Megestrol acetate

Medical uses

MGA is used mainly as an appetite stimulant in a variety of conditions and as an antineoplastic agent in the treatment of breast, endometrial, and prostate cancers. When given in relatively high doses, it can substantially increase appetite in most individuals, even those with advanced cancer, and is often used to boost appetite and induce weight gain in patients with cancer or HIV/AIDS-associated cachexia. It is also used as a contraceptive in combination with an estrogen at relatively low doses.

In addition to its use in humans, MGA has been used extensively in veterinary medicine in the treatment of medical conditions in cats and dogs.

Available forms

MGA is available as 5 mg, 20 mg and 40 mg tablets and in oral suspensions of 125 mg/ml and 40 mg/ml. It is used at a dose of 5 mg in combination with an estrogen for contraception. Appetite stimulation is achieved with doses ranging from 400 mg to 800 mg/day. Doses used to treat cancer usually range from 40 mg to 320 mg.

Contraindications

MGA should not be used in pregnancy under any circumstance as it crosses the placenta and malignantly affects the fetus.

Side effects

The most common side effect of MGA is weight gain. Other side effects may include nausea, vomiting, nightmares, impotence, edema, breakthrough bleeding, and shortness of breath. Rare and more severe side effects may include thrombophlebitis and pulmonary embolism. It may also cause glucocorticoid-related adverse effects such as adrenal insufficiency in some individuals and/or cases (especially if the medication is suddenly discontinued following prolonged use).

Progestogenic activity

MGA acts predominantly as a potent agonist of the progesterone receptor (PR) to exert its effects.

Antigonadotropic activity

MGA has strong antigonadotropic effects in humans at sufficient doses, capable of dramatically suppressing circulating androgen and estrogen concentrations in both sexes. It can also decrease sex hormone receptors in certain parts of the body; as an example, one study in men with benign prostatic hyperplasia who were treated with 120–160 mg MGA per day for 3 to 11 days found average decreases in AR quantity of 73% and 86% in the cytoplasm and nucleus of prostatic cells, respectively. The antigonadotropic effects of MGA are the result of strong activation of the PR, 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 (HPG) axis, resulting in decreased levels of the sex hormones. It is the antiandrogenic and antiestrogenic effects of MGA mediated by suppression of the HPG axis that are mainly responsible for its beneficial effects against androgen and estrogen-sensitive cancers, respectively.

Antiandrogenic activity

MGA is a high-affinity antagonist/weak partial agonist of the AR, where it binds with very similar but slightly less affinity relative to the PR (about 75% of the affinity according to one assay). Despite its weak intrinsic activity at the AR, at clinical doses in humans, MGA appears to behave, for all intents and purposes, purely as an antiandrogen. No androgenic side effects have been observed with the use of MGA in patients of either sex at dosages up to as high as 1,600 mg per day (which is the highest that has been used). Furthermore, it 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.

Estrogenic activity

Unlike the case of the AR, MGA has no significant affinity for the ER. As such, it does not possess the capacity to directly activate the ER. Furthermore, unlike antiandrogens such as cyproterone acetate and flutamide, there is relatively little risk of indirectly mediated estrogenic side effects (e.g., gynecomastia) with MGA. This is because MGA strongly suppresses both androgen and estrogen levels at the same time.

Glucocorticoid activity

MGA is an agonist of the glucocorticoid receptor (GR), with similar but less affinity in comparison to the PR and the AR (about 37% and 50% of the affinity, respectively, according to one assay). One study found that, in the dose range tested, it possesses about 50% of the eosinopenic and hyperglycemic activity (markers of glucocorticoid activity) of an equal amount of medroxyprogesterone acetate, and about 25% that of cortisol. Accordingly, manifestations of its glucocorticoid properties, including symptoms of Cushing's syndrome, steroid diabetes, and adrenal insufficiency, have been reported with the use of MGA in the medical literature, albeit sporadically.

Appetite stimulant

MGA is frequently used as an appetite stimulant. The direct mechanism of appetite enhancement is unclear, but it is known that MGA induces a variety of downstream changes to cause the effect, including stimulation of the release of neuropeptide Y in the hypothalamus, modulation of calcium channels in the ventromedial hypothalamus, and inhibition of the secretion of proinflammatory cytokines including IL-1α, IL-1β, IL-6, and TNF-α, all of which have been implicated in facilitation of appetite.

History

MGA was first synthesized, in 1959, from medroxyprogesterone acetate, which itself had been synthesized the year prior in 1958. MGA in combination with ethinylestradiol (EE) was introduced in 1963 by British Drug Houses in the United Kingdom under the brand name Volidan (4 mg MGA and 50 μg EE tablets) as an oral contraceptive, and this was followed by Serial 28 (1 mg MGA and 100 μg EE tablets) and Volidan 21 (4 mg MGA and 50 μg EE tablets) in 1964 and Nuvacon (2 mg MGA and 100 μg EE tablets) in 1967, all by British Drug Houses also in the U.K. MGA was approved in 1967 for the treatment of breast cancer. In the 1970s, it was found to be associated with mammary tumors in beagle dogs, and along with several other progestogens, was withdrawn from several markets as an oral contraceptive. Subsequent research revealed that there is no similar risk in humans.