Estrogen (medication)
Drug class
Estradiol, the major estrogen sex hormone in humans and a widely used medication
Class identifiers
Use	Contraception,menopause,hypogonadism,transgender women,prostate cancer,breast cancer, others
ATC code	G03C
Biological target	Estrogen receptors (ERα,ERβ,mERs (e.g.,GPER, others))
External links
MeSH	D004967
Legal status
Legal status	Rx-only, illegal in countries whereHRT is banned
In Wikidata

Anestrogen (E) is a type ofmedication which is used most commonly inhormonal birth control andmenopausal hormone therapy, and as part offeminizing hormone therapy fortransgender women.^[1] They can also be used in the treatment ofhormone-sensitive cancers likebreast cancer andprostate cancer and for various other indications. Estrogens are used alone or in combination withprogestogens.^[1] They are available in a wide variety offormulations and for use by many differentroutes of administration.^[1] Examples of estrogens includebioidenticalestradiol,naturalconjugated estrogens,syntheticsteroidal estrogens likeethinylestradiol, and syntheticnonsteroidal estrogens likediethylstilbestrol.^[1] Estrogens are one of three types ofsex hormone agonists, the others beingandrogens/anabolic steroids liketestosterone andprogestogens likeprogesterone.

Side effects of estrogens includebreast tenderness,breast enlargement,headache,nausea, andedema among others.^[1] Other side effects of estrogens include an increased risk ofblood clots,cardiovascular disease, and, when combined with most progestogens,breast cancer.^[1] In men, estrogens can causebreast development,feminization,infertility,low testosterone levels, andsexual dysfunction among others.

Estrogens areagonists of theestrogen receptors, thebiological targets ofendogenous estrogens likeestradiol. They have important effects in manytissues in the body, including in thefemale reproductive system (uterus,vagina, andovaries), thebreasts,bone,fat, theliver, and thebrain among others.^[1] Unlike other medications likeprogestins and anabolic steroids, estrogens do not have other hormonal activities.^[1] Estrogens also haveantigonadotropic effects and at sufficiently high dosages can strongly suppresssex hormone production.^[1] Estrogens mediate their contraceptive effects in combination with progestins by inhibitingovulation.

Estrogens were first introduced for medical use in the early 1930s. They started to be used in birth control in combination with progestins in the 1950s.^[2] A variety of different estrogens have been marketed for clinical use in humans or use inveterinary medicine, although only a handful of these are widely used.^{[3][4][5][6][7]} These medications can be grouped into different types based on origin andchemical structure.^[1] Estrogens are available widely throughout the world and are used in most forms of hormonal birth control and in all menopausal hormone therapy regimens.^{[3][4][6][5][1]}

Estrogens havecontraceptive effects and are used in combination withprogestins (syntheticprogestogens) inbirth control to preventpregnancy in women. This is referred to ascombined hormonal contraception. The contraceptive effects of estrogens are mediated by theirantigonadotropic effects and hence by inhibition ofovulation. Mostcombined oral contraceptives contain ethinylestradiol or itsprodrugmestranol as the estrogen component, but a few contain estradiol or estradiol valerate. Ethinylestradiol is generally used in oral contraceptives instead of estradiol because it has superiororalpharmacokinetics (higherbioavailability and lessinterindividual variability) and controlsvaginal bleeding more effectively. This is due to its synthetic nature and its resistance tometabolism in certaintissues such as theintestines,liver, anduterus relative to estradiol. Besides oral contraceptives, other forms of combined hormonal contraception includecontraceptive patches,contraceptive vaginal rings, andcombined injectable contraceptives. Contraceptive patches and vaginal rings contain ethinylestradiol as the estrogen component, while combined injectable contraceptives contain estradiol or more typically anestradiol ester.

Estrogen and other hormones are given to postmenopausal women in order to preventosteoporosis as well as treat the symptoms of menopause such as hot flashes, vaginal dryness, urinary stress incontinence, chilly sensations, dizziness, fatigue, irritability, and sweating. Fractures of the spine, wrist, and hips decrease by 50 to 70% and spinal bone density increases by approximately 5% in those women treated with estrogen within 3 years of the onset of menopause and for 5 to 10 years thereafter.

Before the specific dangers of conjugated estrogens were well understood, standard therapy was 0.625 mg/day of conjugated estrogens (such as Premarin). There are, however, risks associated with conjugated estrogen therapy. Among the older postmenopausal women studied as part of theWomen's Health Initiative (WHI), an orally administered conjugated estrogen supplement was found to be associated with an increased risk of dangerousblood clotting. The WHI studies used one type of estrogen supplement, a high oral dose of conjugated estrogens (Premarin alone and with medroxyprogesterone acetate asPrempro).^[10]

In a study by the NIH, esterified estrogens were not proven to pose the same risks to health as conjugated estrogens.Menopausal hormone therapy has favorable effects on serum cholesterol levels, and when initiated immediately upon menopause may reduce the incidence of cardiovascular disease, although this hypothesis has yet to be tested in randomized trials. Estrogen appears to have a protector effect on atherosclerosis: it lowers LDL and triglycerides, it raises HDL levels and has endothelial vasodilatation properties plus an anti-inflammatory component.

