Estradiol-containing oral contraceptive Type Hormonal First use 1993 (Finland ) Perfect use ? Typical use ? Reversibility Yes User reminders ? STI protectionNo
Combined birth control pills that contain natural estradiol or an estradiol ester (e.g., estradiol valerate ) include:[1] [2] [3]
Estradiol, mainly as esters including estradiol valerate, estradiol cypionate , and estradiol enanthate , is also the exclusive estrogen used in combined injectable contraceptives .[6]
As of 2021, more than 95% of prescriptions are for combined hormonal birth control forms containing the synthetic estrogen ethinylestradiol (EE).[7] Hence, estradiol-based birth control pills are still not widely used.[7]
Side effects [ edit ] Birth control pills containing estradiol have less impact on liver protein synthesis than ethinylestradiol -containing birth control pills, and it is thought that for this reason, they may pose less of a risk of venous thromboembolism (VTE).[8] [9] In accordance, although birth control pills containing estradiol valerate/dienogest are associated with a significantly increased risk of VTE, they are associated with a significantly lower risk of venous thromboembolism than birth control pills containing ethinylestradiol and a progestin.[10] The risk of VTE with estradiol/nomegestrol acetate birth control pills is under study.[11]
Incidence of irregular vaginal bleeding may be higher with estradiol-containing birth control pills in relation to the fact that estradiol is a weaker estrogen than ethinylestradiol in the endometrium .[3]
Pharmacology [ edit ] The pharmacodynamics and pharmacokinetics of estradiol in the context of use in birth control pills have been studied and reviewed.[12] [2] [9]
Research [ edit ] Experimental estradiol-containing birth control pills that were studied but never marketed include:[3]
A large randomized controlled trial of a birth control pill containing ethinylestradiol/norethisterone acetate versus a birth control pill containing estradiol/estriol/norethisterone acetate has been conducted.[13]
See also [ edit ] References [ edit ] ^ De Leo V, Musacchio MC, Cappelli V, Piomboni P, Morgante G (2016). "Hormonal contraceptives: pharmacology tailored to women's health" . Human Reproduction Update . 22 (5): 634–46. doi :10.1093/humupd/dmw016 . PMID 27307386 . ^ a b Stanczyk FZ, Archer DF, Bhavnani BR (2013). "Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment". Contraception . 87 (6): 706–27. doi :10.1016/j.contraception.2012.12.011 . PMID 23375353 . ^ a b c d Fruzzetti F, Bitzer J (2010). "Review of clinical experience with estradiol in combined oral contraceptives". Contraception . 81 (1): 8–15. doi :10.1016/j.contraception.2009.08.010 . PMID 20004267 . ^ Guida M, Bifulco G, Di Spiezio Sardo A, Scala M, Fernandez LM, Nappi C (2010). "Review of the safety, efficacy and patient acceptability of the combined dienogest/estradiol valerate contraceptive pill" . International Journal of Women's Health . 2 : 279–90. doi :10.2147/IJWH.S6954 . PMC 2990895 . PMID 21151673 . ^ Burke A (2013). "Nomegestrol acetate-17b-estradiol for oral contraception" . Patient Preference and Adherence . 7 : 607–19. doi :10.2147/PPA.S39371 . PMC 3702550 . PMID 23836965 . ^ "WJPPS | ABSTRACT" (PDF) . World Journal of Pharmacy and Pharmaceutical Sciences . ^ a b Mawet, M; Gaspard, Ulysse; Foidart, JM (2021). "Estetrol as estrogen in a combined oral contraceptive, from the first in-human study to the contraceptive efficacy" (PDF) . European Gynecology and Obstetrics . 3 (1): 13–21. On the other side, only three different estrogens have been used in COC since 1961: the first one was the pro-drug mestranol rapidly replaced by its potent active form, ethinylestradiol (EE). Ethinylestradiol has remained the only estrogen used in COC during more than four decades. After initial unsuccessful attempts, estradiol (E2) was finally introduced into two COCs in the early 2010': in the form of the pro-drug E2 valerate in combination with dienogest (E2V/DNG) and in the form of E2 in combination with nomegestrol acetate [4, 5]. However, these E2-containing COCs are less prescribed as over 95% of combined hormonal contraceptive users still utilize an EE-containing product. ^ Nelson AL (2015). "An update on new orally administered contraceptives for women". Expert Opinion on Pharmacotherapy . 16 (18): 2759–72. doi :10.1517/14656566.2015.1100173 . PMID 26512437 . S2CID 207481206 . ^ a b Jensen, Jeffrey; Bitzer, Johannes; Serrani, Marco (2013). "Comparison of the pharmacologic and clinical profiles of new combined oral contraceptives containing estradiol" . Open Access Journal of Contraception : 39. doi :10.2147/OAJC.S50693 . ISSN 1179-1527 . ^ Fruzzetti F, Cagnacci A (2018). "Venous thrombosis and hormonal contraception: what's new with estradiol-based hormonal contraceptives?" . Open Access J Contracept . 9 : 75–79. doi :10.2147/OAJC.S179673 . PMC 6239102 . PMID 30519125 . ^ Douxfils J, Morimont L, Bouvy C (October 2020). "Oral Contraceptives and Venous Thromboembolism: Focus on Testing that May Enable Prediction and Assessment of the Risk". Semin Thromb Hemost . 46 (8): 872–886. doi :10.1055/s-0040-1714140 . PMID 33080636 . S2CID 224821517 . ^ Kuhnz W, Gansau C, Mahler M (September 1993). "Pharmacokinetics of estradiol, free and total estrone, in young women following single intravenous and oral administration of 17β-estradiol". Arzneimittelforschung . 43 (9): 966–73. ISSN 0004-4172 . PMID 8240460 . ^ "A randomized, double-blind study of two combined oral contraceptives containing the same progestogen, but different estrogens. World Health Organization Task Force on Oral Contraception". Contraception . 21 (5): 445–59. May 1980. doi :10.1016/0010-7824(80)90010-4 . PMID 7428356 .
