer and other diseases that limit lifespan.

The researchers developed a strain of dwarf rats that were naturally deficient in both growth hormone and in IGF-1. To mimic the rise in growth hormone and IGF-1 during adolescence in normal rats, some of these deficient rats were given growth hormone while they were between 4 and 14 weeks of age rat adolescence. Then hormone treatment was stopped and the animals had lower growth hormone and IGF-1 levels the rest of their lives.

That had an effect on cancer: 88 percent of "normal" male rats have tumors at death. The male rats that had a lifelong deficiency of growth hormone had substantially fewer tumors 63 percent and the percent of tumors that were fatal was reduced from 57 percent to 31 percent.

The same pattern occurred for kidney disease, which was found in 74 percent of the normal male animals at the time of their deaths. None of the growth-hormone deficient animals developed kidney disease.

They found that animals with a deficiency in growth hormone initiated after adolescence had up to a 14.6 percent increase in lifespan. All animals in the study lived until they died of natural causes.

The researchers used several tests to measure memory and learning. They found that growth-hormone-deficient rats had impaired learning ability compared to normal animals of the same age. A similar pattern occurred in memory tests.

"The presence of growth hormone and IGF-1 are required for optimal performance on tests of learning and memory throughout life," they said. "Growth hormone/IGF-1 replacement in older animals reverses the age-related decline in cognitive function."

The group also found that "cartilage degeneration that normally accompanies aging is accelerated by the absence of growth hormone."

The researchers concluded that cancer risk as well as other age-related pathologies could be substantially decreased in these animals by inducing a modest deficiency of growth hormone and IGF-1 early in life. However, there is a tradeoff and deficiency of growth hormone and IGF-1 may impair learning and memory and accelerate some degenerative diseases.

Note: This story has been adapted from a news release issued by Wake Forest University Baptist Medical Center.

No Proof That Growth Hormone Therapy Makes You Live Longer, Study Finds

Science Daily — Surveyors of anti-aging elixirs tout human growth hormone as a remedy for all things sagging-from skin to libidos - and claim it can even prevent or reverse aging. But researchers at the Stanford University School of Medicine say there's no evidence to suggest that this purported fountain of youth has any more effect than a trickle of tap water when it comes to fending off Father Time.

"There is certainly no data out there to suggest that giving growth hormone to an otherwise healthy person will make him or her live longer," said Hau Liu, MD, a research fellow in the division of endocrinology and in the Center for Primary Care and Outcomes Research, and first author of a review study to be published in the Jan. 16 issue of Annals of Internal Medicine. "We did find, however, that there was substantial potential for adverse side effects."

Those negative side effects included joint swelling and pain, carpal tunnel syndrome and a trend toward increased new diagnoses of diabetes or pre-diabetes. "You're paying a lot of money for a therapy that may have minimal or no benefit and yet has a potential for some serious side effects," Liu said. "You've got to really think about what this drug is doing for you."

Growth hormone is widely promoted on the Internet and its use as a purported anti-aging drug has caught the attention of the popular media, ranging from the "Today Show" to Business Week.

Between 20,000 and 30,000 people in the United States used growth hormone as an anti-aging therapy in 2004, a tenfold increase since the mid-1990s, according to the authors of an unrelated study published in the Journal of the American Medical Association in 2005. This increase comes despite both the high cost of such therapy - often more than $1,000 a month - and the illegality of distributing growth hormone for anti-aging therapy in this country. Those numbers prompted Liu and some colleagues to see if the medical literature provided any support for such therapy.

Growth hormone is naturally produced by the pituitary gland, a pea-sized organ at the base of the brain. Production is highest during childhood and the hormone-drenched adolescent years, then typically starts tapering off around age 30, continuing to decline into old age. Growth hormone is critical to proper development in children, particularly their height, and injections of growth hormone are considered a legitimate treatment for short children and for adults whose pituitary glands don't produce enough growth hormone to maintain normal metabolism. But most promoters of growth hormone as an anti-aging therapy target the healthy elderly.

