View source for Progestogen (medication)

{{short description|Medication producing effects similar to progesterone}}
{{cs1 config|name-list-style=vanc}}
{{About|progestogens as medications|the role of progestogens as hormones|Progestogen}}
{{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
| Synonyms = Progestagen, gestagen, gestogen; progestin (synthetic progestogen); progesterone receptor agonist
<!-- Class identifiers -->
| Use = [[Hormonal contraceptive|Hormonal birth control]], [[hormone replacement therapy|hormone therapy]], [[gynecological disorder]]s, [[fertility medicine]] and [[pregnancy]] support, [[antigonadotropin|sex-hormone suppression]], others
| ATC_prefix = G03
| Biological_target = [[Progesterone receptor]]s ([[Progesterone receptor A|PR-A]], [[Progesterone receptor B|PR-B]], [[Progesterone receptor C|PR-C]]); [[membrane progesterone receptor]]s ([[mPRα]], [[mPRβ]], [[mPRγ]], [[mPRδ]], [[mPRε]]); [[progesterone receptor membrane component]]s ([[PGRMC1]], [[PGRMC2]])
| Chemical_class = [[Steroid]]s ([[pregnane]]s, [[norpregnane]]s, [[retropregnane]]s, [[androstane]]s, [[estrane]]s)
<!-- Clinical data -->
| Drugs.com = {{Drugs.com|drug-class|progestins}}
| Consumer_Reports = 
<!-- External links -->
| MeshID = D011372
}}
<!-- Definition and medical uses -->
A '''progestogen''', also referred to as a '''progestagen''', '''gestagen''', or '''gestogen''', is a type of [[medication]] which produces effects similar to those of the [[natural product|natural]] female [[sex hormone]] [[progesterone]] in the body.<ref name="pmid16112947t">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | pages = 3–63 | year = 2005 | issue = Suppl 1 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf}}</ref> A '''progestin''' is a ''[[synthetic compound|synthetic]]'' progestogen.<ref name="pmid16112947t" /> Progestogens are used most commonly in [[hormonal contraception|hormonal birth control]] and [[menopausal hormone therapy]].<ref name="pmid16112947t" /> They can also be used in the treatment of [[gynecological condition]]s, to support [[fertility]] and [[pregnancy]], to lower [[sex hormone]] levels for various purposes, and for other indications.<ref name="pmid16112947t" /> Progestogens are used alone or in combination with [[estrogen (medication)|estrogen]]s.<ref name="pmid16112947t" /> They are available in a wide variety of [[drug formulation|formulation]]s and for use by many different [[route of administration|routes of administration]].<ref name="pmid16112947t" /> Examples of progestogens include natural or [[bioidentical]] [[progesterone (medication)|progesterone]] as well as progestins such as [[medroxyprogesterone acetate]] and [[norethisterone]].<ref name="pmid16112947t" />

<!--Side effects-->
[[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 }}</ref>

<!-- Mechanism of action -->
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" />

<!-- 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&nbsp;progestins have been marketed for clinical use in humans or use in [[veterinary medicine]].<ref name="Micromedex">{{cite 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">{{cite 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" />

{{TOC limit|3}}

==Medical uses==

===Available forms===
{| class="wikitable floatright plainrowheaders" style="font-size:small; margin-left: auto; margin-right: auto; border: none;"
|+ class="nowrap" | Progestogens marketed for clinical or veterinary use
|-
! scope="col" style="width:100px;" | Generic name
! scope="col" style="width:50px;" | Class{{efn|group=progmarA1|1=Classes: P = [[progesterone]] derivative, T = [[testosterone]] derivative}}
! scope="col" style="width:80px;" | Brand name
! scope="col" style="width:50px;" | Route{{efn|group=progmarA1|1=Routes: IUD = [[intrauterine device]], PO = [[Oral administration|by mouth]], SC = [[Subcutaneous injection|subcutaneous injection or implant]], SL = [[sublingual|under the tongue]], TD = [[transdermal]], V = [[Vaginal administration|vaginal]]}}
! scope="col" style="width:50px;" | {{abbr|Intr.|Introduced in}} 
|-
! scope="row" style="background: #f8f9fa; | [[Acetomepregenol]]
| P{{efn-lr|group=progmarA2|name=17a|[[17α-Hydroxyprogesterone|17α-hydroxy]]}}{{efn-lr|group=progmarA2|name=ester|Ester}} || Diamol || {{abbrlink|PO|Oral administration}} || 1981 
|-
! scope="row" style="background: #f8f9fa; | [[Algestone acetophenide]]
| P{{efn-lr|group=progmarA2|name=17a}}{{efn-lr|group=progmarA2|name=cyke|Cyclic ketal}} || Deladroxate{{efn|group=progmarA1|name=others|Also marketed under other brand names.}} || {{abbrlink|IM|Intramuscular injection}} || 1964 
|-
! scope="row" style="background: #f8f9fa; | [[Allylestrenol]]
| T{{efn-lr|group=progmarA2|name=19nt|[[19-Nortestosterone|19-nor]]}}{{efn-lr|group=progmarA2|name=estrane|estrane}} || Gestanin{{efn|group=progmarA1|name=others}} || PO || 1961 
|-
! scope="row" style="background: #f8f9fa; | [[Altrenogest]]{{efn|group=progmarA1|name=vet|Veterinary use only.}}
| T{{efn-lr|group=progmarA2|name=19nt}}{{efn-lr|group=progmarA2|name=estrane}} || Regumate{{efn|group=progmarA1|name=others}} || PO || 1980s 
|-
! scope="row" style="background: #f8f9fa; | [[Chlormadinone acetate]]
| P{{efn-lr|group=progmarA2|name=17a}}{{efn-lr|group=progmarA2|name=ester}} || Belara{{efn|group=progmarA1|name=others}} || PO || 1965 
|-
! scope="row" style="background: #f8f9fa; | [[Cyproterone acetate]]
| P{{efn-lr|group=progmarA2|name=17a}}{{efn-lr|group=progmarA2|name=ester}} || Androcur{{efn|group=progmarA1|name=others}} || PO, IM || 1973 
|-
! scope="row" style="background: #f8f9fa; | [[Danazol]]
| T{{efn-lr|group=progmarA2|name=estrane}} || Danocrine || PO || 1971 
|-
! scope="row" style="background: #f8f9fa; | [[Delmadinone acetate]]{{efn|group=progmarA1|name=vet}}
| P{{efn-lr|group=progmarA2|name=17a}}{{efn-lr|group=progmarA2|name=ester}}  || Tardak || PO || 1972 
|-
! scope="row" style="background: #f8f9fa; | [[Desogestrel]]
| T{{efn-lr|group=progmarA2|name=19nt}}{{efn-lr|group=progmarA2|name=gonane|Gonane}} || Cerazette{{efn|group=progmarA1|name=others}} || PO || 1981 
|-
! scope="row" style="background: #f8f9fa; | [[Dienogest]]
| T{{efn-lr|group=progmarA2|name=19nt}}{{efn-lr|group=progmarA2|name=estrane}} || Natazia{{efn|group=progmarA1|name=others}} || PO || 1995 
|-
! scope="row" style="background: #f8f9fa; | [[Drospirenone]]
| S{{efn-lr|group=progmarA2|name=spiro|Spironolactone}} || Angeliq{{efn|group=progmarA1|name=others}} || PO || 2000 
|-
! scope="row" style="background: #f8f9fa; | [[Dydrogesterone]]
| {{abbrlink|RP|retroprogesterone}} || Duphaston || PO || 1961 
|-
! scope="row" style="background: #f8f9fa; | [[Etonogestrel]]
| T{{efn-lr|group=progmarA2|name=19nt}}{{efn-lr|group=progmarA2|name=gonane}} || Implanon (SC), NuvaRing (V) || [[Subcutaneous injection|{{abbr|SC|Subcutaneous injection or implant}}]], {{abbrlink|V|Vaginal administration}} || 1998 
|-
! scope="row" style="background: #f8f9fa; | [[Etynodiol diacetate]]
| T{{efn-lr|group=progmarA2|name=19nt}}{{efn-lr|group=progmarA2|name=estrane}}{{efn-lr|group=progmarA2|name=ester}} || Demulen{{efn|group=progmarA1|name=others}} || PO || 1965 
|-
! scope="row" style="background: #f8f9fa; | [[Flugestone acetate]]{{efn|group=progmarA1|name=vet}}
| P{{efn-lr|group=progmarA2|name=17a}}{{efn-lr|group=progmarA2|name=ester}} || Chronogest || PO || 1960s
|-
! scope="row" style="background: #f8f9fa; | [[Gestodene]]
| T{{efn-lr|group=progmarA2|name=19nt}}{{efn-lr|group=progmarA2|name=gonane}} || Femodene{{efn|group=progmarA1|name=others}} || PO || 1987 
|-
! scope="row" style="background: #f8f9fa; | [[Gestonorone caproate]]
| P{{efn-lr|group=progmarA2|name=17a}}{{efn-lr|group=progmar2|name=19np|[[19-norprogesterone|19-nor]]}}{{efn-lr|group=progmarA2|name=ester}} || Depostat{{efn|group=progmarA1|name=others}} || IM || 1968 
|-
! scope="row" style="background: #f8f9fa; | [[Gestrinone]]
| T{{efn-lr|group=progmarA2|name=19nt}}{{efn-lr|group=progmarA2|name=gonane}} || Dimetriose{{efn|group=progmarA1|name=others}} || PO || 1986 
|-
! scope="row" style="background: #f8f9fa; | [[Hydroxyprogesterone caproate]]
| P{{efn-lr|group=progmarA2|name=17a}}{{efn-lr|group=progmarA2|name=ester}} || Makena{{efn|group=progmarA1|name=others}} || IM || 1954 
|-
! scope="row" style="background: #f8f9fa; | [[Levonorgestrel]]
| T{{efn-lr|group=progmarA2|name=19nt}}{{efn-lr|group=progmarA2|name=gonane}} || Plan B{{efn|group=progmarA1|name=others}} || PO, {{abbrlink|TD|Transdermal}},<br />{{abbr|IUD|intrauterine device}}, SC || 1970 
|-
! scope="row" style="background: #f8f9fa; | [[Lynestrenol]]
| T{{efn-lr|group=progmarA2|name=19nt}}{{efn-lr|group=progmarA2|name=estrane}} || Exluton{{efn|group=progmarA1|name=others}} || PO || 1961 
|-
! scope="row" style="background: #f8f9fa; | [[Medrogestone]]
| P{{efn-lr|group=progmarA2|name=17m|[[17α-Methylprogesterone|17α-methyl]]}} || Colprone || PO || 1966 
|-
! scope="row" style="background: #f8f9fa; | [[Medroxyprogesterone acetate]]
| P{{efn-lr|group=progmarA2|name=17a}}{{efn-lr|group=progmarA2|name=ester}} || Provera{{efn|group=progmarA1|name=others}} || PO, IM, SC || 1958 
|-
! scope="row" style="background: #f8f9fa; | [[Megestrol acetate]]
| P{{efn-lr|group=progmarA2|name=17a}}{{efn-lr|group=progmarA2|name=ester}} || Megace || PO, IM || 1963 
|-
! scope="row" style="background: #f8f9fa; | [[Melengestrol acetate]]{{efn|group=progmarA1|name=vet}}
| P{{efn-lr|group=progmarA2|name=17a}}{{efn-lr|group=progmarA2|name=ester}} || Heifermax{{efn|group=progmarA1|name=others}} || IM || 1960s 
|-
! scope="row" style="background: #f8f9fa; | [[Nomegestrol acetate]]
| P{{efn-lr|group=progmarA2|name=19np}}{{efn-lr|group=progmarA2|name=ester}} || Lutenyl{{efn|group=progmarA1|name=others}} || PO || 1986 
|-
! scope="row" style="background: #f8f9fa; | [[Norelgestromin]]
| T{{efn-lr|group=progmarA2|name=19nt}}{{efn-lr|group=progmarA2|name=gonane}} || Evra{{efn|group=progmarA1|name=others}} || TD patch || 2002 
|-
! scope="row" style="background: #f8f9fa; | [[Norethisterone]]
| T{{efn-lr|group=progmarA2|name=19nt}}{{efn-lr|group=progmarA2|name=estrane}} || Aygestin{{efn|group=progmarA1|name=others}} || PO || 1957 
|-
! scope="row" style="background: #f8f9fa; | [[Norethisterone acetate]]
| T{{efn-lr|group=progmarA2|name=19nt}}{{efn-lr|group=progmarA2|name=estrane}}{{efn-lr|group=progmarA2|name=ester}} || Primolut-Nor || PO, TD patch || 1964 
|-
! scope="row" style="background: #f8f9fa; | [[Norethisterone enanthate]]
| T{{efn-lr|group=progmarA2|name=19nt}}{{efn-lr|group=progmarA2|name=estrane}}{{efn-lr|group=progmarA2|name=ester}} || Noristerat{{efn|group=progmarA1|name=others}} || IM || 1957 
|-
! scope="row" style="background: #f8f9fa; | [[Norgestimate]]
| T{{efn-lr|group=progmarA2|name=19nt}}{{efn-lr|group=progmarA2|name=gonane}}{{efn-lr|group=progmarA2|name=ester}} || Ortho-Cyclen{{efn|group=progmarA1|name=others}} || PO || 1986 
|-
! scope="row" style="background: #f8f9fa; | [[Norgestomet]]{{efn|group=progmarA1|name=vet}}
| P{{efn-lr|group=progmarA2|name=19np}}{{efn-lr|group=progmarA2|name=ester}} || Syncro-Mate B || PO || 1970s 
|-
! scope="row" style="background: #f8f9fa; | [[Norgestrel]]
| T{{efn-lr|group=progmarA2|name=19nt}}{{efn-lr|group=progmarA2|name=gonane}} || Ovral || PO || 1966 
|-
! scope="row" style="background: #f8f9fa; | [[Normethandrone]]
| T{{efn-lr|group=progmarA2|name=19nt}}{{efn-lr|group=progmarA2|name=estrane}} || Metalutin || PO || 1957 
|-
! scope="row" style="background: #f8f9fa; | [[Osaterone acetate]]{{efn|group=progmarA1|name=vet}}
| P{{efn-lr|group=progmarA2|name=17a}}{{efn-lr|group=progmarA2|name=ester}} || Ypozane || PO || 2007 
|-
! scope="row" style="background: #f8f9fa; | [[Oxendolone]]
| T{{efn-lr|group=progmarA2|name=19nt}}{{efn-lr|group=progmarA2|name=estrane}} || Prostetin{{efn|group=progmarA1|name=others}} || IM || 1981 
|-
! scope="row" style="background: #f8f9fa; | [[Progesterone (medication)|Progesterone]]
| {{abbr|BI|bio-identical}} || Prometrium{{efn|group=progmarA1|name=others}} || PO, V, IM || 1934 
|-
! scope="row" style="background: #f8f9fa; | [[Proligestone]]{{efn|group=progmarA1|name=vet}}
| P{{efn-lr|group=progmarA2|name=17a}}{{efn-lr|group=progmarA2|name=cyke}} || Corvinan{{efn|group=progmarA1|name=others}} || PO || 1975 
|-
! scope="row" style="background: #f8f9fa; | [[Promegestone]]
| P{{efn-lr|group=progmarA2|name=19np}} || Surgestone || PO || 1983 
|-
! scope="row" style="background: #f8f9fa; | [[Segesterone acetate]]
| P{{efn-lr|group=progmarA2|name=17a}}{{efn-lr|group=progmarA2|name=ester}} || Elcometrine{{efn|group=progmarA1|name=others}} || SC, V || 2000
|-
! scope="row" style="background: #f8f9fa; | [[Tibolone]]
| T{{efn-lr|group=progmarA2|name=19nt}}{{efn-lr|group=progmarA2|name=estrane}} || Livial{{efn|group=progmarA1|name=others}} || PO || 1988
|-
! scope="row" style="background: #f8f9fa; | [[Trimegestone]]
| P{{efn-lr|group=progmarA2|name=19np}} || Lovelle{{efn|group=progmarA1|name=others}} || PO || 2001
|- class="sortbottom"
| colspan="6" style="width: 1px; background-color:#eaecf0; text-align: center;" |{{hidden|header=Legend for class of molecule|content={{notelist-lr|group=progmarA2}}}}
|-
| colspan="6" style="width: 1px; background-color:#eaecf0; text-align: center;" |{{notelist|group=progmarA1}}
|}
Progestogens are available in many different [[pharmaceutical form|form]]s for use by many different [[routes of administration]]. These include [[oral administration|oral]] [[tablet (pharmacy)|tablet]]s and [[capsule (pharmacy)|capsule]]s, [[oil]] and [[aqueous solution]]s and [[suspension (chemistry)|suspension]]s for [[intramuscular injection|intramuscular]] or [[subcutaneous injection]], and various others (e.g., [[transdermal patch]]es, [[vaginal ring]]s, [[intrauterine device]]s, [[subcutaneous implant]]s).

