Estrone Explained

Estrone (E1), also spelled oestrone, is a steroid, a weak estrogen, and a minor female sex hormone.[1] It is one of three major endogenous estrogens, the others being estradiol and estriol. Estrone, as well as the other estrogens, are synthesized from cholesterol and secreted mainly from the gonads, though they can also be formed from adrenal androgens in adipose tissue.[2] Relative to estradiol, both estrone and estriol have far weaker activity as estrogens. Estrone can be converted into estradiol, and serves mainly as a precursor or metabolic intermediate of estradiol. It is both a precursor and metabolite of estradiol.[3]

In addition to its role as a natural hormone, estrone has been used as a medication, for instance in menopausal hormone therapy; for information on estrone as a medication, see the estrone (medication) article.

Biological activity

Estrone is an estrogen, specifically an agonist of the estrogen receptors ERα and ERβ.[4] It is a far less potent estrogen than is estradiol, and as such, is a relatively weak estrogen.[5] Given by subcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol.[6] According to one study, the relative binding affinities of estrone for the human ERα and ERβ were 4.0% and 3.5% of those estradiol, respectively, and the relative transactivational capacities of estrone at the ERα and ERβ were 2.6% and 4.3% of those of estradiol, respectively. In accordance, the estrogenic activity of estrone has been reported to be approximately 4% of that of estradiol. In addition to its low estrogenic potency, estrone, unlike estradiol and estriol, is not accumulated in estrogen target tissues. Because estrone can be transformed into estradiol, most or all of the estrogenic potency of estrone in vivo is actually due to conversion into estradiol.[7] As such, estrone is considered to be a precursor or prohormone of estradiol.[8] In contrast to estradiol and estriol, estrone is not a ligand of the G protein-coupled estrogen receptor (affinity >10,000 nM).[9]

Clinical research has confirmed the nature of estrone as a relatively inert precursor of estradiol.[10] [11] [12] With oral administration of estradiol, the ratio of estradiol levels to estrone levels is about 5 times higher on average than under normal physiological circumstances in premenopausal women and with parenteral (non-oral) routes of estradiol. Oral administration of menopausal replacement dosages of estradiol results in low, follicular phase levels of estradiol, whereas estrone levels resemble the high levels seen during the first trimester of pregnancy.[13] [14] In spite of markedly elevated levels of estrone with oral estradiol but not with transdermal estradiol, clinical studies have shown that dosages of oral and transdermal estradiol achieving similar levels of estradiol possess equivalent and non-significantly different potency in terms of measures including suppression of luteinizing hormone and follicle-stimulating hormone levels, inhibition of bone resorption, and relief of menopausal symptoms such as hot flashes.[11] [12] [15] In addition, estradiol levels were found to correlate with these effects, while estrone levels did not. These findings confirm that estrone has very low estrogenic activity, and also indicate that estrone does not diminish the estrogenic activity of estradiol. This contradicts some cell-free in-vitro research suggesting that high concentrations of estrone might be able to partially antagonize the actions of estradiol.[16] [17] [18]

Biochemistry

Biosynthesis

Estrone is biosynthesized from cholesterol. The principal pathway involves androstenedione as an intermediate, with androstenedione being transformed into estrone by the enzyme aromatase. This reaction occurs in both the gonads and in certain other tissues, particularly adipose tissue, and estrone is subsequently secreted from these tissues. In addition to aromatization of androstenedione, estrone is also formed reversibly from estradiol by the enzyme 17β-hydroxysteroid dehydrogenase (17β-HSD) in various tissues, including the liver, uterus, and mammary gland.

