Megestrol acetate

From Wikipedia, the free encyclopedia
Jump to navigation Jump to search
Megestrol acetate
Megestrol acetate.svg
Megestrol acetate molecule ball.png
Clinical data
Trade names Megace, others
Synonyms MGA; BDH-1298; NSC-71423; SC-10363; 17α-Acetoxy-6-dehydro-6-methylprogesterone; 17α-Acetoxy-6-methylpregna-4,6-diene-3,20-dione
Pregnancy
category
  • US: X (Contraindicated)
Routes of
administration
By mouth (tablets, suspension)
Drug class Progestin; Progestogen; Progestogen ester; Antigonadotropin; Steroidal antiandrogen
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability ~100%[2]
Protein binding Majority to albumin (no affinity for SHBG or CBG)[2][3][2]
Metabolism Liver (hydroxylation, reduction, conjugation)[1]
Elimination half-life Mean: 34 hours[4]
Range:13–105 hours[4]
Excretion Urine: 57–78%[1]
Feces: 8–30%[1]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ECHA InfoCard 100.008.969 Edit this at Wikidata
Chemical and physical data
Formula C24H32O4
Molar mass 384.516 g/mol
3D model (JSmol)

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.[2][5][4][6] It is also used to treat breast cancer and endometrial cancer, and has been used in birth control.[5][4][7][8] MGA is generally formulated alone, although it has been combined with estrogens in birth control formulations.[9] It is usually taken by mouth.[2]

Side effects of MGA include increased appetite, weight gain, vaginal bleeding, nausea, edema, low sex hormone levels, sexual dysfunction, osteoporosis, cardiovascular complications, glucocorticoid effects, and others.[5] MGA is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone.[2] It has weak partial androgenic activity, weak glucocorticoid activity, and no other important hormonal activity.[2] Due to its progestogenic activity, MGA has antigonadotropic effects.[5] The mechanism of action of the appetite stimulant effects of MGA is unknown.[10][11][12]

MGA was discovered in 1959 and was introduced for medical use, specifically in birth control pills, in 1963.[13][7][8] It may be considered a "first-generation" progestin.[14] The medication was withdrawn in some countries in 1970 due to concerns about mammary toxicity observed in dogs, but this turned out not to apply to humans.[15][16][17][18][19] MGA was approved for the treatment of endometrial cancer in 1971 and wasting syndromes in 1993.[5][20] It is marketed widely throughout the world.[21][22] It is available as a generic medication.[23]

Medical uses[edit]

MGA is used mainly as an appetite stimulant to promote weight gain in a variety of situations.[24][25][26] 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.[24] In addition to its effects on appetite, MGA appears to have antiemetic effects.[27][28] MGA is also used as an antineoplastic agent in the treatment of breast cancer and endometrial cancer.[24][29] It is significantly inferior to aromatase inhibitors in both clinical effectiveness and tolerability as a second-line therapy for breast cancer after tamoxifen failure.[30] MGA was formerly used in combined oral contraceptives in combination with ethinylestradiol or mestranol,[7][8][31] and has been used in a combined injectable contraceptive in combination with estradiol as well.[32]

Although it has not been approved for these uses, MGA has been studied and/or used off-label for a variety of indications including menopausal hormone therapy[33][34][35] and the treatment of hot flashes,[36][37][38][39] gynecological/menstrual disorders,[40][41] endometriosis,[42] endometrial hyperplasia,[43] ovarian cancer,[44][45][46][47] prostate cancer,[48][49][50][51][52][53][54] benign prostatic hyperplasia,[55][56] male breast cancer,[57] and precocious puberty.[58][1][5]

Appetite stimulation is achieved with MGA with oral dosages of 400 to 800 mg/day.[59] The optimal dosage with maximum effect for appetite stimulation has been determined to be 800 mg/day.[60] 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.[59][4] 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.[7][8][31][32]

Available forms[edit]

MGA 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.[61][59] It was used at doses of 1 mg, 2 mg, 4 mg, and 5 mg in combined oral contraceptives.[7][8][31][32] MGA has been used at a dose of 25 mg in combination with an estrogen in combined injectable contraceptives.[32]

Contraindications[edit]

Contraindications of MGA include hypersensitivity to MGA or any component of its formulation, known or suspected pregnancy, and breastfeeding.[6] MGA is a teratogen in animals and may have the potential to cause fetal harm, such as decreased fetal weight and feminization of male fetuses.[6]

Side effects[edit]

The most common side effect of MGA is weight gain, with an incidence of 15 to 70% at the high dosages used to treat breast cancer.[1][4] Other side effects include vaginal bleeding (7–8%), nausea (7%), and edema (5%), as well as others such as dizziness and shortness of breath.[1][4][62] MGA can cause hypogonadism and associated symptoms like diminished secondary sexual characteristics, sexual dysfunction, osteoporosis, and reversible infertility in men and premenopausal women.[63][64][65] Combining MGA with an androgen/anabolic steroid like oxandrolone, nandrolone decanoate, or testosterone in men can alleviate MGA-associated symptoms of hypoandrogenism as well as further increase appetite and weight gain.[64][66][67][68] Less common but more serious side effects of MGA include cardiovascular/thromboembolic complications such as thrombophlebitis.[4] It may also cause glucocorticoid side effects such as Cushing syndrome-like symptoms, steroid diabetes, and adrenal insufficiency at high dosages.[69][70][71] Case reports of deep vein thrombosis, pulmonary embolism, jaundice, intrahepatic cholestasis, and meningiomas in association with high-dosage MGA have been published.[72][73][74][75]

Overdose[edit]

MGA has been studied at very high dosages of as much as 1,600 mg/day with no serious adverse effects observed.[6][76] No clear increase in rate or severity of side effects have been observed up to 1,600 mg/day MGA except for weight gain, mild increases in blood pressure, and some fluid retention.[76] In post-marketing experience, limited reports of overdose have been received.[6] Signs and symptoms described in these reports have included diarrhea, nausea, abdominal pain, shortness of breath, cough, unsteady gait, listlessness, and chest pain.[6] There is no specific antidote for overdose of MGA.[6] Treatment should be supportive and based on symptoms.[6] MGA has not been assessed for dialyzability.[6] However, due to its low solubility, it is thought that dialysis would not be useful for treating MGA overdose.[6]

Interactions[edit]

Interactions of MGA include significantly decreased exposure to indinavir, which may necessitate an increased dosage of the medication.[6] 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.[6]

Pharmacology[edit]

Pharmacodynamics[edit]

MGA has progestogenic activity, antigonadotropic effects, weak partial androgenic activity, and weak glucocorticoid activity.[2][3][77]

Progestogenic activity[edit]

MGA is a progestogen, or an agonist of the progesterone receptor (PR).[77][78][2] It has about 65% of the affinity of promegestone and 130% of the affinity of progesterone for the PR.[77][78] Like other progestogens, MGA has functional antiestrogenic effects in certain tissues such as the endometrium and has antigonadotropic effects.[2][79][24] The total endometrial transformation dose of MGA is 50 mg per cycle, while its ovulation-inhibiting dosage appears to be unknown.[79][80] However, doses of 1 to 5 mg MGA were previously used in combined birth control pills in combination with the estrogen ethinylestradiol or mestranol.[7][8][31]

