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{{Infobox drug class
| Image = Progesterone.svg
| ImageClass = skin-invert-image
| Caption = [[Progesterone (medication)|Progesterone]], the natural progestogen in the body and one of the most widely used progestogen medications
| Width = 225px
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<!-- History, society, and culture -->
Progesterone was first introduced for medical use in 1934 and the first progestin, [[ethisterone]], was introduced for medical use in 1939.<ref name="Kuhl2011t">{{cite journal | author = Kuhl H | title = Pharmacology of Progestogens | journal = J Reproduktionsmed Endokrinol | year = 2011 | volume = 8 | issue = 1 | pages = 157–177 | url = http://www.kup.at/kup/pdf/10168.pdf}}</ref><ref name="LauritzenStudd2005">{{cite book|author1=Christian Lauritzen|author2=John W. W. Studd|title=Current Management of the Menopause|url=https://books.google.com/books?id=WD7S7677xUUC&pg=PA45|date=22 June 2005|publisher=CRC Press|isbn=978-0-203-48612-2|page=45|quote=Ethisterone, the first orally effective progestagen, was synthesized by Inhoffen and Hohlweg in 1938. Norethisterone, a progestogen still used worldwide, was synthesized by Djerassi in 1951. But this progestogen was not used immediately and in 1953 Colton discovered norethynodrel, used by Pincus in the first oral contraceptive. Numerous other progestogens were subsequently synthesized, e.g., lynestrenol and ethynodiol diacetate, which were, in fact, prhormones converted in vivo to norethisterone. All these progestogens were also able to induce androgenic effects when high doses were used. More potent progestogens were synthesized in the 1960s, e.g. norgestrel, norgestrienone. These progestogens were also more androgenic.}}</ref><ref name="Roth2014">{{cite book|author=Klaus Roth|title=Chemische Leckerbissen|url=https://books.google.com/books?id=FsKpBAAAQBAJ&pg=PA69|year=2014|publisher=John Wiley & Sons|isbn=978-3-527-33739-2|page=69|quote=Im Prinzip hatten Hohlweg und Inhoffen die Lösung schon 1938 in der Hand, denn ihr Ethinyltestosteron (11) war eine oral wirksame gestagene Verbindung und Schering hatte daraus bereits 1939 ein Medikament (Proluton C®) entwickelt.}}</ref> More [[potency (pharmacology)|potent]] progestins, such as [[norethisterone]], were developed and started to be used in birth control in the 1950s.<ref name="Kuhl2011t" /> Around 60 progestins have been marketed for clinical use in humans or use in [[veterinary medicine]].<ref name="Micromedex">{{
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Mood with birth control pills may be better with monophasic and continuous formulations than with triphasic and cyclic formulations.<ref name="pmid27636867" /><ref name="pmid22136510" /> Limited and inconsistent evidence supports differences in mood with hormonal birth control using different doses of ethinylestradiol or different [[route of administration|routes of administration]], such as birth control pills versus [[contraceptive vaginal ring]]s and [[contraceptive patch]]es.<ref name="pmid27636867" /><ref name="pmid22136510" /> Combined birth control with less [[androgenic]] or [[antiandrogen]]ic progestins like [[desogestrel]], [[gestodene]], and [[drospirenone]] may have a more favorable influence on mood than birth control with more androgenic progestins like [[levonorgestrel]].<ref name="pmid27636867" /><ref name="pmid22136510" /> However, [[androgen]] supplementation with hormonal birth control has also been reported to improve mood.<ref name="pmid27636867" />
Hormonal birth control that suppresses [[ovulation]] is effective in the treatment of [[premenstrual dysphoric disorder]] (PMDD).<ref name="pmid31172309" /><ref name="pmid31078196">{{cite journal | vauthors = Lanza di Scalea T, Pearlstein T | title = Premenstrual Dysphoric Disorder | journal = The Medical Clinics of North America | volume = 103 | issue = 4 | pages = 613–628 | date = July 2019 | pmid = 31078196 | doi = 10.1016/j.mcna.2019.02.007 | s2cid = 153307984 }}</ref> Combined birth control pills containing [[drospirenone]] are approved for the treatment of PMDD and may be particularly beneficial due to the [[antimineralocorticoid]] activity of drospirenone.<ref name="pmid31172309" /><ref>{{cite journal | vauthors = Ma S, Song SJ | title = Oral contraceptives containing drospirenone for premenstrual syndrome | journal = The Cochrane Database of Systematic Reviews | volume = 2023 | issue = 6 | pages = CD006586 | date = June 2023 | pmid = 37365881 | pmc = 10289136 | doi = 10.1002/14651858.CD006586.pub5
Studies suggest a [[negativity bias]] in [[emotion recognition]] and [[emotionality|reactivity]] with hormonal birth control.<ref name="pmid31701260" /> Some data suggests blunted [[reward system|reward]] responses and potential dysregulation of the [[stress response]] with hormonal birth control in some women.<ref name="pmid31701260" /><ref name="pmid31172309" />
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===Blood clots===
[[Venous thromboembolism]] (VTE) consists of [[deep vein thrombosis]] (DVT) and [[pulmonary embolism]] (PE).<ref name="NIH2019">{{cite web|title=Deep Vein Thrombosis|url=https://www.nhlbi.nih.gov/health-topics/venous-thromboembolism|website=NHLBI, NIH|access-date=28 December 2019|language=en}}</ref> DVT is a [[blood clot]] in a [[deep vein]], most commonly in the [[leg]]s, while PE occurs when a clot breaks free and blocks an [[pulmonary artery|artery]] in the [[lung]]s.<ref name="NIH2019" /> VTE is a rare but potentially fatal [[cardiovascular event]].<ref name="NIH2019" /> [[Estrogen (medication)|Estrogen]]s and progestogens can increase [[coagulation]] by modulating [[biosynthesis|synthesis]] of [[coagulation factor]]s.