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{{See also|Comparison of progestogens#Pharmacology}}
{{See also|Comparison of progestogens#Pharmacology}}


Progestins act by binding to and activating the [[progesterone receptor]] (PR).<ref name="pmid16112947" /> Major targets of action include the [[uterus]], [[cervix]], [[vagina]], [[breast]]s, and [[brain]].<ref name="pmid16112947" /> By activating PRs in the [[hypothalamus]] and [[pituitary gland]], progestins suppress the secretion of [[gonadotropin]]s and thereby function as [[antigonadotropin]]s at sufficiently high dosages.<ref name="pmid16112947" />
Progestins 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="pmid16112947" /><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 | url = }}</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 | issue = | pages = e009 | year = 2009 | pmid = 20087430 | pmc = 2807635 | doi = 10.1621/nrs.07009 | url = }}</ref> Major [[tissue (biology)|tissue]]s affected by progestogens include the [[uterus]], [[cervix]], [[vagina]], [[breast]]s, and [[brain]].<ref name="pmid16112947" /> By activating PRs in the [[hypothalamus]] and [[pituitary gland]], progestins suppress the secretion of [[gonadotropin]]s and thereby function as [[antigonadotropin]]s at sufficiently high dosages.<ref name="pmid16112947" /> Interaction of progestins with [[membrane progesterone receptor]]s 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 | issue = | pages = 164 | year = 2013 | pmid = 24065878 | pmc = 3776953 | doi = 10.3389/fnins.2013.00164 }}</ref>


===Antigonadotropic effects===
===Antigonadotropic effects===
Progestogens, similarly to the androgens and estrogens through their own respective [[receptor (biochemistry)|receptor]]s, inhibit the secretion of the [[gonadotropin]]s [[follicle-stimulating hormone]] (FSH) and [[luteinizing hormone]] (LH) via activation of the PR in the [[pituitary gland]]. This effect is a form of [[negative feedback]] on the [[hypothalamic–pituitary–gonadal axis]] (HPG axis) and takes advantage of the mechanism that the body uses to prevent [[sex hormone]] levels from becoming too high.<ref name="pmid10997774">{{cite journal |vauthors=de Lignières B, Silberstein S | title = Pharmacodynamics of oestrogens and progestogens | journal = Cephalalgia : an International Journal of Headache | volume = 20 | issue = 3 | pages = 200–7 |date=April 2000 | pmid = 10997774 | doi = 10.1046/j.1468-2982.2000.00042.x| url = http://cep.sagepub.com/cgi/pmidlookup?view=long&pmid=10997774}}</ref><ref name="pmid15752663">{{cite journal |vauthors=Chassard D, Schatz B | title = [The antigonadrotropic activity of chlormadinone acetate in reproductive women] | language = French | journal = Gynécologie, Obstétrique & Fertilité | volume = 33 | issue = 1-2 | pages = 29–34 | year = 2005 | pmid = 15752663 | doi = 10.1016/j.gyobfe.2004.12.002 | url = http://linkinghub.elsevier.com/retrieve/pii/S1297-9589(04)00378-9}}</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| url = http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0300-0664&date=2003&volume=58&issue=4&spage=506}}</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 Suppl 2 | issue = | pages = 11–24 | year = 1978 | pmid = 368741 | doi = | url = }}</ref> and progestins 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, similarly to the androgens and estrogens through their own respective [[receptor (biochemistry)|receptor]]s, inhibit the secretion of the [[gonadotropin]]s [[follicle-stimulating hormone]] (FSH) and [[luteinizing hormone]] (LH) via activation of the PR in the [[pituitary gland]]. This effect is a form of [[negative feedback]] on the [[hypothalamic–pituitary–gonadal axis]] (HPG axis) and takes advantage of the mechanism that the body uses to prevent [[sex hormone]] levels from becoming too high.<ref name="pmid10997774">{{cite journal |vauthors=de Lignières B, Silberstein S | title = Pharmacodynamics of oestrogens and progestogens | journal = Cephalalgia : an International Journal of Headache | volume = 20 | issue = 3 | pages = 200–7 |date=April 2000 | pmid = 10997774 | doi = 10.1046/j.1468-2982.2000.00042.x| url = http://cep.sagepub.com/cgi/pmidlookup?view=long&pmid=10997774}}</ref><ref name="pmid15752663">{{cite journal |vauthors=Chassard D, Schatz B | title = [The antigonadrotropic activity of chlormadinone acetate in reproductive women] | language = French | journal = Gynécologie, Obstétrique & Fertilité | volume = 33 | issue = 1-2 | pages = 29–34 | year = 2005 | pmid = 15752663 | doi = 10.1016/j.gyobfe.2004.12.002 | url = http://linkinghub.elsevier.com/retrieve/pii/S1297-9589(04)00378-9}}</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| url = http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0300-0664&date=2003&volume=58&issue=4&spage=506}}</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 Suppl 2 | issue = | pages = 11–24 | year = 1978 | pmid = 368741 | doi = | url = }}</ref> and progestins in sufficiently high amounts can markedly suppress the body's normal production of progestogens, androgens, and estrogens as well as inhibit [[fertility]] ([[ovulation]] in women and [[spermatogenesis]] in men).<ref name="pmid12641635" />