Antigonadotropic and anticorticotropic effects[edit]

MGA has antigonadotropic effects in humans at sufficient doses, capable of profoundly suppressing circulating androgen and estrogen concentrations.[24][51][81][82][83][84] The antigonadotropic effects of MGA are the result of 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 axis (HPG axis), resulting in decreased levels of the sex hormones.[85] As such, MGA has functional antiandrogenic and antiestrogenic effects via its antigonadotropic effects.[5]

Suppression of testosterone levels by MGA is responsible for its effectiveness in the treatment of conditions like prostate cancer and benign prostatic hyperplasia.[5][86] In one study, 120–160 mg/day MGA suppressed testosterone levels in men by 72%.[83] 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.[24][87][88][89] The combination of high-dosage MGA (40–160 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.[24][5][87][51][52][90][91][92][93] In spite of these results however, this combination has been very rarely used to treat prostate cancer in the United States.[87]

The antigonadotropic as well as anticorticotropic effects of MGA 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%.[94][95][96]

Androgenic and antiandrogenic activity[edit]

MGA is a high-affinity weak partial agonist of the androgen receptor (AR),[97][98][99] where it binds with very similar but slightly less affinity relative to the PR (about 75% of the affinity according to one assay).[100] 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, as 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.[101] 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.[102] However, the medication does have moderate androgenic effects on serum lipids, causing a significant reduction of HDL cholesterol and LDL cholesterol levels and no change in triglyceride levels at a dosage of only 5 mg/day.[2] The weak but significant androgenic activity of MGA may serve to limit its clinical effectiveness in the treatment of prostate cancer.[103][104][99][98]

Glucocorticoid activity[edit]

MGA is an agonist of the glucocorticoid receptor (GR), 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).[100][99] 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.[105] Accordingly, manifestations of its glucocorticoid activity, including symptoms of Cushing's syndrome, steroid diabetes, and adrenal insufficiency, have been reported with the use of MGA in the literature, albeit sporadically.[69]

Appetite stimulation[edit]

MGA is frequently used as an appetite stimulant to promote weight gain.[24][25][26] The direct mechanism of appetite enhancement is unclear, but it is known that MGA 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 interleukin 1α, interleukin 1β, interleukin 6, and tumor necrosis factor α, all of which have been implicated in facilitation of appetite.[10][11][12] Increased levels of insulin-like growth factor 1 (IGF-1) may also be involved, specifically in its anabolic effects.[106]

Other activities and effects[edit]

Unlike the case of the AR, MGA has no significant affinity for the ER.[2][100] As such, it does not possess the capacity to directly activate the ER.[2] Furthermore, unlike antiandrogens such as spironolactone and bicalutamide but similarly to cyproterone acetate, there is relatively little risk of indirectly mediated estrogenic side effects (e.g., gynecomastia) with MGA.[107] This is because MGA strongly suppresses both androgen and estrogen levels at the same time.[citation needed]

MGA has been found to dose-dependently increase total and free IGF-1 levels up to a dosage of 120 mg/day.[106] 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.[106] 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".[106] 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.[106]

Pharmacokinetics[edit]

The oral bioavailability of MGA is approximately 100%.[2] After a single low oral dose of 4 mg MGA, peak serum concentrations of MGA were about 7 ng/dL (18 nmol/L) and occurred after 3 hours.[2] Following a single high oral dose of 160 mg micronized MGA in men, peak circulating levels of MGA were 125 ng/mL (325 nmol/L) and occurred after 6.3 hours.[108] This study found that micronized MGA at this dose showed considerably improved absorption relative to its conventional tablet form.[108] In terms of plasma protein binding, MGA is bound mostly to albumin and is not bound to sex hormone-binding globulin or to corticosteroid-binding globulin.[2][3] The medication is metabolized in the liver mainly by hydroxylation of the C21, C2α, and C6 positions, as well as by reduction and conjugation.[2][1] Its elimination half-life is 34 hours on average, with a range of 13 to 105 hours.[4] MGA is excreted 57 to 78% in urine and 8 to 30% in feces.[1]

At high dosages, MGA has profoundly greater bioavailability and potency than medroxyprogesterone acetate, regardless of whether the route of administration of the latter is oral or parenteral.[1][109][110] Following oral administration of 80 to 160 mg MGA or 500 to 1,000 mg medroxyprogesterone acetate, circulating levels of MGA were 2- to 10-fold higher than those of medroxyprogesterone acetate.[110][109][1] Similar findings have been found for oral MGA relative to medroxyprogesterone acetate administered via intramuscular injection.[1] MGA also reaches steady-state levels more quickly than medroxyprogesterone acetate.[110] The improved potency of MGA compared to medroxyprogesterone acetate may be due to increased resistance to metabolism of MGA afforded by its C6(7) double bond (medroxyprogesterone acetate being identical to MGA in structure except lacking this feature).[1][111][112]

Chemistry[edit]

MGA, 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.[113][21] 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.[113][21] MGA is the C17α acetate ester of megestrol, which, in contrast to MGA, was never marketed.[113][21] Analogues of MGA include other 17α-hydroxyprogesterone derivatives such as acetomepregenol, anagestone acetate, chlormadinone acetate, cyproterone acetate, hydroxyprogesterone caproate, medroxyprogesterone acetate, and nomegestrol acetate.[113][21] MGA differs from medroxyprogesterone acetate only by its C6(7) double bond.[114] Close analogues of MGA that were never marketed include cymegesolate (megestrol acetate 3β-cypionate) and megestrol caproate.[115][116][117]

Synthesis[edit]

Chemical syntheses of MGA have been published.[118][119]

History[edit]

MGA was synthesized at Syntex in 1959.[79] It was derived from medroxyprogesterone acetate, which had been synthesized at Syntex in 1957.[79][13] MGA was the third synthetic derivative of progesterone to be developed for use as a medication, following hydroxyprogesterone caproate in 1954 and medroxyprogesterone acetate in 1957.[79] The medication was introduced for medical use in combination with ethinylestradiol (EE) as an oral contraceptive in 1963 by British Drug Houses in the United Kingdom under the brand name Volidan (4 mg MGA and 50 μg EE tablets),[7][8] 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.[31] It was also marketed under the brand name Delpregnin (5 mg MGA and 100 μg mestranol tablets) by 1965, among others.[120][121][122][109]

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.[15][16][17] 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.[17][18][123] Subsequent research, such as monkey studies, revealed that there is no similar risk in humans.[19][1] Following its withdrawal from the market, MGA was eventually reintroduced for the treatment of hormone-sensitive cancers.[123] In addition, MGA was marketed for veterinary use in dogs in 1969 in the United Kingdom and in 1974 in the United States.[124][125][126]

Progesterone was first found to be effective in the treatment of endometrial hyperplasia in 1951,[1] and progestins were first found to be effective in the treatment of endometrial cancer in 1959.[127] MGA was reported to be effective in the treatment of endometrial hyperplasia in the mid-1960s.[1] It first started to be studied as a treatment for endometrial cancer in 1967, with findings published in 1973.[1][128][129] MGA was reportedly introduced for the treatment of endometrial cancer in the United States in 1971.[5] Progesterone was studied in the treatment of breast cancer in 1951 and 1952, but with relatively modest results.[130][131][132] 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.[1][133][29] A second study was conducted in 1974.[1][134] 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.[130][135] A third study of MGA for breast cancer was published in 1980, and this was followed by additional studies in the 1980s and beyond.[1][136][137] MGA was approved for the treatment of breast cancer in the United States by at least 1983.[1]