Research is underway to determine if risks of estrogen supplement use are the same for all methods of delivery. In particular, estrogen appliedtopically may have a different spectrum of side effects than when administered orally,^[11] and transdermal estrogens do not affect clotting as they are absorbed directly into the systemic circulation, avoiding first-pass metabolism in the liver. This route of administration is thus preferred in women with a history ofthromboembolic disease.

Estrogen is also used in the therapy of vaginal atrophy, hypoestrogenism (as a result of hypogonadism,oophorectomy, or primary ovarian failure), amenorrhea, dysmenorrhea, and oligomenorrhea. Estrogens can also be used to suppresslactation after child birth.

Synthetic estrogens, such as 17α-substituted estrogens likeethinylestradiol and its C3esters andethersmestranol,quinestrol, andethinylestradiol sulfonate, andnonsteroidal estrogens like thestilbestrolsdiethylstilbestrol,hexestrol, anddienestrol, are no longer used in menopausal hormone therapy, owing to their disproportionate effects onliver protein synthesis and associated health risks.^[12]

Estrogens are used along with progestogens to treathypogonadism anddelayed puberty in women.

Estrogens are used along withantiandrogens and progestogens as a component offeminizing hormone therapy fortransgender women and othertransfeminine individuals.^[13][14][15]

High-dose estrogen therapy with a variety of estrogens such asdiethylstilbestrol,ethinylestradiol,polyestradiol phosphate,estradiol undecylate,estradiol valerate, andestradiol has been used to treatprostate cancer in men.^[16] It is effective because estrogens are functionalantiandrogens, capable of suppressing testosterone levels tocastrate concentrations and decreasing free testosterone levels by increasingsex hormone-binding globulin (SHBG) production. High-dose estrogen therapy is associated with poortolerability and safety, namelygynecomastia andcardiovascular complications such asthrombosis.^{[additional citation(s) needed]} For this reason, has largely been replaced by newer antiandrogens such asgonadotropin-releasing hormone analogues andnonsteroidal antiandrogens. It is still sometimes used in the treatment of prostate cancer however,^[16] and newer estrogens with atypical profiles such asGTx-758 that have improved tolerability profiles are being studied for possible application in prostate cancer.

High-dose estrogen therapy withpotentsynthetic estrogens such asdiethylstilbestrol andethinylestradiol was used in the past in thepalliation treatment ofbreast cancer.^[17] Its effectiveness is approximately equivalent to that ofantiestrogen therapy withselective estrogen receptor modulators (SERMs) liketamoxifen andaromatase inhibitors likeanastrozole.^[17] The use of high-dose estrogen therapy in breast cancer has mostly been superseded by antiestrogen therapy due to the improvedsafety profile of the latter.^[17] High-dose estrogen therapy was the standard of care for the palliative treatment of breast cancer in women up to the late 1970s or early 1980s.^[18]

Estrogens may be used in treatment ofinfertility in women when there is a need to developsperm-friendlycervical mucus or an appropriateuterine lining.^[35][36]

Estrogens likediethylstilbestrol were formerly used in high doses to help supportpregnancy.^[37] However, subsequent research showed diethylstilbestrol to be ineffective as well as harmful.^[37]

Estrogens can be used to suppresslactation, for instance in the treatment ofbreast engorgement orgalactorrhea.^[38] However, high doses are needed, the effectiveness is uncertain, and high doses of estrogens in thepostpartum period can increase the risk ofblood clots.^[39]

Estrogen has been used to inducegrowth attenuation in tall girls.^[40]

Estrogen-induced growth attenuation was used as part of the controversialAshley Treatment to keep adevelopmentally disabled girl from growing to adult size.^[41]

Estrogens have been used to treatacromegaly.^[42][43][44] This is because they suppressgrowth hormone-inducedinsulin-like growth factor 1 (IGF-1) production in theliver.^[42][43][44]

High-dose estrogen therapy has been used successfully in the treatment ofsexual deviance such asparaphilias in men.^[45][46] However, it has been found to produce manyside effects (e.g.,gynecomastia,feminization,cardiovascular disease,blood clots), and so is no longer recommended for such purposes.^[45] High-dose estrogen therapy works by suppressing testosterone levels, similarly to high-doseprogestogen therapy andgonadotropin-releasing hormone (GnRH)modulator therapy.^[45] Lower dosages of estrogens have also been used in combination with high-dose progestogen therapy in the treatment of sexual deviance in men.^[45] High incidence ofsexual dysfunction has similarly been associated with high-dose estrogen therapy in men treated with it forprostate cancer.^[47]

Estrogens are involved inbreast development and may be used as a form of hormonal breast enhancement to increase thesize of the breasts.^{[48][49][50][51][52]} However, acute or temporarybreast enlargement is a well-known side effect of estrogens, and increases in breast size tend to regress following discontinuation of treatment.^[48][50][51] Aside from those without prior established breast development, evidence is lacking for a sustained increase in breast size with estrogens.^[48][50][51]