Progestins have been found to suppress circulating testosterone levels by up to 70 to 80% in men at sufficiently high dosages.<ref name="WeinKavoussi2011">{{cite book| first1 = Alan J. | last1 = Wein | first2 = Louis R. | last2 = Kavoussi | first3 = Andrew C. | last3 = Novick | first4 = Alan W. | last4 = Partin | first5 = Craig A. | last5 = Peters | name-list-format = vanc | 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| url = }}</ref> This is notably less than that achieved by [[GnRH analogue]]s, which 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> In addition, it is less than that achieved by estrogens, which can suppress testosterone levels into the castrate range at sufficiently high dosages 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| url = }}</ref>
Progestins have been found to suppress circulating testosterone levels by up to 70 to 80% in men at sufficiently high dosages.<ref name="WeinKavoussi2011">{{cite book| first1 = Alan J. | last1 = Wein | first2 = Louis R. | last2 = Kavoussi | first3 = Andrew C. | last3 = Novick | first4 = Alan W. | last4 = Partin | first5 = Craig A. | last5 = Peters | name-list-format = vanc | 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| url = }}</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| url = }}</ref>


[[Dydrogesterone]] is an atypical progestin and does not have antigonadotropic effects nor inhibit ovulation even at very high dosages.<ref name="pmid16112947" /> It is the only clinically used progestin that is known to lack such effects, and also shows a number of other atypical properties.<ref name="pmid16112947" /> This may be related to selective agonism of the [[progesterone receptor B|PR-B]].<ref name="CabezaHeuze2014">{{cite journal|last1=Cabeza|first1=Marisa|last2=Heuze|first2=Yvonne|last3=Sánchez|first3=Araceli|last4=Garrido|first4=Mariana|last5=Bratoeff|first5=Eugene|title=Recent advances in structure of progestins and their binding to progesterone receptors|journal=Journal of Enzyme Inhibition and Medicinal Chemistry|volume=30|issue=1|year=2014|pages=152–159|issn=1475-6366|doi=10.3109/14756366.2014.895719}}</ref>
[[Dydrogesterone]] is an atypical progestin and does not have antigonadotropic effects nor inhibit ovulation even at very high dosages.<ref name="pmid16112947" /> It is the only clinically used progestin that is known to lack such effects, and also shows a number of other atypical properties.<ref name="pmid16112947" /> This may be related to selective agonism of the [[progesterone receptor B|PR-B]].<ref name="CabezaHeuze2014">{{cite journal|last1=Cabeza|first1=Marisa|last2=Heuze|first2=Yvonne|last3=Sánchez|first3=Araceli|last4=Garrido|first4=Mariana|last5=Bratoeff|first5=Eugene|title=Recent advances in structure of progestins and their binding to progesterone receptors|journal=Journal of Enzyme Inhibition and Medicinal Chemistry|volume=30|issue=1|year=2014|pages=152–159|issn=1475-6366|doi=10.3109/14756366.2014.895719}}</ref>

