2116 Sex Hormones and their Modulators

Profile Uses and Administration (BAN, rINN) ⊗ Melengestrol is a that is used as an animal has androgenic properties (see , Metenolon; Metenolona; Méténolone; Metenoloni; Metenolon- feed in beef heifers to improve feed efficiency, increase the rate p.2131) but is reported to have less inhibitory effect on intrinsic um; Methenolone. 17β-Hydroxy-1-methyl-5α-androst-1-en-3- of body-weight gain, and suppress oestrus. testicular function than testosterone. one. ◊ WHO specifies an acceptable daily intake of melengestrol ac- Mesterolone is given orally in the treatment of defi- ciency or male infertility associated with hypogonadism Метенолон etate as a residue in foods, and recommends maximum residue C H O = 302.5. limits in various animal tissues.1 However, it should be noted (p.2079) in initial doses of 75 to 100 mg daily followed by doses 20 30 2 of 50 to 75 mg daily for maintenance, in divided doses. CAS — 153-00-4. that, in the EU the use of melengestrol acetate and other steroidal ATC — A14AA04. hormones as growth promotors is banned. Preparations ATC Vet — QA14AA04. 1. FAO/WHO. Evaluation of certain veterinary drug residues in Proprietary Preparations (details are given in Part 3) food: sixty-sixth report of the joint FAO/WHO expert committee Austral.: Proviron; Austria: Proviron; Belg.: Proviron; Braz.: Proviron; on food additives. WHO Tech Rep Ser 939 2006. Also available Chile: Proviron; Cz.: Proviron; Denm.: Mestoranum†; Fin.: Proviron†; OH at: http://libdoc.who.int/publications/2006/9241209399_eng.pdf Ger.: Proviron†; Vistimon†; Gr.: Proviron; Hong Kong: Proviron†; Hung.: H3C (accessed 24/06/08) Proviron; India: Provironum; Indon.: Androlon; Infelon; Proviron; Israel: Proviron; Ital.: Proviron; Malaysia: Provironum†; Vistimon†; Mex.: Provi- H3C ron; Neth.: Proviron; Philipp.: Proviron; Pol.: Proviron; Port.: Proviron; CH H S.Afr.: Proviron; Singapore: Provironum; Spain: Proviron; Thai.: Proviro- 3 (rINN) ⊗ num; Turk.: Proviron; UK: Proviron; Venez.: Proviron. HH Mépitiostane; Mepitiostano; Mepitiostanum; S-10364. 17β-(1- Methoxycyclopentyloxy)-2α,3α-epithio-5α-; Cyclo- O pentanone 2α,3α-epithio-5α-androstan-17β-yl methyl acetal. Mestranol (BAN, USAN, rINN) H Мепитиостан Compound 33355; EE3ME; Ethinyloestradiol-3-methyl Ether; C25H40O2S = 404.6. Mestranoli; Mestranolis; Mestranolum; Mesztranol. 3-Methoxy- Metenolone Acetate (BANM, rINNM) ⊗ CAS — 21362-69-6. 19-nor-17α-pregna-1,3,5(10)-trien-20-yn-17β-ol. Acetato de metenolona; Acetato de metilandrostenolona; Местранол Méténolone, Acétate de; Metenoloni Acetas; Methenolone Ac- C H O = 310.4. etate (USAN); NSC-74226; SH-567; SQ-16496. 17β-Hydroxy-1- H CO 21 26 2 3 CAS — 72-33-3. methyl-5α-androst-1-en-3-one acetate. Метенолона Ацетат O C H O = 344.5. H3C 22 32 3 OH CH CAS — 434-05-9. H3C ATC — A14AA04. H3C H ATC Vet — QA14AA04. In Jpn. H Pharmacopoeias. S HH Metenolone Enantate (BANM, rINNM) ⊗ HH H Enantato de metenolona; Enantato de metilandrostenolona; H3CO Méténolone, Enantate de; Metenoloni Enantas; Methenolone Pharmacopoeias. In Jpn. Enanthate (USAN); Methenolone Oenanthate; NSC-64967; SH- Pharmacopoeias. In Eur. (see p.vii), Jpn, and US. 601; SQ-16374. 