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{{Short description|Type of medication}}{{cs1 config|name-list-style=vanc}}{{About|estrogens as medications|their role as hormones|Estrogen}}{{Use dmy dates|date=August 2018}}

factoids

An estrogen (E) is a type of medication which is used most commonly in hormonal birth control and menopausal hormone therapy, and as part of feminizing hormone therapy for transgender women.JOURNAL, Kuhl H, Pharmacology of estrogens and progestogens: influence of different routes of administration, Climacteric, 8, Suppl 1, 3–63, 2005, 16112947, 10.1080/13697130500148875, 24616324,hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf, They can also be used in the treatment of hormone-sensitive cancers like breast cancer and prostate cancer and for various other indications. Estrogens are used alone or in combination with progestogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of estrogens include bioidentical estradiol, natural conjugated estrogens, synthetic steroidal estrogens like ethinylestradiol, and synthetic nonsteroidal estrogens like diethylstilbestrol. Estrogens are one of three types of sex hormone agonists, the others being androgens/anabolic steroids like testosterone and progestogens like progesterone.Side effects of estrogens include breast tenderness, breast enlargement, headache, nausea, and edema among others. Other side effects of estrogens include an increased risk of blood clots, cardiovascular disease, and, when combined with most progestogens, breast cancer. In men, estrogens can cause breast development, feminization, infertility, low testosterone levels, and sexual dysfunction among others.Estrogens are agonists of the estrogen receptors, the biological targets of endogenous estrogens like estradiol. They have important effects in many tissues in the body, including in the female reproductive system (uterus, vagina, and ovaries), the breasts, bone, fat, the liver, and the brain among others. Unlike other medications like progestins and anabolic steroids, estrogens do not have other hormonal activities. Estrogens also have antigonadotropic effects and at sufficiently high dosages can strongly suppress sex hormone production. Estrogens mediate their contraceptive effects in combination with progestins by inhibiting ovulation.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.JOURNAL, Kuhl H, Pharmacology of Progestogens, J Reproduktionsmed Endokrinol, 2011, 8, 1, 157–177,www.kup.at/kup/pdf/10168.pdf, A variety of different estrogens have been marketed for clinical use in humans or use in veterinary medicine, although only a handful of these are widely used.WEB,www.micromedexsolutions.com, IBM Watson Health Products: Please Login, WEB,www.drugs.com/drug-class/estrogens.html, List of Estrogens, BOOK, Index Nominum 2000: International Drug Directory,books.google.com/books?id=5GpcTQD_L2oC, January 2000, Taylor & Francis, 978-3-88763-075-1, BOOK, J. Elks, The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies,books.google.com/books?id=0vXTBwAAQBAJ, 14 November 2014, Springer, 978-1-4757-2085-3, These medications can be grouped into different types based on origin and chemical structure. Estrogens are available widely throughout the world and are used in most forms of hormonal birth control and in all menopausal hormone therapy regimens.{{TOC limit|3}}

Medical uses

Birth control

Estrogens have contraceptive effects and are used in combination with progestins (synthetic progestogens) in birth control to prevent pregnancy in women. This is referred to as combined hormonal contraception. The contraceptive effects of estrogens are mediated by their antigonadotropic effects and hence by inhibition of ovulation. Most combined oral contraceptives contain ethinylestradiol or its prodrug mestranol 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 superior oral pharmacokinetics (higher bioavailability and less interindividual variability) and controls vaginal bleeding more effectively. This is due to its synthetic nature and its resistance to metabolism in certain tissues such as the intestines, liver, and uterus relative to estradiol. Besides oral contraceptives, other forms of combined hormonal contraception include contraceptive patches, contraceptive vaginal rings, and combined injectable contraceptives. Contraceptive patches and vaginal rings contain ethinylestradiol as the estrogen component, while combined injectable contraceptives contain estradiol or more typically an estradiol ester.

Hormone therapy

Menopause

File:Hot flashes with placebo and different doses of oral estradiol in menopausal women.png|thumb|right|400px|Mean number of moderate-to-severe hot flashes per week with placebo and different doses of oral estradiol in a randomized controlled trialrandomized controlled trialEstrogen and other hormones are given to postmenopausal women in order to prevent osteoporosis 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 the Women’s Health Initiative (WHI), an orally administered conjugated estrogen supplement was found to be associated with an increased risk of dangerous blood clotting. The WHI studies used one type of estrogen supplement, a high oral dose of conjugated estrogens (Premarin alone and with medroxyprogesterone acetate as Prempro).WEB,www.nih.gov/PHTindex.htm, NIH â€“ Menopausal Hormone Therapy Information, 4 March 2008, 27 August 2007, National Institutes of Health, 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 applied topically may have a different spectrum of side effects than when administered orally,JOURNAL, Menon DV, Vongpatanasin W, Effects of transdermal estrogen replacement therapy on cardiovascular risk factors, Treat Endocrinol, 5, 1, 37–51, 2006, 16396517, 10.2165/00024677-200605010-00005, 24041216, 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 of thromboembolic 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 suppress lactation after child birth.Synthetic estrogens, such as 17α-substituted estrogens like ethinylestradiol and its C3 esters and ethers mestranol, quinestrol, and ethinylestradiol sulfonate, and nonsteroidal estrogens like the stilbestrols diethylstilbestrol, hexestrol, and dienestrol, are no longer used in menopausal hormone therapy, owing to their disproportionate effects on liver protein synthesis and associated health risks.BOOK, Alfred S. Wolf, H.P.G. Schneider, Östrogene in Diagnostik und Therapie,books.google.com/books?id=IArLBgAAQBAJ&pg=PA77, 12 March 2013, Springer-Verlag, 978-3-642-75101-1, 77–, {{Estrogen dosages for menopausal hormone therapy}}

Hypogonadism

Estrogens are used along with progestogens to treat hypogonadism and delayed puberty in women.

Transgender women

Estrogens are used along with antiandrogens and progestogens as a component of feminizing hormone therapy for transgender women and other transfeminine individuals.JOURNAL, Wesp LM, Deutsch MB, Hormonal and Surgical Treatment Options for Transgender Women and Transfeminine Spectrum Persons, Psychiatr. Clin. North Am., 40, 1, 99–111, March 2017, 28159148, 10.1016/j.psc.2016.10.006, JOURNAL, Unger CA, Hormone therapy for transgender patients, Transl Androl Urol, 5, 6, 877–884, December 2016, 28078219, 5182227, 10.21037/tau.2016.09.04, free, JOURNAL, Tangpricha V, den Heijer M, Oestrogen and anti-androgen therapy for transgender women, Lancet Diabetes Endocrinol, 5, 4, 291–300, April 2017, 27916515, 10.1016/S2213-8587(16)30319-9, 5366074,

Hormonal cancer

Prostate cancer

{{See also|Management of prostate cancer#Estrogen therapy}}High-dose estrogen therapy with a variety of estrogens such as diethylstilbestrol, ethinylestradiol, polyestradiol phosphate, estradiol undecylate, estradiol valerate, and estradiol has been used to treat prostate cancer in men.JOURNAL, Oh WK, The evolving role of estrogen therapy in prostate cancer, Clin Genitourinary Cancer, 1, 2, 81–9, 2002, 15046698, 10.3816/CGC.2002.n.009, William K. Oh, It is effective because estrogens are functional antiandrogens, capable of suppressing testosterone levels to castrate concentrations and decreasing free testosterone levels by increasing sex hormone-binding globulin (SHBG) production. High-dose estrogen therapy is associated with poor tolerability and safety, namely gynecomastia and cardiovascular complications such as thrombosis.{{Additional citation needed|date=February 2018}} For this reason, has largely been replaced by newer antiandrogens such as gonadotropin-releasing hormone analogues and nonsteroidal antiandrogens. It is still sometimes used in the treatment of prostate cancer however, and newer estrogens with atypical profiles such as GTx-758 that have improved tolerability profiles are being studied for possible application in prostate cancer.{{Estrogen dosages for prostate cancer}}

Breast cancer

{{See also|Breast cancer management#Hormonal therapy}}High-dose estrogen therapy with potent synthetic estrogens such as diethylstilbestrol and ethinylestradiol was used in the past in the palliation treatment of breast cancer.BOOK, William R. Miller, James N. Ingle, Endocrine Therapy in Breast Cancer,books.google.com/books?id=00_LBQAAQBAJ&pg=PA49, 8 March 2002, CRC Press, 978-0-203-90983-6, 49–, Its effectiveness is approximately equivalent to that of antiestrogen therapy with selective estrogen receptor modulators (SERMs) like tamoxifen and aromatase inhibitors like anastrozole. The use of high-dose estrogen therapy in breast cancer has mostly been superseded by antiestrogen therapy due to the improved safety profile of the latter. 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.BOOK, Maximov, Philipp Y., McDaniel, Russell E., Jordan, V. Craig, Tamoxifen, Discovery and Pharmacology of Nonsteroidal Estrogens and Antiestrogens, Milestones in Drug Therapy, 2013, 1–30, 2296-6056, 10.1007/978-3-0348-0664-0_1, 978-3-0348-0663-3, {{Estrogen dosages for breast cancer}}

Other uses

Infertility

Estrogens may be used in treatment of infertility in women when there is a need to develop sperm-friendly cervical mucous or an appropriate uterine lining.BOOK, J. Aiman, Infertility: Diagnosis and Management,books.google.com/books?id=D4_TBwAAQBAJ&pg=PA133, 6 December 2012, Springer Science & Business Media, 978-1-4613-8265-2, 133–134, BOOK, Glenn L. Schattman, Sandro Esteves, Ashok Agarwal, Unexplained Infertility: Pathophysiology, Evaluation and Treatment,books.google.com/books?id=wCdACQAAQBAJ&pg=PA266, 12 May 2015, Springer, 978-1-4939-2140-9, 266–,

Pregnancy support

Estrogens like diethylstilbestrol were formerly used in high doses to help support pregnancy.JOURNAL, Bamigboye AA, Morris J, Oestrogen supplementation, mainly diethylstilbestrol, for preventing miscarriages and other adverse pregnancy outcomes, Cochrane Database Syst Rev, 3, CD004353, 2003, 2010, 12918007, 10.1002/14651858.CD004353, 9039959, However, subsequent research showed diethylstilbestrol to be ineffective as well as harmful.

Lactation suppression

Estrogens can be used to suppress lactation, for instance in the treatment of breast engorgement or galactorrhea.BOOK, J.B. Josimovich, Gynecologic Endocrinology,books.google.com/books?id=9vv2BwAAQBAJ&pg=PA482, 11 November 2013, Springer Science & Business Media, 978-1-4613-2157-6, 482–, However, high doses are needed, the effectiveness is uncertain, and high doses of estrogens in the postpartum period can increase the risk of blood clots.BOOK, Marshall S. Shapo, Experimenting with the Consumer: The Mass Testing of Risky Products on the American Public: The Mass Testing of Risky Products on the American Public,books.google.com/books?id=VoVfwfe339oC&pg=PA137, 30 December 2008, ABC-CLIO, 978-0-313-36529-4, 137–,

Tall stature

Estrogen has been used to induce growth attenuation in tall girls.JOURNAL, Lee JM, Howell JD, Tall girls: the social shaping of a medical therapy, Arch Pediatr Adolesc Med, 160, 10, 1077–8, 2006, 17018462, 10.1001/archpedi.160.10.1035, free, Estrogen-induced growth attenuation was used as part of the controversial Ashley Treatment to keep a developmentally disabled girl from growing to adult size.JOURNAL, Gunther DF, Diekema DS, Attenuating growth in children with profound developmental disability: a new approach to an old dilemma, Arch Pediatr Adolesc Med, 160, 10, 1013–7, 2006, 17018459, 10.1001/archpedi.160.10.1013,

Acromegaly

Estrogens have been used to treat acromegaly.JOURNAL, Duarte FH, Jallad RS, Bronstein MD, Estrogens and selective estrogen receptor modulators in acromegaly, Endocrine, 54, 2, 306–314, November 2016, 27704479, 10.1007/s12020-016-1118-z, 10136018, JOURNAL, Stone JC, Clark J, Cuneo R, Russell AW, Doi SA, Estrogen and selective estrogen receptor modulators (SERMs) for the treatment of acromegaly: a meta-analysis of published observational studies, Pituitary, 17, 3, 284–95, June 2014, 23925896, 10.1007/s11102-013-0504-2, 30697394, JOURNAL, Shimon I, Barkan A, Estrogen treatment for acromegaly, Pituitary, 15, 4, 601–7, December 2012, 22933045, 10.1007/s11102-012-0426-4, 1917058, This is because they suppress growth hormone-induced insulin-like growth factor 1 (IGF-1) production in the liver.