Liu's team undertook a systematic review and analysis of published studies, excluding any that looked at diseases for which growth hormone is an accepted therapy. They focused solely on studies using growth hormone to treat the elderly, specifically those whose main maladies were nothing worse than age and being mildly to moderately overweight. They also included only studies that evaluated the use of the hormone in randomized, controlled clinical trials.

Of all the papers contained in two of the largest databases of medical literature in the world, only 31 met the team's criteria. The 31 studies had a combined total of slightly more than 500 participants, and the average duration of therapy was about a half-year, said Liu, adding that he was surprised at the limited amount of data in the literature.

"These studies were designed to look at what happens when you give growth hormone to a healthy elderly person," said Liu. "For example, what happens to their bone density, to their exercise levels and to their exercise capacity."

The researchers found that growth hormone had a modest effect on body composition, increasing lean body mass, or muscle, by slightly more than 2 kilograms and decreasing body fat by roughly the same amount.

But, Liu said, "It did not change other clinically important outcomes, such as bone density measurements, cholesterol and lipid measurements, and maximal oxygen consumption." In short, the studies provided no real evidence that the therapy resulted in increased fitness.

"From our review, there's no data to suggest that growth hormone prolongs life, and none of the studies makes that claim," said Liu.

That finding, according to Liu, highlights one of the fundamental problems in the whole debate over the use of growth hormone to combat the effects of aging-misinterpretation of the data.

The promotion of growth hormone as an anti-aging treatment took off in 1990 when a paper published in the New England Journal of Medicine presented results of a small study in which 12 men over the age of 60 were injected with growth hormone three times a week for six months. At the end of treatment, they had statistically significant increases in lean body mass and bone mineral, unlike a group of nine men who had received no treatment.

The authors of that study made no claims that the treatment had reversed the aging process and stated that many questions remained unanswered, but they did note that the increase in muscle and decrease in fat were "equivalent in magnitude to the changes incurred during 10 to 20 years of aging."

That statement triggered a wave of misinterpretation-inadvertent or otherwise-that persists to this day, despite repeated efforts by the journal to play down the sensational claims now made for growth hormone or growth hormone "releasing agents" widely sold on the Internet. The original study was accompanied by an editorial warning against the general use of growth hormone as a therapy in adults.

In 2003 another NEJM editorial specifically addressed the issue again, as the 1990 paper was receiving as many online "hits" in a week as other 1990 articles got in a year, owing largely to promoters of growth hormone citing it as supporting evidence.

The researchers participating in this study were supported by grants from the U.S. Agency for Healthcare Research and Quality, the U.S. Department of Veterans Affairs and the National Institute of Aging.

Other Stanford researchers participating in the study were Dena Bravata, MD, senior research scientist in medicine; Ingram Olkin, PhD, professor emeritus of statistics and of education; Smita Nayak, MD, who is now an assistant professor of medicine at the University of Pittsburgh; Brian Roberts, MD, research fellow in the division of endocrinology; Alan Garber, MD, PhD, the Henry J. Kaiser Jr. Professor, and Andrew Hoffman, MD, professor of medicine.

Note: This story has been adapted from a news release issued by Stanford University Medical Center.

Growth Hormone May Shorten Life Span, Study Finds

Science Daily — ATHENS, Ohio Growth hormone often is prescribed to counteract such common effects of aging as loss of muscle tone and increase in body fat. But new animal studies of the natural hormone suggest that while it may improve quality of life, it may actually shorten the life span.

Researchers at Ohio University's Edison Biotechnology Institute found that mice engineered without the receptor for growth hormone lived almost one year longer than normal mice. The study, published in a recent issue of the journal Endocrinology, is the first to isolate growth hormone and analyze its impact on longevity.

Scientists say the findings have important implications for physicians who prescribe growth hormone replacement therapy for elderly patients and say doctors should use caution with these remedies until more studies are done.

"You may be improving quality of life, but you may be shortening the quantity of life," said Karen Coschigano, a scientist at the institute (EBI) and lead author of the recent study.

