Side Effects of Growth Hormone Therapy

The side effects of GH therapy arise from the hormonal impact of overreplacement because rhGH is identical to the endogenous hormone and thus should not elicit hypersensitivity reactions, except in the very rare patients with congenital GH gene deletions. Fluid retention due to the antinatriuretic actions of GH is by far the most common untoward effect among adults with GHD receiving replacement therapy. In experimental trials, ~40% of subjects reported clinically apparent edema, ~20% developed joint swelling (especially in the hands) and/or noninflammatory arthralgias, and ~15% suffered from myalgias [36]. Arthralgias probably result from fluid accumulation in joint spaces as inflammatory changes and radiographic anomalies are not found. These side effects are generally mild and resolve within a few weeks of therapy. However, ~10% of subjects develop carpal tunnel syndrome. Increased hypertension is typically not reported even after up to 3 years of treatment. Gynecomastia and atrial fibrillation have occasionally been attributed to GH administration in elderly patients. All GHrelated side effects are dose related, and older people are particularly susceptible to them.

As GH directly antagonizes insulin action, a theoretical risk of its use is hyperglycemia. This is a particularly important concern for the elderly as ~40% of people 65–74 years old and ~50% of those older than 80 years have impaired glucose tolerance or diabetes mellitus [36]. Careful studies specifically examining this risk in GHD adults have shown that GH replacement does, indeed, initially decrease insulin sensitivity. However, the effect is reversed within 3–6 months of therapy, and carbohydrate metabolism returns to baseline. This is presumably due to the counteracting effect of losing central body fat and thus increasing insulin sensitivity. Although GH-induced increases in basal insulin or glucose have been seen in some studies, these values generally remained within normal ranges and have never been associated with significant increases in hemoglobin A_1c.

Warnings have been voiced that GH could have mitogenic properties. These theoretical concerns derive from highly controversial in vitro data obtained with a variety of cell lineages fromthe observation that most human solid tumors express IGF-I receptors [37] and from epidemiological evidence that patients with acromegaly have increased incidences of colon and breast cancer [38, 39]. At present, the prudent course of action for patients receiving GH would be to adhere strictly to guidelines regarding prostate examinations and PSA levels in men and breast examinations and mammograms in women. Doctors should also inform high-risk patients of these reports. However, it is inappropriate to extrapolate conclusions drawn from patients with acromegaly who have grossly elevated GH levels to adults with GHD receiving only physiological restitution.

Reports of associations between circulating IGF-I concentrations and the development of prostate and breast cancer have further raised concerns about the long-term risks of GH therapy [40]. However, IGF-I levels in the groups with increased cancer incidences were higher than those that would be sought in carefully titrated physiological replacement therapy.Thus, the applicability of these observations to the latter situation is questionable. Furthermore, there is no strong evidence for increased incidences of prostate or breast cancer in patients with acromegaly, which argues against a causal relationship between IGF-I and these malignancies.

GH administration is currently contraindicated for patients with active malignancy, benign intracranial hypertension, and proliferative or preproliferative diabetic retinopathy [34]. Early pregnancy is not a contraindication, but GH therapy may be discontinued in the second trimester as a GH variant is secreted by the placenta.

One setting in which GH therapy has proved detrimental is in the critically ill. These individuals have impairments of both GH secretion and action. Hence, two randomized, multicenter trials were undertaken to determine whether GH treatment in several hundred intensive care unit patients might speed recovery [41]. Unexpectedly, there was a near doubling of mortality, from 20 to 38%, in both studies.