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. It is also used to treat breast cancer and endometrial cancer, and has been used in birth control. Megestrol acetate is generally formulated alone, although it has been combined with estrogens in birth control formulations. It is usually taken by mouth.
Side effects of megestrol acetate include increased appetite, weight gain, vaginal bleeding, nausea, edema, low sex hormone levels, sexual dysfunction, osteoporosis, cardiovascular complications, glucocorticoid effects, and others. Megestrol acetate is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. It has weak partial androgenic activity, weak glucocorticoid activity, and no other important hormonal activity. Due to its progestogenic activity, megestrol acetate has antigonadotropic effects. The mechanism of action of the appetite stimulant effects of megestrol acetate is unknown.
Megestrol acetate was discovered in 1959 and was introduced for medical use, specifically in birth control pills, in 1963. It may be considered a "first-generation" progestin. The medication was withdrawn in some countries in 1970 due to concerns about mammary toxicity observed in dogs, but this turned out not to apply to humans. Megestrol acetate was approved for the treatment of endometrial cancer in 1971 and wasting syndromes in 1993. It is marketed widely throughout the world. It is available as a generic medication.
Medical uses Megestrol acetate is used mainly as an appetite stimulant to promote weight gain in a variety of situations. When given at very high dosages, 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. In addition to its effects on appetite, megestrol acetate appears to have antiemetic effects. Megestrol acetate is also used as an antineoplastic agent in the treatment of breast cancer and endometrial cancer. It is significantly inferior to aromatase inhibitors in both clinical effectiveness and tolerability as a second-line therapy for breast cancer after tamoxifen failure. Megestrol acetate was formerly used in combined oral contraceptives in combination with ethinylestradiol or mestranol, and has been used in a combined injectable contraceptive in combination with estradiol as well.
Although it has not been approved for these uses, megestrol acetate has been studied and/or used off-label for a variety of indications including menopausal hormone therapy and the treatment of hot flashes, gynecological/menstrual disorders, endometriosis, endometrial hyperplasia, ovarian cancer, prostate cancer, benign prostatic hyperplasia, male breast cancer, and precocious puberty. Megestrol acetate can also be used to treat pattern hair loss in men, but its side effects generally make it unacceptable for this purpose.
Appetite stimulation is achieved with megestrol acetate with oral dosages of 400 to 800 mg/day. The optimal dosage with maximum effect for appetite stimulation has been determined to be 800 mg/day.
Available forms
Megestrol acetate is available as 5 mg, 20 mg, and 40 mg oral tablets and in oral suspensions of 40 mg/mL, 125 mg/mL, 625 mg/5 mL, and 820 mg/20 mL. It was used at doses of 1 mg, 2 mg, 4 mg, and 5 mg in combined oral contraceptives. Megestrol acetate is formulated at a dose of 25 mg in combination with a dose of 3.75 mg estradiol in a microcrystalline aqueous suspension for use as a once-monthly combined injectable contraceptive in women.
Contraindications Contraindications of megestrol acetate include hypersensitivity to megestrol acetate or any component of its formulation, known or suspected pregnancy, and breastfeeding. Megestrol acetate is a teratogen in animals and may have the potential to cause fetal harm, such as decreased fetal weight and feminization of male fetuses.
Side effects 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. Other side effects include vaginal bleeding (7–8%), nausea (7%), and edema (5%), as well as others such as dizziness and shortness of breath. Megestrol acetate can cause hypogonadism and associated symptoms like diminished secondary sexual characteristics, sexual dysfunction, osteoporosis, and reversible infertility in men and premenopausal women. Combining megestrol acetate with an androgen/anabolic steroid like oxandrolone, nandrolone decanoate, or testosterone in men can alleviate megestrol acetate-associated symptoms of hypoandrogenism as well as further increase appetite and weight gain. Less common but more serious side effects of megestrol acetate include cardiovascular/thromboembolic complications such as thrombophlebitis. It may also cause glucocorticoid side effects such as Cushing syndrome-like symptoms, steroid diabetes, and adrenal insufficiency at high dosages. Case reports of deep vein thrombosis, pulmonary embolism, jaundice, intrahepatic cholestasis, and meningiomas in association with high-dosage megestrol acetate have been published. In older patients who take megestrol acetate, one in 23 will have an adverse event leading to death.
Overdose Megestrol acetate has been studied at very high dosages of as much as 1,600 mg/day with no serious adverse effects observed. No clear increase in rate or severity of side effects have been observed up to 1,600 mg/day megestrol acetate except for weight gain, mild increases in blood pressure, and some fluid retention. In post-marketing experience, limited reports of overdose have been received. Signs and symptoms described in these reports have included diarrhea, nausea, abdominal pain, shortness of breath, cough, unsteady gait, listlessness, and chest pain. There is no specific antidote for overdose of megestrol acetate. Treatment should be supportive and based on symptoms. Megestrol acetate has not been assessed for dialyzability. However, due to its low solubility, it is thought that dialysis would not be useful for treating megestrol acetate overdose.
Interactions Interactions of megestrol acetate include significantly decreased exposure to indinavir, which may necessitate an increased dosage of the medication. 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.
Pharmacology
Pharmacodynamics Megestrol acetate has progestogenic activity, antigonadotropic effects, weak partial androgenic activity, and weak glucocorticoid activity.
Relative affinities (%) of megestrol acetate Compound Megestrol acetate 65 5 0 30 0 0 0 Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the , metribolone for the , estradiol for the , dexamethasone for the , aldosterone for the , dihydrotestosterone for , and cortisol for . Sources:
Progestogenic activity Megestrol acetate is a progestogen, or an agonist of the progesterone receptor (PR). It has about 65% of the affinity of promegestone and 130% of the affinity of progesterone for the progesterone receptor. Like other progestogens, megestrol acetate has functional antiestrogenic effects in certain tissues such as the endometrium and has antigonadotropic effects. The total endometrial transformation dose of megestrol acetate is 50 mg per cycle.
Antigonadotropic and anticorticotropic effects Megestrol acetate has antigonadotropic effects in humans at sufficient doses, capable of profoundly suppressing circulating androgen and estrogen concentrations. 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. As such, megestrol acetate has functional antiandrogenic and antiestrogenic effects as well as contraceptive effects via its antigonadotropic effects.
The precise ovulation-inhibiting dosage of megestrol acetate is unknown. However, doses of 1 to 5 mg megestrol acetate were previously used in combined birth control pills in combination with the estrogen ethinylestradiol or mestranol. Megestrol acetate is an effective contraceptive by itself at dosages of 0.35 to 0.5 mg/day, but is not effective at a dosage of 0.25 mg/day. Megestrol acetate alone does not inhibit ovulation at a dosage of 0.5 mg/day, nor does it fully inhibit ovulation at a dosage of 0.7 mg/day or even at a dosage of 5 mg/day. The combination of 2 to 5 mg/day megestrol acetate and 100 μg/day mestranol has been found to consistently inhibit ovulation, whereas either medication alone did not completely inhibit ovulation in all women.
Suppression of testosterone levels by megestrol acetate is responsible for its effectiveness in the treatment of conditions like prostate cancer and benign prostatic hyperplasia. In one study, 120 to 160 mg/day megestrol acetate suppressed testosterone levels in men by 72%. 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. 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. In spite of these results, however, this combination has been very rarely used to treat prostate cancer in the United States.
The antigonadotropic as well as anticorticotropic effects of megestrol acetate may be involved in its effectiveness in the treatment of postmenopausal breast cancer via substantially decreasing gonadal and adrenal production of sex steroids and by extension circulating levels of estrogens, by about 80%.
Androgenic and antiandrogenic activity