Progestogen (medication): Difference between revisions

| Caption = [[Progesterone (medication)|Progesterone]] (Prometrium, Utrogestan), the natural progestogen in the body and one of the most widely used progestogen medications.

| Synonyms = Progestagen;, Gestagen;gestagen, Gestogengestogen; Progestinprogestin (synthetic progestogen); Progesteroneprogesterone receptor agonist

| Biological_target = [[Progesterone receptor]]s ([[Progesterone receptor A|PR-A]], [[Progesterone receptor B|PR-B]], [[Progesterone receptor C|PR-C]]); [[Membranemembrane progesterone receptor]]s ([[mPRα]], [[mPRβ]], [[mPRγ]], [[mPRδ]], [[mPRε]]); [[Progesteroneprogesterone receptor membrane component]]s ([[PGRMC1]], [[PGRMC2]])

[[Side effect]]s of progestogens include [[irregular menstruation|menstrual irregularities]], [[headache]]s, [[nausea]], [[breast tenderness]], [[mood (psychology)|mood]] changes, [[acne]], [[hirsutism|increased hair growth]], and changes in [[liver protein production]] among others.<ref name="pmid16112947t" /><ref name="pmid15358281" /> Other side effects of progestogens may include an increased risk of [[breast cancer]], [[cardiovascular disease]], and [[blood clot]]s.<ref name="pmid15358281" /> At high doses, progestogens can cause [[hypogonadism|low sex hormone levels]] and associated side effects like [[sexual dysfunction]] and an [[osteoporosis|increased risk of bone fractures]].<ref name="pmid20459370">{{cite journal | vauthors = Thibaut F, De La Barra F, Gordon H, Cosyns P, Bradford JM | title = The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of paraphilias | journal = World J. Biol. Psychiatry | volume = 11 | issue = 4 | pages = 604–55 | year = 2010 | pmid = 20459370 | doi = 10.3109/15622971003671628 | s2cid = 14949511 | url = https://semanticscholar.org/paper/09ad815325dc2de07b38f237ada6b8b95faf8d45}}</ref>

Progestogens are [[agonist]]s of the [[progesterone receptor]]s (PRs) and produce '''progestogenic''', or '''progestational''', effects.<ref name="pmid16112947t" /> They have important effects in the [[female reproductive system]] ([[uterus]], [[cervix]], and [[vagina]]), the [[breast]]s, and the [[brain]].<ref name="pmid16112947t" /> In addition, many progestogens also have other hormonal activities, such as [[androgen]]ic, [[antiandrogen]]ic, [[estrogen (medication)|estrogen]]ic, [[glucocorticoid]], or [[antimineralocorticoid]] activity.<ref name="pmid16112947t" /> They also have [[antigonadotropic]] effects and at high doses can strongly suppress [[sex hormone]] production.<ref name="pmid16112947t" /> Progestogens mediate their contraceptive effects both by inhibiting [[ovulation]] and by thickening [[Cervix#Cervical mucus|cervical mucus]], thereby preventing [[fertilization]].<ref name="JamesonDeGroot2015">{{cite book | vauthors = Glasier A |author-link=Anna Glasier |date=March 20, 2015|chapter=Chapter 134. Contraception| veditors = Jameson JL, De Groot LJ, de Krester D, Giudice LC, Grossman A, Melmed S, Potts Jr JT, Weir GC |title=Endocrinology: Adult and Pediatric|edition=7th|location=Philadelphia|publisher=Saunders Elsevier|page=2306|isbn=978-0-323-18907-1}}</ref><ref name="PattmanNathan2010">{{cite book|title=Oxford Handbook of Genitourinary Medicine, HIV, and Sexual Health|date=November 19, 2010|publisher=Oxford University Press|isbn=978-0-19-957166-6| veditors = Pattman R, Sankar KN, Elewad B, Handy P, Price DA |edition=2nd|location=Oxford|page=360|chapter=Chapter 33. Contraception including contraception in HIV infection and infection reduction|quote=Ovulation may be suppressed in 15–40% of cycles by POPs containing levonorgestrel, norethisterone, or etynodiol diacetate, but in 97–99% by those containing desogestrel. |chapter-url=https://books.google.com/books?id=sTWXAwAAQBAJ&pg=PA353}}</ref> They have functional [[antiestrogen]]ic effects in certain tissues like the [[endometrium]], and this underlies their use in menopausal hormone therapy.<ref name="pmid16112947t" />