Progestogens, including progesterone and ethisterone, were studied in the treatment prostate cancer in 1949.[138][1] MGA was first studied in the treatment of prostate cancer in 1970.[1][139] Additional studies were conducted in 1975 and 1978, followed by others thereafter.[1][53][49][5] However, results of MGA therapy for prostate cancer have been "disappointing",[140] and the medication has not been approved for the treatment of prostate cancer in the United States or elsewhere.[87]

Clinical studies of very high dosages of MGA for breast cancer conducted in the 1980s observed markedly increased appetite and weight gain in treated patients despite them having advanced cancer.[141][142] This led to potential interest in MGA as an appetite stimulant,[141] and in 1986, a paper was published proposing the study and potential use of MGA in cachexia.[142][143][144] MGA was subsequently studied for this indication[145] 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.[20][146]

Society and culture[edit]

Generic names[edit]

Megestrol acetate is the generic name of the drug and its INNM, USAN, USP, and BANM, while megestrol is the INN and BAN and mégestrol the DCF of megestrol, the free alcohol form of MGA.[113][21][9][22] The medication is also known by its developmental code names BDH-1298, NSC-71423, and SC-10363.[113][21][22][9]

Brand names[edit]

MGA is marketed under a variety of brand names throughout the world but is most commonly sold under the brand name Megace.[113][21][22] It is also available under the brand name Megace ES in the United States and under the brand name Megace OS in Canada.[22] For use in veterinary medicine, MGA is sold as Ovaban in the United States and as Ovarid in the United Kingdom.[22]

Availability[edit]

MGA is available widely throughout the world, including in the United States, Canada, the United Kingdom, Ireland, elsewhere throughout Europe, Australia, New Zealand, Latin America, Asia, and a few African countries.[21][22] It does not appear to be marketed in Germany, Russia, South Africa, Japan, India, or Mexico, among other countries.[22]

Generation[edit]

Progestins in birth control pills are sometimes grouped by generation.[147][148] 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 as "miscellaneous" or "pregnanes".[147][148] In any case, based on its date of introduction in such formulations of 1963, MGA could be considered a "first-generation" progestin.[14]

Research[edit]

MGA has been studied in men in combination with testosterone as a male hormonal contraceptive to suppress spermatogenesis.[149]

Veterinary use[edit]

In addition to its use in humans, MGA has been used in veterinary medicine in the treatment of medical conditions in cats and dogs.[21][150]

References[edit]

