When Wisconsin-based endocrinologist Daniel Rudman, M.D., published his landmark study on the effects of growth hormone in 12 men, ages 61 to 81, in the prestigious New England Journal of Medicine in 1990, he couldn't have imagined the uproar his results would set off.1 All of Rudman's subjects had one thing in common: They were all clinically deficient in growth hormone release, as determined by their levels of insulinlike growth factor 1 (IGF-1), a product of growth hormone made in the liver and other tissues. After six months of receiving GH injections, the subjects showed body changes indicating a reversal of the aging process by as much as 20 years.
The men showed significant improvements in body composition, such as an average gain in lean mass of nearly 10 percent coupled with an average bodyfat loss that was close to 15 percent. Cosmetic and psychological changes accompanied those general improvements. The subjects felt they had much more energy, one man's hair color returned, and another's wrinkles, which he'd had for a long time, lessened noticeably. It seemed that science had finally found the fountain of youth.
Or had it?
Less publicized was that fact that all the improvements generated by GH disappeared when the study ended, not unlike the way Cinderella's grand carriage turned back into a pumpkin at the stroke of midnight. Even worse, those who stayed on GH for a year in a follow-up study began to show bothersome side effects, such as carpal tunnel syndrome, a narrowing of connective tissue in the wrist that impedes nerve conduction, and gynecomastia, a side effect well-known to bodybuilders who overuse anabolic steroids.(Gyno is characterized by the development of excess glandular tissue in the breasts and is also known 'bitch tits.') Others began to feel excessive joint pain.
The Case Against GH Therapy
Few medical professionals would argue the fact that GH levels drop as people get older. The debate is whether age-related GH deficiency should be treated. On the one hand, women who are deficient in estrogen are treated with hormones to offset various symptoms related to menopause. An emerging trend in recent years has been the growth of therapy centers that provide testosterone replacement to aging males.The therapy is based on numerous solid studies showing that it may ease mental problems, cardiovascular risk factors and other conditions brought on by a lack of testosterone. It's tricky, however, because the need for testosterone must be balanced with the known association between testosterone and prostate cancer.
In fact, some medical theorists suggest that it's normal for the body to downgrade hormone secretion as it reaches advanced age. Adding back such hormones, including estrogen, testosterone and GH, may be 'unnatural,' they assert. While the hormones may be vital in the growing stages of life, they can become harmful as people age. The critics even have a term for this Jekyll and Hyde characteristic of hormones: antagonistic pleiotropy. While some scientists worry about the links between testosterone and prostate cancer and between estrogen and breast cancer in women, the concern about GH is more general: As a general growth factor it may stimulate the wrong kind of growth'that is, tumors. Skeptics of GH therapy point to the problems experienced by people afflicted with acromegaly.
Acromegaly is caused by a benign adenoma, or tumor, in the pituitary gland, which is located at the base of the brain. It leads to GH levels that are 10 to 20 times normal. People who've had acromegaly for a long time often become extremely tall; for example, Robert Wadlow, the 8'11' man listed in the Guinness Book of World Records as the tallest human ever. Wadlow died at 23 due to an infection brought on by the leg braces he was forced to wear due to his weak leg muscles. (Myopathy, or muscle weakness, is common in people with acromegaly.)
Besides the excessive height'which occurs only if the disease begins in childhood, when bone endings are still open'acromegalics also have huge hands and feet and facial deformities that give them a cavemanlike appearance. The average life expectancy is 50, and most die from either heart disease or complications related to diabetes. Both the heart disease and diabetic aspects are thought to be related to acromegalics' extensive overproduction of GH. That said, acromegaly is without question a worst-case scenario when it comes to the effects of GH.
Bodybuilders who've used GH have also experienced some side effects. A few have had gynecomastia, although it would be difficult to pinpoint the cause due to the fact that some anabolic steroids can also produce gyno. More specific to GH is carpal tunnel syndrome, a condition that a few well-known bodybuilders have undergone surgery to correct. On the other hand, not all cases of carpal tunnel syndrome are caused by GH use. You can get it by doing too much typing or certain other repetitive motions of the wrist and hand (No, I'm not talking about masturbating!).