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&nbsp;progestins have been marketed for clinical use in humans or use in [[veterinary medicine]].<ref name="Micromedex">{{Citecite web | url=http://www.micromedexsolutions.com | title=IBM Watson Health Products: Please Login}}</ref><ref name="Martindale">{{cite book |editor=Sweetman, Sean C. |chapter=Sex hormones and their modulators |title=Martindale: The Complete Drug Reference |edition=36th |year=2009 |publisher=Pharmaceutical Press |location=London|isbn=978-0-85369-840-1|chapter-url=https://www.medicinescomplete.com/mc/martindale/}}</ref><ref name="Drugs.com">{{Citecite web | url=https://www.drugs.com/drug-class/progestins.html | title=List of Progestins}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1}}</ref><ref name="Elks2014">{{cite book|author=J. Elks|title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3}}</ref> These progestins can be grouped into different classes and generations.<ref name="pmid16112947t" /><ref name="GordonRydfors2007" /><ref name="Gibbs2008" /> Progestogens are available widely throughout the world and are used in all forms of hormonal birth control and in most menopausal hormone therapy regimens.<ref name="pmid16112947t" /><ref name="Micromedex" /><ref name="Martindale" /><ref name="IndexNominum2000" /><ref name="Drugs.com" />

Certain progestogens, including [[megestrol acetate]], medroxyprogesterone acetate, cyproterone acetate, and [[chlormadinone acetate]], have been used at high doses to reduce [[hot flash]]es in men undergoing [[androgen deprivation therapy]], for instance to treat [[prostate cancer]].<ref name="pmid18231613">{{cite journal | vauthors = Guise TA, Oefelein MG, Eastham JA, Cookson MS, Higano CS, Smith MR | title = Estrogenic side effects of androgen deprivation therapy | journal = Rev Urol | volume = 9 | issue = 4 | pages = 163–80 | year = 2007 | pmid = 18231613 | pmc = 2213888}}</ref><ref name="pmid19962840">{{cite journal | vauthors = Frisk J | title = Managing hot flushes in men after prostate cancer--a systematic review | journal = Maturitas | volume = 65 | issue = 1 | pages = 15–22 | year = 2010 | pmid = 19962840 | doi = 10.1016/j.maturitas.2009.10.017| doi-access = free }}</ref><ref name="pmid24223412">{{cite journal | vauthors = Koike H, Morikawa Y, Matsui H, Shibata Y, Ito K, Suzuki K | title = Chlormadinone acetate is effective for hot flush during androgen deprivation therapy | journal = Prostate Int | volume = 1 | issue = 3 | pages = 113–6 | year = 2013 | pmid = 24223412 | pmc = 3814123 | doi = 10.12954/PI.12010}}</ref>