The project is one of many conducted at EBI to determine growth hormone's role in human health and illness, including acromegaly, diabetic kidney and eye diseases and breast cancer. To investigate its impact on aging, researchers studied three groups of mice: mice with normal or nearly normal levels of the growth hormone receptor, as well as mice with no growth hormone receptor. Mice in the last group were less than half the size of the other mice but lived almost one year longer than the other animals in the study. The normal life span for the mice used in the study was about two years, Coschigano said. Studies elsewhere have shown a similar increase in life span for mice with impaired pituitary function which includes a lack of growth hormone activity.

Though the study suggests that disruption of the signal that activates growth hormone may prolong life, she added, the researchers have yet to determine the mechanism by which the process works. One possibility is that this disruption lowers levels of insulin another growth stimulus which helps to increase longevity. The Ohio University research may lend support to that theory, as the mice that lived longer also had significantly lower insulin levels than the other mice under study, she said.

More research is needed to determine how the study findings in mice may be relevant to humans, particularly elderly individuals who undergo therapy to replace growth hormone lost during the natural aging process. As growth hormone plays many important, beneficial roles in the human body including maintaining bone and tissue health Coschigano says halting the body's production of growth hormone isn't the best approach. For example, researchers found that while the mice without the growth hormone receptor lived longer, they also were less fertile and had weaker bones.

"Growth hormone needs to be maintained at an intermediate level," said study co-author John Kopchick, Goll-Ohio Eminent Scholar and professor of molecular and cellular biology at EBI and the university's College of Osteopathic Medicine. "Not enough is not good, but too much is definitely not good."

Instead, the researchers are searching for genes regulated by growth hormone that might play a specific role in life span. Then, a therapy could be developed that would interrupt specific gene function, allowing the body to continue to reap the benefits of growth hormone without suffering the substance's sometimes negative effects.

The study was funded in part by the State of Ohio's Eminent Scholar Program and the Sensus Drug Development Corporation. Co-authors of the study are Kopchick, Linda Bellush, a former scientist with EBI and David Clemmons of the University of North Carolina at Chapel Hill.

The Edison Biotechnology Institute is a biomedical genetics institute at Ohio University and part of the Ohio Department of Development's Thomas Edison Program.

Note: This story has been adapted from a news release issued by Ohio University.

Growth Hormone, Sex Steroid Combination "Not Ready For Prime Time"

Science Daily — In the first study of the separate and combined effects of growth hormone and sex steroids in healthy older men and women, investigators found that growth hormone replacement substantially increased lean body mass and decreased fat mass in both sexes. In combination with testosterone, growth hormone significantly improved cardiovascular endurance in older men. But the researchers also reported a number of side effects, including an increased incidence of glucose intolerance and diabetes among men, which raise important questions about the safety of using growth hormone alone or in combination with other treatments that are often touted as so-called "anti-aging" therapies.

"Although this study suggests that growth hormone or related substances, particularly given in combination with testosterone in older men, may one day be a promising therapeutic agent in the treatment of certain age-related conditions, it is not ready for prime time," said Marc R. Blackman, M.D., the study's lead investigator. "There is much that we still don't know about its efficacy and, more importantly, there are too many known and potential adverse consequences associated with it. It is a fascinating and promising area of research, but at this time we can't recommend it for use outside of a carefully controlled and monitored clinical trial."

The study*, published in the November 13, 2002 issue of the Journal of the American Medical Association (JAMA), was conducted jointly by investigators from the National Institute on Aging (NIA) Intramural Research Program and investigators from the Johns Hopkins University School of Medicine in Baltimore, supported by grants from the NIA and the National Center Research Resources.

Human growth hormone (hGH) is made by the pituitary gland, a pea-sized structure located at the base of the brain, and is important for normal development and maintenance of tissues and organs. Testosterone and estrogen, two important sex steroids, work in combination with hGH to spark puberty and maturation during adolescence. Dr. Blackman, who is now Clinical Director and Director of Intramural Research at the National Center for Complementary and Alternative Medicine, hypothesizes that similar interactions are involved in the natural declines of hGH and sex steroids in later decades, contributing to the onset of age-related changes such as decreased muscle mass and increased body fat. So in theory, replenishing these hormones could slow or reverse some age-related effects.

