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Combined Estrogen–Progestogen Menopausal Therapy

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Combined Estrogen–Progestogen Menopausal Therapy PHARMACEUTICALS volume 100 A A review of humAn cArcinogens This publication represents the views and expert opinions of an IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, which met in Lyon, 14-21 October 2008 LYON, FRANCE - 2012 iArc monogrAphs on the evAluAtion of cArcinogenic risks to humAns COMBINED ESTROGEN–PROGESTOGEN MENOPAUSAL THERAPY Combined estrogen–progestogen menopausal therapy was considered by previous IARC Working Groups in 1998 and 2005 (IARC, 1999, 2007). Since that time, new data have become available, these have been incorporated into the Monograph, and taken into consideration in the present evaluation. 1. Exposure Data 1.1.2 Progestogens (a) Chlormadinone acetate Combined estrogen–progestogen meno- Chem. Abstr. Serv. Reg. No.: 302-22-7 pausal therapy involves the co-administration Chem. Abstr. Name: 17-(Acetyloxy)-6-chlo- of an estrogen and a progestogen to peri- or ropregna-4,6-diene-3,20-dione menopausal women. The use of estrogens with IUPAC Systematic Name: 6-Chloro-17-hy- progestogens has been recommended to prevent droxypregna-4,6-diene-3,20-dione, acetate the estrogen-associated risk of endometrial Synonyms: 17α-Acetoxy-6-chloro-4,6- cancer. Evidence from the Women’s Health pregnadiene-3,20-dione; 6-chloro-Δ6-17- Initiative (WHI) of adverse effects from the use acetoxyprogesterone; 6-chloro-Δ6-[17α] of a continuous combined estrogen–progestogen acetoxyprogesterone has affected prescribing. Patterns of exposure Structural and molecular formulae, and relative are also changing rapidly as the use of hormonal molecular mass therapy declines, the indications are restricted, O CH and the duration of the therapy is reduced (IARC, 3 C 2007). CH3 CH3 O C 1.1 Identification of the agents CH3 H O 1.1.1 Estrogens HH For Estrogens, see the Monograph on O Estrogen-only Menopausal Therapy in this Cl volume. C23H29ClO4 Relative molecular mass: 404.9 249 IARC MONOGRAPHS – 100A (b) Cyproterone acetate Structural and molecular formulae, and relative Chem. Abstr. Serv. Reg. No.: 427-51-0 molecular mass H C Chem. Abstr. Name: (1β,2β)-17- 3 OH ′ CH2 (Acetyloxy)-6-chloro-1,2-dihydro-3 H- H C cyclopropa[1,2]pregna-1,4,6-triene-3,20- 2 C CH dione H H IUPAC Systematic Name: 6-Chloro-1β,2β- dihydro-17-hydroxy-3′H-cyclopropa[1,2] HH pregna-1,4,6-triene-3,20-dione acetate Synonyms: Cyproterone 17-O-acetate; cyproterone 17α-acetate; 1,2α-methylene- C H O 6-chloro-17α-acetoxy-4,6-pregnadiene- 22 30 Relative molecular mass: 310.5 3,20-dione; 1,2α-methylene-6-chloro-Δ4,6- pregnadien-17α-ol-3,20-dione acetate; (d) Drospirenone 1,2α-methylene-6-chloro-pregna-4,6- diene-3,20-dione 17α-acetate; methylene- Chem. Abst. Services Reg. No.: 67392-87-4 6-chloro-17-hydroxy-1α,2α-pregna-4,6- Chem. Abstr. Name: (2′S,6R,7R,8R,9S,10R,- diene-3,20-dione acetate 13S,14S,15S,16S)-1,3′,4′,6,7,8,9,10,11,- 12,13,14,15,16,20,21-Hexadecahydro