Sexual deviance

High-dose estrogen therapy has been used successfully in the treatment of sexual deviance such as paraphilias in men.JOURNAL, Thibaut F, De La Barra F, Gordon H, Cosyns P, Bradford JM, The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of paraphilias, World J. Biol. Psychiatry, 11, 4, 604–55, 2010, 20459370, 10.3109/15622971003671628, 14949511, BOOK, Handbook of Sexual Assault, Bradford, J. M. W., The Antiandrogen and Hormonal Treatment of Sex Offenders, 1990, 297–310, Springer US, 10.1007/978-1-4899-0915-2_17, 978-1-4899-0917-6, However, it has been found to produce many side effects (e.g., gynecomastia, feminization, cardiovascular disease, blood clots), and so is no longer recommended for such purposes. High-dose estrogen therapy works by suppressing testosterone levels, similarly to high-dose progestogen therapy and gonadotropin-releasing hormone (GnRH) modulator therapy. Lower dosages of estrogens have also been used in combination with high-dose progestogen therapy in the treatment of sexual deviance in men. High incidence of sexual dysfunction has similarly been associated with high-dose estrogen therapy in men treated with it for prostate cancer.JOURNAL, Brogden RN, Clissold SP, Flutamide. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in advanced prostatic cancer, Drugs, 38, 2, 185–203, August 1989, 2670515, 10.2165/00003495-198938020-00003, 262018256, A favourable feature of flutamide therapy has been its lesser effect on libido and sexual potency; fewer than 20% of patients treated with flutamide alone reported such changes. In contrast, nearly all patients treated with oestrogens or estramustine phosphate reported loss of sexual potency. [...] In comparative therapeutic trials, loss of potency has occurred in all patients treated with stilboestrol or estramustine phosphate compared with 0 to 20% of those given flutamide alone (Johansson et al. 1987; Lund & Rasmussen 1988).,

Breast enhancement

{{See also|Estradiol (medication)#Breast enhancement}}Estrogens are involved in breast development and may be used as a form of hormonal breast enhancement to increase the size of the breasts.BOOK, Gunther Göretzlehner, Christian Lauritzen, Thomas Römer, Winfried Rossmanith, Praktische Hormontherapie in der Gynäkologie,books.google.com/books?id=TIs2WhfYzZ4C&pg=PA385, 1 January 2012, Walter de Gruyter, 978-3-11-024568-4, 385–, BOOK, R.E. Mansel, Oystein Fodstad, Wen G. Jiang, Metastasis of Breast Cancer,books.google.com/books?id=14pb5b6gT-oC&pg=PA217, 14 June 2007, Springer Science & Business Media, 978-1-4020-5866-0, 217–, JOURNAL, Hartmann BW, Laml T, Kirchengast S, Albrecht AE, Huber JC, Hormonal breast augmentation: prognostic relevance of insulin-like growth factor-I, Gynecol. Endocrinol., 12, 2, 123–7, 1998, 9610425, 10.3109/09513599809024960, JOURNAL, Lauritzen, C, Hormonkur kann hypoplastischer Mamma aufhelfen, Hormone therapy can help hypoplastic breasts, Selecta, de, 1980, 22, 43, 3798–3801, Selecta-Verlag, Planegg, 0582-4877, 643821347, BOOK, Kaiser, Rolf, Leidenberger, Freimut A., Hormonbehandlung in der gynäkologischen Praxis, 1991, 6, Georg Thieme Verlag, Stuttgart, New York, 138–139, 978-3-13-357407-5, However, acute or temporary breast enlargement is a well-known side effect of estrogens, and increases in breast size tend to regress following discontinuation of treatment. Aside from those without prior established breast development, evidence is lacking for a sustained increase in breast size with estrogens.

Depression

Published 2019 and 2020 guidelines from the North American Menopause Society (NAMS) and European Menopause and Andropause Society (EMAS) have reviewed the topic of estrogen therapy for depressive symptoms in the peri- and postmenopause. There is some evidence that estrogens are effective in the treatment of depression in perimenopausal women.JOURNAL, Maki PM, Kornstein SG, Joffe H, Bromberger JT, Freeman EW, Athappilly G, Bobo WV, Rubin LH, Koleva HK, Cohen LS, Soares CN, Guidelines for the Evaluation and Treatment of Perimenopausal Depression: Summary and Recommendations, J Womens Health (Larchmt), 28, 2, 117–134, February 2019, 30182804, 10.1089/jwh.2018.27099.mensocrec, free, JOURNAL, Stute P, Spyropoulou A, Karageorgiou V, Cano A, Bitzer J, Ceausu I, Chedraui P, Durmusoglu F, Erkkola R, Goulis DG, Lindén Hirschberg A, Kiesel L, Lopes P, Pines A, Rees M, van Trotsenburg M, Zervas I, Lambrinoudaki I, Management of depressive symptoms in peri- and postmenopausal women: EMAS position statement, Maturitas, 131, 91–101, January 2020, 31740049, 10.1016/j.maturitas.2019.11.002, free, JOURNAL, Raglan GB, Schulkin J, Micks E, Depression during perimenopause: the role of the obstetrician-gynecologist, Arch Womens Ment Health, 23, 1, 1–10, 30758732, 10.1007/s00737-019-0950-6, 2020, 61155969, JOURNAL, Gava G, Orsili I, Alvisi S, Mancini I, Seracchioli R, Meriggiola MC, Cognition, Mood and Sleep in Menopausal Transition: The Role of Menopause Hormone Therapy, Medicina, 55, 10, 668, October 2019, 31581598, 6843314, 10.3390/medicina55100668, free, JOURNAL, Toffol E, Heikinheimo O, Partonen T, Hormone therapy and mood in perimenopausal and postmenopausal women: a narrative review, Menopause, 22, 5, 564–78, May 2015, 25203891, 10.1097/GME.0000000000000323, 5830652, JOURNAL, Garay RP, Charpeaud T, Logan S, Hannaert P, Garay RG, Llorca PM, Shorey S, Pharmacotherapeutic approaches to treating depression during the perimenopause, Expert Opin Pharmacother, 20, 15, 1837–1845, October 2019, 31355688, 10.1080/14656566.2019.1645122, 198967172, JOURNAL, Rubinow DR, Johnson SL, Schmidt PJ, Girdler S, Gaynes B, Efficacy of estradiol in perimenopausal depression: so much promise and so few answers, Depress Anxiety, 32, 8, 539–49, August 2015, 26130315, 6309886, 10.1002/da.22391, JOURNAL, Zweifel JE, O’Brien WH, A meta-analysis of the effect of hormone replacement therapy upon depressed mood, Psychoneuroendocrinology, 22, 3, 189–212, April 1997, 9203229, 10.1016/s0306-4530(96)00034-0, 44630030, JOURNAL, Rubinow DR, Schmidt PJ, Is there a role for reproductive steroids in the etiology and treatment of affective disorders?, Dialogues Clin Neurosci, 20, 3, 187–196, September 2018, 30581288, 6296393, 10.31887/DCNS.2018.20.3/drubinow, JOURNAL, Myoraku, Alison, Robakis, Thalia, Rasgon, Natalie, Estrogen-Based Hormone Therapy for Depression Related to Reproductive Events, Current Treatment Options in Psychiatry, 5, 4, 2018, 416–424, 2196-3061, 10.1007/s40501-018-0156-y, 81770543, {{citation |title=Hormonal and Pharmacologic Interventions for Depressive Symptoms in Peri- And/Or Post-Menopausal Women: A Network Meta-Analysis of Randomized Controlled Trials |first1=Yu-Shian |last1=Cheng |first2=Ping-Tao |last2=Tseng |first3=Yu-Kang |last3=Tu |first4=Yi-Cheng |last4=Wu |first5=Kuan-Pin |last5=Su |first6=Ching-Kuan |last6=Wu |first7=Dian-Jeng |last7=Li |first8=Tien-Yu |last8=Chen |first9=Brendon |last9=Stubbs |first10=Andre F. |last10=Carvalho|first11=Marco|last11=Solmi |first12=Trevor |last12=Thompson|first13=Maria Gabriella |last13=Caruso |first14=Yutaka J. |last14=Matsuoka |first15=Yen-Wen |last15=Chen |first16=Pao-Yen |last16=Lin |first17=Ming-Kung |last17=Wu |first18=Cheuk-Kwan |last18=Sun|date=19 September 2019 |doi=10.2139/ssrn.3457416 |ssrn=3457416|s2cid=216575787 }} The magnitude of benefit appears to be similar to that of classical antidepressants. There is also some evidence that estrogens may improve mood and well-being in non-depressed perimenopausal women. Estrogens do not appear to be effective in the treatment of depression in postmenopausal women. This suggests that there is a window of opportunity for effective treatment of depressive symptoms with estrogens. Research on combined estrogen and progestogen therapy for depressive symptoms in the peri- and postmenopause is scarce and inconclusive. Estrogens may augment the mood benefits of antidepressants in middle-aged and older women. Menopausal hormone therapy is not currently approved for the treatment of depressive symptoms in the peri- or postmenopause in either the United States or the United Kingdom due to insufficient evidence of effectiveness. More research is needed on the issue of estrogen therapy for depressive symptoms associated with menopause.

