BMJ Sex Reprod Health: first published as 10.1136/bmjsrh-2020-200619 on 12 May 2020. Downloaded from Review Norethisterone and its acetate – what’s so special about them? Emilia Huvinen , Elina Holopainen , Oskari Heikinheimo Obstetrics and Gynecology, ABSTRACT Key message points University of Helsinki and Introduction Progestogens (progestins) Helsinki University Hospital, are widely used for contraception, in Helsinki 00029, Finland ► Norethisterone (NET) converts in part postmenopausal hormone therapy, and in to ethinylestradiol (EE); 10–20 mg NET Correspondence to treatment of abnormal uterine bleeding and equals 20–30 µg EE. Dr Emilia Huvinen, Obstetrics endometriosis. Norethisterone (NET) and its and Gynecology, University of ► NET has a strong influence on the acetate (NETA) differ from other progestogens by Helsinki and Helsinki University endometrium and it is a good option for Hospital, Helsinki 00029, Finland; their partial conversion to ethinylestradiol (EE). treatment of endometrial hyperplasia. emilia. huvinen@ helsinki. fi We review their special characteristics and focus ► Special consideration is needed in cases on the clinically relevant risk factors associated Received 17 February 2020 of high risk for thromboembolic events Revised 6 April 2020 with estrogen action, such as migraine with aura and when treating women experiencing Accepted 13 April 2020 and risk of thrombosis. migraine with aura. Published Online First Methods Narrative review based on a medical 12 May 2020 literature (OvidMedline and PubMed) search. Results NET converts to significant amounts of EE; 10–20 mg NET corresponds to 20–30 µg used for contraception, postponing EE. The effects of NET on the endometrium are menstruation, as part of postmenopausal pronounced, making it a good choice for treating hormonal therapy (HT), and for the treat- abnormal uterine bleeding, endometriosis, and ment of abnormal uterine bleeding and endometrial hyperplasia. NET also has beneficial endometriosis. Although all progestogens effects on bone mineral density and positive imitate natural progesterone, each proges- or neutral effects on cardiovascular health. togen also has its individual characteristics Conversely, long- term use of NET is associated based on the different pharmacokinetic with a slightly increased breast cancer risk, and pharmacodynamic characteristics, http://jfprhc.bmj.com/ and the risk of venous thromboembolism is namely different binding affinities to moderately increased. This risk seems to be dose- estrogen, androgen, and glucocorticoid dependent; contraceptive use carries no risk, and mineralocorticoid receptors.1 The but therapeutic doses might be associated with availability and use of different progesto- an increased risk. Studies suggest an association gens vary globally. between combinations of EE and progestogens Norethisterone (NET) (and simi- and ischaemic stroke, which in particular larly norethisterone acetate, NETA, and on September 28, 2021 by guest. Protected copyright. concerns women with migraine. No studies norethindrone) is the most widely used have, however, assessed this risk related to the progestogen in several European coun- therapeutic use of NET. tries. It is an effective progestogen with a Conclusions NET is a potent progestogen, strong endometrial effect.2 In contrast to especially when considering the endometrium. other progestogens, NET partly converts Its partial conversion to EE, however, is important (approximately 0.4%–1%) to ethinyl- to remember. Clinical consideration is required estradiol (EE) in the liver, therefore also with women at high risk for either breast cancer 3 4 causing estrogenic effects in the body. or thromboembolism, or experiencing migraine © Author(s) (or their As preceding estrogen action is needed for employer(s)) 2021. No with aura. progestogen activity, the resulting EE also commercial re- use. See rights strengthens the progestogenic proper- and permissions. Published by BMJ. ties of NET. However, considering the 5 thromboembolic risk associated with EE, To cite: Huvinen E, Holopainen E, Heikinheimo O. INTRODUCTION this conversion might be of importance BMJ Sex Reprod Health Progestogens (progestins) are synthetic concerning the possible adverse effects of 2021;47:102–109. analogues of progesterone, and are widely NET(A). 