Estrogen (medication)
Estrogen (medication) | |
---|---|
Drug class | |
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 | |
In Wikidata |
Anestrogen(E) is a type ofmedicationwhich is used most commonly inhormonal birth controlandmenopausal hormone therapy,and as part offeminizing hormone therapyfortransgender women.[1]They can also be used in the treatment ofhormone-sensitive cancerslikebreast cancerandprostate cancerand for various other indications. Estrogens are used alone or in combination withprogestogens.[1]They are available in a wide variety offormulationsand for use by many differentroutes of administration.[1]Examples of estrogens includebioidenticalestradiol,naturalconjugated estrogens,syntheticsteroidalestrogens likeethinylestradiol,and syntheticnonsteroidalestrogens likediethylstilbestrol.[1]Estrogens are one of three types ofsex hormone agonists,the others beingandrogens/anabolic steroidsliketestosteroneandprogestogenslikeprogesterone.
Side effectsof estrogens includebreast tenderness,breast enlargement,headache,nausea,andedemaamong 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 dysfunctionamong others.
Estrogens areagonistsof theestrogen receptors,thebiological targetsofendogenousestrogens likeestradiol.They have important effects in manytissuesin the body, including in thefemale reproductive system(uterus,vagina,andovaries), thebreasts,bone,fat,theliver,and thebrainamong others.[1]Unlike other medications likeprogestinsand anabolic steroids, estrogens do not have other hormonal activities.[1]Estrogens also haveantigonadotropiceffects and at sufficiently high dosages can strongly suppresssex hormoneproduction.[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]
Medical uses
[edit]Birth control
[edit]Estrogens havecontraceptiveeffects and are used in combination withprogestins(syntheticprogestogens) inbirth controlto preventpregnancyin women. This is referred to ascombined hormonal contraception.The contraceptive effects of estrogens are mediated by theirantigonadotropiceffects and hence by inhibition ofovulation.Mostcombined oral contraceptivescontain ethinylestradiol or itsprodrugmestranolas 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(higherbioavailabilityand lessinterindividual variability) and controlsvaginal bleedingmore effectively. This is due to its synthetic nature and its resistance tometabolismin certaintissuessuch as theintestines,liver,anduterusrelative 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.
Hormone therapy
[edit]Menopause
[edit]Estrogen and other hormones are given to postmenopausal women in order to preventosteoporosisas 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 therapyhas 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 appliedtopicallymay 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 suppresslactationafter child birth.
Syntheticestrogens, such as 17α-substituted estrogens likeethinylestradioland its C3estersandethersmestranol,quinestrol,andethinylestradiol sulfonate,andnonsteroidal estrogenslike thestilbestrolsdiethylstilbestrol,hexestrol,anddienestrol,are no longer used in menopausal hormone therapy, owing to their disproportionate effects onliver protein synthesisand associated health risks.[12]
Route/form | Estrogen | Low | Standard | High | |||
---|---|---|---|---|---|---|---|
Oral | Estradiol | 0.5–1 mg/day | 1–2 mg/day | 2–4 mg/day | |||
Estradiol valerate | 0.5–1 mg/day | 1–2 mg/day | 2–4 mg/day | ||||
Estradiol acetate | 0.45–0.9 mg/day | 0.9–1.8 mg/day | 1.8–3.6 mg/day | ||||
Conjugated estrogens | 0.3–0.45 mg/day | 0.625 mg/day | 0.9–1.25 mg/day | ||||
Esterified estrogens | 0.3–0.45 mg/day | 0.625 mg/day | 0.9–1.25 mg/day | ||||
Estropipate | 0.75 mg/day | 1.5 mg/day | 3 mg/day | ||||
Estriol | 1–2 mg/day | 2–4 mg/day | 4–8 mg/day | ||||
Ethinylestradiola | 2.5–10 μg/day | 5–20 μg/day | – | ||||
Nasal spray | Estradiol | 150 μg/day | 300 μg/day | 600 μg/day | |||
Transdermal patch | Estradiol | 25 μg/dayb | 50 μg/dayb | 100 μg/dayb | |||
Transdermal gel | Estradiol | 0.5 mg/day | 1–1.5 mg/day | 2–3 mg/day | |||
Vaginal | Estradiol | 25 μg/day | – | – | |||
Estriol | 30 μg/day | 0.5 mg 2x/week | 0.5 mg/day | ||||
IM orSCinjection | Estradiol valerate | – | – | 4 mg 1x/4 weeks | |||
Estradiol cypionate | 1 mg 1x/3–4 weeks | 3 mg 1x/3–4 weeks | 5 mg 1x/3–4 weeks | ||||
Estradiol benzoate | 0.5 mg 1x/week | 1 mg 1x/week | 1.5 mg 1x/week | ||||
SCimplant | Estradiol | 25 mg 1x/6 months | 50 mg 1x/6 months | 100 mg 1x/6 months | |||
Footnotes:a= No longer used or recommended, due to health concerns.b= As a single patch applied once or twice per week (worn for 3–4 days or 7 days), depending on the formulation.Note:Dosages are not necessarily equivalent.Sources:See template. |
Hypogonadism
[edit]Estrogens are used along with progestogens to treathypogonadismanddelayed pubertyin women.
Transgender women
[edit]Estrogens are used along withantiandrogensand progestogens as a component offeminizing hormone therapyfortransgender womenand othertransfeminine individuals.[13][14][15]
Hormonal cancer
[edit]Prostate cancer
[edit]High-dose estrogentherapy with a variety of estrogens such asdiethylstilbestrol,ethinylestradiol,polyestradiol phosphate,estradiol undecylate,estradiol valerate,andestradiolhas been used to treatprostate cancerin men.[16]It is effective because estrogens are functionalantiandrogens,capable of suppressing testosterone levels tocastrateconcentrations and decreasing free testosterone levels by increasingsex hormone-binding globulin(SHBG) production. High-dose estrogen therapy is associated with poortolerabilityand safety, namelygynecomastiaandcardiovascularcomplications such asthrombosis.[additional citation(s) needed]For this reason, has largely been replaced by newer antiandrogens such asgonadotropin-releasing hormone analoguesandnonsteroidal antiandrogens.It is still sometimes used in the treatment of prostate cancer however,[16]and newer estrogens with atypical profiles such asGTx-758that have improved tolerability profiles are being studied for possible application in prostate cancer.
Route/form | Estrogen | Dosage | |
---|---|---|---|
Oral | Estradiol | 1–2 mg 3x/day | |
Conjugated estrogens | 1.25–2.5 mg 3x/day | ||
Ethinylestradiol | 0.15–3 mg/day | ||
Ethinylestradiol sulfonate | 1–2 mg 1x/week | ||
Diethylstilbestrol | 1–3 mg/day | ||
Dienestrol | 5 mg/day | ||
Hexestrol | 5 mg/day | ||
Fosfestrol | 100–480 mg 1–3x/day | ||
Chlorotrianisene | 12–48 mg/day | ||
Quadrosilan | 900 mg/day | ||
Estramustine phosphate | 140–1400 mg/day | ||
Transdermal patch | Estradiol | 2–6x 100 μg/day Scrotal:1x 100 μg/day | |
IM orSCinjection | Estradiol benzoate | 1.66 mg 3x/week | |
Estradiol dipropionate | 5 mg 1x/week | ||
Estradiol valerate | 10–40 mg 1x/1–2 weeks | ||
Estradiol undecylate | 100 mg 1x/4 weeks | ||
Polyestradiol phosphate | Alone:160–320 mg 1x/4 weeks With oralEE:40–80 mg 1x/4 weeks | ||
Estrone | 2–4 mg 2–3x/week | ||
IVinjection | Fosfestrol | 300–1200 mg 1–7x/week | |
Estramustine phosphate | 240–450 mg/day | ||
Note:Dosages are not necessarily equivalent.Sources:See template. |
Breast cancer
[edit]High-dose estrogentherapy withpotentsyntheticestrogens such asdiethylstilbestrolandethinylestradiolwas used in the past in thepalliation treatmentofbreast cancer.[17]Its effectiveness is approximately equivalent to that ofantiestrogentherapy withselective estrogen receptor modulators(SERMs) liketamoxifenandaromatase inhibitorslikeanastrozole.[17]The use of high-dose estrogen therapy in breast cancer has mostly been superseded by antiestrogen therapy due to the improvedsafetyprofile 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]
Route/form | Estrogen | Dosage | Ref(s) |