Dozens of different progestogens have been marketed for [[clinical medicine|clinical]] and/or [[veterinary medicine|veterinary]] use.

===Birth control===
Progestogens are used in a variety of different forms of [[hormonal contraception|hormonal birth control]] for females, including [[combined hormonal contraception|combined estrogen and progestogen forms]] like [[combined oral contraceptive pill]]s, [[contraceptive patch|combined contraceptive patch]]es, [[contraceptive vaginal ring|combined contraceptive vaginal ring]]s, and [[combined injectable birth control|combined injectable contraceptive]]s; and [[progestogen-only contraception|progestogen-only form]]s like [[progestogen-only pill|progestogen-only contraceptive pill]]s ("mini-pills"), [[emergency contraception|progestogen-only emergency contraceptive pill]]s ("day-after pills"), [[contraceptive implant|progestogen-only contraceptive implant]]s, [[intrauterine device|progestogen-only intrauterine device]]s, [[contraceptive vaginal ring|progestogen-only contraceptive vaginal ring]]s, and [[progestogen-only injectable contraceptive]]s.<ref name="JamesonGroot2015">{{cite book|author1=J. Larry Jameson|author2=Leslie J. De Groot|title=Endocrinology: Adult and Pediatric E-Book|url=https://books.google.com/books?id=xmLeBgAAQBAJ&pg=PA2304|date=25 February 2015|publisher=Elsevier Health Sciences|isbn=978-0-323-32195-2|pages=2304–}}</ref><ref name="ClarkHarvey2011">{{cite book | author1 = Michelle A. Clark | author2 = Richard A. Harvey | author3 = Richard Finkel |author4=Jose A. Rey |author5=Karen Whalen | title = Pharmacology | url = https://books.google.com/books?id=Y558dgp_PjoC&pg=PA322 | date = 15 December 2011 | publisher = Lippincott Williams & Wilkins | isbn = 978-1-4511-1314-3 | page = 322}}</ref><ref name="Bhattacharya2003">{{cite book | author = Bhattacharya | title = Pharmacology, 2/e | url = https://books.google.com/books?id=X3cCZQCrrjcC&pg=PA378 | date = 1 January 2003 | publisher = Elsevier India | isbn = 978-81-8147-009-6 | page = 378}}</ref><ref name="KellermanBope2017">{{cite book|author1=Rick D. Kellerman|author2=Edward T. Bope|title=Conn's Current Therapy 2018 E-Book|url=https://books.google.com/books?id=3xNBDwAAQBAJ&pg=PT1124|date=10 November 2017|publisher=Elsevier Health Sciences|isbn=978-0-323-52961-7|pages=1124–}}</ref>

Progestogens mediate their contraceptive effects by multiple mechanisms, including prevention of [[ovulation]] via their [[antigonadotropic]] effects; thickening of [[cervical mucus]], making the [[cervix]] largely impenetrable to [[sperm]]; preventing [[capacitation]] of [[sperm]] due to changes in cervical fluid, thereby making sperm unable to penetrate the [[ovum]]; and [[atrophy|atrophic]] changes in the [[endometrium]], making the endometrium unsuitable for [[implantation (human embryo)|implantation]].<ref name="VarneyKriebs2004">{{cite book|author1=Helen Varney|author2=Jan M. Kriebs|author3=Carolyn L. Gegor|title=Varney's Midwifery|url=https://archive.org/details/varneysmidwifery0000varn|url-access=registration|year=2004|publisher=Jones & Bartlett Learning|isbn=978-0-7637-1856-5|pages=[https://archive.org/details/varneysmidwifery0000varn/page/513 513]–}}</ref><ref name="Golan2008" /><ref name="MilesRayburn2012">{{cite book|author1=Pamela S. Miles|author2=William F. Rayburn|author3=J.Christopher Carey|title=Obstetrics and Gynecology|url=https://books.google.com/books?id=tKigBwAAQBAJ&pg=PA109|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4684-0220-9|pages=109–}}</ref><ref name="pmid15715527">{{cite journal | vauthors = Erkkola R, Landgren BM | title = Role of progestins in contraception | journal = Acta Obstet Gynecol Scand | volume = 84 | issue = 3 | pages = 207–16 | date = March 2005 | pmid = 15715527 | doi = 10.1111/j.0001-6349.2005.00759.x | s2cid = 6887415| doi-access = free }}</ref> They may also decrease [[tubule|tubal]] [[motility]] and [[cilia]]ry action.<ref name="pmid15715527" />

===Hormone therapy===

====Menopause and hypogonadism====
Progestogens are used in combination with [[estrogen (medication)|estrogen]]s in [[menopausal hormone therapy]] in women. They are also used in combination with estrogens in hormone therapy for [[hypogonadism]] and [[delayed puberty]] in girls and women. They are used mainly to prevent [[endometrial hyperplasia]] and increased risk of [[endometrial cancer]] from unopposed estrogen therapy.

====Transgender hormone therapy====
Progestogens are used as a component of [[transgender hormone therapy|hormone therapy]] for [[transgender women]] and [[transgender men]]. They are used in transgender women in combination with estrogens to help suppress and block [[testosterone]]. Progestogens might also have other beneficial effects in transgender women, but these are controversial and unsupported at present. Examples of progestogens used in hormone therapy for transgender women include [[cyproterone acetate]], [[medroxyprogesterone acetate]], and [[progesterone (medication)|progesterone]]. Progestogens, such as medroxyprogesterone and [[lynestrenol]], are used in transgender men to help suppress [[menses]]. Progestogens have also been used to delay [[puberty]] in [[transgender youth|transgender boys and girls]].

====Other uses====
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>

===Gynecological disorders===

====Menstrual disorders====
Progestogens are used to treat [[menstrual disorder]]s such as [[secondary amenorrhea]] and [[dysfunctional uterine bleeding]].<ref name="ClarkHarvey2011" /><ref name="Bhattacharya2003" /> In a normal [[menstrual cycle]], declining levels of progesterone trigger [[menstruation]]. Progestogens such as [[norethisterone acetate]] and [[medroxyprogesterone acetate]] may be used to artificially induce progesterone-associated [[breakthrough bleeding]].<ref name="pmid11041215">{{cite journal |vauthors=Hickey M, Fraser IS | title = A functional model for progestogen-induced breakthrough bleeding | journal = Hum. Reprod. | volume = 15 | issue = Suppl 3 | pages = 1–6 |date=August 2000 | pmid = 11041215 | doi = 10.1093/humrep/15.suppl_3.1| doi-access = free}}</ref>

The [[progestogen challenge test]] or progestogen withdrawal test is used to diagnose [[amenorrhea]]. Due to the availability of assays to measure estrogen levels, it is now rarely used.

====Uterine disorders====
Progestogens are used in the prevention and treatment of [[uterine disorder]]s such as [[endometrial hyperplasia]], [[endometriosis]], [[uterine fibroids]], and [[uterine hypoplasia]].

====Breast disorders====
Progestogens are used to treat [[benign tumor|benign]] [[breast disorder]]s.<ref name="pmid20383772">{{cite journal | vauthors = Schindler AE | title = Dydrogesterone and other progestins in benign breast disease: an overview | journal = Archives of Gynecology and Obstetrics | volume = 283 | issue = 2 | pages = 369–371 | date = February 2011 | pmid = 20383772 | doi = 10.1007/s00404-010-1456-7 | s2cid = 9125889 }}</ref><ref name="pmid12227885">{{cite journal | vauthors = Winkler UH, Schindler AE, Brinkmann US, Ebert C, Oberhoff C | title = Cyclic progestin therapy for the management of mastopathy and mastodynia | journal = Gynecological Endocrinology | volume = 15 | issue = Suppl 6 | pages = 37–43 | date = December 2001 | pmid = 12227885 | doi = 10.1080/gye.15.s6.37.43 | s2cid = 27589741 }}</ref> They are associated not only with a reduction in [[breast pain]], but also a decrease in [[breast]] [[cell proliferation]], a decrease in [[mammary gland|breast gland]] size, and a disappearance of breast [[nodule (medicine)|nodularity]].<ref name="pmid20383772" /><ref name="pmid12227885" /><ref name="pmid25113944" /> Progestogens that have been used for such purposes include [[topical progesterone]], [[dydrogesterone]], [[promegestone]], [[lynestrenol]], [[medroxyprogesterone acetate]], [[dienogest]], and [[medrogestone]].<ref name="pmid20383772" /><ref name="pmid12227885" /><ref name="BińkowskaWoroń2015">{{cite journal | vauthors = Bińkowska M, Woroń J | title = Progestogens in menopausal hormone therapy | journal = Przeglad Menopauzalny = Menopause Review | volume = 14 | issue = 2 | pages = 134–143 | date = June 2015 | pmid = 26327902 | pmc = 4498031 | doi = 10.5114/pm.2015.52154 }}</ref><ref name="pmid25113944">{{cite journal | vauthors = Ruan X, Mueck AO | title = Systemic progesterone therapy--oral, vaginal, injections and even transdermal? | journal = Maturitas | volume = 79 | issue = 3 | pages = 248–255 | date = November 2014 | pmid = 25113944 | doi = 10.1016/j.maturitas.2014.07.009 }}</ref>

Progestogens are used in the treatment of [[breast hypoplasia]] and [[lactation insufficiency]]. This is because they induce [[lobuloalveolar]] [[breast development|development]] of the [[breast]]s, which is required for [[lactation]] and [[breastfeeding]].

===Enlarged prostate===
Progestogens have been used at high doses to treat [[benign prostatic hyperplasia]] (BPH). They act by suppressing [[gonad]]al [[testosterone]] [[biosynthesis|production]] and hence circulating testosterone levels. Androgens like testosterone stimulate the growth of the [[prostate gland]].

===Hormone-sensitive cancers===

====Endometrial cancer====
Progestogens were first found to be effective at high doses in the treatment of [[endometrial hyperplasia]] and [[endometrial cancer]] in 1959.<ref name="pmid14409476">{{cite journal | vauthors = Kistner RW | title = Histological effects of progestins on hyperplasia and carcinoma in situ of the endometrium | journal = Cancer | volume = 12 | issue = 6| pages = 1106–22 | date = 1959 | pmid = 14409476 | doi = 10.1002/1097-0142(195911/12)12:6<1106::aid-cncr2820120607>3.0.co;2-m| doi-access = free}}</ref><ref name="AcademicPress2009">{{cite book|title=Regulatory Mechanisms in Transcriptional Signaling|url=https://books.google.com/books?id=yIESHM-P-ZIC&pg=PA62|date=25 July 2009|publisher=Academic Press|isbn=978-0-08-091198-4|pages=62–}}</ref><ref name="MD2011">{{cite book|author=Loren K. Mell, MD|title=Gynecologic Cancer|url=https://books.google.com/books?id=K0CaWNG4L6sC&pg=PA393|date=20 December 2011|publisher=Demos Medical Publishing|isbn=978-1-61705-095-4|pages=393–}}</ref> Subsequently, high-dose [[gestonorone caproate]], [[hydroxyprogesterone caproate]], [[medroxyprogesterone acetate]], and [[megestrol acetate]] were approved for the treatment of endometrial cancer.<ref name="McKinnell1998">{{cite book|author=Robert G. McKinnell|title=The Biological Basis of Cancer|url=https://books.google.com/books?id=7DPzBK27R_EC&pg=PA262|date=13 March 1998|publisher=Cambridge University Press|isbn=978-0-521-59695-4|pages=262–}}</ref><ref name="BurchumRosenthal2014">{{cite book|author1=Jacqueline Burchum|author2=Laura Rosenthal|title=Lehne's Pharmacology for Nursing Care - E-Book|url=https://books.google.com/books?id=C7_NBQAAQBAJ&pg=PA740|date=2 December 2014|publisher=Elsevier Health Sciences|isbn=978-0-323-34026-7|pages=740–}}</ref><ref name="SmithWilliams2005">{{cite book|author1=H. John Smith|author2=Hywel Williams|title=Smith and Williams' Introduction to the Principles of Drug Design and Action, Fourth Edition|url=https://books.google.com/books?id=P2W6B9FQRKsC&pg=PA493|date=10 October 2005|publisher=CRC Press|isbn=978-0-203-30415-0|pages=493–}}</ref>

====Breast cancer====
Progestogens, such as megestrol acetate and medroxyprogesterone acetate, are effective at high doses in the treatment of [[metastatic breast cancer|advanced]] [[menopause|postmenopausal]] [[breast cancer]].<ref name="Winchester2006">{{cite book|author=David J. Winchester|title=Breast Cancer|url=https://books.google.com/books?id=aHetwn61JigC&pg=PA333|year=2006|publisher=PMPH-USA|isbn=978-1-55009-272-1|pages=333–}}</ref><ref name="pmid10685337">{{cite journal | vauthors = Gadducci A, Genazzani AR | title = Endocrine therapy for gynecological cancer | journal = Gynecol. Endocrinol. | volume = 13 | issue = 6 | pages = 441–56 | date = December 1999 | pmid = 10685337 | doi = 10.3109/09513599909167590}}</ref> They have been extensively evaluated as a second-line therapy for this indication.<ref name="Winchester2006" /> However, they produce various [[side effect]]s, such as [[dyspnea]], [[weight gain]], [[vaginal bleeding]], [[nausea]], [[water retention (medicine)|fluid retention]], [[hypertension]], [[thrombophlebitis]], and [[thromboembolism|thromboembolic complication]]s.<ref name="Winchester2006" /><ref name="pmid10685337" /> In addition, megestrol acetate has been found to be significantly inferior to [[aromatase inhibitor]]s in the treatment of breast cancer, and in relation to this, progestogens have been moved down in the sequential therapy of the disease.<ref name="Winchester2006" /> Megestrol acetate is the only [[Food and Drug Administration]]-approved progestogen for breast cancer.<ref name="Winchester2006" /> The [[mechanism of action]] of progestogens in the treatment of breast cancer is unknown, but may be related to their functional [[antiestrogen]]ic and/or [[antigonadotropic]] effects.<ref name="Winchester2006" />

====Prostate cancer====
Certain progestogens, particularly those with antiandrogenic properties, have been used at high doses in the treatment of [[prostate cancer]].<ref name="pmid16406864">{{cite journal | vauthors = Lam JS, Leppert JT, Vemulapalli SN, Shvarts O, Belldegrun AS | title = Secondary hormonal therapy for advanced prostate cancer | journal = J. Urol. | volume = 175 | issue = 1 | pages = 27–34 | date = January 2006 | pmid = 16406864 | doi = 10.1016/S0022-5347(05)00034-0}}</ref><ref name="pmid9712436">{{cite journal | vauthors = Fourcade RO, Chatelain C | title = Androgen deprivation for prostatic carcinoma: a rationale for choosing components | journal = Int. J. Urol. | volume = 5 | issue = 4 | pages = 303–11 | date = July 1998 | pmid = 9712436 | doi = 10.1111/j.1442-2042.1998.tb00356.x | s2cid = 25107178 | doi-access = free}}</ref> These include [[cyproterone acetate]], [[chlormadinone acetate]], and [[megestrol acetate]].<ref name="pmid16406864" /><ref name="pmid9712436" /> Other progestogens such as [[medroxyprogesterone acetate]], [[hydroxyprogesterone caproate]], and [[gestonorone caproate]] have also been studied, but have inadequate effectiveness. They act by suppressing [[gonad]]al [[testosterone]] [[biosynthesis|production]] and hence circulating testosterone levels. Androgens like testosterone stimulate the growth of prostate [[tumor]]s.