Schizophrenia

Estrogens appear to be useful in the treatment of schizophrenia in both women and men.JOURNAL, Begemann MJ, Dekker CF, van Lunenburg M, Sommer IE, Estrogen augmentation in schizophrenia: a quantitative review of current evidence, Schizophr. Res., 141, 2–3, 179–84, November 2012, 22998932, 10.1016/j.schres.2012.08.016, 40584474, JOURNAL, Brzezinski A, Brzezinski-Sinai NA, Seeman MV, Treating schizophrenia during menopause, Menopause, 24, 5, 582–588, May 2017, 27824682, 10.1097/GME.0000000000000772, 3452898, JOURNAL, McGregor C, Riordan A, Thornton J, Estrogens and the cognitive symptoms of schizophrenia: Possible neuroprotective mechanisms, Front Neuroendocrinol, 47, 19–33, October 2017, 28673758, 10.1016/j.yfrne.2017.06.003, 43291520, JOURNAL, Owens SJ, Murphy CE, Purves-Tyson TD, Weickert TW, Shannon Weickert C, Considering the role of adolescent sex steroids in schizophrenia, J. Neuroendocrinol., 30, 2, e12538, February 2018, 28941299, 10.1111/jne.12538, 3391650, 1959.4/unsworks_49994, free,

Acne

Systemic estrogen therapy at adequate doses is effective for and has been used in the treatment of acne in both females and males, but causes major side effects such as feminization and gynecomastia in males.JOURNAL, Clayton RW, Göbel K, Niessen CM, Paus R, ((van Steensel MAM)), Lim X, Homeostasis of the sebaceous gland and mechanisms of acne pathogenesis, Br. J. Dermatol., 181, 4, 677–690, October 2019, 31056753, 10.1111/bjd.17981, 145822633, JOURNAL, Andrews GC, Domonkos AN, Post CF, Treatment of acne vulgaris, J Am Med Assoc, 146, 12, 1107–13, July 1951, 14841085, 10.1001/jama.1951.03670120017005, JOURNAL, White CB, Lehmann CF, Diethylstilbestrol therapy in young men with acne; correlation with the urinary 17-ketosteroids, AMA Arch Derm Syphilol, 65, 5, 601–8, May 1952, 14914180, 10.1001/archderm.1952.01530240093012, JOURNAL, Welsh AL, Use of synthetic estrogenic substance chlorotrianisene (TACE) in treatment of acne, AMA Arch Derm Syphilol, 69, 4, 418–27, April 1954, 13147544, 10.1001/archderm.1954.01540160020004, JOURNAL, Becker FT, The acne problem, AMA Arch Derm Syphilol, 67, 2, 173–83, February 1953, 13029903, 10.1001/archderm.1953.01540020051010, JOURNAL, Day RL, Anderson NP, The management of acne vulgaris, Postgrad Med, 12, 1, 34–40, July 1952, 14957675, 10.1080/00325481.1952.11708046, JOURNAL, Mullins JF, McCash WB, Lamar JK, Acne, estrogens and spermatozoa, Arch Dermatol, 81, 53–8, January 1960, 14425194, 10.1001/archderm.1960.03730010057006, JOURNAL, Pochi PE, Strauss JS, Sebaceous gland suppression with ethinyl estradiol and diethylstilbestrol, Arch Dermatol, 108, 2, 210–4, August 1973, 4269283, 10.1001/archderm.1973.01620230010003,

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Major estrogens marketed for clinical or veterinary use! scope=“col” style="width: 100px;” | Generic name! scope=“col” style="width: 30px;” | Class! scope=“col” style="width: 80px;” | Brand name! scope=“col” style="width: 30px;” | Route! scope=“col” style="width: 35px;” | {{abbr|Intr.|First introduced in}}! scope=“row” style="background:#f8f9fa;” | Conjugated estrogensgroup=estrogensFrom equine sources}} Premarin PO, {{abbrintramuscular injection}}, {{abbrtransdermal}}, {{abbrvaginally}} 1941! scope=“row” style="background:#f8f9fa;” | Dienestrol{{efn|group=estrogens|name=limited|Limited availability}}group=estrogens1=Has multiple other brand names}} PO 1947! scope=“row” style="background:#f8f9fa;” | Diethylstilbestrol{{efn|group=estrogens|name=limited}}group=estrogens| 1939! scope=“row” style="background:#f8f9fa;” | Esterified estrogensgroup=estrogens| 1970! scope=“row” style="background:#f8f9fa;” | Estetrol{{efn|group=estrogens|name=exp|Not approved yet in humans; currently in phase III clinical trials}}group=estrogens| N/A! scope=“row” style="background:#f8f9fa;” | Estradiolgroup=estrogensSCsubcutaneous injection}}, {{abbr>SLsublingual}}, TD, V >| 1935! scope=“row” style="background:#f8f9fa;” | Estradiol acetategroup=estrogens| 2001! scope=“row” style="background:#f8f9fa;” | Estradiol benzoate| 1933! scope=“row” style="background:#f8f9fa;” | Estradiol cypionate| 1952! scope=“row” style="background:#f8f9fa;” | Estradiol enanthategroup=estrogens| 1970s! scope=“row” style="background:#f8f9fa;” | Estradiol valerategroup=estrogens| 1954! scope=“row” style="background:#f8f9fa;” | Estramustine phosphate{{efn|group=estrogens|Used as a chemotherapeutic agent, not as a hormone}}group=estrogens| 1970s! scope=“row” style="background:#f8f9fa;” | Estriolgroup=estrogens| 1930! scope=“row” style="background:#f8f9fa;” | Estropipate{{efn|group=estrogens|name=limited}}| 1968! scope=“row” style="background:#f8f9fa;” | Ethinylestradiolalkylgroup=estrogens| 1943! scope=“row” style="background:#f8f9fa;” | Fosfestrol{{efn|group=estrogens|name=limited}}group=estrogens| 1947! scope=“row” style="background:#f8f9fa;” | Hexestrol{{efn|group=estrogens|name=limited}}group=estrogens| 1940s! scope=“row” style="background:#f8f9fa;” | Mestranol{{efn|group=estrogens|name=limited}}group=estrogens| 1957! scope=“row” style="background:#f8f9fa;” | Methylestradiol{{efn|group=estrogens|name=limited}}group=estrogens| 1955! scope=“row” style="background:#f8f9fa;” | Polyestradiol phosphate{{efn|group=estrogens|name=limited}}| 1957! scope=“row” style="background:#f8f9fa;” | Prasterone{{efn|group=estrogens|Also known as dehydroepiandrosterone or DHEA}}group=estrogens| 1970s! scope=“row” style="background:#f8f9fa;” | Zeranol{{efn|group=estrogens|name=vet|Veterinary use only}}group=estrogens| 1970s class=“sortbottom”steroidal estrogens and nonsteroidal estrogens.JOURNAL, Hermkens PH, Kamp S, Lusher S, Veeneman GH, Non-steroidal steroid receptor modulators, IDrugs, 9, 7, 488–94, July 2006, 16821162, 10.2174/0929867053764671,

Steroidal estrogens

Estradiol, estrone, and estriol have all been approved as pharmaceutical drugs and are used medically. Estetrol is currently under development for medical indications, but has not yet been approved in any country.WEB,adisinsight.springer.com/drugs/800034634, Drospirenone/Estetrol - Mithra Pharmaceuticals - AdisInsight, A variety of synthetic estrogen esters, such as estradiol valerate, estradiol cypionate, estradiol acetate, estradiol benzoate, estradiol undecylate, and polyestradiol phosphate, are used clinically. The aforementioned compounds behave as prodrugs to estradiol, and are much longer-lasting in comparison when administered by intramuscular or subcutaneous injection. Esters of estrone and estriol also exist and are or have been used in clinical medicine, for example estrone sulfate (e.g., as estropipate), estriol succinate, and estriol glucuronide (as Emmenin and Progynon).Ethinylestradiol is a more potent synthetic analogue of estradiol that is used widely in hormonal contraceptives. Other synthetic derivatives of estradiol related to ethinylestradiol that are used clinically include mestranol, quinestrol, ethinylestradiol sulfonate, moxestrol, and methylestradiol. Conjugated estrogens (brand name Premarin), an estrogen product manufactured from the urine of pregnant mares and commonly used in menopausal hormone therapy, is a mixture of natural estrogens including estrone sulfate and equine estrogens such as equilin sulfate and 17β-dihydroequilin sulfate. A related and very similar product to conjugated estrogens, differing from it only in composition, is esterified estrogens.Testosterone, prasterone (dehydroepiandrosterone; DHEA), boldenone (δ1-testosterone), and nandrolone (19-nortestosterone) are naturally occurring androgens/anabolic steroids (AAS) which form estradiol as an active metabolite in small amounts and can produce estrogenic effects, most notably gynecomastia in men at sufficiently high dosages.BOOK, William, Llewellyn, Anabolics,books.google.com/books?id=afKLA-6wW0oC&pg=PT10, 2011, Molecular Nutrition Llc, 978-0-9828280-1-4, 9–10,294–297,385–394,402–412,444–454,460–467,483–490,575–583, Similarly, a number of synthetic AAS, including methyltestosterone, metandienone, normethandrone, and norethandrolone, produce methylestradiol or ethylestradiol as an active metabolite in small quantities, and can produce estrogenic effects as well. A few progestins, specifically the 19-nortestosterone derivatives norethisterone, noretynodrel, and tibolone, metabolize into estrogens (e.g., ethinylestradiol) and can produce estrogenic effects as well.JOURNAL, Paulsen CA, Leach RB, Lanman J, Goldston N, Maddock WO, Heller CG, Inherent estrogenicity of norethindrone and norethynodrel: comparison with other synthetic progestins and progesterone, J. Clin. Endocrinol. Metab., 22, 10, 1033–9, 1962, 13942007, 10.1210/jcem-22-10-1033,

Nonsteroidal estrogens

Diethylstilbestrol is a nonsteroidal estrogen that is no longer used medically. It is a member of the stilbestrol group. Other stilbestrol estrogens that have been used clinically include benzestrol, dienestrol, dienestrol acetate, diethylstilbestrol dipropionate, fosfestrol, hexestrol, and methestrol dipropionate. Chlorotrianisene, methallenestril, and doisynoestrol 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.

Contraindications

Estrogens have various contraindications.JOURNAL, Lauritzen C, Clinical use of oestrogens and progestogens, Maturitas, 12, 3, 199–214, September 1990, 2215269, 10.1016/0378-5122(90)90004-P, BOOK, Christian Lauritzen, John W. W. Studd, Current Management of the Menopause,books.google.com/books?id=WD7S7677xUUC&pg=PA95, 22 June 2005, CRC Press, 978-0-203-48612-2, 95–98,488, BOOK, Laurtizen, Christian, Hormone Substitution Before, During and After Menopause, 67–88,www.kup.at/kup/pdf/4978.pdf, Fisch, Franz H., Menopause – Andropause: Hormone Replacement Therapy Through the Ages, 2001, Krause & Pachernegg: Gablitz, 978-3-901299-34-6, BOOK, Midwinter, Audrey, Contraindications to estrogen therapy and management of the menopausal syndrome in these cases, 377–382, 10.1007/978-94-011-6165-7_33, Campbell, Stuart, The Management of the Menopause & Post-Menopausal Years: The Proceedings of the International Symposium held in London 24–26 November 1975 Arranged by the Institute of Obstetrics and Gynaecology, The University of London, 1976, 978-94-011-6167-1, MTP Press Limited, An example is history of thromboembolism (blood clots).