---|---|---|---|
Oral | Estradiol | 10 mg 3x/day AI-resistant:2 mg 1–3x/day |
[19][20] [19][21] |
Estradiol valerate | AI-resistant:2 mg 1–3x/day | [19][21] | |
Conjugated estrogens | 10 mg 3x/day | [22][23][24][25] | |
Ethinylestradiol | 0.5–1 mg 3x/day | [23][19][26][25] | |
Diethylstilbestrol | 5 mg 3x/day | [23][27][28] | |
Dienestrol | 5 mg 3x/day | [26][25][28] | |
Dimestrol | 30 mg/day | [22][25][28] | |
Chlorotrianisene | 24 mg/day | [22][28] | |
IM orSCinjection | Estradiol benzoate | 5 mg 2–3x/week | [26][29][27][30] |
Estradiol dipropionate | 5 mg 2–3x/week | [26][27][31][30] | |
Estradiol valerate | 30 mg 1x/2 weeks | [29] | |
Polyestradiol phosphate | 40–80 mg 1x/4 weeks | [32][33] | |
Estrone | 5 mg ≥3x/week | [34] | |
Notes:(1) Only in women who are at least 5 yearspostmenopausal.[19](2) Dosages are not necessarily equivalent. |
Other uses
[edit]Infertility
[edit]Estrogens may be used in treatment ofinfertilityin women when there is a need to developsperm-friendlycervical mucusor an appropriateuterine lining.[35][36]
Pregnancy support
[edit]Estrogens likediethylstilbestrolwere formerly used in high doses to help supportpregnancy.[37]However, subsequent research showed diethylstilbestrol to be ineffective as well as harmful.[37]
Lactation suppression
[edit]Estrogens can be used to suppresslactation,for instance in the treatment ofbreast engorgementorgalactorrhea.[38]However, high doses are needed, the effectiveness is uncertain, and high doses of estrogens in thepostpartumperiod can increase the risk ofblood clots.[39]
Tall stature
[edit]Estrogen has been used to inducegrowth attenuationin tall girls.[40]
Estrogen-induced growth attenuation was used as part of the controversialAshley Treatmentto keep adevelopmentally disabledgirl from growing to adult size.[41]
Acromegaly
[edit]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]
Sexual deviance
[edit]High-dose estrogentherapy has been used successfully in the treatment ofsexual deviancesuch asparaphiliasin 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-doseprogestogentherapy andgonadotropin-releasing hormone(GnRH)modulatortherapy.[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 dysfunctionhas similarly been associated with high-dose estrogen therapy in men treated with it forprostate cancer.[47]
Breast enhancement
[edit]Estrogens are involved inbreast developmentand 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 enlargementis 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]
Depression
[edit]Published 2019 and 2020 guidelines from theNorth American Menopause Society(NAMS) andEuropean Menopause and Andropause Society(EMAS) have reviewed the topic of estrogen therapy fordepressivesymptoms in theperi-andpostmenopause.[53][54]There is some evidence that estrogens are effective in the treatment of depression in perimenopausal women.[53][54][55][56][57][58][59][60][61][62][63]The magnitude of benefit appears to be similar to that of classicalantidepressants.[53][54]There is also some evidence that estrogens may improvemoodandwell-beingin non-depressed perimenopausal women.[53][54][58][56]Estrogens do not appear to be effective in the treatment of depression inpostmenopausalwomen.[53][54]This suggests that there is a window of opportunity for effective treatment of depressive symptoms with estrogens.[53]Research on combined estrogen andprogestogentherapy 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 Statesor theUnited Kingdomdue 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]
Schizophrenia
[edit]Estrogens appear to be useful in the treatment ofschizophreniain both women and men.[64][65][66][67]
Acne
[edit]Systemic estrogen therapy at adequate doses is effective for and has been used in the treatment ofacnein both females and males, but causes major side effects such asfeminizationandgynecomastiain males.[68][69][70][71][72][73][74][75]
Available forms
[edit]Generic name | Class | Brand name | Route | Intr. |
---|---|---|---|---|
Conjugated estrogens | S/ester[a] | Premarin | PO,IM,TD,V | 1941 |
Dienestrol[b] | NS | Synestrol[c] | PO | 1947 |
Diethylstilbestrol[b] | NS | Stilbestrol[c] | PO, TD, V | 1939 |
Esterified estrogens | NS/ester[a] | Estratab | PO | 1970 |
Estetrol[d] | S | Donesta[c] | PO | N/A |
Estradiol | S | Estrace[c] | PO, IM,SC,SL,TD, V | 1935 |
Estradiol acetate | S/ester | Femring[c] | PO, V | 2001 |
Estradiol benzoate | S/ester | Progynon B | IM | 1933 |
Estradiol cypionate | S/ester | Depo-Estradiol | IM | 1952 |
Estradiol enanthate | S/ester | Deladroxate[c] | IM | 1970s |
Estradiol valerate | S/ester | Progynon Depot[c] | PO, IM | 1954 |
Estramustine phosphate[e] | S/ester | Emcyt[c] | PO | 1970s |
Estriol | S | Theelol[c] | PO, V | 1930 |
Estropipate[b] | S/ester | Ogen | PO | 1968 |
Ethinylestradiol | S/alkyl | Estinyl[c] | PO, TD, V | 1943 |
Fosfestrol[b] | NS/ester | Honvan[c] | IM | 1947 |
Hexestrol[b] | NS | Synestrol[c] | PO, IM | 1940s |
Mestranol[b] | S/alkyl/ether | Enovid[c] | PO | 1957 |
Methylestradiol[b] | S/alkyl | Ginecosid[c] | PO | 1955 |
Polyestradiol phosphate[b] | S/ester | Estradurin | IM | 1957 |
Prasterone[f] | Prohormone | Intrarosa[c] | PO, IM, V | 1970s |
Zeranol[g] | NS | Ralgro[c] | PO | 1970s |
Estrogens that have been marketed come in two major types,steroidalestrogens andnonsteroidal estrogens.[1][76]
Steroidal estrogens
[edit]Estradiol,estrone,andestriolhave all been approved aspharmaceutical drugsand are used medically.[1]Estetrolis 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 asprodrugsto 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(asEmmeninandProgynon).[1]
Ethinylestradiolis a more potent syntheticanalogueof 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 pregnantmaresand commonly used in menopausal hormone therapy, is a mixture of natural estrogens including estrone sulfate andequine estrogenssuch asequilin sulfateand17β-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 metabolitein small amounts and can produce estrogenic effects, most notablygynecomastiain men at sufficiently high dosages.[78]Similarly, a number of synthetic AAS, includingmethyltestosterone,metandienone,normethandrone,andnorethandrolone,producemethylestradiolorethylestradiolas an active metabolite in small quantities, and can produce estrogenic effects as well.[78]A few progestins, specifically the19-nortestosteronederivativesnorethisterone,noretynodrel,andtibolone,metabolize into estrogens (e.g., ethinylestradiol) and can produce estrogenic effects as well.[1][79]
Nonsteroidal estrogens
[edit]Diethylstilbestrolis anonsteroidal estrogenthat is no longer used medically. It is a member of thestilbestrolgroup. Other stilbestrol estrogens that have been used clinically includebenzestrol,dienestrol,dienestrol acetate,diethylstilbestrol dipropionate,fosfestrol,hexestrol,andmethestrol dipropionate.Chlorotrianisene,methallenestril,anddoisynoestrolare 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.
Contraindications
[edit]Estrogens have variouscontraindications.[80][81][82][83]An example is history ofthromboembolism(blood clots).[80][81][82][83]
Side effects
[edit]The most commonside effectsof 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 libidoanderectile dysfunction),hypogonadism,testicular atrophy,andinfertility.
Estrogens can or may increase the risk of uncommon or rare but potentially serious issues includingendometrial hyperplasia,endometrial cancer,cardiovascularcomplications (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 withepilepsywhomenstruatehave a loweredseizure thresholdaroundovulation,most likely from the heightened estrogen levels at that time. This results in an increased risk ofseizuresin these women.