An important and often overlooked fact about side effects associated with GH is that they always occur when the user is taking too high or too frequent a dose. Physicians now realize that replacement doses of GH are just that: doses to replace what the body is no longer secreting. The goal of such therapy is to bring IGF-1 levels back to 250 to 350 nanograms per milliliter of blood, or the amount produced by a 25-year-old. (IGF-1 is considered an accurate method of judging GH levels, since GH itself breaks down in only about an hour.) That usually involves taking no more than one to two units of GH a day. In contrast, some pro bodybuilders are rumored to use six to 12 units a day or more. That's asking for trouble, especially if you take it long-term, for more than six months.
Does Growth Hormone Extend Life?
Perhaps the best way to determine the true effects of growth hormone on longevity is to look at what happens when the body naturally secretes too much or too little. As noted above, people with acromegaly have a benign tumor in the pituitary gland that leads to GH levels 10 to 20 times normal. Even so, the GH excess is often not apparent until after they're 15 to 20 years old. Untreated, it leads to a mortality rate that's two to three times that of normal people. The primary causes of death for acromegalics are cardiovascular disease (39 to 62 percent), respiratory disease (25 percent) or various types of cancer (9 to 25 percent).2
The key word there is untreated. With most cases of acromegaly, doctors see an increase in left ventricular mass in the heart and a slight increase in prostate size but no higher incidence of prostate cancer. They also see a small increase in colon polyps but not in colon cancer. Nearly all those effects are linked to the increased IGF-1 secretion fostered by higher GH release.
For most people, though, the problem isn't too much GH but, rather, too little. That's especially true for older people. GH levels decline an average of 50 percent every seven years after age 20, while IGF-1 levels drop 15 percent per decade. The rate varies depending on such factors as abdominal obesity (which suppresses GH release because of increased fatty acid release into the blood), genetics and exercise. If you've exercised for many years, it may help to curtail the usual drop in GH. The same is true for other hormones, such as testosterone.
While most physicians wouldn't hesitate to treat estrogen, testosterone and thyroid deficiencies, until a few years ago the only indication for growth hormone therapy was in the treatment of dwarfism, and it was only given to children. In 1958, when GH was first produced in drug form, the supplies were limited, since the only available source involved extraction of the hormone from the pituitary glands of cadavers. The cadaver source proved problematic years later, when it was discovered that some pituitary glands used in the GH extraction process also harbored a prion organism, leading to long-term development of a fatal brain disease called Creutzfeldt-Jakob disease.
With the advent of genetic engineering'and a process that synthesizes GH using recombinant DNA from bacteria'GH became more readily available and safe from the prions that caused Creutzfeldt-Jakob disease. The increased availability enabled scientists to examine a previously overlooked aspect of GH: deficiencies in adults. In the past they'd believed that the drop in GH was an inevitable consequence of the aging process, but studies such as the one conducted by Daniel Rudman in 1990 proved that using GH to correct established deficiencies appeared to lead to a pronounced rejuvenating effect.
GH and Bodyfat
Correcting GH deficiency offers an overlapping effect in preventing other medical conditions. For example, adults who are GH-deficient are heavier than other people, with the added weight composed mainly of bodyfat.3 The extra bodyfat also comes with a decrease in lean mass, including muscle.4 Much of the added fat is located in the abdominal area, which in turn leads to insulin resistance and a fivefold increase in the rate of cardiovascular disease. People who are GH-deficient also show 10 percent decreased bone mass, which increases the risk for bone-wasting diseases such as osteoporosis.5
As noted, the added abdominal fat leads to insulin resistance and a higher prevalence of glucose intolerance.6 People who lack sufficient GH are also predisposed to blood lipid abnormalities associated with cardiovascular disease, including lower HDL cholesterol levels (the good cholesterol) and higher LDL cholesterol levels (the bad cholesterol). The result is a greater incidence of atherosclerosis in people who are GH-deficient. HDL, or high-density lipoprotein, is a protein carrier of cholesterol in the blood that protects against cardiovascular disease by helping to remove excess cholesterol from the blood. LDL, or low-density lipoprotein, is linked to cardiovascular disease when it's oxidized in the blood.