Published 2019 and 2020 guidelines from theNorth American Menopause Society (NAMS) andEuropean Menopause and Andropause Society (EMAS) have reviewed the topic of estrogen therapy fordepressive symptoms in theperi- andpostmenopause.^[53][54] There is some evidence that estrogens are effective in the treatment of depression in perimenopausal women.^[a] The magnitude of benefit appears to be similar to that of classicalantidepressants.^[53][54] There is also some evidence that estrogens may improvemood andwell-being in non-depressed perimenopausal women.^{[53][54][58][56]} Estrogens do not appear to be effective in the treatment of depression inpostmenopausal women.^[53][54] This suggests that there is a window of opportunity for effective treatment of depressive symptoms with estrogens.^[53] Research on combined estrogen andprogestogen therapy for depressive symptoms in the peri- and postmenopause is scarce and inconclusive.^[53][54] Estrogens may augment the mood benefits of antidepressants in middle-aged and older women.^[53][54] Menopausal hormone therapy is not currently approved for the treatment of depressive symptoms in the peri- or postmenopause in either theUnited States or theUnited Kingdom due to insufficient evidence of effectiveness.^[53][54][58] More research is needed on the issue of estrogen therapy for depressive symptoms associated withmenopause.^[61][59]

Estrogens appear to be useful in the treatment ofschizophrenia in both women and men.^{[64][65][66][67]}

Systemic estrogen therapy at adequate doses is effective for and has been used in the treatment ofacne in both females and males, but causes major side effects such asfeminization andgynecomastia in males.^{[68][69][70][71][72][73][74][75]}

Estrogens that have been marketed come in two major types,steroidal estrogens andnonsteroidal estrogens.^[1][76]

Estradiol,estrone, andestriol have all been approved aspharmaceutical drugs and are used medically.^[1]Estetrol is currently under development for medical indications, but has not yet been approved in any country.^[77] A variety of syntheticestrogen esters, such asestradiol valerate,estradiol cypionate,estradiol acetate,estradiol benzoate,estradiol undecylate, andpolyestradiol phosphate, are used clinically.^[1] The aforementioned compounds behave asprodrugs to estradiol, and are much longer-lasting in comparison when administered by intramuscular or subcutaneous injection.^[1] Esters of estrone and estriol also exist and are or have been used in clinical medicine, for exampleestrone sulfate (e.g., asestropipate),estriol succinate, andestriol glucuronide (asEmmenin andProgynon).^[1]

Ethinylestradiol is a more potent syntheticanalogue of estradiol that is used widely inhormonal contraceptives.^[1] Other synthetic derivatives of estradiol related to ethinylestradiol that are used clinically includemestranol,quinestrol,ethinylestradiol sulfonate,moxestrol, andmethylestradiol.Conjugated estrogens (brand name Premarin), an estrogen product manufactured from the urine of pregnantmares and commonly used in menopausal hormone therapy, is a mixture of natural estrogens including estrone sulfate andequine estrogens such asequilin sulfate and17β-dihydroequilin sulfate.^[1] A related and very similar product to conjugated estrogens, differing from it only in composition, isesterified estrogens.^[1]

Testosterone,prasterone (dehydroepiandrosterone; DHEA),boldenone (δ¹-testosterone), andnandrolone (19-nortestosterone) are naturally occurringandrogens/anabolic steroids (AAS) which form estradiol as anactive metabolite in small amounts and can produce estrogenic effects, most notablygynecomastia in men at sufficiently high dosages.^[78] Similarly, a number of synthetic AAS, includingmethyltestosterone,metandienone,normethandrone, andnorethandrolone, producemethylestradiol orethylestradiol as an active metabolite in small quantities, and can produce estrogenic effects as well.^[78] A few progestins, specifically the19-nortestosterone derivativesnorethisterone,noretynodrel, andtibolone, metabolize into estrogens (e.g., ethinylestradiol) and can produce estrogenic effects as well.^[1][79]

Diethylstilbestrol is anonsteroidal estrogen that is no longer used medically. It is a member of thestilbestrol group. Other stilbestrol estrogens that have been used clinically includebenzestrol,dienestrol,dienestrol acetate,diethylstilbestrol dipropionate,fosfestrol,hexestrol, andmethestrol dipropionate.Chlorotrianisene,methallenestril, anddoisynoestrol are nonsteroidal estrogens structurally distinct from the stilbestrols that have also been used clinically. While used widely in the past, nonsteroidal estrogens have mostly been discontinued and are now rarely if ever used medically.

Estrogens have variouscontraindications.^{[80][81][82][83]} An example is history ofthromboembolism (blood clots).^{[80][81][82][83]}

The most commonside effects of estrogens in general includebreast tenderness,breast enlargement,headache,nausea,fluid retention, andedema. In women, estrogens can additionally causevaginal bleeding,vaginal discharge, andanovulation, whereas in men, estrogens can additionally causegynecomastia (malebreast development),feminization,demasculinization,sexual dysfunction (reduced libido anderectile dysfunction),hypogonadism,testicular atrophy, andinfertility.

Estrogens can or may increase the risk of uncommon or rare but potentially serious issues includingendometrial hyperplasia,endometrial cancer,cardiovascular complications (e.g.,blood clots,stroke,heart attack),cholestatic hepatotoxicity,gallbladder disease (e.g.,gallstones),hyperprolactinemia,prolactinoma, anddementia. These adverse effects are moderated by the concomitant use of aprogestogen, the type of progestogen used, and the dosage and route of estrogen used.

Around half of women withepilepsy whomenstruate have a loweredseizure threshold aroundovulation, most likely from the heightened estrogen levels at that time. This results in an increased risk ofseizures in these women.