17β-Hydroxy-1-methyl-5α-androst-1-en-3-one Profile heptanoate. Mepitiostane has androgenic and anabolic properties (see Testo- Ph. Eur. 6.2 (Mestranol). A white or almost white crystalline sterone, p.2129) and is given in usual oral doses of 10 mg twice powder. Practically insoluble in water; sparingly soluble in alco- Метенолона Энантат daily for the management of neoplasms of the breast and anae- hol. Protect from light. C27H42O3 = 414.6. mia associated with renal failure. USP 31 (Mestranol). A white to creamy-white, odourless, crys- CAS — 303-42-4. talline powder. Insoluble in water; sparingly soluble in dehydrat- ATC — A14AA04. Preparations ed alcohol; freely soluble in chloroform; soluble in dioxan; ATC Vet — QA14AA04. Proprietary Preparations (details are given in Part 3) slightly soluble in methyl alcohol. Protect from light. Pharmacopoeias. In Jpn. Jpn: Thioderon. Profile Adverse Effects and Precautions Metenolone is an anabolic (see Testosterone, p.2129) that As for oestrogens in general (see , p.2097). has been used in treating aplastic anaemia, breast cancer, and Mesterolone (BAN, USAN, rINN) ⊗ See also under Hormonal Contraceptives, p.2059. postmenopausal osteoporosis. Metenolone acetate has been giv- en in oral doses of 100 to 150 mg daily for aplastic anaemia. In- Mesterolon; Mesterolona; Mesterolonas; Mestérolone; Mesterol- Porphyria. Mestranol is considered to be unsafe in patients with tramuscular depot injections of metenolone enantate have been oni; Mesterolonum; Meszterolon; NSC-75054; SH-723. 17β-Hy- porphyria because it has been shown to be porphyrinogenic in given for osteoporosis in doses of 100 mg every 2 weeks, reduc- droxy-1α-methyl-5α-androstan-3-one. animals or in-vitro systems. ing to once every 3 to 4 weeks after an initial response. The ace- Местеролон tate was also used orally in the past for osteoporosis. Intramuscu- lar injections of 100 mg of the enantate every 1 to 2 weeks, or C H O = 304.5. Interactions 20 32 2 See under Hormonal Contraceptives, p.2067. 200 mg every 2 to 3 weeks, have been used in progressive breast CAS — 1424-00-6. cancer. ATC — G03BB01. ATC Vet — QG03BB01. Pharmacokinetics Preparations Proprietary Preparations (details are given in Part 3) Mestranol is readily absorbed from the gastrointestinal Austral.: Primobolan; Ger.: Primobolan†; Gr.: Primobolan Depot†; Mex.: tract, and about 70% is rapidly metabolised in the liver Primobolan; S.Afr.: Primobolan; Spain: Primobolan Depot. OH to (p.2102). Multi-ingredient: Ger.: NeyPulpin N (Revitorgan-Dilutionen N Nr 10)†; H3C NeyTumorin N (Revitorgan-Dilutionen N Nr 66)†. H3C Uses and Administration CH H 3 Mestranol is a synthetic oestrogen prodrug that is rap- Methandienone (BAN) ⊗ idly metabolised to ethinylestradiol; it therefore has ac- HH tions similar to those of estradiol (see p.2098). It is used (pINN); Metandienon; Metandienona; Métan- diénone; Metandienoni; Metandienonum; Methandrostenolone; O as the oestrogen component of combined oral contra- H NSC-42722. 17β-Hydroxy-17α-methylandrosta-1,4-dien-3-one. ceptive preparations (see p.2069) in a usual dose of Метандиенон 50 micrograms daily. The progestogen component is Pharmacopoeias. In Eur. (see p.vii). C20H28O2 = 300.4. Ph. Eur. 6.2 (Mesterolone). A white or yellowish crystalline often . Mestranol has also been used as CAS — 72-63-9. powder. Practically insoluble in water; sparingly soluble in ace- the oestrogen component of some preparations for ATC — A14AA03; D11AE01. tone, in ethyl acetate, and in methyl alcohol. menopausal HRT (see p.2076), although natural oes- ATC Vet — QA14AA03; QD11AE01. Adverse Effects and Precautions trogens are often preferred. It has been given in a se- As for in general (see Testosterone, p.2130). quential regimen in a dose of 50 micrograms daily, OH H C CH Mesterolone is reported not to inhibit gonadotrophin secretion or with a cyclical progestogen. 