| Progestogen (medication) | |
|---|---|
| Drug class | |
 Progesterone, the natural progestogen in the body and one of the most widely used progestogen medications | |
| Class identifiers | |
| Synonyms | Progestagen, gestagen, gestogen; progestin (synthetic progestogen); progesterone receptor agonist |
| Use | Hormonal birth control,hormone therapy,gynecological disorders,fertility medicine andpregnancy support,sex-hormone suppression, others |
| ATC code | G03 |
| Biological target | Progesterone receptors (PR-A,PR-B,PR-C);membrane progesterone receptors (mPRα,mPRβ,mPRγ,mPRδ,mPRε);progesterone receptor membrane components (PGRMC1,PGRMC2) |
| Chemical class | Steroids (pregnanes,norpregnanes,retropregnanes,androstanes,estranes) |
| Clinical data | |
| Drugs.com | Drug Classes |
| External links | |
| MeSH | D011372 |
| Legal status | |
| In Wikidata | |
Aprogestogen, also referred to as aprogestagen,gestagen, orgestogen, is a type ofmedication which produces effects similar to those of thenatural femalesex hormoneprogesterone in the body.[1] Aprogestin is asynthetic progestogen.[1] Progestogens are used most commonly inhormonal birth control andmenopausal hormone therapy.[1] They can also be used in the treatment ofgynecological conditions, to supportfertility andpregnancy, to lowersex hormone levels for various purposes, and for other indications.[1] Progestogens are used alone or in combination withestrogens.[1] They are available in a wide variety offormulations and for use by many differentroutes of administration.[1] Examples of progestogens include natural orbioidenticalprogesterone as well as progestins such asmedroxyprogesterone acetate andnorethisterone.[1]
Side effects of progestogens includemenstrual irregularities,headaches,nausea,breast tenderness,mood changes,acne,increased hair growth, and changes inliver protein production among others.[1][2] Other side effects of progestogens may include an increased risk ofbreast cancer,cardiovascular disease, andblood clots.[2] At high doses, progestogens can causelow sex hormone levels and associated side effects likesexual dysfunction and anincreased risk of bone fractures.[3]
Progestogens areagonists of theprogesterone receptors (PRs) and produceprogestogenic, orprogestational, effects.[1] They have important effects in thefemale reproductive system (uterus,cervix, andvagina), thebreasts, and thebrain.[1] In addition, many progestogens also have other hormonal activities, such asandrogenic,antiandrogenic,estrogenic,glucocorticoid, orantimineralocorticoid activity.[1] They also haveantigonadotropic effects and at high doses can strongly suppresssex hormone production.[1] Progestogens mediate their contraceptive effects both by inhibitingovulation and by thickeningcervical mucus, thereby preventingfertilization.[4][5] They have functionalantiestrogenic effects in certain tissues like theendometrium, and this underlies their use in menopausal hormone therapy.[1]
Progesterone was first introduced for medical use in 1934 and the first progestin,ethisterone, was introduced for medical use in 1939.[6][7][8] Morepotent progestins, such asnorethisterone, were developed and started to be used in birth control in the 1950s.[6] Around 60 progestins have been marketed for clinical use in humans or use inveterinary medicine.[9][10][11][12][13] These progestins can be grouped into different classes and generations.[1][14][15] Progestogens are available widely throughout the world and are used in all forms of hormonal birth control and in most menopausal hormone therapy regimens.[1][9][10][12][11]
Progestogens are available in many differentforms for use by many differentroutes of administration. These includeoraltablets andcapsules,oil andaqueous solutions andsuspensions forintramuscular orsubcutaneous injection, and various others (e.g.,transdermal patches,vaginal rings,intrauterine devices,subcutaneous implants).
Dozens of different progestogens have been marketed forclinical and/orveterinary use.
Progestogens are used in a variety of different forms ofhormonal birth control for females, includingcombined estrogen and progestogen forms likecombined oral contraceptive pills,combined contraceptive patches,combined contraceptive vaginal rings, andcombined injectable contraceptives; andprogestogen-only forms likeprogestogen-only contraceptive pills ("mini-pills"),progestogen-only emergency contraceptive pills ("day-after pills"),progestogen-only contraceptive implants,progestogen-only intrauterine devices,progestogen-only contraceptive vaginal rings, andprogestogen-only injectable contraceptives.[16][17][18][19]
Progestogens mediate their contraceptive effects by multiple mechanisms, including prevention ofovulation via theirantigonadotropic effects; thickening ofcervical mucus, making thecervix largely impenetrable tosperm; preventingcapacitation ofsperm due to changes in cervical fluid, thereby making sperm unable to penetrate theovum; andatrophic changes in theendometrium, making the endometrium unsuitable forimplantation.[20][21][22][23] They may also decreasetubalmotility andciliary action.[23]
Progestogens are used in combination withestrogens inmenopausal hormone therapy in women. They are also used in combination with estrogens in hormone therapy forhypogonadism anddelayed puberty in girls and women. They are used mainly to preventendometrial hyperplasia and increased risk ofendometrial cancer from unopposed estrogen therapy.
Progestogens are used as a component ofhormone therapy fortransgender women andtransgender men. They are used in transgender women in combination with estrogens to help suppress and blocktestosterone. 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 includecyproterone acetate,medroxyprogesterone acetate, andprogesterone. Progestogens, such as medroxyprogesterone andlynestrenol, are used in transgender men to help suppressmenses. Progestogens have also been used to delaypuberty intransgender boys and girls.
Certain progestogens, includingmegestrol acetate, medroxyprogesterone acetate, cyproterone acetate, andchlormadinone acetate, have been used at high doses to reducehot flashes in men undergoingandrogen deprivation therapy, for instance to treatprostate cancer.[24][25][26]
Progestogens are used to treatmenstrual disorders such assecondary amenorrhea anddysfunctional uterine bleeding.[17][18] In a normalmenstrual cycle, declining levels of progesterone triggermenstruation. Progestogens such asnorethisterone acetate andmedroxyprogesterone acetate may be used to artificially induce progesterone-associatedbreakthrough bleeding.[27]
Theprogestogen challenge test or progestogen withdrawal test is used to diagnoseamenorrhea. Due to the availability of assays to measure estrogen levels, it is now rarely used.
Progestogens are used in the prevention and treatment ofuterine disorders such asendometrial hyperplasia,endometriosis,uterine fibroids, anduterine hypoplasia.
Progestogens are used to treatbenignbreast disorders.[28][29] They are associated not only with a reduction inbreast pain, but also a decrease inbreastcell proliferation, a decrease inbreast gland size, and a disappearance of breastnodularity.[28][29][30] Progestogens that have been used for such purposes includetopical progesterone,dydrogesterone,promegestone,lynestrenol,medroxyprogesterone acetate,dienogest, andmedrogestone.[28][29][31][30]
Progestogens are used in the treatment ofbreast hypoplasia andlactation insufficiency. This is because they inducelobuloalveolardevelopment of thebreasts, which is required forlactation andbreastfeeding.
Progestogens have been used at high doses to treatbenign prostatic hyperplasia (BPH). They act by suppressinggonadaltestosteroneproduction and hence circulating testosterone levels. Androgens like testosterone stimulate the growth of theprostate gland.
Progestogens were first found to be effective at high doses in the treatment ofendometrial hyperplasia andendometrial cancer in 1959.[32][33][34] Subsequently, high-dosegestonorone caproate,hydroxyprogesterone caproate,medroxyprogesterone acetate, andmegestrol acetate were approved for the treatment of endometrial cancer.[35][36][37]
Progestogens, such as megestrol acetate and medroxyprogesterone acetate, are effective at high doses in the treatment ofadvancedpostmenopausalbreast cancer.[38][39] They have been extensively evaluated as a second-line therapy for this indication.[38] However, they produce variousside effects, such asdyspnea,weight gain,vaginal bleeding,nausea,fluid retention,hypertension,thrombophlebitis, andthromboembolic complications.[38][39] In addition, megestrol acetate has been found to be significantly inferior toaromatase inhibitors in the treatment of breast cancer, and in relation to this, progestogens have been moved down in the sequential therapy of the disease.[38] Megestrol acetate is the onlyFood and Drug Administration-approved progestogen for breast cancer.[38] Themechanism of action of progestogens in the treatment of breast cancer is unknown, but may be related to their functionalantiestrogenic and/orantigonadotropic effects.[38]
Certain progestogens, particularly those with antiandrogenic properties, have been used at high doses in the treatment ofprostate cancer.[40][41] These includecyproterone acetate,chlormadinone acetate, andmegestrol acetate.[40][41] Other progestogens such asmedroxyprogesterone acetate,hydroxyprogesterone caproate, andgestonorone caproate have also been studied, but have inadequate effectiveness. They act by suppressinggonadaltestosteroneproduction and hence circulating testosterone levels. Androgens like testosterone stimulate the growth of prostatetumors.
Progestogens are used infertility medicine for women. For example, progesterone (or sometimesdydrogesterone orhydroxyprogesterone caproate) is used forluteal support inin-vitro fertilization protocols.[42]
Certain progestogens are used to supportpregnancy, includingprogesterone,hydroxyprogesterone caproate,dydrogesterone, andallylestrenol. They are used questionably for treatment ofrecurrent pregnancy loss and for prevention ofpreterm birth in pregnant women with a history of at least one spontaneous preterm birth.[42]
Progestogens have been used to treatprecocious puberty in both boys and girls. They have also been used to delay puberty intransgender youth.
Certain progestogens, such ascyproterone acetate andmedroxyprogesterone acetate, are used as a form ofchemical castration to treatsexual deviance in men, particularlysex offenders. They are specifically used to treatparaphilias andhypersexuality. They work by suppressinggonadaltestosteroneproduction and hence circulating testosterone levels. This results in decreasedlibido and interference witherectile function and ability to attainorgasm.
Progestogens are used to treatandrogen-dependentskin andhair conditions in women. These includeoily skin,acne,seborrhea,hirsutism,scalp hair loss, andhidradenitis suppurativa. They act by suppressing testosterone levels and, in the case of antiandrogenic progestogens, by directly blocking the actions of androgens.
Progestogens are used to treathyperandrogenism, such as due topolycystic ovary syndrome andcongenital adrenal hyperplasia, in women. Examples includecyproterone acetate andchlormadinone acetate.