Structural and molecular formulae, and relative -10,13-dimethyl-spiro[17H-dicyclop molecular mass ropa[6,7:15,16]cyclopenta[a]phenan- O CH3 threne-17,2′ (5′H)-furan]-3,5′ (2H)-dione C CH3 CH3 Synonyms: Dihydrospirorenone; 1,2-di- O C hydrospirorenone; drospirenona; spiro[17H-dicyclopropa[6,7:15,16] CH3 H O cyclopenta[a]phenanthrene-17,2′(5′H)- furan]-3,5′(2H)-dione, 1,3′,4′,6,7,8,9,10,11 HH ,12,13,14,15,16,20,21-hexadecahydro-10,13- O dimethyl-, [6R-(6α,7α,8β,9α,10β,13β,14α,1 Cl 5α,16α,17β)]- Structural and molecular formulae, and relative C H ClO 24 29 4 molecular mass Relative molecular mass: 416.9 O (c) Desogestrel H C Chem. Abstr. Serv. Reg. No.: 54024-22-5 3 O Chem. Abstr. Name: (17α)-13-Ethyl-11- methylene-18,19-dinorpregn-4-en-20-yn- CH3 H 17-ol IUPAC Systematic Name: 13-Ethyl-11- HH methylene-18,19-dinor-17α-pregn-4-en- 20-yn-17-ol O Synonyms: 13-Ethyl-11-methylene- 18,19-dinor-17α-4-pregnen-20-yn-17-ol; C24H30O3 17α-ethynyl-18-methyl-11-methylene-Δ4- Relative molecular mass: 366.5 oestren-17β-ol 250 Combined estrogen-progestogen menopausal therapy (e) Dydrogesterone (g) Gestodene Chem. Abstr. Serv. Reg. No.: 152-62-5 Chem. Abstr. Serv. Reg. No.: 60282-87-3 Chem. Abstr. Name: (9β,10α)-Pregna-4,6- Deleted CAS Reg. No.: 110541-55-4 diene-3,20-dione Chem. Abstr. Name: (17α)-13-Ethyl-17- IUPAC Systematic Name: 10α-Pregna-4,6- hydroxy-18,19-dinorpregna-4,15-dien-20- diene-3,20-dione yn-3-one Synonyms: 10α-Isopregnenone; dehydro- IUPAC Systematic Name: 13-Ethyl-17- retroprogesterone; dehydroprogesterone hydroxy-18,19-dinor-17α-pregna-4,15- Structural and molecular formulae, and relative dien-20-yn-3-one molecular mass Structural and molecular formulae, and relative O molecular mass CH3 C H 3C CH3 OH CH2 C CH CH H 3 H H H H H H O O C21H28O2 C21H26O2 Relative molecular mass: 312.5 Relative molecular mass: 310.4 (f) Ethynodiol diacetate (h) Levonorgestrel Chem. Abstr. Serv. Reg. No.: 297-76-7 Chem. Abstr. Name: (3β,17α)-19-Norpregn- Chem. Abstr. Serv. Reg. No.: 797-63-7 4-en-20-yne-3,17-diol, diacetate Deleted CAS Reg. No.: 797-62-6; 4222-79-1; IUPAC Systematic Name: 19-Nor-17α- 121714-72-5 pregn-4-en-20-yne-3β,17β-diol, diacetate Chem. Abstr. Name: (17α)-13-Ethyl-17- Synonyms: Ethinodiol diacetate; ethynodiol hydroxy-18,19-dinorpregn-4-en-20-yn-3- acetate; β-ethynodiol diacetate one IUPAC Systematic Name: 13-Ethyl-17- Structural and molecular formulae, and relative hydroxy-18,19-dinor-17α-pregn-4-en-20- molecular mass yn-3-one O Synonyms: 13-Ethyl-17-ethynyl- O C CH3 17β-hydroxy-4-gonen-3-one; CH3 C CH 13-ethyl-17α-ethynyl-17- hydroxygon-4-en-3-one; 13-ethyl-17α- H H ethynylgon-4-en-17β-ol-3-one; 13β-ethyl- H H 17α-ethynyl-17β-hydroxygon-4-en-3-one; O 13-ethyl-17-hydroxy-18,19-dinor-17α- C CH O 3 H pregn-4-en-20-yn-3-one; 17-ethynyl- 18-methyl-19-nortestosterone; 18-methyl- C24H32O4 norethindrone; l-norgestrel; dl-norgestrel; Relative molecular mass: 384.5 d-norgestrel 251 IARC MONOGRAPHS – 100A Structural and molecular formulae, and relative (j) Medroxyprogesterone acetate molecular mass Chem. Abstr. Serv. Reg. No.: 71-58-9 H C