Growth hormone helps control bodyfat in a number of ways. It opposes the fat-promoting effects of insulin and directs the body to use fat as fuel rather than glucose, or carbohydrate. GH promotes the conversion of the relatively inactive thyroid hormone, T4, into the far more metabolically active T3 form. It also maintains the activity of beta-adrenergic cell receptors, which interact with hormones of the sympathetic nervous system, such as epinephrine and norepinephrine, to help release fatty acids from fat cells. That sympathetic response fades as you age, which explains why it's so much easier to get fat and so much harder to lose accumulated fat as you get older. By normalizing this sympathetic response, GH helps older people burn fat as readily as they did in the past.
The Benefits of GH Therapy
People who don't have sufficient GH show atrophic skin changes, which make them appear older than their chronological age and are linked to a loss of size and function of sweat glands. The veins of GH-deficient people are also unusually small and weak, as are their hearts, kidneys and lungs. Due to the diminished size, kidney function is often compromised. Since the kidneys are also involved in the production of red blood cells, it's not surprising that blood plasma and red blood cell mass are likewise lower in GH-deficient people.
As you might expect, some of those negative aspects also adversely affect physical abilities. Physical work capacity and muscle strength are lesser in people whose GH is below normal.7 Maximal oxygen uptake, a measure of aerobic capacity, is reduced an average of 20 to 30 percent, and heart function, which is diminished with GH deficiency, also plays a major role. The lack of adequately developed sweat glands in GH-deficient people increases the chances of overheating during exercise, which limits exercise ability.8
One of the most obvious benefits of GH therapy is the improvement in mental state. Older people using the hormone often display more positive attitudes, while those lacking it show rapid fatigue and display a general lack of vitality. They feel that their quality of life is lower, and they are often more prone to anxiety reactions.
Nearly all of the negative aspects of GH deficiency are relieved when people use growth hormone. Bodyfat drops, muscle mass increases, and the cardiovascular risk profile returns to normal.9 The skin thickens, and there's increased body hair growth. The atrophied internal organs, including the heart and kidneys, return to normal size and function. The limitations on exercise performance disappear and are replaced with a pronounced sense of vitality. Considering the positive changes it brings, it's not hard to understand why some consider growth hormone a fountain of youth, since it does appear to set the clock back in many respects.
Beyond all the enthusiasm, however, the question still looms: Is it safe?
GH Side Effects
Most of the side effects that occur with GH use are related to dosage: Taking too much is likely to lead to such symptoms as carpal tunnel syndrome, water retention, glucose intolerance and joint pain. The goal of optimal GH therapy is to replace what the body normally synthesizes and secretes. Any more than that can lead to problems. When trouble does arise, the first step in counteracting the problem is to reduce the dose of GH. That usually resolves it.
GH has been linked to the onset of diabetes, since diabetes occurs in some people with long-term untreated acromegaly. GH antagonizes insulin activity in the body (one reason why many athletes also use insulin with GH) and could lead to hyperglycemia, or elevated blood glucose levels. Most scientists who've examined that aspect of GH use believe that only people who are genetically predisposed to diabetes have any chance of getting it, and the disease almost never occurs with GH use. In fact, a more probable pattern is a decreased incidence of diabetes with normal GH levels, since GH tends to normalize insulin sensitivity through reduction of excess abdominal fat'an established cause of insulin resistance.
Another worry is an increased risk of cancer with GH use. While some studies show a connection between GH use and increased incidence of leukemia, a more careful evaluation of 32,000 children in Japan, where the initial link was discovered, showed that GH doesn't increase the incidence of leukemia without the presence of preexisting risk factors.10
A product of GH metabolism, IGF-1, was recently linked to several cancers, such as those affecting the breast and prostate. What isn't yet known is whether the increased IGF-1 seen with those cancers is a marker or a promoter of the cancer. It remains open to question because if IGF-1 was such a potent promotor of cancer, acromegalics, who secrete far greater levels of GH and IGF-1, would show increased rates of those types of cancer, and there's no evidence of that. In fact, a study of more than 1,000 people with acromegaly found their overall cancer rates to be lower than the general population.11
An overlooked aspect of the GH/IGF-1 cancer controversy is that even if IGF-1 levels rise, the rise is accompanied by an equal rise in IGF-1 binding protein-3, which binds IGF-1 in the blood, inactivating it. Only the free form of IGF-1 has any biological activity.12
Also still open to question is GH's purported effects on longevity. We know that a lack of sufficient GH with age does predispose people to earlier mortality, as discussed above; however, we haven't established whether an optimal level of GH will extend life. On the other hand, too much will likely lead one to an early grave.