High doses ofsyntheticestrogens likeethinylestradiolanddiethylstilbestrolcan 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 inpregnantwomen, 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 theliverandhepatic protein synthesisthan natural estrogens.[1][87][88][86][89]This is related to the fact that synthetic estrogens like ethinylestradiol are much more resistant tometabolismin the liver than natural estrogens.[1][90][89]
Serious adverse event | Estradiol 6 mg/day (n = 34) | Estradiol 30 mg/day (n = 32) | ||
---|---|---|---|---|
n | % | n | % | |
Nausea/vomiting | 0 | 0.0 | 5 | 15.6 |
Hyponatremia | 1 | 2.9 | 5 | 15.6 |
Pleural effusion | 0 | 0.0 | 4 | 12.5 |
Pain | 6 | 17.6 | 4 | 12.5 |
Thrombosis/embolism | 1 | 2.9 | 1 | 3.1 |
Brain ischemia | 1 | 2.9 | 0 | 0.0 |
Infection | 2 | 5.9 | 3 | 9.4 |
Hypercalcemia | 0 | 0.0 | 2 | 6.3 |
Other | 6 | 17.6 | 10 | 31.3 |
Summary:Side effectsin a small phase 2 study of women withmetastatic breast cancerrandomized to receive either 6 or 30 mg/day oforal estradiol as therapy. "The adverse event rate (≥grade 3) in the 30-mg group (11/32 [34%]; 95% confidence interval [CI], 23%-47%) was higher than in the 6-mg group (4/34 [18%]; 95% CI, 5%-22%; p=0.03). Clinical benefit rates were 9 of 32 (28%; 95% CI, 18%-41%) in the 30-mg group and 10 of 34 (29%; 95% CI, 19%-42%) in the 6-mg group."Sources:See template. |
Long-term effects
[edit]Endometrial hyperplasia and cancer
[edit]Unopposed estrogen therapy stimulates the growth of theendometriumand is associated with a dramatically increased risk ofendometrial hyperplasiaandendometrial cancerin postmenopausal women.[91]The risk of endometrial hyperplasia is greatly increased by 6 months of treatment (OR = 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,RR = 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]
Cardiovascular events
[edit]Estrogens affectliver protein synthesisand thereby influence thecardiovascular system.[1]They have been found to affect the production of a variety ofcoagulationandfibrinolytic factors,including increasedfactor IX,von Willebrand factor,thrombin–antithrombin complex(TAT),fragment 1+2,andD-dimerand 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 ofstrokeandmyocardial infarction(heart attack) in healthy, non-smokingpremenopausal 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 (OR = 2.08) and oralesterified estrogens(OR = 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 acetatewas found to be equivalent (RR = 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 (RR = 3.5 in one,OR = 3.54 in first year of use in another).[97][102]As of present, there are norandomized controlled trialscomparing 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 (RR = 2.05 for estrogen monotherapy, andRR = 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, cardiovascularmortalityhas 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 lipidsand 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 againstatherosclerosisandcoronary heart diseasein menopausal women with intactarterialendotheliumthat 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 oralbioavailabilityof 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 eventsandheart decompensation) has been observed with polyestradiol phosphate.[117][118][119]
Sex hormone-binding globulin(SHBG) levels indicate hepatic estrogenic exposure and may be asurrogate markerforcoagulationand 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 withdesogestrelandgestodene,3.5- to 4-fold withdrospirenoneanddienogest,and 4- to 5-fold withcyproterone acetate.[120]Contraceptive vaginal ringsandcontraceptive patcheslikewise 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 phosphatetherapy has been found to increase SHBG levels by about 1.5-fold.[127]
Type | Route | Medications | Odds ratio(95%CI ) |
---|---|---|---|
Menopausal hormone therapy | Oral | Estradiolalone ≤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 estrogensalone ≤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/norgestrelorestradiol/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)* | ||
Tibolonealone | 1.02 (0.90–1.15) | ||
Raloxifenealone | 1.49 (1.24–1.79)* | ||
Transdermal | Estradiolalone ≤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 | Estradiolalone | 0.84 (0.73–0.97) | |
Conjugated estrogensalone | 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 theQResearchandClinical Practice Research Datalink(CPRD) databases. (2)Bioidenticalprogesteronewas 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. |
Absolute incidence of first VTE per 10,000 person–years during pregnancy and the postpartum period | ||||||||
---|---|---|---|---|---|---|---|---|
Swedish data A | Swedish data B | English data | Danish data | |||||
Time period | N | Rate (95% CI) | N | Rate (95% CI) | N | Rate (95% CI) | N | Rate (95% CI) |
Outside pregnancy | 1105 | 4.2 (4.0–4.4) | 1015 | 3.8 (?) | 1480 | 3.2 (3.0–3.3) | 2895 | 3.6 (3.4–3.7) |
Antepartum | 995 | 20.5 (19.2–21.8) | 690 | 14.2 (13.2–15.3) | 156 | 9.9 (8.5–11.6) | 491 | 10.7 (9.7–11.6) |
Trimester 1 | 207 | 13.6 (11.8–15.5) | 172 | 11.3 (9.7–13.1) | 23 | 4.6 (3.1–7.0) | 61 | 4.1 (3.2–5.2) |
Trimester 2 | 275 | 17.4 (15.4–19.6) | 178 | 11.2 (9.7–13.0) | 30 | 5.8 (4.1–8.3) | 75 | 5.7 (4.6–7.2) |
Trimester 3 | 513 | 29.2 (26.8–31.9) | 340 | 19.4 (17.4–21.6) | 103 | 18.2 (15.0–22.1) | 355 | 19.7 (17.7–21.9) |
Around delivery | 115 | 154.6 (128.8–185.6) | 79 | 106.1 (85.1–132.3) | 34 | 142.8 (102.0–199.8) | –
| |
Postpartum | 649 | 42.3 (39.2–45.7) | 509 | 33.1 (30.4–36.1) | 135 | 27.4 (23.1–32.4) | 218 | 17.5 (15.3–20.0) |
Early postpartum | 584 | 75.4 (69.6–81.8) | 460 | 59.3 (54.1–65.0) | 177 | 46.8 (39.1–56.1) | 199 | 30.4 (26.4–35.0) |
Late postpartum | 65 | 8.5 (7.0–10.9) | 49 | 6.4 (4.9–8.5) | 18 | 7.3 (4.6–11.6) | 319 | 3.2 (1.9–5.0) |
Incidence rate ratios (IRRs) of first VTE during pregnancy and the postpartum period | ||||||||
Swedish data A | Swedish data B | English data | Danish data | |||||
Time period | IRR* (95% CI) | IRR* (95% CI) | IRR (95% CI)† | IRR (95% CI)† | ||||
Outside pregnancy | Reference (i.e., 1.00)
| |||||||
Antepartum | 5.08 (4.66–5.54) | 3.80 (3.44–4.19) | 3.10 (2.63–3.66) | 2.95 (2.68–3.25) | ||||
Trimester 1 | 3.42 (2.95–3.98) | 3.04 (2.58–3.56) | 1.46 (0.96–2.20) | 1.12 (0.86–1.45) | ||||
Trimester 2 | 4.31 (3.78–4.93) | 3.01 (2.56–3.53) | 1.82 (1.27–2.62) | 1.58 (1.24–1.99) | ||||
Trimester 3 | 7.14 (6.43–7.94) | 5.12 (4.53–5.80) | 5.69 (4.66–6.95) | 5.48 (4.89–6.12) | ||||
Around delivery | 37.5 (30.9–44.45) | 27.97 (22.24–35.17) | 44.5 (31.68–62.54) | –
| ||||
Postpartum | 10.21 (9.27–11.25) | 8.72 (7.83–9.70) | 8.54 (7.16–10.19) | 4.85 (4.21–5.57) | ||||
Early postpartum | 19.27 (16.53–20.21) | 15.62 (14.00–17.45) | 14.61 (12.10–17.67) | 8.44 (7.27–9.75) | ||||
Late postpartum | 2.06 (1.60–2.64) | 1.69 (1.26–2.25) | 2.29 (1.44–3.65) | 0.89 (0.53–1.39) | ||||
Notes:Swedish data A = Using any code for VTE regardless of confirmation. Swedish data B = Using only algorithm-confirmed VTE. Early postpartum = First 6 weeks after delivery. Late postpartum = More than 6 weeks after delivery. * = Adjusted for age and calendar year. † = Unadjusted ratio calculated based on the data provided.Source:[129] |
Breast cancer
[edit]Estrogens are responsible forbreast developmentand, 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,antiestrogenslike theselective estrogen receptor modulator(SERM)tamoxifen,the ER antagonistfulvestrant,and thearomatase inhibitors(AIs)anastrozoleandexemestaneare 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 estrogentherapy 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 reviewandmeta-analysisof 14 studies assessed the risk ofbreast cancerin 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 (OR = 0.90 inRCTs 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 becauseoophorectomyin 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 cyclein 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 (RR = 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]
Therapy | <5 years | 5–14 years | 15+ years | |||
---|---|---|---|---|---|---|
Cases | RR (95%CI ) | Cases | RR (95%CI ) | Cases | RR (95%CI ) | |
Estrogen alone | 1259 | 1.18 (1.10–1.26) | 4869 | 1.33 (1.28–1.37) | 2183 | 1.58 (1.51–1.67) |
By estrogen | ||||||
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 | ||||||
Oralestrogens | – | – | 3633 | 1.33 (1.27–1.38) | – | – |
Transdermalestrogens | – | – | 919 | 1.35 (1.25–1.46) | – | – |
Vaginalestrogens | – | – | 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) |
Byprogestogen | ||||||
(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-analysisof worldwideepidemiologicalevidence onmenopausal hormone therapyandbreast cancerrisk by theCollaborative Group on Hormonal Factors in Breast Cancer(CGHFBC). Fully adjustedrelative risksfor current versus never-users of menopausal hormone therapy.Source:See template. |
Study | Therapy | Hazard ratio(95%CI ) |
---|---|---|
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 plusprogesteroneordydrogesterone | 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%CI ) |
---|---|---|
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 plusprogesteroneordydrogesterone <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. |
Cholestatic hepatotoxicity
[edit]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]
Gallbladder disease
[edit]Estrogen therapy has been associated withgallbladder disease,including risk ofgallstoneformation.[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 sludgeappears in 5 to 30% of women during pregnancy, and definitive gallstones persisting postpartum become established in approximately 5%.[165]
Overdose
[edit]Estrogens are relatively safe inoverdoseand symptoms manifest mainly as reversible feminization.
Interactions
[edit]Inducersofcytochrome P450enzymeslikecarbamazepineandphenytoincan accelerate themetabolismof estrogens and thereby decrease theirbioavailabilityand circulating levels.Inhibitorsof such enzymes can have the opposite effect and can increase estrogen levels and bioavailability.