Side effects

The most common side effects of estrogens in general include breast tenderness, breast enlargement, headache, nausea, fluid retention, and edema. In women, estrogens can additionally cause vaginal bleeding, vaginal discharge, and anovulation, whereas in men, estrogens can additionally cause gynecomastia (male breast development), feminization, demasculinization, sexual dysfunction (reduced libido and erectile dysfunction), hypogonadism, testicular atrophy, and infertility.Estrogens can or may increase the risk of uncommon or rare but potentially serious issues including endometrial hyperplasia, endometrial cancer, cardiovascular complications (e.g., blood clots, stroke, heart attack), cholestatic hepatotoxicity, gallbladder disease (e.g., gallstones), hyperprolactinemia, prolactinoma, and dementia. These adverse effects are moderated by the concomitant use of a progestogen, the type of progestogen used, and the dosage and route of estrogen used.Around half of women with epilepsy who menstruate have a lowered seizure threshold around ovulation, most likely from the heightened estrogen levels at that time. This results in an increased risk of seizures in these women.High doses of synthetic estrogens like ethinylestradiol and diethylstilbestrol can produce prominent untoward side effects like nausea, vomiting, headache, malaise, and dizziness, among others.JOURNAL, Jeffcoate TN, Lister UM, Ethinyl oestradiol, Br Med J, 2, 4583, 809–12, November 1948, 18890306, 2091954, 10.1136/bmj.2.4583.809, BOOK, Consensus on Menopause Research, Lebech, P. E., Effects and Side-effects of Estrogen Therapy, 1976, 44–47, Springer Netherlands, 10.1007/978-94-011-7179-3_10, 978-94-011-7181-6, JOURNAL, Hammond CB, Maxson WS, Estrogen replacement therapy, Clin Obstet Gynecol, 29, 2, 407–30, June 1986, 3522011, 10.1097/00003081-198606000-00022, 31166713, Conversely, natural estrogens like estradiol and conjugated estrogens are rarely associated with such effects. The preceding side effects of synthetic estrogens do not appear to occur in pregnant women, who already have very high estrogen levels. This suggests that these effects are due to estrogenic activity. Synthetic estrogens have markedly stronger effects on the liver and hepatic protein synthesis than natural estrogens.JOURNAL, Coelingh Bennink HJ, Are all estrogens the same?, Maturitas, 47, 4, 269–75, April 2004, 15063479, 10.1016/j.maturitas.2003.11.009, JOURNAL, Cust MP, Gangar KF, Hillard TC, Whitehead MI, A risk-benefit assessment of estrogen therapy in postmenopausal women, Drug Saf, 5, 5, 345–58, 1990, 2222868, 10.2165/00002018-199005050-00004, 29182738, This is related to the fact that synthetic estrogens like ethinylestradiol are much more resistant to metabolism in the liver than natural estrogens.JOURNAL, Mattison DR, Karyakina N, Goodman M, LaKind JS, Pharmaco- and toxicokinetics of selected exogenous and endogenous estrogens: a review of the data and identification of knowledge gaps, Crit Rev Toxicol, 44, 8, 696–724, September 2014, 25099693, 10.3109/10408444.2014.930813, 11212469, JOURNAL, Whitehead, M., Oestrogens: Relative Potencies and Hepatic Effects After Different Routes of Administration, Journal of Obstetrics and Gynaecology, January 1982, 3, sup1, S11–S16, 0144-3615, 1364-6893, 10.3109/01443618209083065, {{Side effects of lower versus higher dose oral estradiol}}

Long-term effects

Endometrial hyperplasia and cancer

Unopposed estrogen therapy stimulates the growth of the endometrium and is associated with a dramatically increased risk of endometrial hyperplasia and endometrial cancer in postmenopausal women.JOURNAL, Sturdee DW, Are progestins really necessary as part of a combined HRT regimen?, Climacteric, 16, Suppl 1, 79–84, 2013, 23651281, 10.3109/13697137.2013.803311, 21894200, The risk of endometrial hyperplasia is greatly increased by 6 months of treatment ({{abbrlink|OR|odds ratio}} = 5.4) and further increased after 36 months of treatment ({{abbr|OR|odds ratio}} = 16.0). This can eventually progress to endometrial cancer, and the risk of endometrial cancer similarly increases with duration of treatment (less than one year, {{abbrlink|RR|relative risk}} = 1.4; many years (e.g., more than 10 years), {{abbr|RR|relative risk}} = 15.0). The risk of endometrial cancer also stays significantly elevated many years after stopping unopposed estrogen therapy, even after 15 years or more ({{abbr|RR|relative risk}} = 5.8).Progestogens prevent the effects of estrogens on the endometrium. 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 ({{abbr|OR|odds ratio}} = 0.3 with continuous estrogen–progestogen therapy). Continuous estrogen–progestogen therapy is more protective than sequential therapy, and a longer duration of treatment with continuous therapy is also more protective. The increase in risk of endometrial cancer is similarly decreased with continuous estrogen–progestogen therapy ({{abbr|RR|relative risk}} = 0.2–0.7). For these reasons, progestogens are always used alongside estrogens in women who have intact uteruses.