High doses ofsynthetic estrogens likeethinylestradiol anddiethylstilbestrol can produce prominent untoward side effects likenausea,vomiting,headache,malaise, anddizziness, among others.^[84][85][86] Conversely, natural estrogens like estradiol and conjugated estrogens are rarely associated with such effects.^[84][85][86] The preceding side effects of synthetic estrogens do not appear to occur inpregnant women, who already have very high estrogen levels.^[84] This suggests that these effects are due to estrogenic activity.^[84] Synthetic estrogens have markedly stronger effects on theliver andhepatic protein synthesis than natural estrogens.^{[1][87][88][86][89]} This is related to the fact that synthetic estrogens like ethinylestradiol are much more resistant tometabolism in the liver than natural estrogens.^[1][90][89]

Unopposed estrogen therapy stimulates the growth of theendometrium and is associated with a dramatically increased risk ofendometrial hyperplasia andendometrial cancer in postmenopausal women.^[91] The risk of endometrial hyperplasia is greatly increased by 6 months of treatment (ORTooltip odds ratio = 5.4) and further increased after 36 months of treatment (OR = 16.0).[91] This can eventually progress to endometrial cancer, and the risk of endometrial cancer similarly increases with duration of treatment (less than one year,RRTooltip relative risk = 1.4; many years (e.g., more than 10 years),RR = 15.0).[91] The risk of endometrial cancer also stays significantly elevated many years after stopping unopposed estrogen therapy, even after 15 years or more (RR = 5.8).[91]

Progestogens prevent the effects of estrogens on the endometrium.^[91] As a result, they are able to completely block the increase in risk of endometrial hyperplasia caused by estrogen therapy in postmenopausal women, and are even able to decrease it below baseline (OR = 0.3 with continuous estrogen–progestogen therapy).[91] Continuous estrogen–progestogen therapy is more protective than sequential therapy, and a longer duration of treatment with continuous therapy is also more protective.^[91] The increase in risk of endometrial cancer is similarly decreased with continuous estrogen–progestogen therapy (RR = 0.2–0.7).[91] For these reasons, progestogens are always used alongside estrogens in women who have intact uteruses.^[91]

Estrogens affectliver protein synthesis and thereby influence thecardiovascular system.^[1] They have been found to affect the production of a variety ofcoagulation andfibrinolytic factors, including increasedfactor IX,von Willebrand factor,thrombin–antithrombin complex (TAT),fragment 1+2, andD-dimer and decreasedfibrinogen,factor VII,antithrombin,protein S,protein C,tissue plasminogen activator (t-PA), andplasminogen activator inhibitor-1 (PAI-1).^[1] Although this is true for oral estrogen, transdermal estradiol has been found only to reduce PAI-1 and protein S, and to a lesser extent than oral estrogen.^[1] Due to its effects on liver protein synthesis, oral estrogen isprocoagulant, and has been found to increase the risk ofvenous thromboembolism (VTE), including of bothdeep vein thrombosis (DVT) andpulmonary embolism (PE).^[1] Conversely, modern oral contraceptives are not associated with an increase in the risk ofstroke andmyocardial infarction (heart attack) in healthy, non-smoking premenopausal women of any age, except in those withhypertension (high blood pressure).^[92][93] However, a small but significant increase in the risk of stroke, though not of myocardial infarction, has been found in menopausal women taking hormone replacement therapy.^[94] An increase in the risk of stroke has also been associated with older high-dose oral contraceptives that are no longer used.^[95]

Menopausal hormone therapy with replacement dosages of estrogens and progestogens has been associated with a significantly increased risk of cardiovascular events such as VTE.^[96][97] However, such risks have been found to vary depending on the type of estrogen and the route of administration.^[96][97] The risk of VTE is increased by approximately 2-fold in women taking oral estrogen for menopausal hormone therapy.^[96][97] However, clinical research to date has generally not distinguished between conjugated estrogens and estradiol.^[97] This is of importance because conjugated estrogens have been found to be more resistant to hepatic metabolism than estradiol and to increase clotting factors to a greater extent.^[1] Only a few clinical studies have compared oral conjugated estrogens and oral estradiol.^[97] Oral conjugated estrogens have been found to possess a significantly greater risk of thromboembolic and cardiovascular complications than oral estradiol (ORTooltip Odds ratio = 2.08) and oralesterified estrogens (ORTooltip Odds ratio = 1.78).^[97][98][99] However, in another study, the increase in VTE risk with 0.625 mg/day oral conjugated estrogens plus medroxyprogesterone acetate and 1 or 2 mg/day oral estradiol plusnorethisterone acetate was found to be equivalent (RRTooltip Relative risk = 4.0 and 3.9, respectively).^[100][101] Other studies have found oral estradiol to be associated with an increase in risk of VTE similarly (RRTooltip Relative risk = 3.5 in one,ORTooltip odds ratio = 3.54 in first year of use in another).^[97][102] As of present, there are norandomized controlled trials comparing oral conjugated estrogens and oral estradiol in terms of thromboembolic and cardiovascular risks that would allow for unambiguous conclusions, and additional research is needed to clarify this issue.^[97][96] In contrast to oral estrogens as a group, transdermal estradiol at typical menopausal replacement dosages has not been found to increase the risk of VTE or other cardiovascular events.^[96][94][97]