<ref name="pmid16112947t" /><ref name="pmid23384742">{{cite journal | vauthors = Sitruk-Ware R, Nath A | title = Characteristics and metabolic effects of estrogen and progestins contained in oral contraceptive pills | journal = Best Practice & Research. Clinical Endocrinology & Metabolism | volume = 27 | issue = 1 | pages = 13–24 | date = February 2013 | pmid = 23384742 | doi = 10.1016/j.beem.2012.09.004 }}</ref><ref name="pmid27793376">{{cite journal | title = Combined hormonal contraception and the risk of venous thromboembolism: a guideline | journal = Fertility and Sterility | volume = 107 | issue = 1 | pages = 43–51 | date = January 2017 | pmid = 27793376 | doi = 10.1016/j.fertnstert.2016.09.027 | doi-access = free | last1 = Pfeifer | first1 = Samantha | last2 = Butts | first2 = Samantha | last3 = Dumesic | first3 = Daniel | last4 = Fossum | first4 = Gregory | last5 = Gracia | first5 = Clarisa | last6 = La Barbera | first6 = Andrew | last7 = Mersereau | first7 = Jennifer | last8 = Odem | first8 = Randall | last9 = Penzias | first9 = Alan | last10 = Pisarska | first10 = Margareta | last11 = Rebar | first11 = Robert | last12 = Reindollar | first12 = Richard | last13 = Rosen | first13 = Mitchell | last14 = Sandlow | first14 = Jay | last15 = Sokol | first15 = Rebecca | last16 = Vernon | first16 = Michael | last17 = Widra | first17 = Eric }}</ref><ref name="pmid30447140">{{cite journal | vauthors = Skouby SO, Sidelmann JJ | title = Impact of progestogens on hemostasis | journal = Hormone Molecular Biology and Clinical Investigation | volume = 37 | issue = 2 | date = November 2018 | pmid = 30447140 | doi = 10.1515/hmbci-2018-0041 | s2cid = 53875910 }}</ref> As a result, they increase the risk of VTE, especially during [[pregnancy]] when estrogen and progesterone levels are very high as well as during the [[postpartum]] period.<ref name="pmid23384742" /><ref name="pmid27793376" /><ref name="pmid23633191">{{cite journal | vauthors = Barco S, Nijkeuter M, Middeldorp S | title = Pregnancy and venous thromboembolism | journal = Seminars in Thrombosis and Hemostasis | volume = 39 | issue = 5 | pages = 549–558 | date = July 2013 | pmid = 23633191 | doi = 10.1055/s-0033-1343893 | s2cid = 5521763 }}</ref> [[Physiological]] levels of estrogen and/or progesterone may also influence risk of VTE—with late [[menopause]] (≥55 years) being associated with greater risk than early menopause (≤45 years).<ref name="pmid16409454">{{cite journal | vauthors = Simon T, Beau Yon de Jonage-Canonico M, Oger E, Wahl D, Conard J, Meyer G, Emmerich J, Barrellier MT, Guiraud A, Scarabin PY
====Progestogen monotherapy====
Progestogens when used by themselves at typical clinical dosages, for instance in [[progestogen-only birth control]], do not affect coagulation<ref name="pmid21538049" /><ref name="pmid14670643" /><ref name="pmid17056444" /><ref name="pmid8794429">{{cite journal | vauthors = Kuhl H | title = Effects of progestogens on haemostasis | journal = Maturitas | volume = 24 | issue = 1–2 | pages = 1–19 | date = May 1996 | pmid = 8794429 | doi = 10.1016/0378-5122(96)00994-2 }}</ref><ref name="pmid23384742" /><ref name="pmid30447140" /> and are not generally associated with a higher risk of [[venous thromboembolism]] (VTE).<ref name="pmid27153743">{{cite journal | vauthors = Tepper NK, Whiteman MK, Marchbanks PA, James AH, Curtis KM | title = Progestin-only contraception and thromboembolism: A systematic review | journal = Contraception | volume = 94 | issue = 6 | pages = 678–700 | date = December 2016 | pmid = 27153743 | doi = 10.1016/j.contraception.2016.04.014 | pmc = 11034842 }}</ref><ref name="pmid22872710">{{cite journal | vauthors = Mantha S, Karp R, Raghavan V, Terrin N, Bauer KA, Zwicker JI | title = Assessing the risk of venous thromboembolic events in women taking progestin-only contraception: a meta-analysis | journal = BMJ | volume = 345 | pages = e4944 | date = August 2012 | pmid = 22872710 | pmc = 3413580 | doi = 10.1136/bmj.e4944 }}</ref><ref name="pmid22425318">{{cite journal | vauthors = Blanco-Molina MA, Lozano M, Cano A, Cristobal I, Pallardo LP, Lete I | title = Progestin-only contraception and venous thromboembolism | journal = Thrombosis Research | volume = 129 | issue = 5 | pages = e257–e262 | date = May 2012 | pmid = 22425318 | doi = 10.1016/j.thromres.2012.02.042 | s2cid = 261804433 }}</ref><ref name="pmid30669160">{{cite journal | vauthors = Rott H | title = Birth Control Pills and Thrombotic Risks: Differences of Contraception Methods with and without Estrogen | journal = Hamostaseologie | volume = 39 | issue = 1 | pages = 42–48 | date = February 2019 | pmid = 30669160 | doi = 10.1055/s-0039-1677806 | s2cid = 58947063 }}</ref> An exception is medroxyprogesterone acetate as a [[progestogen-only injectable contraceptive]], which has been associated with a 2- to 4-fold increase in risk of VTE relative to other progestogens and non-use.<ref name="pmid30008249">{{cite journal | vauthors = Beyer-Westendorf J, Bauersachs R, Hach-Wunderle V, Zotz RB, Rott H | title = Sex hormones and venous thromboembolism - from contraception to hormone replacement therapy | journal = VASA. Zeitschrift für Gefässkrankheiten | volume = 47 | issue = 6 | pages = 441–450 | date = October 2018 | pmid = 30008249 | doi = 10.1024/0301-1526/a000726 | s2cid = 51628832 }}</ref><ref name="pmid21559819">{{cite journal | vauthors = DeLoughery TG | title = Estrogen and thrombosis: controversies and common sense | journal = Reviews in Endocrine & Metabolic Disorders | volume = 12 | issue = 2 | pages = 77–84 | date = June 2011 | pmid = 21559819 | doi = 10.1007/s11154-011-9178-0 | s2cid = 28053690 }}</ref><ref name="ManthaKarp2012">{{cite journal | vauthors = Mantha S, Karp R, Raghavan V, Terrin N, Bauer KA, Zwicker JI | title = Assessing the risk of venous thromboembolic events in women taking progestin-only contraception: a meta-analysis | journal = BMJ | volume = 345 | issue = aug07 2 | pages = e4944 | date = August 2012 | pmid = 22872710 | pmc = 3413580 | doi = 10.1136/bmj.e4944 }}</ref><ref name="pmid29570359" /><ref name="pmid30741807">{{cite journal | vauthors = Tepper NK, Jeng G, Curtis KM, Boutot ME, Boulet SL, Whiteman MK | title = Venous Thromboembolism Among Women Initiating Depot Medroxyprogesterone Acetate Immediately Postpartum | journal = Obstetrics and Gynecology | volume = 133 | issue = 3 | pages = 533–540 | date = March 2019 | pmid = 30741807 | doi = 10.1097/AOG.0000000000003135 | doi-access = free | pmc = 10983016 }}</ref><ref name="pmid23078975">{{cite journal | vauthors = Gourdy P, Bachelot A, Catteau-Jonard S, Chabbert-Buffet N, Christin-Maître S, Conard J, Fredenrich A, Gompel A, Lamiche-Lorenzini F, Moreau C, Plu-Bureau G, Vambergue A, Vergès B, Kerlan V