Cardiovascular events

Estrogens affect liver protein synthesis and thereby influence the cardiovascular system. They have been found to affect the production of a variety of coagulation and fibrinolytic factors, including increased factor IX, von Willebrand factor, thrombin–antithrombin complex (TAT), fragment 1+2, and D-dimer and decreased fibrinogen, factor VII, antithrombin, protein S, protein C, tissue plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-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. Due to its effects on liver protein synthesis, oral estrogen is procoagulant, and has been found to increase the risk of venous thromboembolism (VTE), including of both deep vein thrombosis (DVT) and pulmonary embolism (PE). Conversely, modern oral contraceptives are not associated with an increase in the risk of stroke and myocardial infarction (heart attack) in healthy, non-smoking premenopausal women of any age, except in those with hypertension (high blood pressure). 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. An increase in the risk of stroke has also been associated with older high-dose oral contraceptives that are no longer used.BOOK, Gregory Y. H. Lip, John E. Hall, Comprehensive Hypertension E-Book,books.google.com/books?id=XQajBQAAQBAJ&pg=PA865, 28 June 2007, Elsevier Health Sciences, 978-0-323-07067-6, 865–, Menopausal hormone therapy with replacement dosages of estrogens and progestogens has been associated with a significantly increased risk of cardiovascular events such as VTE.JOURNAL, Scarabin PY, Hormones and venous thromboembolism among postmenopausal women, Climacteric, 17, Suppl 2, 34–7, 2014, 25223916, 10.3109/13697137.2014.956717, 5084606, JOURNAL, BiÅ„kowska M, Menopausal hormone therapy and venous thromboembolism, Prz Menopauzalny, 13, 5, 267–72, October 2014, 26327865, 4520375, 10.5114/pm.2014.46468, However, such risks have been found to vary depending on the type of estrogen and the route of administration. The risk of VTE is increased by approximately 2-fold in women taking oral estrogen for menopausal hormone therapy. However, clinical research to date has generally not distinguished between conjugated estrogens and estradiol. 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. Only a few clinical studies have compared oral conjugated estrogens and oral estradiol. Oral conjugated estrogens have been found to possess a significantly greater risk of thromboembolic and cardiovascular complications than oral estradiol ({{abbrlink|OR|Odds ratio}} = 2.08) and oral esterified estrogens ({{abbrlink|OR|Odds ratio}} = 1.78).JOURNAL, Smith NL, Blondon M, Wiggins KL, Harrington LB, van Hylckama Vlieg A, Floyd JS, Hwang M, Bis JC, McKnight B, Rice KM, Lumley T, Rosendaal FR, Heckbert SR, Psaty BM, Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens, JAMA Intern Med, 174, 1, 25–31, January 2014, 24081194, 4636198, 10.1001/jamainternmed.2013.11074, JOURNAL, Smith NL, Heckbert SR, Lemaitre RN, Reiner AP, Lumley T, Weiss NS, Larson EB, Rosendaal FR, Psaty BM, Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis, JAMA, 292, 13, 1581–7, October 2004, 15467060, 10.1001/jama.292.13.1581, free, 1887/5083, free, 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 plus norethisterone acetate was found to be equivalent ({{abbrlink|RR|Relative risk}} = 4.0 and 3.9, respectively).JOURNAL, Lekovic D, Miljic P, Dmitrovic A, Thachil J, How do you decide on hormone replacement therapy in women with risk of venous thromboembolism?, Blood Rev., 31, 3, 151–157, May 2017, 27998619, 10.1016/j.blre.2016.12.001, JOURNAL, Roach RE, Lijfering WM, Helmerhorst FM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A, The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy, J. Thromb. Haemost., 11, 1, 124–31, January 2013, 23136837, 10.1111/jth.12060, 22306721, free, Other studies have found oral estradiol to be associated with an increase in risk of VTE similarly ({{abbrlink|RR|Relative risk}} = 3.5 in one, {{abbrlink|OR|odds ratio}} = 3.54 in first year of use in another).JOURNAL, Høibraaten E, Abdelnoor M, Sandset PM, Hormone replacement therapy with estradiol and risk of venous thromboembolism—a population-based case-control study, Thromb. Haemost., 82, 4, 1218–21, October 1999, 10544901, 10.1055/s-0037-1614363, 37238717, As of present, there are no randomized 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. 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.JOURNAL, Mohammed K, Abu Dabrh AM, Benkhadra K, Al Nofal A, Carranza Leon BG, Prokop LJ, Montori VM, Faubion SS, Murad MH, Oral vs Transdermal Estrogen Therapy and Vascular Events: A Systematic Review and Meta-Analysis, J. Clin. Endocrinol. Metab., 100, 11, 4012–20, 2015, 26544651, 10.1210/jc.2015-2237, free, 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 ({{abbr|OR|odds ratio}} = 4.03 and 4.24, respectively).JOURNAL, Heit JA, Spencer FA, White RH, The epidemiology of venous thromboembolism, J. Thromb. Thrombolysis, 41, 1, 3–14, 2016, 26780736, 4715842, 10.1007/s11239-015-1311-6, The risk of VTE during the postpartum period is 5-fold higher than during pregnancy. 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.WEB,www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-updated-information-about-risk-blood-clots-women-taking-birth-control, FDA Drug Safety Communication: Updated information about the risk of blood clots in women taking birth control pills containing drospirenone, Food and Drug Administration,web.archive.org/web/20190427143241/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-updated-information-about-risk-blood-clots-women-taking-birth-control, 27 April 2019, For birth control pills, VTE risk with high doses of ethinylestradiol (>50 Î¼g, e.g., 100 to 150 Î¼g) has been reported to be approximately twice that of low doses of ethinylestradiol (e.g., 20 to 50 Î¼g).JOURNAL, Gialeraki A, Valsami S, Pittaras T, Panayiotakopoulos G, Politou M, Oral Contraceptives and HRT Risk of Thrombosis, Clin. Appl. Thromb. Hemost., 24, 2, 217–225, 2018, 28049361, 6714678, 10.1177/1076029616683802, As such, high doses of ethinylestradiol are no longer used in combined oral contraceptives, and all modern combined oral contraceptives contain 50 Î¼g ethinylestradiol or less.BOOK, Pramilla Senanayake, Malcolm Potts, Atlas of Contraception, Second Edition,books.google.com/books?id=7dDKBQAAQBAJ&pg=PA44, 14 April 2008, CRC Press, 978-0-203-34732-4, 44–, BOOK, Shlomo Melmed, Williams Textbook of Endocrinology,books.google.com/books?id=YZ8_CwAAQBAJ&pg=PA665, 2016, Elsevier Health Sciences, 978-0-323-29738-7, 665–, The absolute risk of VTE in pregnancy is about 0.5 to 2 in 1,000 (0.125%).JOURNAL, Ralli E, Zezza L, Caserta D, Pregnancy and venous thromboembolism, Curr. Opin. Obstet. Gynecol., 26, 6, 469–75, 2014, 25304605, 10.1097/GCO.0000000000000115, 30535761,dx.doi.org/10.1097%2FGCO.0000000000000115, subscription, 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, and smoking.JOURNAL, Davey DA, Menopausal hormone therapy: a better and safer future, Climacteric, 21, 5, 454–461, March 2018, 29526116, 10.1080/13697137.2018.1439915, 3850275, The combination of oral estrogen and a progestogen has been found to double the risk of VTE relative to oral estrogen alone ({{abbrlink|RR|Relative risk}} = 2.05 for estrogen monotherapy, and {{abbrlink|RR|relative risk}} = 2.02 for combined estrogen–progestogen therapy in comparison). 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 progestin dydrogesterone.JOURNAL, Stevenson JC, Panay N, Pexman-Fieth C, Oral estradiol and dydrogesterone combination therapy in postmenopausal women: review of efficacy and safety, Maturitas, 76, 1, 10–21, September 2013, 23835005, 10.1016/j.maturitas.2013.05.018, Dydrogesterone did not increase the risk of VTE associated with oral estrogen (odds ratio (OR) 0.9, 95% CI 0.4–2.3). Other progestogens (OR 3.9, 95% CI 1.5–10.0) were found to further increase the risk of VTE associated with oral estrogen (OR 4.2, 95% CI 1.5–11.6)., JOURNAL, Schneider C, Jick SS, Meier CR, Risk of cardiovascular outcomes in users of estradiol/dydrogesterone or other HRT preparations, Climacteric, 12, 5, 445–53, October 2009, 19565370, 10.1080/13697130902780853, 45890629, The adjusted relative risk of developing a VTE tended to be lower for E/D users (OR 0.84; 95% CI 0.37–1.92) than for users of other HRT (OR 1.42; 95% CI 1.10–1.82), compared to non-users., 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). The risk of VTE and other cardiovascular complications with oral estrogen–progestogen therapy increases dramatically with age. 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, {{abbr|RR|relative risk}} = 2.27; age 60 to 69, {{abbr|RR|relative risk}} = 4.28; and age 70 to 79, {{abbr|RR|relative risk}} = 7.46. 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, {{abbr|RR|relative risk}} = 1.22; age 60 to 69, {{abbr|RR|relative risk}} = 1.3; and age 70 to 79, {{abbr|RR|relative risk}} = 1.44. In addition to menopausal hormone therapy, cardiovascular mortality has been found to increase considerably with age in women taking ethinylestradiol-containing combined oral contraceptives and in pregnant women.JOURNAL, Schwingl PJ, Ory HW, Visness CM, Estimates of the risk of cardiovascular death attributable to low-dose oral contraceptives in the United States, Am. J. Obstet. Gynecol., 180, 1 Pt 1, 241–9, January 1999, 9914611, 10.1016/S0002-9378(99)70182-1, BOOK, Kenneth L. Becker, Principles and Practice of Endocrinology and Metabolism,books.google.com/books?id=FVfzRvaucq8C&pg=PA1027, 2001, Lippincott Williams & Wilkins, 978-0-7817-1750-2, 1027–, In addition, smoking has been found to exponentially increase cardiovascular mortality in conjunction with combined oral contraceptive use and older age. 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. 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.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 of blood lipids and can have beneficial effects on the cardiovascular system. With oral estradiol, there are increases in circulating triglycerides, HDL cholesterol, apolipoprotein A1, and apolipoprotein A2, and decreases in total cholesterol, LDL cholesterol, apolipoprotein B, and lipoprotein(a). Transdermal estradiol has less-pronounced effects on these proteins and, in contrast to oral estradiol, reduces triglycerides. Through these effects, both oral and transdermal estrogens can protect against atherosclerosis and coronary heart disease in menopausal women with intact arterial endothelium that is without severe lesions.Approximately 95% of orally ingested estradiol is inactivated during first-pass metabolism.JOURNAL, De Leo V, Musacchio MC, Cappelli V, Piomboni P, Morgante G, Hormonal contraceptives: pharmacology tailored to women’s health, Hum. Reprod. Update, 22, 5, 634–46, 2016, 27307386, 10.1093/humupd/dmw016, free, 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.BOOK, Marc A. Fritz, Leon Speroff, Clinical Gynecologic Endocrinology and Infertility,books.google.com/books?id=KZLubBxJEwEC&pg=PA753, 28 March 2012, Lippincott Williams & Wilkins, 978-1-4511-4847-3, 753–, This does not occur with parenteral routes of estradiol, such as transdermal, vaginal, or injection. In contrast to estradiol, ethinylestradiol is much more resistant to hepatic metabolism, with a mean oral bioavailability of approximately 45%,JOURNAL, Stanczyk FZ, Archer DF, Bhavnani BR, Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment, Contraception, 87, 6, 706–27, 2013, 23375353, 10.1016/j.contraception.2012.12.011, and the transdermal route has a similar impact on hepatic protein synthesis as the oral route.BOOK, Rogerio A. Lobo, Treatment of the Postmenopausal Woman: Basic and Clinical Aspects,books.google.com/books?id=gywV9hkcyOMC&pg=PA770, 5 June 2007, Academic Press, 978-0-08-055309-2, 177, 770–771, 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. These differences are considered to be responsible for the greater risk of cardiovascular events with ethinylestradiol and conjugated estrogens relative to estradiol.High-dosage oral synthetic estrogens like diethylstilbestrol and ethinylestradiol are associated with fairly high rates of severe cardiovascular complications.JOURNAL, Turo R, Smolski M, Esler R, Kujawa ML, Bromage SJ, Oakley N, Adeyoju A, Brown SC, Brough R, Sinclair A, Collins GN, Diethylstilboestrol for the treatment of prostate cancer: past, present and future, Scand J Urol, 48, 1, 4–14, February 2014, 24256023, 10.3109/21681805.2013.861508, 34563641, JOURNAL, Phillips I, Shah SI, Duong T, Abel P, Langley RE, Androgen Deprivation Therapy and the Re-emergence of Parenteral Estrogen in Prostate Cancer, Oncol Hematol Rev, 10, 1, 42–47, 2014, 24932461, 4052190, 10.17925/ohr.2014.10.1.42, 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. 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-fatal ischemic heart events and heart decompensation) has been observed with polyestradiol phosphate.BOOK, Waun Ki Hong, James F. Holland, Holland-Frei Cancer Medicine 8,books.google.com/books?id=R0FbhLsWHBEC&pg=PA753, 2010, PMPH-USA, 978-1-60795-014-1, 753–, JOURNAL, Russell N, Cheung A, Grossmann M, Estradiol for the mitigation of adverse effects of androgen deprivation therapy, Endocr. Relat. Cancer, 24, 8, R297–R313, August 2017, 28667081, 10.1530/ERC-17-0153, free, Sex hormone-binding globulin (SHBG) levels indicate hepatic estrogenic exposure and may be a surrogate marker for coagulation and VTE risk with estrogen therapy, although this topic has been debated.JOURNAL, Odlind V, Milsom I, Persson I, Victor A, Can changes in sex hormone binding globulin predict the risk of venous thromboembolism with combined oral contraceptive pills?, Acta Obstet Gynecol Scand, 81, 6, 482–90, June 2002, 12047300, 10.1034/j.1600-0412.2002.810603.x, 26054257, free, JOURNAL, Raps M, Helmerhorst F, Fleischer K, Thomassen S, Rosendaal F, Rosing J, Ballieux B, VAN Vliet H, Sex hormone-binding globulin as a marker for the thrombotic risk of hormonal contraceptives, J. Thromb. Haemost., 10, 6, 992–7, June 2012, 22469296, 10.1111/j.1538-7836.2012.04720.x, 20803995, free, JOURNAL, Stanczyk FZ, Grimes DA, Sex hormone-binding globulin: not a surrogate marker for venous thromboembolism in women using oral contraceptives, Contraception, 78, 3, 201–3, September 2008, 18692609, 10.1016/j.contraception.2008.04.004, SHBG levels with birth control pills containing different progestins are increased by 1.5 to 2-fold with levonorgestrel, 2.5- to 4-fold with desogestrel and gestodene, 3.5- to 4-fold with drospirenone and dienogest, and 4- to 5-fold with cyproterone acetate. Contraceptive vaginal rings and contraceptive patches likewise have been found to increase SHBG levels by 2.5-fold and 3.5-fold, respectively. Birth control pills containing high doses of ethinylestradiol (>50 Î¼g) can increase SHBG levels by 5- to 10-fold, which is similar to the increase that occurs during pregnancy.BOOK, Stephen J. Winters, Ilpo T. Huhtaniemi, Male Hypogonadism: Basic, Clinical and Therapeutic Principles,books.google.com/books?id=UFi-DgAAQBAJ&pg=PA307, 25 April 2017, Humana Press, 978-3-319-53298-1, 307–, Conversely, increases in SHBG levels are much lower with estradiol, especially when used parenterally.JOURNAL, Notelovitz M, Clinical opinion: the biologic and pharmacologic principles of estrogen therapy for symptomatic menopause, MedGenMed, 8, 1, 85, March 2006, 16915215, 1682006, JOURNAL, Goodman MP, Are all estrogens created equal? A review of oral vs. transdermal therapy, J Womens Health (Larchmt), 21, 2, 161–9, February 2012, 22011208, 10.1089/jwh.2011.2839, JOURNAL, Stege R, Carlström K, Collste L, Eriksson A, Henriksson P, Pousette A, Single drug polyestradiol phosphate therapy in prostatic cancer, Am. J. Clin. Oncol., 11, Suppl 2, S101–3, 1988, 3242384, 10.1097/00000421-198801102-00024, 32650111, JOURNAL, von Schoultz B, Carlström K, Collste L, Eriksson A, Henriksson P, Pousette A, Stege R, Estrogen therapy and liver function--metabolic effects of oral and parenteral administration, Prostate, 14, 4, 389–95, 1989, 2664738, 10.1002/pros.2990140410, 21510744, JOURNAL, Ottosson UB, Carlström K, Johansson BG, von Schoultz B, Estrogen induction of liver proteins and high-density lipoprotein cholesterol: comparison between estradiol valerate and ethinyl estradiol, Gynecol. Obstet. Invest., 22, 4, 198–205, 1986, 3817605, 10.1159/000298914, High-dose parenteral polyestradiol phosphate therapy has been found to increase SHBG levels by about 1.5-fold.{{Risk of venous thromboembolism with hormone therapy and birth control pills (QResearch/CPRD)}}{{Venous thromboembolism incidence during pregnancy and the postpartum period}}