Certain progestins can be used at very high doses toincrease appetite in conditions likecachexia,anorexia, andwasting syndromes. In general, they are used in combination with certain other steroid medications such asdexamethasone. Their effects take several weeks to become apparent, but are relatively long-lived when compared to those ofcorticosteroids. Furthermore, they are recognized as being the only medications to increaselean body mass.Megestrol acetate is the lead drug of this class for the management of cachexia, andmedroxyprogesterone acetate is also used.[43][44] Themechanism 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, likecyproterone acetate, have minimal or no influence on appetite and weight.
Contraindications of progestogens may includebreast cancer and a history ofvenous thromboembolism among others.[45][citation needed]
Progestogens have relatively fewside effects at typical dosages.[46] Side effects of progestogens may includetiredness,dysphoria,depression,mood changes,menstrual irregularities,hypomenorrhea,edema,vaginal dryness,vaginal atrophy,headaches,nausea,breast tenderness, decreasedlibido.[1][2][46] Progestins with androgenic activity, namely 19-nortestosterone derivatives, can also causeacne,hirsutism,seborrhea,voice deepening, changes inliver protein production (e.g., decreasedHDL cholesterol,sex hormone-binding globulin), increasedappetite, andweight gain, among others.[1][46] Other side effects of progestogens may include an increased risk ofbreast cancer,cardiovascular disease, andblood clots, among others.[2] Some of the side effects of progestogens are due not to their progestogenic activity but rather due tooff-target activities (e.g.,androgenic activity,glucocorticoid activity,antimineralocorticoid activity).[1][47] At high doses, due to theirantigonadotropic effects, progestogens can causelow sex hormone levels and associated side effects like diminishedsecondary sexual characteristics,sexual dysfunction (e.g., reducedsex drive anderectile dysfunction), reversibleinfertility, reducedbone mineral density, and an increased risk ofbone fractures, both in men and inpremenopausal women.[3]
| Clinical outcome | Hypothesized effect on risk | Estrogen and progestogen (CEsTooltip conjugated estrogens 0.625 mg/day p.o. +MPATooltip medroxyprogesterone acetate 2.5 mg/day p.o.) (n = 16,608, with uterus, 5.2–5.6 years follow up) | Estrogen alone (CEsTooltip Conjugated estrogens 0.625 mg/day p.o.) (n = 10,739, no uterus, 6.8–7.1 years follow up) | ||||
|---|---|---|---|---|---|---|---|
| HRTooltip Hazard ratio | 95%CITooltip Confidence interval | ARTooltip Attributable risk | HRTooltip Hazard ratio | 95%CITooltip Confidence interval | ARTooltip Attributable risk | ||
| Coronary heart disease | Decreased | 1.24 | 1.00–1.54 | +6 / 10,000 PYs | 0.95 | 0.79–1.15 | −3 / 10,000 PYs |
| Stroke | Decreased | 1.31 | 1.02–1.68 | +8 / 10,000 PYs | 1.37 | 1.09–1.73 | +12 / 10,000 PYs |
| Pulmonary embolism | Increased | 2.13 | 1.45–3.11 | +10 / 10,000 PYs | 1.37 | 0.90–2.07 | +4 / 10,000 PYs |
| Venous thromboembolism | Increased | 2.06 | 1.57–2.70 | +18 / 10,000 PYs | 1.32 | 0.99–1.75 | +8 / 10,000 PYs |
| Breast cancer | Increased | 1.24 | 1.02–1.50 | +8 / 10,000 PYs | 0.80 | 0.62–1.04 | −6 / 10,000 PYs |
| Colorectal cancer | Decreased | 0.56 | 0.38–0.81 | −7 / 10,000 PYs | 1.08 | 0.75–1.55 | +1 / 10,000 PYs |
| Endometrial cancer | – | 0.81 | 0.48–1.36 | −1 / 10,000 PYs | – | – | – |
| Hip fractures | Decreased | 0.67 | 0.47–0.96 | −5 / 10,000 PYs | 0.65 | 0.45–0.94 | −7 / 10,000 PYs |
| Totalfractures | Decreased | 0.76 | 0.69–0.83 | −47 / 10,000 PYs | 0.71 | 0.64–0.80 | −53 / 10,000 PYs |
| Totalmortality | Decreased | 0.98 | 0.82–1.18 | −1 / 10,000 PYs | 1.04 | 0.91–1.12 | +3 / 10,000 PYs |
| Global index | – | 1.15 | 1.03–1.28 | +19 / 10,000 PYs | 1.01 | 1.09–1.12 | +2 / 10,000 PYs |
| Diabetes | – | 0.79 | 0.67–0.93 | 0.88 | 0.77–1.01 | ||
| Gallbladder disease | Increased | 1.59 | 1.28–1.97 | 1.67 | 1.35–2.06 | ||
| Stress incontinence | – | 1.87 | 1.61–2.18 | 2.15 | 1.77–2.82 | ||
| Urge incontinence | – | 1.15 | 0.99–1.34 | 1.32 | 1.10–1.58 | ||
| Peripheral artery disease | – | 0.89 | 0.63–1.25 | 1.32 | 0.99–1.77 | ||
| Probabledementia | Decreased | 2.05 | 1.21–3.48 | 1.49 | 0.83–2.66 | ||
| Abbreviations: CEs =conjugated estrogens. MPA =medroxyprogesterone acetate. p.o. =per oral. HR =hazard ratio. AR =attributable risk. PYs =person–years. CI =confidence interval.Notes:Sample sizes (n) includeplacebo recipients, which were about half of patients. "Global index" is defined for each woman as the time to earliest diagnosis forcoronary heart disease,stroke,pulmonary embolism,breast cancer,colorectal cancer,endometrial cancer (estrogen plus progestogen group only),hip fractures, anddeath from other causes.Sources: See template. | |||||||
The available evidence on the risk ofmood changes anddepression with progestogens inhormonal birth control is limited.[48][49] As of 2019, there is no consistent evidence for adverse effects on mood of hormonal birth control, includingprogestogen-only birth control andcombined birth control, in the general population.[50][51] Most women takingcombined birth control experience no influence or a beneficial effect on mood.[48][51][49] Adverse effects on mood appear to be infrequent, occurring only in a small percentage of women.[48][51][49] 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.[52][48] A study of about 4,000 women found that progestogen-only birth control withdepotmedroxyprogesterone acetate had an incidence of depression of 1.5% and discontinuation due to depression of 0.5%.[51][53][54] Beneficial effects of hormonal birth control such as decreasedmenstrual pain andbleeding may positively influence mood.[48]
A 2018systematic review of 26 studies, including 5 randomized controlled trials and 21 observational studies, found that the overall evidence showed no association betweenprogestogen-only birth control and depression.[51] The progestins assessed included depotmedroxyprogesterone acetate,levonorgestrel-containingcontraceptive implants andintrauterine devices, andprogestogen-only birth control pills.[51] Findings of large observational studies are mixed due to prominentconfounding factors, but overall show no association of hormonal birth control with depression.[50][51] Randomized controlled trials typically do not find clinically significant influences of hormonal birth control on mood.[50][51]Reviews from before 1980 reported a high incidence of adverse mood effects with combined birth control pills.[48] 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.[48][55]
Mood with birth control pills may be better with monophasic and continuous formulations than with triphasic and cyclic formulations.[48][52] Limited and inconsistent evidence supports differences in mood with hormonal birth control using different doses of ethinylestradiol or differentroutes of administration, such as birth control pills versuscontraceptive vaginal rings andcontraceptive patches.[48][52] Combined birth control with lessandrogenic orantiandrogenic progestins likedesogestrel,gestodene, anddrospirenone may have a more favorable influence on mood than birth control with more androgenic progestins likelevonorgestrel.[48][52] However,androgen supplementation with hormonal birth control has also been reported to improve mood.[48]
Hormonal birth control that suppressesovulation is effective in the treatment ofpremenstrual dysphoric disorder (PMDD).[50][56] Combined birth control pills containingdrospirenone are approved for the treatment of PMDD and may be particularly beneficial due to theantimineralocorticoid activity of drospirenone.[50][57][58] Studies on the influence of hormonal birth control on mood in women with existingmood disorders orpolycystic ovary syndrome are limited and mixed.[50][48] Women with underlying mood disorders may be more likely to experience mood changes with hormonal birth control.[48][50][59] A 2016 systematic review found based on limited evidence from 6 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 withdepressive orbipolar disorders.[60] A 2008Cochrane review found a greater likelihood ofpostpartum depression in women givennorethisterone enanthate as a form ofprogestogen-only injectable birth control, and recommended caution on the use of progestogen-only birth control in thepostpartum period.[61]
Studies suggest anegativity bias inemotion recognition andreactivity with hormonal birth control.[59] Some data suggests bluntedreward responses and potential dysregulation of thestress response with hormonal birth control in some women.[59][50]
Estrogen therapy appears to have a beneficial influence on mood indepressed andeuthymicperimenopausal women.[62][63][64] Conversely, research on combined estrogen and progestogen therapy for depressive symptoms in menopausal women is scarce and inconclusive.[62][63] Some researchers contend that progestogens have an adverse influence on mood and reduce the benefits of estrogens on mood,[65][66][2] whereas other researchers maintain that progestogens have no adverse influence on mood.[67][68] Progesterone differs from progestins in terms of effects in thebrain and might have different effects on mood in comparison.[2][69][1] The available evidence, although limited, suggests no adverse influence of progesterone on mood when used in menopausal hormone therapy.[70]