Estrogens
ER Tooltip Estrogen receptor agonists Steroidal: Alfatradiol Certain androgens /anabolic steroids (e.g., testosterone , testosterone esters , methyltestosterone , metandienone , nandrolone esters ) (via estrogenic metabolites) Certain progestins (e.g., norethisterone , noretynodrel , etynodiol diacetate , tibolone ) Clomestrone Cloxestradiol acetate Conjugated estriol Conjugated estrogens Epiestriol Epimestrol Esterified estrogens Estetrol † Estradiol Estradiol esters (e.g., estradiol acetate , estradiol benzoate , estradiol cypionate , estradiol enanthate , estradiol undecylate , estradiol valerate , polyestradiol phosphate , estradiol ester mixtures (Climacteron )) Estramustine phosphate Estriol Estriol esters (e.g., estriol succinate , polyestriol phosphate ) Estrogenic substances Estrone Estrone esters Ethinylestradiol # Hydroxyestrone diacetate Mestranol Methylestradiol Moxestrol Nilestriol Prasterone (dehydroepiandrosterone; DHEA) Promestriene Quinestradol Quinestrol Progonadotropins
Antiestrogens
ER Tooltip Estrogen receptor antagonists (incl. SERMs Tooltip selective estrogen receptor modulators /SERDs Tooltip selective estrogen receptor downregulators )Aromatase inhibitors Antigonadotropins Androgens /anabolic steroids (e.g., testosterone , testosterone esters , nandrolone esters , oxandrolone , fluoxymesterone ) D2 receptor antagonists (prolactin releasers) (e.g., domperidone , metoclopramide , risperidone , haloperidol , chlorpromazine , sulpiride ) GnRH agonists (e.g., leuprorelin , goserelin ) GnRH antagonists (e.g., cetrorelix , elagolix ) Progestogens (e.g., chlormadinone acetate , cyproterone acetate , gestonorone caproate , hydroxyprogesterone caproate , medroxyprogesterone acetate , megestrol acetate ) Others
ER Tooltip Estrogen receptor
Agonists Steroidal: 2-Hydroxyestradiol 2-Hydroxyestrone 3-Methyl-19-methyleneandrosta-3,5-dien-17β-ol 3α-Androstanediol 3α,5α-Dihydrolevonorgestrel 3β,5α-Dihydrolevonorgestrel 3α-Hydroxytibolone 3β-Hydroxytibolone 3β-Androstanediol 4-Androstenediol 4-Androstenedione 4-Fluoroestradiol 4-Hydroxyestradiol 4-Hydroxyestrone 4-Methoxyestradiol 4-Methoxyestrone 5-Androstenediol 7-Oxo-DHEA 7α-Hydroxy-DHEA 7α-Methylestradiol 7β-Hydroxyepiandrosterone 8,9-Dehydroestradiol 8,9-Dehydroestrone 8β-VE2 10β,17β-Dihydroxyestra-1,4-dien-3-one (DHED) 11β-Chloromethylestradiol 11β-Methoxyestradiol 15α-Hydroxyestradiol 16-Ketoestradiol 16-Ketoestrone 16α-Fluoroestradiol 16α-Hydroxy-DHEA 16α-Hydroxyestrone 16α-Iodoestradiol 16α-LE2 16β-Hydroxyestrone 16β,17α-Epiestriol (16β-hydroxy-17α-estradiol) 17α-Estradiol (alfatradiol ) 17α-Dihydroequilenin 17α-Dihydroequilin 17α-Epiestriol (16α-hydroxy-17α-estradiol) 17α-Ethynyl-3α-androstanediol 17α-Ethynyl-3β-androstanediol 17β-Dihydroequilenin 17β-Dihydroequilin 17β-Methyl-17α-dihydroequilenin Abiraterone Abiraterone acetate Alestramustine Almestrone Anabolic steroids (e.g., testosterone and esters , methyltestosterone , metandienone (methandrostenolone) , nandrolone and esters , many others; via estrogenic metabolites) Atrimustine Bolandiol Bolandiol dipropionate Butolame Clomestrone Cloxestradiol Conjugated estriol Conjugated estrogens Cyclodiol Cyclotriol DHEA DHEA-S ent -Estradiol Epiestriol (16β-epiestriol, 16β-hydroxy-17β-estradiol) Epimestrol Equilenin Equilin ERA-63 (ORG-37663) Esterified estrogens Estetrol Estradiol Estramustine Estramustine phosphate Estrapronicate Estrazinol Estriol Estrofurate Estrogenic substances Estromustine Estrone Etamestrol (eptamestrol) Ethinylandrostenediol Ethinylestradiol Ethinylestriol Ethylestradiol Etynodiol Etynodiol diacetate Hexolame Hippulin Hydroxyestrone diacetate Lynestrenol