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 | pmc-embargo-date = June 23, 2024 }}</ref><ref name="pmid29137347">{{cite journal | vauthors = Regidor PA, Schindler AE | title = Antiandrogenic and antimineralocorticoid health benefits of COC containing newer progestogens: dienogest and drospirenone | journal = Oncotarget | volume = 8 | issue = 47 | pages = 83334–83342 | date = October 2017 | pmid = 29137347 | pmc = 5669973 | doi = 10.18632/oncotarget.19833 }}</ref> Studies on the influence of hormonal birth control on mood in women with existing [[mood disorder]]s or [[polycystic ovary syndrome]] are limited and mixed.<ref name="pmid31172309" /><ref name="pmid27636867" /> Women with underlying mood disorders may be more likely to experience mood changes with hormonal birth control.<ref name="pmid27636867" /><ref name="pmid31172309" /><ref name="pmid31701260">{{cite journal | vauthors = Lewis CA, Kimmig AS, Zsido RG, Jank A, Derntl B, Sacher J | title = Effects of Hormonal Contraceptives on Mood: A Focus on Emotion Recognition and Reactivity, Reward Processing, and Stress Response | journal = Current Psychiatry Reports | volume = 21 | issue = 11 | pages = 115 | date = November 2019 | pmid = 31701260 | pmc = 6838021 | doi = 10.1007/s11920-019-1095-z }}</ref> A 2016 systematic review found based on limited evidence from 6&nbsp;studies that hormonal birth control, including combined birth control pills, depot medroxyprogesterone acetate, and levonorgestrel-containing intrauterine devices, was not associated with worse outcomes compared to non-use in women with [[depressive disorder|depressive]] or [[bipolar disorder]]s.<ref name="pmid27364100">{{cite journal | vauthors = Pagano HP, Zapata LB, Berry-Bibee EN, Nanda K, Curtis KM | title = Safety of hormonal contraception and intrauterine devices among women with depressive and bipolar disorders: a systematic review | journal = Contraception | volume = 94 | issue = 6 | pages = 641–649 | date = December 2016 | pmid = 27364100 | doi = 10.1016/j.contraception.2016.06.012 | pmc = 10994544 }}</ref> A 2008 [[Cochrane (organization)|Cochrane]] review found a greater likelihood of [[postpartum depression]] in women given [[norethisterone enanthate]] as a form of [[progestogen-only injectable birth control]], and recommended caution on the use of progestogen-only birth control in the [[postpartum]] period.<ref name="pmid18843619">{{cite journal | vauthors = Dennis CL, Ross LE, Herxheimer A | title = Oestrogens and progestins for preventing and treating postpartum depression | journal = The Cochrane Database of Systematic Reviews | volume = 2008 | issue = 4 | pages = CD001690 | date = October 2008 | pmid = 18843619 | pmc = 7061327 | doi = 10.1002/14651858.CD001690.pub2 }}</ref>

[[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&nbsp;years) being associated with greater risk than early menopause (≤45&nbsp;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 | display-authors = 6 | title = Indicators of lifetime endogenous estrogen exposure and risk of venous thromboembolism | journal = Journal of Thrombosis and Haemostasis | volume = 4 | issue = 1 | pages = 71–76 | date = January 2006 | pmid = 16409454 | doi = 10.1111/j.1538-7836.2005.01693.x | s2cid = 24161765 | doi-access = free }}</ref><ref name="pmid23760439">{{cite journal | vauthors = Canonico M, Plu-Bureau G, O'Sullivan MJ, Stefanick ML, Cochrane B, Scarabin PY, Manson JE | title = Age at menopause, reproductive history, and venous thromboembolism risk among postmenopausal women: the Women's Health Initiative Hormone Therapy clinical trials | journal = Menopause | volume = 21 | issue = 3 | pages = 214–220 | date = March 2014 | pmid = 23760439 | pmc = 3815514 | doi = 10.1097/GME.0b013e31829752e0 }}</ref>

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 GefasskrankheitenGefässkrankheiten | 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 | display-authors = 6 | title = Hormonal contraception in women at risk of vascular and metabolic disorders: guidelines of the French Society of Endocrinology | journal = Annales d'Endocrinologie | volume = 73 | issue = 5 | pages = 469–487 | date = November 2012 | pmid = 23078975 | doi = 10.1016/j.ando.2012.09.001 }}</ref><ref name="pmid30669160" /> The reasons for this are unknown, but the observations might be a [[statistical artifact]] of preferential prescription of depot medroxyprogesterone acetate to women at risk for VTE.<ref name="pmid21559819" /> Alternatively, medroxyprogesterone acetate may be an exception among progestogens in terms of influence on VTE risk,<ref name="pmid30669160"/><ref name="pmid29570359">{{cite journal | vauthors = Scarabin PY | title = Progestogens and venous thromboembolism in menopausal women: an updated oral versus transdermal estrogen meta-analysis | journal = Climacteric | volume = 21 | issue = 4 | pages = 341–345 | date = August 2018 | pmid = 29570359 | doi = 10.1080/13697137.2018.1446931 | s2cid = 4229701 }}</ref><ref name="pmid21538049">{{cite journal | vauthors = Sitruk-Ware R, Nath A | title = Metabolic effects of contraceptive steroids | journal = Reviews in Endocrine & Metabolic Disorders | volume = 12 | issue = 2 | pages = 63–75 | date = June 2011 | pmid = 21538049 | doi = 10.1007/s11154-011-9182-4 | s2cid = 23760705 }}</ref><ref name="pmid23078975" /> possibly due to its [[partial agonist|partial]] [[glucocorticoid]] activity.<ref name="pmid16112947t" /><ref name="Kuhl2011t" /><ref name="pmid21538049" /> In contrast to depot medroxyprogesterone acetate, no increase in VTE risk has been observed with moderately high doses of the related progestin [[chlormadinone acetate]] (10&nbsp;mg/day for 18–20&nbsp;days/cycle), though based on limited data.<ref name="pmid23078975" /><ref name="pmid15541404">{{cite journal | vauthors = Conard J, Plu-Bureau G, Bahi N, Horellou MH, Pelissier C, Thalabard JC | title = Progestogen-only contraception in women at high risk of venous thromboembolism | journal = Contraception | volume = 70 | issue = 6 | pages = 437–441 | date = December 2004 | pmid = 15541404 | doi = 10.1016/j.contraception.2004.07.009 }}</ref>