In most women,sexual desire is unchanged or increased with combined birth control pills.[71] This is despite an increase insex hormone-binding globulin (SHBG) levels and a decrease in total and freetestosterone levels.[71][72] However, findings are conflicting, and more research is needed.[73]
Venous thromboembolism (VTE) consists ofdeep vein thrombosis (DVT) andpulmonary embolism (PE).[74] DVT is ablood clot in adeep vein, most commonly in thelegs, while PE occurs when a clot breaks free and blocks anartery in thelungs.[74] VTE is a rare but potentially fatalcardiovascular event.[74]Estrogens and progestogens can increasecoagulation by modulatingsynthesis ofcoagulation factors.[1][75][76][77] As a result, they increase the risk of VTE, especially duringpregnancy when estrogen and progesterone levels are very high as well as during thepostpartum period.[75][76][78]Physiological levels of estrogen and/or progesterone may also influence risk of VTE—with latemenopause (≥55 years) being associated with greater risk than early menopause (≤45 years).[79][80]
Progestogens when used by themselves at typical clinical dosages, for instance inprogestogen-only birth control, do not affect coagulation[81][82][83][84][75][77] and are not generally associated with a higher risk ofvenous thromboembolism (VTE).[85][86][87][88] An exception is medroxyprogesterone acetate as aprogestogen-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.[89][90][91][92][93][94][88] The reasons for this are unknown, but the observations might be astatistical artifact of preferential prescription of depot medroxyprogesterone acetate to women at risk for VTE.[90] Alternatively, medroxyprogesterone acetate may be an exception among progestogens in terms of influence on VTE risk,[88][92][81][94] possibly due to itspartialglucocorticoid activity.[1][6][81] In contrast to depot medroxyprogesterone acetate, no increase in VTE risk has been observed with moderately high doses of the related progestinchlormadinone acetate (10 mg/day for 18–20 days/cycle), though based on limited data.[94][95]
Very-high-dose progestogen therapy, including with medroxyprogesterone acetate,megestrol acetate, andcyproterone acetate, has been associated with activation of coagulation and a dose-dependent increased risk of VTE.[82][87][96][97][98][99] In studies with high-dose cyproterone acetate specifically, the increase in VTE risk has ranged from 3- to 5-fold.[96][98][99] The incidence of VTE in studies with very-high-dose progestogen therapy has been found to range from 2 to 8%.[82][100][101] However, the relevant patient populations, namely aged individuals withcancer, are already predisposed to VTE, and this greatly amplifies the risk.[82][87][102]
In contrast to progestogen-only birth control, the addition of progestins tooralestrogen therapy, including incombined birth control pills andmenopausal hormone therapy, is associated with a higher risk of VTE than with oral estrogen therapy alone.[103][104][105][106][107] 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 containingethinylestradiol, both relative to non-use.[103][76][106][107] In contrast to oral estrogen therapy,parenteral estradiol, such as withtransdermalestradiol, is not associated with a higher risk of VTE.[103][92][106] This is likely due to its lack offirst-pass effect in theliver.[1][89] 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.[103][92][106] Unlike the case of transdermal estradiol, VTE risk is not lower with ethinylestradiol-containingcontraceptive vaginal rings andcontraceptive patches compared to combined birth control pills with ethinylestradiol.[76][108][81] This is thought to be due to the resistance of ethinylestradiol tohepaticmetabolism.[1][109][89][81]
The type of progestin in combined birth control may modulate the risk of VTE.[104][105][94] Studies have found that combined birth control pills containingnewer-generation progestins such asdesogestrel,gestodene,norgestimate,drospirenone, andcyproterone acetate are associated with a 1.5- to 3-fold higher risk of VTE than birth control pills containingfirst-generation progestins such aslevonorgestrel andnorethisterone.[104][105][107][94][110][111] However, although this has been apparent inretrospective cohort andnested case–control studies, no greater risk of VTE has been observed inprospective cohort andcase–control studies.[104][105][112][113][107] These kinds ofobservational studies have certain advantages over the aforementioned types of studies, such as better ability to control forconfounding factors like new-user bias.[113][81] 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.[113] Androgenic progestins have been found toantagonize to some degree the effect of estrogens on coagulation.[83][84][75][114][81] 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.[104][115][75][114] The type of estrogen also influences VTE risk.[109][116][117] Birth control pills containingestradiol valerate are associated with about half the VTE risk of birth control pills with ethinylestradiol.[116][117]
The type of progestogen in combined menopausal hormone therapy may also modulate VTE risk.[118][119] Oral estrogens plusdydrogesterone appears to have lower VTE risk relative to inclusion of other progestins.[120][121][106]Norpregnane derivatives such asnomegestrol acetate andpromegestone have been associated with a significantly greater risk of VTE thanpregnane derivatives such asmedroxyprogesterone acetate and dydrogesterone andnortestosterone derivatives such asnorethisterone andlevonorgestrel.[118][119] However, these findings may just be statistical artifacts.[119] In contrast to progestins, the addition of oralprogesterone to either oral or transdermal estrogen therapy is not associated with a higher risk of VTE.[92][122] 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.[122] Parenteral progesterone, such asvaginal orinjectable progesterone, which can achieveluteal-phase levels of progesterone and associated progestogenic effects, has not been characterized in terms of VTE risk.[122]
A 2012meta-analysis estimated that theabsolute 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.[76] 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.[76] Risk of VTE with estrogen and progestogen therapy is highest at the start of treatment, particularly during the first year, and decreases over time.[89][123] Olderage, higherbody weight, lowerphysical activity, andsmoking are all associated with a higher risk of VTE with oral estrogen and progestogen therapy.[89][122][123][124] Women withthrombophilia have a dramatically higher risk of VTE with estrogen and progestogen therapy than women without thrombophilia.[76][108] Depending on the condition, risk of VTE can be increased as much as 50-fold in such women relative to non-use.[76][108]
Estrogens induce the production ofsex hormone-binding globulin (SHBG) in the liver.[1][81] As such, SHBG levels indicate hepatic estrogenic exposure and may be a reliablesurrogate marker for coagulation and VTE risk with estrogen therapy.[125][126][127] 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 anddienogest, and 4- to 5-fold with cyproterone acetate.[125] SHBG levels differ depending on the progestin because androgenic progestins oppose the effect of ethinylestradiol on hepatic SHBG production as with its procoagulatory effects.[1][81]Contraceptive vaginal rings andcontraceptive patches likewise have been found to increase SHBG levels by 2.5-fold and 3.5-fold, respectively.[125][81] Birth control pills containing high doses of ethinylestradiol (>50 μg) can increase SHBG levels by 5- to 10-fold, which is similar to the increase that occurs during pregnancy.[128] Conversely, increases in SHBG levels are much lower with estradiol, especially when it is used parenterally.[129][130][131][132][133]Estradiol-containing combined birth control pills, likeestradiol valerate/dienogest andestradiol/nomegestrol acetate, and high-dose parenteralpolyestradiol phosphate therapy have both been found to increase SHBG levels by about 1.5-fold.[81][134][132][131]
Hormone therapy with high-dose ethinylestradiol and cyproterone acetate intransgender women has been associated with a 20- to 45-fold higher risk of VTE relative to non-use.[102][123] The absolute incidence was about 6%.[102][123] Conversely, the risk of VTE in transgender women is much lower with oral or transdermal estradiol plus high-dose cyproterone acetate.[102][123] Ethinylestradiol is thought to have been primarily responsible for the VTE risk, but cyproterone acetate may have contributed as well.[102] Ethinylestradiol is no longer used in transgender hormone therapy,[135][136][137] and doses of cyproterone acetate have been reduced.[138][139]
| Type | Route | Medications | Odds ratio (95%CITooltip confidence interval) |
|---|---|---|---|
| Menopausal hormone therapy | Oral | Estradiol alone ≤1 mg/day >1 mg/day | 1.27 (1.16–1.39)* 1.22 (1.09–1.37)* 1.35 (1.18–1.55)* |
| Conjugated estrogens alone ≤0.625 mg/day >0.625 mg/day | 1.49 (1.39–1.60)* 1.40 (1.28–1.53)* 1.71 (1.51–1.93)* | ||
| Estradiol/medroxyprogesterone acetate | 1.44 (1.09–1.89)* | ||