Lynestrenol phenylpropionate Mestranol Methylestradiol Moxestrol Mytatrienediol Nilestriol Norethisterone Noretynodrel Orestrate Pentolame Prodiame Prolame Promestriene RU-16117 Quinestradol Quinestrol Tibolone Xenoestrogens: Anise -related (e.g., anethole , anol , dianethole , dianol , photoanethole ) Chalconoids (e.g., isoliquiritigenin , phloretin , phlorizin (phloridzin) , wedelolactone ) Coumestans (e.g., coumestrol , psoralidin ) Flavonoids (incl. 7,8-DHF , 8-prenylnaringenin , apigenin , baicalein , baicalin , biochanin A , calycosin , catechin , daidzein , daidzin , ECG , EGCG , epicatechin , equol , formononetin , glabrene , glabridin , genistein , genistin , glycitein , kaempferol , liquiritigenin , mirificin , myricetin , naringenin , penduletin , pinocembrin , prunetin , puerarin , quercetin , tectoridin , tectorigenin ) Lavender oil Lignans (e.g., enterodiol , enterolactone , nyasol (cis -hinokiresinol) ) Metalloestrogens (e.g., cadmium ) Pesticides (e.g., alternariol , dieldrin , endosulfan , fenarimol , HPTE , methiocarb , methoxychlor , triclocarban , triclosan ) Phytosteroids (e.g., digitoxin (digitalis ), diosgenin , guggulsterone ) Phytosterols (e.g., β-sitosterol , campesterol , stigmasterol ) Resorcylic acid lactones (e.g., zearalanone , α-zearalenol , β-zearalenol , zearalenone , zeranol (α-zearalanol) , taleranol (teranol, β-zearalanol) ) Steroid -like (e.g., deoxymiroestrol , miroestrol ) Stilbenoids (e.g., resveratrol , rhaponticin ) Synthetic xenoestrogens (e.g., alkylphenols , bisphenols (e.g., BPA , BPF , BPS ), DDT , parabens , PBBs , PHBA , phthalates , PCBs ) Others (e.g., agnuside , rotundifuran ) Mixed (SERMs Tooltip Selective estrogen receptor modulators ) Antagonists Coregulator-binding modulators: ERX-11
GPER Tooltip G protein-coupled estrogen receptor
Agonists Antagonists Unknown
PR Tooltip Progesterone receptor
Agonists Testosterone derivatives: Progestins: 6,6-Difluoronorethisterone 6,6-Difluoronorethisterone acetate 17α-Allyl-19-nortestosterone Allylestrenol Altrenogest Chloroethynylnorgestrel Cingestol Danazol Desogestrel Dienogest Ethinylandrostenediol Ethisterone Ethynerone Etonogestrel Etynodiol Etynodiol diacetate Gestodene Gestrinone Levonorgestrel Levonorgestrel esters (e.g., levonorgestrel butanoate ) Lynestrenol Lynestrenol phenylpropionate Metynodiol Metynodiol diacetate Norelgestromin Norethisterone (norethindrone) Norethisterone esters (e.g., norethisterone acetate , norethisterone enanthate ) Noretynodrel Norgesterone Norgestimate Norgestrel Norgestrienone Norvinisterone Oxendolone Quingestanol Quingestanol acetate Tibolone Tigestol Tosagestin ; Anabolic–androgenic steroids: 11β-Methyl-19-nortestosterone 11β-Methyl-19-nortestosterone dodecylcarbonate 19-Nor-5-androstenediol 19-Nor-5-androstenedione 19-Nordehydroepiandrosterone Bolandiol Bolandiol dipropionate Bolandione Dimethisterone Dienedione Dienolone Dimethandrolone Dimethandrolone buciclate Dimethandrolone dodecylcarbonate Dimethandrolone undecanoate Dimethyldienolone Dimethyltrienolone Ethyldienolone Ethylestrenol (ethylnandrol) Methyldienolone Metribolone (R-1881) Methoxydienone (methoxygonadiene) Mibolerone Nandrolone Nandrolone esters (e.g., nandrolone decanoate , nandrolone phenylpropionate ) Norethandrolone Normethandrone (methylestrenolone, normethandrolone, normethisterone) RU-2309 Tetrahydrogestrinone Trenbolone (trienolone) Trenbolone esters (e.g., trenbolone acetate , trenbolone enanthate ) Trendione Trestolone Trestolone acetate Mixed (SPRMs Tooltip Selective progesterone receptor modulators ) Antagonists
mPR Tooltip Membrane progesterone receptor (PAQR Tooltip Progestin and adipoQ receptor )