3 3 spermatogenesis. Preparations H3CH Pharmacokinetics USP 31: Ethynodiol Diacetate and Mestranol Tablets; Norethindrone and Mesterolone is rapidly and almost completely absorbed after an Mestranol Tablets. oral dose, producing maximum serum concentrations after about Proprietary Preparations (details are given in Part 3) H H 1.6 hours. It is rapidly metabolised, with an absolute bioavaila- Multi-ingredient: Austral.: Norinyl-1; Braz.: Biofim†; Megestran†; Ca- O bility of about 3% of the oral dose, and a terminal half-life of 12 nad.: Ortho-Novum 1/50†; Chile: Anovulatorios; Cz.: Menophase†; to 13 hours. Unlike other androgens (see Testosterone, p.2131), Ger.: Esticia; Gestamestrol N†; Ovosiston†; Hong Kong: Norinyl-1; Mex.: mesterolone is not metabolised to oestrogenic compounds. Mes- Lutoral-E; Norace; Norinyl; Ortho-Novum†; Secuentex-21; NZ: Norinyl-1; NOTE. The following terms have been used as ‘street names’ (see terolone is bound to serum proteins; about 40% to albumin and S.Afr.: Norinyl-1/28; Thai.: Anamai†; UK: Norinyl-1; USA: Necon 1/50; p.vi) or slang names for various forms of methandienone: 58% to sex-hormone binding globulin. About 77% of the metab- Norinyl 1 + 50; Ortho-Novum 1/50. Iron Brew. olites are excreted in the urine, and about 13% in the faeces. Pharmacopoeias. In Pol. Mepitiostane/Nafarelin Acetate 2117 Adverse Effects and Precautions Effects on the liver. Reports of peliosis hepatis1 and liver As for androgens and anabolic in general (see Testoster- damage2-4 associated with . one, p.2130). See also under Malignant Neoplasms, below. OH H C CH As with other 17α-alkylated compounds, methandienone is asso- 1. Bagheri SA, et al. Peliosis hepatis associated with androgenic- 3 3 ciated with and hepatic function should be moni- therapy: a severe form of hepatic injury. Ann tored during therapy. It should probably be avoided in patients Intern Med 1974; 81: 610–18. H H with hepatic impairment, and certainly if this is severe. 2. Westaby D, et al. Liver damage from long-term methyltestoster- one. Lancet 1977; ii: 261–3. Uses and Administration 3. Lowdell CP, Murray-Lyon IM. Reversal of liver damage due to HH Methandienone has anabolic and some androgenic properties long term methyltestosterone and safety of non-17 α-alkylated (see Testosterone, p.2131). It has little progestogenic activity. androgens. BMJ 1985; 291: 637. OCH3 Methandienone has been given orally as an anabolic drug. 4. Borhan-Manesh F, Farnum JB. Methyltestosterone-induced cholestasis: the importance of disproportionately low serum al- Preparations kaline phosphatase level. Arch Intern Med 1989; 124: 2127–9. Pharmacopoeias. In US for veterinary use only. Proprietary Preparations (details are given in Part 3) USP 31 (). A white to off-white powder. Practically MALIGNANT NEOPLASMS. Hepatocellular carcinoma1-7 and he- Pol.: Metanabol; Thai.: Anabol; Danabol†; Melic. 5,8 insoluble in water; slightly soluble in chloroform, in dioxan, and patic adenoma have been associated with methyltestoster- in dichloromethane. one. A review9 of reports of liver tumours associated with an- abolic androgens found that methyltestosterone was an Profile Methyl-1-testosterone ⊗ androgen that had been commonly implicated, and that the Mibolerone is an androgen that is used in veterinary practice as a majority of tumours were hepatocellular carcinomas. 