Pharmacology
[edit]Pharmacodynamics
[edit]Estrogens act asselectiveagonistsof theestrogen receptors(ERs), theERαand theERβ.They may also bind to and activatemembrane estrogen receptors(mERs) such as theGPER.Estrogens do not haveoff-target activityat othersteroid hormone receptorssuch as theandrogen,progesterone,glucocorticoid,ormineralocorticoid receptors,nor do they haveneurosteroidactivity by interacting withneurotransmitter receptors,unlike variousprogestogensand some other steroids. Given bysubcutaneous injectionin mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol.[166]
Estrogens haveantigonadotropiceffects 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 insecretionand decreased circulating levels offollicle-stimulating hormone(FSH) andluteinizing hormone(LH). The antigonadotropic effects of estrogens interfere withfertilityandgonadalsex hormoneproduction.They are responsible for the hormonal contraceptive effects of estrogens. In addition, they allow estrogens to act as functionalantiandrogensby 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 likeethinylestradiolanddiethylstilbestrolare not inactivated as efficiently as estradiol in tissues like theliveranduterusand as a result have disproportionate effects in these tissues.[1]This can result in issues such as a relatively higher risk ofthromboembolism.[1]
In-vitropharmacodynamics
[edit]Ligand | Other names | Relative binding affinities(RBA, %)a | Absolute binding affinities(Ki,nM)a | Action | ||
---|---|---|---|---|---|---|
ERα | ERβ | ERα | ERβ | |||
Estradiol | E2; 17β-Estradiol | 100 | 100 | 0.115 (0.04–0.24) | 0.15 (0.10–2.08) | Estrogen |
Estrone | E1; 17-Ketoestradiol | 16.39 (0.7–60) | 6.5 (1.36–52) | 0.445 (0.3–1.01) | 1.75 (0.35–9.24) | Estrogen |
Estriol | E3; 16α-OH-17β-E2 | 12.65 (4.03–56) | 26 (14.0–44.6) | 0.45 (0.35–1.4) | 0.7 (0.63–0.7) | Estrogen |
Estetrol | E4; 15α,16α-Di-OH-17β-E2 | 4.0 | 3.0 | 4.9 | 19 | Estrogen |
Alfatradiol | 17α-Estradiol | 20.5 (7–80.1) | 8.195 (2–42) | 0.2–0.52 | 0.43–1.2 | Metabolite |
16-Epiestriol | 16β-Hydroxy-17β-estradiol | 7.795 (4.94–63) | 50 | ? | ? | Metabolite |
17-Epiestriol | 16α-Hydroxy-17α-estradiol | 55.45 (29–103) | 79–80 | ? | ? | Metabolite |
16,17-Epiestriol | 16β-Hydroxy-17α-estradiol | 1.0 | 13 | ? | ? | Metabolite |
2-Hydroxyestradiol | 2-OH-E2 | 22 (7–81) | 11–35 | 2.5 | 1.3 | Metabolite |
2-Methoxyestradiol | 2-MeO-E2 | 0.0027–2.0 | 1.0 | ? | ? | Metabolite |
4-Hydroxyestradiol | 4-OH-E2 | 13 (8–70) | 7–56 | 1.0 | 1.9 | Metabolite |
4-Methoxyestradiol | 4-MeO-E2 | 2.0 | 1.0 | ? | ? | Metabolite |
2-Hydroxyestrone | 2-OH-E1 | 2.0–4.0 | 0.2–0.4 | ? | ? | Metabolite |
2-Methoxyestrone | 2-MeO-E1 | <0.001–<1 | <1 | ? | ? | Metabolite |
4-Hydroxyestrone | 4-OH-E1 | 1.0–2.0 | 1.0 | ? | ? | Metabolite |
4-Methoxyestrone | 4-MeO-E1 | <1 | <1 | ? | ? | Metabolite |
16α-Hydroxyestrone | 16α-OH-E1; 17-Ketoestriol | 2.0–6.5 | 35 | ? | ? | Metabolite |
2-Hydroxyestriol | 2-OH-E3 | 2.0 | 1.0 | ? | ? | Metabolite |
4-Methoxyestriol | 4-MeO-E3 | 1.0 | 1.0 | ? | ? | Metabolite |
Estradiol sulfate | E2S; Estradiol 3-sulfate | <1 | <1 | ? | ? | Metabolite |
Estradiol disulfate | Estradiol 3,17β-disulfate | 0.0004 | ? | ? | ? | Metabolite |
Estradiol 3-glucuronide | E2-3G | 0.0079 | ? | ? | ? | Metabolite |
Estradiol 17β-glucuronide | E2-17G | 0.0015 | ? | ? | ? | Metabolite |
Estradiol 3-gluc. 17β-sulfate | E2-3G-17S | 0.0001 | ? | ? | ? | Metabolite |
Estrone sulfate | E1S; Estrone 3-sulfate | <1 | <1 | >10 | >10 | Metabolite |
Estradiol benzoate | EB; Estradiol 3-benzoate | 10 | ? | ? | ? | Estrogen |
Estradiol 17β-benzoate | E2-17B | 11.3 | 32.6 | ? | ? | Estrogen |
Estrone methyl ether | Estrone 3-methyl ether | 0.145 | ? | ? | ? | Estrogen |
ent-Estradiol | 1-Estradiol | 1.31–12.34 | 9.44–80.07 | ? | ? | Estrogen |
Equilin | 7-Dehydroestrone | 13 (4.0–28.9) | 13.0–49 | 0.79 | 0.36 | Estrogen |
Equilenin | 6,8-Didehydroestrone | 2.0–15 | 7.0–20 | 0.64 | 0.62 | Estrogen |
17β-Dihydroequilin | 7-Dehydro-17β-estradiol | 7.9–113 | 7.9–108 | 0.09 | 0.17 | Estrogen |
17α-Dihydroequilin | 7-Dehydro-17α-estradiol | 18.6 (18–41) | 14–32 | 0.24 | 0.57 | Estrogen |
17β-Dihydroequilenin | 6,8-Didehydro-17β-estradiol | 35–68 | 90–100 | 0.15 | 0.20 | Estrogen |
17α-Dihydroequilenin | 6,8-Didehydro-17α-estradiol | 20 | 49 | 0.50 | 0.37 | Estrogen |
Δ8-Estradiol | 8,9-Dehydro-17β-estradiol | 68 | 72 | 0.15 | 0.25 | Estrogen |
Δ8-Estrone | 8,9-Dehydroestrone | 19 | 32 | 0.52 | 0.57 | Estrogen |
Ethinylestradiol | EE; 17α-Ethynyl-17β-E2 | 120.9 (68.8–480) | 44.4 (2.0–144) | 0.02–0.05 | 0.29–0.81 | Estrogen |
Mestranol | EE 3-methyl ether | ? | 2.5 | ? | ? | Estrogen |
Moxestrol | RU-2858; 11β-Methoxy-EE | 35–43 | 5–20 | 0.5 | 2.6 | Estrogen |
Methylestradiol | 17α-Methyl-17β-estradiol | 70 | 44 | ? | ? | Estrogen |
Diethylstilbestrol | DES; Stilbestrol | 129.5 (89.1–468) | 219.63 (61.2–295) | 0.04 | 0.05 | Estrogen |
Hexestrol | Dihydrodiethylstilbestrol | 153.6 (31–302) | 60–234 | 0.06 | 0.06 | Estrogen |
Dienestrol | Dehydrostilbestrol | 37 (20.4–223) | 56–404 | 0.05 | 0.03 | Estrogen |
Benzestrol (B2) | – | 114 | ? | ? | ? | Estrogen |
Chlorotrianisene | TACE | 1.74 | ? | 15.30 | ? | Estrogen |
Triphenylethylene | TPE | 0.074 | ? | ? | ? | Estrogen |
Triphenylbromoethylene | TPBE | 2.69 | ? | ? | ? | Estrogen |
Tamoxifen | ICI-46,474 | 3 (0.1–47) | 3.33 (0.28–6) | 3.4–9.69 | 2.5 | SERM |
Afimoxifene | 4-Hydroxytamoxifen; 4-OHT | 100.1 (1.7–257) | 10 (0.98–339) | 2.3 (0.1–3.61) | 0.04–4.8 | SERM |
Toremifene | 4-Chlorotamoxifen; 4-CT | ? | ? | 7.14–20.3 | 15.4 | SERM |
Clomifene | MRL-41 | 25 (19.2–37.2) | 12 | 0.9 | 1.2 | SERM |
Cyclofenil | F-6066; Sexovid | 151–152 | 243 | ? | ? | SERM |
Nafoxidine | U-11,000A | 30.9–44 | 16 | 0.3 | 0.8 | SERM |
Raloxifene | – | 41.2 (7.8–69) | 5.34 (0.54–16) | 0.188–0.52 | 20.2 | SERM |
Arzoxifene | LY-353,381 | ? | ? | 0.179 | ? | SERM |
Lasofoxifene | CP-336,156 | 10.2–166 | 19.0 | 0.229 | ? | SERM |
Ormeloxifene | Centchroman | ? | ? | 0.313 | ? | SERM |
Levormeloxifene | 6720-CDRI; NNC-460,020 | 1.55 | 1.88 | ? | ? | SERM |