Revision as of 23:40, 20 January 2018

Progestogen (medication)
Drug class
Norethisterone (norethindrone), one of the most widely used progestins.
Class identifiers
UseContraception, menopause, hypogonadism, transgender women, others
ATC codeG03D
Biological targetProgesterone receptors (PRA, PRB, PRC)
External links
MeSHD011372
Legal status
In Wikidata

A progestin is a type of medication which is used most commonly in hormonal birth control and menopausal hormone therapy.[1] They can also be used in the treatment of gynecological conditions, to support fertility and pregnancy, to lower sex hormone levels for various purposes, and for other indications.[1] Progestins are used alone or in combination with estrogens.[1] They are available in a wide variety of formulations and for use by many different routes of administration.[1]

Side effects of progestins include menstrual irregularities, headaches, nausea, breast tenderness, mood changes, acne, increased hair growth, and changes in liver protein production among others.[1][2] Other side effects of progestins include an increased risk of breast cancer, cardiovascular disease, and blood clots.[2] At high dosages, progestins can cause low sex hormone levels and associated side effects like sexual dysfunction and an increased risk of bone fractures.[3]

Progestins are synthetic progestogens and have similar effects to those of the natural hormone progesterone.[1] They act as agonists of the progesterone receptor and have important effects in the female reproductive system (uterus, cervix, and vagina), the breasts, and the brain.[1] In addition, many progestins also have other hormonal activities, such as androgenic, antiandrogenic, estrogenic, glucocorticoid, or antimineralocorticoid activity.[1] They also have antigonadotropic effects and at sufficiently high dosages can strongly suppress sex hormone production.[1]

Progestins were first introduced for medical use in 1939.[4][5][6] They started to be used in birth control in the 1950s.[4] Around 60 progestins have been marketed for clinical use in humans or use in veterinary medicine.[7][8][9][10][11] These progestins can be grouped into different classes and generations.[1][12][13] Progestins are available widely throughout the world and are present in all forms of hormonal birth control and in most menopausal hormone therapy regimens.[7][8][10][9][1]

Medical uses

Birth control

Progestins are used in a variety of different forms of hormonal birth control, including combined estrogen and progestogen forms like combined birth control pills, patches, and combined injectables; progestogen-only forms like progestin-only pills, implants, and intrauterine devices; and mixed forms like rings.[14][15][additional citation(s) needed]

It has been found that the most effective method of hormonal contraception is with a combination of an estrogen and a progestin. This can be done in a monophasic, biphasic, or triphasic manner. In the monophasic method, both an estrogen and a progestin are administered for 20 or 21 days and stopped for a 7- or 8-day period that includes the 5-day menstrual period. Sometimes, a 28-day regimen that includes 6 or 7 inert tablets is used. Newer biphasic and triphasic methods are now used to more closely simulate the normal menstrual cycle. Yet another method is to administer a small dose of progestin only (no estrogen) in order to decrease certain risks associated with administering estrogen, but a major side-effect is irregular bleeding usually observed during the first 18 months of such therapy.

Some progestins can be delivered by intramuscular injection every several months or released over time by diffusion from an implant or an intrauterine device depending on their solubility characteristics.

Combined androgen and progestin birth control forms have been studied for use in men.