Very-high-dose progestogen therapy, including with medroxyprogesterone acetate, [[megestrol acetate]], and [[cyproterone acetate]], has been associated with activation of coagulation and a dose-dependent increased risk of VTE.<ref name="pmid14670643">{{cite journal | vauthors = Schindler AE | title = Differential effects of progestins on hemostasis | journal = Maturitas | volume = 46 | issue = Suppl 1 | pages = S31–7 | date = December 2003 | pmid = 14670643 | doi = 10.1016/j.maturitas.2003.09.016 }}</ref><ref name="pmid22425318" /><ref name="pmid20433997">{{cite journal | vauthors = Beyer-Westendorf J, Werth S, Halbritter K, Weiss N | title = Cancer in males and risk of venous thromboembolism | journal = Thromb. Res. | volume = 125 | issue = Suppl 2 | pages = S155–9 | date = April 2010 | pmid = 20433997 | doi = 10.1016/S0049-3848(10)70035-9 }}</ref><ref name="pmid19161930">{{cite journal | vauthors = Guay DR | title = Inappropriate sexual behaviors in cognitively impaired older individuals | journal = Am J Geriatr Pharmacother | volume = 6 | issue = 5 | pages = 269–88 | date = December 2008 | pmid = 19161930 | doi = 10.1016/j.amjopharm.2008.12.004 }}</ref><ref name="pmid17537215">{{cite journal | vauthors = Seaman HE, Langley SE, Farmer RD, de Vries CS | title = Venous thromboembolism and cyproterone acetate in men with prostate cancer: a study using the General Practice Research Database | journal = BJU Int. | volume = 99 | issue = 6 | pages = 1398–403 | date = June 2007 | pmid = 17537215 | doi = 10.1111/j.1464-410X.2007.06859.x | s2cid = 21350686 | doi-access = free }}</ref><ref name="pmid20395174">{{cite journal | vauthors = Van Hemelrijck M, Adolfsson J, Garmo H, Bill-Axelson A, Bratt O, Ingelsson E, Lambe M, Stattin P, Holmberg L | title = Risk of thromboembolic diseases in men with prostate cancer: results from the population-based PCBaSe Sweden | journal = Lancet Oncol. | volume = 11 | issue = 5 | pages = 450–8 | date = May 2010 | pmid = 20395174 | pmc = 2861771 | doi = 10.1016/S1470-2045(10)70038-3 }}</ref> In studies with high-dose cyproterone acetate specifically, the increase in VTE risk has ranged from 3- to 5-fold.<ref name="pmid20433997" /><ref name="pmid17537215" /><ref name="pmid20395174"/> The incidence of VTE in studies with very-high-dose progestogen therapy has been found to range from 2 to 8%.<ref name="pmid14670643" /><ref name="SchröderRadlmaier2009">{{cite book | vauthors = Schröder FH, Radlmaier A | chapter = Steroidal Antiandrogens | pages = 325–346 | doi = 10.1007/978-1-59259-152-7_15 | title = Hormone Therapy in Breast and Prostate Cancer | veditors = Jordan VC, Furr BJ | year = 2009 | publisher = Humana Press | isbn = 978-1-60761-471-5}}</ref><ref name="pmid2462132">{{cite journal | vauthors = Namer M | title = Clinical applications of antiandrogens | journal = J. Steroid Biochem. | volume = 31 | issue = 4B | pages = 719–29 | date = October 1988 | pmid = 2462132 | doi = 10.1016/0022-4731(88)90023-4 }}</ref> However, the relevant patient populations, namely aged individuals with [[cancer]], are already predisposed to VTE, and this greatly amplifies the risk.<ref name="pmid14670643" /><ref name="pmid22425318" /><ref name="pmid23944849">{{cite journal | vauthors = Asscheman H, T'Sjoen G, Lemaire A, Mas M, Meriggiola MC, Mueller A, Kuhn A, Dhejne C, Morel-Journel N, Gooren LJ | title = Venous thrombo-embolism as a complication of cross-sex hormone treatment of male-to-female transsexual subjects: a review | journal = Andrologia | volume = 46 | issue = 7 | pages = 791–5 | date = September 2014 | pmid = 23944849 | doi = 10.1111/and.12150 | hdl = 11585/413984 | s2cid = 5363824 | doi-access = free }}</ref>
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In contrast to progestogen-only birth control, the addition of progestins to [[oral administration|oral]] [[estrogen (medication)|estrogen]] therapy, including in [[combined birth control pill]]s and [[menopausal hormone therapy]], is associated with a higher risk of VTE than with oral estrogen therapy alone.<ref name="pmid29936403">{{cite journal | vauthors = Rovinski D, Ramos RB, Fighera TM, Casanova GK, Spritzer PM | title = Risk of venous thromboembolism events in postmenopausal women using oral versus non-oral hormone therapy: A systematic review and meta-analysis | journal = Thromb. Res. | volume = 168 | pages = 83–95 | date = August 2018 | pmid = 29936403 | doi = 10.1016/j.thromres.2018.06.014 | s2cid = 49421543 }}</ref><ref name="pmid26598309">{{cite journal | vauthors = Han L, Jensen JT | title = Does the Progestogen Used in Combined Hormonal Contraception Affect Venous Thrombosis Risk? | journal = Obstet. Gynecol. Clin. North Am. | volume = 42 | issue = 4 | pages = 683–98 | date = December 2015 | pmid = 26598309 | doi = 10.1016/j.ogc.2015.07.007 | doi-access = free }}</ref><ref name="pmid27051991">{{cite journal | vauthors = Bateson D, Butcher BE, Donovan C, Farrell L, Kovacs G, Mezzini T, Raynes-Greenow C, Pecoraro G, Read C, Baber R | title = Risk of venous thromboembolism in women taking the combined oral contraceptive: A systematic review and meta-analysis | journal = Aust Fam Physician | volume = 45 | issue = 1 | pages = 59–64 | date = 2016 | pmid = 27051991 | url = https://www.racgp.org.au/afp/2016/januaryfebruary/risk-of-venous-thromboembolism-in-women-taking-the-combined-oral-contraceptive-a-systematic-review-and-meta-analysis/}}</ref><ref name="pmid30626577" /><ref name="pmid26013557">{{cite journal | vauthors = Vinogradova Y, Coupland C, Hippisley-Cox J | title = Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases | journal = BMJ | volume = 350 | pages = h2135 | date = May 2015 | pmid = 26013557 | pmc = 4444976 | doi = 10.1136/bmj.h2135 }}</ref> The risk of VTE is increased by about 2-fold or less with such regimens in menopausal hormone therapy and by 2- to 4-fold with combined birth control pills containing [[ethinylestradiol]], both relative to non-use.