MGA 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 The medication was withdrawn in some countries in 1970 due to concerns about mammarytoxicity observed in dogs, but this turned out not to apply to humans. MGA 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.
Appetite stimulation is achieved with MGA 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. The recommended oral dosage of MGA for breast cancer is 40 mg four times per day (160 mg/day total), while the medication is used at an oral dosage of 40 to 320 mg/day in divided doses for endometrial cancer. It has been used at far lower dosages (e.g., 1–5 mg/day oral, 25 mg/month i.m.) in combination with an estrogen for contraceptive purposes.
Interactions of MGA include significantly decreased exposure to indinavir, which may necessitate an increased dosage of the medication. When MGA is co-administered with zidovudine and rifabutin, there is no significant change in exposure to these medications and no dosage adjustment is necessary.
Notes: (1): Reference ligands (100%) were testosterone for the AR, progesterone for the PR, estradiol for the ER, dexamethasone for the GR, and aldosterone for the MR. (2): Tissues were rat prostate (AR), rabbit uterus (PR), mouse uterus (ER), rat thymus (GR), and rat kidney (MR). (3): Incubation times (0°C) were 24 hours (AR, a), 2 hours (PR, ER), 4 hours (GR), and 1 hour (MR). (4): Assay methods were different for bicalutamide for receptors besides the AR. Sources: See template.
The precise ovulation-inhibiting dosage of MGA is unknown. However, doses of 1 to 5 mg MGA were previously used in combinedbirth control pills in combination with the estrogenethinylestradiol or mestranol. MGA 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. MGA 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 MGA 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 MGA 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 MGA 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 MGA therapy, and this has limited the usefulness of the medication. The combination of a lower dosage of MGA (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.
MGA 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 steroidmetribolone. 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. This is based on the fact that no virilizing 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, the highest that has been assessed. Furthermore, MGA 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. However, the medication does have moderate androgenic effects on serum lipids in humans, causing a significant reduction of HDL and LDL cholesterol levels and no change in triglyceride levels at a dosage of only 5 mg/day. The weak but significant androgenic activity of MGA may serve to limit its clinical effectiveness in the treatment of prostate cancer.
Affinities of selected ligands at the androgen receptor
Notes: (1) Human skin fibroblasts used for assays. (2) Situation in vivo is different for flutamide and spironolactone due biotransformation. (3) Conflicting findings for spironolactone. Sources: See template.
MGA has been found to dose-dependently increase total and free IGF-1 levels up to a dosage of 120 mg/day. 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. Free (readily dissociable) concentrations of IGF-1 were increased to a smaller extent, by 1.23–2.15-fold, and were described as increasing "moderately". It was suggested that the increase in IGF-1 levels with high-dosage MGA therapy may explain the anabolic effects of MGA in patients with cachexia.
In the early 1970s, MGA 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 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 MGA was never marketed as an oral contraceptive in the United States. Subsequent research, such as monkey studies, revealed that there is no similar risk in humans. Following its withdrawal from the market, MGA was eventually reintroduced for the treatment of hormone-sensitive cancers. In addition, MGA 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, and progestins were first found to be effective in the treatment of endometrial cancer in 1959. MGA was reported to be effective in the treatment of endometrial hyperplasia in the mid-1960s. It first started to be studied as a treatment for endometrial cancer in 1967, with findings published in 1973. MGA was reportedly introduced for the treatment of endometrial cancer in the United States in 1971. Progesterone was studied in the treatment of breast cancer in 1951 and 1952, but with relatively modest results. MGA 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 MGA for breast cancer was published in 1980, and this was followed by additional studies in the 1980s and beyond. MGA was approved for the treatment of breast cancer in the United States by at least 1983.
Progestogens, including progesterone and ethisterone, were studied in the treatment prostate cancer in 1949. MGA 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 MGA 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.
MGA is marketed under a variety of brand names throughout the world but is most commonly sold under the brand name Megace. It is also available under the brand name Megace ES in the United States and under the brand name Megace OS in Canada. For use in veterinary medicine, MGA is sold as Ovaban in the United States and as Ovarid in the United Kingdom.
Progestins in birth control pills are sometimes grouped by generation. 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, MGA could be considered a "first-generation" progestin.