Hormone therapy

Progestins are commonly used as a component of menopausal hormone therapy in women to prevent endometrial hyperplasia and increased risk of endometrial cancer from unopposed estrogen therapy. They are also used in transgender hormone therapy, including in both feminizing hormone therapy for transgender women (e.g., cyproterone acetate and medroxyprogesterone acetate to help suppress testosterone levels) and masculinizing hormone therapy in transgender men (e.g., medroxyprogesterone acetate to help suppress menses).

Certain progestins, including megestrol acetate, medroxyprogesterone acetate, cyproterone acetate, and chlormadinone acetate have been used to reduce hot flashes in men with prostate cancer.[16][17][18]

Gynecological disorders

Progestins are used to treat secondary amenorrhea, dysfunctional uterine bleeding, and endometriosis.[14][15] In a normal menstrual cycle, declining levels of progesterone triggers menstruation. Norethisterone acetate and medroxyprogesterone acetate may be used to artificially induce progestogen-associated breakthrough bleeding.[19]

Fertility medicine

Progestogens are used in fertility medicine for women. For example, progesterone (or sometimes dydrogesterone or hydroxyprogesterone caproate) is used for luteal support in IVF protocols.[20]

Pregnancy support

Certain progestins are used to support pregnancy, including hydroxyprogesterone caproate, dydrogesterone, and allylestrenol. They are used questionably for treatment of recurrent pregnancy loss and for prevention of preterm birth in pregnant women with a history of at least one spontaneous preterm birth.[20]

Sex-hormone suppression

Certain progestins are used at high doses to suppress sex hormone levels as a form of medical castration for a variety of androgen and estrogen-dependent conditions. Examples of indications include treating hormone-sensitive cancers (e.g., breast cancer, prostate cancer, endometrial cancer), benign prostatic hyperplasia, suppressing precocious puberty and puberty in transgender youth, suppressing sex hormone production in transgender patients, and reducing sex drive in men with sexual deviance such as in sex offenders, paraphilias, and hypersexuality. Progestins that have been used for such purposes include chlormadinone acetate,[21] cyproterone acetate, gestonorone caproate, hydroxyprogesterone caproate, medroxyprogesterone acetate,[22] and megestrol acetate,[23]

Some progestins are also antiandrogens, for instance cyproterone acetate, and can be used to treat androgen-dependent conditions like acne and hirsutism in women.

Appetite stimulation

Certain progestins can be used at very high dosages to increase appetite in conditions like cachexia, anorexia, and wasting syndromes. 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 corticosteroids. Furthermore, they are recognized as being the only drugs 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.[24][25] The mechanism of action of the appetite-related effects of these two drugs is unknown and may not be related to their progestogenic activity.

Available forms

Progestins are available in the form of oral tablets, solutions and suspensions for intramuscular or subcutaneous injection, and a number of other forms (e.g., transdermal patches, vaginal rings, intrauterine devices, subcutaneous implants).

Some examples of progestins that are used in hormonal contraceptives are norethisterone (many brand names, most notably Ortho-Novum and Ovcon), norgestimate (Ortho Tricyclen, Ortho-Cyclen), levonorgestrel (Alesse, Trivora-28, Plan B, Mirena), medroxyprogesterone acetate (Provera, Depo-Provera), cyproterone acetate (Diane-35), desogestrel, etonogestrel (Nexplanon), and drospirenone (Yasmin, Yasminelle, YAZ).

Side effects

Pure progestogens have relatively few side effects at typical dosages.[citation needed] Many of the side effects of progestins are due not to their progestogenic activity but rather due to off-target activities such as androgenic, estrogenic, glucocorticoid, and antimineralocorticoid activity.[1] At high dosages, progestins also have potent antigonadotropic effects, and can produce prominent side effects related to hypogonadism (low sex hormone levels) in premenopausal women and in men.[citation needed]