<ref name="pmid29936403" /><ref name="pmid27793376" /><ref name="pmid30626577" /><ref name="pmid26013557" /> In contrast to oral estrogen therapy, [[parenteral]] estradiol, such as with [[transdermal administration|transdermal]] [[estradiol (medication)|estradiol]], is not associated with a higher risk of VTE.<ref name="pmid29936403" /><ref name="pmid29570359" /><ref name="pmid30626577" /> This is likely due to its lack of [[first-pass effect]] in the [[liver]].<ref name="pmid16112947t" /><ref name="pmid30008249" /> Research is mixed on whether addition of progestins to transdermal estradiol is associated with a greater risk of VTE, with some studies finding no increase in risk and others finding higher risk.<ref name="pmid29936403" /><ref name="pmid29570359"/><ref name="pmid30626577">{{cite journal | vauthors = Vinogradova Y, Coupland C, Hippisley-Cox J | title = Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases | journal = BMJ | volume = 364 | pages = k4810 | date = January 2019 | pmid = 30626577 | pmc = 6326068 | doi = 10.1136/bmj.k4810 }}</ref> Unlike the case of transdermal estradiol, VTE risk is not lower with ethinylestradiol-containing [[contraceptive vaginal ring]]s and [[contraceptive patch]]es compared to combined birth control pills with ethinylestradiol.<ref name="pmid27793376" /><ref name="pmid23384743">{{cite journal | vauthors = Plu-Bureau G, Maitrot-Mantelet L, Hugon-Rodin J, Canonico M | title = Hormonal contraceptives and venous thromboembolism: an epidemiological update | journal = Best Pract. Res. Clin. Endocrinol. Metab. | volume = 27 | issue = 1 | pages = 25–34 | date = February 2013 | pmid = 23384743 | doi = 10.1016/j.beem.2012.11.002 }}</ref><ref name="pmid21538049"/> This is thought to be due to the resistance of ethinylestradiol to [[liver|hepatic]] [[metabolism]].<ref name="pmid16112947t" /><ref name="pmid31465627">{{cite journal | vauthors = Connors JM, Middeldorp S | title = Transgender patients and the role of the coagulation clinician | journal = J. Thromb. Haemost. | volume = 17 | issue = 11 | pages = 1790–1797 | date = November 2019 | pmid = 31465627 | doi = 10.1111/jth.14626 | s2cid = 201673648 }}</ref><ref name="pmid30008249" /><ref name="pmid21538049" />
The type of progestin in combined birth control may modulate the risk of VTE.<ref name="pmid26598309" /><ref name="pmid27051991" /><ref name="pmid23078975" /> Studies have found that combined birth control pills containing [[third-generation progestin|newer-generation progestin]]s such as [[desogestrel]], [[gestodene]], [[norgestimate]], [[drospirenone]], and [[cyproterone acetate]] are associated with a 1.5- to 3-fold higher risk of VTE than birth control pills containing [[first-generation progestin]]s such as [[levonorgestrel]] and [[norethisterone]].<ref name="pmid26598309" /><ref name="pmid27051991" /><ref name="pmid26013557" /><ref name="pmid23078975" /><ref name="pmid29573722">{{cite journal | vauthors = Oedingen C, Scholz S, Razum O | title = Systematic review and meta-analysis of the association of combined oral contraceptives on the risk of venous thromboembolism: The role of the progestogen type and estrogen dose | journal = Thromb. Res. | volume = 165 | pages = 68–78 | date = May 2018 | pmid = 29573722 | doi = 10.1016/j.thromres.2018.03.005 }}</ref><ref name="pmid29388678">{{cite journal | vauthors = Dragoman MV, Tepper NK, Fu R, Curtis KM, Chou R, Gaffield ME | title = A systematic review and meta-analysis of venous thrombosis risk among users of combined oral contraception | journal = Int J Gynaecol Obstet | volume = 141 | issue = 3 | pages = 287–294 | date = June 2018 | pmid = 29388678 | pmc = 5969307 | doi = 10.1002/ijgo.12455 }}</ref> However, although this has been apparent in [[retrospective cohort study|retrospective cohort]] and [[nested case control study|nested case–control studies]], no greater risk of VTE has been observed in [[prospective cohort study|prospective cohort]] and [[case–control study|case–control studies]].<ref name="pmid26598309" /><ref name="pmid27051991" /><ref name="pmid27854556">{{cite journal | vauthors = Batur P, Casey PM | title = Drospirenone Litigation: Does the Punishment Fit the Crime? | journal = J Womens Health (Larchmt) | volume = 26 | issue = 2 | pages = 99–102 | date = February 2017 | pmid = 27854556 | doi = 10.1089/jwh.2016.6092 | doi-access = free }}</ref><ref name="pmid27678035" /><ref name="pmid26013557" /> These kinds of [[observational study|observational studies]] have certain advantages over the aforementioned types of studies, such as better ability to control for [[confounding factor]]s like new-user bias.<ref name="pmid27678035">{{cite journal | vauthors = Sitruk-Ware R | title = Hormonal contraception and thrombosis | journal = Fertil. Steril. | volume = 106 | issue = 6 | pages = 1289–1294 | date = November 2016 | pmid = 27678035 | doi = 10.1016/j.fertnstert.2016.08.039 | doi-access = free }}</ref><ref name="pmid21538049" /> As such, it is unclear whether the higher risk of VTE with newer-generation birth control pills is a real finding or a statistical artifact.<ref name="pmid27678035" /> Androgenic progestins have been found to [[receptor antagonist|antagonize]] to some degree the effect of estrogens on coagulation.