^ abChu YH, Li Q, Zhao ZF (April 1986). "Pharmacokinetics of megestrol acetate in women receiving IM injection of estradiol-megestrol long-acting injectable contraceptive". The Chinese Journal of Clinical Pharmacology. A radioimmunoassay (RIA), radioligand assay and equilibrium dialysis for determination of plasma and salivary megestrol acetate (MA) concentration, sex hormone binding globulin (SHBG) capacity in plasma and percentage albumin bound MA were studied in healthy women receiving single im injection of estradiol-megestrol long-acting injectable contraceptive. The results showed that after injection the concentration of plasma MA increased rapidly. The meantime of peak plasma MA level was 3rd day, there was a linear relationship between log of plasma MA concentration and time (day) after administration in all subjects, elimination phase half-life t1/2β = 14.35 ± 9.1 days. The plasma SHBG capacity significantly increased at 7th, 14th day and decreased at 21st, 29th day after injection. The percentage albumin bound MA was 82.4%. There was no specific SHBG bound MA. There was a positive correlation between the MA concentrations in saliva and those in plasma.
^ abNelson LW, Weikel JH, Reno FE (October 1973). "Mammary nodules in dogs during four years' treatment with megestrol acetate or chlormadinone acetate". J. Natl. Cancer Inst. 51 (4): 1303–11. doi:10.1093/jnci/51.4.1303. PMID4126857.
^ abcFDA Consumer. U.S. Department of Health, Education, and Welfare, Public Health Service, Food and Drug Administration. February 1976. Several foreign countries, including Germany, Canada, and Great Britain, have banned the sale of birth control pills containing megestrol acetate after a study done at FDA's request indicated it caused breast cancer in dogs. Megestrol acetate has never been marketed in the United States as an oral contraceptive. FDA routinely requires long-term animal studies before any drug can be marketed for human use. Following animal studies with megestrol acetate, FDA in the late sixties and early seventies allowed limited studies of the drug in women. In 1972, after noticing a significant number of test dogs developing breast nodules (none of them malignant), FDA ordered that megestrol acetate be discontinued in human oral contraceptive studies.
^ abUnited States. Congress. Senate. Committee on Labor and Public Welfare (1976). Hearings, Reports and Prints of the Senate Committee on Labor and Public Welfare. U.S. Government Printing Office. Megestrol was never marketed in the United States for contraceptive use because in 1972, FDA took prompt action to discontinue investigational studies on megestrol after dogs exposed to the drug for four years In a chronic toxicity study developed benign breast tumors.
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^ abMann M, Koller E, Murgo A, Malozowski S, Bacsanyi J, Leinung M (1997). "Glucocorticoidlike activity of megestrol. A summary of Food and Drug Administration experience and a review of the literature". Archives of Internal Medicine. 157 (15): 1651–6. doi:10.1001/archinte.1997.00440360053005. PMID9250225.
^Gruber T, Dare AO, Balos LL, Lele S, Fenstermaker RA (February 2004). "Multiple meningiomas arising during long-term therapy with the progesterone agonist megestrol acetate. Case report". J. Neurosurg. 100 (2): 328–31. doi:10.3171/jns.2004.100.2.0328. PMID15086241.
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^Martine El-Etr; Michaël Schumacher; Etienne-Emile Baulieu (10 November 1999). "Effects of Progesterone and Related Steroids in the Brain". In Régine Sitruk-Ware; Daniel R. Mishell (eds.). Progestins and Antiprogestins in Clinical Practice. Taylor & Francis. pp. 15–58. ISBN978-0-8247-8291-7. Specific actions of neurosteroids on ion transport across the neuronal plasma membrane have been described (see Fig. 2[10). In hippocampal CA1 neurons, Ffrench Mullen et al. (76) observed an inhibition by PREG, PREGS, and 3α,5β-TH PROG (but not PROG) of both the N- and L-type calcium channel currents, mediated by a pertussis toxin-sensitive G protein mechanism, associated with the activation of protein kinase C. PROG still has no effect on calcium channels of hypothalamic neurons from the ventromedial nucleus; however, the synthetic progestin megestrol acetate inhibits some high-threshold Ca2+ channel currents: not the N-type nor the P-type Ca2+ channel currents, but the residual current. Appetite enhancement induced by megestrol acetate might be partly due to the inhibition of these Ca2+ channel currents, and the attenuation of the firing of ventromedial nucleus neurons, involved in satiety mechanisms (77).
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