Leinung and colleagues [1] provided the first convincing report of a patient who became Addisonian after abrupt discontinuation of therapy with megestrol acetate. It has been well established that patients receiving megestrol acetate have markedly suppressed serum cortisol levels and decreased adrenocorticotropic hormone levels, consistent with a central suppression of the pituitary-adrenal axis [2]. This suppression of the pituitary-adrenal axis appears to be asymptomatic in most patients receiving megestrol acetate. Patients generally do not become Cushingoid while receiving megestrol acetate, and previous episodes of Addisonian crises with abrupt discontinuation of megestrol acetate therapy have not been reported (despite the widespread use of megestrol acetate for decades). Nonetheless, recent experience from a randomized clinical trial [3] suggests that patients receiving megestrol acetate might have inadequate adrenal function during episodes of infection and, thus, an increased likelihood of septic deaths. This clinical trial involved patients with late-stage small-cell lung cancer who received a combination of cisplatin and etoposide. Patients were randomly assigned to receive either megestrol acetate (800 mg/d) or placebo. Despite less severe myelosuppression in the megestrol acetate arm, a tendency toward more septic deaths was noted in the patients receiving megestrol acetate (11 of 122 patients compared with 5 of 121 patients; P = 0.12).

One can hypothesize that the increased incidence of septic deaths could be due to adrenal suppression. Thus, it appears rational to recommend that patients receiving megestrol acetate receive stress doses of corticosteroids during periods of acute illness in a manner similar to that used in patients receiving long-term corticosteroid therapy.

Regarding the abrupt withdrawal of megestrol acetate in patients who had been receiving this medication, common clinical practice has been to stop the drug without tapering the dose. In doing so, no untoward clinical sequelae have been seen in most patients. Thus, it appears reasonable to continue to stop megestrol acetate without tapering the dose. Nonetheless, we recommend that patients be counseled about a "stress dose of corticosteroids" if they become acutely ill after abrupt withdrawal of megestrol acetate.

Finally, we emphasize that the effect of megestrol acetate on the pituitary-adrenal axis does not appear to cause clinically evident toxicity in most patients, and it should not be a major deterrent for the clinically appropriate use of megestrol in the treatment of breast cancer, endometrial cancer, or anorexia and cachexia.