<ref name="pmid17056444" /><ref name="pmid8794429" /><ref name="pmid23384742" /><ref name="pmid26512437">{{cite journal | vauthors = Nelson AL | title = An update on new orally administered contraceptives for women | journal = Expert Opin Pharmacother | volume = 16 | issue = 18 | pages = 2759–72 | date = 2015 | pmid = 26512437 | doi = 10.1517/14656566.2015.1100173 | s2cid = 207481206 }}</ref><ref name="pmid21538049" /> First-generation progestins are more androgenic, while newer-generation progestins are weakly androgenic or antiandrogenic, and this might explain the observed differences in risk of VTE.<ref name="pmid26598309" /><ref name="pmid28712325">{{cite journal | vauthors = Farris M, Bastianelli C, Rosato E, Brosens I, Benagiano G | title = Pharmacodynamics of combined estrogen-progestin oral contraceptives: 2. effects on hemostasis | journal = Expert Rev Clin Pharmacol | volume = 10 | issue = 10 | pages = 1129–1144 | date = October 2017 | pmid = 28712325 | doi = 10.1080/17512433.2017.1356718 | s2cid = 205931204 }}</ref><ref name="pmid23384742" /><ref name="pmid26512437" /> The type of estrogen also influences VTE risk.<ref name="pmid31465627" /><ref name="pmid30519125">{{cite journal | vauthors = Fruzzetti F, Cagnacci A | title = Venous thrombosis and hormonal contraception: what's new with estradiol-based hormonal contraceptives? | journal = Open Access J Contracept | volume = 9 | pages = 75–79 | date = 2018 | pmid = 30519125 | pmc = 6239102 | doi = 10.2147/OAJC.S179673 | doi-access = free }}</ref><ref name="pmid28902531" /> Birth control pills containing [[estradiol valerate]] are associated with about half the VTE risk of birth control pills with ethinylestradiol.<ref name="pmid30519125" /><ref name="pmid28902531">{{cite journal | vauthors = Grandi G, Facchinetti F, Bitzer J | title = Estradiol in hormonal contraception: real evolution or just same old wine in a new bottle? | journal = Eur J Contracept Reprod Health Care | volume = 22 | issue = 4 | pages = 245–246 | date = August 2017 | pmid = 28902531 | doi = 10.1080/13625187.2017.1372571 | doi-access = free | hdl = 11380/1153791 | hdl-access = free }}</ref>
The type of progestogen in combined menopausal hormone therapy may also modulate VTE risk.<ref name="pmid23238854" /><ref name="pmid22024394">{{cite journal | vauthors = Canonico M, Plu-Bureau G, Scarabin PY | title = Progestogens and venous thromboembolism among postmenopausal women using hormone therapy | journal = Maturitas | volume = 70 | issue = 4 | pages = 354–60 | date = December 2011 | pmid = 22024394 | doi = 10.1016/j.maturitas.2011.10.002 | url = https://www.hal.inserm.fr/inserm-01148705/file/Canonico_Maturitas_2011.pdf}}</ref> Oral estrogens plus [[dydrogesterone]] appears to have lower VTE risk relative to inclusion of other progestins.<ref name="pmid23835005">{{cite journal | vauthors = Stevenson JC, Panay N, Pexman-Fieth C | title = Oral estradiol and dydrogesterone combination therapy in postmenopausal women: review of efficacy and safety | journal = Maturitas | volume = 76 | issue = 1 | pages = 10–21 | date = September 2013 | pmid = 23835005 | doi = 10.1016/j.maturitas.2013.05.018 | quote = Dydrogesterone did not increase the risk of VTE associated with oral estrogen (odds ratio (OR) 0.9, 95% CI 0.4–2.3). Other progestogens (OR 3.9, 95% CI 1.5–10.0) were found to further increase the risk of VTE associated with oral estrogen (OR 4.2, 95% CI 1.5–11.6).}}</ref><ref name="pmid19565370">{{cite journal | vauthors = Schneider C, Jick SS, Meier CR | title = Risk of cardiovascular outcomes in users of estradiol/dydrogesterone or other HRT preparations | journal = Climacteric | volume = 12 | issue = 5 | pages = 445–53 | date = October 2009 | pmid = 19565370 | doi = 10.1080/13697130902780853 | s2cid = 45890629 }}</ref><ref name="pmid30626577" /> [[Norpregnane]] derivatives such as [[nomegestrol acetate]] and [[promegestone]] have been associated with a significantly greater risk of VTE than [[pregnane]] derivatives such as [[medroxyprogesterone acetate]] and dydrogesterone and [[nortestosterone]] derivatives such as [[norethisterone]] and [[levonorgestrel]].<ref name="pmid23238854" /><ref name="pmid22024394" /> However, these findings may just be statistical artifacts.<ref name="pmid22024394" /> In contrast to progestins, the addition of oral [[progesterone (medication)|progesterone]] to either oral or transdermal estrogen therapy is not associated with a higher risk of VTE.<ref name="pmid29570359" /><ref name="pmid29526116" /> However, oral progesterone achieves very low progesterone levels and has relatively weak progestogenic effects, which might be responsible for the absence of increase in VTE risk.<ref name="pmid29526116" /> Parenteral progesterone, such as [[vaginal administration|vaginal]] or [[injection (medicine)|injectable]] progesterone, which can achieve [[luteal phase|luteal-phase]] levels of progesterone and associated progestogenic effects, has not been characterized in terms of VTE risk.<ref name="pmid29526116" />