===Fertility and pregnancy===
Progestogens are used in [[fertility medicine]] for women. For example, progesterone (or sometimes [[dydrogesterone]] or [[hydroxyprogesterone caproate]]) is used for [[luteal support]] in [[in vitro fertilisation|''in-vitro'' fertilization]] protocols.<ref name="Loose 2006">{{cite book |author1=Loose, Davis S. |author2=Stancel, George M. |editor1=Brunton, Laurence L. |editor2=Lazo, John S. |editor3=Parker, Keith L. |year=2006 |chapter=Estrogens and Progestins |title=Goodman & Gilman's The Pharmacological Basis of Therapeutics |edition=11th |pages=1541–71 |location=New York |publisher=McGraw-Hill |isbn=978-0-07-142280-2}}</ref>

Certain progestogens are used to support [[pregnancy]], including [[progesterone (medication)|progesterone]], [[hydroxyprogesterone caproate]], [[dydrogesterone]], and [[allylestrenol]]. They are used questionably for treatment of [[habitual abortion|recurrent pregnancy loss]] and for prevention of [[premature birth|preterm birth]] in pregnant women with a history of at least one spontaneous preterm birth.<ref name="Loose 2006" />

===Puberty suppression===
Progestogens have been used to treat [[precocious puberty]] in both boys and girls. They have also been used to delay puberty in [[transgender youth]].

===Sexual deviance===
Certain progestogens, such as [[cyproterone acetate]] and [[medroxyprogesterone acetate]], are used as a form of [[chemical castration]] to treat [[sexual deviance]] in men, particularly [[sex offender]]s. They are specifically used to treat [[paraphilia]]s and [[hypersexuality]]. They work by suppressing [[gonad]]al [[testosterone]] [[biosynthesis|production]] and hence circulating testosterone levels. This results in decreased [[libido]] and interference with [[erectile function]] and ability to attain [[orgasm]].

===Skin and hair conditions===
Progestogens are used to treat [[androgen-dependent condition|androgen-dependent]] [[skin condition|skin]] and [[hair condition]]s in women. These include [[oily skin]], [[acne]], [[seborrhea]], [[hirsutism]], [[scalp hair loss]], and [[hidradenitis suppurativa]]. They act by suppressing testosterone levels and, in the case of antiandrogenic progestogens, by directly blocking the actions of androgens.

===Androgen excess===
Progestogens are used to treat [[hyperandrogenism]], such as due to [[polycystic ovary syndrome]] and [[congenital adrenal hyperplasia]], in women. Examples include [[cyproterone acetate]] and [[chlormadinone acetate]].

===Appetite stimulation===
Certain progestins can be used at very high doses to [[appetite stimulant|increase appetite]] in conditions like [[cachexia]], [[anorexia (symptom)|anorexia]], and [[wasting syndrome]]s. In general, they are used in combination with certain other steroid medications such as [[dexamethasone]]. Their effects take several weeks to become apparent, but are relatively long-lived when compared to those of [[corticosteroid]]s. Furthermore, they are recognized as being the only medications to increase [[lean body mass]]. [[Megestrol acetate]] is the lead drug of this class for the management of cachexia, and [[medroxyprogesterone acetate]] is also used.<ref name="pmid11332139">{{cite journal |vauthors=Maltoni M, Nanni O, Scarpi E, Rossi D, Serra P, Amadori D | title = High-dose progestins for the treatment of cancer anorexia-cachexia syndrome: a systematic review of randomised clinical trials | journal = Ann. Oncol. | volume = 12 | issue = 3 | pages = 289–300 |date=March 2001 | pmid = 11332139 | doi = 10.1023/a:1011156811739 | doi-access = free}}</ref><ref name="pmid12868546">{{cite journal |vauthors=Lelli G, Montanari M, Gilli G, Scapoli D, Antonietti C, Scapoli D | title = Treatment of the cancer anorexia-cachexia syndrome: a critical reappraisal | journal = J Chemother | volume = 15 | issue = 3 | pages = 220–5 |date=June 2003 | pmid = 12868546 | doi = 10.1179/joc.2003.15.3.220 | s2cid = 29442148}}</ref> The [[mechanism of action]] of the appetite-related effects of these two medications is unknown and may not be related to their progestogenic activity. Very high doses of other progestogens, like [[cyproterone acetate]], have minimal or no influence on appetite and weight.

==Contraindications==
[[Contraindication]]s of progestogens may include [[breast cancer]] and a history of [[venous thromboembolism]] among others.<ref>{{cite web|url=https://www.stoptheclot.org/about-clots/webinar_contra/birth_control_clots/|title=IS IT TRUE THAT BIRTH CONTROL PILLS CAUSE BLOOD CLOTS?|work=[[National Blood Clot Alliance]]|access-date=15 April 2019|url-status=live|archive-url=https://web.archive.org/web/20190415024630/https://www.stoptheclot.org/about-clots/webinar_contra/birth_control_clots/|archive-date=15 April 2019}}</ref>{{citation needed|date=July 2018}}

==Side effects==
Progestogens have relatively few [[side effect]]s at typical dosages.<ref name="pmid2215269t">{{cite journal | vauthors = Lauritzen C | title = Clinical use of oestrogens and progestogens | journal = Maturitas | volume = 12 | issue = 3 | pages = 199–214 | date = September 1990 | pmid = 2215269 | doi = 10.1016/0378-5122(90)90004-P}}</ref> Side effects of progestogens may include [[tiredness]], [[dysphoria]], [[depression (mood)|depression]], [[mood (psychology)|mood]] changes, [[irregular menstruation|menstrual irregularities]], [[hypomenorrhea]], [[edema]], [[vaginal dryness]], [[vaginal atrophy]], [[headache]]s, [[nausea]], [[breast tenderness]], decreased [[libido]].<ref name="pmid16112947t" /><ref name="pmid15358281" /><ref name="pmid2215269t" /> Progestins with androgenic activity, namely 19-nortestosterone derivatives, can also cause [[acne]], [[hirsutism]], [[seborrhea]], [[voice deepening]], changes in [[liver protein production]] (e.g., decreased [[HDL cholesterol]], [[sex hormone-binding globulin]]), increased [[appetite]], and [[weight gain]], among others.<ref name="pmid16112947t" /><ref name="pmid2215269t" /> Other side effects of progestogens may include an increased risk of [[breast cancer]], [[cardiovascular disease]], and [[blood clot]]s, among others.<ref name="pmid15358281" /> Some of the side effects of progestogens are due not to their progestogenic activity but rather due to [[off-target activity|off-target activities]] (e.g., [[androgen]]ic activity, [[glucocorticoid]] activity, [[antimineralocorticoid]] activity).<ref name="pmid16112947t" /><ref name="pmid21414337" /> At high doses, due to their [[antigonadotropic]] effects, progestogens can cause [[hypogonadism|low sex hormone levels]] and associated side effects like diminished [[secondary sexual characteristics]], [[sexual dysfunction]] (e.g., reduced [[sex drive]] and [[erectile dysfunction]]), reversible [[infertility]], reduced [[bone mineral density]], and an increased risk of [[bone fracture]]s, both in men and in [[premenopause|premenopausal]] women.<ref name="pmid20459370" />

{{Health risks in the conjugated estrogens and medroxyprogesterone acetate substudy of the Women's Health Initiative}}

===Mood changes===

====Birth control====
The available evidence on the risk of [[mood (psychology)|mood]] changes and [[depression (mood)|depression]] with progestogens in [[hormonal birth control]] is limited.<ref name="pmid27636867">{{cite journal | vauthors = Schaffir J, Worly BL, Gur TL | title = Combined hormonal contraception and its effects on mood: a critical review | journal = Eur J Contracept Reprod Health Care | volume = 21 | issue = 5 | pages = 347–55 | date = October 2016 | pmid = 27636867 | doi = 10.1080/13625187.2016.1217327 | s2cid = 11959163}}</ref><ref name="pmid22467147">{{cite journal | vauthors = Böttcher B, Radenbach K, Wildt L, Hinney B | title = Hormonal contraception and depression: a survey of the present state of knowledge | journal = Arch. Gynecol. Obstet. | volume = 286 | issue = 1 | pages = 231–6 | date = July 2012 | pmid = 22467147 | doi = 10.1007/s00404-012-2298-2 | s2cid = 26204975}}</ref> As of 2019, there is no consistent evidence for adverse effects on mood of hormonal birth control, including [[progestogen-only birth control]] and [[combined birth control]], in the general population.<ref name="pmid31172309">{{cite journal | vauthors = Robakis T, Williams KE, Nutkiewicz L, Rasgon NL | title = Hormonal Contraceptives and Mood: Review of the Literature and Implications for Future Research | journal = Curr Psychiatry Rep | volume = 21 | issue = 7 | page = 57 | date = June 2019 | pmid = 31172309 | doi = 10.1007/s11920-019-1034-z | s2cid = 174818119}}</ref><ref name="pmid29496297" /> Most women taking [[combined birth control]] experience no influence or a beneficial effect on mood.<ref name="pmid27636867" /><ref name="pmid29496297" /><ref name="pmid22467147" /> Adverse effects on mood appear to be infrequent, occurring only in a small percentage of women.<ref name="pmid27636867" /><ref name="pmid29496297" /><ref name="pmid22467147" /> About 5 to 10% of women experience negative mood changes with combined birth control pills, and about 5% of women discontinue birth control pills due to such changes.<ref name="pmid22136510">{{cite journal | vauthors = Poromaa IS, Segebladh B | title = Adverse mood symptoms with oral contraceptives | journal = Acta Obstet Gynecol Scand | volume = 91 | issue = 4 | pages = 420–7 | date = April 2012 | pmid = 22136510 | doi = 10.1111/j.1600-0412.2011.01333.x | s2cid = 43671664| doi-access = free }}</ref><ref name="pmid27636867" /> A study of about 4,000&nbsp;women found that progestogen-only birth control with [[depot effect|depot]] [[medroxyprogesterone acetate]] had an incidence of depression of 1.5% and discontinuation due to depression of 0.5%.<ref name="pmid29496297" /><ref name="pmid18470526">{{cite journal | vauthors = Bakry S, Merhi ZO, Scalise TJ, Mahmoud MS, Fadiel A, Naftolin F | title = Depot-medroxyprogesterone acetate: an update | journal = Arch. Gynecol. Obstet. | volume = 278 | issue = 1 | pages = 1–12 | date = July 2008 | pmid = 18470526 | doi = 10.1007/s00404-007-0497-z | s2cid = 11340062}}</ref><ref name="pmid9649914">{{cite journal | vauthors = Westhoff C, Truman C, Kalmuss D, Cushman L, Davidson A, Rulin M, Heartwell S | title = Depressive symptoms and Depo-Provera | journal = Contraception | volume = 57 | issue = 4 | pages = 237–40 | date = April 1998 | pmid = 9649914 | doi = 10.1016/s0010-7824(98)00024-9| doi-access = free }}</ref> Beneficial effects of hormonal birth control such as decreased [[menstrual pain]] and [[menstrual bleeding|bleeding]] may positively influence mood.<ref name="pmid27636867" />

A 2018 [[systematic review]] of 26&nbsp;studies, including 5&nbsp;[[randomized controlled trial]]s and 21&nbsp;[[observational study|observational studies]], found that the overall evidence showed no association between [[progestogen-only birth control]] and depression.<ref name="pmid29496297">{{cite journal | vauthors = Worly BL, Gur TL, Schaffir J | title = The relationship between progestin hormonal contraception and depression: a systematic review | journal = Contraception | volume = 97 | issue = 6 | pages = 478–489 | date = June 2018 | pmid = 29496297 | doi = 10.1016/j.contraception.2018.01.010| s2cid = 3644828 }}</ref> The progestins assessed included depot [[medroxyprogesterone acetate]], [[levonorgestrel]]-containing [[contraceptive implant]]s and [[hormonal IUDs|intrauterine device]]s, and [[progestogen-only birth control pill]]s.<ref name="pmid29496297" /> Findings of large observational studies are mixed due to prominent [[confounding factor]]s, but overall show no association of hormonal birth control with depression.<ref name="pmid31172309" /><ref name="pmid29496297" /> Randomized controlled trials typically do not find clinically significant influences of hormonal birth control on mood.<ref name="pmid31172309" /><ref name="pmid29496297" /> [[Literature review|Reviews]] from before 1980 reported a high incidence of adverse mood effects with combined birth control pills.<ref name="pmid27636867" /> However, doses of estrogens and progestogens in birth control pills before 1980 were considerably higher than those used today, and these doses frequently caused unpleasant side effects that may have unfavorably influenced mood.<ref name="pmid27636867" /><ref name="pmid11585017">{{cite journal | vauthors = Kahn LS, Halbreich U | title = Oral contraceptives and mood | journal = Expert Opin Pharmacother | volume = 2 | issue = 9 | pages = 1367–82 | date = September 2001 | pmid = 11585017 | doi = 10.1517/14656566.2.9.1367 | s2cid = 45061663}}</ref>

