Catabolic Hormones and Growth Hormone Resistance in Acquired Immunodeficiency Syndrome and Other Catabolic States

Abstract

Summary and Conclusions

The classification of metabolically active hormones as either regulatory or counterregulatory is inappropriate; all of these hormones regulate metabolic and growth processes. In fact, some “counterregulators” elicit insulin-like effects including the aforementioned actions of GH and the glycogenic action of glucocorticoids. By contrast, the proposed reclassification of these hormones based on their somatotropic actions in anabolic and catabolic conditions is free from contradiction (Table I). In anabolic states, insulin and the insulin-antagonists participate in the homeostatic control of metabolism and stimulate growth. Preliminary studies in our laboratory suggest that, like glucagon, glucocorticoids and catecholamines maintain GH resistance in primary hepatocytes as well. Thus, in catabolic states, elevated circulating levels of the catabolic growth inhibitors (Table I) may help to maintain GH resistance and growth suppression. Although thyroid hormones stimulate GH receptor gene expression, they inhibit chondrocyte clonal expansion and cartilage formation (4). However, in catabolic states, circulating thyroid hormone concentrations and tissue sensitivity are reduced (93); thus, they should be classified as anabolic growth promoters.

Adrenal insufficiency may develop in some AIDS patients. Altered steroidogenesis can impair glucocorticoid, mineralocorticoid and androgen secretion (94-102). However, long-term studies suggest that circulating concentrations of basal and ACTH-stimulated cortisol are generally normal or elevated in HIV ⁺ men (96, 103). Opportunistic infections of cytomegalovirus, mycobacteria, and fungi, as well as the development of Kaposi's sarcoma and lymphoma in the glands themselves, are likely responsible for the development of adrenal insufficiency (104, 105).

Although the metabolic rate increases throughout the progression of AIDS, it does not correlate with cachexia, which often occurs only after secondary infection (106). Because cachexia, hypercortisolism, and opportunistic infections occur within the terminal stages of the disease, it is possible that host reaction to the opportunistic infections activates the HPA axis, which contributes to wasting and immunosuppression. Thus, it is also possible that the prevention of hypercortisolism could revive immune function by partially restoring circulating CD4⁺ T cell numbers in addition to GH responsiveness and restored body composition. The glucocorticoid synthesis inhibitors metyrapone and aminoglutethimide, which are typically used to treat patients with Cushing's syndrome, or the glucocorticoid receptor antagonist mifeprisone (RU486) could be administered orally to counteract the effects of hypercortisolism. Administration of these agents in combination with GH would likely prove to be even more effective. Circulating cortisol levels may change dramatically in AIDS patients depending on the presence or absence of opportunistic infections. The possible development of adrenal insufficiency in a small percentage of subjects may complicate data interpretation further. Therefore, future intervention studies regarding the endocrine abnormalities associated with AIDS should take into account symptom variability. Such variability could be avoided if HIV⁺ study subjects met the Center for Disease Control's criteria for Group IV AIDS and had CD4⁺ T cell counts of 0 to 200 cells/mm³.