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Estrogens induce the production of [[sex hormone-binding globulin]] (SHBG) in the liver.<ref name="pmid16112947t" /><ref name="pmid21538049" /> As such, SHBG levels indicate hepatic estrogenic exposure and may be a reliable [[surrogate marker]] for coagulation and VTE risk with estrogen therapy.<ref name="pmid12047300">{{cite journal | vauthors = Odlind V, Milsom I, Persson I, Victor A | title = Can changes in sex hormone binding globulin predict the risk of venous thromboembolism with combined oral contraceptive pills? | journal = Acta Obstet Gynecol Scand | volume = 81 | issue = 6 | pages = 482–90 | date = June 2002 | pmid = 12047300 | doi = 10.1034/j.1600-0412.2002.810603.x| s2cid = 26054257 | doi-access = free }}</ref><ref name="pmid22469296">{{cite journal | vauthors = Raps M, Helmerhorst F, Fleischer K, Thomassen S, Rosendaal F, Rosing J, Ballieux B, VAN Vliet H | title = Sex hormone-binding globulin as a marker for the thrombotic risk of hormonal contraceptives | journal = J. Thromb. Haemost. | volume = 10 | issue = 6 | pages = 992–7 | date = June 2012 | pmid = 22469296 | doi = 10.1111/j.1538-7836.2012.04720.x | s2cid = 20803995 | doi-access = free }}</ref><ref name="Christin-Maitre2016">{{cite journal| vauthors = Christin-Maitre S |title=Risque cardiovasculaire de la contraception hormonale chez la femme|trans-title=Cardiovacular risk of hormonal contraception in women|journal=Bulletin de l'Académie Nationale de Médecine|volume=200|issue=7|year=2016|pages=1485–1496|issn=0001-4079|doi=10.1016/S0001-4079(19)30619-3|doi-access=free}}</ref> Combined birth control pills containing different progestins result in SHBG levels that are increased 1.5- to 2-fold with levonorgestrel, 2.5- to 4-fold with desogestrel and gestodene, 3.5- to 4-fold with drospirenone and [[dienogest]], and 4- to 5-fold with cyproterone acetate.<ref name="pmid12047300" /> SHBG levels differ depending on the progestin because androgenic progestins oppose the effect of ethinylestradiol on hepatic SHBG production as with its procoagulatory effects.<ref name="pmid16112947t" /><ref name="pmid21538049" /> [[Contraceptive vaginal ring]]s and [[contraceptive patch]]es likewise have been found to increase SHBG levels by 2.5-fold and 3.5-fold, respectively.<ref name="pmid12047300" /><ref name="pmid21538049" /> Birth control pills containing high doses of ethinylestradiol (>50 μg) can increase SHBG levels by 5- to 10-fold, which is similar to the increase that occurs during pregnancy.<ref name="WintersHuhtaniemi2017">{{cite book|author1=Stephen J. Winters|author2=Ilpo T. Huhtaniemi|title=Male Hypogonadism: Basic, Clinical and Therapeutic Principles|url=https://books.google.com/books?id=UFi-DgAAQBAJ&pg=PA307|date=25 April 2017|publisher=Humana Press|isbn=978-3-319-53298-1|pages=307–}}</ref> Conversely, increases in SHBG levels are much lower with estradiol, especially when it is used parenterally.<ref name="pmid16915215">{{cite journal | vauthors = Notelovitz M | title = Clinical opinion: the biologic and pharmacologic principles of estrogen therapy for symptomatic menopause | journal = MedGenMed | volume = 8 | issue = 1 | page = 85 | date = March 2006 | pmid = 16915215 | pmc = 1682006 }}</ref><ref name="pmid22011208">{{cite journal | vauthors = Goodman MP | title = Are all estrogens created equal? A review of oral vs. transdermal therapy | journal = J Womens Health (Larchmt) | volume = 21 | issue = 2 | pages = 161–9 | date = February 2012 | pmid = 22011208 | doi = 10.1089/jwh.2011.2839 }}</ref><ref name="pmid3242384">{{cite journal | vauthors = Stege R, Carlström K, Collste L, Eriksson A, Henriksson P, Pousette A | title = Single drug polyestradiol phosphate therapy in prostatic cancer | journal = Am. J. Clin. Oncol. | volume = 11 | issue = Suppl 2 | pages = S101–3 | year = 1988 | pmid = 3242384 | doi = 10.1097/00000421-198801102-00024 | s2cid = 32650111 }}</ref><ref name="pmid2664738">{{cite journal | vauthors = von Schoultz B, Carlström K, Collste L, Eriksson A, Henriksson P, Pousette A, Stege R | title = Estrogen therapy and liver function--metabolic effects of oral and parenteral administration | journal = Prostate | volume = 14 | issue = 4 | pages = 389–95 | year = 1989 | pmid = 2664738 | doi = 10.1002/pros.2990140410 | s2cid = 21510744 }}</ref><ref name="pmid3817605">{{cite journal | vauthors = Ottosson UB, Carlström K, Johansson BG, von Schoultz B | title = Estrogen induction of liver proteins and high-density lipoprotein cholesterol: comparison between estradiol valerate and ethinyl estradiol | journal = Gynecol. Obstet. Invest. | volume = 22 | issue = 4 | pages = 198–205 | date = 1986 | pmid = 3817605 | doi = 10.1159/000298914 }}</ref> [[Estradiol-containing combined birth control pill]]s, like [[estradiol valerate/dienogest]] and [[estradiol/nomegestrol acetate]], and high-dose parenteral [[polyestradiol phosphate]] therapy have both been found to increase SHBG levels by about 1.5-fold.<ref name="pmid21538049" /><ref name="pmid22468839">{{cite journal | vauthors = Fruzzetti F, Trémollieres F, Bitzer J | title = An overview of the development of combined oral contraceptives containing estradiol: focus on estradiol valerate/dienogest | journal = Gynecol. Endocrinol. | volume = 28 | issue = 5 | pages = 400–8 | date = May 2012 | pmid = 22468839 | pmc = 3399636 | doi = 10.3109/09513590.2012.662547 }}</ref><ref name="pmid2664738" /><ref name="pmid3242384" />
[[Transgender hormone therapy (male-to-female)|Hormone therapy]] with high-dose ethinylestradiol and cyproterone acetate in [[transgender women]] has been associated with a 20- to 45-fold higher risk of VTE relative to non-use.<ref name="pmid23944849"/><ref name="pmid31372078" /> The absolute incidence was about 6%.<ref name="pmid23944849" /><ref name="pmid31372078" /> Conversely, the risk of VTE in transgender women is much lower with oral or transdermal estradiol plus high-dose cyproterone acetate.<ref name="pmid23944849" /><ref name="pmid31372078" /> Ethinylestradiol is thought to have been primarily responsible for the VTE risk, but cyproterone acetate may have contributed as well.