| Estradiol/dydrogesterone ≤1 mg/dayE2 >1 mg/dayE2 | 1.18 (0.98–1.42) 1.12 (0.90–1.40) 1.34 (0.94–1.90) | ||
| Estradiol/norethisterone ≤1 mg/dayE2 >1 mg/dayE2 | 1.68 (1.57–1.80)* 1.38 (1.23–1.56)* 1.84 (1.69–2.00)* | ||
| Estradiol/norgestrel orestradiol/drospirenone | 1.42 (1.00–2.03) | ||
| Conjugated estrogens/medroxyprogesterone acetate | 2.10 (1.92–2.31)* | ||
| Conjugated estrogens/norgestrel ≤0.625 mg/dayCEEs >0.625 mg/dayCEEs | 1.73 (1.57–1.91)* 1.53 (1.36–1.72)* 2.38 (1.99–2.85)* | ||
| Tibolone alone | 1.02 (0.90–1.15) | ||
| Raloxifene alone | 1.49 (1.24–1.79)* | ||
| Transdermal | Estradiol alone ≤50 μg/day >50 μg/day | 0.96 (0.88–1.04) 0.94 (0.85–1.03) 1.05 (0.88–1.24) | |
| Estradiol/progestogen | 0.88 (0.73–1.01) | ||
| Vaginal | Estradiol alone | 0.84 (0.73–0.97) | |
| Conjugated estrogens alone | 1.04 (0.76–1.43) | ||
| Combined birth control | Oral | Ethinylestradiol/norethisterone | 2.56 (2.15–3.06)* |
| Ethinylestradiol/levonorgestrel | 2.38 (2.18–2.59)* | ||
| Ethinylestradiol/norgestimate | 2.53 (2.17–2.96)* | ||
| Ethinylestradiol/desogestrel | 4.28 (3.66–5.01)* | ||
| Ethinylestradiol/gestodene | 3.64 (3.00–4.43)* | ||
| Ethinylestradiol/drospirenone | 4.12 (3.43–4.96)* | ||
| Ethinylestradiol/cyproterone acetate | 4.27 (3.57–5.11)* | ||
| Notes: (1)Nested case–control studies (2015, 2019) based on data from theQResearch andClinical Practice Research Datalink (CPRD) databases. (2)Bioidenticalprogesterone was not included, but is known to be associated with no additional risk relative to estrogen alone.Footnotes: * =Statistically significant (p < 0.01).Sources: See template. | |||
Progestogens may influence the risk ofcardiovascular disease in women.[118] In thewomen's Health Initiative (WHI), the risk ofcoronary heart disease was greater with the combination of estrogen plus a progestin (specificallymedroxyprogesterone acetate) than with estrogen alone.[140][141][142] However, progestogens have varying activities and may differ in terms of cardiovascular risk.[118][143][144][145][146][147] 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 ofstroke andvenous thromboembolic events.[148] It is thought thatandrogenic progestins likemedroxyprogesterone acetate andnorethisterone may antagonize the beneficial effects of estrogens onbiomarkers of cardiovascular health (e.g., favorablelipid profile changes).[118][149] However, these findings are mixed and controversial.[149] Differences of progestogens on cardiovascular health and risk have been reviewed and summarized:[118]
Route of administration might also influence the cardiovascular health effects of progestogens, but more research is needed similarly.[150]
Estrogen alone, progestogen alone, and combined estrogen and progestogen therapy are all associated with increased risks of breast cancer when used inmenopausal hormone therapy forperi- andpostmenopausal women relative to non-use.[151][152][153] These risks are higher for combined estrogen and progestogen therapy than with estrogen alone or progestogen alone.[151][153] In addition to breast cancer risk, estrogen alone and estrogen plus progestogen therapy are associated with higher breast cancermortality.[154] With 20 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.[151] The increase in breast cancer risk with estrogen and progestogen therapy was shown to be causal withconjugated estrogens plusmedroxyprogesterone acetate in theWomen's Health Initiativerandomized controlled trials.[122][155]
Breast cancer risk with combined estrogen and progestogen therapy may differ depending on the progestogen used.[152][151][118][156] Progestins includingchlormadinone acetate,cyproterone acetate,medrogestone,medroxyprogesterone acetate,nomegestrol acetate,norethisterone acetate,promegestone, andtibolone have all been associated with similarly increased risk of breast cancer.[156][152][151] Some research has found thatoral progesterone anddydrogesterone with short-term use (<5 years) may be associated with lower risk of breast cancer relative to other progestins.[152][151][118][156] In the long-term however (>5 years), oral progesterone and dydrogesterone have been associated with significantly increased breast cancer risk similarly to other progestogens.[151][157] 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.[158][122][6]
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 years of use being associated with significantly greater risk than less than five years of use.[151][152] In addition, continuous estrogen and progestogen therapy is associated with a higher risk of breast cancer than cyclic use.[151][152]
A nationwideobservational study found thattransfeminine hormone therapy with estrogen plus high-dosecyproterone acetate was associated with a 46-fold increased risk of breast cancer intransgender women relative to the expected incidence forcisgender men.[159][160][161][162] However, the risk of breast cancer was still lower than that incisgender women.[159][160][161][162] The extent to which the increase in breast cancer risk was related to estrogen versus cyproterone acetate is unknown.[159][160][161][162]
| Therapy | <5 years | 5–14 years | 15+ years | |||
|---|---|---|---|---|---|---|
| Cases | RRTooltip Adjusted relative risk (95%CITooltip confidence interval) | Cases | RRTooltip Adjusted relative risk (95%CITooltip confidence interval) | Cases | RRTooltip Adjusted relative risk (95%CITooltip confidence interval) | |
| Estrogen alone | 1259 | 1.18 (1.10–1.26) | 4869 | 1.33 (1.28–1.37) | 2183 | 1.58 (1.51–1.67) |
| Byestrogen | ||||||
| Conjugated estrogens | 481 | 1.22 (1.09–1.35) | 1910 | 1.32 (1.25–1.39) | 1179 | 1.68 (1.57–1.80) |
| Estradiol | 346 | 1.20 (1.05–1.36) | 1580 | 1.38 (1.30–1.46) | 435 | 1.78 (1.58–1.99) |
| Estropipate (estrone sulfate) | 9 | 1.45 (0.67–3.15) | 50 | 1.09 (0.79–1.51) | 28 | 1.53 (1.01–2.33) |
| Estriol | 15 | 1.21 (0.68–2.14) | 44 | 1.24 (0.89–1.73) | 9 | 1.41 (0.67–2.93) |
| Other estrogens | 15 | 0.98 (0.46–2.09) | 21 | 0.98 (0.58–1.66) | 5 | 0.77 (0.27–2.21) |
| By route | ||||||
| Oral estrogens | – | – | 3633 | 1.33 (1.27–1.38) | – | – |
| Transdermal estrogens | – | – | 919 | 1.35 (1.25–1.46) | – | – |
| Vaginal estrogens | – | – | 437 | 1.09 (0.97–1.23) | – | – |
| Estrogen and progestogen | 2419 | 1.58 (1.51–1.67) | 8319 | 2.08 (2.02–2.15) | 1424 | 2.51 (2.34–2.68) |
| By progestogen | ||||||
| (Levo)norgestrel | 343 | 1.70 (1.49–1.94) | 1735 | 2.12 (1.99–2.25) | 219 | 2.69 (2.27–3.18) |
| Norethisterone acetate | 650 | 1.61 (1.46–1.77) | 2642 | 2.20 (2.09–2.32) | 420 | 2.97 (2.60–3.39) |
| Medroxyprogesterone acetate | 714 | 1.64 (1.50–1.79) | 2012 | 2.07 (1.96–2.19) | 411 | 2.71 (2.39–3.07) |
| Dydrogesterone | 65 | 1.21 (0.90–1.61) | 162 | 1.41 (1.17–1.71) | 26 | 2.23 (1.32–3.76) |
| Progesterone | 11 | 0.91 (0.47–1.78) | 38 | 2.05 (1.38–3.06) | 1 | – |
| Promegestone | 12 | 1.68 (0.85–3.31) | 19 | 2.06 (1.19–3.56) | 0 | – |
| Nomegestrol acetate | 8 | 1.60 (0.70–3.64) | 14 | 1.38 (0.75–2.53) | 0 | – |
| Other progestogens | 12 | 1.70 (0.86–3.38) | 19 | 1.79 (1.05–3.05) | 0 | – |
| By progestogen frequency | ||||||
| Continuous | – | – | 3948 | 2.30 (2.21–2.40) | – | – |
| Intermittent | – | – | 3467 | 1.93 (1.84–2.01) | – | – |
| Progestogen alone | 98 | 1.37 (1.08–1.74) | 107 | 1.39 (1.11–1.75) | 30 | 2.10 (1.35–3.27) |
| By progestogen | ||||||
| Medroxyprogesterone acetate | 28 | 1.68 (1.06–2.66) | 18 | 1.16 (0.68–1.98) | 7 | 3.42 (1.26–9.30) |
| Norethisterone acetate | 13 | 1.58 (0.77–3.24) | 24 | 1.55 (0.88–2.74) | 6 | 3.33 (0.81–13.8) |
| Dydrogesterone | 3 | 2.30 (0.49–10.9) | 11 | 3.31 (1.39–7.84) | 0 | – |
| Other progestogens | 8 | 2.83 (1.04–7.68) | 5 | 1.47 (0.47–4.56) | 1 | – |
| Miscellaneous | ||||||
| Tibolone | – | – | 680 | 1.57 (1.43–1.72) | – | – |
| Notes:Meta-analysis of worldwideepidemiological evidence onmenopausal hormone therapy andbreast cancer risk by theCollaborative Group on Hormonal Factors in Breast Cancer (CGHFBC). Fully adjustedrelative risks for current versus never-users of menopausal hormone therapy.Source: See template. | ||||||
| Study | Therapy | Hazard ratio (95%CITooltip confidence interval) |
|---|---|---|
| E3N-EPIC: Fournier et al. (2005) | Estrogen alone | 1.1 (0.8–1.6) |
| Estrogen plusprogesterone Transdermal estrogen Oral estrogen | 0.9 (0.7–1.2) 0.9 (0.7–1.2) No events | |
| Estrogen plus progestin Transdermal estrogen Oral estrogen | 1.4 (1.2–1.7) 1.4 (1.2–1.7) 1.5 (1.1–1.9) | |
| E3N-EPIC: Fournier et al. (2008) | Oral estrogen alone | 1.32 (0.76–2.29) |
| Oral estrogen plus progestogen Progesterone Dydrogesterone Medrogestone Chlormadinone acetate Cyproterone acetate Promegestone Nomegestrol acetate Norethisterone acetate Medroxyprogesterone acetate | Not analyzeda 0.77 (0.36–1.62) 2.74 (1.42–5.29) 2.02 (1.00–4.06) 2.57 (1.81–3.65) 1.62 (0.94–2.82) 1.10 (0.55–2.21) 2.11 (1.56–2.86) 1.48 (1.02–2.16) | |
| Transdermal estrogen alone | 1.28 (0.98–1.69) | |
| Transdermal estrogen plus progestogen Progesterone Dydrogesterone Medrogestone Chlormadinone acetate Cyproterone acetate Promegestone Nomegestrol acetate Norethisterone acetate Medroxyprogesterone acetate | 1.08 (0.89–1.31) 1.18 (0.95–1.48) 2.03 (1.39–2.97) 1.48 (1.05–2.09) Not analyzeda 1.52 (1.19–1.96) 1.60 (1.28–2.01) Not analyzeda Not analyzeda | |
| E3N-EPIC: Fournier et al. (2014) | Estrogen alone | 1.17 (0.99–1.38) |