Pharmacology

See also: Comparison of progestogens § Pharmacology

Progestins act by binding to and activating the progesterone receptors (PRs), including the PR-A, PR-B, and PR-C.[1][26][27] Major tissues affected by progestogens include the uterus, cervix, vagina, breasts, and brain.[1] By activating PRs in the hypothalamus and pituitary gland, progestins suppress the secretion of gonadotropins and thereby function as antigonadotropins at sufficiently high dosages.[1] Interaction of progestins with membrane progesterone receptors is less clear.[28][29]

Antigonadotropic effects

Progestogens, similarly to the androgens and estrogens through their own respective receptors, inhibit the secretion of the gonadotropins 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.[30][21][31] Accordingly, progestogens, both endogenous and exogenous (i.e., progestins), have antigonadotropic effects,[23] and progestins 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).[31]

Progestins have been found to suppress circulating testosterone levels by up to 70 to 80% in men at sufficiently high dosages.[32][33] This is notably less than that achieved by GnRH analogues, which can effectively abolish gonadal production of testosterone and suppress circulating testosterone levels by as much as 95%.[34] 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.[35]

Dydrogesterone is an atypical progestin and does not have antigonadotropic effects nor inhibit ovulation even at very high dosages.[1] It is the only clinically used progestin that is known to lack such effects, and also shows a number of other atypical properties.[1] This may be related to selective agonism of the PR-B.[36]

Off-target activities

Other hormonal activities of progestogens[37][1][38]
Progestogen ES ANTooltip Androgenic AATooltip Antiandrogenic GCTooltip Glucocorticoid AMTooltip Antimineralocorticoid
Progesterone – – ± + +
Dydrogesterone – – – – ±
Chlormadinone acetate – – + + –
Cyproterone acetate – – ++ + –
Megestrol acetate – ± + + –
Medroxyprogesterone acetate       – ± – + –
Medrogestone – – ± – –
Demegestone – – – – –
Nomegestrol acetate – – + – –
Promegestone – – – – –
Trimegestone – – ± – ±
Segesterone acetate – – – – –
Norethisterone + + – – –
Norethisterone acetate + + – – –
Lynestrenol + + – – –
Noretynodrel + ± – – –
Levonorgestrel – + – – –
Norgestimate – + – – –
Desogestrel – + – – –
Etonogestrel – + – – –
Gestodene – + – + +
Dienogest – – + – –
Tibolone + ++ – – –
Drospirenone – – + – +
++ = High. + = Moderate. ± = Low. – = None.
ES = Estrogenic. AN = Androgenic. AA = Antiandrogenic.
GC = Glucocorticoid. AM = Antimineralocorticoid.

Many progestins have off-target activities such as androgenic, antiandrogenic, estrogenic, glucocorticoid, or antimineralocorticoid activity.[1][2] Such actions can contribute both to their beneficial or desirable effects and to their side effects.[1][2][39]

Androgenic activity

See also: Progestin-induced virilisation

Some progestins have androgenic activity and can produce androgenic side effects such as increased sebum production (oilier skin), acne, and hirsutism (excessive facial/body hair growth), as well as changes in liver protein production.[40][41][42] Only certain progestins are androgenic however, these being the testosterone (19-nortestosterone and 17α-ethynyltestosterone) derivatives and, to a lesser extent, the 17α-hydroxyprogesterone derivatives medroxyprogesterone acetate and megestrol acetate.[43][41][37] No other progestins have such activity (though some, conversely, possess antiandrogenic activity (see above)).[41][37] 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.[44][45]

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.[46] 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.[46] An exception is progestin-only contraceptives, which do not also contain an estrogen.[46]

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

It should be noted however that the clinical androgenic and anabolic activity of these androgenic progestins is still far lower than that of conventional androgens and anabolic steroids like testosterone and nandrolone esters. As such, they are only generally associated with such effects in women. In men, due to their concomitant progestogenic activity and by extension antigonadotropic effects, these progestins can have potent functional antiandrogenic effects by suppressing testosterone levels.