17β-Hydroxy-17α-methyl-5α-androst-1-en-3-one; M1T. contraceptive for female dogs. It also has anabolic properties. 1. Johnson FL, et al. Association of androgenic-anabolic steroid Метил-1-тестостерон therapy with development of hepatocellular carcinoma. Lancet C20H30O2 = 302.5. 1972; ii: 1273–6. CAS — 65-04-3. 2. Henderson JT, et al. Androgenic-anabolic steroid therapy and hepatocellular carcinoma. Lancet 1973; i: 934. Nafarelin Acetate (BANM, USAN, rINNM) ⊗ 3. Farrell GC, et al. Androgen-induced hepatoma. Lancet 1975; i: 430–2. Acetato de nafarelina; Nafareliiniasetaatti; Nafarelin Asetat; Na- OH 4. Goodman MA, Laden AMJ. Hepatocellular carcinoma in associ- D H3C CH3 ation with androgen therapy. Med J Aust 1977; 1: 220–1. farelinacetat; Nafaréline, Acétate de; Nafarelini Acetas; - 6 5. Boyd PR, Mark GJ. Multiple hepatic adenomas and a hepatocel- Nal(2) -LHRH acetate hydrate; RS-94991298. 5-Oxo-L-prolyl-L- lular carcinoma in a man on oral methyl testosterone for eleven histidyl-L-tryptophyl-L-seryl-L-tyrosyl-3-(2-naphthyl)-D-alanyl-L- H C H 3 years. Cancer 1977; 40: 1765–70. leucyl-L-arginyl-L-prolylglycinamide acetate hydrate. 6. Cocks JR. Methyltestosterone-induced liver-cell tumours. Med J H H Aust 1981; 2: 617–19. Нафарелина Ацетат 7. Gleeson D, et al. Androgen associated hepatocellular carcinoma C H N O ,xC H O ,yH O. O with an aggressive course. Gut 1991; 32: 1084–6. 66 83 17 13 2 4 2 2 H 8. Coombes GB, et al. An androgen-associated hepatic adenoma in CAS — 76932-56-4 (nafarelin); 86220-42-0 (nafarelin a trans-sexual. Br J Surg 1978; 65: 869–70. acetate). 9. Velazquez I, Alter BP. Androgens and liver tumors: Fanconi’s Profile anemia and non-Fanconi’s conditions. Am J Hematol 2004; 77: ATC — H01CA02. Methyl-1-testosterone is an anabolic steroid (see Testosterone, 257–67. p.2129) that appears to be widely abused by body-builders. ATC Vet — QH01CA02. Pregnancy. For reference to virilisation of a female fetus whose ◊ References. mother received methyltestosterone during pregnancy, see 1. Health Canada. Health Canada warns consumers not to use sup- p.2131. plements containing methyl-1-testosterone due to potential seri- ous health risks (issued February 2006). Available at: http:// www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2006/ Interactions 2006_06_e.html (accessed 13/11/07) As for androgens and anabolic steroids in general (see 5—oxoPro—His—Trp—Ser—Tyr N C C Leu—Arg—Pro—GlyNH Testosterone, p.2131). H H O

Methyltestosterone (BAN, rINN) ⊗ Pharmacokinetics (nafarelin) Methyltestosterone is absorbed from the gastrointesti- Methyltestosteron; Méthyltestostérone; Methyltestosteronum; nal tract and from the oral mucosa. It undergoes less Metiltestosterona; Metiltestosteronas; Metiltesztoszteron; Mety- extensive first-pass hepatic metabolism than testoster- lotestosteron; Metyltestosteron; Metyylitestosteroni; NSC-9701. Adverse Effects and Precautions 17β-Hydroxy-17α-methylandrost-4-en-3-one. one after oral doses, and has a longer half-life. As for Gonadorelin, p.2106. Метилтестостерон Uses and Administration Effects on electrolytes. Severe hyperkalaemia occurred in a C20H30O2 = 302.5. woman receiving nafarelin therapy for uterine fibroids.1 Despite CAS — 58-18-4. As for androgens and anabolic steroids in general (see serum-potassium greater than 10 mmol/litre she had no symp- ATC — G03BA02. Testosterone, p.2131). toms and the electrocardiogram was normal. Hyperkalaemia re- ATC Vet — QG03BA02; QG03EK01. Methyltestosterone is effective when given orally; its solved without treatment on stopping nafarelin. effect is increased about twofold when given buccally, 1. Hata T, et al. Severe hyperkalaemia with nafarelin. Lancet 1996; as this avoids first-pass hepatic metabolism. 