Mechanism of Action:

The way estrone works is by entering the cells of certain tissues in the body and attaching to nuclear receptors. This interaction then influences how genes are expressed, leading to various physiological responses in the body.[19]

Distribution

Estrone is bound approximately 16% to sex hormone-binding globulin (SHBG) and 80% to albumin in the circulation, with the remainder (2.0 to 4.0%) circulating freely or unbound.[20] It has about 24% of the relative binding affinity of estradiol for SHBG. As such, estrone is relatively poorly bound to SHBG.[21]

Metabolism

Estrone is conjugated into estrogen conjugates such as estrone sulfate and estrone glucuronide by sulfotransferases and glucuronidases, and can also be hydroxylated by cytochrome P450 enzymes into catechol estrogens such as 2-hydroxyestrone and 4-hydroxyestrone or into estriol. Both of these transformations take place predominantly in the liver. Estrone can also be reversibly converted into estradiol by 17β-HSD. The blood half-life of estrone is about 10 to 70 minutes and is similar to that of estradiol.[22] [23]

Excretion

Estrone is excreted in urine in the form of estrogen conjugates such as estrone sulfate. Following an intravenous injection of labeled estrone in women, almost 90% is excreted in urine and feces within 4 to 5 days. Enterohepatic recirculation causes a delay in excretion of estrone.

It is one of the three primary types of estrogen and is produced in various parts of the body, including the placenta, ovaries, and peripheral tissues.[24]

Levels

Toxicity:

When estrone is used too much or taken in large amounts, it can cause toxicity, leading to symptoms like nausea and vomiting. Estrone should be stored in its original package or container to maintain its quality and effectiveness.

Chemistry

See also: List of estrogens.

Estrone, also known as estra-1,3,5(10)-trien-3-ol-17-one, is a naturally occurring estrane steroid with double bonds at the C1, C3, and C5 positions, a hydroxyl group at the C3 position, and a ketone group at the C17 position. The name estrone was derived from the chemical terms estrin (estra-1,3,5(10)-triene) and ketone.

The chemical formula of estrone is C18H22O2 and its molecular weight is 270.366 g/mol. It is a white, odorless, solid crystalline powder, with a melting point of 254.5 °C (490 °F) and a specific gravity of 1.23.[25] Estrone is combustible at high temperatures, with the products carbon monoxide (CO) and carbon dioxide (CO2).[26]

Medical use

See main article: Estrone (medication).

Estrone has been available as an injected estrogen for medical use, for instance in hormone therapy for menopausal symptoms, but it is now mostly no longer marketed.[27]

Estrone, as part of hormone replacement therapy (HRT), is frequently used to treat symptoms caused by estrogen deficiency in peri and post-menopausal women. This therapy aims to enhance overall health and relieve menopausal symptoms related to estrogen imbalance. Additionally, estrone and other estrogens are used to prevent osteoporosis in postmenopausal women who are at high risk of fractures and cannot tolerate alternative medications. Estrogens are absorbed efficiently by the body and subsequently inactivated in the liver, making them effective in HRT and osteoporosis prevention.

Contraindications

The use of estrone has several contraindications, some examples including: hypersensitivity, history of some cancers, stroke, venous thromboembolism (VTE), and those currently pregnant or breastfeeding. Estrogens hold a boxed warning to be used at the lowest effective dose and for the shortest possible treatment period if used alone or with another hormone in the progestogen class.

Breast Cancer

Estrone is contraindicated for those that have or are suspected of having breast cancer. The use of estrogens hold a boxed warning with breast cancer for post-menopausal women as this can increase the risk of developing invasive breast cancer.[28] Those with breast cancer become at a greater risk of hypercalcemia and bone metastases when taking estrogens.[29] Post-menopausal women with breast cancer can be seen to develop frailty syndrome when there are changes in blood hormonal levels, including an increased level of estrone. Estrone, the major type of estrogen produced in post-menopausal women, was seen in greater concentrations from standard levels in those that were categorized as prefrail and in those that classified as frail.[30]

Venous Thromboembolism

The risk of VTE is increased in those that use estrogens, those that currently have or have a history with VTE are at a greater risk of reoccurring VTE with the usage of estrogens.[31] The use of estrogens within three weeks postpartum may increase the risk of developing a VTE. Risk of developing initial VTE is also increased with familial history, genetic mutations: factor V Leiden and prothrombin-G20210A, and pregnancy-postpartum with the use of estrogens.[32]

Breastfeeding

The use of estrogens may affect the ability to breastfeed and can change the composition of breastmilk. Estrogens have been used to suppress lactation which can result in a reduced total duration of lactation and reduced volume or inability to produce breastmilk. Composition of breastmilk produced was also seen to be different resulting in a reduced concentration of proteins in the milk. Babies of mothers that were taking estrogens while breastfeeding were seen to experience slower weight gain.

