A recent meta-analysis of human growth hormone studies hit the major newswires in early January questioning the safety and appropriateness of the use of human growth hormone in adults. This is a very topical subject. What are we to make of these stories? A typical journalistic example appeared in the San Jose Mercury wherein we were quoted.
[Systematic Review: The Safety and Efficacy of Growth Hormone in the Healthy Elderly Liu et al. Ann Intern Med.2007; 146: 104-115 -- January 15, 2007 issue of the Annals of Internal Medicine]
Initially, we had referred you to the official response by the American Academy on Anti-Aging Medicine (A4M). This is a detailed and rational rebuttal to this journal article. Not a quick read.
The understanding and explanation of this meta-analysis involves two separate phenomena. One is a detailed scientific and rational explanation to which we have just referred. But there is a larger issue to which this speaks – social/political. What is the agenda? Who are the people who conducted this meta-analysis? Just what is a meta-analysis?
A meta-analysis is an attempt to survey the literature on a particular subject, hopefully, to formulate a more powerful view of the results of a number of studies conducted over a significant time span. "Power" is a statistical notion indicating the ability to formulate a set of results based on a sizable enough population to make "significant" and more legitimate conclusions.
When you do any type of Google search you are constructing your own meta-analysis. And you have probably found that the results of a Google search can sometimes be quite accurate and at other times be baffling or almost irrelevant. It all depends on the precision of the words that you use to conduct research.
In reviewing the initial data it became quite clear that most of these studies were using doses that would be considered excessive by today's standards. Some of studies date back to a time when the injection dosing schedule of the growth hormone in adults was not precisely known. The first study of significance was the classical New England Journal of Medicine, Rudman et al study in 1990 using three times weekly doses.
It has always been quite baffling how the material and dosing schedules for any particular study is chosen. None of this decision making is ever thoroughly explained in the methodology section of a study. Here is the reality. The initial dosing schedules were most likely derived from the use of human growth hormone in the treatment of children of short stature. In these children, massive weekly doses were used because the endpoint was true bone elongation and height enhancement. That is not the endpoint in adults. It is a different endpoint. So the doses is being used in adults initially were not well known.
Today, in clinical practice, the daily doses used to treat adults with adult growth hormone deficiency syndrome are far lower. Even the manufacturer's currently recommend doses equal to about 1.0 to 2.0 IU daily.
“Adult replacement therapy: It is recommended to start treatment with a low dose 0.15-0.3 mg/day (equal to 0.45-0.9 IU/day) and to increase the dosage gradually at monthly intervals to meet individual patient needs. Serum IGF-I can be used as guidance for the dose titration. Dose requirements decline with age. Maintenance dosage varies from person to person, but seldom exceeds 1.0 mg/day (equal to 3 IU/day).”
It is well-known in the clinical community that any doses over to 2.0 to 2.5 IU daily will inevitably result in joint pains, swelling and other uncomfortable side effects.
In reviewing all of the studies in this meta-analysis, not one study used doses less than 2.5 IU and in fact one study used upwards of 10 IU daily. There is absolutely no doubt that one would encounter side effects of these doses. We think the authors were disingenuous in not recognizing and discussing the change in recommendations of daily dosing over the last 10 to 15 years.
A time-honored convention in pharmacology is the dose-response curve and the “therapeutic window.” It is well-known that any drug at low dose is ineffective. In its therapeutic window it is considered to be effective and appropriate. And above that window is considered to be toxic.
An example. Lipitor® is a drug that is being widely used to treat elevated cholesterol. The conventional dose is 10 mg. If a study was constructed using 1 mg daily the result would be no effect. The headline would read: drug found to be ineffective. On the other hand, if a study was constructed using 100 mg , the likelihood of severe and possibly even fatal reactions (rhabdomyolysis) would be markedly enhanced. The headlines would read: drug found to be too toxic for human use. Now this may seem a rather facetious example, but this is the best illustration of dose-response relationships.
So we come back again to the example of the meta-analysis that concluded that the doses being used in each of the studies, was accompanied by an unacceptable rate of swelling, joint pains, and abnormal glucose tolerance curves.
In each of these studies, it is highly unlikely that any of the individuals were paying for their monthly supply of human growth hormone. Virtually no one, if paying for their own daily injections of growth hormone without reimbursement, would ever use more than 2.5 units daily. It would just be too expensive.
So we come to the second phenomenon which is more social and political. What is the agenda here? What is to be gained by publishing and massaging the data in such a way as to almost assure a set of adverse outcomes? If you look at the eventual study you will see that one of the authors has significant financial relationships with various pharmaceutical companies. It is becoming more and more rare to find American studies or authors who have no financial relationships with large pharmaceutical companies. In fact, it is becoming well-known that many studies are now being ghostwritten by representatives of these large pharmaceutical companies. [See Red Orbit Breaking News The Guardian Medical News Today.]
Our goal is always to inform the public of these inevitably negative stories and to foster a greater sense of critical thinking.
Finally, what will it take to engage the paradigm shift that is so urgently needed? We need to change an approach prevalent in the last 100 years of American Medicine that is pathology and disease-based to a newer, more inclusive and realistic form of medicine that is functionally-based. Our goal increasingly is restoration of function (functional medicine) and not prescription based drug treatment of disease.
This is the source of a much greater discussion.
Philip Lee Miller, M.D.
Los Gatos longevity Institute
author, life extension revolution
February 4, 2007