Both combined birth control pills (which contain ethinylestradiol and a progestin) and pregnancy are associated with about a 4-fold increase in risk of VTE, with the risk increase being slightly greater with the latter (OR = 4.03 and 4.24, respectively).[103] The risk of VTE during the postpartum period is 5-fold higher than during pregnancy.^[103] Other research has found that the rate of VTE is 1 to 5 in 10,000 woman-years in women who are not pregnant or taking a birth control pill, 3 to 9 in 10,000 woman-years in women who are on a birth control pill, 5 to 20 in 10,000 women-years in pregnant women, and 40 to 65 in 10,000 women-years in postpartum women.^[104] For birth control pills, VTE risk with high doses of ethinylestradiol (>50 μg, e.g., 100 to 150 μg) has been reported to be approximately twice that of low doses of ethinylestradiol (e.g., 20 to 50 μg).^[92] As such, high doses of ethinylestradiol are no longer used in combined oral contraceptives, and all modern combined oral contraceptives contain 50 μg ethinylestradiol or less.^[105][106] The absolute risk of VTE in pregnancy is about 0.5 to 2 in 1,000 (0.125%).^[107]

Aside from type of estrogen and the route of administration, the risk of VTE with oral estrogen is also moderated by other factors, including the concomitant use of a progestogen, dosage, age, andsmoking.^[108][101] The combination of oral estrogen and a progestogen has been found to double the risk of VTE relative to oral estrogen alone (RRTooltip Relative risk = 2.05 for estrogen monotherapy, andRRTooltip relative risk = 2.02 for combined estrogen–progestogen therapy in comparison).^[108] However, while this is true for most progestogens, there appears to be no increase in VTE risk relative to oral estrogen alone with the addition of oral progesterone or the atypical progestindydrogesterone.^{[108][109][110]} The dosage of oral estrogen appears to be important for VTE risk, as 1 mg/day oral estradiol increased VTE incidence by 2.2-fold while 2 mg/day oral estradiol increased VTE incidence by 4.5-fold (both in combination with norethisterone acetate).^[101] The risk of VTE and other cardiovascular complications with oral estrogen–progestogen therapy increases dramatically with age.^[108] In the oral conjugated estrogens and medroxyprogesterone acetate arm of the WHI, the risks of VTE stratified by age were as follows: age 50 to 59,RR = 2.27; age 60 to 69,RR = 4.28; and age 70 to 79,RR = 7.46.[108] Conversely, in the oral conjugated estrogens monotherapy arm of the WHI, the risk of VTE increased with age similarly but was much lower: age 50 to 59,RR = 1.22; age 60 to 69,RR = 1.3; and age 70 to 79,RR = 1.44.[108] In addition to menopausal hormone therapy, cardiovascularmortality has been found to increase considerably with age in women taking ethinylestradiol-containing combined oral contraceptives and in pregnant women.^[111][112] In addition, smoking has been found to exponentially increase cardiovascular mortality in conjunction with combined oral contraceptive use and older age.^[111][112] Whereas the risk of cardiovascular death is 0.06 per 100,000 in women who are age 15 to 34 years, are taking a combined oral contraceptive, and do not smoke, this increases by 50-fold to 3.0 per 100,000 in women who are age 35 to 44 years, are taking a combined oral contraceptive, and do not smoke.^[111][112] Moreover, in women who do smoke, the risk of cardiovascular death in these two groups increases to 1.73 per 100,000 (29-fold higher relative to non-smokers) and 19.4 per 100,000 (6.5-fold higher relative to non-smokers), respectively.^[111][112]

Although estrogens influence the hepatic production of coagulant and fibrinolytic factors and increase the risk of VTE and sometimes stroke, they also influence the liver synthesis ofblood lipids and can have beneficial effects on the cardiovascular system.^[1] With oral estradiol, there are increases in circulatingtriglycerides,HDL cholesterol,apolipoprotein A1, andapolipoprotein A2, and decreases in totalcholesterol,LDL cholesterol,apolipoprotein B, andlipoprotein(a).^[1] Transdermal estradiol has less-pronounced effects on these proteins and, in contrast to oral estradiol, reduces triglycerides.^[1] Through these effects, both oral and transdermal estrogens can protect againstatherosclerosis andcoronary heart disease in menopausal women with intactarterialendothelium that is without severelesions.^[1]

Approximately 95% of orally ingested estradiol is inactivated during first-pass metabolism.^[93] Nonetheless, levels of estradiol in the liver with oral administration are supraphysiological and approximately 4- to 5-fold higher than in circulation due to the first-pass.^[1][113] This does not occur with parenteral routes of estradiol, such as transdermal, vaginal, or injection.^[1] In contrast to estradiol, ethinylestradiol is much more resistant to hepatic metabolism, with a mean oralbioavailability of approximately 45%,^[114] and the transdermal route has a similar impact on hepatic protein synthesis as the oral route.^[115] Conjugated estrogens are also more resistant to hepatic metabolism than estradiol and show disproportionate effects on hepatic protein production as well, although not to the same magnitude as ethinylestradiol.^[1] These differences are considered to be responsible for the greater risk of cardiovascular events with ethinylestradiol and conjugated estrogens relative to estradiol.^[1]