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 }}</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>

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" />

====Hormone therapy====
Estrogen therapy appears to have a beneficial influence on mood in [[depression (mood)|depressed]] and [[euthymia (medicine)|euthymic]] [[perimenopausal]] women.<ref name="pmid30182804">{{cite journal | vauthors = Maki PM, Kornstein SG, Joffe H, Bromberger JT, Freeman EW, Athappilly G, Bobo WV, Rubin LH, Koleva HK, Cohen LS, Soares CN | title = Guidelines for the Evaluation and Treatment of Perimenopausal Depression: Summary and Recommendations | journal = J Womens Health (Larchmt) | volume = 28 | issue = 2 | pages = 117–134 | date = February 2019 | pmid = 30182804 | doi = 10.1089/jwh.2018.27099.mensocrec | doi-access = free}}</ref><ref name="pmid31740049">{{cite journal | vauthors = Stute P, Spyropoulou A, Karageorgiou V, Cano A, Bitzer J, Ceausu I, Chedraui P, Durmusoglu F, Erkkola R, Goulis DG, Lindén Hirschberg A, Kiesel L, Lopes P, Pines A, Rees M, van Trotsenburg M, Zervas I, Lambrinoudaki I | title = Management of depressive symptoms in peri- and postmenopausal women: EMAS position statement | journal = Maturitas | volume = 131 | pages = 91–101 | date = January 2020 | pmid = 31740049 | doi = 10.1016/j.maturitas.2019.11.002 | doi-access = free}}</ref><ref name="pmid31581598">{{cite journal | vauthors = Gava G, Orsili I, Alvisi S, Mancini I, Seracchioli R, Meriggiola MC | title = Cognition, Mood and Sleep in Menopausal Transition: The Role of Menopause Hormone Therapy | journal =  Medicina| volume = 55 | issue = 10 | page = 668| date = October 2019 | pmid = 31581598 | pmc = 6843314 | doi = 10.3390/medicina55100668| doi-access = free }}</ref> Conversely, research on combined estrogen and progestogen therapy for depressive symptoms in menopausal women is scarce and inconclusive.<ref name="pmid30182804" /><ref name="pmid31740049" /> Some researchers contend that progestogens have an adverse influence on mood and reduce the benefits of estrogens on mood,<ref name="pmid25203891">{{cite journal | vauthors = Toffol E, Heikinheimo O, Partonen T | title = Hormone therapy and mood in perimenopausal and postmenopausal women: a narrative review | journal = Menopause | volume = 22 | issue = 5 | pages = 564–78 | date = May 2015 | pmid = 25203891 | doi = 10.1097/GME.0000000000000323 | s2cid = 5830652}}</ref><ref name="pmid9203229">{{cite journal | vauthors = Zweifel JE, O'Brien WH | title = A meta-analysis of the effect of hormone replacement therapy upon depressed mood | journal = Psychoneuroendocrinology | volume = 22 | issue = 3 | pages = 189–212 | date = April 1997 | pmid = 9203229 | doi = 10.1016/s0306-4530(96)00034-0 | s2cid = 44630030}}</ref><ref name="pmid15358281">{{cite journal | vauthors = Wiegratz I, Kuhl H | title = Progestogen therapies: differences in clinical effects? | journal = Trends Endocrinol. Metab. | volume = 15 | issue = 6 | pages = 277–85 | date = August 2004 | pmid = 15358281 | doi = 10.1016/j.tem.2004.06.006 | s2cid = 35891204}}</ref> whereas other researchers maintain that progestogens have no adverse influence on mood.<ref name="Lobo2007">{{cite book|author=Rogerio A. Lobo|title=Treatment of the Postmenopausal Woman: Basic and Clinical Aspects|url=https://books.google.com/books?id=gywV9hkcyOMC&pg=PA211|date=5 June 2007|publisher=Elsevier|isbn=978-0-08-055309-2|pages=211–}}</ref><ref name="pmid25308388">{{cite journal | vauthors = Gordon JL, Girdler SS | title = Hormone replacement therapy in the treatment of perimenopausal depression | journal = Curr Psychiatry Rep | volume = 16 | issue = 12 | page = 517 | date = December 2014 | pmid = 25308388 | doi = 10.1007/s11920-014-0517-1 | s2cid = 23794180}}</ref> Progesterone differs from progestins in terms of effects in the [[brain]] and might have different effects on mood in comparison.<ref name="pmid15358281" /><ref name="pmid24680649">{{cite journal | vauthors = Fischer B, Gleason C, Asthana S | title = Effects of hormone therapy on cognition and mood | journal = Fertil. Steril. | volume = 101 | issue = 4 | pages = 898–904 | date = April 2014 | pmid = 24680649 | pmc = 4330961 | doi = 10.1016/j.fertnstert.2014.02.025}}</ref><ref name="pmid16112947t" /> The available evidence, although limited, suggests no adverse influence of progesterone on mood when used in menopausal hormone therapy.<ref name="pmid29962247">{{cite journal | vauthors = Prior JC | title = Progesterone for treatment of symptomatic menopausal women | journal = Climacteric | volume = 21 | issue = 4 | pages = 358–365 | date = August 2018 | pmid = 29962247 | doi = 10.1080/13697137.2018.1472567 | doi-access = free}}</ref>

===Sexual function===
In most women, [[sexual desire]] is unchanged or increased with combined birth control pills.<ref name="pmid23320933">{{cite journal | vauthors = Pastor Z, Holla K, Chmel R | title = The influence of combined oral contraceptives on female sexual desire: a systematic review | journal = Eur J Contracept Reprod Health Care | volume = 18 | issue = 1 | pages = 27–43 | date = February 2013 | pmid = 23320933 | doi = 10.3109/13625187.2012.728643 | s2cid = 34748865}}</ref> This is despite an increase in [[sex hormone-binding globulin]] (SHBG) levels and a decrease in total and free [[testosterone]] levels.<ref name="pmid23320933" /><ref name="pmid24082040">{{cite journal | vauthors = Zimmerman Y, Eijkemans MJ, Coelingh Bennink HJ, Blankenstein MA, Fauser BC | title = The effect of combined oral contraception on testosterone levels in healthy women: a systematic review and meta-analysis | journal = Hum. Reprod. Update | volume = 20 | issue = 1 | pages = 76–105 | date = 2014 | pmid = 24082040 | pmc = 3845679 | doi = 10.1093/humupd/dmt038}}</ref> However, findings are conflicting, and more research is needed.<ref name="pmid31242625">{{cite journal | vauthors = Casado-Espada NM, de Alarcón R, de la Iglesia-Larrad JI, Bote-Bonaechea B, Montejo ÁL | title = Hormonal Contraceptives, Female Sexual Dysfunction, and Managing Strategies: A Review | journal =  Journal of Clinical Medicine| volume = 8 | issue = 6 | page = 908| date = June 2019 | pmid = 31242625 | pmc = 6617135 | doi = 10.3390/jcm8060908| doi-access = free }}</ref>

===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&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 | 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>

====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 | 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>

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>

====Estrogen plus progestogen therapy====
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" />

A 2012 [[meta-analysis]] estimated that the [[absolute risk]] of VTE is 2 per 10,000 women for non-use, 8 per 10,000 women for ethinylestradiol and levonorgestrel-containing birth control pills, and 10 to 15 per 10,000 women for birth control pills containing ethinylestradiol and a newer-generation progestin.<ref name="pmid27793376" /> For comparison, the absolute risk of VTE is generally estimated as 1 to 5 per 10,000 woman-years for non-use, 5 to 20 per 10,000 woman-years for pregnancy, and 40 to 65 per 10,000 woman-years for the postpartum period.<ref name="pmid27793376" /> Risk of VTE with estrogen and progestogen therapy is highest at the start of treatment, particularly during the first year, and decreases over time.<ref name="pmid30008249" /><ref name="pmid31372078">{{cite journal | vauthors = Goldstein Z, Khan M, Reisman T, Safer JD | title = Managing the risk of venous thromboembolism in transgender adults undergoing hormone therapy | journal = J Blood Med | volume = 10 | pages = 209–216 | date = 2019 | pmid = 31372078 | pmc = 6628137 | doi = 10.2147/JBM.S166780 | doi-access = free }}</ref> Older [[ageing|age]], higher [[body weight]], lower [[physical activity]], and [[smoking]] are all associated with a higher risk of VTE with oral estrogen and progestogen therapy.<ref name="pmid30008249"/><ref name="pmid29526116">{{cite journal | vauthors = Davey DA | title = Menopausal hormone therapy: a better and safer future | journal = Climacteric | volume = 21| issue = 5| pages = 454–461 | date = March 2018 | pmid = 29526116 | doi = 10.1080/13697137.2018.1439915 | s2cid = 3850275 }}</ref><ref name="pmid31372078" /><ref name="pmid23136837">{{cite journal | vauthors = Roach RE, Lijfering WM, Helmerhorst FM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A | title = The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy | journal = J. Thromb. Haemost. | volume = 11 | issue = 1 | pages = 124–31 | date = January 2013 | pmid = 23136837 | doi = 10.1111/jth.12060 | s2cid = 22306721 | doi-access = free }}</ref> Women with [[thrombophilia]] have a dramatically higher risk of VTE with estrogen and progestogen therapy than women without thrombophilia.<ref name="pmid27793376" /><ref name="pmid23384743" /> Depending on the condition, risk of VTE can be increased as much as 50-fold in such women relative to non-use.<ref name="pmid27793376" /><ref name="pmid23384743" />

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 | 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>

{{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 | 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" />

:"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" />

[[Route of administration]] might also influence the cardiovascular health effects of progestogens, but more research is needed similarly.<ref name="pmid19340703">{{cite journal | vauthors = Nath A, Sitruk-Ware R | title = Parenteral administration of progestins for hormonal replacement therapy | journal = Eur J Contracept Reprod Health Care | volume = 14 | issue = 2 | pages = 88–96 | date = April 2009 | pmid = 19340703 | doi = 10.1080/13625180902747425 | s2cid = 43025098 }}</ref>

===Breast cancer===
Estrogen alone, progestogen alone, and combined estrogen and progestogen therapy are all associated with increased risks of breast cancer when used in [[menopausal hormone therapy]] for [[perimenopausal|peri-]] and [[postmenopausal]] women relative to non-use.<ref name="pmid31474332">{{cite journal | title = Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence | journal = Lancet | volume = 394 | issue = 10204 | pages = 1159–1168 | date = September 2019 | pmid = 31474332 | pmc = 6891893 | doi = 10.1016/S0140-6736(19)31709-X | author1 = Collaborative Group on Hormonal Factors in Breast Cancer }}</ref><ref name="pmid27898258">{{cite journal | vauthors = Yang Z, Hu Y, Zhang J, Xu L, Zeng R, Kang D | title = Estradiol therapy and breast cancer risk in perimenopausal and postmenopausal women: a systematic review and meta-analysis | journal = Gynecol. Endocrinol. | volume = 33 | issue = 2 | pages = 87–92 | year = 2017 | pmid = 27898258 | doi = 10.1080/09513590.2016.1248932 | s2cid = 205631264 }}</ref><ref name="pmid24485796">{{cite journal | vauthors = Lambrinoudaki I | title = Progestogens in postmenopausal hormone therapy and the risk of breast cancer | journal = Maturitas | volume = 77 | issue = 4 | pages = 311–7 | year = 2014 | pmid = 24485796 | doi = 10.1016/j.maturitas.2014.01.001 }}</ref> These risks are higher for combined estrogen and progestogen therapy than with estrogen alone or progestogen alone.<ref name="pmid31474332" /><ref name="pmid24485796" /> In addition to breast cancer risk, estrogen alone and estrogen plus progestogen therapy are associated with higher breast cancer [[mortality rate|mortality]].<ref name="pmid31474331">{{cite journal | vauthors = Beral V, Peto R, Pirie K, Reeves G | title = Menopausal hormone therapy and 20-year breast cancer mortality | journal = Lancet | volume = 394 | issue = 10204 | page = 1139 | date = September 2019 | pmid = 31474331 | doi = 10.1016/S0140-6736(19)32033-1 | doi-access = free }}</ref> With 20&nbsp;years of use, breast cancer incidence is about 1.5-fold higher with estrogen alone and about 2.5-fold higher with estrogen plus progestogen therapy relative to non-use.<ref name="pmid31474332" /> The increase in breast cancer risk with estrogen and progestogen therapy was shown to be causal with [[conjugated estrogens]] plus [[medroxyprogesterone acetate]] in the [[Women's Health Initiative]] [[randomized controlled trial]]s.<ref name="pmid29526116"/><ref name="pmid24291402">{{cite journal | vauthors = Stanczyk FZ, Bhavnani BR | title = Use of medroxyprogesterone acetate for hormone therapy in postmenopausal women: is it safe? | journal = J. Steroid Biochem. Mol. Biol. | volume = 142 | pages = 30–8 | date = July 2014 | pmid = 24291402 | doi = 10.1016/j.jsbmb.2013.11.011 | s2cid = 22731802 }}</ref>

Breast cancer risk with combined estrogen and progestogen therapy may differ depending on the progestogen used.<ref name="pmid27898258" /><ref name="pmid31474332" /><ref name="pmid23238854" /><ref name="pmid23651281" /> Progestins including [[chlormadinone acetate]], [[cyproterone acetate]], [[medrogestone]], [[medroxyprogesterone acetate]], [[nomegestrol acetate]], [[norethisterone acetate]], [[promegestone]], and [[tibolone]] have all been associated with similarly increased risk of breast cancer.<ref name="pmid23651281" /><ref name="pmid27898258" /><ref name="pmid31474332" /> Some research has found that [[oral progesterone]] and [[dydrogesterone]] with short-term use (<5&nbsp;years) may be associated with lower risk of breast cancer relative to other progestins.<ref name="pmid27898258" /><ref name="pmid31474332" /><ref name="pmid23238854" /><ref name="pmid23651281">{{cite journal | vauthors = Sturdee DW | title = Are progestins really necessary as part of a combined HRT regimen? | journal = Climacteric | volume = 16 | issue = Suppl 1 | pages = 79–84 | date = August 2013 | pmid = 23651281 | doi = 10.3109/13697137.2013.803311 | s2cid = 21894200}}</ref> In the long-term however (>5&nbsp;years), oral progesterone and dydrogesterone have been associated with significantly increased breast cancer risk similarly to other progestogens.<ref name="pmid31474332" /><ref name="pmid29630427">{{cite journal | vauthors = Mirkin S | title = Evidence on the use of progesterone in menopausal hormone therapy | journal = Climacteric | volume = 21 | issue = 4 | pages = 346–354 | date = August 2018 | pmid = 29630427 | doi = 10.1080/13697137.2018.1455657 | doi-access = free}}</ref> The lower risk of breast cancer with oral progesterone than with other progestogens may be related to the very low progesterone levels and relatively weak progestogenic effects it produces.<ref name="pmid23336704" /><ref name="pmid29526116" /><ref name="Kuhl2011t" />