  1. ^ a b c d e f g h i j k l m n o p q r s t u v w Canetta R, Florentine S, Hunter H, Lenaz L (September 1983). "Megestrol acetate". Cancer Treat. Rev. 10 (3): 141–57. PMID 6352021. 
  2. ^ a b c d e f g h i j k l m n o p q r Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947. 
  3. ^ a b c d 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. 
  4. ^ a b c d e f g h i Richard R. Barakat; Maurie Markman; Marcus Randall (2009). Principles and Practice of Gynecologic Oncology. Lippincott Williams & Wilkins. pp. 447–. ISBN 978-0-7817-7845-9. 
  5. ^ a b c d e f g h i j k Schacter L, Rozencweig M, Canetta R, Kelley S, Nicaise C, Smaldone L (March 1989). "Megestrol acetate: clinical experience". Cancer Treat. Rev. 16 (1): 49–63. PMID 2471590. 
  6. ^ a b c d e f g h i j k l https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021778s018lbl.pdf
  7. ^ a b c d e f g Lara Marks (2010). Sexual Chemistry: A History of the Contraceptive Pill. Yale University Press. pp. 77–78. ISBN 978-0-300-16791-7. 
  8. ^ a b c d e f g MEARS E (1963). "A new type of oral contraceptive". Br Med J. 1 (5341): 1318–20. doi:10.1136/bmj.1.5341.1318. PMC 2123904Freely accessible. PMID 13934321. 
  9. ^ a b c 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. 
  10. ^ a b 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. 
  11. ^ a b Achim Jörres (19 February 2010). Management of Acute Kidney Problems. Springer. p. 210. ISBN 978-3-540-69413-7. Retrieved 27 May 2012. 
  12. ^ a b David S. Ettinger (11 November 2008). Supportive Care in Cancer Therapy. Springer. p. 61. ISBN 978-1-58829-941-3. Retrieved 27 May 2012. 
  13. ^ a b Benign Prostatic Hypertrophy. Springer Science & Business Media. 6 December 2012. pp. 277–. ISBN 978-1-4612-5476-8. 
  14. ^ a b John David Gordon (2007). Obstetrics, Gynecology & Infertility: Handbook for Clinicians. Scrub Hill Press, Inc. pp. 228–. ISBN 978-0-9645467-7-6. 
  15. ^ a b Consolidated List of Products Whose Consumption And/or Sale Have Been Banned, Withdrawn, Severely Restricted Or Not Approved by Governments. United Nations Publications. 1983. pp. 137–. ISBN 978-92-1-130230-1. 
  16. ^ a b Nelson 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. PMID 4126857. 
  17. ^ a b c FDA 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. 
  18. ^ a b United 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. 
  19. ^ a b Benno Clemens Runnebaum; Thomas Rabe; Ludwig Kiesel (6 December 2012). Female Contraception: Update and Trends. Springer Science & Business Media. pp. 134–. ISBN 978-3-642-73790-9. 
  20. ^ a b Guido Eibl; Mouad Edderkaoui (22 April 2015). Risk Factors for Pancreatic Cancer: Underlying Mechanisms and Potential Targets. Frontiers Media SA. pp. 96–. ISBN 978-2-88919-468-1. 
  21. ^ a b c d e f g h i j Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 641. ISBN 978-3-88763-075-1. Retrieved 2 June 2012. 
  22. ^ a b c d e f g h https://www.drugs.com/international/megestrol.html
  23. ^ https://www.drugs.com/availability/generic-megace.html
  24. ^ a b c d e f g h Kenneth L. Becker (24 April 2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. p. 1195–1196. ISBN 978-0-7817-1750-2. Retrieved 27 May 2012. 
  25. ^ a b Taylor JK, Pendleton N (September 2016). "Progesterone therapy for the treatment of non-cancer cachexia: a systematic review". BMJ Support Palliat Care. 6 (3): 276–86. doi:10.1136/bmjspcare-2015-001041. PMID 27098973. 
  26. ^ a b Ruiz Garcia V, López-Briz E, Carbonell Sanchis R, Gonzalvez Perales JL, Bort-Marti S (March 2013). "Megestrol acetate for treatment of anorexia-cachexia syndrome". Cochrane Database Syst Rev (3): CD004310. doi:10.1002/14651858.CD004310.pub3. PMID 23543530. 
  27. ^ Loprinzi C, Jatoi A (April 2006). "Antiemetic properties of megestrol acetate". J Palliat Med. 9 (2): 239–40. doi:10.1089/jpm.2006.9.239. PMID 16629544. 
  28. ^ Zang J, Hou M, Gou HF, Qiu M, Wang J, Zhou XJ, Luo de Y, Yang Y, Jiang M, Cao D, Bi F, Xu F, Shen Y, Yi C (May 2011). "Antiemetic activity of megestrol acetate in patients receiving chemotherapy". Support Care Cancer. 19 (5): 667–73. doi:10.1007/s00520-010-0886-x. PMID 20419494. 
  29. ^ a b 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. 
  30. ^ Charles Swanton; Stephen R. D. Johnston (14 November 2011). Handbook of Metastatic Breast Cancer, Second Edition. CRC Press. pp. 18–. ISBN 978-1-84184-812-9. 
  31. ^ a b c d e Lara Marks (2001). Sexual Chemistry: A History of the Contraceptive Pill. Yale University Press. pp. 78–. ISBN 978-0-300-08943-1. 
  32. ^ a b c d Newton JR, D'arcangues C, Hall PE (1994). "A review of "once-a-month" combined injectable contraceptives". J Obstet Gynaecol (Lahore). 4 Suppl 1: S1–34. PMID 12290848. 
  33. ^ Kauppila A, Kivinen S, Leinonen P, Tuimala R, Vihko R, Ylöstalo P (1983). "Comparison of megestrol acetate and clomiphene citrate as supplemental medication in postmenopausal oestrogen replacement therapy". Arch. Gynecol. 234 (1): 49–58. PMID 6660928. 
  34. ^ Erlik Y, Meldrum DR, Lagasse LD, Judd HL (August 1981). "Effect of megestrol acetate on flushing and bone metabolism in post-menopausal women". Maturitas. 3 (2): 167–72. PMID 7289887. 
  35. ^ Farish E, Barnes JF, O'Donoghue F, Fletcher CD, Ekevall K, Hart DM (June 2000). "The role of megestrol acetate as an alternative to conventional hormone replacement therapy". Climacteric. 3 (2): 125–34. PMID 11910653. 
  36. ^ Loprinzi CL, Michalak JC, Quella SK, O'Fallon JR, Hatfield AK, Nelimark RA, Dose AM, Fischer T, Johnson C, Klatt NE (August 1994). "Megestrol acetate for the prevention of hot flashes". N. Engl. J. Med. 331 (6): 347–52. doi:10.1056/NEJM199408113310602. PMID 8028614. 
  37. ^ Guise TA, Oefelein MG, Eastham JA, Cookson MS, Higano CS, Smith MR (2007). "Estrogenic side effects of androgen deprivation therapy". Rev Urol. 9 (4): 163–80. PMC 2213888Freely accessible. PMID 18231613. 
  38. ^ Frisk J (2010). "Managing hot flushes in men after prostate cancer--a systematic review". Maturitas. 65 (1): 15–22. doi:10.1016/j.maturitas.2009.10.017. PMID 19962840. 
  39. ^ Bertelli G, Venturini M, Del Mastro L, Bergaglio M, Sismondi P, Biglia N, Venturini S, Porcile G, Pronzato P, Costantini M, Rosso R (June 2002). "Intramuscular depot medroxyprogesterone versus oral megestrol for the control of postmenopausal hot flashes in breast cancer patients: a randomized study". Ann. Oncol. 13 (6): 883–8. PMID 12123333. 
  40. ^ Ostergaard E (February 1965). "The oral progestational and anti-ovulatory properties of megestrol acetate and its therapeutic use in gynaecological disorders". J Obstet Gynaecol Br Emp. 72 (1): 45–48. PMID 12332461. 
  41. ^ Palti Z (August 1966). "Clinical results of treatment with megestrol acetate in menstrual disorders and contraception". Indian Pract. 19 (8): 597–600. PMID 5916119. 