Ospemifene | Deaminohydroxytoremifene | 0.82–2.63 | 0.59–1.22 | ? | ? | SERM |
Bazedoxifene | – | ? | ? | 0.053 | ? | SERM |
Etacstil | GW-5638 | 4.30 | 11.5 | ? | ? | SERM |
ICI-164,384 | – | 63.5 (3.70–97.7) | 166 | 0.2 | 0.08 | Antiestrogen |
Fulvestrant | ICI-182,780 | 43.5 (9.4–325) | 21.65 (2.05–40.5) | 0.42 | 1.3 | Antiestrogen |
Propylpyrazoletriol | PPT | 49 (10.0–89.1) | 0.12 | 0.40 | 92.8 | ERα agonist |
16α-LE2 | 16α-Lactone-17β-estradiol | 14.6–57 | 0.089 | 0.27 | 131 | ERα agonist |
16α-Iodo-E2 | 16α-Iodo-17β-estradiol | 30.2 | 2.30 | ? | ? | ERα agonist |
Methylpiperidinopyrazole | MPP | 11 | 0.05 | ? | ? | ERα antagonist |
Diarylpropionitrile | DPN | 0.12–0.25 | 6.6–18 | 32.4 | 1.7 | ERβ agonist |
8β-VE2 | 8β-Vinyl-17β-estradiol | 0.35 | 22.0–83 | 12.9 | 0.50 | ERβ agonist |
Prinaberel | ERB-041; WAY-202,041 | 0.27 | 67–72 | ? | ? | ERβ agonist |
ERB-196 | WAY-202,196 | ? | 180 | ? | ? | ERβ agonist |
Erteberel | SERBA-1; LY-500,307 | ? | ? | 2.68 | 0.19 | ERβ agonist |
SERBA-2 | – | ? | ? | 14.5 | 1.54 | ERβ agonist |
Coumestrol | – | 9.225 (0.0117–94) | 64.125 (0.41–185) | 0.14–80.0 | 0.07–27.0 | Xenoestrogen |
Genistein | – | 0.445 (0.0012–16) | 33.42 (0.86–87) | 2.6–126 | 0.3–12.8 | Xenoestrogen |
Equol | – | 0.2–0.287 | 0.85 (0.10–2.85) | ? | ? | Xenoestrogen |
Daidzein | – | 0.07 (0.0018–9.3) | 0.7865 (0.04–17.1) | 2.0 | 85.3 | Xenoestrogen |
Biochanin A | – | 0.04 (0.022–0.15) | 0.6225 (0.010–1.2) | 174 | 8.9 | Xenoestrogen |
Kaempferol | – | 0.07 (0.029–0.10) | 2.2 (0.002–3.00) | ? | ? | Xenoestrogen |
Naringenin | – | 0.0054 (<0.001–0.01) | 0.15 (0.11–0.33) | ? | ? | Xenoestrogen |
8-Prenylnaringenin | 8-PN | 4.4 | ? | ? | ? | Xenoestrogen |
Quercetin | – | <0.001–0.01 | 0.002–0.040 | ? | ? | Xenoestrogen |
Ipriflavone | – | <0.01 | <0.01 | ? | ? | Xenoestrogen |
Miroestrol | – | 0.39 | ? | ? | ? | Xenoestrogen |
Deoxymiroestrol | – | 2.0 | ? | ? | ? | Xenoestrogen |
β-Sitosterol | – | <0.001–0.0875 | <0.001–0.016 | ? | ? | Xenoestrogen |
Resveratrol | – | <0.001–0.0032 | ? | ? | ? | Xenoestrogen |
α-Zearalenol | – | 48 (13–52.5) | ? | ? | ? | Xenoestrogen |
β-Zearalenol | – | 0.6 (0.032–13) | ? | ? | ? | Xenoestrogen |
Zeranol | α-Zearalanol | 48–111 | ? | ? | ? | Xenoestrogen |
Taleranol | β-Zearalanol | 16 (13–17.8) | 14 | 0.8 | 0.9 | Xenoestrogen |
Zearalenone | ZEN | 7.68 (2.04–28) | 9.45 (2.43–31.5) | ? | ? | Xenoestrogen |
Zearalanone | ZAN | 0.51 | ? | ? | ? | Xenoestrogen |
Bisphenol A | BPA | 0.0315 (0.008–1.0) | 0.135 (0.002–4.23) | 195 | 35 | Xenoestrogen |
Endosulfan | EDS | <0.001–<0.01 | <0.01 | ? | ? | Xenoestrogen |
Kepone | Chlordecone | 0.0069–0.2 | ? | ? | ? | Xenoestrogen |
o,p'-DDT | – | 0.0073–0.4 | ? | ? | ? | Xenoestrogen |
p,p'-DDT | – | 0.03 | ? | ? | ? | Xenoestrogen |
Methoxychlor | p,p'-Dimethoxy-DDT | 0.01 (<0.001–0.02) | 0.01–0.13 | ? | ? | Xenoestrogen |
HPTE | Hydroxychlor;p,p'-OH-DDT | 1.2–1.7 | ? | ? | ? | Xenoestrogen |
Testosterone | T; 4-Androstenolone | <0.0001–<0.01 | <0.002–0.040 | >5000 | >5000 | Androgen |
Dihydrotestosterone | DHT; 5α-Androstanolone | 0.01 (<0.001–0.05) | 0.0059–0.17 | 221–>5000 | 73–1688 | Androgen |
Nandrolone | 19-Nortestosterone; 19-NT | 0.01 | 0.23 | 765 | 53 | Androgen |
Dehydroepiandrosterone | DHEA; Prasterone | 0.038 (<0.001–0.04) | 0.019–0.07 | 245–1053 | 163–515 | Androgen |
5-Androstenediol | A5; Androstenediol | 6 | 17 | 3.6 | 0.9 | Androgen |
4-Androstenediol | – | 0.5 | 0.6 | 23 | 19 | Androgen |
4-Androstenedione | A4; Androstenedione | <0.01 | <0.01 | >10000 | >10000 | Androgen |
3α-Androstanediol | 3α-Adiol | 0.07 | 0.3 | 260 | 48 | Androgen |
3β-Androstanediol | 3β-Adiol | 3 | 7 | 6 | 2 | Androgen |
Androstanedione | 5α-Androstanedione | <0.01 | <0.01 | >10000 | >10000 | Androgen |
Etiocholanedione | 5β-Androstanedione | <0.01 | <0.01 | >10000 | >10000 | Androgen |
Methyltestosterone | 17α-Methyltestosterone | <0.0001 | ? | ? | ? | Androgen |
Ethinyl-3α-androstanediol | 17α-Ethynyl-3α-adiol | 4.0 | <0.07 | ? | ? | Estrogen |
Ethinyl-3β-androstanediol | 17α-Ethynyl-3β-adiol | 50 | 5.6 | ? | ? | Estrogen |
Progesterone | P4; 4-Pregnenedione | <0.001–0.6 | <0.001–0.010 | ? | ? | Progestogen |
Norethisterone | NET; 17α-Ethynyl-19-NT | 0.085 (0.0015–<0.1) | 0.1 (0.01–0.3) | 152 | 1084 | Progestogen |
Norethynodrel | 5(10)-Norethisterone | 0.5 (0.3–0.7) | <0.1–0.22 | 14 | 53 | Progestogen |
Tibolone | 7α-Methylnorethynodrel | 0.5 (0.45–2.0) | 0.2–0.076 | ? | ? | Progestogen |
Δ4-Tibolone | 7α-Methylnorethisterone | 0.069–<0.1 | 0.027–<0.1 | ? | ? | Progestogen |
3α-Hydroxytibolone | – | 2.5 (1.06–5.0) | 0.6–0.8 | ? | ? | Progestogen |
3β-Hydroxytibolone | – | 1.6 (0.75–1.9) | 0.070–0.1 | ? | ? | Progestogen |
Footnotes:a= (1)Binding affinityvalues are of the format "median (range)" (# (#–#)), "range" (#–#), or "value" (#) depending on the values available. The full sets of values within the ranges can be found in the Wiki code. (2) Binding affinities were determined via displacement studies in a variety ofin-vitrosystems withlabeledestradiol and humanERαandERβproteins (except the ERβ values from Kuiper et al. (1997), which are rat ERβ).Sources:See template page. |
Estrogen | Relative binding affinities(%) | ||||||
---|---|---|---|---|---|---|---|
ER | AR | PR | GR | MR | SHBG | CBG | |
Estradiol | 100 | 7.9 | 2.6 | 0.6 | 0.13 | 8.7–12 | <0.1 |
Estradiol benzoate | ? | ? | ? | ? | ? | <0.1–0.16 | <0.1 |
Estradiol valerate | 2 | ? | ? | ? | ? | ? | ? |
Estrone | 11–35 | <1 | <1 | <1 | <1 | 2.7 | <0.1 |
Estrone sulfate | 2 | 2 | ? | ? | ? | ? | ? |
Estriol | 10–15 | <1 | <1 | <1 | <1 | <0.1 | <0.1 |
Equilin | 40 | ? | ? | ? | ? | ? | 0 |
Alfatradiol | 15 | <1 | <1 | <1 | <1 | ? | ? |
Epiestriol | 20 | <1 | <1 | <1 | <1 | ? | ? |
Ethinylestradiol | 100–112 | 1–3 | 15–25 | 1–3 | <1 | 0.18 | <0.1 |
Mestranol | 1 | ? | ? | ? | ? | <0.1 | <0.1 |
Methylestradiol | 67 | 1–3 | 3–25 | 1–3 | <1 | ? | ? |
Moxestrol | 12 | <0.1 | 0.8 | 3.2 | <0.1 | <0.2 | <0.1 |
Diethylstilbestrol | ? | ? | ? | ? | ? | <0.1 | <0.1 |
