Megestrol acetate (MGA), sold under the brand name Megace among others, is a progestin medication which is used mainly as an appetite stimulant to treat wasting syndromes such as cachexia.

[11][12][13] Megestrol acetate was discovered in 1959 and was introduced for medical use, specifically in birth control pills, in 1963.

[15] The medication was withdrawn in some countries in 1970 due to concerns about mammary toxicity observed in dogs, but this turned out not to apply to humans.

[24] Megestrol acetate is used mainly as an appetite stimulant to promote weight gain in a variety of situations.

[25][30] It is significantly inferior to aromatase inhibitors in both clinical effectiveness and tolerability as a second-line therapy for breast cancer after tamoxifen failure.

[6][7][59] Megestrol acetate can also be used to treat pattern hair loss in men, but its side effects generally make it unacceptable for this purpose.

[1] The most common side effect of megestrol acetate is weight gain, with an incidence of 15–70% at the high dosages used to treat breast cancer.

[5] It may also cause glucocorticoid side effects such as Cushing syndrome-like symptoms, steroid diabetes, and adrenal insufficiency at high dosages.

[71][72][73] Case reports of deep vein thrombosis, pulmonary embolism, jaundice, intrahepatic cholestasis, and meningiomas in association with high-dosage megestrol acetate have been published.

[1] Interactions of megestrol acetate include significantly decreased exposure to indinavir, which may necessitate an increased dosage of the medication.

[1] When megestrol acetate is co-administered with zidovudine and rifabutin, there is no significant change in exposure to these medications and no dosage adjustment is necessary.

[82] Megestrol acetate has antigonadotropic effects in humans at sufficient doses, capable of profoundly suppressing circulating androgen and estrogen concentrations.

[25][52][102][103][104][105] The antigonadotropic effects of megestrol acetate are the result of activation of the progesterone receptor, which suppresses the secretion of the gonadotropins—peptide hormones responsible for signaling the body to produce not only progesterone but also the androgens and the estrogens—from the pituitary gland as a form of negative feedback inhibition, and hence downregulates the hypothalamic–pituitary–gonadal axis (HPG axis), resulting in decreased levels of the sex hormones and interference with fertility.

[104] However, a recovery or "escape" of testosterone levels, gradually returning to near-normal values, has been observed in most men after 2 to 6 months of megestrol acetate therapy, and this has limited the usefulness of the medication.

[25][111][112][113] The combination of a lower dosage of megestrol acetate (40–80 mg/day) and a low oral dosage of an estrogen such as estradiol (0.5–1.5 mg/day), diethylstilbestrol (0.1–0.2 mg/day) or ethinylestradiol (50 μg/day) is able to suppress testosterone levels into the castrate range in men, maintain this suppression long-term, and achieve equivalent effectiveness to high-dosage estrogen monotherapy in the treatment of prostate cancer with comparatively greatly reduced toxicity and side effects.

[2][4][80] Despite its weak intrinsic activity at the androgen receptor, at clinical doses in humans, megestrol acetate appears to behave, for all intents and purposes, purely as an antiandrogen.

[124] This is based on the fact that no virilizing side effects have been observed with the use of megestrol acetate in patients of either sex at dosages up to as high as 1,600 mg per day, the highest that has been assessed.

[124] Furthermore, megestrol acetate produces detectable androgenic effects in animals only at a dose that is the equivalent of approximately 200 times that typically used for the treatment of prostate cancer in men.

[126] The weak but significant androgenic activity of megestrol acetate may serve to limit its clinical effectiveness in the treatment of prostate cancer.

[129] Accordingly, manifestations of its glucocorticoid activity, including symptoms of Cushing's syndrome, steroid diabetes, and adrenal insufficiency, have been reported with the use of megestrol acetate in the literature, albeit sporadically.

[133][134][135] This study found that micronized megestrol acetate at this dose showed considerably improved absorption relative to its conventional tablet form.

[136][148][149][150] Megestrol acetate-containing birth control pills were withdrawn after reports in the early 1970s of a high incidence of venous thromboembolism with the preparations.

[170][171][172] Megestrol acetate was subsequently studied for this indication[173] and, following completion of phase III clinical trials, was approved as an oral suspension for the treatment of anorexia–cachexia syndrome due to cancer and other chronic conditions such as HIV/AIDS in the United States in 1993.

[21][174] Thereafter, the branded product, Megace ES, has been heavily promoted by its maker, Par Pharmaceutical, for treatment of unintentional weight loss in elderly patients, especially those living in long-term care facilities.

This use was not approved as safe and effective by the Food and Drug Administration (FDA), and not covered by federal health care programs.

The lawsuit claimed that Par marketed the product as effective for this use, despite having conducted no well-controlled studies to support a claim of greater efficacy for Megace ES, and prior knowledge of the severe adverse side effects for geriatric patients, including deep vein thrombosis, toxic reactions with impaired renal function, and mortality.

[15] Megestrol acetate has been studied in men in combination with testosterone as a male hormonal contraceptive to suppress spermatogenesis.

[7][178] Megestrol acetate has been used in veterinary medicine under the brand name Ovaban in the treatment of medical conditions in cats and dogs.

[22][179] Due to its ability to suppress testosterone levels, megestrol acetate can control sexually dimorphic traits in males.

[180][181] As a result, megestrol acetate has been used to reduce dominance, inter-male aggression, mounting, urine spraying, and roaming in male dogs and cats.