  42. ^ Schlaff WD, Dugoff L, Damewood MD, Rock JA (April 1990). "Megestrol acetate for treatment of endometriosis". Obstet Gynecol. 75 (4): 646–8. PMID 2314784. 
  43. ^ Gal D, Edman CD, Vellios F, Forney JP (June 1983). "Long-term effect of megestrol acetate in the treatment of endometrial hyperplasia". Am. J. Obstet. Gynecol. 146 (3): 316–22. PMID 6859142. 
  44. ^ Geisler HE (January 1983). "Megestrol acetate for the palliation of advanced ovarian carcinoma". Obstet Gynecol. 61 (1): 95–8. PMID 6185891. 
  45. ^ Geisler HE (March 1985). "The use of high-dose megestrol acetate in the treatment of ovarian adenocarcinoma". Semin. Oncol. 12 (1 Suppl 1): 20–2. PMID 3975647. 
  46. ^ Sikic BI, Scudder SA, Ballon SC, Soriero OM, Christman JE, Suey L, Ehsan MN, Brandt AE, Evans TL (December 1986). "High-dose megestrol acetate therapy of ovarian carcinoma: a phase II study by the Northern California Oncology Group". Semin. Oncol. 13 (4 Suppl 4): 26–32. PMID 3099393. 
  47. ^ Veenhof CH, van der Burg ME, Nooy M, Aalders JG, Pecorelli S, Oliveira CF, Rotmensz N, Vermorken JB (1994). "Phase II study of high-dose megestrol acetate in patients with advanced ovarian carcinoma". Eur. J. Cancer. 30A (5): 697–8. PMID 8080689. 
  48. ^ Frick J, Marberger H, Swoboda HP (May 1971). "[Hormone therapy of prostatic neoplasms]". Urologe (in German). 10 (3): 117–9. PMID 4104209. 
  49. ^ a b Geller J, Albert J, Yen SS (November 1978). "Treatment of advanced cancer of prostate with megestrol acetate". Urology. 12 (5): 537–41. PMID 153029. 
  50. ^ Block M, Bonomi P, Anderson K, Wolter J, Showel J, Pessis D, Slayton R (1981). "Treatment of stage D prostatic carcinoma with megestrol acetate". J Surg Oncol. 17 (4): 367–71. PMID 7265976. 
  51. ^ a b c Geller J, Albert J, Yen SS, Geller S, Loza D (March 1981). "Medical castration of males with megestrol acetate and small doses of diethylstilbestrol". J. Clin. Endocrinol. Metab. 52 (3): 576–80. doi:10.1210/jcem-52-3-576. PMID 6161942. 
  52. ^ a b Geller J, Albert J, Yen SS, Geller S, Loza D (April 1981). "Medical castration with megestrol acetate and minidose of diethylstilbestrol". Urology. 17 (4 Suppl): 27–33. PMID 6782738. 
  53. ^ a b Johnson DE, Kaesler KE, Ayala AG (1975). "Megestrol acetate for treatment of advanced carcinoma of the prostate". J Surg Oncol. 7 (1): 9–15. PMID 1177459. 
  54. ^ Bonomi P, Pessis D, Bunting N, Block M, Anderson K, Wolter J, Rossof A, Slayton R, Harris J (March 1985). "Megestrol acetate used as primary hormonal therapy in stage D prostatic cancer". Semin. Oncol. 12 (1 Suppl 1): 36–9. PMID 3975650. 
  55. ^ Lebech PE, Nordentoft EL (1967). "A study of endocrine function in the treatment of benign prostatic hypertrophy with megestrol acetate". Acta Obstet Gynecol Scand. 46: Suppl 9:25–38. PMID 4169449. 
  56. ^ Donkervoort T, Zinner NR, Sterling AM, Donker PJ, Van Ness J, Ritter RC (November 1975). "Megestrol acetate in treatment of benign prostatic hypertrophy". Urology. 6 (5): 580–7. PMID 52933. 
  57. ^ Mitsuyasu R, Bonomi P, Anderson K, Fischer W (May 1981). "Response to megestrol in male breast carcinoma". Arch. Intern. Med. 141 (6): 809–10. PMID 6263202. 
  58. ^ Cai DP, Ji ZY, Shi YM (October 2001). "[Clinical study on treatment of female idiopathic precocious puberty with combined therapy of Chinese medicine and megestrol acetate]". Zhongguo Zhong Xi Yi Jie He Za Zhi (in Chinese). 21 (10): 732–5. PMID 12575602. 
  59. ^ a b c Shamim Tejani; Cynthia Sanoski (16 March 2009). Davis's Pocket Clinical Drug Reference. F.A. Davis. pp. 167–. ISBN 978-0-8036-2305-7. 
  60. ^ Loprinzi CL, Bernath AM, Schaid DJ, Malliard JA, Athmann LM, Michalak JC, Tschetter LK, Hatfield AK, Morton RF (October 1994). "Phase III evaluation of 4 doses of megestrol acetate as therapy for patients with cancer anorexia and/or cachexia". Oncology. 51 Suppl 1: 2–7. doi:10.1159/000227407. PMID 7970505. 
  61. ^ Mari J. Wirfs, PhD, MN, APRN, ANP-BC, FNP-BC, CNE (26 July 2017). The APRN’s Complete Guide to Prescribing Pediatric Drug Therapy 2. Springer Publishing Company. pp. 18–. ISBN 978-0-8261-6669-2. 
  62. ^ Willemse PH, van der Ploeg E, Sleijfer DT, Tjabbes T, van Veelen H (March 1990). "A randomized comparison of megestrol acetate (MA) and medroxyprogesterone acetate (MPA) in patients with advanced breast cancer". Eur. J. Cancer. 26 (3): 337–43. PMID 2141491. 
  63. ^ Stephen J. Winters; Ilpo T. Huhtaniemi (25 April 2017). Male Hypogonadism: Basic, Clinical and Therapeutic Principles. Humana Press. pp. 407–. ISBN 978-3-319-53298-1. 
  64. ^ a b Gullett NP, Hebbar G, Ziegler TR (2010). "Update on clinical trials of growth factors and anabolic steroids in cachexia and wasting". Am. J. Clin. Nutr. 91 (4): 1143S–1147S. doi:10.3945/ajcn.2010.28608E. PMC 2844687Freely accessible. PMID 20164318. 
  65. ^ Wermers RA, Hurley DL, Kearns AE (December 2004). "Osteoporosis associated with megestrol acetate". Mayo Clin. Proc. 79 (12): 1557–61. doi:10.4065/79.12.1557. PMID 15595341. 
  66. ^ Cuerda C, Zugasti A, Bretón I, Camblor M, Miralles P, García P (February 2005). "Treatment with nandrolone decanoate and megestrol acetate in HIV-infected men". Nutr Clin Pract. 20 (1): 93–7. doi:10.1177/011542650502000193. PMID 16207650. 
  67. ^ Mulligan K, Zackin R, Von Roenn JH, Chesney MA, Egorin MJ, Sattler FR, Benson CA, Liu T, Umbleja T, Shriver S, Auchus RJ, Schambelan M (February 2007). "Testosterone supplementation of megestrol therapy does not enhance lean tissue accrual in men with human immunodeficiency virus-associated weight loss: a randomized, double-blind, placebo-controlled, multicenter trial". J. Clin. Endocrinol. Metab. 92 (2): 563–70. doi:10.1210/jc.2006-0954. PMID 17090640. 
  68. ^ Casaburi R, Nakata J, Bistrong L, Torres E, Rambod M, Porszasz J (November 2015). "Effect of Megestrol Acetate and Testosterone on Body Composition and Hormonal Responses in COPD Cachexia". Chronic Obstr Pulm Dis. 3 (1): 389–397. doi:10.15326/jcopdf.3.1.2015.0128. PMC 5559120Freely accessible. PMID 28848861. 
  69. ^ a b 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. 
  70. ^ 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. 
  71. ^ 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. 
  72. ^ Marshall LL (September 2003). "Megestrol acetate therapy in geriatric patients: case reviews and associated deep vein thrombosis". Consult Pharm. 18 (9): 764–73. PMID 16563066. 
  73. ^ Foitl DR, Hyman G, Lefkowitch JH (February 1989). "Jaundice and intrahepatic cholestasis following high-dose megestrol acetate for breast cancer". Cancer. 63 (3): 438–9. PMID 2912522. 
  74. ^ 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. PMID 15086241. 
