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Megestrol acetate

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Megestrol acetate
Clinical data
Other namesBDH-1298, NSC-71423[1]
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability100% (oral)[2]
Protein bindingYes (to albumin, but not to sex hormone-binding globulin or transcortin)[2]
Elimination half-life13 to 105 hours (mean 34 hours)[3]
Identifiers
  • 17-(acetyloxy)-6-methyl-pregna-4,6-diene-3,20-dione
CAS Number
PubChem CID
DrugBank
ChemSpider
CompTox Dashboard (EPA)
ECHA InfoCard100.008.969 Edit this at Wikidata
Chemical and physical data
FormulaC24H32O4
Molar mass384.509 g/mol
3D model (JSmol)
  • O=C4\C=C3\C(=C/[C@@H]1[C@H](CC[C@@]2([C@@](OC(=O)C)(C(=O)C)CC[C@@H]12)C)[C@@]3(C)CC4)C
  • InChI=1S/C24H32O4/c1-14-12-18-19(22(4)9-6-17(27)13-21(14)22)7-10-23(5)20(18)8-11-24(23,15(2)25)28-16(3)26/h12-13,18-20H,6-11H2,1-5H3/t18-,19+,20+,22-,23+,24+/m1/s1
  • Key:RQZAXGRLVPAYTJ-GQFGMJRRSA-N

Megestrol acetate (INN, USAN, BAN, JAN; sold mainly under the brand names Megace and Megace ES), also known as 17α-acetoxy-6-dehydro-6-methylprogesterone, and sometimes abbreviated as MGA or MA, 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. It is used at a dose of 5 mg in combination with an estrogen for contraception. Appetite stimulation is achieved with doses ranging from 20 mg to 40 mg three times a day, 30 minutes before meals. Doses used to treat cancer usually range from 160 mg to 800 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 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.[3] 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).[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]

See also

References

  1. ^ Dr. Ian Morton; Ian K. M. Morton; Judith M. Hall (1999). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer. p. 173. ISBN 978-0-7514-0499-9. Retrieved 2 June 2012. {{cite book}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  2. ^ a b Schindler AE, Campagnoli C, Druckmann R; et al. (2003). "Classification and pharmacology of progestins". Maturitas. 46 Suppl 1: S7–S16. PMID 14670641. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ a b 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.
  4. ^ F.. Macdonald (1997). Dictionary of Pharmacological Agents. CRC Press. p. 1267. ISBN 978-0-412-46630-4. Retrieved 12 May 2012.
  5. ^ a b c Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 641. ISBN 978-3-88763-075-1. Retrieved 2 June 2012. Cite error: The named reference "Index Nominum 2000: International Drug Directory" was defined multiple times with different content (see the help page).
  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. ^ a b c d Teulings FA, van Gilse HA, Henkelman MS, Portengen H, Alexieva-Figusch J (1980). "Estrogen, androgen, glucocorticoid, and progesterone receptors in progestin-induced regression of human breast cancer". Cancer Research. 40 (7): 2557–61. PMID 6248208. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ Geller J, Albert J, Yen SS, Geller S, Loza D (1981). "Medical castration of males with megestrol acetate and small doses of diethylstilbestrol". The Journal of Clinical Endocrinology and Metabolism. 52 (3): 576–80. PMID 6161942. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ Venner PM (1990). "Therapeutic options in treatment of advanced carcinoma of the prostate". Seminars in Oncology. 17 (6 Suppl 9): 73–7. PMID 2259929. {{cite journal}}: Unknown parameter |month= ignored (help)
  11. ^ Lundgren S, Lønning PE, Utaaker E, Aakvaag A, Kvinnsland S (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. PMID 2362454. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ a b 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. PMID 6176985.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Blumenschein GR (1983). "The role of progestins in the treatment of breast cancer". Seminars in Oncology. 10 (4 Suppl 4): 7–10. PMID 6230722. {{cite journal}}: Unknown parameter |month= ignored (help)
  14. ^ Alexieva-Figusch J, Blankenstein MA, de Jong FH, Lamberts SW (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  15. ^ Schacter L, Rozencweig M, Canetta R, Kelley S, Nicaise C, Smaldone L (1989). "Megestrol acetate: clinical experience". Cancer Treatment Reviews. 16 (1): 49–63. PMID 2471590. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  16. ^ Sedlacek SM (1988). "An overview of megestrol acetate for the treatment of advanced breast cancer". Seminars in Oncology. 15 (2 Suppl 1): 3–13. PMID 3285483. {{cite journal}}: Unknown parameter |month= ignored (help)
  17. ^ Eil C, Edelson SK (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. PMID 6725525. {{cite journal}}: Unknown parameter |month= ignored (help)
  18. ^ Luthy IA, Begin DJ, Labrie F (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. PMID 2462135. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  19. ^ a b Poyet P, Labrie F (1985). "Comparison of the antiandrogenic/androgenic activities of flutamide, cyproterone acetate and megestrol acetate". Molecular and Cellular Endocrinology. 42 (3): 283–8. PMID 3930312. {{cite journal}}: Unknown parameter |month= ignored (help)
  20. ^ Farrar DJ (1999). "Megestrol acetate: promises and pitfalls". AIDS Patient Care and STDs. 13 (3): 149–52. PMID 10375262. {{cite journal}}: Unknown parameter |month= ignored (help)
  21. ^ Tisell LE, Salander H (1975). "Androgenic properties and adrenal depressant activity of megestrol acetate observed in castrated male rats". Acta Endocrinologica. 78 (2): 316–24. PMID 1172901. {{cite journal}}: Unknown parameter |month= ignored (help)
  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 (1973). "Glucocorticoid properties of progestogens". Steroids. 22 (4): 555–9. PMID 4747450. {{cite journal}}: Unknown parameter |month= ignored (help)
  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. PMID 9250225.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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 (2006). "High prevalence of adrenal suppression during acute illness in hospitalized patients receiving megestrol acetate". Journal of Endocrinological Investigation. 29 (2): 136–40. PMID 16610239. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  29. ^ Bulchandani D, Nachnani J, Amin A, May J (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  30. ^ http://www.answers.com/topic/megestrol-megace
  • 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • Deutsch J, Kolhouse JF (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. {{cite journal}}: Unknown parameter |month= ignored (help)


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