347: 333. OH Suggested doses of methyltestosterone for androgen H3C CH3 Interactions replacement therapy in male hypogonadism (p.2079) As for Gonadorelin, p.2107. H3C H have been 10 to 50 mg daily orally or 5 to 25 mg daily buccally. Doses of 50 to 200 mg daily orally or 25 to Pharmacokinetics HH 100 mg daily buccally have been given for metastatic breast carcinoma (p.661) in postmenopausal women. Nafarelin is rapidly absorbed on intranasal use with O Oral doses of 1.25 to 2.5 mg daily, for 21 days of a 28- peak plasma concentrations achieved within 20 min- day cycle, have been given with oestrogens for the utes of a dose, although bioavailability is only about Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, and US. short-term treatment of menopausal vasomotor symp- 3%. The plasma half-life is about 3 to 4 hours. Nafare- Ph. Eur. 6.2 (Methyltestosterone). A white or slightly yellow- lin is metabolised by peptidases in the body; after sub- ish-white, crystalline powder. Practically insoluble in water; toms (p.2077) unresponsive to oestrogens alone. freely soluble in alcohol. Protect from light. cutaneous dosage it is excreted in urine, as metabolites USP 31 (Methyltestosterone). White or creamy-white, odour- Preparations and a small amount of unchanged drug, and in the fae- less, slightly hygroscopic, crystals or crystalline powder. Practi- USP 31: Methyltestosterone Capsules; Methyltestosterone Tablets. ces. cally insoluble in water; soluble in alcohol, in ether, in methyl al- Proprietary Preparations (details are given in Part 3) cohol, and in other organic solvents; sparingly soluble in USA: Android; Testred; Virilon. Uses and Administration vegetable oils. Protect from light. Multi-ingredient: Austria: Pasuma-Dragees; Braz.: Gabecon M†; Tes- tonus†; Chile: Delitan; Feminova-T; Fin.: Potentol†; Hong Kong: Wari- Nafarelin acetate is an analogue of gonadorelin Adverse Effects and Precautions Procomil; India: Mixogen; Mex.: Bigenol; Thai.: Hormone Multicap†; (p.2107) with similar properties. It is used in the treat- Horon†; Men Hormone; Wari-Procomil†; UK: Prowess; USA: Covaryx; As for androgens and anabolic steroids in general (see Estratest; Syntest. ment of endometriosis and central precocious puberty, Testosterone, p.2130). and as an adjunct to ovulation induction with gonado- trophins in the treatment of infertility. As with other 17α-alkylated compounds, methyltesto- sterone can produce a cholestatic hepatitis with jaun- Mibolerone (BAN, USAN, rINN) ⊗ For endometriosis it is given in usual doses equivalent dice, and has caused peliosis hepatis and hepatic neo- Mibolerona; Mibolérone; Miboleronum; NSC-72260; U-10997. to 200 micrograms of nafarelin twice daily intranasal- plasms (see below). Methyltestosterone should be used 17β-Hydroxy-7α,17-dimethylestr-4-en-3-one. ly, doubled after 2 months if amenorrhoea has not oc- with caution in patients with liver impairment, and is Миболерон curred. Treatment should begin on days 2 to 4 of the probably best avoided if this is severe. Liver function C20H30O2 = 302.5. menstrual cycle, and may be continued for up to 6 should be monitored during therapy. CAS — 3704-09-4. months. The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)