  75. ^ Gruber TJ, Fabiano AJ, Deeb G, Lele SB, Fenstermaker RA (November 2011). "Intracranial meningiomas in patients with uterine sarcoma treated with long-term megestrol acetate therapy". World Neurosurg. 76 (5): 477.e16–20. doi:10.1016/j.wneu.2011.03.035. PMID 22152580. 
  76. ^ a b Schacter LP, Rozencweig M, Canetta R, Kelley S, Nicaise C, Smaldone L (December 1990). "Overview of hormonal therapy in advanced breast cancer". Semin. Oncol. 17 (6 Suppl 9): 38–46. PMID 2148026. Doses [of megestrol acetate] of as high as 1,600 mg/d, given in divided doses three or four times daily, have been given with no clear increase in side effects except for weight gain, mild increases in blood pressure (BP), and some fluid retention.45 
  77. ^ a b c d Schindler, Adolf E. (2015). "Pharmacology of Progestogens": 33–40. doi:10.1007/978-3-319-14385-9_2. 
  78. ^ a b Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JH (2008). "Classification and pharmacology of progestins". Maturitas. 61 (1-2): 171–80. PMID 19434889. 
  79. ^ a b c d e Kuhl H (2011). "Pharmacology of progestogens" (PDF). Journal für Reproduktionsmedizin und Endokrinologie-Journal of Reproductive Medicine and Endocrinology. 8 (Special Issue 1): 157–176. 
  80. ^ Endrikat J, Gerlinger C, Richard S, Rosenbaum P, Düsterberg B (December 2011). "Ovulation inhibition doses of progestins: a systematic review of the available literature and of marketed preparations worldwide". Contraception. 84 (6): 549–57. doi:10.1016/j.contraception.2011.04.009. PMID 22078182. 
  81. ^ 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. 
  82. ^ 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. 
  83. ^ 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. doi:10.1002/pros.2990030103. PMID 6176985. 
  84. ^ 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. 
  85. ^ 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. 
  86. ^ Louis Denis (6 December 2012). The Medical Management of Prostate Cancer. Springer Science & Business Media. pp. 45–. ISBN 978-3-642-73238-6. 
  87. ^ a b c d James P. Karr; Hidetoshi Yamanaka (6 December 2012). Prostate Cancer and Bone Metastasis. Springer Science & Business Media. pp. 309–. ISBN 978-1-4615-3398-6. 
  88. ^ Kenneth A. Foon; Hyman B. Muss (6 December 2012). Biological and Hormonal Therapies of Cancer. Springer Science & Business Media. pp. 73–. ISBN 978-1-4615-6189-7. 
  89. ^ Smith JA (January 1987). "New methods of endocrine management of prostatic cancer". J. Urol. 137 (1): 1–10. PMID 3540320. 
  90. ^ Venner PM, Klotz PG, Klotz LH, Stewart DJ, Davis IR, Orovan WL, Ramsey EW (April 1988). "Megestrol acetate plus minidose diethylstilbestrol in the treatment of carcinoma of the prostate". Semin. Oncol. 15 (2 Suppl 1): 62–7. PMID 3285485. 
  91. ^ Johnson DE, Babaian RJ, Swanson DA, von Eschenbach AC, Wishnow KI, Tenney D (May 1988). "Medical castration using megestrol acetate and minidose estrogen". Urology. 31 (5): 371–4. PMID 3284149. 
  92. ^ Geller J (September 1988). "Megestrol acetate and minidose estrogen in prostatic carcinoma". Urology. 32 (3): 281–3. PMID 3413920. 
  93. ^ Geller J (February 1991). "Megestrol acetate plus low-dose estrogen in the management of advanced prostatic carcinoma". Urol. Clin. North Am. 18 (1): 83–91. PMID 1825145. 
  94. ^ Lundgren S, Helle SI, Lonning PE (September 1996). "Profound suppression of plasma estrogens by megestrol acetate in postmenopausal breast cancer patients". Clin. Cancer Res. 2 (9): 1515–21. PMID 9816328. 
  95. ^ Pommier RF, Woltering EA, Fletcher WS (December 1994). "Changes in serum sex steroid levels during megestrol acetate therapy". Surg Oncol. 3 (6): 351–9. PMID 7773452. 
  96. ^ Lønning PE (2009). "Additive endocrine therapy for advanced breast cancer - back to the future". Acta Oncol. 48 (8): 1092–101. doi:10.3109/02841860903117816. PMID 19863216. 
  97. ^ 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. 
  98. ^ a b 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. 
  99. ^ a b c 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. 
  100. ^ a b c 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. 
  101. ^ 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. 
  102. ^ 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. 
  103. ^ Timothy L. Ratliff; William J. Catalona (6 December 2012). Genitourinary Cancer: Basic and Clinical Aspects. Springer Science & Business Media. pp. 171–. ISBN 978-1-4613-2033-3. 
  104. ^ Labrie C, Cusan L, Plante M, Lapointe S, Labrie F (October 1987). "Analysis of the androgenic activity of synthetic "progestins" currently used for the treatment of prostate cancer". J. Steroid Biochem. 28 (4): 379–84. PMID 2444770. 
  105. ^ 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. 
  106. ^ a b c d e Helle SI, Lundgren S, Geisler S, Ekse D, Holly JM, Lønning PE (July 1999). "Effects of treatment with megestrol acetate on the insulin-like growth factor system: time and dose dependency". Eur. J. Cancer. 35 (7): 1070–5. PMID 10533450. 
  107. ^ Kenneth A. Foon (1998). Biological and Hormonal Therapies of Cancer. Springer. p. 73. ISBN 978-0-7923-9997-1. Retrieved 2 June 2012. 
  108. ^ a b Stanczyk FZ (September 2002). "Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception". Rev Endocr Metab Disord. 3 (3): 211–24. PMID 12215716. 
  109. ^ a b c Harry W. Rudel; Fred A. Kincl; Milan R. Henzl (1973). Birth Control; Contraception and Abortion. Macmillan. 
  110. ^ a b c Gadducci A, Genazzani AR (December 1999). "Endocrine therapy for gynecological cancer". Gynecol. Endocrinol. 13 (6): 441–56. PMID 10685337. 
  111. ^ Gerald Litwack (2 December 2012). Biochemical Actions of Hormones. Elsevier. pp. 330–. ISBN 978-0-323-15344-7. 
  112. ^ David A. Williams; William O. Foye; Thomas L. Lemke (2002). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 699–. ISBN 978-0-683-30737-5. 
  113. ^ a b c d e f g J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 657–. ISBN 978-1-4757-2085-3. 
  114. ^ Aman U. Buzdar (8 November 2007). Endocrine Therapies in Breast Cancer. OUP Oxford. pp. 75–. ISBN 978-0-19-921814-1. 
  115. ^ Yang YQ, Li SX, Gu XG (August 1985). "[Effect of progestin no. 1 (cymegesolate) on menstrual cycles and plasma levels of progesterone in rhesus monkeys]". Sheng Li Xue Bao (in Chinese). 37 (4): 368–73. PMID 3837333. 
  116. ^ Wu JZ, Yun XJ, Wu MZ, Shen HY, Wang AL (February 1983). "[Clinical study of a long-acting progestogen contraceptive 3-cyclopentyl propionate of megestrol acetate (progestin no. 1)]". Shengzhi Yu Biyun (in Chinese). 3 (2): 36–8. PMID 12339176. 
  117. ^ Pirzada OL (June 2002). "Effect of megestrol caproate on the reproductive function of laboratory animals". Bull. Exp. Biol. Med. 133 (6): 574–6. PMID 12447469. 
