|Systematic (IUPAC) name|
|Protein binding||Yes (to albumin, but not to sex hormone-binding globulin or transcortin)|
|Half-life||13 to 105 hours (mean 34 hours)|
Megestrol acetate (INN, USAN, BAN, JAN) (abbreviated as MGA or MA, and sold mainly under the brand names Megace and Megace ES), also known as 17α-acetoxy-6-dehydro-6-methylprogesterone, is a steroidal progestin and progesterone derivative (specifically, a 17-hydroxylated progesterone) with predominantly progestational and antigonadotropic effects.
Megestrol acetate 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.
Megestrol acetate 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 a day. Doses used to treat cancer usually range from 40 mg to 320 mg.
Megestrol acetate has powerful antiandrogenic and antiestrogenic effects in humans at sufficient doses, capable of decreasing circulating androgen and estrogen concentrations to castrate levels in both sexes and significantly lowering the expression of the androgen receptor (AR) and the estrogen receptor (ER) in the body; as an example, one study in men with benign prostatic hyperplasia who were treated with 120–160 mg of megestrol acetate 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. These actions are likely the result of a 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 and their associated enzymes, carriers (e.g., sex hormone-binding globulin), and receptors. It is the antiandrogenic and antiestrogenic effects of megestrol acetate mediated by suppression of the HPG axis that are believed to be largely responsible for its beneficial effects against androgen and estrogen-sensitive cancers, respectively.
Megestrol acetate is a high-affinity, weak partial agonist/antagonist 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). However, at clinical doses in humans, it appears to behave, for all intents and purposes, purely as an antiandrogen. No androgenic side effects have been observed with the use of megestrol acetate in patients of either sex at doses 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.
Unlike the case of the AR, megestrol acetate has no significant affinity for the ER. As such, it does not possess the capacity to directly activate the ER. Furthermore, unlike conventional antiandrogens like cyproterone acetate and flutamide, there is relatively little risk of indirectly mediated estrogenic side effects (e.g., gynecomastia) with megestrol acetate. This is because conventional antiandrogens only suppress androgen activity (which, because androgen and estrogen activities are typically inversely proportional, results in heightened estrogen levels), whereas megestrol acetate suppresses both androgen and estrogen levels at the same time.
Megestrol acetate is an agonist of the glucocorticoid receptor, 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 megestrol acetate in the medical literature, albeit sporadically.
Megestrol acetate is frequently used as an appetite stimulant. The direct mechanism of appetite enhancement is unclear, but it is known that megestrol acetate 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.
The most common side effect of megestrol acetate is weight gain. Other side effects may include nausea, vomiting, 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).
- Medroxyprogesterone acetate
- Melengestrol acetate
- Chlormadinone acetate
- Cyproterone acetate
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