<ref name="pmid23944849" /> Ethinylestradiol is no longer used in transgender hormone therapy,<ref name="pmid27916515">{{cite journal | vauthors = Tangpricha V, den Heijer M | title = Oestrogen and anti-androgen therapy for transgender women | journal = The Lancet. Diabetes & Endocrinology | volume = 5 | issue = 4 | pages = 291–300 | date = April 2017 | pmid = 27916515 | pmc = 5366074 | doi = 10.1016/S2213-8587(16)30319-9 }}</ref><ref name="pmid28090436">{{cite journal | vauthors = Weinand JD, Safer JD | title = Hormone therapy in transgender adults is safe with provider supervision; A review of hormone therapy sequelae for transgender individuals | journal = Journal of Clinical & Translational Endocrinology | volume = 2 | issue = 2 | pages = 55–60 | date = June 2015 | pmid = 28090436 | pmc = 5226129 | doi = 10.1016/j.jcte.2015.02.003 }}</ref><ref name="PriceMcManus2019">{{cite journal| vauthors = Price S, McManus J, Barrett J |title=The transgender population: improving awareness for gynaecologists and their role in the provision of care|journal=The Obstetrician & Gynaecologist|volume=21|issue=1|year=2019|pages=11–20|issn=1467-2561|doi=10.1111/tog.12521|doi-access=free}}</ref> and doses of cyproterone acetate have been reduced.<ref name="AsschemanGooren1993">{{cite journal| vauthors = Asscheman H, Gooren LJ |title=Hormone Treatment in Transsexuals|journal=Journal of Psychology & Human Sexuality|volume=5|issue=4|year=1993|pages=39–54|issn=0890-7064|doi=10.1300/J056v05n04_03|s2cid=144580633 }}</ref><ref name="pmid29320642">{{cite journal | vauthors = Hembree WC, Cohen-Kettenis PT, Gooren L, Hannema SE, Meyer WJ, Murad MH, Rosenthal SM, Safer JD, Tangpricha V, T'Sjoen GG
{{Risk of venous thromboembolism with hormone therapy and birth control pills (QResearch/CPRD)}}
===Cardiovascular health===
Progestogens may influence the risk of [[cardiovascular disease]] in women.<ref name="pmid23238854" /> In the [[women's Health Initiative]] (WHI), the risk of [[coronary heart disease]] was greater with the combination of estrogen plus a progestin (specifically [[medroxyprogesterone acetate]]) than with estrogen alone.<ref name="pmid18348708">{{cite journal | vauthors = Prentice RL, Anderson GL | title = The women's health initiative: lessons learned | journal = Annual Review of Public Health | volume = 29 | pages = 131–150 | date = 2008 | pmid = 18348708 | doi = 10.1146/annurev.publhealth.29.020907.090947 | doi-access = free }}</ref><ref name="pmid25321418">{{cite journal | vauthors = Prentice RL | title = Postmenopausal hormone therapy and the risks of coronary heart disease, breast cancer, and stroke | journal = Seminars in Reproductive Medicine | volume = 32 | issue = 6 | pages = 419–425 | date = November 2014 | pmid = 25321418 | pmc = 4212810 | doi = 10.1055/s-0034-1384624 }}</ref><ref name="BassukManson2008">{{cite book| vauthors = Bassuk SS, Manson JE |title=Wiley Encyclopedia of Clinical Trials|chapter=Women's Health Initiative Hormone Therapy Trials|year=2008|pages=1–10 |doi=10.1002/9780471462422.eoct391|isbn=978-0-471-46242-2}}</ref> However, progestogens have varying activities and may differ in terms of cardiovascular risk.<ref name="pmid23238854">{{cite journal | vauthors = Stanczyk FZ, Hapgood JP, Winer S, Mishell DR | title = Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects | journal = Endocrine Reviews | volume = 34 | issue = 2 | pages = 171–208 | date = April 2013 | pmid = 23238854 | pmc = 3610676 | doi = 10.1210/er.2012-1008 }}</ref><ref name="pmid18521110">{{cite journal | vauthors = Hermsmeyer RK, Thompson TL, Pohost GM, Kaski JC | title = Cardiovascular effects of medroxyprogesterone acetate and progesterone: a case of mistaken identity? | journal = Nature Clinical Practice. Cardiovascular Medicine | volume = 5 | issue = 7 | pages = 387–395 | date = July 2008 | pmid = 18521110 | doi = 10.1038/ncpcardio1234 | s2cid = 39945411 }}</ref><ref name="pmid23647429">{{cite journal | vauthors = Sitruk-Ware R, El-Etr M | title = Progesterone and related progestins: potential new health benefits | journal = Climacteric | volume = 16 | pages = 69–78 | date = August 2013 | issue = Suppl 1 | pmid = 23647429 | doi = 10.3109/13697137.2013.802556 | s2cid = 25447915 }}</ref><ref name="pmid19811251">{{cite journal | vauthors = Nath A, Sitruk-Ware R | title = Different cardiovascular effects of progestins according to structure and activity | journal = Climacteric | volume = 12 | issue = Suppl 1 | pages = 96–101 | date = 2009 | pmid = 19811251 | doi = 10.1080/13697130902905757 | s2cid = 2987558 }}</ref><ref name="pmid16203650">{{cite journal | vauthors = Sitruk-Ware R | title = Pharmacology of different progestogens: the special case of drospirenone | journal = Climacteric | volume = 8 | issue = Suppl 3 | pages = 4–12 | date = October 2005 | pmid = 16203650 | doi = 10.1080/13697130500330382 | s2cid = 24205704 }}</ref><ref name="pmid15018245">{{cite journal | vauthors = Sitruk-Ware RL | title = Hormone therapy and the cardiovascular system: the critical role of progestins | journal = Climacteric | volume = 6 | issue = Suppl 3 | pages = 21–28 | date = October 2003 | pmid = 15018245 }}</ref> A 2015 Cochrane review provided strong evidence that the treatment of post-menopausal women with hormone therapy for cardiovascular disease had little if any effect and increased the risk of [[stroke]] and [[Venous thromboembolic disease|venous thromboembolic]] events.<ref>{{cite journal | vauthors = Boardman HM, Hartley L, Eisinga A, Main C, Roqué i Figuls M, Bonfill Cosp X, Gabriel Sanchez R, Knight B
:"Unfortunately, there are few long-term clinical studies comparing different progestogens used in [hormone therapy] with respect to cardiovascular outcomes. However, some aspects of potential cardiovascular risk have been examined, namely effects on lipids, vascular function/blood pressure, inflammation, thrombosis, and carbohydrate metabolism. [...] Although progestins have differing effects on aspects of cardiovascular risk, in general, those more similar to progesterone have been associated with a lower impact than the more androgenic progestins on the beneficial effects of concomitant estrogen therapy. However, the limited number of long-term clinical studies makes it difficult to extrapolate the short-term effects on various markers of cardiovascular risk to long-term cardiovascular morbidity."<ref name="pmid23238854" />
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====Antigonadotropic effects====
