Responses

December 15, 2002

Response to the New York Times article "Growth Hormone Changed Older Bodies, for Better and Worse," by Gina Kolata

In the November 13, 2002 issue of the Journal of the American Medical Association, Dr. Marc Blackman and colleagues reported the results of a 6 month study of the effect of growth hormone, alone and in combination with either testosterone or estrogen, in healthy aged adults. The study was funded by the National Institute on Aging in 1992 in response to the very promising results of the 1990 study by Dr. Daniel Rudman in which growth hormone given to elderly men resulted in body composition changes equivalent to an age reversal of 10 to 20 years.[1]

The Blackman study resulted in very similar changes: men gained almost 10 pounds of muscle and lost 9 lbs of body fat, while women gained a few pounds of muscle and lost 5 lbs of fat. All of this occurred without any change in diet or exercise. Aerobic capacity increased in men as well; while strength started to show improvement, it was not statistically significant. These results were not surprising because there are many studies[2] showing similar results in growth hormone deficient adults (those who have very low growth hormone levels because of life long deficiency or pituitary surgery), and the levels of these patients are only marginally lower than aged adults.

While this aspect of the study is very encouraging, it is also uncontroversial, hence not particularly newsworthy. So in her article in the New York Times[3], Ms. Kolata focuses attention on the adverse effects published in the study, but without looking closely at the data, and uncritically accepts the interpretation of the investigators. She writes, "The side effects, however, were serious, afflicting 24 percent to 46 percent of the men and women taking growth hormone and including swollen feet and ankles, joint pain and carpal tunnel syndrome, which is caused by a swelling of a tendon sheath over a nerve in the wrist." At face value, this sounds like a very high rate, one that justifies the investigators' comments that growth hormone is "not ready for prime time" and "should only be used in a controlled clinical trial." This focus also sets up the final comments by Dr. Harman, another author of the study, regarding the use of growth hormone by anti-aging physicians: "It's a tremendous scam." His implication is that anti-aging physicians are putting their patients at risk because they are giving a therapy with frequent side effects.

Were these adverse effects so serious? Is there an explanation for this high rate of adverse effects? If growth hormone can have such potent effects on body composition and not have this high a rate of adverse effects, would it be ready for 'prime time?' To answer these questions, we must do what Ms. Kolata apparently did not do: read the study closely to ascertain how the adverse effect rates were generated and place these rates in the context of the profound dose reductions that were made during the course of the study.

The participants, 57 women and 74 men, were recruited between 1992 and 1998 to participate in a randomized, placebo-controlled trial of 6 months of growth hormone, alone or in combination with estrogen, in women, or testosterone, in men. They were seen every week for the duration of the 26 week study to assess adverse effects, vital signs, and body weight. If at any of these assessments, a subject complained of aching or swelling joints, then he or she was marked as having an adverse effect. If a subject had tingling or numbness of the hands on two or more occasions without a precipitating event, then he or she was marked as having the adverse effect of carpal tunnel symptoms, but not carpal tunnel syndrome, as Ms. Kolata reports inaccurately. The syndrome has more stringent diagnostic criteria and none of the subjects had persistent symptoms consistent with the syndrome after the study. Finally, if a subject complained of swelling of the lower extremities which could be depressed with a finger, such as a slightly deeper version of the line that forms from a sock on one's ankle at the end of the day, then he or she was noted to have the adverse effect of edema. Such a low threshold for reporting adverse effects is standard practice in clinical trials, but I detail them so that you can judge just how "serious" they are.

Still, the rate of the mild side effects seems higher than desirable, even given the beneficial effects of the hormones. This magnitude of this rate, however, is entirely explainable by a fact not at all emphasized by Ms. Kolata or the investigators in their discussion of the results. The study was started with a dose of growth hormone that we now know was far too high and the average dose was reduced over the course of the study by over 60 percent. Yet for some reason the investigators chose to include adverse effects from the high doses in the overall rate. Let's see what role this decision had in generating the "22 percent to 46 percent" adverse effect rate.

During the first year of the study, the starting dose of growth hormone was 30 micrograms per kilogram of body weight and was administered three times a week. This is equivalent to 6 units per dose for the women and 7.5 units per dose for the men, or 18 and 22.5 units per week for women and men, respectively. To put this in perspective, it is well established today, through many studies on growth hormone deficient adults, that the standard starting dose of growth hormone is about 1 unit per day given every day rather than the more unphysiological three times a week. This total weekly dose of 7 units is less than half of the dose given to the women and one third that given to the men at the beginning of this study. Why were such high doses given? I can only surmise that the investigators wanted to replicate the doses in the Rudman study, and the high adverse effect rate of that study was not published until 1993.[4]

Unfortunately, 14 out of 65 subjects, 22 percent, who received growth hormone during the study received this high dose in the first year. This means that if all of these subjects experienced even one adverse effect (which is likely given the Rudman data and the very high doses administered), then half of all the adverse events recorded can be accounted for by this early high dose.

In the second year of the study, the investigators lowered the starting dose by 33 percent, most likely because of this high adverse effect rate. This reduced dose is still twice that now recommend for treating growth hormone deficiency of adulthood-an FDA approved indication for growth hormone since 1996. As you might have expected, further reductions were necessitated even from this reduced dose: another 13 reductions were made during the course of the study.