Breast cancer

Estrogens are responsible for breast development and, in relation to this, are strongly implicated in the development of breast cancer.JOURNAL, Russo J, Russo IH, The role of estrogen in the initiation of breast cancer, J. Steroid Biochem. Mol. Biol., 102, 1–5, 89–96, 2006, 17113977, 1832080, 10.1016/j.jsbmb.2006.09.004, JOURNAL, Germain D, Estrogen carcinogenesis in breast cancer, Endocrinol. Metab. Clin. North Am., 40, 3, 473–84, vii, 2011, 21889715, 10.1016/j.ecl.2011.05.009, In addition, estrogens stimulate the growth and accelerate the progression of ER-positive breast cancer.JOURNAL, Jameera Begam A, Jubie S, Nanjan MJ, Estrogen receptor agonists/antagonists in breast cancer therapy: A critical review, Bioorg. Chem., 71, 257–274, 2017, 28274582, 10.1016/j.bioorg.2017.02.011, JOURNAL, Yip CH, Rhodes A, 22988559, Estrogen and progesterone receptors in breast cancer, Future Oncol, 10, 14, 2293–301, 2014, 25471040, 10.2217/fon.14.110, In accordance, antiestrogens like the selective estrogen receptor modulator (SERM) tamoxifen, the ER antagonist fulvestrant, and the aromatase inhibitors (AIs) anastrozole and exemestane are all effective in the treatment of ER-positive breast cancer.JOURNAL, Schiavon G, Smith IE, Endocrine therapy for advanced/metastatic breast cancer, Hematol. Oncol. Clin. North Am., 27, 4, 715–36, viii, 2013, 23915741, 10.1016/j.hoc.2013.05.004, JOURNAL, Lumachi F, Santeufemia DA, Basso SM, Current medical treatment of estrogen receptor-positive breast cancer, World J Biol Chem, 6, 3, 231–9, 2015, 26322178, 4549764, 10.4331/wjbc.v6.i3.231, free, JOURNAL, Lee CI, Goodwin A, Wilcken N, Fulvestrant for hormone-sensitive metastatic breast cancer, Cochrane Database Syst Rev, 1, CD011093, 2017, 1, 28043088, 6464820, 10.1002/14651858.CD011093.pub2, Antiestrogens are also effective in the prevention of breast cancer.JOURNAL, Mallick S, Benson R, Julka PK, Breast cancer prevention with anti-estrogens: review of the current evidence and future directions, Breast Cancer, 23, 2, 170–7, 2016, 26439380, 10.1007/s12282-015-0647-2, 37377540, JOURNAL, Li F, Dou J, Wei L, Li S, Liu J, The selective estrogen receptor modulators in breast cancer prevention, Cancer Chemother. Pharmacol., 77, 5, 895–903, 2016, 26787504, 10.1007/s00280-016-2959-0, 24240700, JOURNAL, Mocellin S, Pilati P, Briarava M, Nitti D, Breast Cancer Chemoprevention: A Network Meta-Analysis of Randomized Controlled Trials, J. Natl. Cancer Inst., 108, 2, djv318, 2016, 26582062, 10.1093/jnci/djv318, free, 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.JOURNAL, Coelingh Bennink HJ, Verhoeven C, Dutman AE, Thijssen J, The use of high-dose estrogens for the treatment of breast cancer, Maturitas, 95, 11–23, January 2017, 27889048, 10.1016/j.maturitas.2016.10.010, free, JOURNAL, Jordan VC, The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer, Endocr. Relat. Cancer, 22, 1, R1–31, 2015, 25339261, 4494663, 10.1530/ERC-14-0448, 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 undergo apoptosis, in contrast to lower concentrations of estrogens which stimulate their growth.A 2017 systematic review and meta-analysis of 14 studies assessed the risk of breast cancer in perimenopausal and postmenopausal women treated with estrogens for menopausal symptoms.JOURNAL, Yang Z, Hu Y, Zhang J, Xu L, Zeng R, Kang D, Estradiol therapy and breast cancer risk in perimenopausal and postmenopausal women: a systematic review and meta-analysis, Gynecol. Endocrinol., 33, 2, 87–92, 2017, 27898258, 10.1080/09513590.2016.1248932, 205631264, They found that treatment with estradiol only is not associated with an increased risk of breast cancer ({{abbrlink|OR|odds ratio}} = 0.90 in {{abbrlink|RCTs|randomized controlled trials}} and {{abbr|OR|odds ratio}} = 1.11 in observational studies). This was in accordance with a previous analysis of estrogen-only treatment with estradiol or conjugated estrogens which similarly found no increased risk ({{abbr|RR|relative risk}} = 0.99). Moreover, another study found that the risk of breast cancer with estradiol and conjugated estrogens was not significantly different ({{abbr|RR|relative risk}} = 1.15 for conjugated estrogens versus estradiol). These findings are paradoxical because oophorectomy in premenopausal women and antiestrogen therapy in postmenopausal women are well-established as considerably reducing the risk of breast cancer ({{abbr|RR|relative risk}} = 0.208 to 0.708 for chemoprevention with antiestrogens in postmenopausal women). 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.JOURNAL, Pike MC, Wu AH, Spicer DV, Lee S, Pearce CL, Estrogens, progestins, and risk of breast cancer, Ernst Schering Found Symp Proc, 2007/1, 1, 127–50, 2007, 18540571, 10.1007/2789_2007_059, Ernst Schering Foundation Symposium Proceedings, 978-3-540-73492-5, There are also indications that the fluctuations in estrogen levels across the normal menstrual cycle in premenopausal women may be important for breast cancer risk.JOURNAL, Atashgaran V, Wrin J, Barry SC, Dasari P, Ingman WV, Dissecting the Biology of Menstrual Cycle-Associated Breast Cancer Risk, Front Oncol, 6, 267, 2016, 28083513, 5183603, 10.3389/fonc.2016.00267, free, 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.JOURNAL, Lambrinoudaki I, Progestogens in postmenopausal hormone therapy and the risk of breast cancer, Maturitas, 77, 4, 311–7, 2014, 24485796, 10.1016/j.maturitas.2014.01.001, The increase in risk is dependent on the duration of treatment, with more than five years ({{abbr|OR|odds ratio}} = 2.43) having a significantly greater risk than less than five years ({{abbr|OR|odds ratio}} = 1.49). In addition, sequential estrogen–progestogen treatment ({{abbr|OR|odds ratio}} = 1.76) is associated with a lower risk increase than continuous treatment ({{abbr|OR|odds ratio}} = 2.90), which has a comparably much higher risk. The increase in risk also differs according to the specific progestogen used. Treatment with estradiol plus medroxyprogesterone acetate ({{abbr|OR|odds ratio}} = 1.19), norethisterone acetate ({{abbr|OR|odds ratio}} = 1.44), levonorgestrel ({{abbr|OR|odds ratio}} = 1.47), or a mixed progestogen subgroup ({{abbr|OR|odds ratio}} = 1.99) were all associated with an increased risk. In a previous review, the increase in breast cancer risk was found to not be significantly different between these three progestogens. Conversely, there is no significant increase in risk of breast cancer with bioidentical progesterone ({{abbr|OR|odds ratio}} = 1.00) or with the atypical progestin dydrogesterone ({{abbr|OR|odds ratio}} = 1.10). In accordance, another study found similarly that the risk of breast cancer was not significantly increased with estrogen–progesterone ({{abbrlink|RR|relative risk}} = 1.00) or estrogen–dydrogesterone ({{abbr|RR|relative risk}} = 1.16) but was increased for estrogen combined with other progestins ({{abbr|RR|relative risk}} = 1.69). These progestins included chlormadinone acetate, cyproterone acetate, medrogestone, medroxyprogesterone acetate, nomegestrol acetate, norethisterone acetate, and promegestone, with the associations for breast cancer risk not differing significantly between the different progestins in this group.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.JOURNAL, Hembree WC, Cohen-Kettenis P, Delemarre-van de Waal HA, Gooren LJ, Meyer WJ, Spack NP, Tangpricha V, Montori VM, Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline, J. Clin. Endocrinol. Metab., 94, 9, 3132–54, 2009, 19509099, 10.1210/jc.2009-0345, free, 20486653, JOURNAL, Gooren LJ, van Trotsenburg MA, Giltay EJ, van Diest PJ, Breast cancer development in transsexual subjects receiving cross-sex hormone treatment, J Sex Med, 10, 12, 3129–34, 2013, 24010586, 10.1111/jsm.12319, JOURNAL, Brown GR, Jones KT, Incidence of breast cancer in a cohort of 5,135 transgender veterans, Breast Cancer Res. Treat., 149, 1, 191–8, 2015, 25428790, 10.1007/s10549-014-3213-2, 10935304,www.researchgate.net/publication/268877998, JOURNAL, Cuhaci N, Polat SB, Evranos B, Ersoy R, Cakir B, Gynecomastia: Clinical evaluation and management, Indian J Endocrinol Metab, 18, 2, 150–8, 2014, 24741509, 3987263, 10.4103/2230-8210.129104, free, Likewise, breast cancer has never been reported in women with complete androgen insensitivity syndrome, who similarly have a male genotype (46,XY), in spite of the fact that these women have well-developed breasts.BOOK, Shlomo Melmed, Kenneth S. Polonsky, P. Reed Larsen, Henry M. Kronenberg, Williams Textbook of Endocrinology,books.google.com/books?id=YZ8_CwAAQBAJ&pg=PA934, 30 November 2015, Elsevier Health Sciences, 978-0-323-29738-7, 934–, JOURNAL, Hughes IA, Werner R, Bunch T, Hiort O, Androgen insensitivity syndrome, Semin. Reprod. Med., 30, 5, 432–42, 2012, 23044881, 10.1055/s-0032-1324728, 33580939, The reasons for these differences are unknown. However, the dramatically increased risk of breast cancer (20- to 58-fold) in men with Klinefelter’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 the sex chromosomes.JOURNAL, Niewoehner CB, Schorer AE, Gynaecomastia and breast cancer in men, BMJ, 336, 7646, 709–13, 2008, 18369226, 2276281, 10.1136/bmj.39511.493391.BE, BOOK, Christopher Li, Breast Cancer Epidemiology,books.google.com/books?id=m3MtuTKbkbUC&pg=PA266, 11 November 2009, Springer Science & Business Media, 978-1-4419-0685-4, 266–, {{Worldwide epidemiological evidence on breast cancer risk with menopausal hormone therapy}}{{Risk of breast cancer with menopausal hormone therapy in large observational studies}}{{Risk of breast cancer with menopausal hormone therapy by duration in large observational studies}}

Cholestatic hepatotoxicity

Estrogens, along with progesterone, can rarely cause cholestatic hepatotoxicity, particularly at very high concentrations.JOURNAL, Chen J, Zhao KN, Liu GB, Estrogen-induced cholestasis: pathogenesis and therapeuticimplications, Hepatogastroenterology, 60, 126, 1289–96, 2013, 23933920, 10.5754/hge121061, 29 March 2024, 0172-6390, JOURNAL, Chitturi S, Farrell GC, Drug-induced cholestasis, Semin. Gastrointest. Dis., 12, 2, 113–24, 2001, 11352118, JOURNAL, Velayudham LS, Farrell GC, Drug-induced cholestasis, Expert Opin Drug Saf, 2, 3, 287–304, 2003, 12904107, 10.1517/eods.2.3.287.21377, This is seen in intrahepatic cholestasis of pregnancy, which occurs in 0.4 to 15% of pregnancies (highly variable depending on the country).JOURNAL, Arrese M, Reyes H, Intrahepatic cholestasis of pregnancy: a past and present riddle, Ann Hepatol, 5, 3, 202–5, 2006, 17060884, 10.1016/S1665-2681(19)32012-5, free, JOURNAL, Pusl T, Beuers U, Intrahepatic cholestasis of pregnancy, Orphanet J Rare Dis, 2, 26, 2007, 17535422, 1891276, 10.1186/1750-1172-2-26, free, JOURNAL, Arrese M, Macias RI, Briz O, Perez MJ, Marin JJ, Molecular pathogenesis of intrahepatic cholestasis of pregnancy, Expert Rev Mol Med, 10, e9, 2008, 18371245, 10.1017/S1462399408000628, 39759941, JOURNAL, Pauli-Magnus C, Meier PJ, Stieger B, Genetic determinants of drug-induced cholestasis and intrahepatic cholestasis of pregnancy, Semin. Liver Dis., 30, 2, 147–59, 2010, 20422497, 10.1055/s-0030-1253224, 260312828,www.zora.uzh.ch/id/eprint/33976/1/Stieger_2010_ReviewCPM_final19JAN.pdf, 4 November 2018, 15 May 2022,web.archive.org/web/20220515002113/https://www.zora.uzh.ch/id/eprint/33976/1/Stieger_2010_ReviewCPM_final19JAN.pdf, dead,

Gallbladder disease

Estrogen therapy has been associated with gallbladder disease, including risk of gallstone formation.JOURNAL, Uhler ML, Marks JW, Judd HL, Estrogen replacement therapy and gallbladder disease in postmenopausal women, Menopause, 7, 3, 162–7, 2000, 10810961, 10.1097/00042192-200007030-00006, 37022601, JOURNAL, Dhiman RK, Chawla YK, Is there a link between oestrogen therapy and gallbladder disease?, Expert Opin Drug Saf, 5, 1, 117–29, 2006, 16370961, 10.1517/14740338.5.1.117, 2173767, JOURNAL, Wang HH, Liu M, Clegg DJ, Portincasa P, Wang DQ, New insights into the molecular mechanisms underlying effects of estrogen on cholesterol gallstone formation, Biochim. Biophys. Acta, 1791, 11, 1037–47, 2009, 19589396, 2756670, 10.1016/j.bbalip.2009.06.006, JOURNAL, Wang S, Wang Y, Xu J, Chen Y, Is the oral contraceptive or hormone replacement therapy a risk factor for cholelithiasis: A systematic review and meta-analysis, Medicine (Baltimore), 96, 14, e6556, 2017, 28383429, 5411213, 10.1097/MD.0000000000006556, A 2017 systematic review and meta-analysis found that menopausal hormone therapy significantly increased the risk of gallstones ({{abbr|RR|relative risk}} = 1.79) while oral contraceptives did not significantly increase the risk ({{abbr|RR|relative risk}} = 1.19). Biliary sludge appears in 5 to 30% of women during pregnancy, and definitive gallstones persisting postpartum become established in approximately 5%.JOURNAL, Stinton LM, Shaffer EA, Epidemiology of gallbladder disease: cholelithiasis and cancer, Gut Liver, 6, 2, 172–87, 2012, 22570746, 3343155, 10.5009/gnl.2012.6.2.172,

Overdose

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

Interactions

Inducers of cytochrome P450 enzymes like carbamazepine and phenytoin can accelerate the metabolism of estrogens and thereby decrease their bioavailability and circulating levels. Inhibitors of such enzymes can have the opposite effect and can increase estrogen levels and bioavailability.