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>

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&nbsp;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 | display-authors = 6 | title = Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline | journal = Endocrine Practice | volume = 23 | issue = 12 | pages = 1437 | date = December 2017 | pmid = 29320642 | doi = 10.4158/1934-2403-23.12.1437 | s2cid = 3639218 }}</ref>

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 | display-authors = 6 | title = Hormone therapy for preventing cardiovascular disease in post-menopausal women | journal = The Cochrane Database of Systematic Reviews | volume = 2015 | issue = 3 | pages = CD002229 | date = March 2015 | pmid = 25754617 | doi = 10.1002/14651858.CD002229.pub4 | pmc = 10183715 | hdl-access = free | hdl = 20.500.12105/9999 }}</ref> It is thought that [[androgen]]ic progestins like [[medroxyprogesterone acetate]] and [[norethisterone]] may antagonize the beneficial effects of estrogens on [[biomarker]]s of cardiovascular health (e.g., favorable [[lipid profile]] changes).<ref name="pmid23238854" /><ref name="pmid29157280">{{cite journal | vauthors = Jiang Y, Tian W | title = The effects of progesterones on blood lipids in hormone replacement therapy | journal = Lipids in Health and Disease | volume = 16 | issue = 1 | pages = 219 | date = November 2017 | pmid = 29157280 | pmc = 5697110 | doi = 10.1186/s12944-017-0612-5 | doi-access = free }}</ref> However, these findings are mixed and controversial.<ref name="pmid29157280" /> Differences of progestogens on cardiovascular health and risk have been reviewed and summarized:<ref name="pmid23238854" />

Progestogens, similarly to the androgens and estrogens through their own respective [[receptor (biochemistry)|receptorreceptors]]s, inhibit the secretion of the [[gonadotropin]]s [[follicle-stimulating hormone]] (FSH) and [[luteinizing hormone]] (LH) via activation of the PR in the [[pituitary gland]]. This effect is a form of [[negative feedback]] on the [[hypothalamic–pituitary–gonadal axis]] (HPG axis) and takes advantage of the mechanism that the body uses to prevent [[sex hormone]] levels from becoming too high.<ref name="pmid10997774">{{cite journal |vauthors=de Lignières B, Silberstein S | title = Pharmacodynamics of oestrogens and progestogens | journal = Cephalalgia: An International Journal of Headache | volume = 20 | issue = 3 | pages = 200–7 |date=April 2000 | pmid = 10997774 | doi = 10.1046/j.1468-2982.2000.00042.x| s2cid = 40392817 | doi-access = free }}</ref><ref name="pmid15752663">{{cite journal |vauthors=Chassard D, Schatz B | title = [The antigonadrotropic activity of chlormadinone acetate in reproductive women] | language = fr | journal = Gynécologie, Obstétrique & Fertilité | volume = 33 | issue = 1–2 | pages = 29–34 | year = 2005 | pmid = 15752663 | doi = 10.1016/j.gyobfe.2004.12.002 }}</ref><ref name="pmid12641635">{{cite journal |vauthors=Brady BM, Anderson RA, Kinniburgh D, Baird DT | title = Demonstration of progesterone receptor-mediated gonadotrophin suppression in the human male | journal = Clinical Endocrinology | volume = 58 | issue = 4 | pages = 506–12 |date=April 2003 | pmid = 12641635 | doi = 10.1046/j.1365-2265.2003.01751.x| s2cid = 12567639 | doi-access = free }}</ref> Accordingly, progestogens, both endogenous and exogenous (i.e., progestins), have [[antigonadotropic]] effects,<ref name="pmid368741">{{cite journal | author = Neumann F | title = The physiological action of progesterone and the pharmacological effects of progestogens--a short review | journal = Postgraduate Medical Journal | volume = 54 | issue = Suppl 2 | pages = 11–24 | year = 1978 | pmid = 368741 }}</ref> and progestogens in sufficiently high amounts can markedly suppress the body's normal production of progestogens, androgens, and estrogens as well as inhibit [[fertility]] ([[ovulation]] in women and [[spermatogenesis]] in men).<ref name="pmid12641635" />