  118. ^ Ringold, H. J.; Ruelas, J. Perez; Batres, E.; Djerassi, Carl (1959). "Steroids. CXVIII.16-Methyl Derivatives of 17α-Hydroxyprogesterone and of Reichstein's Substance "S"". Journal of the American Chemical Society. 81 (14): 3712–3716. doi:10.1021/ja01523a055. ISSN 0002-7863. 
  119. ^ Cooley G, Kellie AE (October 1964). "Synthesis of [1,2-3H2]medroxyprogesterone acetate (17-alpha-acetoxy-6-alpha-methyl[1,2-3H2]pregn-4-ene-3,20-dione) and [1,2-3H2]megestrol acetate (17-alpha-acetoxy-6-methyl[1,2-3H2]pregna-4,6-diene-3,20-dione)". Biochem. J. 93 (1): 8C–9C. PMID 5320316. 
  120. ^ David P. Rose (1973). Oral Contraceptives: Psychological and Physiological Effects. Ardent Media. pp. 12–. ISBN 978-0-8422-7101-1. 
  121. ^ Statens seruminstitut (Denmark) (1966). Communications: Extraits. Each Delpregnin tablet contains 5 mg megestrol acetate + 0.1 mg mestranol. 
  122. ^ Unlisted Drugs. Pharmaceutical Section, Special Libraries Association. 1965. 
  123. ^ a b Bakke OM, Wardell WM, Lasagna L (May 1984). "Drug discontinuations in the United Kingdom and the United States, 1964 to 1983: issues of safety". Clin. Pharmacol. Ther. 35 (5): 559–67. PMID 6713769. 
  124. ^ Modern Veterinary Practice. 1971. Your Q & A concerning megestrol acetate (Oct MVP, p 27), a product containing this compound (Ovarid: Glaxo) has been commercially available for controlling estrus in bitches in the UK for nearly 2 years. 
  125. ^ VM/SAC, Veterinary Medicine/small Animal Clinician. Veterinary Medicine Publishing Company. 1977. In England, where megestrol acetate has been marketed for eight years, it is recommended to treat false pregnancy and estrogen-dependent mammary tumors in dogs. It has also been used successfully to treat hypersexuality in male dogs, and miliary dermatitis and eosinophilic granulomas in cats. In 1974, megestrol acetate was approved in the United States for postponement of es- trus and treatment of false pregnancy in dogs. 
  126. ^ Upjohn Company (1978). Proceedings of the Symposium on Cheque® for Canine Estrus Prevention, Brook Lodge, Augusta, Michigan, March 13-15, 1978. Upjohn Company. In 1974, Sobering marketed megestrol acetate3 (Figure 1) under the trade name of Ovaban® (Ovarid® in Europe). 
  127. ^ KISTNER RW (1959). "Histological effects of progestins on hyperplasia and carcinoma in situ of the endometrium". Cancer. 12: 1106–22. PMID 14409476. 
  128. ^ Geisler, Hans E. (1973). "The use of megestrol acetate in the treatment of advanced malignant lesions of the endometrium". Gynecologic Oncology. 1 (4): 340–344. doi:10.1016/0090-8258(73)90026-7. ISSN 0090-8258. 
  129. ^ Wait RB (January 1973). "Megestrol acetate in the management of advanced endometrial carcinoma". Obstet Gynecol. 41 (1): 129–36. PMID 4682608. 
  130. ^ a b Lundgren S (1992). "Progestins in breast cancer treatment. A review". Acta Oncol. 31 (7): 709–22. PMID 1476750. 
  131. ^ Taylor SG, Morris RS (January 1951). "Hormones in breast metastasis therapy". Med. Clin. North Am. 35 (1): 51–61. PMID 14796108. 
  132. ^ Gordon D, Horwitt BN, Segaloff A, Murison PJ, Schlosser JV (March 1952). "Hormonal therapy in cancer of the breast. III. Effect of progesterone on clinical course and hormonal excretion". Cancer. 5 (2): 275–7. PMID 14905411. 
  133. ^ Stoll BA (August 1967). "Progestin therapy of breast cancer: comparison of agents". Br Med J. 3 (5561): 338–41. PMC 1841969Freely accessible. PMID 6029163. 
  134. ^ Ansfield FJ, Davis HL, Ellerby RA, Ramirez G (April 1974). "A clinical trial of megestrol acetate in advanced breast cancer". Cancer. 33 (4): 907–10. PMID 4819220. 
  135. ^ Pannuti F, Martoni A, Lenaz GR, Piana E, Nanni P (April 1978). "A possible new approach to the treatment of metastatic breast cancer: massive doses of medroxyprogesterone acetate". Cancer Treat Rep. 62 (4): 499–504. PMID 350387. 
  136. ^ Alexieva-Figusch J, van Gilse HA, Hop WC, Phoa CH, Blonk-van der Wijst J, Treurniet RE (December 1980). "Progestin therapy in advanced breast cancer: megestrol acetate--an evaluation of 160 treated cases". Cancer. 46 (11): 2369–72. PMID 7438013. 
  137. ^ Bines J, Dienstmann R, Obadia RM, Branco LG, Quintella DC, Castro TM, Camacho PG, Soares FA, Costa ME (April 2014). "Activity of megestrol acetate in postmenopausal women with advanced breast cancer after nonsteroidal aromatase inhibitor failure: a phase II trial". Ann. Oncol. 25 (4): 831–6. doi:10.1093/annonc/mdu015. PMID 24615412. 
  138. ^ Gutierrez R (August 1949). "New horizons in the surgical management of carcinoma of the prostate gland". Am. J. Surg. 78 (2): 147–69. PMID 18135629. 
  139. ^ Maltry, E. (1970). Use of megestrol acetate (a new progestational agent) in the treatment of carcinoma of the prostate. In Proceedings of the Kimbrough Urological Seminar, 18th Annual Meeting (pp. 135-137).
  140. ^ Nicholas Vogelzang (2006). Comprehensive Textbook of Genitourinary Oncology. Lippincott Williams & Wilkins. pp. 317–. ISBN 978-0-7817-4984-8. 
  141. ^ a b Barry Kinzbrunner; Neil J. Weinreb; Joel S. Policzer (2002). 20 Common Problems: End-of-Life Care. McGraw Hill Professional. ISBN 978-0-07-034883-7. 
  142. ^ a b Tchekmedyian NS, Tait N, Moody M, Greco FA, Aisner J (December 1986). "Appetite stimulation with megestrol acetate in cachectic cancer patients". Semin. Oncol. 13 (4 Suppl 4): 37–43. PMID 3798127. 
  143. ^ Tchekmedyian NS, Tait N, Moody M, Aisner J (March 1987). "High-dose megestrol acetate. A possible treatment for cachexia". JAMA. 257 (9): 1195–8. PMID 3806918. 
  144. ^ Aisner J, Tchekmedyian NS, Tait N, Parnes H, Novak M (April 1988). "Studies of high-dose megestrol acetate: potential applications in cachexia". Semin. Oncol. 15 (2 Suppl 1): 68–75. PMID 3285486. 
  145. ^ Aisner J, Parnes H, Tait N, Hickman M, Forrest A, Greco FA, Tchekmedyian NS (December 1990). "Appetite stimulation and weight gain with megestrol acetate". Semin. Oncol. 17 (6 Suppl 9): 2–7. PMID 2259925. 
  146. ^ Porche DJ (1994). "Megestrol acetate oral suspension". J Assoc Nurses AIDS Care. 5 (4): 35–6, 44. PMID 7948971. 
  147. ^ a b V. Unzeitig; Rick H.W. van Lunsen (15 February 2000). Contraceptive Choices and Realities: Proceedings of the 5th Congress of the European Society of Contraception. CRC Press. pp. 73–. ISBN 978-1-85070-067-8. 
  148. ^ a b IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; World Health Organization; International Agency for Research on Cancer (2007). Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy. World Health Organization. p. 44. ISBN 978-92-832-1291-1. 
  149. ^ Frick, J. (1973). "Control of spermatogenesis in men by combined administration of progestin and androgen". Contraception. 8 (3): 191–206. doi:10.1016/0010-7824(73)90030-9. ISSN 0010-7824. 
  150. ^ Romatowski J (March 1989). "Use of megestrol acetate in cats". J. Am. Vet. Med. Assoc. 194 (5): 700–2. PMID 2647696. 