Notes:Referenceligands(100%) wereprogesteronefor thePR ,testosteronefor theAR ,estradiolfor theER ,dexamethasonefor theGR ,aldosteronefor theMR ,dihydrotestosteroneforSHBG ,andcortisolforCBG .Sources:See template. |
Estrogen | Other names | RBA (%)a | REP(%)b | |||
---|---|---|---|---|---|---|
ER | ERα | ERβ | ||||
Estradiol | E2 | 100 | 100 | 100 | ||
Estradiol 3-sulfate | E2S; E2-3S | ? | 0.02 | 0.04 | ||
Estradiol 3-glucuronide | E2-3G | ? | 0.02 | 0.09 | ||
Estradiol 17β-glucuronide | E2-17G | ? | 0.002 | 0.0002 | ||
Estradiol benzoate | EB; Estradiol 3-benzoate | 10 | 1.1 | 0.52 | ||
Estradiol 17β-acetate | E2-17A | 31–45 | 24 | ? | ||
Estradiol diacetate | EDA; Estradiol 3,17β-diacetate | ? | 0.79 | ? | ||
Estradiol propionate | EP; Estradiol 17β-propionate | 19–26 | 2.6 | ? | ||
Estradiol valerate | EV; Estradiol 17β-valerate | 2–11 | 0.04–21 | ? | ||
Estradiol cypionate | EC; Estradiol 17β-cypionate | ?c | 4.0 | ? | ||
Estradiol palmitate | Estradiol 17β-palmitate | 0 | ? | ? | ||
Estradiol stearate | Estradiol 17β-stearate | 0 | ? | ? | ||
Estrone | E1; 17-Ketoestradiol | 11 | 5.3–38 | 14 | ||
Estrone sulfate | E1S; Estrone 3-sulfate | 2 | 0.004 | 0.002 | ||
Estrone glucuronide | E1G; Estrone 3-glucuronide | ? | <0.001 | 0.0006 | ||
Ethinylestradiol | EE; 17α-Ethynylestradiol | 100 | 17–150 | 129 | ||
Mestranol | EE 3-methyl ether | 1 | 1.3–8.2 | 0.16 | ||
Quinestrol | EE 3-cyclopentyl ether | ? | 0.37 | ? | ||
Footnotes:a=Relative binding affinities(RBAs) were determined viain-vitrodisplacement oflabeledestradiolfromestrogen receptors(ERs) generally ofrodentuterinecytosol.Estrogen estersare variablyhydrolyzedinto estrogens in these systems (shorter ester chain length -> greater rate of hydrolysis) and the ER RBAs of the esters decrease strongly when hydrolysis is prevented.b= Relative estrogenic potencies (REPs) were calculated fromhalf-maximal effective concentrations(EC50) that were determined viain-vitroβ‐galactosidase(β-gal) andgreen fluorescent protein(GFP)productionassaysinyeastexpressing humanERαand humanERβ.Bothmammaliancellsand yeast have the capacity to hydrolyze estrogen esters.c= The affinities ofestradiol cypionatefor the ERs are similar to those ofestradiol valerateandestradiol benzoate(figure).Sources:See template page. |
In-vivopharmacodynamics
[edit]Estrogen | ERRBA (%) | Uterine weight(%) | Uterotrophy | LH levels (%) | SHBGRBA (%) |
---|---|---|---|---|---|
Control | – | 100 | – | 100 | – |
Estradiol (E2) | 100 | 506 ± 20 | +++ | 12–19 | 100 |
Estrone (E1) | 11 ± 8 | 490 ± 22 | +++ | ? | 20 |
Estriol (E3) | 10 ± 4 | 468 ± 30 | +++ | 8–18 | 3 |
Estetrol (E4) | 0.5 ± 0.2 | ? | Inactive | ? | 1 |
17α-Estradiol | 4.2 ± 0.8 | ? | ? | ? | ? |
2-Hydroxyestradiol | 24 ± 7 | 285 ± 8 | +b | 31–61 | 28 |
2-Methoxyestradiol | 0.05 ± 0.04 | 101 | Inactive | ? | 130 |
4-Hydroxyestradiol | 45 ± 12 | ? | ? | ? | ? |
4-Methoxyestradiol | 1.3 ± 0.2 | 260 | ++ | ? | 9 |
4-Fluoroestradiola | 180 ± 43 | ? | +++ | ? | ? |
2-Hydroxyestrone | 1.9 ± 0.8 | 130 ± 9 | Inactive | 110–142 | 8 |
2-Methoxyestrone | 0.01 ± 0.00 | 103 ± 7 | Inactive | 95–100 | 120 |
4-Hydroxyestrone | 11 ± 4 | 351 | ++ | 21–50 | 35 |
4-Methoxyestrone | 0.13 ± 0.04 | 338 | ++ | 65–92 | 12 |
16α-Hydroxyestrone | 2.8 ± 1.0 | 552 ± 42 | +++ | 7–24 | <0.5 |
2-Hydroxyestriol | 0.9 ± 0.3 | 302 | +b | ? | ? |
2-Methoxyestriol | 0.01 ± 0.00 | ? | Inactive | ? | 4 |
Notes:Values are mean ± SD or range.ERRBA=Relative binding affinitytoestrogen receptorsof ratuterinecytosol.Uterine weight = Percentage change in uterine wet weight ofovariectomizedrats after 72 hours with continuous administration of 1 μg/hour viasubcutaneously implantedosmotic pumps.LHlevels =Luteinizing hormonelevels relative to baseline of ovariectomized rats after 24 to 72 hours of continuous administration via subcutaneous implant.Footnotes:a=Synthetic(i.e., notendogenous).b= Atypical uterotrophic effect which plateaus within 48 hours (estradiol's uterotrophy continues linearly up to 72 hours).Sources:See template. |
Compound | Dosage for specific uses (mg usually)[a] | ||||||
---|---|---|---|---|---|---|---|
ETD[b] | EPD[b] | MSD[b] | MSD[c] | OID[c] | TSD[c] | ||
Estradiol (non-micronized) | 30 | ≥120–300 | 120 | 6 | - | - | |
Estradiol (micronized) | 6–12 | 60–80 | 14–42 | 1–2 | >5 | >8 | |
Estradiol valerate | 6–12 | 60–80 | 14–42 | 1–2 | - | >8 | |
Estradiol benzoate | - | 60–140 | - | - | - | - | |
Estriol | ≥20 | 120–150[d] | 28–126 | 1–6 | >5 | - | |
Estriol succinate | - | 140–150[d] | 28–126 | 2–6 | - | - | |
Estrone sulfate | 12 | 60 | 42 | 2 | - | - | |
Conjugated estrogens | 5–12 | 60–80 | 8.4–25 | 0.625–1.25 | >3.75 | 7.5 | |
Ethinylestradiol | 200 μg | 1–2 | 280 μg | 20–40 μg | 100 μg | 100 μg | |
Mestranol | 300 μg | 1.5–3.0 | 300–600 μg | 25–30 μg | >80 μg | - | |
Quinestrol | 300 μg | 2–4 | 500 μg | 25–50 μg | - | - | |
Methylestradiol | - | 2 | - | - | - | - | |
Diethylstilbestrol | 2.5 | 20–30 | 11 | 0.5–2.0 | >5 | 3 | |
DES dipropionate | - | 15–30 | - | - | - | - | |
Dienestrol | 5 | 30–40 | 42 | 0.5–4.0 | - | - | |
Dienestrol diacetate | 3–5 | 30–60 | - | - | - | - | |
Hexestrol | - | 70–110 | - | - | - | - | |
Chlorotrianisene | - | >100 | - | - | >48 | - | |
Methallenestril | - | 400 | - | - | - | - | |
Estrogen | HF | VE | UCa | FSH | LH | HDL -C | SHBG | CBG | AGT | Liver |
---|---|---|---|---|---|---|---|---|---|---|
Estradiol | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 |
Estrone | ? | ? | ? | 0.3 | 0.3 | ? | ? | ? | ? | ? |
Estriol | 0.3 | 0.3 | 0.1 | 0.3 | 0.3 | 0.2 | ? | ? | ? | 0.67 |
Estrone sulfate | ? | 0.9 | 0.9 | 0.8–0.9 | 0.9 | 0.5 | 0.9 | 0.5–0.7 | 1.4–1.5 | 0.56–1.7 |
Conjugated estrogens | 1.2 | 1.5 | 2.0 | 1.1–1.3 | 1.0 | 1.5 | 3.0–3.2 | 1.3–1.5 | 5.0 | 1.3–4.5 |
Equilin sulfate | ? | ? | 1.0 | ? | ? | 6.0 | 7.5 | 6.0 | 7.5 | ? |
Ethinylestradiol | 120 | 150 | 400 | 60–150 | 100 | 400 | 500–600 | 500–600 | 350 | 2.9–5.0 |
Diethylstilbestrol | ? | ? | ? | 2.9–3.4 | ? | ? | 26–28 | 25–37 | 20 | 5.7–7.5 |
Sources and footnotes
