Megestrol acetate

Megestrol acetate
Systematic (IUPAC) name
17-(acetyloxy)-6-methyl-pregna-4,6-diene-3,20-dione
Clinical data
  • US: X (Contraindicated)
  • ℞ (Prescription only)
Oral
Pharmacokinetic data
Bioavailability 100% (oral)[1]
Protein binding Yes (to albumin, but not to sex hormone-binding globulin or transcortin)[1]
Half-life 13 to 105 hours (mean 34 hours)[2]
Identifiers
3562-63-8
G03AC05
PubChem CID 11683
DrugBank DB00351
ChemSpider 11192
Synonyms BDH-1298, NSC-71423[3]
Chemical data
Formula C24H32O4
384.509 g/mol

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.[4][5][6]

Though sometimes referred to simply as megestrol, it is important to clarify that megestrol acetate is not the same as megestrol, which is a closely related but different compound.[5]

Uses

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.[7] 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, megestrol acetate has been used extensively in veterinary medicine in the treatment of medical conditions in cats and dogs.[5]

Dosage

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.

Pharmacology

Megestrol acetate acts predominantly as a potent agonist of the progesterone receptor (PR) to exert its effects.[8]

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;[9][10][11][12][13] 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.[12] 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.[14] 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.[15][16]

Megestrol acetate is a high-affinity, weak partial agonist/antagonist of the AR,[17][18][19] where it binds with very similar but slightly less affinity relative to the PR (about 75% of the affinity according to one assay).[8] 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).[20] 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.[21]

Unlike the case of the AR, megestrol acetate has no significant affinity for the ER.[8] 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.[22] 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).[8][19] 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.[23] 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.[24]

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.[25][26][27]

Side effects

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.[2] 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).[28][29]

Contraindications

Megestrol acetate should not be used in pregnancy under any circumstance as it crosses the placenta and malignantly affects the fetus.[30]