The risk of breast cancer with estrogen and progestogen therapy in peri- and postmenopausal women is dependent on the duration of treatment, with more than 5&nbsp;years of use being associated with significantly greater risk than less than five years of use.<ref name="pmid31474332" /><ref name="pmid27898258" /> In addition, continuous estrogen and progestogen therapy is associated with a higher risk of breast cancer than cyclic use.<ref name="pmid31474332" /><ref name="pmid27898258" />

A nationwide [[observational study]] found that [[transfeminine hormone therapy]] with estrogen plus high-dose [[cyproterone acetate]] was associated with a 46-fold increased risk of breast cancer in [[transgender women]] relative to the expected incidence for [[cisgender men]].<ref name="pmid31088823">{{cite journal | vauthors = de Blok CJ, Wiepjes CM, Nota NM, van Engelen K, Adank MA, Dreijerink KM, Barbé E, Konings IR, den Heijer M | title = Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands | journal = BMJ | volume = 365 | pages = l1652 | date = May 2019 | pmid = 31088823 | pmc = 6515308 | doi = 10.1136/bmj.l1652 }}</ref><ref name="pmid31027551">{{cite journal | vauthors = de Blok CJ, Dreijerink KM, den Heijer M | title = Cancer Risk in Transgender People | journal = Endocrinol. Metab. Clin. North Am. | volume = 48 | issue = 2 | pages = 441–452 | date = June 2019 | pmid = 31027551 | doi = 10.1016/j.ecl.2019.02.005 | s2cid = 135382400 }}</ref><ref name="pmid31343858">{{cite journal | vauthors = Feingold KR, Anawalt B, Boyce A, Chrousos G, Dungan K, Grossman A, Hershman JM, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Perreault L, Purnell J, Rebar R, Singer F, Trence DL, Vinik A, Wilson DP, Nota NM, den Heijer M, Gooren LJ | title = Evaluation and Treatment of Gender-Dysphoric/Gender Incongruent Adults | year = 2000 |journal=Endotext [Internet] | pmid = 31343858 | url = https://www.ncbi.nlm.nih.gov/sites/books/NBK544426/}}</ref><ref name="pmid31516689">{{cite journal | vauthors = Iwamoto SJ, Defreyne J, Rothman MS, Van Schuylenbergh J, Van de Bruaene L, Motmans J, T'Sjoen G | title = Health considerations for transgender women and remaining unknowns: a narrative review | journal = Ther Adv Endocrinol Metab | volume = 10 | page = 2042018819871166 | date = 2019 | pmid = 31516689 | pmc = 6719479 | doi = 10.1177/2042018819871166 }}</ref> However, the risk of breast cancer was still lower than that in [[cisgender women]].<ref name="pmid31088823" /><ref name="pmid31027551" /><ref name="pmid31343858" /><ref name="pmid31516689" /> The extent to which the increase in breast cancer risk was related to estrogen versus cyproterone acetate is unknown.<ref name="pmid31088823" /><ref name="pmid31027551" /><ref name="pmid31343858" /><ref name="pmid31516689" />

{{Worldwide epidemiological evidence on breast cancer risk with menopausal hormone therapy}}

{{Risk of breast cancer with menopausal hormone therapy in large observational studies}}

{{Risk of breast cancer with menopausal hormone therapy by duration in large observational studies}}

==Overdose==
Progestogens are relatively safe in acute [[overdose]].{{Citation needed|date=July 2018}}

==Interactions==
[[Enzyme inhibitor|Inhibitor]]s and [[enzyme inducer|inducer]]s of [[cytochrome P450]] [[enzyme]]s and other enzymes such as [[5α-reductase]] may [[drug interaction|interact]] with progestogens.{{Citation needed|date=July 2018}}

==Pharmacology==

===Pharmacodynamics===
{{See also|Pharmacodynamics of progesterone}}

Progestogens act by binding to and activating the [[progesterone receptor]]s (PRs), including the [[progesterone receptor A|PR-A]], [[progesterone receptor B|PR-B]], and [[progesterone receptor C|PR-C]].<ref name="pmid16112947t" /><ref name="pmid21952082">{{cite journal | vauthors = Jacobsen BM, Horwitz KB | title = Progesterone receptors, their isoforms and progesterone regulated transcription | journal = Mol. Cell. Endocrinol. | volume = 357 | issue = 1–2 | pages = 18–29 | year = 2012 | pmid = 21952082 | pmc = 3272316 | doi = 10.1016/j.mce.2011.09.016 }}</ref><ref name="pmid20087430">{{cite journal | vauthors = Scarpin KM, Graham JD, Mote PA, Clarke CL | title = Progesterone action in human tissues: regulation by progesterone receptor (PR) isoform expression, nuclear positioning and coregulator expression | journal = Nucl Recept Signal | volume = 7 | pages = e009 | year = 2009 | pmid = 20087430 | pmc = 2807635 | doi = 10.1621/nrs.07009 }}</ref> Major [[tissue (biology)|tissue]]s affected by progestogens include the [[uterus]], [[cervix]], [[vagina]], [[breast]]s, and [[brain]].<ref name="pmid16112947t" /> By activating PRs in the [[hypothalamus]] and [[pituitary gland]], progestogens suppress the secretion of [[gonadotropin]]s and thereby function as [[antigonadotropin]]s at sufficiently high doses.<ref name="pmid16112947t" /> Progesterone interacts with [[membrane progesterone receptor]]s, but interaction of progestins with these receptors is less clear.<ref name="pmid22687885">{{cite journal | vauthors = Thomas P, Pang Y | title = Membrane progesterone receptors: evidence for neuroprotective, neurosteroid signaling and neuroendocrine functions in neuronal cells | journal = Neuroendocrinology | volume = 96 | issue = 2 | pages = 162–71 | year = 2012 | pmid = 22687885 | pmc = 3489003 | doi = 10.1159/000339822 }}</ref><ref name="pmid24065878">{{cite journal | vauthors = Petersen SL, Intlekofer KA, Moura-Conlon PJ, Brewer DN, Del Pino Sans J, Lopez JA | title = Novel progesterone receptors: neural localization and possible functions | journal = Frontiers in Neuroscience | volume = 7 | page = 164 | year = 2013 | pmid = 24065878 | pmc = 3776953 | doi = 10.3389/fnins.2013.00164 | doi-access = free }}</ref> In addition to their progestogenic activity, many progestogens have [[off-target activity|off-target activities]] such as [[androgen]]ic, [[antiandrogen]]ic, [[estrogen (medication)|estrogen]]ic, [[glucocorticoid]], and [[antimineralocorticoid]] activity.<ref name="pmid16112947t" /><ref name="pmid15358281" /><ref name="pmid21414337">{{cite journal | vauthors = Africander D, Verhoog N, Hapgood JP | title = Molecular mechanisms of steroid receptor-mediated actions by synthetic progestins used in HRT and contraception | journal = Steroids | volume = 76 | issue = 7 | pages = 636–52 | date = June 2011 | pmid = 21414337 | doi = 10.1016/j.steroids.2011.03.001 | s2cid = 23630452 }}</ref>

Progestogens mediate their contraceptive effects in women both by inhibiting [[ovulation]] (via their antigonadotropic effects) and by thickening [[Cervix#Cervical mucus|cervical mucus]], thereby preventing the possibility of [[fertilization]] of the [[egg cell|ovum]] by [[sperm]].<ref name="JamesonDeGroot2015" /><ref name="PattmanNathan2010" /> Progestogens have functional [[antiestrogen]]ic effects in various tissues like the [[endometrium]] via activation of the PR, and this underlies their use in menopausal hormone therapy (to prevent unopposed [[estrogen (medication)|estrogen]]-induced [[endometrial hyperplasia]] and [[endometrial cancer]]).<ref name="pmid16112947t" /> The PRs are induced in the breasts by estrogens, and for this reason, it is assumed that progestogens cannot mediate breast changes in the absence of estrogens.<ref name="pmid29852797">{{cite journal | vauthors = Gompel A, Plu-Bureau G | title = Progesterone, progestins and the breast in menopause treatment | journal = Climacteric | volume = 21 | issue = 4 | pages = 326–332 | date = August 2018 | pmid = 29852797 | doi = 10.1080/13697137.2018.1476483 | s2cid = 46922084 }}</ref> The off-target activities of progestogens can contribute both to their beneficial effects and to their adverse effects.<ref name="pmid16112947t" /><ref name="pmid15358281" /><ref name="pmid29137347" />

{{Pharmacodynamics of progestogens}}

{{Oral potencies of progestogens}}

{{Parenteral potencies of progestogens}}

====Antigonadotropic effects====
Progestogens, similarly to the androgens and estrogens through their own respective [[receptor (biochemistry)|receptors]], 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" />

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>

The [[retroprogesterone]] [[chemical derivative|derivative]]s [[dydrogesterone]] and [[trengestone]] are atypical progestogens and unlike all other clinically used progestogens do not have antigonadotropic effects nor inhibit ovulation even at very high doses.<ref name="pmid16112947t" /><ref name="HorskyPresl2012">{{cite book|author1=J. Horsky|author2=J. Presl|title=Ovarian Function and its Disorders: Diagnosis and Therapy|url=https://books.google.com/books?id=7IrpCAAAQBAJ&pg=PA329|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-009-8195-9|pages=329–}}</ref> In fact, trengestone may have [[progonadotropic]] effects, and is actually able to [[ovulation induction|''induce'' ovulation]], with about a 50% success rate on average.<ref name="HorskyPresl2012" /> These progestins also show other atypical properties relative to other progestogens, such as a lack of a [[hyperthermia|hyperthermic]] effect.<ref name="pmid16112947t" /><ref name="HorskyPresl2012" />

====Androgenic activity====
{{See also|Progestin-induced virilization}}

Some progestins have [[androgen]]ic activity and can produce androgenic [[side effect]]s such as increased [[sebum]] production ([[oily skin|oilier skin]]), [[acne]], and [[hirsutism]] (excessive facial/body hair growth), as well as changes in [[liver protein production]].<ref name="BullockBardin1977">{{cite journal | vauthors = Bullock LP, Bardin CW | title = Androgenic, synandrogenic, and antiandrogenic actions of progestins | journal = Annals of the New York Academy of Sciences | volume = 286 | issue = 1 Biochemical A | pages = 321–330 | date = March 1977 | pmid = 281183 | doi = 10.1111/j.1749-6632.1977.tb29427.x | s2cid = 33611807 | bibcode = 1977NYASA.286..321B }}</ref><ref name="Darney1995">{{cite journal | vauthors = Darney PD | title = The androgenicity of progestins | journal = The American Journal of Medicine | volume = 98 | issue = 1A | pages = 104S–110S | date = January 1995 | pmid = 7825629 | doi = 10.1016/S0002-9343(99)80067-9 }}</ref><ref name="CampagnoliClavel-Chapelon2005">{{cite journal | vauthors = Campagnoli C, Clavel-Chapelon F, Kaaks R, Peris C, Berrino F | title = Progestins and progesterone in hormone replacement therapy and the risk of breast cancer | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 96 | issue = 2 | pages = 95–108 | date = July 2005 | pmid = 15908197 | pmc = 1974841 | doi = 10.1016/j.jsbmb.2005.02.014 }}</ref> Only certain progestins are androgenic however, these being the [[testosterone]] derivatives and, to a lesser extent, the [[17α-hydroxyprogesterone]] derivatives [[medroxyprogesterone acetate]] and [[megestrol acetate]].<ref name="HugdahlWesterhausen2010">{{cite book|author1=Kenneth Hugdahl|author2=René Westerhausen|title=The Two Halves of the Brain: Information Processing in the Cerebral Hemispheres|url=https://books.google.com/books?id=v0RsKYmpe0UC&pg=PA272|year=2010|publisher=MIT Press|isbn=978-0-262-01413-7|pages=272–}}</ref><ref name="Darney1995" /><ref name="pmid14670641k">{{cite journal | vauthors = Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JH | title = Classification and pharmacology of progestins | journal = Maturitas | volume = 46 | issue = Suppl 1 | pages = S7–S16 | date = December 2003 | pmid = 14670641 | doi = 10.1016/j.maturitas.2003.09.014 }}</ref> No other progestins have such activity (though some, conversely, possess antiandrogenic activity).<ref name="Darney1995" /><ref name="pmid14670641k" /> Moreover, the androgenic activity of progestins within the testosterone derivatives also varies, and while some may have high or moderate androgenic activity, others have only low or no such activity.<ref name="Golan2008">{{cite book|author=David E. Golan|title=Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy|url=https://books.google.com/books?id=az8uSDkB0mgC&pg=PA520|year=2008|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-8355-2|pages=520–521}}</ref><ref name="WilliamsFoye2002">{{cite book|author1=David A. Williams|author2=William O. Foye|author3=Thomas L. Lemke|title=Foye's Principles of Medicinal Chemistry|url=https://books.google.com/books?id=qLJ6Bs1Qml4C&pg=PA700|date=January 2002|publisher=Lippincott Williams & Wilkins|isbn=978-0-683-30737-5|pages=700–}}</ref>

The androgenic activity of androgenic progestins is mediated by two mechanisms: 1) direct binding to and activation of the [[androgen receptor]]; and 2) displacement of [[testosterone]] from [[sex hormone-binding globulin]] (SHBG), thereby increasing free (and thus bioactive) testosterone levels.<ref name="Azziz2007">{{cite book|author=Ricardo Azziz|title=Androgen Excess Disorders in Women|url=https://books.google.com/books?id=Ch-BsGAOtucC&pg=PA124|date=8 November 2007|publisher=Springer Science & Business Media|isbn=978-1-59745-179-6|pages=124–}}</ref> The androgenic activity of many androgenic progestins is offset by combination with [[ethinylestradiol]], which robustly increases SHBG levels, and most oral contraceptives in fact markedly reduce free testosterone levels and can treat or improve acne and hirsutism.<ref name="Azziz2007" /> An exception is progestin-only contraceptives, which do not also contain an estrogen.<ref name="Azziz2007" />

The relative androgenic activity of testosterone-derivative progestins and other progestins that have androgenic activity can be roughly ranked as follows:

* Very high: [[danazol]], [[ethisterone]], [[gestrinone]], [[normethandrone]], [[norvinisterone]]<ref name="Bentley1980">{{cite book|author=P. J. Bentley|title=Endocrine Pharmacology: Physiological Basis and Therapeutic Applications|url=https://books.google.com/books?id=W6M9AAAAIAAJ&pg=PA4|year=1980|publisher=CUP Archive|isbn=978-0-521-22673-8|pages=4–}}</ref><ref name="Sengupta2007">{{cite book|author=Sengupta|title=Gynaecology For Postgraduate And Practitioners|url=https://books.google.com/books?id=ELkWa34eBz4C&pg=PA137|date=1 January 2007|publisher=Elsevier India|isbn=978-81-312-0436-8|pages=137–}}</ref><ref name="Ferin1962">{{cite journal | vauthors = Ferin J | title = Artificial induction of hypo-oestrogenic amenorrhea with methylestrenolone, or with lynestrenol | journal = Acta Endocrinologica | volume = 39 | issue = 1 | pages = 47–67 | date = January 1962 | pmid = 13892354 | doi = 10.1530/acta.0.0390047 }}</ref><ref name="SaundersDrill1956">{{cite journal | vauthors = Saunders FJ, Drill VA | title = The myotrophic and androgenic effects of 17-ethyl-19-nortestosterone and related compounds | journal = Endocrinology | volume = 58 | issue = 5 | pages = 567–572 | date = May 1956 | pmid = 13317831 | doi = 10.1210/endo-58-5-567 }}</ref>
* High: [[levonorgestrel]], [[norgestrel]], [[norgestrienone]], [[tibolone]]<ref name="Golan2008" /><ref name="WilliamsFoye2002" /><ref name="Bentley1980"/><ref name="LauritzenStudd2005" /><ref name="TashjianArmstrong2011">{{cite book|author1=Armen H. Tashjian|author2=Ehrin J. Armstrong|title=Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy|url=https://books.google.com/books?id=kjCCMZHInigC&pg=PA523|date=21 July 2011|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-1805-6|pages=523–}}</ref><ref name="de GooyerDeckers2003">{{cite journal | vauthors = de Gooyer ME, Deckers GH, Schoonen WG, Verheul HA, Kloosterboer HJ | title = Receptor profiling and endocrine interactions of tibolone | journal = Steroids | volume = 68 | issue = 1 | pages = 21–30 | date = January 2003 | pmid = 12475720 | doi = 10.1016/S0039-128X(02)00112-5 | quote = [Norethisterone] has similar and [norethynodrel] weaker androgenic effects compared to tibolone. | s2cid = 40426061 }}</ref><ref name="pmid16112947t" />
* Moderate: [[norethisterone]] and its [[prodrug]]s ([[norethisterone acetate]], [[norethisterone enanthate]], [[etynodiol diacetate]], [[lynestrenol]], [[quingestanol acetate]])<ref name="pmid3543501">{{cite journal | vauthors = Raynaud JP, Ojasoo T | title = The design and use of sex-steroid antagonists | journal = J. Steroid Biochem. | volume = 25 | issue = 5B | pages = 811–33 | year = 1986 | pmid = 3543501 | doi = 10.1016/0022-4731(86)90313-4| quote = Similar androgenic potential is inherent to norethisterone and its prodrugs (norethisterone acetate, ethynodiol diacetate, lynestrenol, norethynodrel, quingestanol).}}</ref><ref name="Golan2008" /><ref name="WilliamsFoye2002" /><ref name="TashjianArmstrong2011" /><ref name="Chaudhuri2007">{{cite book|author=Chaudhuri|title=Practice Of Fertility Control: A Comprehensive Manual|url=https://books.google.com/books?id=pzanxKlcU74C&pg=PA122|date=1 January 2007|publisher=Elsevier India|isbn=978-81-312-1150-2|pages=122–|edition=7Th}}</ref>
* Low: [[desogestrel]], [[etonogestrel]], [[gestodene]], [[norgestimate]]<ref name="TashjianArmstrong2011" /><ref name="Chaudhuri2007" /><ref name="pmid8808163">{{cite journal | vauthors = Kuhl H | title = Comparative pharmacology of newer progestogens | journal = Drugs | volume = 51 | issue = 2 | pages = 188–215 | year = 1996 | pmid = 8808163 | doi = 10.2165/00003495-199651020-00002| s2cid = 1019532}}</ref>
* Very low or negligible: [[allylestrenol]], [[dimethisterone]], [[medroxyprogesterone acetate]], [[megestrol acetate]], [[norelgestromin]], [[noretynodrel]], [[norgesterone]]<ref name="pmid16112947t" /><ref name="OffermannsRosenthal2008">{{cite book| vauthors = Offermanns S, Rosenthal W |title=Encyclopedia of Molecular Pharmacology|url=https://books.google.com/books?id=iwwo5gx8aX8C&pg=PA391|date=14 August 2008|publisher=Springer Science & Business Media|isbn=978-3-540-38916-3|pages=391–}}</ref><ref name="Marks2001">{{cite book|author=Lara Marks|title=Sexual Chemistry: A History of the Contraceptive Pill|url=https://books.google.com/books?id=GgvLA3bqwnoC&pg=PA77|year=2001|publisher=Yale University Press|isbn=978-0-300-08943-1|pages=73–75, 77–78}}</ref><ref name="pmid13753182">{{cite journal | vauthors = Korn GW | title = The use of norethynodrel (enovid) in clinical practice | journal = Canadian Medical Association Journal | volume = 84 | issue = 11 | pages = 584–587 | date = March 1961 | pmid = 13753182 | pmc = 1939348 | quote = Pseudohermaphroditism should not be a problem in these patients as it appears that norethynodrel does not possess androgenic properties, but it is believed that Wilkins has now found one such case in a patient who has been on norethynodrel therapy. }}</ref><ref name="pmid12475720">{{cite journal | vauthors = de Gooyer ME, Deckers GH, Schoonen WG, Verheul HA, Kloosterboer HJ | title = Receptor profiling and endocrine interactions of tibolone | journal = Steroids | volume = 68 | issue = 1 | pages = 21–30 | date = January 2003 | pmid = 12475720 | doi = 10.1016/s0039-128x(02)00112-5 | s2cid = 40426061 }}</ref><ref name="RuggieriMatscher1965">{{cite journal| vauthors = de Ruggieri P, Matscher R, Lupo C, Spazzoli G |title=Biological properties of 17α-vinyl-5(10)-estrene-17β-ol-3-one (norvinodrel) as a progestational and claudogenic compound|journal=Steroids|volume=5|issue=1|year=1965|pages=73–91|issn=0039-128X|doi=10.1016/0039-128X(65)90133-9}}</ref><ref name="SimpsonWeiner1997">{{cite book|author1=J. A. Simpson|author2=E. S. C. Weiner|title=Oxford English Dictionary Additions Series|url=https://books.google.com/books?id=gUGcAQAAQBAJ&pg=PA36|year=1997|publisher=Clarendon Press|isbn=978-0-19-860027-5|pages=36–}}</ref><ref name="JUCKER2013">{{cite book|author=JUCKER|title=Fortschritte der Arzneimittelforschung / Progress in Drug Research / Progrès des recherches pharmaceutiques|url=https://books.google.com/books?id=BH4ECAAAQBAJ&pg=PA166|date=8 March 2013|publisher=Birkhäuser|isbn=978-3-0348-7053-5|pages=166–}}</ref>
* Antiandrogenic: [[dienogest]], [[oxendolone]]<ref name="AcademicPress1989"/><ref name="pmid16112947t" />

The clinical androgenic and [[anabolic]] activity of the androgenic progestins listed above is still far lower than that of conventional [[androgen]]s and [[anabolic steroid]]s like [[testosterone (medication)|testosterone]] and [[nandrolone ester]]s. As such, they are only generally associated with such effects in women and often only at high doses. In men, due to their concomitant progestogenic activity and by extension antigonadotropic effects, these progestins can have potent functional antiandrogenic effects via suppression of testosterone production and levels.

====Antiandrogenic activity====
Some progestogens have [[antiandrogen]]ic activity in addition to their progestogenic activity.<ref name="pmid12600226">{{cite journal | vauthors = Raudrant D, Rabe T | title = Progestogens with antiandrogenic properties | journal = Drugs | volume = 63 | issue = 5 | pages = 463–492 | year = 2003 | pmid = 12600226 | doi = 10.2165/00003495-200363050-00003 | s2cid = 28436828 }}</ref> These progestogens, with varying degrees of potency as antiandrogens, include [[chlormadinone acetate]], [[cyproterone acetate]], [[dienogest]], [[drospirenone]], [[medrogestone]], [[megestrol acetate]], [[nomegestrol acetate]], [[osaterone acetate]] (veterinary), and [[oxendolone]].<ref name="pmid12600226" /><ref name="AcademicPress1989">{{cite book|title=Annual Reports in Medicinal Chemistry|url=https://books.google.com/books?id=HrALiG-4t7UC&pg=PA199|date=8 September 1989|publisher=Academic Press|isbn=978-0-08-058368-6|pages=199–}}</ref><ref name="pmid14644837">{{cite journal | vauthors = Schneider HP | title = Androgens and antiandrogens | journal = Annals of the New York Academy of Sciences | volume = 997 | issue = 1 | pages = 292–306 | date = November 2003 | pmid = 14644837 | doi = 10.1196/annals.1290.033 | s2cid = 8400556 | bibcode = 2003NYASA.997..292S }}</ref><ref name="BotellaParis1987">{{cite journal | vauthors = Botella J, Paris J, Lahlou B | title = The cellular mechanism of the antiandrogenic action of nomegestrol acetate, a new 19-nor progestagen, on the rat prostate | journal = Acta Endocrinologica | volume = 115 | issue = 4 | pages = 544–550 | date = August 1987 | pmid = 3630545 | doi = 10.1530/acta.0.1150544 }}</ref> The relative antiandrogenic activity in animals of some of these progestogens has been ranked as follows: cyproterone acetate (100%) > nomegestrol acetate (90%) > dienogest (30–40%) ≥ chlormadinone acetate (30%) = drospirenone (30%).<ref name="pmid16112947t" /><ref name="pmid17056444">{{cite journal | vauthors = Wiegratz I, Kuhl H | title = Metabolic and clinical effects of progestogens | journal = The European Journal of Contraception & Reproductive Health Care | volume = 11 | issue = 3 | pages = 153–161 | date = September 2006 | pmid = 17056444 | doi = 10.1080/13625180600772741 | s2cid = 27088428 }}</ref> Antiandrogenic activity in certain progestogens may help to improve symptoms of [[acne]], [[seborrhea]], [[hirsutism]], and other [[androgen-dependent condition]]s in women.<ref name="pmid16112947t" /><ref name="pmid12600226" />

====Estrogenic activity====
A few progestins have weak [[estrogen (medication)|estrogen]]ic activity.<ref name="pmid16112947t" /> These include the 19-nortestosterone derivatives [[norethisterone]], [[noretynodrel]], and [[tibolone]], as well as the norethisterone [[prodrug]]s<ref name="pmid2256526">{{cite journal | vauthors = Hammerstein J | title = Prodrugs: advantage or disadvantage? | journal = Am. J. Obstet. Gynecol. | volume = 163 | issue = 6 Pt 2 | pages = 2198–203 | year = 1990 | pmid = 2256526 | doi = 10.1016/0002-9378(90)90561-K}}</ref> [[norethisterone acetate]], [[norethisterone enanthate]], [[lynestrenol]], and [[etynodiol diacetate]].<ref name="pmid16112947t" /> The estrogenic activity of norethisterone and its prodrugs are due to [[metabolism]] into [[ethinylestradiol]].<ref name="pmid16112947t" /> High doses of norethisterone and noretynodrel have been associated with estrogenic side effects such as [[breast enlargement]] in women and [[gynecomastia]] in men, but also with alleviation of [[menopause|menopausal]] symptoms in postmenopausal women.<ref name="pmid13942007">{{cite journal | vauthors = Paulsen CA, Leach RB, Lanman J, Goldston N, Maddock WO, Heller CG | title = Inherent estrogenicity of norethindrone and norethynodrel: comparison with other synthetic progestins and progesterone | journal = J. Clin. Endocrinol. Metab. | volume = 22 | issue = 10| pages = 1033–9 | year = 1962 | pmid = 13942007 | doi = 10.1210/jcem-22-10-1033 }}</ref> In contrast, non-estrogenic progestins were not found to be associated with such effects.<ref name="pmid13942007" />

====Glucocorticoid activity====
Some progestogens, mainly certain [[17α-hydroxyprogesterone]] derivatives, have weak [[glucocorticoid]] activity.<ref name="NeumannDuesterberg1988">{{cite book| vauthors = Neumann F, Düsterberg B, Laurent H |title=Female Contraception |chapter=Development of Progestogens |year=1988|pages=129–140|doi=10.1007/978-3-642-73790-9_11|isbn=978-3-642-73792-3}}</ref> This can result, at sufficiently high doses, in side effects such as symptoms of [[Cushing's syndrome]], [[steroid diabetes]], [[adrenal insufficiency|adrenal suppression and insufficiency]], and [[neuropsychiatric]] symptoms like [[depression (mood)|depression]], [[anxiety]], [[irritability]], and [[cognitive impairment]].<ref name="NeumannDuesterberg1988" /><ref name="Harvey1996">{{cite book| vauthors = Harvey PW |title=Adrenal in Toxicology: Target Organ and Modulator of Toxicity|url=https://books.google.com/books?id=ifDqvypO4ikC&pg=PA284|date=28 March 1996|publisher=CRC Press|isbn=978-0-7484-0330-1|pages=284–}}</ref><ref name="CuschieriHanna2015">{{cite book| vauthors = Cuschieri A, Hanna G |title=Essential Surgical Practice: Higher Surgical Training in General Surgery, Fifth Edition|url=https://books.google.com/books?id=m2EDCwAAQBAJ&pg=PA899|date=20 January 2015|publisher=CRC Press|isbn=978-1-4441-3763-7|pages=899–}}</ref> Progestogens with the potential for clinically relevant glucocorticoid effects include the 17α-hydroxyprogesterone derivatives [[chlormadinone acetate]], [[cyproterone acetate]], [[medroxyprogesterone acetate]], [[megestrol acetate]], [[promegestone]], and [[segesterone acetate]] and the testosterone derivatives [[desogestrel]], [[etonogestrel]], and [[gestodene]].<ref name="pmid16112947t" /><ref name="Harvey1996" /><ref name="Thomas1997">{{cite book|author=John A. Thomas|title=Endocrine Toxicology, Second Edition|url=https://books.google.com/books?id=URc5JMoNirgC&pg=PA152|date=12 March 1997|publisher=CRC Press|isbn=978-1-4398-1048-4|pages=152–}}</ref><ref name="PanayBriggs2015">{{cite book|author1=Nick Panay|author2=Paula Briggs|author3=Gab Kovacs|title=Managing the Menopause|url=https://books.google.com/books?id=l0pLCgAAQBAJ&pg=PA126|date=20 August 2015|publisher=Cambridge University Press|isbn=978-1-107-45182-7|pages=126–}}</ref> Conversely, [[hydroxyprogesterone caproate]] possesses no such activity, while [[progesterone (medication)|progesterone]] itself has very weak glucocorticoid activity.<ref name="Meis2005">{{cite journal | vauthors = Meis PJ | title = 17 hydroxyprogesterone for the prevention of preterm delivery | journal = Obstetrics and Gynecology | volume = 105 | issue = 5 Pt 1 | pages = 1128–1135 | date = May 2005 | pmid = 15863556 | doi = 10.1097/01.AOG.0000160432.95395.8f }}</ref><ref name="pmid16112947t" />