Progestins with potent antimineralocorticoid activity like drospirenone may have properties more similar to those of natural progesterone, such as counteraction of cyclical estrogen-induced [[sodium retention|sodium]] and [[water retention (medicine)|fluid retention]], [[edema]], and associated [[weight gain]]; lowered [[blood pressure]]; and possibly improved [[cardiovascular]] health.<ref name="pmid12659403">{{cite journal | vauthors = Oelkers W | title = Antimineralocorticoid activity of a novel oral contraceptive containing drospirenone, a unique progestogen resembling natural progesterone | journal = Eur J Contracept Reprod Health Care | volume = 7 | issue = Suppl 3 | pages = 19–26; discussion 42–3 | year = 2002 | pmid = 12659403 }}</ref><ref name="pmid18075844">{{cite journal | vauthors = Foidart JM, Faustmann T | title = Advances in hormone replacement therapy: weight benefits of drospirenone, a 17alpha-spirolactone-derived progestogen | journal = Gynecol. Endocrinol. | volume = 23 | issue = 12 | pages = 692–9 | year = 2007 | pmid = 18075844 | doi = 10.1080/09513590701582323 | s2cid = 12572825 }}</ref><ref name="pmid17364593">{{cite journal | vauthors = Genazzani AR, Mannella P, Simoncini T | title = Drospirenone and its antialdosterone properties | journal = Climacteric | volume = 10 | issue = Suppl 1 | pages = 11–8 | year = 2007 | pmid = 17364593 | doi = 10.1080/13697130601114891 | s2cid = 24872884 }}</ref><ref name="pmid16949774">{{cite journal | vauthors = Palacios S, Foidart JM, Genazzani AR | title = Advances in hormone replacement therapy with drospirenone, a unique progestogen with aldosterone receptor antagonism | journal = Maturitas | volume = 55 | issue = 4 | pages = 297–307 | year = 2006 | pmid = 16949774 | doi = 10.1016/j.maturitas.2006.07.009 | hdl = 2268/9932 | url = http://orbi.ulg.ac.be/handle/2268/9932| hdl-access = free }}</ref>

Progesterone has [[neurosteroid]] activity via metabolism into [[allopregnanolone]] and [[pregnanolone]], potent [[positive allosteric modulator]]s of the [[GABAA receptor|GABA_A receptor]].<ref name="pmid16112947t" /> As a result, it has associated effects such as [[sedation]], [[somnolence]], and [[cognitive impairment]].<ref name="pmid16112947t" /> No progestin is known to have similar such neurosteroid activity or effects.<ref name="pmid16112947t" /> However, [[promegestone]] has been found to act as a [[Receptor antagonist#Non-competitive|non-competitive antagonist]] of the [[nicotinic acetylcholine receptor]] similarly to progesterone.<ref name="pmid9927618">{{cite journal |vauthors=Blanton MP, Xie Y, Dangott LJ, Cohen JB | title = The steroid promegestone is a noncompetitive antagonist of the Torpedo nicotinic acetylcholine receptor that interacts with the lipid-protein interface | journal = Mol. Pharmacol. | volume = 55 | issue = 2 | pages = 269–78 |date=February 1999 | pmid = 9927618 | doi = 10.1124/mol.55.2.269| s2cid = 491327 | url = https://semanticscholar.org/paper/5fa3beb0a2df86501c531b5d00c499bc78df9bae}}</ref>