| Estrogen plusprogesterone ordydrogesterone | 1.22 (1.11–1.35) | |
| Estrogen plus progestin | 1.87 (1.71–2.04) | |
| CECILE: Cordina-Duverger et al. (2013) | Estrogen alone | 1.19 (0.69–2.04) |
| Estrogen plus progestogen Progesterone Progestins Progesterone derivatives Testosterone derivatives | 1.33 (0.92–1.92) 0.80 (0.44–1.43) 1.72 (1.11–2.65) 1.57 (0.99–2.49) 3.35 (1.07–10.4) | |
| Footnotes:a = Not analyzed, fewer than 5 cases.Sources: See template. | ||
| Study | Therapy | Hazard ratio (95%CITooltip confidence interval) |
|---|---|---|
| E3N-EPIC: Fournier et al. (2005)a | Transdermal estrogen plusprogesterone <2 years 2–4 years ≥4 years | 0.9 (0.6–1.4) 0.7 (0.4–1.2) 1.2 (0.7–2.0) |
| Transdermal estrogen plus progestin <2 years 2–4 years ≥4 years | 1.6 (1.3–2.0) 1.4 (1.0–1.8) 1.2 (0.8–1.7) | |
| Oral estrogen plus progestin <2 years 2–4 years ≥4 years | 1.2 (0.9–1.8) 1.6 (1.1–2.3) 1.9 (1.2–3.2) | |
| E3N-EPIC: Fournier et al. (2008) | Estrogen plusprogesterone <2 years 2–4 years 4–6 years ≥6 years | 0.71 (0.44–1.14) 0.95 (0.67–1.36) 1.26 (0.87–1.82) 1.22 (0.89–1.67) |
| Estrogen plusdydrogesterone <2 years 2–4 years 4–6 years ≥6 years | 0.84 (0.51–1.38) 1.16 (0.79–1.71) 1.28 (0.83–1.99) 1.32 (0.93–1.86) | |
| Estrogen plus other progestogens <2 years 2–4 years 4–6 years ≥6 years | 1.36 (1.07–1.72) 1.59 (1.30–1.94) 1.79 (1.44–2.23) 1.95 (1.62–2.35) | |
| E3N-EPIC: Fournier et al. (2014) | Estrogens plusprogesterone ordydrogesterone <5 years ≥5 years | 1.13 (0.99–1.29) 1.31 (1.15–1.48) |
| Estrogen plus other progestogens <5 years ≥5 years | 1.70 (1.50–1.91) 2.02 (1.81–2.26) | |
| Footnotes:a = Oral estrogen plus progesterone was not analyzed because there was a low number of women who used this therapy.Sources: See template. | ||
Progestogens are relatively safe in acuteoverdose.[citation needed]
Inhibitors andinducers ofcytochrome P450enzymes and other enzymes such as5α-reductase mayinteract with progestogens.[citation needed]
Progestogens act by binding to and activating theprogesterone receptors (PRs), including thePR-A,PR-B, andPR-C.[1][163][164] Majortissues affected by progestogens include theuterus,cervix,vagina,breasts, andbrain.[1] By activating PRs in thehypothalamus andpituitary gland, progestogens suppress the secretion ofgonadotropins and thereby function asantigonadotropins at sufficiently high doses.[1] Progesterone interacts withmembrane progesterone receptors, but interaction of progestins with these receptors is less clear.[165][166] In addition to their progestogenic activity, many progestogens haveoff-target activities such asandrogenic,antiandrogenic,estrogenic,glucocorticoid, andantimineralocorticoid activity.[1][2][47]
Progestogens mediate their contraceptive effects in women both by inhibitingovulation (via their antigonadotropic effects) and by thickeningcervical mucus, thereby preventing the possibility offertilization of theovum bysperm.[4][5] Progestogens have functionalantiestrogenic effects in various tissues like theendometrium via activation of the PR, and this underlies their use in menopausal hormone therapy (to prevent unopposedestrogen-inducedendometrial hyperplasia andendometrial cancer).[1] 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.[167] The off-target activities of progestogens can contribute both to their beneficial effects and to their adverse effects.[1][2][58]
| Progestogen | Class | Off-target activities | Relative binding affinities (%) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ES | ANTooltip Androgenic | AATooltip Antiandrogenic | GCTooltip Glucocorticoid | AMTooltip Antimineralocorticoid | PRTooltip Progesterone receptor | ARTooltip Androgen receptor | ERTooltip Estrogen receptor | GRTooltip Glucocorticoid receptor | MRTooltip Mineralocorticoid receptor | SHBGTooltip Sex hormone-binding globulin | CBGTooltip Corticosteroid binding globulin | |||
| Allylestrenola | Estrane | – | ± | – | – | – | 1 | 0 | 0 | 0 | ? | 0 | ? | |
| Chlormadinone acetate | Pregnane | – | – | + | + | – | 67 | 5 | 0 | 8 | 0 | 0 | 0 | |
| Cyproterone acetate | Pregnane | – | – | ++ | + | – | 90 | 6 | 0 | 6 | 8 | 0 | 0 | |
| Demegestone | Norpregnane | – | – | – | – | – | 115 | 1 | 0 | 5 | 1–2 | ? | ? | |
| Desogestrela | Gonane | – | + | – | ± | – | 1 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Dienogest | Gonane | – | – | + | – | – | 5 | 10 | 0 | 1 | 0 | 0 | 0 | |
| Drospirenone | Spirolactone | – | – | + | – | + | 35 | 65 | 0 | 6 | 230 | 0 | 0 | |
| Dydrogesteronea | Pregnane | – | – | – | – | ± | 75 | 0 | ? | ? | ? | ? | ? | |
| Ethisterone | Androstane | – | + | – | – | – | 18 | 0 | 0 | 0 | 0 | ? | ? | |
| Etonogestrel | Gonane | – | + | – | ± | – | 150 | 20 | 0 | 14 | 0 | 15 | 0 | |
| Etynodiola,b | Estrane | + | + | – | – | – | 1 | 0 | 11–18 | 0 | ? | ? | ? | |
| Etynodiol diacetatea | Estrane | + | + | – | – | – | 1 | 0 | 0 | 0 | 0 | ? | ? | |
| Gestodene | Gonane | – | + | – | + | + | 90–432 | 85 | 0 | 27–38 | 97–290 | 40 | 0 | |
| Gestonorone caproate | Pregnane | – | – | – | – | – | ? | ? | ? | ? | ? | ? | ? | |
| Hydroxyprogesterone caproate | Pregnane | – | – | – | – | ± | ? | ? | ? | ? | ? | ? | ? | |
| Levonorgestrel | Gonane | – | + | – | – | – | 150–162 | 45 | 0 | 1–8 | 17–75 | 50 | 0 | |
| Lynestrenola | Estrane | + | + | – | – | – | 1 | 1 | 3 | 0 | 0 | ? | ? | |
| Medrogestone | Pregnane | – | – | ± | – | – | ? | ? | ? | ? | ? | ? | ? | |
| Medroxyprogesterone acetate | Pregnane | – | ± | – | + | – | 115–149 | 5 | 0 | 29–58 | 3–160 | 0 | 0 | |
| Megestrol acetate | Pregnane | – | ± | + | + | – | 65 | 5 | 0 | 30 | 0 | 0 | 0 | |
| Nomegestrol acetate | Norpregnane | – | – | + | – | – | 125 | 42 | 0 | 6 | 0 | 0 | 0 | |
| Norelgestromin | Gonane | – | ± | – | – | – | 10 | 0 | ? | ? | ? | 0 | ? | |
| Norethisterone | Estrane | + | + | – | – | – | 67–75 | 15 | 0 | 0–1 | 0–3 | 16 | 0 | |
| Norethisterone acetatea | Estrane | + | + | – | – | – | 20 | 5 | 1 | 0 | 0 | ? | ? | |
| Norethisterone enanthatea | Estrane | + | + | – | – | – | ? | ? | ? | ? | ? | ? | ? | |
| Noretynodrela | Estrane | + | ± | – | – | – | 6 | 0 | 2 | 0 | 0 | 0 | 0 | |
| Norgestimatea | Gonane | – | + | – | – | – | 15 | 0 | 0 | 1 | 0 | 0 | 0 | |
| Progesterone | Pregnane | – | – | ± | + | + | 50 | 0 | 0 | 10 | 100 | 0 | 36 | |
| Promegestonea | Norpregnane | – | – | – | + | – | 100 | 0 | 0 | 5 | 53 | 0 | 0 | |
| Segesterone acetate | Norpregnane | – | – | – | – | – | 136 | 0 | 0 | 38 | ? | 0 | ? | |
| Tibolonea | Estrane | + | ++ | – | – | – | 6 | 6 | 1 | ? | ? | ? | ||
| Δ4-Tiboloneb | Estrane | – | ++ | – | – | – | 90 | 35 | 1 | 0 | 2 | 1 | 0 | |
| Trimegestone | Norpregnane | – | – | ± | – | ± | 294–330 | 1 | 0 | 9–13 | 42–120 | ? | ? | |
| Footnotes:a =Prodrug.b =Metabolite (non-marketed).Class: Pregnane =Progesterone derivative. Norpregnane =19-Norprogesterone derivative. Androstane =Testosterone derivative. Estrane =19-Nortestosterone derivative. Gonane = 13β-Ethylgonane =18-Methyl-19-nortestosterone derivative. Spirolactone =Spirolactone derivative.Magnitude:++ = High.+ = Moderate.± = Low.– = None.Activity: ES =Estrogenic. AN =Androgenic. AA =Antiandrogenic. GC =Glucocorticoid. AM =Antimineralocorticoid.Binding:PRTooltip Progesterone receptor:Promegestone = 100%.ARTooltip Androgen receptor:Metribolone = 100%.ERTooltip estrogen receptor:Estradiol = 100%.GRTooltip Glucocorticoid receptor:Dexamethasone = 100%.MRTooltip Mineralocorticoid receptor:Aldosterone = 100%.SHBGTooltip Sex hormone-binding globulin:DHT = 100%.CBGTooltip Corticosteroid-binding globulin:Cortisol = 100%.Sources: See template. | ||||||||||||||
| Compound | Doses for specific uses (mg/day)[a] | |||||||
|---|---|---|---|---|---|---|---|---|
| OID | TFD | MDT | BCPD | ECD | ||||
| Cycle | Daily | |||||||
| Allylestrenol | 25 | 150–300 | – | 30 | – | – | ||
| Bromoketoprogesterone[b] | – | – | 100–160 | – | – | – | ||
| Chlormadinone acetate | 1.5–4.0 | 20–30 | 3–10 | 1.0–4.0 | 2.0 | 5–10 | ||
| Cyproterone acetate | 1.0 | 20–30 | 1.0–3.0 | 1.0–4.0 | 2.0 | 1.0 | ||
| Desogestrel | 0.06 | 0.4–2.5 | 0.15 | 0.25 | 0.15 | 0.15 | ||
| Dienogest | 1.0 | 6.0–6.3 | – | – | 2.0–3.0 | 2.0 | ||
| Drospirenone | 2.0 | 40–80 | – | – | 3.0 | 2.0 | ||
| Dydrogesterone | >30 | 140–200 | 10–20 | 20 | – | 10 | ||
| Ethisterone | – | 200–700 | 50–250 | – | – | – | ||
| Etynodiol diacetate | 2.0 | 10–15 | – | 1.0 | 1.0–20 | – | ||
| Gestodene | 0.03 | 2.0–3.0 | – | – | 0.06–0.075 | 0.20 | ||
| Hydroxyprogest. acetate | – | – | 70–125 | – | 100 | – | ||
| Hydroxyprogest. caproate | – | 700–1400 | 70 | – | – | – | ||
| Levonorgestrel | 0.05 | 2.5–6.0 | 0.15–0.25 | 0.5 | 0.1–0.15 | 0.075 | ||
| Lynestrenol | 2.0 | 35–150 | 5.0 | 10 | – | – | ||
| Medrogestone | 10 | 50–100 | 10 | 15 | – | 10 | ||
| Medroxyprogest. acetate | 10 | 40–120 | 2.5–10 | 20–30 | 5–10 | 5.0 | ||
| Megestrol acetate | >5[c] | 30–70 | – | 5–10 | 1.0–5.0 | 5.0 | ||
| Nomegestrol acetate | 1.25–5.0 | 100 | 5.0 | – | 2.5 | 3.75–5.0 | ||
| Norethandrolone[b] | – | – | 10 | – | – | – | ||
| Norethisterone | 0.4–0.5 | 100–150 | 5–10 | 10–15 | 0.5 | 0.7–1.0 | ||
| Norethisterone acetate | 0.5 | 30–60 | 2.5–5.0 | 7.5 | 0.6 | 1.0 | ||
| Norethist. acetate (micron.) | – | 12–14 | – | – | – | – | ||
| Noretynodrel | 4.0 | 150–200 | – | 14 | 2.5–10 | – | ||
| Norgestimate | 0.2 | 2.0–10 | – | – | 0.25 | 0.09 | ||
