Growth hormone should be used only for approved indications

Abstract

We are writing to express our strong disagreement with the editorial by Sonksen (1), who commented on a review of the syndrome of adult GH deficiency by Melmed (2). The review focused on adult GH deficiency in the context of patients with pituitary disease, it noted known diagnostic confounders such as obesity and aging, and it emphasized that most of the studies that have measured improvement in response to GH therapy have primarily involved subjects who have multiple pituitary hormone deficits and structural evidence of hypothalamic/pituitary disease, thereby making it difficult to conclude that patients with isolated, idiopathic GH deficiency and no structural changes will derive the same benefit. In his editorial, Sonksen criticizes Melmed's recommendation that strict GH stimulation testing criteria be used to establish the diagnosis of isolated GH deficiency and expresses the viewpoint that a decision to initiate GH treatment can be based solely on clinical criteria. Sonksen then deviates significantly from a discussion of the issues in that review and expresses opinions that support the unsubstantiated use of GH therapy in normal elderly patients and the use of GH to enhance athletic performance. First, the concept that GH should be administered therapeutically to elderly adults without structural evidence of hypothalamic/pituitary disease is completely unsubstantiated, with most studies suggesting that the side effects outweigh any purported benefits (3). Sonksen argues that there is a clear rationale for prescribing GH for the prevention of frailty. He also states that GH is relatively safe in the elderly because side effects are only noted when very high doses were used. However, in the published trials that he cites, relatively high doses were used and a significant number of side effects occurred. Sonksen concludes that the physiological decline in GH in the elderly can be used as the basis for predicting a positive response to therapy. He argues that the decision whether or not to treat the elderly is best made by a family doctor, but the clinical criteria on which a physician would base this decision are not delineated. He abjures biochemical testing to make the diagnosis, which he claims is just a “semantic issue.” The studies cited by Sonksen do not conclude that this question has been answered definitively. Sonksen repeatedly cites the study by Rudman et al (4), omitting the fact that no functional benefits were observed in the participants in that study. Similarly, the study by Papadakis et al (5) also failed to detect any functional benefits, but reported significant side effects in the elderly treated with exogenous GH in a placebo-controlled fashion. Similarly, the report by Blackman et al (6) did not show clear benefit. The study of Giannoulis et al (7) evaluated patients for 6 months who received GH alone or GH plus T. GH was administered in a dose that increased IGF-1 2-fold, and clearly some of the subjects were receiving doses that were greater than those required for physiological replacement. Maximal aerobic capacity was used as a measure of physical performance. Importantly, only the group that received GH plus T had a significant increase. GH alone had no effect on these exercise parameters. Therefore, this study certainly does not definitively answer the question as to whether this would be an acceptable long-term treatment in this population. In a study by Sattler et al (8) in which patients received GH plus T, IGF-1 increased 2.5-fold. However, although strength testing improved in the subjects receiving both hormones, there was no difference in the degree of improvement compared to subjects receiving T alone (8). Therefore, there is no evidence that GH administration had any added benefit. The study by Weissberger et al (9) analyzed the effect of GH in a dose of 16 μg/kg, which is clearly a pharmacological dose, in elderly subjects in a catabolic state. The subjects were undergoing hip surgery and did have a modest improvement in strength. However, although three functional tests were conducted, only one showed significant improvement. It is important to point out that this effect was only achieved using pharmacological doses of GH that induced side effects and increased IGF-1 to supraphysiological levels. Edema developed in 13 of 17 patients, and joint pain developed in nine of 17 patients. IGF-1 was greater than the upper limit of normal in 11 of 17 patients. Importantly, this study investigated the role of GH in accelerating recovery from surgery, and the results may not be applicable to noncatabolic elderly patients. We conclude that the studies cited by Sonksen do not support the concept that GH administration to elderly subjects who are secreting relatively low amounts of GH improves functional performance. It is also clear that in elderly subjects, whether they are GH deficient or not, the potential for toxicity is high. Furthermore, prospective determination of what