In total, 27 out of 65 subjects who received growth hormone required dose reductions. That's 41 percent of those subjects who received growth hormone, either alone or with testosterone or estrogen. This could account for virtually all of the adverse effects reported in the 24 to 46 percent. It is clear that the problem was not so much with growth hormone as with the choice of dose. To put this in perspective, a good measure of the seriousness of adverse effects is the number of subjects getting the treatment under study who drop out of the study because of an adverse effect attributable to the treatment. In this study, that rate is 2 men and no women out of the 65 who received growth hormone-just 3 percent. This is because once the doses of growth hormone were adjusted down to the level that we now know is correct for treating adults-as opposed to children in whom much higher doses are needed and tolerated-the adverse effects were likely quite low. Yet this rate for adverse effects once a patient was on a steady dose was not published.

What about the high rate of "developing pre-diabetes or diabetes?" The investigators again chose to report the rate of adverse effects on blood sugar in a way that overstated them and Ms. Kolata uncritically reports their figures. They report that nearly half of the men who received growth hormone developed either pre-diabetes or diabetes. Yet they neglected to emphasize or comment on the fact that none of the women developed diabetes, and the same number (2) in each group of women, including placebo, developed pre-diabetes, i.e., there was no effect of growth hormone on blood sugar control in the women in the study.

Still, even if it occurred only in men, this sounds like a dangerously high rate of problems with blood sugar control. But does it mean the same as what the average lay person reading the article understands when he or she reads that a treatment caused diabetes? I bet it does not, as you will see.

How did the investigators determine if a subject should be placed in the group who "developed pre-diabetes or diabetes?" Let's look at the fine print. Laboratory tests were obtained once every 4 weeks after the baseline studies for a total of 5 blood draws over the 6 month treatment period. The blood sugar abnormality criteria were 110-126 mg/dL for pre-diabetes (impaired glucose tolerance) and for diabetes greater than 126 mg/dL. The important factor for determining who was marked as having blood sugar adverse effects is tucked away as a footnote in a table: "Impaired glucose tolerance and diabetes were defined as = 2 measurements meeting the criteria (italics added)." In other words, if on only 2 out of 5 occasions, a subject's fasting blood sugar was between 110 and 126 mg/dL, or greater than 126, then he or she was marked as having developed impaired glucose tolerance or diabetes, respectively. This remains the case even if at subsequent blood draws a subject's blood sugar decreased or normalized; and remember, over 40 percent of the subjects receiving growth hormone had their doses reduced.

Under this system, the following scenario could lead to a subject's being marked as having developed diabetes. If in the first year of the study, a subject is started on high dose growth hormone and at the first follow up his blood sugar rises to 150 mg/dL (above the diabetes cutoff) from a baseline of 107 mg/dL (normal), then by the study protocol he requires a 25 percent dose reduction. If at the next blood draw, his blood sugar has decreased to 130 mg/dL (still above the diabetes cut-off), then he is then labeled as having developed diabetes as a results of growth hormone therapy. By the study protocol, however, he requires another 25 percent dose reduction. If at the next draw, now only half way through the study and on a dose we now know is within the correct range, his blood sugar has come back down to 105 mg/dL and is not abnormal, then he will still be reported as having developed diabetes. In other words, from the way in which the data is reported, there is no way of knowing how many subjects' blood sugars normalized after dose reductions, but it is conceivable that it was quite a few, or even the majority, for the following reasons.

First, we know from other studies that growth hormone can initially cause insulin resistance, the cause of the elevated blood sugars. But after about 6 months of therapy these initially elevated blood sugars generally normalize and in fact even improve from baseline because of the loss of body fat growth hormone causes.[5] Second, the investigators state that all of the blood sugar changes reversed at the end of the study with discontinuation of the growth hormone. This not what the lay person thinks of as a subject's "developing diabetes." Generally, we think of diabetes as a condition that is permanent unless dietary change, weight loss, or medication therapy is initiated.

What emerges from actually reading the data reported in this study is a far different view of the risk benefit ratio of administering growth hormone to aged adults from that offered by the investigators and Ms. Kolata. The investigators chose to report the adverse effects on the initial high dose growth hormone together with those on the lower, currently more accepted dose, which most likely grossly inflated the risk. The "tremendous scam," to use Dr. Harman's phrase, is the way in which the study's data were reported. If the investigators truly want to know what effect-both good and bad-growth hormone has on aged adults receiving doses used in anti-aging medicine, they should reanalyze the data they already have.

Joseph M. Raffaele, MD

PhysioAge Medical Group

Rudman, D., M. D., et al., Effects of Human Growth Hormone in Men Over 60 Years Old. The New England Journal of Medicine, 1990. 323(1): p. 1-6.
Lonn, L., et al., Body composition and tissue distributions in growth hormone deficient adults before and after growth hormone treatment. Obes Res, 1996. 4(1): p. 45-54.
Growth Hormone Changed Older Bodies, for Better and Worse," by Gina Kolata November 13, 2002 http://query.nytimes.com/gst/fullpage.html?sec=health&res=9C0DEED91E31F930A25752C1A9649C8B63
Cohn, L., et al., Carpal tunnel syndrome and gynaecomastia during growth hormone treatment of elderly men with low circulating IGF-I concentrations. Clin Endocrinol (Oxf), 1993. 39(4): p. 417-25.
Johannsson, G., et al., Growth hormone treatment of abdominally obese men reduces abdominal fat mass, improves glucose and lipoprotein metabolism, and reduces diastolic blood pressure [see comments]. J Clin Endocrinol Metab, 1997. 82(3): p. 727-34.