Synthesis

Megestrol synthesis:[31] U.S. Patent 2,891,079

See also

References

  1. ↑ 1.0 1.1 Schindler AE, Campagnoli C, Druckmann R et al. (December 2003). "Classification and pharmacology of progestins". Maturitas. 46 Suppl 1: S7–S16. doi:10.1016/j.maturitas.2003.09.014. PMID 14670641.
  2. ↑ 2.0 2.1 Richard R. Barakat; Maurie Markman; Marcus Randall (29 May 2009). Principles and Practice of Gynecologic Oncology. Lippincott Williams & Wilkins. p. 447. ISBN 978-0-7817-7845-9. Retrieved 2 June 2012.
  3. ↑ Dr. Ian Morton; Ian K. M. Morton; Judith M. Hall; Dr. Judith Hall (1999). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer. p. 173. ISBN 978-0-7514-0499-9. Retrieved 2 June 2012.
  4. ↑ F.. Macdonald (1997). Dictionary of Pharmacological Agents. CRC Press. p. 1267. ISBN 978-0-412-46630-4. Retrieved 12 May 2012.
  5. ↑ 5.0 5.1 5.2 Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 641. ISBN 978-3-88763-075-1. Retrieved 2 June 2012.
  6. ↑ Neumann F (1978). "The physiological action of progesterone and the pharmacological effects of progestogens--a short review". Postgraduate Medical Journal. 54 Suppl 2: 11–24. PMID 368741.
  7. ↑ Kenneth L. Becker (24 April 2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. p. 1195. ISBN 978-0-7817-1750-2. Retrieved 27 May 2012.
  8. ↑ 8.0 8.1 8.2 8.3 Teulings FA, van Gilse HA, Henkelman MS, Portengen H, Alexieva-Figusch J (July 1980). "Estrogen, androgen, glucocorticoid, and progesterone receptors in progestin-induced regression of human breast cancer". Cancer Research 40 (7): 2557–61. PMID 6248208.
  9. ↑ Geller J, Albert J, Yen SS, Geller S, Loza D (March 1981). "Medical castration of males with megestrol acetate and small doses of diethylstilbestrol". The Journal of Clinical Endocrinology and Metabolism 52 (3): 576–80. doi:10.1210/jcem-52-3-576. PMID 6161942.
  10. ↑ Venner PM (December 1990). "Therapeutic options in treatment of advanced carcinoma of the prostate". Seminars in Oncology 17 (6 Suppl 9): 73–7. PMID 2259929.
  11. ↑ Lundgren S, Lønning PE, Utaaker E, Aakvaag A, Kvinnsland S (June 1990). "Influence of progestins on serum hormone levels in postmenopausal women with advanced breast cancer--I. General findings". Journal of Steroid Biochemistry 36 (1-2): 99–104. doi:10.1016/0022-4731(90)90118-c. PMID 2362454.
  12. ↑ 12.0 12.1 Geller J, Albert J, Geller S (1982). "Acute therapy with megestrol acetate decreases nuclear and cytosol androgen receptors in human BPH tissue". The Prostate 3 (1): 11–5. doi:10.1002/pros.2990030103. PMID 6176985.
  13. ↑ Blumenschein GR (December 1983). "The role of progestins in the treatment of breast cancer". Seminars in Oncology 10 (4 Suppl 4): 7–10. PMID 6230722.
  14. ↑ Alexieva-Figusch J, Blankenstein MA, de Jong FH, Lamberts SW (September 1984). "Endocrine effects of the combination of megestrol acetate and tamoxifen in the treatment of metastatic breast cancer". European Journal of Cancer & Clinical Oncology 20 (9): 135–40. PMID 6434315.
  15. ↑ Schacter L, Rozencweig M, Canetta R, Kelley S, Nicaise C, Smaldone L (March 1989). "Megestrol acetate: clinical experience". Cancer Treatment Reviews 16 (1): 49–63. doi:10.1016/0305-7372(89)90004-2. PMID 2471590.
  16. ↑ Sedlacek SM (April 1988). "An overview of megestrol acetate for the treatment of advanced breast cancer". Seminars in Oncology 15 (2 Suppl 1): 3–13. PMID 3285483.
  17. ↑ Eil C, Edelson SK (July 1984). "The use of human skin fibroblasts to obtain potency estimates of drug binding to androgen receptors". The Journal of Clinical Endocrinology and Metabolism 59 (1): 51–5. doi:10.1210/jcem-59-1-51. PMID 6725525.
  18. ↑ Luthy IA, Begin DJ, Labrie F (November 1988). "Androgenic activity of synthetic progestins and spironolactone in androgen-sensitive mouse mammary carcinoma (Shionogi) cells in culture". Journal of Steroid Biochemistry 31 (5): 845–52. doi:10.1016/0022-4731(88)90295-6. PMID 2462135.
  19. ↑ 19.0 19.1 Poyet P, Labrie F (October 1985). "Comparison of the antiandrogenic/androgenic activities of flutamide, cyproterone acetate and megestrol acetate". Molecular and Cellular Endocrinology 42 (3): 283–8. doi:10.1016/0303-7207(85)90059-0. PMID 3930312.
  20. ↑ Farrar DJ (March 1999). "Megestrol acetate: promises and pitfalls". AIDS Patient Care and STDs 13 (3): 149–52. doi:10.1089/apc.1999.13.149. PMID 10375262.
  21. ↑ Tisell LE, Salander H (February 1975). "Androgenic properties and adrenal depressant activity of megestrol acetate observed in castrated male rats". Acta Endocrinologica 78 (2): 316–24. doi:10.1530/acta.0.0780316. PMID 1172901.
  22. ↑ Kenneth A. Foon (1998). Biological and Hormonal Therapies of Cancer. Springer. p. 73. ISBN 978-0-7923-9997-1. Retrieved 2 June 2012.
  23. ↑ Briggs MH, Briggs M (October 1973). "Glucocorticoid properties of progestogens". Steroids 22 (4): 555–9. doi:10.1016/0039-128x(73)90011-1. PMID 4747450.
  24. ↑ Mann 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.157.15.1651. PMID 9250225.
  25. ↑ Ann M. Berger; John L. Shuster; Jamie H. Von Roenn (6 October 2006). Principles And Practice of Palliative Care And Supportive Oncology. Lippincott Williams & Wilkins. p. 128. ISBN 978-0-7817-9595-1. Retrieved 27 May 2012.
  26. ↑ Achim Jörres (19 February 2010). Management of Acute Kidney Problems. Springer. p. 210. ISBN 978-3-540-69413-7. Retrieved 27 May 2012.
  27. ↑ David S. Ettinger (11 November 2008). Supportive Care in Cancer Therapy. Springer. p. 61. ISBN 978-1-58829-941-3. Retrieved 27 May 2012.
  28. ↑ Chidakel AR, Zweig SB, Schlosser JR, Homel P, Schappert JW, Fleckman AM (February 2006). "High prevalence of adrenal suppression during acute illness in hospitalized patients receiving megestrol acetate". Journal of Endocrinological Investigation 29 (2): 136–40. doi:10.1007/bf03344086. PMID 16610239.
  29. ↑ Bulchandani D, Nachnani J, Amin A, May J (August 2008). "Megestrol acetate-associated adrenal insufficiency". The American Journal of Geriatric Pharmacotherapy 6 (3): 167–72. doi:10.1016/j.amjopharm.2008.08.004. PMID 18775392.
  30. ↑ http://www.answers.com/topic/megestrol-megace
  31. ↑ Ringold, H. J.; Ruelas, J. P.; Batres, E.; Djerassi, C. (1959). "Steroids. CXVIII.16-Methyl Derivatives of 17α-Hydroxyprogesterone and of Reichstein's Substance "S"". Journal of the American Chemical Society 81 (14): 3712. doi:10.1021/ja01523a055.

Further reading

  • Raney MS, Anding R, Fay V, Polk G (2000). "A pilot study to assess the use of megesterol acetate to promote weight gain in frail elderly persons residing in long-term care". J Am Med Dir Assoc 1 (4): 154–8. PMID 12816553.
  • Deutsch J, Kolhouse JF (July 2004). "Assessment of gastrointestinal function and response to megesterol acetate in subjects with gastrointestinal cancers and weight loss". Support Care Cancer 12 (7): 503–10. doi:10.1007/s00520-004-0615-4. PMID 15064933.