| Norgestrel | 0.1 | 12 | – | 0.5–2.0 | – | – | ||
| Normethandrone | – | 150 | 10 | – | – | – | ||
| Progesterone (non-micron.) | >300[d] | – | – | – | – | – | ||
| Progesterone (micronized) | – | 4200 | 200–300 | 1000 | – | 200 | ||
| Promegestone | 0.5 | 10 | 0.5 | – | – | 0.5 | ||
| Tibolone | 2.5 | – | – | – | – | – | ||
| Trengestone | – | 50–70 | – | – | – | – | ||
| Trimegestone | 0.5 | – | 0.25–0.5 | – | – | 0.0625–0.5 | ||
Notes and sources
| ||||||||
| Compound | Form | Dose for specific uses (mg)[c] | DOA[d] | |||
|---|---|---|---|---|---|---|
| TFD[e] | POICD[f] | CICD[g] | ||||
| Algestone acetophenide | Oil soln. | – | – | 75–150 | 14–32 d | |
| Gestonorone caproate | Oil soln. | 25–50 | – | – | 8–13 d | |
| Hydroxyprogest. acetate[h] | Aq. susp. | 350 | – | – | 9–16 d | |
| Hydroxyprogest. caproate | Oil soln. | 250–500[i] | – | 250–500 | 5–21 d | |
| Medroxyprog. acetate | Aq. susp. | 50–100 | 150 | 25 | 14–50+ d | |
| Megestrol acetate | Aq. susp. | – | – | 25 | >14 d | |
| Norethisterone enanthate | Oil soln. | 100–200 | 200 | 50 | 11–52 d | |
| Progesterone | Oil soln. | 200[i] | – | – | 2–6 d | |
| Aq. soln. | ? | – | – | 1–2 d | ||
| Aq. susp. | 50–200 | – | – | 7–14 d | ||
Notes and sources:
| ||||||
Progestogens, similarly to the androgens and estrogens through their own respectivereceptors, inhibit the secretion of thegonadotropinsfollicle-stimulating hormone (FSH) andluteinizing hormone (LH) via activation of the PR in thepituitary gland. This effect is a form ofnegative feedback on thehypothalamic–pituitary–gonadal axis (HPG axis) and takes advantage of the mechanism that the body uses to preventsex hormone levels from becoming too high.[215][216][217] Accordingly, progestogens, both endogenous and exogenous (i.e., progestins), haveantigonadotropic effects,[218] and progestogens in sufficiently high amounts can markedly suppress the body's normal production of progestogens, androgens, and estrogens as well as inhibitfertility (ovulation in women andspermatogenesis in men).[217]
Progestogens have been found to maximally suppress circulating testosterone levels in men by up to 70 to 80% at sufficiently high doses.[219][220] This is notably less than that achieved byGnRH analogues, which can effectively abolish gonadal production of testosterone and suppress circulating testosterone levels by as much as 95%.[221] It is also less than that achieved byhigh-dose estrogen therapy, which can suppress testosterone levels into the castrate range similarly to GnRH analogues.[222]
Theretroprogesteronederivativesdydrogesterone andtrengestone are atypical progestogens and unlike all other clinically used progestogens do not have antigonadotropic effects nor inhibit ovulation even at very high doses.[1][223] In fact, trengestone may haveprogonadotropic effects, and is actually able toinduce ovulation, with about a 50% success rate on average.[223] These progestins also show other atypical properties relative to other progestogens, such as a lack of ahyperthermic effect.[1][223]
Some progestins haveandrogenic activity and can produce androgenicside effects such as increasedsebum production (oilier skin),acne, andhirsutism (excessive facial/body hair growth), as well as changes inliver protein production.[224][225][226] Only certain progestins are androgenic however, these being thetestosterone derivatives and, to a lesser extent, the17α-hydroxyprogesterone derivativesmedroxyprogesterone acetate andmegestrol acetate.[227][225][228] No other progestins have such activity (though some, conversely, possess antiandrogenic activity).[225][228] 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.[21][229]
The androgenic activity of androgenic progestins is mediated by two mechanisms: 1) direct binding to and activation of theandrogen receptor; and 2) displacement oftestosterone fromsex hormone-binding globulin (SHBG), thereby increasing free (and thus bioactive) testosterone levels.[230] The androgenic activity of many androgenic progestins is offset by combination withethinylestradiol, which robustly increases SHBG levels, and most oral contraceptives in fact markedly reduce free testosterone levels and can treat or improve acne and hirsutism.[230] An exception is progestin-only contraceptives, which do not also contain an estrogen.[230]
The relative androgenic activity of testosterone-derivative progestins and other progestins that have androgenic activity can be roughly ranked as follows:
The clinical androgenic andanabolic activity of the androgenic progestins listed above is still far lower than that of conventionalandrogens andanabolic steroids liketestosterone andnandrolone esters. 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.
Some progestogens haveantiandrogenic activity in addition to their progestogenic activity.[248] These progestogens, with varying degrees of potency as antiandrogens, includechlormadinone acetate,cyproterone acetate,dienogest,drospirenone,medrogestone,megestrol acetate,nomegestrol acetate,osaterone acetate (veterinary), andoxendolone.[248][247][249][250] 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%).[1][83] Antiandrogenic activity in certain progestogens may help to improve symptoms ofacne,seborrhea,hirsutism, and otherandrogen-dependent conditions in women.[1][248]
A few progestins have weakestrogenic activity.[1] These include the 19-nortestosterone derivativesnorethisterone,noretynodrel, andtibolone, as well as the norethisteroneprodrugs[251]norethisterone acetate,norethisterone enanthate,lynestrenol, andetynodiol diacetate.[1] The estrogenic activity of norethisterone and its prodrugs are due tometabolism intoethinylestradiol.[1] High doses of norethisterone and noretynodrel have been associated with estrogenic side effects such asbreast enlargement in women andgynecomastia in men, but also with alleviation ofmenopausal symptoms in postmenopausal women.[252] In contrast, non-estrogenic progestins were not found to be associated with such effects.[252]
Some progestogens, mainly certain17α-hydroxyprogesterone derivatives, have weakglucocorticoid activity.[253] This can result, at sufficiently high doses, in side effects such as symptoms ofCushing's syndrome,steroid diabetes,adrenal suppression and insufficiency, andneuropsychiatric symptoms likedepression,anxiety,irritability, andcognitive impairment.[253][254][255] Progestogens with the potential for clinically relevant glucocorticoid effects include the 17α-hydroxyprogesterone derivativeschlormadinone acetate,cyproterone acetate,medroxyprogesterone acetate,megestrol acetate,promegestone, andsegesterone acetate and the testosterone derivativesdesogestrel,etonogestrel, andgestodene.[1][254][256][257] Conversely,hydroxyprogesterone caproate possesses no such activity, whileprogesterone itself has very weak glucocorticoid activity.[258][1]
| Steroid | Class | TRTooltip Thrombin receptor (↑)a | GRTooltip glucocorticoid receptor (%)b |
|---|---|---|---|
| Dexamethasone | Corticosteroid | ++ | 100 |
| Ethinylestradiol | Estrogen | – | 0 |
| Etonogestrel | Progestin | + | 14 |
| Gestodene | Progestin | + | 27 |
| Levonorgestrel | Progestin | – | 1 |
| Medroxyprogesterone acetate | Progestin | + | 29 |
| Norethisterone | Progestin | – | 0 |
| Norgestimate | Progestin | – | 1 |
| Progesterone | Progestogen | + | 10 |
| Footnotes:a =Thrombin receptor (TR)upregulation (↑) invascular smooth muscle cells (VSMCs).b =RBATooltip Relative binding affinity (%) for theglucocorticoid receptor (GR).Strength: – = No effect. + = Pronounced effect. ++ = Strong effect.Sources:[259] | |||
Certain progestogens, includingprogesterone,drospirenone, andgestodene, as well as to a lesser extentdydrogesterone andtrimegestone, have varying degrees ofantimineralocorticoid activity.[1][58] Other progestins might also have significant antimineralocorticoid activity.[260]Progesterone itself has potent antimineralocorticoid activity.[1] No clinically used progestogens are known to havemineralocorticoid activity.[1]
Progestins with potent antimineralocorticoid activity like drospirenone may have properties more similar to those of natural progesterone, such as counteraction of cyclical estrogen-inducedsodium andfluid retention,edema, and associatedweight gain; loweredblood pressure; and possibly improvedcardiovascular health.[261][262][263][264]
Progesterone hasneurosteroid activity via metabolism intoallopregnanolone andpregnanolone, potentpositive allosteric modulators of theGABAA receptor.[1] As a result, it has associated effects such assedation,somnolence, andcognitive impairment.[1] No progestin is known to have similar such neurosteroid activity or effects.[1] However,promegestone has been found to act as anon-competitive antagonist of thenicotinic acetylcholine receptor similarly to progesterone.[265]
Certain progestins have been found to stimulate theproliferation ofMCF-7breast cancercellsin vitro, an action that is independent of the classical PRs and is instead mediated via theprogesterone receptor membrane component-1 (PGRMC1).[266]Norethisterone,desogestrel,levonorgestrel, anddrospirenone strongly stimulate proliferation andmedroxyprogesterone acetate,dienogest, anddydrogesterone weakly stimulate proliferation, whereasprogesterone,nomegestrol acetate, andchlormadinone acetate act neutrally in the assay and do not stimulate proliferation.[266][267] 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 inclinical studies.[268]