Notes:Values are ratios, with estradiol as standard (i.e., 1.0).Abbreviations:HF= Clinical relief ofhot flashes.VE= Increasedproliferationofvaginal epithelium.UCa= Decrease inUCa .FSH= Suppression ofFSH levels.LH= Suppression ofLH levels.HDL-C,SHBG,CBG,andAGT= Increase in the serum levels of theseliver proteins.Liver = Ratio of liver estrogenic effects to general/systemic estrogenic effects (hot flashes/gonadotropins).Sources:See template. |
Estrogen | Form | Dose (mg) | Duration by dose (mg) | ||
---|---|---|---|---|---|
EPD | CICD | ||||
Estradiol | Aq. soln. | ? | – | <1 d | |
Oil soln. | 40–60 | – | 1–2 ≈ 1–2 d | ||
Aq. susp. | ? | 3.5 | 0.5–2 ≈ 2–7 d; 3.5 ≈ >5 d | ||
Microsph. | ? | – | 1 ≈ 30 d | ||
Estradiol benzoate | Oil soln. | 25–35 | – | 1.66 ≈ 2–3 d; 5 ≈ 3–6 d | |
Aq. susp. | 20 | – | 10 ≈ 16–21 d | ||
Emulsion | ? | – | 10 ≈ 14–21 d | ||
Estradiol dipropionate | Oil soln. | 25–30 | – | 5 ≈ 5–8 d | |
Estradiol valerate | Oil soln. | 20–30 | 5 | 5 ≈ 7–8 d; 10 ≈ 10–14 d; 40 ≈ 14–21 d; 100 ≈ 21–28 d | |
Estradiol benz. butyrate | Oil soln. | ? | 10 | 10 ≈ 21 d | |
Estradiol cypionate | Oil soln. | 20–30 | – | 5 ≈ 11–14 d | |
Aq. susp. | ? | 5 | 5 ≈ 14–24 d | ||
Estradiol enanthate | Oil soln. | ? | 5–10 | 10 ≈ 20–30 d | |
Estradiol dienanthate | Oil soln. | ? | – | 7.5 ≈ >40 d | |
Estradiol undecylate | Oil soln. | ? | – | 10–20 ≈ 40–60 d; 25–50 ≈ 60–120 d | |
Polyestradiol phosphate | Aq. soln. | 40–60 | – | 40 ≈ 30 d; 80 ≈ 60 d; 160 ≈ 120 d | |
Estrone | Oil soln. | ? | – | 1–2 ≈ 2–3 d | |
Aq. susp. | ? | – | 0.1–2 ≈ 2–7 d | ||
Estriol | Oil soln. | ? | – | 1–2 ≈ 1–4 d | |
Polyestriol phosphate | Aq. soln. | ? | – | 50 ≈ 30 d; 80 ≈ 60 d | |
Notes and sources
Notes:Allaqueous suspensionsare ofmicrocrystallineparticle size.Estradiolproduction during themenstrual cycleis 30–640 µg/d (6.4–8.6 mg total per month or cycle). Thevaginalepitheliummaturation dosage ofestradiol benzoateorestradiol valeratehas been reported as 5 to 7 mg/week. An effectiveovulation-inhibiting doseofestradiol undecylateis 20–30 mg/month.Sources:See template. |
Estrogen | Form | Major brand name(s) | EPD(14 days) | Duration | |
---|---|---|---|---|---|
Diethylstilbestrol(DES) | Oil solution | Metestrol | 20 mg | 1 mg ≈ 2–3 days; 3 mg ≈ 3 days | |
Diethylstilbestrol dipropionate | Oil solution | Cyren B | 12.5–15 mg | 2.5 mg ≈ 5 days | |
Aqueous suspension | ? | 5 mg | ?mg = 21–28 days | ||
Dimestrol (DESdimethyl ether) | Oil solution | Depot-Cyren, Depot-Oestromon, Retalon Retard | 20–40 mg | ? | |
Fosfestrol (DESdiphosphate)a | Aqueous solution | Honvan | ? | <1 day | |
Dienestrol diacetate | Aqueous suspension | Farmacyrol-Kristallsuspension | 50 mg | ? | |
Hexestrol dipropionate | Oil solution | Hormoestrol, Retalon Oleosum | 25 mg | ? | |
Hexestrol diphosphatea | Aqueous solution | Cytostesin, Pharmestrin, Retalon Aquosum | ? | Very short | |
Note:All byintramuscular injectionunless otherwise noted.Footnotes:a= Byintravenous injection.Sources:See template. |
Class | Examples | REcomplex retention | Pharmacodynamic profile | Uterine effects |
---|---|---|---|---|
Short-acting (a.k.a. "weak" or "impeded" ) |
Estriol•16-Epiestriol•17α-Estradiol•ent-Estradiol•16-Ketoestradiol•Dimethylstilbestrol•meso-Butestrol | Short (1–4 hours) | Single or once-daily injections:partial agonistorantagonist | Early responsesa |
Implant or multiple injections per day:full agonist | Early and late responsesb | |||
Long-acting | A.Estradiol•Estrone•Ethinylestradiol•Diethylstilbestrol•Hexestrol | Intermediate (6–24 hours) | Single or once-daily injections: full agonist | Early and late responses |
B.Clomifene•Nafoxidine•Nitromifene•Tamoxifen | Long (>24–48 hours) | Single injection: agonist Repeated injections: antagonist |
Early and late responses | |
Footnotes:a= Early responses occur after 0–6 hours and includewater imbibition,hyperemia,amino acidandnucleotideuptake, activation ofRNA polymerasesIandII,and stimulation of inducedprotein,among others.b= Late responses occur after 6–48 hours and includecellular hypertrophyandhyperplasiaand sustained RNA polymerase I and II activity, among others.Sources:[189][190][191][192][193][194][195] |
Pharmacokinetics
[edit]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 oralbioavailabilitywhile synthetic estrogens have higher bioavailability.Parenteralroutes have higher bioavailability. Estrogens are typically bound toalbuminand/orsex hormone-binding globulinin the circulation. They aremetabolizedin theliverbyhydroxylation(viacytochrome P450enzymes),dehydrogenation(via17β-hydroxysteroid dehydrogenase), andconjugation(viasulfationandglucuronidation). Theelimination half-livesof estrogens vary by estrogen and route of administration. Estrogens areeliminatedmainly by thekidneysvia theurineas conjugates.
Compound | RBA to SHBG (%) |
Bound to SHBG(%) |
Bound to albumin(%) |
Total bound(%) |
MCR (L/day/m2) |
---|---|---|---|---|---|
17β-Estradiol | 50 | 37 | 61 | 98 | 580 |
Estrone | 12 | 16 | 80 | 96 | 1050 |
Estriol | 0.3 | 1 | 91 | 92 | 1110 |
Estrone sulfate | 0 | 0 | 99 | 99 | 80 |
17β-Dihydroequilin | 30 | ? | ? | ? | 1250 |
Equilin | 8 | 26 | 13 | ? | 2640 |
17β-Dihydroequilin sulfate | 0 | ? | ? | ? | 375 |
Equilin sulfate | 0 | ? | ? | ? | 175 |
Δ8-Estrone | ? | ? | ? | ? | 1710 |
Notes:RBAforSHBG(%) is compared to 100% fortestosterone.Sources:See template. |
Estrogen metabolism in humans
|
Chemistry
[edit]
Structures of major endogenous estrogens
|
Estrogens can be grouped as steroidal or nonsteroidal. The steroidal estrogens areestranesand includeestradioland itsanalogues,such asethinylestradiolandconjugated estrogenslikeequilin sulfate.Nonsteroidal estrogens belong predominantly to thestilbestrolgroup of compounds and includediethylstilbestrolandhexestrol,among others.
Estrogen estersareestersandprodrugsof the correspondingparentestrogens. Examples includeestradiol valerateanddiethylstilbestrol dipropionate,which are prodrugs of estradiol and diethylstilbestrol, respectively. Estrogen esters with fatty acid esters have increasedlipophilicityand 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.