{{Glucocorticoid activity of selected steroids in vitro}}

====Antimineralocorticoid activity====
Certain progestogens, including [[progesterone (medication)|progesterone]], [[drospirenone]], and [[gestodene]], as well as to a lesser extent [[dydrogesterone]] and [[trimegestone]], have varying degrees of [[antimineralocorticoid]] activity.<ref name="pmid16112947t" /><ref name="pmid29137347" /> Other progestins might also have significant antimineralocorticoid activity.<ref name="pmid32234237">{{cite journal | vauthors = Louw-du Toit R, Hapgood JP, Africander D | title = A direct comparison of the transcriptional activities of progestins used in contraception and menopausal hormone therapy via the mineralocorticoid receptor | journal = Biochem. Biophys. Res. Commun. | volume = 526 | issue = 2 | pages = 466–471 | date = May 2020 | pmid = 32234237 | doi = 10.1016/j.bbrc.2020.03.100 | pmc = 7287572 }}</ref> [[Progesterone (medication)|Progesterone]] itself has potent antimineralocorticoid activity.<ref name="pmid16112947t" /> No clinically used progestogens are known to have [[mineralocorticoid]] activity.<ref name="pmid16112947t" />

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>

====Neurosteroid activity====
Progesterone has [[neurosteroid]] activity via metabolism into [[allopregnanolone]] and [[pregnanolone]], potent [[positive allosteric modulator]]s of the [[GABAA receptor|GABA<sub>A</sub> 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 }}</ref>

====Other activities====
Certain progestins have been found to stimulate the [[cell proliferation|proliferation]] of [[MCF-7]] [[breast cancer]] [[cell (biology)|cell]]s ''[[in vitro]]'', an action that is independent of the classical PRs and is instead mediated via the [[progesterone receptor membrane component-1]] (PGRMC1).<ref name="pmid23758160">{{cite journal | vauthors = Neubauer H, Ma Q, Zhou J, Yu Q, Ruan X, Seeger H, Fehm T, Mueck AO | title = Possible role of PGRMC1 in breast cancer development | journal = Climacteric | volume = 16 | issue = 5 | pages = 509–13 | date = October 2013 | pmid = 23758160 | doi = 10.3109/13697137.2013.800038 | s2cid = 29808177 }}</ref> [[Norethisterone]], [[desogestrel]], [[levonorgestrel]], and [[drospirenone]] strongly stimulate proliferation and [[medroxyprogesterone acetate]], [[dienogest]], and [[dydrogesterone]] weakly stimulate proliferation, whereas [[progesterone (medication)|progesterone]], [[nomegestrol acetate]], and [[chlormadinone acetate]] act neutrally in the assay and do not stimulate proliferation.<ref name="pmid23758160" /><ref name="pmid22335423">{{cite journal | vauthors = Ruan X, Neubauer H, Yang Y, Schneck H, Schultz S, Fehm T, Cahill MA, Seeger H, Mueck AO | title = Progestogens and membrane-initiated effects on the proliferation of human breast cancer cells | journal = Climacteric | volume = 15 | issue = 5 | pages = 467–72 | date = October 2012 | pmid = 22335423 | doi = 10.3109/13697137.2011.648232 | s2cid = 11302554}}</ref> It is unclear whether these findings may explain the different risks of breast cancer observed with progesterone, dydrogesterone, and other progestins such as medroxyprogesterone acetate and norethisterone in [[clinical trial|clinical studies]].<ref name="pmid31512725">{{cite journal | vauthors = Trabert B, Sherman ME, Kannan N, Stanczyk FZ | title = Progesterone and breast cancer | journal = Endocr. Rev. | volume = 41| issue = 2| pages = 320–344| date = September 2019 | pmid = 31512725 | doi = 10.1210/endrev/bnz001 | pmc = 7156851 | doi-access = free}}</ref>

===Pharmacokinetics===
{{See also|Pharmacokinetics of progesterone}}

[[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 }}</ref>

Due to the poor oral activity of progesterone and its short duration with intramuscular injection, progestins were developed in its place both for oral use and for parenteral administration.<ref name="pmid19434889">{{cite journal | vauthors = Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JH | title = Classification and pharmacology of progestins | journal = Maturitas | volume = 61 | issue = 1–2 | pages = 171–80 | year = 2008 | pmid = 19434889 | doi = 10.1016/j.maturitas.2008.11.013 | url = http://www1.elsevier.com/homepage/sab/womenshealth/doc/journals/maturitas_si/2.pdf}} {{dead link|date=April 2018 |bot=InternetArchiveBot |fix-attempted=yes}}</ref> Orally active progestins have high oral bioavailability in comparison to oral micronized progesterone.<ref name="pmid16112947t" /> Their bioavailability is generally in the range of 60 to 100%.<ref name="pmid16112947t" /> Their elimination half-lives are also much longer than that of progesterone, in the range of 8 to 80&nbsp;hours.<ref name="pmid16112947t" /> Due mainly to their [[pharmacokinetic]] improvements, progestins have oral potency that is up to several orders of magnitude greater than that of oral micronized progesterone.<ref name="pmid16112947t" /> For example, the oral potency of medroxyprogesterone acetate is at least 30-fold that of oral micronized progesterone, while the oral potency of [[gestodene]] is at least 10,000-fold that of oral micronized progesterone.<ref name="pmid16112947t" /> Parenterally administered progestins, such as [[hydroxyprogesterone caproate]] in oil solution, [[norethisterone enanthate]] in oil solution, and medroxyprogesterone acetate in [[microcrystalline]] [[aqueous suspension]], have durations in the range of weeks to months.<ref name="RunnebaumRabe2012t">{{cite book|author1=Benno Clemens Runnebaum|author2=Thomas Rabe|author3=Ludwig Kiesel|title=Female Contraception: Update and Trends|url=https://books.google.com/books?id=LtT6CAAAQBAJ&pg=PA429|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-73790-9|pages=429–}}</ref><ref name="KnörrBeller2013t">{{cite book| vauthors = Knörr K, Knörr-Gärtner H, Beller FK, Lauritzen C |title=Lehrbuch der Gynäkologie|url=https://books.google.com/books?id=ACybBwAAQBAJ&pg=PA214|date=17 April 2013|publisher=Springer-Verlag|isbn=978-3-662-00942-0|pages=214–}}</ref><ref name="KnörrKnörr-Gärtner2013t">{{cite book| vauthors = Knörr K, Knörr-Gärtner H, Beller FK, Lauritzen C |title=Geburtshilfe und Gynäkologie: Physiologie und Pathologie der Reproduktion|url=https://books.google.com/books?id=tpmgBgAAQBAJ&pg=PA583|date=8 March 2013|publisher=Springer-Verlag|isbn=978-3-642-95583-9|pages=583–}}</ref><ref name="Labhart2012x">{{cite book|author=A. Labhart|title=Clinical Endocrinology: Theory and Practice|url=https://books.google.com/books?id=DAgJCAAAQBAJ&pg=PA554|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-96158-8|pages=554–}}</ref><ref name="HorskyPresl1981t">{{cite book| vauthors = Horský J, Presl J |title=Ovarian Function and its Disorders |chapter=Hormonal Treatment of Disorders of the Menstrual Cycle|pages=309–332|doi=10.1007/978-94-009-8195-9_11| veditors = Horsky J, Presl J |chapter-url=https://books.google.com/books?id=7IrpCAAAQBAJ&pg=PA313|date=1981|publisher=Springer Science & Business Media|isbn=978-94-009-8195-9}}</ref>

{{Pharmacokinetics of progestogens}}

==Chemistry==
{{See also|List of progestogens|Progestogen ester|List of progestogen esters}}

All currently available progestogens are [[steroid]]al in terms of [[chemical structure]].<ref name="pmid16112947t" /> Progestogens include the [[natural product|naturally occurring]] [[progesterone (medication)|progesterone]] and the [[synthetic compound|synthetic]] progestogens (otherwise known as progestins).<ref name="pmid16112947t" /> Progestins can be broadly grouped into two structural classes—[[chemical derivative]]s of [[progesterone (medication)|progesterone]] and chemical derivatives of [[testosterone (medication)|testosterone]].<ref name="pmid16112947t" /> Progesterone derivatives can be classified into subgroups including [[pregnane]]s, [[retropregnane]]s, [[norpregnane]]s, and [[spirolactone]]s.<ref name="pmid16112947t" /> Examples of progestins of each of these subgroups include [[medroxyprogesterone acetate]], [[dydrogesterone]], [[nomegestrol acetate]], and [[drospirenone]], respectively.<ref name="pmid16112947t" /> Testosterone derivatives can be classified into subgroups including [[androstane]]s, [[estrane]]s (19-norandrostanes), and [[gonane]]s (18-methylestranes).<ref name="pmid16112947t" /><ref name="pmid10715364">{{cite journal | vauthors = Edgren RA, Stanczyk FZ | title = Nomenclature of the gonane progestins | journal = Contraception | volume = 60 | issue = 6 | page = 313 | date = December 1999 | pmid = 10715364 | doi = 10.1016/s0010-7824(99)00101-8}}</ref> Examples of progestins of each of these subgroups include [[ethisterone]], [[norethisterone]], and [[levonorgestrel]], respectively.<ref name="pmid16112947t" /> Many progestins have [[ester]] and/or [[ether]] [[chemical substituent|substitution]]s (see [[progestogen ester]]) which result in greater [[lipophilicity]] and in some cases cause the progestins in question to act as [[prodrug]]s in the body.<ref name="pmid16112947t" />

{{Structural aspects of progestogens used in clinical and veterinary medicine}}

==History==
{| class="wikitable floatright plainrowheaders" style="font-size:small; margin-left: auto; margin-right: auto; border: none;"
|+ class="nowrap" | Historical progestogens no longer marketed for use
|-
! scope="col" style="width:100px;" | Generic name
! scope="col" style="width:50px;" | Class{{efn|group=progmarB1|1=Classes: P = [[progesterone]] derivative, T = [[testosterone]] derivative}}
! scope="col" style="width:80px;" | Brand name
! scope="col" style="width:50px;" | Route{{efn|group=progmarB1|1=Routes: IUD = [[intrauterine device]], PO = [[Oral administration|by mouth]], SC = [[Subcutaneous injection|subcutaneous injection or implant]], SL = [[sublingual|under the tongue]], TD = [[transdermal]], V = [[Vaginal administration|vaginal]]}}
! scope="col" style="width:50px;" | {{abbr|Intr.|Introduced in}}  
|-
! scope="row" style="background: #f8f9fa; | [[Anagestone acetate]]
| P{{efn-lr|group=progmarB2|name=17a|[[17α-Hydroxyprogesterone|17α-hydroxy]]}}{{efn-lr|group=progmarB2|name=ester|Ester}} || Anatropin || PO || 1968 
|-
! scope="row" style="background: #f8f9fa; | [[Chlormethenmadinone acetate]]
| P{{efn-lr|group=progmarB2|name=17a}}{{efn-lr|group=progmarB2|name=ester}} || Biogest{{efn|group=progmarB1|name=others|Also marketed under other brand names.}} || PO || 1960s 
|-
! scope="row" style="background: #f8f9fa; | [[Demegestone]]
| P{{efn-lr|group=progmarB2|name=19np|[[19-norprogesterone|19-nor]]}} || Lutionex || PO || 1974 
|-
! scope="row" style="background: #f8f9fa; | [[Dimethisterone]]
| T{{efn-lr|group=progmarB2|name=estrane|estrane}} || Lutagan{{efn|group=progmarB1|name=others}} || PO || 1959 
|-
! scope="row" style="background: #f8f9fa; | [[Ethisterone]]
| T{{efn-lr|group=progmarB2|name=estrane}} || Pranone{{efn|group=progmarB1|name=others}} || PO, {{abbrlink|SL|Sublingual}} || 1939 
|-
! scope="row" style="background: #f8f9fa; | [[Flumedroxone acetate]]
| P{{efn-lr|group=progmarB2|name=17a}}{{efn-lr|group=progmarB2|name=ester}} || Demigran{{efn|group=progmarB1|name=others}} || PO || 1960s 
|-
! scope="row" style="background: #f8f9fa; | [[Haloprogesterone]]
| P{{efn-lr|group=progmarB2|name=17b|[[17α-Bromoprogesterone|17-bromo]]}} || Prohalone || PO || 1961 
|-
! scope="row" style="background: #f8f9fa; | [[Hydroxyprogesterone acetate]]
| P{{efn-lr|group=progmarB2|name=17a}}{{efn-lr|group=progmarB2|name=ester}} || Prodox || PO || 1957 
|-
! scope="row" style="background: #f8f9fa; | [[Hydroxyprogesterone heptanoate]]
| P{{efn-lr|group=progmarB2|name=17a}}{{efn-lr|group=progmarB2|name=ester}} || H.O.P.{{efn|group=progmarB1|name=others}} || IM || 1950s 
|-
! scope="row" style="background: #f8f9fa; | [[Methenmadinone acetate]]
| P{{efn-lr|group=progmarB2|name=17a}}{{efn-lr|group=progmarB2|name=ester}} || Superlutin{{efn|group=progmarB1|name=others}} || PO || 1960s 
|-
! scope="row" style="background: #f8f9fa; | [[Noretynodrel]]
| T{{efn-lr|group=progmarB2|name=19nt|[[19-Nortestosterone|19-nor]]}}{{efn-lr|group=progmarB2|name=estrane}} || Enovid || PO || 1957 
|-
! scope="row" style="background: #f8f9fa; | [[Norgesterone]]
| T{{efn-lr|group=progmarB2|name=19nt}}{{efn-lr|group=progmarB2|name=estrane}} || Vestalin || PO || 1960s 
|-
! scope="row" style="background: #f8f9fa; | [[Norgestrienone]]
| T{{efn-lr|group=progmarB2|name=19nt}}{{efn-lr|group=progmarB2|name=estrane}} || Ogyline{{efn|group=progmarB1|name=others}} || PO || 1960s 
|-
! scope="row" style="background: #f8f9fa; | [[Norvinisterone]]
| T{{efn-lr|group=progmarB2|name=19nt}}{{efn-lr|group=progmarB2|name=estrane}} || Neoprogestin{{efn|group=progmarB1|name=others}} || PO || 1960s 
|-
! scope="row" style="background: #f8f9fa; | [[Pentagestrone acetate]]
| P{{efn-lr|group=progmarB2|name=17a}}{{efn-lr|group=progmarB2|name=ester}} || Gestovis{{efn|group=progmarB1|name=others}} || PO || 1961 
|-
! scope="row" style="background: #f8f9fa; | [[Quingestanol acetate]]
| T{{efn-lr|group=progmarB2|name=19nt}}{{efn-lr|group=progmarB2|name=gonane|Gonane}}{{efn-lr|group=progmarB2|name=ester}}{{efn-lr|group=progmarB2|name=ether|ether}} || Demovis{{efn|group=progmarB1|name=others}} || PO || 1972 
|-
! scope="row" style="background: #f8f9fa; | [[Quingestrone]]
| P{{efn-lr|group=progmarB2|name=ether}} || Enol-Luteovis || PO || 1962 
|-
! scope="row" style="background: #f8f9fa; | [[Trengestone]]
| RP || Retrone || PO || 1974 
|-
|- class="sortbottom"
| colspan="6" style="width: 1px; background-color:#eaecf0; text-align: center;" |{{hidden|header=Legend for class of molecule|content={{notelist-lr|group=progmarB2}}}}
|-
| colspan="6" style="width: 1px; background-color:#eaecf0; text-align: center;" |{{notelist|group=progmarB1}}
|}<!--

-->

The recognition of progesterone's ability to suppress [[ovulation]] during pregnancy spawned a search for a similar hormone that could bypass the problems associated with administering progesterone (e.g. low [[bioavailability]] when administered orally and local irritation and pain when continually administered [[parenteral]]ly) and, at the same time, serve the purpose of controlling ovulation. The many synthetic hormones that resulted are known as progestins.