102 Huvinen E, et al. BMJ Sex Reprod Health 2021;47:102–109. doi:10.1136/bmjsrh-2020-200619 none) generationsthehighest. fourth (eg,drospire gestodene anddesogestrel) and thromboembolic complications, andthethird (eg, gens (eg,levonorgestrel) for contraception.Thesecond- estrogen different progestogensincombination with of when discussing thethromboticeffects especially generations accordingtotheirorderofdiscovery, tone)( from spironolac (eg, drospirenone derived and others 17- into 19- ically classified accordingtotheprecursor molecules gens (eg, desogestrel) are prodrugs, and are effective prodrugs, and are are gens (eg,desogestrel) natural progesterone isless complete.Some progesto the gastrointestinaltractis effective,whereasthatof of 19- the absorption example, For characteristics. cokinetic theydifferintheirpharma receptors. Additionally, mineralocorticoid progesterone, glucocorticoid,and steroid receptors,namelyestrogen,androgen, cellular profile basedontheirdistinctiveabilityto bind structure. of discoveryorchemical and steroidresearch. of contraception This keyinvention changedthefield increased absorptionfrom the gastrointestinalcanal. tion ofanethylgrouptoC17resultedinsignificantly theaddi molecule toaprogestogenic one. Moreover, from C19oftestosterone, converting an androgenic The approachinvolvedtheremovalofamethyl group created byCarlDrejassifrom natural testosterone. the firstsyntheticprogestogen, norethisterone, was andfinallyin1951, progesterone had poor efficiency; orally administered of ovulationinhibition.Natural, In theearly1900s,scientistsstrivedtofindameans PROGESTOGENS with NET*. conjunction and psychologic*in metabolism, bone, endometr*, glucose embol*, thrombo*,breast cancer, searchtermswerethrombo in English.Additional only articles and included estradiol/EE with ethinyl and norethindron*, individuallyand incombination norethisterone, norethisteron*, terms progest*,NETA, usedthesearch and reviewsonnorethisterone. We usedOvidMedlineandPubMedtofindstudies We METHODS cations fortheuseofEE. migraine withaura,typicallyconsideredascontraindi women athigherriskforthromboemboliceventsand cially wanted tofocusoncertainriskgroups such as espe use. We to considertheirimplicationsforclinical and of NET, effects potentially negative and beneficial Progestogens can alsobegroupedintodifferent Progestogens All progestogens have a slightly different clinical All progestogens havea to theirtime according classified canbe Progestogens The purposeofthisreviewistoassessthespecific α hydroxyprogesterone derivatives(pregnanes), hydroxyprogesterone table nortestosterone nortest 1 ). osterone (estranes andgonanes) and 6 derivatives (suchasNET)from display thelowestriskof 7–10 generation progesto 1 Theyarechem - - - - - - - - - - Table 1 Pharmacology and biological activity of progesterone and synthetic progestogens (adapted from Schindler et al)1 Progestogen Progestogenic Antigonadotropic Anti- estrogenic Estrogenic Androgenic Anti- androgenic Glucocorticoid Antimineralocorticoid Progesterone + + + – – +/– + + Medroxyprogesterone acetate (MPA) + + + – +/– – + – Dydrogesterone + – + – – +/– – +/– First generation Norethisterone (NET) + + + + + – – – Lynestrenol* + + + + + – – – Cyproterone acetate + + + – – ++ + – Second generation Levonorgestrel + + + – + – – – Third generation Desogestrel + + + – + – – – Norgestimate† + + + – + – – – Gestodene + + + – + – + + Fourth generation Drospirenone + + + – – + – + Nomegestrol acetate + + + – – +/– – – Review Dienogest + + +/– +/– – + – – 103 *Prodrug. †Approximately 22% converts to levonorgestrel.11 Huvinen E, et al. BMJ Sex Reprod Health 2021;47:102–109. doi:10.1136/bmjsrh-2020-200619 BMJ Sex Reprod Health: first published as 10.1136/bmjsrh-2020-200619 on 12 May 2020. Downloaded from from Downloaded 2020. May 12 on 10.1136/bmjsrh-2020-200619 as published first Health: Reprod Sex BMJ http://jfprhc.bmj.com/ on September 28, 2021 by guest. Protected by copyright. by Protected guest. by 2021 28, September on BMJ Sex Reprod Health: first published as 10.1136/bmjsrh-2020-200619 on 12 May 2020. Downloaded from Review only following conversion by first- pass metabolism the androgenic activity of NET might partly compen- to an effective compound (3α-ketodesogestrel, that sate the effects of EE in the liver. is, etonogestrel). Progestogens bind to serum proteins Later in 2007, Chu et al conducted a study on 20 such as sex hormone-binding globulin (SHBG), premenopausal women, randomised to receive either corticosteroid- binding globulin (CBG), and albumin. 10, 20, or 40 mg NETA for 7 days in the follicular In addition, individual differences in metabolism can phase of the menstrual cycle.4 The conversion rate multiply the differences in their serum concentrations of NETA to EE was estimated to be at least 0.14 %, up to five- fold.11 but even up to 0.20%–0.33%. For comparison, inges- Therefore, the equivalent progestogen doses needed tion of 30–40 µg EE leads to a plasma concentration for ovulation inhibition and endometrial transforma- of 100–135 pg/mL, whereas the EE concentration tion vary. The doses required, especially for endo- following 10 mg NETA was 58 pg/mL, and following metrial transformation, are also