Pharmacology

Pharmacodynamics

{{See also|Estrogen#Biological activity|Pharmacodynamics of estradiol}}Estrogens act as selective agonists of the estrogen receptors (ERs), the ERα and the ERβ. They may also bind to and activate membrane estrogen receptors (mERs) such as the GPER. Estrogens do not have off-target activity at other steroid hormone receptors such as the androgen, progesterone, glucocorticoid, or mineralocorticoid receptors, nor do they have neurosteroid activity by interacting with neurotransmitter receptors, unlike various progestogens and some other steroids. Given by subcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol.BOOK, A. Labhart, Clinical Endocrinology: Theory and Practice,books.google.com/books?id=DAgJCAAAQBAJ&pg=PA548, 6 December 2012, Springer Science & Business Media, 978-3-642-96158-8, 548–, Estrogens have antigonadotropic effects at sufficiently high concentrations via activation of the ER and hence can suppress the hypothalamic–pituitary–gonadal axis. This is caused by negative feedback, resulting in a suppression in secretion and decreased circulating levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The antigonadotropic effects of estrogens interfere with fertility and gonadal sex hormone production. They are responsible for the hormonal contraceptive effects of estrogens. In addition, they allow estrogens to act as functional antiandrogens by suppressing gonadal testosterone production. At sufficiently high doses, estrogens are able to suppress testosterone levels into the castrate range in men.JOURNAL, Scott WW, Menon M, Walsh PC, Hormonal Therapy of Prostatic Cancer, Cancer, 45, Suppl 7, 1929–1936, April 1980, 29603164, 10.1002/cncr.1980.45.s7.1929, 4492779, free, Estrogens differ significantly in their pharmacological properties.JOURNAL, Ansbacher R, The pharmacokinetics and efficacy of different estrogens are not equivalent, Am. J. Obstet. Gynecol., 184, 3, 255–63, February 2001, 11228470, 10.1067/mob.2001.109656, JOURNAL, Bennink HJ, Reprint of Are all estrogens the same?, Maturitas, 61, 1–2, 195–201, 2008, 19434891, 10.1016/j.maturitas.2008.11.015, For instance, due to structural differences and accompanying differences in metabolism, estrogens differ from one another in their tissue selectivity; synthetic estrogens like ethinylestradiol and diethylstilbestrol are not inactivated as efficiently as estradiol in tissues like the liver and uterus and as a result have disproportionate effects in these tissues. This can result in issues such as a relatively higher risk of thromboembolism.In-vitro pharmacodynamics“>

In-vitro pharmacodynamics

{{Affinities of estrogen receptor ligands for the ERα and ERβ}}{{Relative affinities of estrogens for steroid hormone receptors and blood proteins}}{{Affinities and estrogenic potencies of estrogen esters and ethers at the estrogen receptors}}In-vivo pharmacodynamics“>

In-vivo pharmacodynamics

{{Selected biological properties of endogenous estrogens in rats}}{{Oral potencies of estrogens}}{{Relative oral potencies of estrogens}}{{Parenteral potencies and durations of steroidal estrogens}}{{Parenteral potencies and durations of nonsteroidal estrogens}}{{Classification of estrogens and antiestrogens after a single injection}}

Pharmacokinetics

{{See also|Pharmacokinetics of estradiol}}Estrogens can be administered via a variety of routes, including by mouth, sublingual, transdermal/topical (gel, patch), vaginal (gel, tablet, ring), rectal, intramuscular, subcutaneous, intravenous, and subcutaneous implant. Natural estrogens generally have low oral bioavailability while synthetic estrogens have higher bioavailability. Parenteral routes have higher bioavailability. Estrogens are typically bound to albumin and/or sex hormone-binding globulin in the circulation. They are metabolized in the liver by hydroxylation (via cytochrome P450 enzymes), dehydrogenation (via 17β-hydroxysteroid dehydrogenase), and conjugation (via sulfation and glucuronidation). The elimination half-lives of estrogens vary by estrogen and route of administration. Estrogens are eliminated mainly by the kidneys via the urine as conjugates.{{Protein binding and metabolic clearance rates of estrogens}}{{Estradiol metabolism|header=Estrogen metabolism in humans}}

Chemistry

{{See also|List of estrogens}}{{Chemical structures of major endogenous estrogens medication version|align=right|caption=Note the hydroxyl (–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 are estranes and include estradiol and its analogues, such as ethinylestradiol and conjugated estrogens like equilin sulfate. Nonsteroidal estrogens belong predominantly to the stilbestrol group of compounds and include diethylstilbestrol and hexestrol, among others.Estrogen esters are esters and prodrugs of the corresponding parent estrogens. Examples include estradiol valerate and diethylstilbestrol dipropionate, which are prodrugs of estradiol and diethylstilbestrol, respectively. Estrogen esters with fatty acid esters have increased lipophilicity and a prolonged duration of action when administered by intramuscular or subcutaneous injection. Some estrogen esters, such as polyestradiol phosphate, polyestriol phosphate, and polydiethylstilbestrol phosphate, are in the form of polymers.{{Structural properties of major estradiol esters}} Discontinued or no longer marketed estrogens“>

History{| class“wikitable sortable floatright plainrowheaders” style@width: 35%;” Discontinued or no longer marketed estrogens