Estrogen | Structure | Ester(s) | Relative mol. weight |
Relative E2contentb |
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 ofesterincarbonatomsforstraight-chain fatty acidsor approximate length of ester in carbon atoms foraromaticorcyclicfatty acids.b= Relative estradiol content by weight (i.e., relativeestrogenicexposure).c= Experimental or predictedoctanol/water partition coefficient(i.e.,lipophilicity/hydrophobicity). Retrieved fromPubChem,ChemSpider,andDrugBank.d= Also known asestradiol normustine phosphate.e=Polymerofestradiol 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. |
History
[edit]Generic name | Class | Brand name | Route | Intr. |
---|---|---|---|---|
Chlorotrianisene | NS | Tace[a] | PO | 1952 |
Conjugated estriol | S/ester | Emmenin[a] | PO | 1930 |
Diethylstilbestrol dipropionate | NS/ester | Synestrin[a] | IM | 1940s |
Estradiol dipropionate | S/ester | Agofollin[a] | IM | 1939 |
Estrogenic substances | S | Amniotin[a] | PO, IM, TD, V | 1929 |
Estrone | S | Theelin[a] | IM | 1929 |
Ethinylestradiol sulfonate | S/alkyl/ester | Deposiston[a] | PO | 1978 |
Methallenestril | NS/ether | Vallestril | PO | 1950s |
Moxestrol | S/alkyl | Surestryl | PO | 1970s |
Polyestriol phosphate | S/ester | Triodurin[a] | IM | 1968 |
Quinestrol | S/alkyl/ether | Estrovis | PO | 1960s |
Ovarianextracts were available in the late 1800s and early 1900s, but were inert or had extremely low estrogenic activity and were regarded as ineffective.[196][197][198]In 1927, Selmar and Aschheim discovered that large amounts of estrogens were present in theurineofpregnantwomen.[197][199][200]This rich source of estrogens, produced by theplacenta,allowed for the development of potent estrogenic formulations forscientificandclinicaluse.[197][200][201]The first pharmaceutical estrogen product was aconjugated estriolcalledProgynon,a placentalextract,and was introduced for medical use by theGermanpharmaceutical companyScheringin 1928.[202][203][204][205][206][207][208][209]In 1929,Adolf ButenandtandEdward Adelbert Doisyindependently isolated and purifiedestrone,the first estrogen to be discovered.[210]The estrogen preparationsAmniotin(Squibb),Progynon(Schering), andTheelin(Parke-Davis) were all on the market by 1929,[196]and various additional preparations such asEmmenin,Folliculin,Menformon,Oestroform,andProgynon B,containing purified estrogens or mixtures of estrogens, were on the market by 1934.[197][211][212]Estrogens were originally known under a variety of different names includingestrogens,estrins,follicular hormones,folliculins,gynecogens,folliculoids,andfemale sex hormones,among others.[213][211]
Anestrogen patchwas reportedly marketed bySearlein 1928,[214][215]and an estrogennasal spraywas studied by 1929.[216]
In 1938, British scientists obtained a patent on a newly formulated nonsteroidal estrogen,diethylstilbestrol(DES), that was cheaper and more powerful than the previously manufactured estrogens. Soon after, concerns over the side effects of DES were raised in scientific journals while the drug manufacturers came together to lobby for governmental approval of DES. It was only until 1941 when estrogen therapy was finally approved by the Food and Drug Administration (FDA) for the treatment of menopausal symptoms.[217]Conjugated estrogens(brand name Premarin) was introduced in 1941 and succeeded Emmenin, the sales of which had begun to drop after 1940 due to competition from DES.[218]Ethinylestradiolwassynthesizedin 1938 by Hans Herloff Inhoffen and Walter Hohlweg atSchering AGinBerlin[219][220][221][222][223]and was approved by theFDA in theU.S. on 25 June 1943 and marketed byScheringas Estinyl.[224]
Micronized estradiol, via the oral route, was first evaluated in 1972,[225]and this was followed by the evaluation of vaginal and intranasal micronized estradiol in 1977.[226]Oral micronized estradiol was first approved in theUnited Statesunder the brand name Estrace in 1975.[227]
Society and culture
[edit]Availability
[edit]Estrogens are widely available throughout the world.[4]
Research
[edit]Male birth control
[edit]High-dose estrogentherapy is effective in suppressingspermatogenesisandfertilityin men, and hence as amale contraceptive.[228][229]It works both by strongly suppressinggonadotropinsecretion andgonadaltestosteroneproduction and via direct effects on thetestes.[229][230]After a sufficient course of therapy, onlySertoli cellsandspermatogoniaremain in theseminiferous tubulesof the testes, with a variety of other testicular abnormalities observable.[228][229]The use of estrogens for contraception in men is precluded by major side effects such assexual dysfunction,feminization,gynecomastia,andmetabolicchanges.[228]In addition, there is evidence that with long-term therapy, fertility and gonadalsex hormoneproduction in men may not return following discontinuation of high-dose estrogen therapy.[230]
Eating disorders
[edit]Estrogen has been used as a treatment for women withbulimia nervosa,in addition tocognitive behavioral therapy,which is the established standard for treatment in bulimia cases. The estrogen research hypothesizes that the disease may be linked to a hormonal imbalance in the brain.[231]
Miscellaneous
[edit]Estrogens have been used in studies which indicate that they may be effective in the treatment oftraumatic liver injury.[232]
In humans and mice, estrogens promotewound healing.[233]
Estrogen therapy has been proposed as a potential treatment forautismbut clinical studies are needed.[234]
References
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There is no doubt that the conversion of the endometrium with injections of both synthetic and native estrogenic hormone preparations succeeds, but the opinion whether native, orally administered preparations can produce a proliferation mucosa changes with different authors. PEDERSEN-BJERGAARD (1939) was able to show that 90% of the folliculin taken up in the blood of the vena portae is inactivated in the liver. Neither KAUFMANN (1933, 1935), RAUSCHER (1939, 1942) nor HERRNBERGER (1941) succeeded in bringing a castration endometrium into proliferation using large doses of orally administered preparations of estrone or estradiol. Other results are reported by NEUSTAEDTER (1939), LAUTERWEIN (1940) and FERIN (1941); they succeeded in converting an atrophic castration endometrium into an unambiguous proliferation mucosa with 120–300 oestradiol or with 380 oestrone.
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When Allen and Doisy heard about the [Ascheim-Zondek test for the diagnosis of pregnancy], they realized there was a rich and easily handled source of hormones in urine from which they could develop a potent extract. [...] Allen and Doisy's research was sponsored by the committee, while that of their main rival, Adolt Butenandt (b. 1903) of the University of Gottingen was sponsored by a German pharmaceutical firm. In 1929, both terms announced the isolation of a pure crystal female sex hormone, estrone, in 1929, although Doisy and Allen did so two months earlier than Butenandt.27 By 1931, estrone was being commercially produced by Parke Davis in this country, and Schering-Kahlbaum in Germany. Interestingly, when Butenandt (who shared the Nobel Prize for chemistry in 1939) isolated estrone and analyzed its structure, he found that it was a steroid, the first hormone to be classed in this molecular family.
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The first sex steroid used as pharmacological agent was Progynon, first sold by Schering AG in 1928. [...]
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Estrogens are highly efficient inhibitors of the hypothalamic-hypophyseal-testicular axis (212–214). Aside from their negative feedback action at the level of the hypothalamus and pituitary, direct inhibitory effects on the testis are likely (215,216). [...] The histology of the testes [with estrogen treatment] showed disorganization of the seminiferous tubules, vacuolization and absence of lumen, and compartmentalization of spermatogenesis.
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Estrogens act primarily through negative feedback at the hypothalamic-pituitary level to reduce LH secretion and testicular androgen synthesis. [...] Interestingly, if the treatment with estrogens is discontinued after 3 yr. of uninterrupted exposure, serum testosterone may remain at castration levels for up to another 3 yr. This prolonged suppression is thought to result from a direct effect of estrogens on the Leydig cells.
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Further reading
[edit]- Alfred S. Wolf, H.P.G. Schneider (12 March 2013).Östrogene in Diagnostik und Therapie.Springer-Verlag. pp. 1–.ISBN978-3-642-75101-1.
- O'Connell MB (September 1995). "Pharmacokinetic and pharmacologic variation between different estrogen products".J Clin Pharmacol.35(9S): 18S–24S.doi:10.1002/j.1552-4604.1995.tb04143.x.PMID8530713.S2CID10159196.
- Michael Oettel, Ekkehard Schillinger (1999).Estrogens and Antiestrogens I: Physiology and Mechanisms of Action of Estrogens and Antiestrogens.Springer Science & Business Media.ISBN978-3-642-58616-3.
- Michael Oettel, Ekkehard Schillinger (1999).Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen.Springer Science & Business Media.ISBN978-3-642-60107-1.
- Ruggiero RJ, Likis FE (2002). "Estrogen: physiology, pharmacology, and formulations for replacement therapy".J Midwifery Womens Health.47(3): 130–8.doi:10.1016/S1526-9523(02)00233-7.PMID12071379.
- Kuhl H (2005)."Pharmacology of estrogens and progestogens: influence of different routes of administration"(PDF).Climacteric.8(Suppl 1): 3–63.doi:10.1080/13697130500148875.PMID16112947.S2CID24616324.