High-dosage oral synthetic estrogens like diethylstilbestrol and ethinylestradiol are associated with fairly high rates of severe cardiovascular complications.^[116][117] Diethylstilbestrol has been associated with an up to 35% risk of cardiovascular toxicity and death and a 15% incidence of VTE in men treated with it for prostate cancer.^[116][117] In contrast to oral synthetic estrogens, high-dosage polyestradiol phosphate and transdermal estradiol have not been found to increase the risk of cardiovascular mortality or thromboembolism in men with prostate cancer, although significantly increased cardiovascular morbidity (due mainly to an increase in non-fatalischemic heart events andheart decompensation) has been observed with polyestradiol phosphate.^{[117][118][119]}

Sex hormone-binding globulin (SHBG) levels indicate hepatic estrogenic exposure and may be asurrogate marker forcoagulation and VTE risk with estrogen therapy, although this topic has been debated.^{[120][121][122]} SHBG levels with birth control pills containing different progestins are increased by 1.5 to 2-fold withlevonorgestrel, 2.5- to 4-fold withdesogestrel andgestodene, 3.5- to 4-fold withdrospirenone anddienogest, and 4- to 5-fold withcyproterone acetate.^[120]Contraceptive vaginal rings andcontraceptive patches likewise have been found to increase SHBG levels by 2.5-fold and 3.5-fold, respectively.^[120] 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.^[123] Conversely, increases in SHBG levels are much lower with estradiol, especially when used parenterally.^{[124][125][126][127][128]} High-dose parenteralpolyestradiol phosphate therapy has been found to increase SHBG levels by about 1.5-fold.^[127]

Estrogens are responsible forbreast development and, in relation to this, are strongly implicated in the development ofbreast cancer.^[130][131] In addition, estrogens stimulate the growth and accelerate the progression ofER-positive breast cancer.^[132][133] In accordance,antiestrogens like theselective estrogen receptor modulator (SERM)tamoxifen, the ER antagonistfulvestrant, and thearomatase inhibitors (AIs)anastrozole andexemestane are all effective in the treatment of ER-positive breast cancer.^{[134][135][136]} Antiestrogens are also effective in the prevention of breast cancer.^{[137][138][139]} Paradoxically,high-dose estrogen therapy is effective in the treatment of breast cancer as well and has about the same degree of effectiveness as antiestrogen therapy, although it is far less commonly used due to adverse effects.^[140][141] The usefulness of high-dose estrogen therapy in the treatment of ER-positive breast cancer is attributed to a bimodal effect in which high concentrations of estrogens signal breast cancer cells to undergoapoptosis, in contrast to lower concentrations of estrogens which stimulate their growth.^[140][141]

A 2017systematic review andmeta-analysis of 14 studies assessed the risk ofbreast cancer in perimenopausal and postmenopausal women treated with estrogens for menopausal symptoms.^[142] They found that treatment with estradiol only is not associated with an increased risk of breast cancer (ORTooltip odds ratio = 0.90 inRCTsTooltip randomized controlled trials andOR = 1.11 inobservational studies).^[142] This was in accordance with a previous analysis of estrogen-only treatment with estradiol or conjugated estrogens which similarly found no increased risk (RR = 0.99).[142] Moreover, another study found that the risk of breast cancer with estradiol and conjugated estrogens was not significantly different (RR = 1.15 for conjugated estrogens versus estradiol).[142] These findings are paradoxical becauseoophorectomy in premenopausal women and antiestrogen therapy in postmenopausal women are well-established as considerably reducing the risk of breast cancer (RR = 0.208 to 0.708 for chemoprevention with antiestrogens in postmenopausal women).[137]^[138][139] However, there are indications that there may be a ceiling effect such that past a certain low concentration threshold (e.g., approximately 10.2 pg/mL for estradiol), additional estrogens alone may not further increase the risk of breast cancer in postmenopausal women.^[143] There are also indications that the fluctuations in estrogen levels across the normalmenstrual cycle in premenopausal women may be important for breast cancer risk.^[144]

In contrast to estrogen-only therapy, combined estrogen and progestogen treatment, although dependent on the progestogen used, is associated with an increased risk of breast cancer.^[142][145] The increase in risk is dependent on the duration of treatment, with more than five years (OR = 2.43) having a significantly greater risk than less than five years (OR = 1.49).[142] In addition, sequential estrogen–progestogen treatment (OR = 1.76) is associated with a lower risk increase than continuous treatment (OR = 2.90), which has a comparably much higher risk.[142] The increase in risk also differs according to the specific progestogen used.^[142] Treatment with estradiol plusmedroxyprogesterone acetate (OR = 1.19),norethisterone acetate (OR = 1.44),levonorgestrel (OR = 1.47), or a mixed progestogen subgroup (OR = 1.99) were all associated with an increased risk.[142] In a previous review, the increase in breast cancer risk was found to not be significantly different between these three progestogens.^[142] Conversely, there is no significant increase in risk of breast cancer with bioidenticalprogesterone (OR = 1.00) or with the atypical progestindydrogesterone (OR = 1.10).[142] In accordance, another study found similarly that the risk of breast cancer was not significantly increased with estrogen–progesterone (RRTooltip relative risk = 1.00) or estrogen–dydrogesterone (RR = 1.16) but was increased for estrogen combined with other progestins (RR = 1.69).[91] These progestins includedchlormadinone acetate,cyproterone acetate,medrogestone,medroxyprogesterone acetate,nomegestrol acetate,norethisterone acetate, andpromegestone, with the associations for breast cancer risk not differing significantly between the different progestins in this group.^[91]