That latter fact was shown in several animal-based studies. One noted that mice deficient in several pituitary hormones, including GH, outlived mice that didn't lack those hormones.13 The paradoxical effects are thought to occur because of a lower core temperature in the deficient rodents coupled with decreased oxidation reactions. Another recent study found that mice bred to totally lack cellular receptors for GH lived a year longer than their normal littermates.14 That doesn't sound too impressive until you realize that the life expectancy of such mice is only two years. The genetically altered mice were also smaller, had weaker bones and weren't as fertile as normal mice, and they had lower insulin levels, which the researchers think may be the underlying cause of their increased longevity.
Other animal studies show no negative long-term effects on longevity after rodents were given growth hormone.15 A 10-year study of 10 humans who were receiving GH therapy showed only beneficial changes, such as improved body composition and cardiovascular risk profiles.16 Another study featuring 33 adults who used GH for up to seven years showed no adverse effects on glucose tolerance or any elevation of insulin levels.17 What we do know about GH today is that adults who don't have enough have a lower quality of life, both physically and mentally. As with many other things, however, too much or too little GH will lead to problems and likely have adverse effects on longevity. The optimal goal is to maintain normal levels of GH in the body.
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1 Rudman, D., et al. (1990). Effects of human growth hormone in men over 60 years old. New Eng J Med. 323:1-6.
2 Melmed, S. (1996). Unwanted effects of growth hormone excess in the adult. J Ped Endocrinol Metab. 9:369-374.
3 Hoffman, D.M., et al. (1995). Adults with growth hormone deficiency have abnormal body composition but normal energy metabolism. J Clin Endocrinol Metab. 80:72-77.
4 Carroll, P.V., et al. (1998). Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. J Clin Endocrinol Metab. 83:382-95.
5 Colao, A., et al. (1999). Bone loss is correlated to the severity of growth hormone deficiency in adult patients with hypopituitarism. J Clin Endocrinol Metab. 84:1919-1924.
6 Beyshah, S.A., et al. (1994). Metabolic abnormalities in growth hormone-deficient adults: carbohydrate intolerance and lipid metabolism. J Endocrinol Metab. 1:173-180.
7 Cuneo, R.C., et al. (1991). Growth hormone treatment of growth-hormone-deficient adults: effects on muscle mass and strength. J Applied Physiol. 70:688-94.
8 Juul, A., et al. (1993). Impaired thermoregulation in adults with growth hormone-deficiency during heat exposure and exercise. Clin Endocrinol. 38:237-44.
9 Pfeifer, M., et al. (1999). Growth hormone (GH) treatment reverses early atherosclerotic changes in GH-deficient adults. J Clin Endocrinol Metab. 84:453-57.
10 Nishi, Y., et al. (1999). Recent status in the occurrence of leukemia in growth-hormone-treated patients in Japan. J Clin Endocrinol Metab. 84:1961-9165.
11 Orme, S.M., et al. (1998). Mortality and cancer incidence in acromegaly: a retrospective cohort study. J Clin Endocrinol Metab. 83:2730-34.
12 Ma, J., et al. (1999). Prospective study of plasma levels of insulinlike growth factor 1, insulinlike growth factor binding protein-3 and colorectal cancer risk among men. J Natl Cancer Inst. 91:620-625.
13 Bartke, A., et al. (1998). Does growth hormone prevent or accelerate aging? Experimental Gerontology. 33:675-87.
14 Coschigano, K.T., et al. (2000). Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinol. 141:2608- 2613. 15 Kalu, D.N., et al. (1998). Aged-rodent models of long-term growth hormone therapy: lack of deleterious effect on longevity. J Gerontol. 53A:B452-B463.
16 Gibney, J., et al. (1999). The effects of 10 years of recombinant human growth hormone (GH) in adult GH-deficient patients. J Clin Endocrinol Metab. 84:2596-2602.
17 Chrisoulidou, A., et al. (2000). Effects of seven years of growth hormone replacement therapy in hypopituitary adults. J Clin Endocrinol Metab. 85:3762-3769. IM