Oral progesterone has very lowbioavailability andpotency.[1][6][158][122][269]Micronization and dissolution inoil-filledcapsules, a formulation known as oral micronized progesterone (OMP), increases the bioavailability of progesterone by several-fold.[269][270] However, the bioavailability of oral micronized progesterone nonetheless remains very low at less than 2.4%.[1][6][158][122][271] Progesterone also has a very shortelimination half-life in thecirculation of no more than 1.5 hours.[272][1][269] Due to the poor oral activity of oral micronized progesterone, it has relatively weak progestogenic effects.[6][158][122] Administration of progesterone inoil solution byintramuscular injection has a duration of about 2 or 3 days, necessitating frequent injections.[1][273][274][275][276][277]Transdermal administration of progesterone in the form ofcreams orgels achieves only very low levels of progesterone and weak progestogenic effects.[278][279]
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.[280] Orally active progestins have high oral bioavailability in comparison to oral micronized progesterone.[1] Their bioavailability is generally in the range of 60 to 100%.[1] Their elimination half-lives are also much longer than that of progesterone, in the range of 8 to 80 hours.[1] Due mainly to theirpharmacokinetic improvements, progestins have oral potency that is up to several orders of magnitude greater than that of oral micronized progesterone.[1] For example, the oral potency of medroxyprogesterone acetate is at least 30-fold that of oral micronized progesterone, while the oral potency ofgestodene is at least 10,000-fold that of oral micronized progesterone.[1] Parenterally administered progestins, such ashydroxyprogesterone caproate in oil solution,norethisterone enanthate in oil solution, and medroxyprogesterone acetate inmicrocrystallineaqueous suspension, have durations in the range of weeks to months.[273][274][275][276][277]
| Progestogen | Class | Dosea | Bioavailability | Half-lifeTooltip Elimination half-life | |
|---|---|---|---|---|---|
| Allylestrenol | Estrane | NA | ? | Prodrug | |
| Chlormadinone acetate | Pregnane | 2 mg | ~100% | 80 hours | |
| Cyproterone acetate | Pregnane | 2 mg | ~100% | 54–79 hours | |
| Desogestrel | Gonane | 0.15 mg | 63% | Prodrug | |
| Dienogest | Gonane | 4 mg | 96% | 11–12 hours | |
| Drospirenone | Spirolactone | 3 mg | 66% | 31–33 hours | |
| Dydrogesterone | Pregnane | 10 mg | 28% | 14–17 hours | |
| Etynodiol diacetate | Estrane | NA | ? | Prodrug | |
| Gestodene | Gonane | 0.075 mg | 88–99% | 12–14 hours | |
| Hydroxyprogesterone caproate | Pregnane | ND | – | 8 daysb | |
| Levonorgestrel | Gonane | 0.15–0.25 mg | 90% | 10–13 hours | |
| Lynestrenol | Estrane | NA | ? | Prodrug | |
| Medrogestone | Pregnane | 5 mg | ~100% | 35 hours | |
| Medroxyprogesterone acetate | Pregnane | 10 mg | ~100% | 24 hours | |
| Megestrol acetate | Pregnane | 160 mg | ~100% | 22 hours | |
| Nomegestrol acetate | Pregnane | 2.5 mg | 60% | 50 hours | |
| Norethisterone | Estrane | 1 mg | 64% | 8 hours | |
| Norethisterone acetate | Estrane | NA | ? | Prodrug | |
| Noretynodrel | Estrane | NA | ? | Prodrug | |
| Norgestimate | Gonane | NA | ? | Prodrug | |
| Progesterone (micronized) | Pregnane | 100–200 mg | <2.4% | 5 hours | |
| Promegestone | Pregnane | NA | ? | Prodrug | |
| Tibolone | Estrane | NA | ? | Prodrug | |
| Trimegestone | Pregnane | 0.5 mg | ~100% | 15 hours | |
| Notes: All byoral administration, unless otherwise noted.Footnotes:a = For the listed pharmacokinetic values.b = Byintramuscular injection.Sources: See template. | |||||
All currently available progestogens aresteroidal in terms ofchemical structure.[1] Progestogens include thenaturally occurringprogesterone and thesynthetic progestogens (otherwise known as progestins).[1] Progestins can be broadly grouped into two structural classes—chemical derivatives ofprogesterone and chemical derivatives oftestosterone.[1] Progesterone derivatives can be classified into subgroups includingpregnanes,retropregnanes,norpregnanes, andspirolactones.[1] Examples of progestins of each of these subgroups includemedroxyprogesterone acetate,dydrogesterone,nomegestrol acetate, anddrospirenone, respectively.[1] Testosterone derivatives can be classified into subgroups includingandrostanes,estranes (19-norandrostanes), andgonanes (18-methylestranes).[1][281] Examples of progestins of each of these subgroups includeethisterone,norethisterone, andlevonorgestrel, respectively.[1] Many progestins haveester and/orethersubstitutions (seeprogestogen ester) which result in greaterlipophilicity and in some cases cause the progestins in question to act asprodrugs in the body.[1]
| Class | Subclass | Progestogen | Structure | Chemical name | Features |
|---|---|---|---|---|---|
| Pregnane | Progesterone | Progesterone |  | Pregn-4-ene-3,20-dione | – |
| Quingestrone |  | Progesterone 3-cyclopentyl enol ether | Ether | ||
| 17α-Hydroxyprogesterone | Acetomepregenol |  | 3-Deketo-3β,17α-dihydroxy-6-dehydro-6-methylprogesterone 3β,17α-diacetate | Ester | |
| Algestone acetophenide |  | 16α,17α-Dihydroxyprogesterone 16α,17α-(cyclic acetal with acetophenone) | Cyclic acetal | ||
| Anagestone acetate |  | 3-Deketo-6α-methyl-17α-hydroxyprogesterone 17α-acetate | Ester | ||
| Chlormadinone acetate |  | 6-Dehydro-6-chloro-17α-hydroxyprogesterone 17α-acetate | Ester | ||
| Chlormethenmadinone acetate |  | 6-Dehydro-6-chloro-16-methylene-17α-hydroxyprogesterone 17α-acetate | Ester | ||
| Cyproterone acetate |  | 1,2α-Methylene-6-dehydro-6-chloro-17α-hydroxyprogesterone 17α-acetate | Ester;Ring-fused | ||
| Delmadinone acetate |  | 1,6-Didehydro-6-chloro-17α-hydroxyprogesterone 17α-acetate | Ester | ||
| Flugestone acetate |  | 9α-Fluoro-11β,17α-dihydroxyprogesterone 17α-acetate | Ester | ||
| Flumedroxone acetate |  | 6α-(Trifluoromethyl)-17α-hydroxyprogesterone 17α-acetate | Ester | ||
| Hydroxyprogesterone acetate |  | 17α-Hydroxyprogesterone 17α-acetate | Ester | ||
| Hydroxyprogesterone caproate |  | 17α-Hydroxyprogesterone 17α-hexanoate | Ester | ||
| Hydroxyprogesterone heptanoate |  | 17α-Hydroxyprogesterone 17α-heptanoate | Ester | ||
| Medroxyprogesterone acetate |  | 6α-Methyl-17α-hydroxyprogesterone 17α-acetate | Ester | ||
| Megestrol acetate |  | 6-Dehydro-6-methyl-17α-hydroxyprogesterone 17α-acetate | Ester | ||
| Melengestrol acetate |  | 6-Dehydro-6-methyl-16-methylene-17α-hydroxyprogesterone 17α-acetate | Ester | ||
| Methenmadinone acetate |  | 6-Dehydro-16-methylene-17α-hydroxyprogesterone 17α-acetate | Ester | ||
| Osaterone acetate |  | 2-Oxa-6-dehydro-6-chloro-17α-hydroxyprogesterone 17α-acetate | Ester | ||
| Pentagestrone acetate |  | 17α-Hydroxyprogesterone 3-cyclopentyl enol ether 17α-acetate | Ester; Ether | ||
| Proligestone |  | 14α,17α-Dihydroxyprogesterone 14α,17α-(cyclic acetal with propionaldehyde) | Cyclic acetal | ||
| Other 17α-substituted progesterone | Haloprogesterone |  | 6α-Fluoro-17α-bromoprogesterone | – | |
| Medrogestone |  | 6-Dehydro-6,17α-dimethylprogesterone | – | ||
| Spirolactone | Drospirenone |  | 6β,7β:15β,16β-Dimethylenespirolactone | Ring-fused | |
| Norpregnane | 19-Norprogesterone; 17α-Hydroxyprogesterone | Gestonorone caproate |  | 17α-Hydroxy-19-norprogesterone 17α-hexanoate | Ester |
| Nomegestrol acetate |  | 6-Dehydro-6-methyl-17α-hydroxy-19-norprogesterone 17α-acetate | Ester | ||
| Norgestomet |  | 11β-Methyl-17α-hydroxy-19-norprogesterone 17α-acetate | Ester | ||
| Segesterone acetate |  | 16-Methylene-17α-hydroxy-19-norprogesterone 17α-acetate | Ester | ||
| 19-Norprogesterone; Other 17α-substituted progesterone | Demegestone |  | 9-Dehydro-17α-methyl-19-norprogesterone | – | |
| Promegestone |  | 9-Dehydro-17α,21-dimethyl-19-norprogesterone | – | ||
| Trimegestone |  | 9-Dehydro-17α,21-dimethyl-19-nor-21β-hydroxyprogesterone | – | ||
| Retropregnane | Retroprogesterone | Dydrogesterone |  | 6-Dehydro-9β,10α-progesterone | – |
| Trengestone |  | 1,6-Didehydro-6-chloro-9β,10α-progesterone | – | ||
| Androstane | 17α-Ethynyltestosterone | Danazol |  | 2,3-d-Isoxazol-17α-ethynyltestosterone | Ring-fused |
| Dimethisterone |  | 6α,21-Dimethyl-17α-ethynyltestosterone | – | ||
| Ethisterone |  | 17α-Ethynyltestosterone | – | ||
| Estrane | 19-Nortestosterone; 17α-Ethynyltestosterone | Etynodiol diacetate |  | 3-Deketo-3β-hydroxy-17α-ethynyl-19-nortestosterone 3β,17β-diacetate | Ester |
| Lynestrenol |  | 3-Deketo-17α-ethynyl-19-nortestosterone | – | ||
| Norethisterone |  | 17α-Ethynyl-19-nortestosterone | – | ||
| Norethisterone acetate |  | 17α-Ethynyl-19-nortestosterone 17β-acetate | Ester | ||
| Norethisterone enanthate |  | 17α-Ethynyl-19-nortestosterone 17β-heptanoate | Ester | ||
| Noretynodrel |  | 5(10)-Dehydro-17α-ethynyl-19-nortestosterone | – | ||
| Norgestrienone |  | 9,11-Didehydro-17α-ethynyl-19-nortestosterone | – | ||
| Quingestanol acetate |  | 17α-Ethynyl-19-nortestosterone 3-cyclopentyl enol ether 17β-acetate | Ester; Ether | ||
| Tibolone |  | 5(10)-Dehydro-7α-methyl-17α-ethynyl-19-nortestosterone | – | ||
| 19-Nortestosterone; Other 17α-substituted testosterone (and 16β-substituted testosterone) | Allylestrenol |  | 3-Deketo-17α-allyl-19-nortestosterone | – | |
