Megestrol acetate

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. 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 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. 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. ==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. 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. 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. It has about 65% of the affinity of promegestone and 130% of the affinity of progesterone for the progesterone receptor. 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. 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. 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%. 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. Androgenic and antiandrogenic activity Megestrol acetate is a weak partial agonist of the androgen receptor (AR). It has been reported to bind to this receptor with 5% of the affinity of the anabolic steroid metribolone. 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. However, the medication does have moderate androgenic effects on serum lipids in humans, causing a significant reduction of HDL cholesterol| and cholesterol levels and no change in triglyceride levels at a dosage of only 5 mg/day. Glucocorticoid activity Megestrol acetate is an agonist of the glucocorticoid receptor (GR), the biological target of glucocorticoids like cortisol. 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. Appetite stimulation Megestrol acetate is frequently used as an appetite stimulant to promote weight gain. and inhibition of the secretion of proinflammatory cytokines including interleukin 1α, interleukin 1β, interleukin 6, and tumor necrosis factor α, all of which have been implicated in facilitation of appetite. Increased levels of insulin-like growth factor 1 (IGF-1) may also be involved, specifically in its anabolic effects. This is because megestrol acetate strongly suppresses both androgen and estrogen levels at the same time. Total IGF-1 levels were described as "profoundly" increased, gradually increasing, significantly by 3 days of treatment, up to a maximum of 2.66-fold by 5 to 6 months of treatment. This study found that micronized megestrol acetate at this dose showed considerably improved absorption relative to its conventional tablet form. Following oral administration of 80 to 160 mg megestrol acetate or 500 to 1,000 mg medroxyprogesterone acetate, circulating levels of megestrol acetate were 2- to 10-fold higher than those of medroxyprogesterone acetate. The pharmacokinetics of megestrol acetate have been reviewed. ==Chemistry==

Megestrol acetate, also known as 17α-acetoxy-6-dehydro-6-methylprogesterone or as 17α-acetoxy-6-methylpregna-4,6-diene-3,20-dione, is a synthetic pregnane steroid and a derivative of progesterone. It is specifically a derivative of 17α-hydroxyprogesterone with a methyl group at the C6 position, a double bond between the C6 and C7 positions, and an acetate ester at the C17α position. Close analogues of megestrol acetate that were never marketed include cymegesolate (megestrol acetate 3β-cypionate) and megestrol caproate. Synthesis Chemical syntheses of megestrol acetate have been published. ==History==

Megestrol acetate was synthesized at Syntex in 1959. It was derived from medroxyprogesterone acetate, which had been synthesized at Syntex in 1957. 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 United Kingdom. It was also marketed under the brand name Delpregnin (5 mg MGA and 100 μg mestranol tablets) by 1965, among others. Megestrol acetate-containing birth control pills were withdrawn after reports in the early 1970s of a high incidence of venous thromboembolism with the preparations. In the early 1970s, megestrol acetate was found to be associated with mammary tumors in beagle dogs, and along with several other progestogens, was withdrawn as an oral contraceptive from several markets including the United Kingdom, Canada, and West Germany. It was also under investigation for use as a contraceptive in the United States, but development was discontinued in 1972 following the mammary toxicity findings in dogs, and megestrol acetate was never marketed as an oral contraceptive in the United States. Following its withdrawal from the market, megestrol acetate was eventually reintroduced for the treatment of hormone-sensitive cancers. In addition, megestrol acetate was marketed for veterinary use in dogs in 1969 in the United Kingdom and in 1974 in the United States. Progesterone was first found to be effective in the treatment of endometrial hyperplasia in 1951, Megestrol acetate was reported to be effective in the treatment of endometrial hyperplasia in the mid-1960s. Megestrol acetate was reportedly introduced for the treatment of endometrial cancer in the United States in 1971. Megestrol acetate was first studied in the treatment of breast cancer in 1967, and was one of the first progestins to be evaluated for the treatment of this disease. A second study was conducted in 1974. A "breakthrough" and surge of interest in progestins for breast cancer occurred in 1978 when a study using a massive dosage of medroxyprogesterone acetate to treat breast cancer was published. A third study of megestrol acetate for breast cancer was published in 1980, and this was followed by additional studies in the 1980s and beyond. Megestrol acetate was approved for the treatment of breast cancer in the United States by at least 1983. Megestrol acetate was first studied in the treatment of prostate cancer in 1970. Additional studies were conducted in 1975 and 1978, followed by others thereafter. However, results of megestrol acetate therapy for prostate cancer have been "disappointing", and the medication has not been approved for the treatment of prostate cancer in the United States or elsewhere. Megestrol acetate was subsequently studied for this indication 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. 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. In March 2013, Par settled a $45 million federal and multi-state criminal and civil lawsuit in which the company was accused of promoting the branded version of megestrol acetate, over the generic version, for use in treating non-AIDS-related geriatric wasting. 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. ==Society and culture==

Generic names Megestrol acetate is the generic name of the drug and its , , , and , while megestrol is the and and mégestrol the of megestrol, the free alcohol form of megestrol acetate. While the 19-nortestosterone progestins are consistently grouped into generations, the pregnane progestins that are or have been used in birth control pills are typically omitted from such classifications or are grouped simply as "miscellaneous" or "pregnanes". In any case, based on its date of introduction in such formulations of 1963, megestrol acetate could be considered a "first-generation" progestin. ==Research==

Megestrol acetate has been studied in men in combination with testosterone as a male hormonal contraceptive to suppress spermatogenesis. ==Veterinary use==

Megestrol acetate has been used in veterinary medicine under the brand name Ovaban in the treatment of medical conditions in cats and dogs. Due to its ability to suppress testosterone levels, megestrol acetate can control sexually dimorphic traits in males. As a result, megestrol acetate has been used to reduce dominance, inter-male aggression, mounting, urine spraying, and roaming in male dogs and cats. ==See also==