Progestogens, similarly to the androgens and estrogens through their own respective [[receptor (biochemistry)|
Progestogens have been found to maximally suppress circulating testosterone levels in men by up to 70 to 80% at sufficiently high doses.<ref name="WeinKavoussi2011">{{cite book| vauthors = Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA | title = Campbell-Walsh Urology: Expert Consult Premium Edition: Enhanced Online Features and Print, 4-Volume Set|url=https://books.google.com/books?id=fu3BBwAAQBAJ&pg=PA2938|date=25 August 2011|publisher=Elsevier Health Sciences|isbn=978-1-4160-6911-9|pages=2938–}}</ref><ref name="pmid519881">{{cite journal | vauthors = Kjeld JM, Puah CM, Kaufman B, Loizou S, Vlotides J, Gwee HM, Kahn F, Sood R, Joplin GF | title = Effects of norgestrel and ethinyloestradiol ingestion on serum levels of sex hormones and gonadotrophins in men | journal = Clinical Endocrinology | volume = 11 | issue = 5 | pages = 497–504 | year = 1979 | pmid = 519881 | doi = 10.1111/j.1365-2265.1979.tb03102.x| s2cid = 5836155 }}</ref> This is notably less than that achieved by [[GnRH analogue]]s, which can effectively abolish gonadal production of testosterone and suppress circulating testosterone levels by as much as 95%.<ref name="Urotext2001">{{cite book|author=Urotext|title=Urotext-Luts: Urology|url=https://books.google.com/books?id=6zjtA37qDsMC&pg=PA71|date=1 January 2001|publisher=Urotext|isbn=978-1-903737-03-3|pages=71–}}</ref> It is also less than that achieved by [[high-dose estrogen]] therapy, which can suppress testosterone levels into the castrate range similarly to GnRH analogues.<ref name="pmid7000222">{{cite journal | vauthors = Jacobi GH, Altwein JE, Kurth KH, Basting R, Hohenfellner R | title = Treatment of advanced prostatic cancer with parenteral cyproterone acetate: a phase III randomised trial | journal = Br J Urol | volume = 52 | issue = 3 | pages = 208–15 | year = 1980 | pmid = 7000222 | doi = 10.1111/j.1464-410x.1980.tb02961.x}}</ref>
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The first orally active progestin, [[ethisterone]] (pregneninolone, 17α-ethynyltestosterone), the C17α [[ethynyl]] [[structural analog|analogue]] of [[testosterone]], was [[organic synthesis|synthesized]] in 1938 from [[dehydroandrosterone]] by [[alkynylation|ethynylation]], either before or after [[oxidation of secondary alcohols to ketones|oxidation of the C3 hydroxyl group]], followed by [[rearrangement reaction|rearrangement]] of the C5(6) double bond to the C4(5) position. The synthesis was designed by chemists Hans Herloff Inhoffen, Willy Logemann, Walter Hohlweg and Arthur Serini at [[Schering AG]] in [[Berlin]] and was marketed in [[Germany]] in 1939 as ''Proluton C'' and by [[Schering-Plough|Schering]] in the [[United States|U.S.]] in 1945 as ''Pranone''.<ref name="Inhoffen 1938">{{cite journal |doi=10.1002/cber.19380710520 |vauthors=Inhoffen HH, Logemann W, Hohlweg W, Serini A |date=May 4, 1938 |title=Untersuchungen in der Sexualhormon-Reihe (Investigations in the sex hormone series) |journal=[[Chemische Berichte|Ber Dtsch Chem Ges]] |volume=71 |issue=5 |pages=1024–32|url=http://www3.interscience.wiley.com/cgi-bin/abstract/112367144/ABSTRACT|archive-url=https://archive.today/20121217214803/http://www3.interscience.wiley.com/cgi-bin/abstract/112367144/ABSTRACT|archive-date=December 17, 2012}}</ref><ref name="Maisel 1965">{{cite book |author=Maisel, Albert Q. |year=1965 |title=The Hormone Quest |url=https://archive.org/details/hormonequest00mais |url-access=registration |location=New York |publisher=Random House |oclc=543168}}</ref><ref name="Petrow 1970">{{cite journal |author=Petrow V |year=1970 |title=The contraceptive progestagens |journal=Chem Rev |volume=70 |issue=6 |pages=713–26 |pmid=4098492 |doi=10.1021/cr60268a004}}</ref><ref name="Sneader 2005">{{cite book |author=Sneader, Walter |year=2005 |title=Drug discovery: a history |location=Hoboken, NJ |publisher=John Wiley & Sons |isbn=978-0-471-89980-8 |chapter=Hormone analogues |pages=188–225}}</ref><ref name="Djerassi 2006">{{cite journal |author=Djerassi C |year=2006 |title=Chemical birth of the pill |journal=Am J Obstet Gynecol |volume=194 |issue=1 |pages=290–8 |pmid=16389046 |doi=10.1016/j.ajog.2005.06.010}}</ref>
A more potent orally active progestin, [[norethisterone]] (norethindrone, 19-nor-17α-ethynyltestosterone), the C19 [[nor-|nor]] analogue of ethisterone, synthesized in 1951 by [[Carl Djerassi]], [[Luis E. Miramontes|Luis Miramontes]], and [[George Rosenkranz]] at [[Syntex]] in [[Mexico City]], was marketed by [[Parke-Davis]] in the U.S. in 1957 as ''Norlutin'', and was used as the progestin in some of the [[combined oral contraceptive pill|first oral contraceptives]] (''Ortho-Novum'', ''Norinyl'', etc.) in the early 1960s.<ref name="Maisel 1965" /><ref name="Petrow 1970"/><ref name="Sneader 2005"/><ref name="Djerassi 2006"/><ref name="Djerassi 1954">{{cite journal |vauthors=Djerassi C, Miramontes L, Rosenkranz G, Sondheimer F |year=1954 |title=Steroids. LIV. Synthesis of 19-Nor-17α-ethynyltestosterone and 19-Nor-17α-methyltestosterone |journal=[[Journal of the American Chemical Society|J Am Chem Soc]] |volume=76 |issue=16 |pages=4089–91
[[Noretynodrel]], an [[isomer]] of norethisterone, was synthesized in 1952 by [[Frank B. Colton]] at [[G. D. Searle & Company|Searle]] in [[Skokie, Illinois]] and used as the progestin in ''Enovid'', marketed in the U.S. in 1957 and approved as the first oral contraceptive in 1960.<ref name="Maisel 1965"/><ref name="Petrow 1970"/><ref name="Sneader 2005"/><ref name="Djerassi 2006"/><ref name="Colton 1992">{{cite journal |author=Colton FB |year=1992 |title=Steroids and "the pill": early steroid research at Searle |journal=Steroids |volume=57 |issue=12 |pages=624–30 |pmid=1481226 |doi=10.1016/0039-128X(92)90015-2|s2cid=28718601}}</ref>
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