In contrast to cisgender women, breast cancer is extremely rare in men and transgender women treated with estrogens and/or progestogens, and gynecomastia or breast development in such individuals does not appear to be associated with an increased risk of breast cancer.^{[146][147][148][149]} Likewise, breast cancer has never been reported in women withcomplete androgen insensitivity syndrome, who similarly have a malegenotype (46,XY), in spite of the fact that these women have well-developed breasts.^[150][151] The reasons for these differences are unknown. However, the dramatically increased risk of breast cancer (20- to 58-fold) in men withKlinefelter's syndrome, who have somewhat of a hybrid of a male and a female genotype (47,XXY), suggests that it may have to do with thesex chromosomes.^{[149][152][153]}

Estrogens, along with progesterone, can rarely causecholestatichepatotoxicity, particularly at very high concentrations.^{[154][155][156]} This is seen inintrahepatic cholestasis of pregnancy, which occurs in 0.4 to 15% ofpregnancies (highly variable depending on the country).^{[157][158][159][160]}

Estrogen therapy has been associated withgallbladder disease, including risk ofgallstone formation.^{[161][162][163][164]} A 2017 systematic review and meta-analysis found that menopausal hormone therapy significantly increased the risk of gallstones (RR = 1.79) while oral contraceptives did not significantly increase the risk (RR = 1.19).[164]Biliary sludge appears in 5 to 30% of women during pregnancy, and definitive gallstones persisting postpartum become established in approximately 5%.^[165]

Estrogens are relatively safe inoverdose and symptoms manifest mainly as reversible feminization.

Inducers ofcytochrome P450enzymes likecarbamazepine andphenytoin can accelerate themetabolism of estrogens and thereby decrease theirbioavailability and circulating levels.Inhibitors of such enzymes can have the opposite effect and can increase estrogen levels and bioavailability.

Estrogens act asselectiveagonists of theestrogen receptors (ERs), theERα and theERβ. They may also bind to and activatemembrane estrogen receptors (mERs) such as theGPER. Estrogens do not haveoff-target activity at othersteroid hormone receptors such as theandrogen,progesterone,glucocorticoid, ormineralocorticoid receptors, nor do they haveneurosteroid activity by interacting withneurotransmitter receptors, unlike variousprogestogens and some other steroids. Given bysubcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol.^[166]

Estrogens haveantigonadotropic effects at sufficiently high concentrations via activation of the ER and hence can suppress thehypothalamic–pituitary–gonadal axis. This is caused bynegative feedback, resulting in a suppression insecretion and decreased circulating levels offollicle-stimulating hormone (FSH) andluteinizing hormone (LH). The antigonadotropic effects of estrogens interfere withfertility andgonadalsex hormoneproduction. They are responsible for the hormonal contraceptive effects of estrogens. In addition, they allow estrogens to act as functionalantiandrogens by suppressing gonadal testosterone production. At sufficiently high doses, estrogens are able to suppress testosterone levels into the castrate range in men.^[167]

Estrogens differ significantly in their pharmacological properties.^{[1][168][169]} For instance, due to structural differences and accompanying differences inmetabolism, estrogens differ from one another in theirtissue selectivity; synthetic estrogens likeethinylestradiol anddiethylstilbestrol are not inactivated as efficiently as estradiol in tissues like theliver anduterus and as a result have disproportionate effects in these tissues.^[1] This can result in issues such as a relatively higher risk ofthromboembolism.^[1]

Estrogens can be administered via a variety ofroutes, includingby mouth,sublingual,transdermal/topical (gel,patch),vaginal (gel, tablet,ring),rectal,intramuscular,subcutaneous,intravenous, andsubcutaneous implant. Natural estrogens generally have low oralbioavailability while synthetic estrogens have higher bioavailability.Parenteral routes have higher bioavailability. Estrogens are typically bound toalbumin and/orsex hormone-binding globulin in the circulation. They aremetabolized in theliver byhydroxylation (viacytochrome P450enzymes),dehydrogenation (via17β-hydroxysteroid dehydrogenase), andconjugation (viasulfation andglucuronidation). Theelimination half-lives of estrogens vary by estrogen and route of administration. Estrogens areeliminated mainly by thekidneys via theurine as conjugates.

v t e Estrogen metabolism in humans Estradiol Estrone sulfate Estrone glucuronide 2-Hydroxyestrone Estrone 4-Hydroxyestrone 2-Methoxyestrone 16α-Hydroxyestrone 4-Methoxyestrone 17-Epiestriol Estriol 16-Epiestriol 17β-HSD EST STS UGT1A3 UGT1A9 CYP450 CYP450 COMT CYP450 COMT unidentified 17β-HSD unidentified Description: Themetabolic pathways involved in themetabolism ofestradiol and othernaturalestrogens (e.g.,estrone,estriol) in humans. In addition to themetabolic transformations shown in the diagram,conjugation (e.g.,sulfation andglucuronidation) occurs in the case of estradiol andmetabolites of estradiol that have one or more availablehydroxyl (–OH)groups.Sources: See template page.

v t e Structures of major endogenous estrogens Estrone (E1) Estradiol (E2) Estriol (E3) Estetrol (E4) Note thehydroxyl (–OH)groups: estrone (E1) has one, estradiol (E2) has two, estriol (E3) has three, and estetrol (E4) has four.