[[Oral administration|Oral]] progesterone has very low [[bioavailability]] and [[potency (pharmacology)|potency]].<ref name="pmid16112947t" /><ref name="Kuhl2011t" /><ref name="pmid23336704">{{cite journal | vauthors = Kuhl H, Schneider HP | title = Progesterone – promoter or inhibitor of breast cancer | journal = Climacteric | volume = 16 | issue = Suppl 1 | pages = 54–68 | date = August 2013 | pmid = 23336704 | doi = 10.3109/13697137.2013.768806 | s2cid = 20808536}}</ref><ref name="pmid29526116" /><ref name="pmid8842581">{{cite journal | vauthors = Fotherby K | title = Bioavailability of orally administered sex steroids used in oral contraception and hormone replacement therapy | journal = Contraception | volume = 54 | issue = 2 | pages = 59–69 | date = August 1996 | pmid = 8842581 | doi = 10.1016/0010-7824(96)00136-9}}</ref> [[Micronization]] and dissolution in [[oil]]-filled [[capsule (pharmacy)|capsule]]s, a formulation known as oral micronized progesterone (OMP), increases the bioavailability of progesterone by several-fold.<ref name="pmid8842581" /><ref name="pmid2801843">{{cite journal | vauthors = Hargrove JT, Maxson WS, Wentz AC | title = Absorption of oral progesterone is influenced by vehicle and particle size | journal = Am. J. Obstet. Gynecol. | volume = 161 | issue = 4 | pages = 948–51 | date = October 1989 | pmid = 2801843 | doi = 10.1016/0002-9378(89)90759-X}}</ref> However, the bioavailability of oral micronized progesterone nonetheless remains very low at less than 2.4%.<ref name="pmid16112947t" /><ref name="Kuhl2011t" /><ref name="pmid23336704" /><ref name="pmid29526116" /><ref name="pmid10689005">{{cite journal | vauthors = Levine H, Watson N | title = Comparison of the pharmacokinetics of Crinone 8% administered vaginally versus Prometrium administered orally in postmenopausal women(3) | journal = Fertil. Steril. | volume = 73 | issue = 3 | pages = 516–21 | date = March 2000 | pmid = 10689005 | doi = 10.1016/S0015-0282(99)00553-1| doi-access = free }}</ref> Progesterone also has a very short [[elimination half-life]] in the [[circulatory system|circulation]] of no more than 1.5&nbsp;hours.<ref name="pmid945344n">{{cite journal | vauthors = Aufrère MB, Benson H | title = Progesterone: an overview and recent advances | journal = J Pharm Sci | volume = 65 | issue = 6 | pages = 783–800 | date = June 1976 | pmid = 945344 | doi = 10.1002/jps.2600650602}}</ref><ref name="pmid16112947t" /><ref name="pmid8842581" /> Due to the poor oral activity of oral micronized progesterone, it has relatively weak progestogenic effects.<ref name="Kuhl2011t" /><ref name="pmid23336704" /><ref name="pmid29526116" /> Administration of progesterone in [[oil solution]] by [[intramuscular injection]] has a duration of about 2 or 3&nbsp;days, necessitating frequent injections.<ref name="pmid16112947t" /><ref name="RunnebaumRabe2012t" /><ref name="KnörrBeller2013t" /><ref name="KnörrKnörr-Gärtner2013t" /><ref name="Labhart2012x" /><ref name="HorskyPresl1981t" /> [[Transdermal administration]] of progesterone in the form of [[cream]]s or [[gel]]s achieves only very low levels of progesterone and weak progestogenic effects.<ref name="pmid25196424">{{cite journal | vauthors = Stanczyk FZ | title = Treatment of postmenopausal women with topical progesterone creams and gels: are they effective? | journal = Climacteric | volume = 17 | issue = Suppl 2 | pages = 8–11 | year = 2014 | pmid = 25196424 | doi = 10.3109/13697137.2014.944496 | s2cid = 20019151}}</ref><ref name="pmid15772572">{{cite journal | vauthors = Stanczyk FZ, Paulson RJ, Roy S | title = Percutaneous administration of progesterone: blood levels and endometrial protection | journal = Menopause | volume = 12 | issue = 2 | pages = 232–7 | year = 2005 | pmid = 15772572 | doi = 10.1097/00042192-200512020-00019 | s2cid = 10982395 | url = https://semanticscholar.org/paper/c33e3212bbe1ee00abb2a9a124c1b242592874a0}}</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 |url=http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/1954/76/i16/f-pdf/f_ja01645a010.pdf |doi=10.1021/ja01645a009}}</ref>