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|url-access=subscription }}</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 |doi=10.1021/ja01645a009}}</ref>

[[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>

==Society and culture==

===Generations===
Progestins used in birth control are sometimes grouped, somewhat arbitrarily and inconsistently, into ''generations''. One categorization of these generations is as follows:<ref name="GordonRydfors2007">{{cite book|author1=John David Gordon|author2=Jan Rydfors|author3=Maurice Druzin|author4=Yasser El-Sayed|author5=Yona Tadir|title=Obstetrics, Gynecology & Infertility: Handbook for Clinicians|url=https://books.google.com/books?id=2JLC6yiA7fcC&pg=PA229|year=2007|publisher=Scrub Hill Press, Inc.|isbn=978-0-9645467-7-6|pages=229–}}</ref>

* First generation: Approved for marketing before 1973. Examples: [[noretynodrel]], [[norethisterone|norethisterone (norethindrone)]], [[lynestrenol]], [[levonorgestrel]].
* Second generation: Approved for marketing between 1973 and 1989. Examples: [[desogestrel]], [[nomegestrol acetate]], [[norgestimate]].
* Third generation: Approved for marketing between 1990 and 2000. Examples: [[dienogest]], [[etonogestrel]].
* Fourth generation: Approved for marketing after 2000. Examples: [[drospirenone]], [[norelgestromin]], [[segesterone acetate]].

Alternatively, [[estrane]]s such as [[noretynodrel]] and [[norethisterone]] are classified as first-generation while [[gonane]]s such as [[norgestrel]] and [[levonorgestrel]] are classified as second-generation, with less androgenic gonanes such as [[desogestrel]], [[norgestimate]], and [[gestodene]] classified as third-generation and newer progestins like [[drospirenone]] classified as fourth-generation.<ref name="Gibbs2008">{{cite book|author=Ronald S. Gibbs|title=Danforth's Obstetrics and Gynecology|url=https://books.google.com/books?id=v4krPhqFG8sC&pg=PA568|year=2008|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-6937-2|pages=568–}}</ref> Yet another classification system considers there to be only first- and second-generation progestins.{{Citation needed|date=October 2016}}

Classification of progestins by generation has been criticized and it has been argued that the classification scheme should be abandoned.<ref name="pmid32504633">{{cite journal | vauthors = Creinin MD, Jensen JT | title = Oral contraceptive generations - Time to stop using a marketing myth to define nomenclature | journal = Contraception | volume = 102 | issue = 3 | pages = 143–144 | date = September 2020 | pmid = 32504633 | doi = 10.1016/j.contraception.2020.05.017 | s2cid = 219529452 | url = https://escholarship.org/uc/item/6fc3157c}}</ref>

===Availability===
{{See also|List of progestogens available in the United States}}

Progestogens are available widely throughout the world in many different forms. They are present in all birth control pills.

===Etymology===
''Progestogens'', also termed ''progestagens'', ''progestogens'', or ''gestagens'', are compounds which act as [[agonist]]s of the [[progesterone receptor]]s.<ref name="pmid23238854"/><ref name="pmid16112947t" /><ref name="pmid18521110"/> Progestogens include ''[[progesterone (medication)|progesterone]]''—which is the main natural and endogenous progestogen—and ''progestins'', which are [[synthetic compound|synthetic]] progestogens.<ref name="pmid16112947t" /> Progestins include the [[17α-hydroxyprogesterone]] [[chemical derivative|derivative]] [[medroxyprogesterone acetate]] and the [[19-nortestosterone]] derivative [[norethisterone]], among many other synthetic progestogens.<ref name="pmid23238854" /><ref name="pmid16112947t" /> As progesterone is a single compound and has no plural form, the term "progesterones" does not exist and is grammatically incorrect.<ref name="pmid18521110" /> The terms describing progestogens are often confused.<ref name="pmid23238854" /><ref name="pmid18521110" /> However, progestogens have differing [[biological activity|activities]] and effects and it is inappropriate to interchange them.<ref name="pmid23238854" /><ref name="pmid16112947t" /><ref name="pmid18521110" />

==Research==
A variety of progestins have been studied for use as potential [[male contraceptive|male hormonal contraceptive]]s in combination with [[androgen]]s in men.<ref name="pmid20933120">{{cite journal | vauthors = Nieschlag E | title = Clinical trials in male hormonal contraception | journal = Contraception | volume = 82 | issue = 5 | pages = 457–70 | year = 2010 | pmid = 20933120 | doi = 10.1016/j.contraception.2010.03.020 | url = http://www.kup.at/kup/pdf/10172.pdf}}</ref> These include the [[pregnane]]s [[medroxyprogesterone acetate]], [[megestrol acetate]], and [[cyproterone acetate]], the [[norpregnane]] [[segesterone acetate]], and the [[estrane]]s [[norethisterone acetate]], [[norethisterone enanthate]], [[levonorgestrel]], [[levonorgestrel butanoate]], [[desogestrel]], and [[etonogestrel]].<ref name="pmid20933120" /><ref name="CoutifarisMastroianni1997">{{cite book|author1=C. Coutifaris|author2=L. Mastroianni|title=New Horizons in Reproductive Medicine|url=https://books.google.com/books?id=dmokq_M-gm8C&pg=PA101|date=15 August 1997|publisher=CRC Press|isbn=978-1-85070-793-6|pages=101–}}</ref><ref name="Singh2015">{{cite book|author=Shio Kumar Singh|title=Mammalian Endocrinology and Male Reproductive Biology|url=https://books.google.com/books?id=Y-KYCgAAQBAJ&pg=PA270|date=4 September 2015|publisher=CRC Press|isbn=978-1-4987-2736-5|pages=270–}}</ref><ref name="Frick1973">{{cite journal| vauthors = Frick J |title=Control of spermatogenesis in men by combined administration of progestin and androgen|journal=Contraception|volume=8|issue=3|year=1973|pages=191–206|issn=0010-7824|doi=10.1016/0010-7824(73)90030-9}}</ref> The androgens that have been used in combination with these progestins include [[testosterone (medication)|testosterone]], [[testosterone ester]]s, [[androstanolone]] (dihydrotestosterone), and [[nandrolone ester]]s.<ref name="pmid20933120" /> Dual androgens and progestogens such as [[trestolone]] and [[dimethandrolone undecanoate]] have also been developed and studied as male contraceptives.<ref name="pmid23063338">{{cite journal | vauthors = Nieschlag E, Kumar N, Sitruk-Ware R | title = 7α-methyl-19-nortestosterone (MENTR): the population council's contribution to research on male contraception and treatment of hypogonadism | journal = Contraception | volume = 87 | issue = 3 | pages = 288–95 | year = 2013 | pmid = 23063338 | doi = 10.1016/j.contraception.2012.08.036}}</ref><ref name="pmid16497801">{{cite journal | vauthors = Attardi BJ, Hild SA, Reel JR | title = Dimethandrolone undecanoate: a new potent orally active androgen with progestational activity | journal = Endocrinology | volume = 147 | issue = 6 | pages = 3016–26 | year = 2006 | pmid = 16497801 | doi = 10.1210/en.2005-1524 | doi-access = free}}</ref> Doses of progestins used in male hormonal contraception have been noted to be in the range of 5 to 12{{nbsp}}times the doses used in female hormonal contraception.<ref name="pmid6415998">{{cite journal | vauthors = Foegh M | title = Evaluation of steroids as contraceptives in men | journal = Acta Endocrinol Suppl (Copenh) | volume = 260 | issue = 3_Supplb| pages = 3–48 | date = 1983 | pmid = 6415998 | doi = 10.1530/acta.0.104S009 | url = | quote = At the time our studies were initiated, 11 different gestagens have been tested in men. All the oral preparations were used in doses 5 to 12 fold that used in the female oral contraceptive. The only exception was levo-norgestrel which was used in a very low dose, namely 100 µg daily (Fotherby et al. 1972). However, no effect was obtained on sperm count and in vitro sperm penetration.}}</ref>

==See also==
* [[Phytoprogestogen]]
* [[Antiprogestogen]]
* [[Selective progesterone receptor modulator]]

==References==
{{Reflist}}

==Further reading==
{{refbegin|30em}}
* {{cite journal | vauthors = Kuhl H | title = Pharmacokinetics of oestrogens and progestogens | journal = Maturitas | volume = 12 | issue = 3 | pages = 171–97 | date = September 1990 | pmid = 2170822 | doi = 10.1016/0378-5122(90)90003-o}}
* {{cite journal | vauthors = Lauritzen C | title = Clinical use of oestrogens and progestogens | journal = Maturitas | volume = 12 | issue = 3 | pages = 199–214 | date = September 1990 | pmid = 2215269 | doi = 10.1016/0378-5122(90)90004-P}}
* {{cite journal | vauthors = Stanczyk FZ | title = Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception | journal = Rev Endocr Metab Disord | volume = 3 | issue = 3 | pages = 211–24 | date = September 2002 | pmid = 12215716 | doi = 10.1023/A:1020072325818 | s2cid = 27018468}}
* {{cite journal | vauthors = Raudrant D, Rabe T | title = Progestogens with antiandrogenic properties | journal = Drugs | volume = 63 | issue = 5 | pages = 463–92 | date = 2003 | pmid = 12600226 | doi = 10.2165/00003495-200363050-00003| s2cid = 28436828}}
* {{cite journal | vauthors = Stanczyk FZ | title = All progestins are not created equal | journal = Steroids | volume = 68 | issue = 10–13 | pages = 879–90 | date = November 2003 | pmid = 14667980 | doi = 10.1016/j.steroids.2003.08.003| s2cid = 44601264}}
* {{cite journal | vauthors = Nieschlag E, Zitzmann M, Kamischke A | title = Use of progestins in male contraception | journal = Steroids | volume = 68 | issue = 10–13 | pages = 965–72 | date = November 2003 | pmid = 14667989 | doi = 10.1016/S0039-128X(03)00135-1| s2cid = 22458746}}
* {{cite journal | vauthors = Wiegratz I, Kuhl H | title = Progestogen therapies: differences in clinical effects? | journal = Trends Endocrinol. Metab. | volume = 15 | issue = 6 | pages = 277–85 | date = August 2004 | pmid = 15358281 | doi = 10.1016/j.tem.2004.06.006 | s2cid = 35891204}}
* {{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | pages = 3–63 | year = 2005 | issue = Suppl 1 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf}}
* {{cite journal | vauthors = Sitruk-Ware R | title = Pharmacology of different progestogens: the special case of drospirenone | journal = Climacteric | volume = 8 | pages = 4–12 | date = October 2005 | issue = Suppl 3 | pmid = 16203650 | doi = 10.1080/13697130500330382 | s2cid = 24205704}}
* {{cite journal | vauthors = Wiegratz I, Kuhl H | title = Metabolic and clinical effects of progestogens | journal = Eur J Contracept Reprod Health Care | volume = 11 | issue = 3 | pages = 153–61 | date = September 2006 | pmid = 17056444 | doi = 10.1080/13625180600772741 | s2cid = 27088428}}
* {{cite book | vauthors = Stanczyk FZ | title=Treatment of the Postmenopausal Woman|chapter=Structure –Function Relationships, Pharmacokinetics, and Potency of Orally and Parenterally Administered Progestogens|year=2007|pages=779–798|doi=10.1016/B978-012369443-0/50067-3|isbn=978-0-12-369443-0}}
* {{cite journal | vauthors = Sitruk-Ware R, Nath A | title = The use of newer progestins for contraception | journal = Contraception | volume = 82 | issue = 5 | pages = 410–7 | date = November 2010 | pmid = 20933114 | doi = 10.1016/j.contraception.2010.04.004}}
* {{cite journal | vauthors = Kuhl H | title = Pharmacology of progestogens | journal = Journal für Reproduktionsmedizin und Endokrinologie-Journal of Reproductive Medicine and Endocrinology | volume = 8 | issue = Special Issue 1 | pages = 157–176 | year = 2011 | url = http://www.kup.at/kup/pdf/10168.pdf}}
* {{cite journal | vauthors = Lawrie TA, Helmerhorst FM, Maitra NK, Kulier R, Bloemenkamp K, Gülmezoglu AM | title = Types of progestogens in combined oral contraception: effectiveness and side-effects | journal = Cochrane Database Syst Rev | issue = 5 | pages = CD004861 | date = May 2011 | pmid = 21563141 | doi = 10.1002/14651858.CD004861.pub2}}
* {{cite journal | vauthors = Endrikat J, Gerlinger C, Richard S, Rosenbaum P, Düsterberg B | title = Ovulation inhibition doses of progestins: a systematic review of the available literature and of marketed preparations worldwide | journal = Contraception | volume = 84 | issue = 6 | pages = 549–57 | date = December 2011 | pmid = 22078182 | doi = 10.1016/j.contraception.2011.04.009}}
* {{cite journal | vauthors = Moore NL, Hickey TE, Butler LM, Tilley WD | title = Multiple nuclear receptor signaling pathways mediate the actions of synthetic progestins in target cells | journal = Mol. Cell. Endocrinol. | volume = 357 | issue = 1–2 | pages = 60–70 | date = June 2012 | pmid = 21945474 | doi = 10.1016/j.mce.2011.09.019 | s2cid = 20006148}}
* {{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 = Endocr. Rev. | volume = 34 | issue = 2 | pages = 171–208 | date = April 2013 | pmid = 23238854 | pmc = 3610676 | doi = 10.1210/er.2012-1008}}
* {{cite journal | vauthors = Grimes DA, Lopez LM, O'Brien PA, Raymond EG | title = Progestin-only pills for contraception | journal = Cochrane Database Syst Rev | issue = 11 | pages = CD007541 | date = November 2013 | pmid = 24226383 | doi = 10.1002/14651858.CD007541.pub3| pmc = 11975192 }}
* {{cite journal | vauthors = Hapgood JP, Africander D, Louw R, Ray RM, Rohwer JM | title = Potency of progestogens used in hormonal therapy: toward understanding differential actions | journal = J. Steroid Biochem. Mol. Biol. | volume = 142 | pages = 39–47 | date = July 2014 | pmid = 23954501 | doi = 10.1016/j.jsbmb.2013.08.001 | s2cid = 12142015}}
* {{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}}
* {{cite journal | vauthors = Bińkowska M, Woroń J | title = Progestogens in menopausal hormone therapy | journal = Prz Menopauzalny | volume = 14 | issue = 2 | pages = 134–43 | date = June 2015 | pmid = 26327902 | pmc = 4498031 | doi = 10.5114/pm.2015.52154}}
{{refend}}

{{Progesterone}}
{{Progestogens and antiprogestogens}}
{{Progesterone receptor modulators}}
{{Portal bar|Medicine}}

[[Category:Contraception for males]]
[[Category:Galactagogues]]
[[Category:IARC Group 2B carcinogens]]
[[Category:Progestogens]]