| Altrenogest |  | 9,11-Didehydro-17α-allyl-19-nortestosterone | – | ||
| Dienogest |  | 9-Dehydro-17α-cyanomethyl-19-nortestosterone | – | ||
| Norgesterone |  | 5(10)-Dehydro-17α-vinyl-19-nortestosterone | – | ||
| Normethandrone |  | 17α-Methyl-19-nortestosterone | – | ||
| Norvinisterone |  | 17α-Vinyl-19-nortestosterone | – | ||
| Oxendolone |  | 16β-Ethyl-19-nortestosterone | – | ||
| Gonane | 19-Nortestosterone; 17α-Ethynyltestosterone; 18-Methyltestosterone | Desogestrel |  | 3-Deketo-11-methylene-17α-ethynyl-18-methyl-19-nortestosterone | – |
| Etonogestrel |  | 11-Methylene-17α-ethynyl-18-methyl-19-nortestosterone | – | ||
| Gestodene |  | 15-Dehydro-17α-ethynyl-18-methyl-19-nortestosterone | – | ||
| Gestrinone |  | 9,11-Didehydro-17α-ethynyl-18-methyl-19-nortestosterone | – | ||
| Levonorgestrel |  | 17α-Ethynyl-18-methyl-19-nortestosterone | – | ||
| Norelgestromin |  | 17α-Ethynyl-18-methyl-19-nortestosterone 3-oxime | Oxime | ||
| Norgestimate |  | 17α-Ethynyl-18-methyl-19-nortestosterone 3-oxime 17β-acetate | Oxime; Ester | ||
| Norgestrel |  | rac-13-Ethyl-17α-ethynyl-19-nortestosterone | – |
The recognition of progesterone's ability to suppressovulation during pregnancy spawned a search for a similar hormone that could bypass the problems associated with administering progesterone (e.g. lowbioavailability when administered orally and local irritation and pain when continually administeredparenterally) 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 C17αethynylanalogue oftestosterone, wassynthesized in 1938 fromdehydroandrosterone byethynylation, either before or afteroxidation of the C3 hydroxyl group, followed byrearrangement 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 atSchering AG inBerlin and was marketed inGermany in 1939 asProluton C and bySchering in theU.S. in 1945 asPranone.[282][283][284][285][286]
A more potent orally active progestin,norethisterone (norethindrone, 19-nor-17α-ethynyltestosterone), the C19nor analogue of ethisterone, synthesized in 1951 byCarl Djerassi,Luis Miramontes, andGeorge Rosenkranz atSyntex inMexico City, was marketed byParke-Davis in the U.S. in 1957 asNorlutin, and was used as the progestin in some of thefirst oral contraceptives (Ortho-Novum,Norinyl, etc.) in the early 1960s.[283][284][285][286][287]
Noretynodrel, anisomer of norethisterone, was synthesized in 1952 byFrank B. Colton atSearle inSkokie, Illinois and used as the progestin inEnovid, marketed in the U.S. in 1957 and approved as the first oral contraceptive in 1960.[283][284][285][286][288]
Progestins used in birth control are sometimes grouped, somewhat arbitrarily and inconsistently, intogenerations. One categorization of these generations is as follows:[14]
Alternatively,estranes such asnoretynodrel andnorethisterone are classified as first-generation whilegonanes such asnorgestrel andlevonorgestrel are classified as second-generation, with less androgenic gonanes such asdesogestrel,norgestimate, andgestodene classified as third-generation and newer progestins likedrospirenone classified as fourth-generation.[15] Yet another classification system considers there to be only first- and second-generation progestins.[citation needed]
Classification of progestins by generation has been criticized and it has been argued that the classification scheme should be abandoned.[289]
Progestogens are available widely throughout the world in many different forms. They are present in all birth control pills.
Progestogens, also termedprogestagens,progestogens, orgestagens, are compounds which act asagonists of theprogesterone receptors.[118][1][143] Progestogens includeprogesterone—which is the main natural and endogenous progestogen—andprogestins, which aresynthetic progestogens.[1] Progestins include the17α-hydroxyprogesteronederivativemedroxyprogesterone acetate and the19-nortestosterone derivativenorethisterone, among many other synthetic progestogens.[118][1] As progesterone is a single compound and has no plural form, the term "progesterones" does not exist and is grammatically incorrect.[143] The terms describing progestogens are often confused.[118][143] However, progestogens have differingactivities and effects and it is inappropriate to interchange them.[118][1][143]
A variety of progestins have been studied for use as potentialmale hormonal contraceptives in combination withandrogens in men.[290] These include thepregnanesmedroxyprogesterone acetate,megestrol acetate, andcyproterone acetate, thenorpregnanesegesterone acetate, and theestranesnorethisterone acetate,norethisterone enanthate,levonorgestrel,levonorgestrel butanoate,desogestrel, andetonogestrel.[290][291][292][293] The androgens that have been used in combination with these progestins includetestosterone,testosterone esters,androstanolone (dihydrotestosterone), andnandrolone esters.[290] Dual androgens and progestogens such astrestolone anddimethandrolone undecanoate have also been developed and studied as male contraceptives.[294][295] Doses of progestins used in male hormonal contraception have been noted to be in the range of 5 to 12 times the doses used in female hormonal contraception.[296]
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.
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.
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.
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).
Zur Transformation des Endometriums benotigten sie 200-400 mg [ethisterone] pro Cyclus und postulierten eine etwa sechsfach schwachere Wirkung gegenuber dem Progesteron i.m. appliziert.
Table 1 Publications on ovulation inhibition doses of progestins: Progestin: Progesterone. Reference: Pincus (1956). Method: Urinary Pdiol. Daily dose (mg): 300.000. Total number of cycles in all subjects: 61. Total number of ovulation in all subjects: 30. % of ovulation in all subjects: 49.
The anti-ovulatory properties of megestrol acetate 5 mg. plus Mestranol 0.1 mg. were demonstrated in thirty-five women by direct inspection of the ovaries. When given alone, megestrol acetate 5 mg. or Mestranol 0.1 mg. did not prevent ovulation in all cases.
At 0.25 mg/day MA has no apparent effect on the histology of the endometrium and is not effective as a contraceptive (53). However, at doses of 0.35 and 0.5 mg/day the drug is an effective contraceptive (10). At the 0.5 mg/day dose MA does not inhibit ovulation but does reduce sperm motility in post-coital tests (68).
Early studies on its use as an oral contraceptive showed that, at 300 mg/day (5th to 25th day of the menstrual cycle), progesterone was effective in preventing ovulation through four cycles (263). The related effect of larger doses of progesterone on gonadotropin excretion also has been investigated. Rothchild (264) found that continuous or intermittent intravenously administered progesterone (100-400 mg/day) for 10 days depressed the total amount of gonadotropin excreted into the urine. However, Paulsen et al. (265) found that oral progesterone at 1000 mg/day for 87 days did not have a significant effect on urinary gonadotropin excretion. The efficacy of progesterone as an oral contraceptive was never fully tested, because synthetic progestational agents, which were orally effective, were available.
Table 1: Effects of oral progesterone on three indexes of ovulation: Medication: Progesterone. Number: 69. Mean cycle length: 25.5 ± 0.59. Per cent positive for ovulation by: Basal temperature: 27. Endometrial biopsy: 18. Vaginal smear: 6. [...] we settled on 300 mg. per day [oral progersterone] as a significantly effective [ovulation inhibition] dosage, and this was administered from the fifth day through the twenty-fourth day of the menstrual cycle. [...] We observed each of 33 volunteer subjects during a control, nontreatment cycle and for one to three successive cycles of medication immediately following the control cycle. As indexes of the occurrence of ovulation, daily basal temperatures and vaginal smears were taken, and at the nineteenth to twenty-second day of the cycle an endometrial biopsy. [...] Although we thus demonstrated the ovulation-inhibiting activity of progesterone in normally ovulating women, oral progesterone medication had two disadvantages: ( l) the large daily dosage ( 300 mg.) which presumably would have to be even larger if one sought 100 per cent inhibition1 [...]
17α-Hydroxyprogesterone caproate is a depot progestogen which is entirely free of side actions. The dose required to induce secretory changes in primed endometrium is about 250 mg. per menstrual cycle.
The results showed that after injection the concentration of plasma MA increased rapidly. The meantime of peak plasma MA level was 3rd day, there was a linear relationship between log of plasma MA concentration and time (day) after administration in all subjects, elimination phase half-life t1/2β = 14.35 ± 9.1 days.
[Norethisterone] has similar and [norethynodrel] weaker androgenic effects compared to tibolone.
Similar androgenic potential is inherent to norethisterone and its prodrugs (norethisterone acetate, ethynodiol diacetate, lynestrenol, norethynodrel, quingestanol).
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.
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.