! scope=“col” style="width: 100px;” | Generic name! scope=“col” style="width: 30px;” | Class! scope=“col” style="width: 80px;” | Brand name! scope=“col” style="width: 30px;” | Route! scope=“col” style="width: 35px;” | {{abbr|Intr.|Originally introduced in}}! scope=“row” style="background:#f8f9fa;” | ChlorotrianiseneNSnonsteroidal estrogen>Non-steroidal}} Tace{{efnname=morePOOral administration>Oral}} 1952! scope=“row” style="background:#f8f9fa;” | Conjugated estriolSSteroidal estrogen>Steroidal}}/ester Emmenin{{efnname=more}} PO 1930! scope=“row” style="background:#f8f9fa;” | Diethylstilbestrol dipropionategroup=estrogens2| 1940s! scope=“row” style="background:#f8f9fa;” | Estradiol dipropionategroup=estrogens2| 1939! scope=“row” style="background:#f8f9fa;” | Estrogenic substancesgroup=estrogens2| 1929! scope=“row” style="background:#f8f9fa;” | Estronegroup=estrogens2| 1929! scope=“row” style="background:#f8f9fa;” | Ethinylestradiol sulfonategroup=estrogens2| 1978! scope=“row” style="background:#f8f9fa;” | Methallenestril| 1950s! scope=“row” style="background:#f8f9fa;” | Moxestrol| 1970s! scope=“row” style="background:#f8f9fa;” | Polyestriol phosphategroup=estrogens2| 1968! scope=“row” style="background:#f8f9fa;” | Quinestrol| 1960s class=“sortbottom”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.JOURNAL, Santen RJ, Simpson E, History of Estrogen: Its Purification, Structure, Synthesis, Biologic Actions, and Clinical Implications, Endocrinology, 160, 3, 605–625, March 2019, 30566601, 10.1210/en.2018-00529, free, JOURNAL, Fluhmann CF, Estrogenic Hormones: Their Clinical Usage, Cal West Med, 49, 5, 362–6, November 1938, 18744783, 1659459, In 1927, Selmar and Aschheim discovered that large amounts of estrogens were present in the urine of pregnant women.BOOK, J.B. Josimovich, Gynecologic Endocrinology,books.google.com/books?id=9vv2BwAAQBAJ&pg=PA8, 11 November 2013, Springer Science & Business Media, 978-1-4613-2157-6, 8–, BOOK, Enrique Ravina, The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs,books.google.com/books?id=iDNy0XxGqT8C&pg=PA175, 18 April 2011, John Wiley & Sons, 978-3-527-32669-3, 174–175, This rich source of estrogens, produced by the placenta, allowed for the development of potent estrogenic formulations for scientific and clinical use.BOOK, Vern L. Bullough, Science In The Bedroom: A History Of Sex Research,books.google.com/books?id=Z7__qJK470AC&pg=PA128, 19 May 1995, Basic Books, 978-0-465-07259-0, 128–, 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., {{Dead link|date=March 2024 |bot=InternetArchiveBot |fix-attempted=yes }} The first pharmaceutical estrogen product was a conjugated estriol called Progynon, a placental extract, and was introduced for medical use by the German pharmaceutical company Schering in 1928.BOOK, Vera Regitz-Zagrosek, Sex and Gender Differences in Pharmacology,books.google.com/books?id=J3VxihGDh9wC&pg=PA549, 2 October 2012, Springer Science & Business Media, 978-3-642-30725-6, 549–, The first sex steroid used as pharmacological agent was Progynon, first sold by Schering AG in 1928. [...], BOOK, Barbara Seaman, The Greatest Experiment Ever Performed on Women: Exploding the Estrogen Myth,books.google.com/books?id=HHm1qkcgFSUC&pg=PA22, 4 January 2011, Seven Stories Press, 978-1-60980-062-8, 22–, BOOK, Thom Rooke, The Quest for Cortisone,books.google.com/books?id=70vvFrtpePoC&pg=PT54, 1 January 2012, MSU Press, 978-1-60917-326-5, 54–, JOURNAL,www.jbc.org/content/87/2/357.short, The Preparation of the Crystalline Follicular Ovarian Hormone: Theelin, Journal of Biological Chemistry, 87, 2, 357–371, 1930, Doisy, Edward A., Thayer, Sidney, Veler, Clement D., 10.1016/S0021-9258(18)76871-3, free, BOOK, Christopher Kobrak, National Cultures and International Competition: The Experience of Schering AG, 1851-1950,books.google.com/books?id=Z3iTsU6_mHsC&pg=PA119, 7 October 2002, Cambridge University Press, 978-0-521-81481-2, 119–, JOURNAL, Streck, Arnulf, “Progynon“-Schering, ein Neues Zyklus-Hormonpräparat, Klinische Wochenschrift, 7, 25, 1928, 1172–1178, 0023-2173, 10.1007/BF01738283, 35945534, Batisweiler, J. (1928). Placentaextrakt Progynon (Schering-Kahlbaum) bei Menstruationsstörungen und Kastrationsfolgen. Zbl. Gynäk, 2227-2232.ChicagoBOOK, Stanley Alstead, Poulsson’s Text-Book of Pharmacology and Therapeutics,books.google.com/books?id=BRIlBQAAQBAJ&pg=PA195, 22 October 2013, Elsevier, 978-1-4832-2584-5, 195–, In 1929, Adolf Butenandt and Edward Adelbert Doisy independently isolated and purified estrone, the first estrogen to be discovered.JOURNAL, Tata JR, One hundred years of hormones, EMBO Reports, 6, 6, 490–6, 2005, 15940278, 10.1038/sj.embor.7400444, 1369102, The estrogen preparations Amniotin (Squibb), Progynon (Schering), and Theelin (Parke-Davis) were all on the market by 1929,JOURNAL, Wallach, Edward E., Hammond, Charles B., Maxson, Wayne S., Current status of estrogen therapy for the menopause, Fertility and Sterility, 37, 1, 1982, 5–25, 0015-0282, 10.1016/S0015-0282(16)45970-4, 6277697, and various additional preparations such as Emmenin, Folliculin, Menformon, Oestroform, and Progynon B, containing purified estrogens or mixtures of estrogens, were on the market by 1934.JOURNAL, Buschbeck, Herbert, Neue Wege der Hormontherapie in der Gynäkologie1, Deutsche Medizinische Wochenschrift, 60, 11, 2009, 389–393, 0012-0472, 10.1055/s-0028-1129842, 72668930, Estrogens were originally known under a variety of different names including estrogens, estrins, follicular hormones, folliculins, gynecogens, folliculoids, and female sex hormones, among others.JOURNAL, Reifenstein, Edward C., Endocrinology: A Synopsis of Normal and Pathologic Physiology, Diagnostic Procedures, and Therapy, Medical Clinics of North America, 28, 5, 1944, 1232–1276, 0025-7125, 10.1016/S0025-7125(16)36180-6, JOURNAL, The Nomenclature of Glandular Products, JAMA: The Journal of the American Medical Association, 103, 15, 1934, 1152, 0098-7484, 10.1001/jama.1934.02750410042012, An estrogen patch was reportedly marketed by Searle in 1928,JOURNAL, Stefanick ML, Estrogens and progestins: background and history, trends in use, and guidelines and regimens approved by the US Food and Drug Administration, Am. J. Med., 118, Suppl 12B, 64–73, December 2005, 16414329, 10.1016/j.amjmed.2005.09.059, free, JOURNAL, Barrett-Connor E, Clinical review 162: cardiovascular endocrinology 3: an epidemiologist looks at hormones and heart disease in women, J. Clin. Endocrinol. Metab., 88, 9, 4031–42, September 2003, 12970259, 10.1210/jc.2003-030876, free, and an estrogen nasal spray was studied by 1929.JOURNAL, Novak, Emil, The Therapeutic Use of Estrogenic Substances, JAMA: The Journal of the American Medical Association, 104, 20, 1935, 1815, 0098-7484, 10.1001/jama.1935.92760200002012, 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.WEB, Rothenberg, Carla J., The Rise and Fall of Estrogen Therapy: The History of HRT, 25 April 2005,leda.law.harvard.edu/leda/data/711/Rothenberg05.pdf, 27 October 2006,leda.law.harvard.edu/leda/data/711/Rothenberg05.pdf," title="web.archive.org/web/20060905132706leda.law.harvard.edu/leda/data/711/Rothenberg05.pdf,">web.archive.org/web/20060905132706leda.law.harvard.edu/leda/data/711/Rothenberg05.pdf, 5 September 2006, dead, 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.BOOK, Alison Li, J.B. Collip and the Development of Medical Research in Canada: Extracts and Enterprise,books.google.com/books?id=9J6Wj1ouzGwC&pg=PA115, 27 October 2003, McGill-Queen’s Press â€” MQUP, 978-0-7735-7145-7, 115–, Ethinylestradiol was synthesized in 1938 by Hans Herloff Inhoffen and Walter Hohlweg at Schering AG in BerlinJOURNAL, Inhoffen, H. H., Hohlweg, W., 10.1007/BF01681040, Neue per os-wirksame weibliche Keimdrüsenhormon-Derivate: 17-Aethinyl-oestradiol und Pregnen-in-on-3-ol-17 (New female glandular derivatives active per os: 17α-ethynyl-estradiol and pregnen-in-on-3-ol-17), Die Naturwissenschaften, Naturwissenschaften, 26, 6, 96, 1938, 1938NW.....26...96I, 46648877, BOOK, Maisel, Albert Q., 1965, The Hormone Quest,archive.org/details/hormonequest00mais, registration, New York, Random House, 543168, JOURNAL, Petrow, Vladimir, December 1970, The contraceptive progestagens, Chem Rev, 70, 6, 713–26, 4098492, 10.1021/cr60268a004, BOOK, Sneader, Walter, 2005, Drug discovery : a history, Hoboken, NJ, John Wiley & Sons, 0-471-89980-1, Hormone analogues, 188–225, JOURNAL, Djerassi, Carl, January 2006, Chemical birth of the pill, American Journal of Obstetrics and Gynecology, 194, 1, 290–8, 16389046, 10.1016/j.ajog.2005.06.010, and was approved by the {{abbrlink|FDA|Food and Drug Administration}} in the {{abbrlink|U.S.|United States}} on 25 June 1943 and marketed by Schering as Estinyl.WEB, FDA, 2007, Approval history: Estinyl (ethinyl estradiol) NDA 005292,www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=005292&DrugName=ESTINYL&ActiveIngred=ETHINYL%20ESTRADIOL&SponsorApplicant=SCHERING&ProductMktStatus=3&goto=Search.Label_ApprovalHistory, Food and Drug Administration, search: EstinylMicronized estradiol, via the oral route, was first evaluated in 1972,JOURNAL, Martin PL, Burnier AM, Greaney MO, Oral menopausal therapy using 17- micronized estradiol. A preliminary study of effectiveness, tolerance and patient preference, Obstet Gynecol, 39, 5, 771–4, 1972, 5023261,journals.lww.com/greenjournal/Abstract/1972/05000/Oral_Menopausal_Therapy_Using_17___Micronized.22.aspx, and this was followed by the evaluation of vaginal and intranasal micronized estradiol in 1977.JOURNAL, Rigg LA, Milanes B, Villanueva B, Yen SS, Efficacy of intravaginal and intranasal administration of micronized estradiol-17beta, J. Clin. Endocrinol. Metab., 45, 6, 1261–4, 1977, 591620, 10.1210/jcem-45-6-1261, free, Oral micronized estradiol was first approved in the United States under the brand name Estrace in 1975.WEB,www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=084499&DrugName=ESTRACE&ActiveIngred=ESTRADIOL&SponsorApplicant=BRISTOL%20MYERS%20SQUIBB&ProductMktStatus=3&goto=Search.DrugDetails, Drugs@FDA: FDA-Approved Drugs,

Society and culture

Availability

{{See also|List of estrogens available in the United States}}Estrogens are widely available throughout the world.BOOK, Sweetman, Sean C., Sex Hormones and their Modulators, Martindale: The Complete Drug Reference, 36th, 2009, Pharmaceutical Press, London, 978-0-85369-840-1,www.medicinescomplete.com/mc/martindale/2009/,

Research

Male birth control

High-dose estrogen therapy is effective in suppressing spermatogenesis and fertility in men, and hence as a male contraceptive.BOOK, Michael Oettel, Ekkehard Schillinger, Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen,books.google.com/books?id=wBvyCAAAQBAJ&pg=PA542, 6 December 2012, Springer Science & Business Media, 978-3-642-60107-1, 542–, BOOK, Anita H., Payne, Matthew P., Hardy, The Leydig Cell in Health and Disease,books.google.com/books?id=x4ttqKIAOg0C&pg=PA422, 28 October 2007, Springer Science & Business Media, 978-1-59745-453-7, 422–431, 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., It works both by strongly suppressing gonadotropin secretion and gonadal testosterone production and via direct effects on the testes. After a sufficient course of therapy, only Sertoli cells and spermatogonia remain in the seminiferous tubules of the testes, with a variety of other testicular abnormalities observable. The use of estrogens for contraception in men is precluded by major side effects such as sexual dysfunction, feminization, gynecomastia, and metabolic changes. In addition, there is evidence that with long-term therapy, fertility and gonadal sex hormone production in men may not return following discontinuation of high-dose estrogen therapy.BOOK, Muhammad A., Salam, Principles & Practice of Urology: A Comprehensive Text,books.google.com/books?id=y50kTcCCfEcC&pg=PA684, 2003, Universal-Publishers, 978-1-58112-412-5, 684–, 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.,

Eating disorders

Estrogen has been used as a treatment for women with bulimia nervosa, in addition to cognitive 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.WEB,ki.se/ki/jsp/polopoly.jsp?d=130&a=22684&l=en&newsdep=130, Bulimia May Result from Hormonal Imbalance, 4 March 2008, Andersson G, 9 January 2007, Karolinska Institutet, 20 February 2012,ki.se/ki/jsp/polopoly.jsp?d=130&a=22684&l=en&newsdep=130," title="web.archive.org/web/20120220102026ki.se/ki/jsp/polopoly.jsp?d=130&a=22684&l=en&newsdep=130,">web.archive.org/web/20120220102026ki.se/ki/jsp/polopoly.jsp?d=130&a=22684&l=en&newsdep=130, dead,

Miscellaneous

Estrogens have been used in studies which indicate that they may be effective in the treatment of traumatic liver injury.JOURNAL, Hsieh YC, Yu HP, Frink M, Suzuki T, Choudhry MA, Schwacha MG, Chaudry IH, G protein-coupled receptor 30-dependent protein kinase A pathway is critical in nongenomic effects of estrogen in attenuating liver injury after trauma-hemorrhage, Am. J. Pathol., 170, 4, 1210–8, 2007, 17392161, 10.2353/ajpath.2007.060883, 1829455, In humans and mice, estrogens promote wound healing.JOURNAL, Oh DM, Phillips, TJ, Sex Hormones and Wound Healing, Wounds, 18, 1, 8–18, 2006,www.woundsresearch.com/article/5190, Estrogen therapy has been proposed as a potential treatment for autism but clinical studies are needed.JOURNAL, Crider A, Pillai A, Estrogen Signaling as a Therapeutic Target in Neurodevelopmental Disorders, J Pharmacol Exp Ther, 360, 1, 48–58, January 2017, 27789681, 5193073, 10.1124/jpet.116.237412,

References

{{Reflist}}

Further reading

• BOOK, Alfred S. Wolf, H.P.G. Schneider, Östrogene in Diagnostik und Therapie,books.google.com/books?id=IArLBgAAQBAJ&pg=PR1, 12 March 2013, Springer-Verlag, 978-3-642-75101-1, 1–,
• JOURNAL, O’Connell MB, Pharmacokinetic and pharmacologic variation between different estrogen products, J Clin Pharmacol, 35, 9S, 18S–24S, September 1995, 8530713, 10.1002/j.1552-4604.1995.tb04143.x, 10159196,
• BOOK, Michael Oettel, Ekkehard Schillinger, Estrogens and Antiestrogens I: Physiology and Mechanisms of Action of Estrogens and Antiestrogens,books.google.com/books?id=0BfrCAAAQBAJ, 1999, Springer Science & Business Media, 978-3-642-58616-3,
• BOOK, Michael Oettel, Ekkehard Schillinger, Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen,books.google.com/books?id=wBvyCAAAQBAJ, 1999, Springer Science & Business Media, 978-3-642-60107-1,
• JOURNAL, Ruggiero RJ, Likis FE, Estrogen: physiology, pharmacology, and formulations for replacement therapy, J Midwifery Womens Health, 47, 3, 130–8, 2002, 12071379, 10.1016/S1526-9523(02)00233-7,
• JOURNAL, Kuhl H, Pharmacology of estrogens and progestogens: influence of different routes of administration, Climacteric, 8, Suppl 1, 3–63, 2005, 16112947, 10.1080/13697130500148875, 24616324,hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf,

External links

• {{MedlinePlusDrugInfo|medmaster|a682922}}

{{Estradiol}}{{Estrogens and antiestrogens}}{{Estrogen receptor modulators}}