To test this, Dr. Blackman and his colleagues studied 57 healthy men and 74 healthy women, ages 65 to 88, divided into eight groups**. These volunteers were given recombinant human growth hormone (hGH) alone, a sex steroid alone, a combination of hGH and sex steroids, or placebos for both hGH and sex steroids. After 26 weeks of treatment, the volunteers were assessed for changes, compared to baseline measures, in lean body mass, total fat mass, muscle strength, cardiovascular endurance and adverse effects. (Cardiac endurance, measured during a treadmill exercise test by the amount of oxygen consumed, is an important gauge of the body's capacity for work).

Overall, both men and women exhibited significant increases in lean body mass and decreases in fat mass after treatment with hGH, and men treated with both hGH and testosterone had greater improvements in these measures than did those who were treated with either hormone alone. Older men who received hGH plus testosterone also had improved cardiovascular endurance. However, this effect was not evident among men treated with hGH or testosterone alone, or among older women treated with hGH, estrogen and progestin, or a combination of growth and sex hormones. The study detected no clear effect of treatment on muscle strength.

Adverse effects of treatment were reported in up to 40 percent of the volunteers, with the greatest percentages occurring among men and women who were treated with hGH, with or without concomitant sex steroid. Common side effects in both sexes included joint pain, swelling, and carpal tunnel syndrome. In general, men experienced more frequent and severe side effects than did women. Eighteen men treated with hGH developed either transient glucose intolerance, a precursor to diabetes, or diabetes, compared with seven men not receiving the hormone. No women developed glucose intolerance or diabetes, but they were more prone than men to develop swelling (edema). All side effects, including diabetes, abated two to six weeks after treatment was discontinued.

The differences in both beneficial and adverse effects of hGH between men and women could have been partly due to dosage, Dr. Blackman said. In the study, both sexes were treated based on body weight. But subsequent studies have found that women need higher doses of hGH to elicit a physiological response similar to that of men.

"This study makes the important point that because adverse effects were common in response to growth hormone administration, individuals, particularly those who are elderly, should not use hGH outside of controlled investigational studies. Growth hormone has not yet been demonstrated to be of clinical utility as an anti-aging intervention," said Stanley Slater, M.D., deputy director of the NIA's Geriatrics and Clinical Gerontology Program. "Nonetheless, there were significant changes in body composition and cardiovascular endurance, which were augmented by the addition of testosterone in men. This remains an interesting area for further research."

The adverse effects found in this study follow a recent report suggesting that long-term treatment of young and middle-aged adults with human pituitary growth hormone increased the risk of subsequent cancer. Whether older persons treated with hGH for extended periods will demonstrate an increased risk of cancer is unknown.

Although there is no conclusive evidence that hGH administration can prevent aging, some people spend a great deal of money on supplements. These supplements are claimed, by some, to increase muscle, decrease fat, and to boost an individual's stamina and sense of well-being. Shots of hGH can cost more than $15,000 a year. They are available only by prescription and should be given by a doctor. But individuals should be wary of this controversial treatment because so little is known about its long-term risks and benefits, Dr. Slater said.

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The National Institute on Aging and the National Center for Research Resources are two of 27 Institutes and Centers that constitute the National Institutes of Health. The NIA leads Federal efforts to support and conduct basic, clinical, epidemiological, and social research on aging and the special needs of older people. For more information about the NIA, visit the website at http://www.nih.gov/nia.

* M.R. Blackman, J.D. Sorkin, T. Munzer, M.F. Bellantoni, J. Busby-Whitehead, T.E. Stevens, J. Jayme, K.G. O'Connor, C. Christmas, J.D. Tobin, K.J. Stewart, E. Cottrell, C. St. Clair, K. M. Pabst, S.M. Harman, "Effects of Growth Hormone and Sex Steroid Administration in Healthy Aged Men and Women," JAMA, 2002; 288: 2282-2292.

** The study volunteers were divided into the following groups: Men either received recombinant human growth hormone (hGH) plus placebo testosterone (T); T plus placebo hGH; hGH plus T; or placebos for both hGH and T. Women either received hGH plus placebo estrogen and progestin (HRT); HRT plus placebo hGH; hGH plus HRT; or placebos for both hGH and HRT.

Note: This story has been adapted from a news release issued by NIH/National Institute On Aging.