Further reading[edit]

  • Canetta R, Florentine S, Hunter H, Lenaz L (September 1983). "Megestrol acetate". Cancer Treat. Rev. 10 (3): 141–57. PMID 6352021. 
  • Sedlacek SM (April 1988). "An overview of megestrol acetate for the treatment of advanced breast cancer". Semin. Oncol. 15 (2 Suppl 1): 3–13. PMID 3285483. 
  • Aisner J, Tchekmedyian NS, Tait N, Parnes H, Novak M (April 1988). "Studies of high-dose megestrol acetate: potential applications in cachexia". Semin. Oncol. 15 (2 Suppl 1): 68–75. PMID 3285486. 
  • Schacter L, Rozencweig M, Canetta R, Kelley S, Nicaise C, Smaldone L (March 1989). "Megestrol acetate: clinical experience". Cancer Treat. Rev. 16 (1): 49–63. PMID 2471590. 
  • Romatowski J (March 1989). "Use of megestrol acetate in cats". J. Am. Vet. Med. Assoc. 194 (5): 700–2. PMID 2647696. 
  • Venner P (1992). "Megestrol acetate in the treatment of metastatic carcinoma of the prostate". Oncology. 49 Suppl 2: 22–7. doi:10.1159/000227123. PMID 1461622. 
  • Tchekmedyian NS (June 1993). "Treatment of anorexia with megestrol acetate". Nutr Clin Pract. 8 (3): 115–8. doi:10.1177/0115426593008003115. PMID 8289758. 
  • Strang P (1997). "The effect of megestrol acetate on anorexia, weight loss and cachexia in cancer and AIDS patients (review)". Anticancer Res. 17 (1B): 657–62. PMID 9066597. 
  • Vyzula R (April 1997). "[Current views on use of megestrol acetate in oncology practice]". Vnitr Lek (in Czech). 43 (4): 250–5. PMID 9601846. 
  • 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". Arch. Intern. Med. 157 (15): 1651–6. PMID 9250225. 
  • Berstein LM (1998). "[Megestrol acetate as hormone therapy in oncology]". Vopr Onkol (in Russian). 44 (2): 142–8. PMID 9615815. 
  • Mantovani G, Macciò A, Lai P, Massa E, Ghiani M, Santona MC (April 1998). "Cytokine activity in cancer-related anorexia/cachexia: role of megestrol acetate and medroxyprogesterone acetate". Semin. Oncol. 25 (2 Suppl 6): 45–52. PMID 9625383. 
  • Chang AY (April 1998). "Megestrol acetate as a biomodulator". Semin. Oncol. 25 (2 Suppl 6): 58–61. PMID 9625385. 
  • Mantovani G, Macciò A, Lai P, Massa E, Ghiani M, Santona MC (1998). "Cytokine involvement in cancer anorexia/cachexia: role of megestrol acetate and medroxyprogesterone acetate on cytokine downregulation and improvement of clinical symptoms". Crit Rev Oncog. 9 (2): 99–106. PMID 9973244. 
  • Stockheim JA, Daaboul JJ, Yogev R, Scully SP, Binns HJ, Chadwick EG (March 1999). "Adrenal suppression in children with the human immunodeficiency virus treated with megestrol acetate". J. Pediatr. 134 (3): 368–70. PMID 10064680. 
  • Farrar DJ (March 1999). "Megestrol acetate: promises and pitfalls". AIDS Patient Care STDS. 13 (3): 149–52. doi:10.1089/apc.1999.13.149. PMID 10375262. 
  • Bonte J (2000). "Third generation aromatase inhibitors in metastatic breast cancer patients failing tamoxifen. Randomized comparisons with megestrol acetate: a critical review". Eur. J. Gynaecol. Oncol. 21 (6): 555–9. PMID 11214609. 
  • Karcic E, Philpot C, Morley JE (May 2002). "Treating malnutrition with megestrol acetate: literature review and review of our experience". J Nutr Health Aging. 6 (3): 191–200. PMID 12152625. 
  • Ruiz-García V, Juan O, Pérez Hoyos S, Peiró R, Ramón N, Rosero MA, García MA (July 2002). "[Megestrol acetate: a systematic review usefulness about the weight gain in neoplastic patients with cachexia]". Med Clin (Barc) (in Spanish; Castilian). 119 (5): 166–70. PMID 12200017. 
  • Thomas DR (2004). "Incidence of venous thromboembolism in megestrol acetate users". J Am Med Dir Assoc. 5 (1): 65–6; author reply 66–7. doi:10.1097/01.JAM.0000105070.61741.9D. PMID 14726802. 
  • Pascual López A, Roqué i Figuls M, Urrútia Cuchi G, Berenstein EG, Almenar Pasies B, Balcells Alegre M, Herdman M (April 2004). "Systematic review of megestrol acetate in the treatment of anorexia-cachexia syndrome". J Pain Symptom Manage. 27 (4): 360–9. doi:10.1016/j.jpainsymman.2003.09.007. PMID 15050664. 
  • Femia RA, Goyette RE (2005). "The science of megestrol acetate delivery: potential to improve outcomes in cachexia". BioDrugs. 19 (3): 179–87. PMID 15984902. 
  • Wentling GK, Sevin BU, Geiger XJ, Bridges MD (2005). "Benign metastasizing leiomyoma responsive to megestrol: case report and review of the literature". Int. J. Gynecol. Cancer. 15 (6): 1213–7. doi:10.1111/j.1525-1438.2005.00190.x. PMID 16343217. 
  • Mateen F, Jatoi A (October 2006). "Megestrol acetate for the palliation of anorexia in advanced, incurable cancer patients". Clin Nutr. 25 (5): 711–5. doi:10.1016/j.clnu.2006.05.009. PMID 16867306. 
  • "Megestrol acetate NCD oral suspension -- Par Pharmaceutical: megestrol acetate nanocrystal dispersion oral suspension, PAR 100.2, PAR-100.2". Drugs R D. 8 (4): 251–4. 2007. PMID 17596111. 
  • Yeh SS, Schuster MW (2006). "Megestrol acetate in cachexia and anorexia". Int J Nanomedicine. 1 (4): 411–6. PMC 2676640Freely accessible. PMID 17722275. 
  • Leśniak W, Bała M, Jaeschke R, Krzakowski M (November 2008). "Effects of megestrol acetate in patients with cancer anorexia-cachexia syndrome--a systematic review and meta-analysis". Pol. Arch. Med. Wewn. 118 (11): 636–44. PMID 19140567. 
  • Fox CB, Treadway AK, Blaszczyk AT, Sleeper RB (April 2009). "Megestrol acetate and mirtazapine for the treatment of unplanned weight loss in the elderly". Pharmacotherapy. 29 (4): 383–97. doi:10.1592/phco.29.4.383. PMID 19323618. 
  • Argilés JM, Anguera A, Stemmler B (June 2013). "A new look at an old drug for the treatment of cancer cachexia: megestrol acetate". Clin Nutr. 32 (3): 319–24. doi:10.1016/j.clnu.2013.01.004. PMID 23395103. 
  • Greenberg M, Lawler D, Zawistowski S, Jöchle W (June 2013). "Low-dose megestrol acetate revisited: a viable adjunct to surgical sterilization in free roaming cats?". Vet. J. 196 (3): 304–8. doi:10.1016/j.tvjl.2013.01.038. PMID 23499239. 
  • Ruiz Garcia V, López-Briz E, Carbonell Sanchis R, Gonzalvez Perales JL, Bort-Marti S (March 2013). "Megestrol acetate for treatment of anorexia-cachexia syndrome". Cochrane Database Syst Rev (3): CD004310. doi:10.1002/14651858.CD004310.pub3. PMID 23543530. 
  • Smith CS, Logomarsino JV (March 2016). "Using megestrol acetate to ameliorate protein-energy wasting in chronic kidney disease". J Ren Care. 42 (1): 53–9. doi:10.1111/jorc.12138. PMID 26537025. 
  • Wazny LD, Nadurak S, Orsulak C, Giles-Smith L, Tangri N (May 2016). "The Efficacy and Safety of Megestrol Acetate in Protein-Energy Wasting due to Chronic Kidney Disease: A Systematic Review". J Ren Nutr. 26 (3): 168–76. doi:10.1053/j.jrn.2015.11.002. PMID 26776251.