Chem. Abstr. Name: (6α)-17-(Acetyloxy)-6- 3 OH CH2 methylpregn-4-ene-3,20-dione C CH IUPAC Systematic Name: 17-Hydroxy-6α- H H methylpregn-4-ene-3,20-dione, acetate Synonyms: 17α-Acetoxy-6α- H H methylprogesterone; depomedroxypro- gesterone acetate; depo-progestin; depot- O medroxyprogesterone acetate; DMPA; C H O 17-hydroxy-6α-methylprogesterone, ac- 21 28 2 etate; 17α-hydroxy-6α-methylprogesterone Relative molecular mass: 312.5 acetate; MAP; MPA; medroxypro- (i) Lynestrenol gesterone 17-acetate; 6α-methyl-17- acetoxyprogesterone; 6α-methyl-17α- Chem. Abstr. Serv. Reg. No.: 52-76-6 hydroxyprogesterone acetate Deleted CAS Reg. No.: 60416-16-2 Chem. Abstr. Name: (17α)-19-Norpregn-4- Structural and molecular formulae, and relative en-20-yn-17-ol molecular mass IUPAC Systematic Name: 19-Nor-17α- O CH3 C pregn-4-en-20-yn-17-ol CH CH 4 3 3 Synonyms: 3-Desoxynorlutin; Δ - O C 17α-ethinylestren-17β-ol; Δ4-17α- CH H ethinyloestren-17β-ol; ethynylestrenol; 3 O ethynyloestrenol; 17α-ethynylestrenol; 17α-ethynyloestrenol; 17α-ethynyl-17β- H H 4 hydroxy-Δ -estrene; 17α-ethynyl-17β- O hydroxy-Δ4-oestrene H CH3 Structural and molecular formulae, and relative C H O molecular mass 24 34 4 Relative molecular mass: 386.5 OH CH3 (k) Megestrol acetate C CH Chem. Abstr. Serv. Reg. No.: 595-33-5 H H Chem. Abstr. Name: 17-(Acetyloxy)- 6-methylpregna-4,6-diene-3,20-dione H H IUPAC Systematic Name: 17-Hydroxy- 6-methylpregna-4,6-diene-3,20-dione, C H O acetate 20 28 Synonyms: DMAP; megestryl acetate; MGA Relative molecular mass: 284.4 252 Combined estrogen-progestogen menopausal therapy Structural and molecular formulae, and relative (m) Norethisterone acetate molecular mass Chem. Abstr. Serv. Reg. No.: 51-98-9 O CH3 Chem. Abstr. Name: (17α)-17-(Acetyloxy)- C 19-norpregn-4-en-20-yn-3-one CH3 CH3 O C IUPAC Systematic Name: 17-Hydroxy-19- nor-17α-pregn-4-en-20-yn-3-one, acetate CH H 3 O Synonyms: 17α-Ethinyl-19-nortestosterone 17β-acetate; 17α-ethinyl-19-nortestosterone H H acetate; 17α-ethynyl-19-nortestosterone O acetate; norethindrone acetate; norethin- drone 17-acetate; norethisteron acetate; CH 3 norethisterone 17-acetate; 19-norethister- one acetate; norethynyltestosterone acetate; C24H32O4 Relative molecular mass: 384.5 19-norethynyltestosterone acetate; nor- ethysterone acetate (l) Norethisterone Structural and molecular formulae, and relative Chem. Abstr. Serv. Reg. No.: 68-22-4 molecular mass Chem. Abstr. Name: (17α)-17-Hydroxy-19- O norpregn-4-en-20-yn-3-one O C CH3 IUPAC Systematic Name: 17-Hydroxy-19- CH3 nor-17α-pregn-4-en-20-yn-3-one C CH Synonyms: Ethinylnortestosterone; H H 17α-ethinyl-19-nortestosterone; ethynyl- nortestosterone; 17-ethynyl-19-nortestos- H H terone; 17α-ethynyl-19-nortestosterone; O norethindrone; norethisteron; norethyno- drone; 19-nor-17α-ethynyltestosterone; C H O norpregneninolone 22 28 3 Relative molecular mass: 340.5 Structural and molecular formulae, and relative molecular mass (n) Norethisterone enanthate OH Chem. Abstr. Serv. Reg. No.: 3836-23-5 CH3 Chem. Abstr.
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