Antiandrogenic activity

Some progestins have antiandrogenic activity in addition to their progestogenic activity.[64] These progestins, with varying degrees of potency as antiandrogens, include chlormadinone acetate, cyproterone acetate, dienogest, drospirenone, medrogestone, megestrol acetate, nomegestrol acetate, osaterone acetate (veterinary), and oxendolone.[64][63][65][66]

Estrogenic activity

A few progestins have weak estrogenic activity.[1] These include the 19-nortestosterone derivatives norethisterone, noretynodrel, and tibolone, as well as the norethisterone prodrugs[67] norethisterone acetate, norethisterone enanthate, lynestrenol, and etynodiol diacetate.[1] High dosages 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 menopausal symptoms in postmenopausal women.[68] In contrast, non-estrogenic progestins were not found to be associated with such effects.[68]

Glucocorticoid activity

Some progestins, mainly certain 17α-hydroxyprogesterone derivatives, have glucocorticoid activity.[69] This can result, at sufficiently high dosages, in side effects such as symptoms of Cushing's syndrome, steroid diabetes, adrenal suppression and insufficiency, and neuropsychiatric symptoms like depression, anxiety, irritability, and cognitive impairment.[69][70][71] Progestins with the potential for clinically relevant glucocorticoid effects include the 17α-hydroxyprogesterone derivatives chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, and megestrol acetate.[70][72][73] Hydroxyprogesterone caproate (another 17α-hydroxyprogesterone derivative), in contrast, possesses no such activity.[74]

Antimineralocorticoid activity

Certain progestins, including drospirenone and gestodene and to a lesser extent dydrogesterone and trimegestone, have antimineralocorticoid activity.[1] Progesterone itself has potent antimineralocorticoid activity.[1] No clinically used progestins are known to have mineralocorticoid activity.[1]

Chemistry

See also: List of steroidal progestogens, Progestogen ester, and List of progestogen esters

All currently available progestins are steroids.[1] They include pregnanes (e.g., dydrogesterone, medroxyprogesterone acetate), norpregnanes (e.g., nomegestrol acetate), androstanes (e.g., danazol, ethisterone), and estranes (e.g., norethisterone, levonorgestrel), and can be further divided into various subgroups.[1]

History

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 parenterally) 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 17α-ethynyl analog of testosterone, was synthesized in 1938 from dehydroandrosterone by ethynylation, either before or after oxidation of the 3-OH group, followed by rearrangement of the 5,6 double bond to the 4,5 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 in the U.S. in 1945 as Pranone.[75][76][77][78][79]

A more potent orally active progestin, norethisterone (norethindrone, 19-nor-17α-ethynyltestosterone), the 19-nor analog of ethisterone, synthesized in 1951 by Carl Djerassi, 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 first oral contraceptives (Ortho-Novum, Norinyl, etc.) in the early 1960s.[76][76][77][78][79][80]

Noretynodrel, an isomer of norethisterone, was synthesized in 1952 by Frank B. Colton at 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.[76][77][78][79][81]

Society and culture

Generations

Contraceptive progestins are sometimes grouped, somewhat arbitrarily and fairly inconsistently, into generations. One definition of these generations is as follows:[12]

Alternatively, estranes such as noretynodrel and norethisterone are classified as first-generation while gonanes 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.[13] Yet another classification system considers there to be only first- and second-generation progestins.[citation needed]

Availability

See also: List of progestogens available in the United States

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

Research

A variety of progestins have been studied for use as potential male hormonal contraceptives in combination with androgens in men.[82] These include the pregnanes medroxyprogesterone acetate and cyproterone acetate, the norpregnane segesterone acetate, and the estranes norethisterone acetate, norethisterone enanthate, levonorgestrel, levonorgestrel butanoate, desogestrel, and etonogestrel.[82][83][84] The androgens that have been used in combination with these progestins include testosterone, testosterone esters, androstanolone (dihydrotestosterone), nandrolone esters, and trestolone.[82]

See also

References

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