Estrogens can be grouped as steroidal or nonsteroidal. The steroidal estrogens areestranes and includeestradiol and itsanalogues, such asethinylestradiol andconjugated estrogens likeequilin sulfate. Nonsteroidal estrogens belong predominantly to thestilbestrol group of compounds and includediethylstilbestrol andhexestrol, among others.

Estrogen esters areesters andprodrugs of the correspondingparent estrogens. Examples includeestradiol valerate anddiethylstilbestrol dipropionate, which are prodrugs of estradiol and diethylstilbestrol, respectively. Estrogen esters with fatty acid esters have increasedlipophilicity and a prolonged duration of action when administered by intramuscular or subcutaneous injection. Some estrogen esters, such aspolyestradiol phosphate,polyestriol phosphate, andpolydiethylstilbestrol phosphate, are in the form ofpolymers.

• v
• t
• e

Structural properties of selected estradiol esters

Estrogen	Structure	Ester(s)				Relative mol. weight	Relative E2 contentb	log Pc
		Position(s)	Moiet(ies)	Type	Lengtha
Estradiol		–	–	–	–	1.00	1.00	4.0
Estradiol acetate		C3	Ethanoic acid	Straight-chain fatty acid	2	1.15	0.87	4.2
Estradiol benzoate		C3	Benzoic acid	Aromatic fatty acid	– (~4–5)	1.38	0.72	4.7
Estradiol dipropionate		C3, C17β	Propanoic acid (×2)	Straight-chain fatty acid	3 (×2)	1.41	0.71	4.9
Estradiol valerate		C17β	Pentanoic acid	Straight-chain fatty acid	5	1.31	0.76	5.6–6.3
Estradiol benzoate butyrate		C3, C17β	Benzoic acid,butyric acid	Mixed fatty acid	– (~6, 2)	1.64	0.61	6.3
Estradiol cypionate		C17β	Cyclopentylpropanoic acid	Cyclic fatty acid	– (~6)	1.46	0.69	6.9
Estradiol enanthate		C17β	Heptanoic acid	Straight-chain fatty acid	7	1.41	0.71	6.7–7.3
Estradiol dienanthate		C3, C17β	Heptanoic acid (×2)	Straight-chain fatty acid	7 (×2)	1.82	0.55	8.1–10.4
Estradiol undecylate		C17β	Undecanoic acid	Straight-chain fatty acid	11	1.62	0.62	9.2–9.8
Estradiol stearate		C17β	Octadecanoic acid	Straight-chain fatty acid	18	1.98	0.51	12.2–12.4
Estradiol distearate		C3, C17β	Octadecanoic acid (×2)	Straight-chain fatty acid	18 (×2)	2.96	0.34	20.2
Estradiol sulfate		C3	Sulfuric acid	Water-soluble conjugate	–	1.29	0.77	0.3–3.8
Estradiol glucuronide		C17β	Glucuronic acid	Water-soluble conjugate	–	1.65	0.61	2.1–2.7
Estramustine phosphated		C3, C17β	Normustine,phosphoric acid	Water-soluble conjugate	–	1.91	0.52	2.9–5.0
Polyestradiol phosphatee		C3–C17β	Phosphoric acid	Water-soluble conjugate	–	1.23f	0.81f	2.9g
Footnotes:a = Length ofester incarbonatoms forstraight-chain fatty acids or approximate length of ester in carbon atoms foraromatic orcyclic fatty acids.b = Relative estradiol content by weight (i.e., relativeestrogenic exposure).c = Experimental or predictedoctanol/water partition coefficient (i.e.,lipophilicity/hydrophobicity). Retrieved fromPubChem,ChemSpider, andDrugBank.d = Also known asestradiol normustine phosphate.e =Polymer ofestradiol phosphate (~13repeat units).f = Relative molecular weight or estradiol content per repeat unit.g = log P of repeat unit (i.e., estradiol phosphate).Sources: See individual articles.

Ovarian extracts were available in the late 1800s and early 1900s, but were inert or had extremely low estrogenic activity and were regarded as ineffective.^{[205][206][207]} In 1927, Selmar and Aschheim discovered that large amounts of estrogens were present in theurine ofpregnant women.^{[206][208][209]} This rich source of estrogens, produced by theplacenta, allowed for the development of potent estrogenic formulations forscientific andclinical use.^{[206][209][210]} The first pharmaceutical estrogen product was aconjugated estriol calledProgynon, a placentalextract, and was introduced for medical use by theGermanpharmaceutical companySchering in 1928.^{[211][212][213][214][215][216][217][218]} In 1929,Adolf Butenandt andEdward Adelbert Doisy independently isolated and purifiedestrone, the first estrogen to be discovered.^[219] The estrogen preparationsAmniotin (Squibb),Progynon (Schering), andTheelin (Parke-Davis) were all on the market by 1929,^[205] and various additional preparations such asEmmenin,Folliculin,Menformon,Oestroform, andProgynon B, containing purified estrogens or mixtures of estrogens, were on the market by 1934.^{[206][220][221]} Estrogens were originally known under a variety of different names includingestrogens,estrins,follicular hormones,folliculins,gynecogens,folliculoids, andfemale sex hormones, among others.^[222][220]