Side effects

Common

Some common side effects seen with the usage of estrogens include: breast swelling, breast tenderness, vaginal itching, abnormal uterine bleeding, weight gain, hair loss, jaundice, and anaphylaxis.[33]

Adverse effect

Some adverse effects seen with the usage of estrogens include: increased risk of venous thromboembolism (VTE), stroke, breast cancer, hypertension, and vaginitis.[34]

History

Estrone was the first steroid hormone to be discovered.[35] [36] It was discovered in 1929 independently by the American scientists Edward Doisy and Edgar Allen and the German biochemist Adolf Butenandt, although Doisy and Allen isolated it two months before Butenandt.[37] [38] They isolated and purified estrone in crystalline form from the urine of pregnant women.[39] Doisy and Allen named it theelin, while Butenandt named it progynon and subsequently referred to it as folliculin in his second publication on the substance.[40] Butenandt was later awarded the Nobel Prize in 1939 for the isolation of estrone and his work on sex hormones in general.[41] The molecular formula of estrone was known by 1931,[42] and its chemical structure had been determined by Butenandt by 1932. Following the elucidation of its structure, estrone was additionally referred to as ketohydroxyestrin or oxohydroxyestrin,[43] [44] and the name estrone, on the basis of its C17 ketone group, was formally established in 1932 at the first meeting of the International Conference on the Standardization of Sex Hormones in London.[45] [46]

A partial synthesis of estrone from ergosterol was accomplished by Russell Earl Marker in 1936, and was the first chemical synthesis of estrone.[47] [48] An alternative partial synthesis of estrone from cholesterol by way of dehydroepiandrosterone (DHEA) was developed by Hans Herloff Inhoffen and Walter Hohlweg in 1939 or 1940, and a total synthesis of estrone was achieved by Anner and Miescher in 1948.

Approval

The FDA has approved estrone based on its safety and effectiveness as per the rules outlined in sections 505 of the Federal Food, Drug, and Cosmetic Act.

Notes and References

  1. Kuhl H . Pharmacology of estrogens and progestogens: influence of different routes of administration . Climacteric . 8 . Suppl 1 . 3–63 . August 2005 . 16112947 . 10.1080/13697130500148875 . 24616324 .
  2. Book: Hornstein T, Schwerin JL . Biology of Women. 1 January 2012. Cengage Learning. 978-1-285-40102-7. 369–.
  3. Chervenak J . Bioidentical hormones for maturing women . Maturitas . 64 . 2 . 86–89 . October 2009 . 19766414 . 10.1016/j.maturitas.2009.08.002 . free .
  4. Escande A, Pillon A, Servant N, Cravedi JP, Larrea F, Muhn P, Nicolas JC, Cavaillès V, Balaguer P . 6 . Evaluation of ligand selectivity using reporter cell lines stably expressing estrogen receptor alpha or beta . Biochemical Pharmacology . 71 . 10 . 1459–1469 . May 2006 . 16554039 . 10.1016/j.bcp.2006.02.002 .
  5. Ruggiero RJ, Likis FE . Estrogen: physiology, pharmacology, and formulations for replacement therapy . Journal of Midwifery & Women's Health . 47 . 3 . 130–138 . 2002 . 12071379 . 10.1016/s1526-9523(02)00233-7 .
  6. Book: Labhart A . Clinical Endocrinology: Theory and Practice. 6 December 2012. Springer Science & Business Media. 978-3-642-96158-8. 548–.
  7. Book: Fishman J, Martucci CP . New Concepts of Estrogenic Activity: The Role of Metabolites in the Expression of Hormone Action . 43–52. 10.1007/978-94-011-7230-1_5. Pasetto N, Paoletti R, Ambrus JL . The Menopause and Postmenopause. 978-94-011-7232-5. 1980. Springer .
  8. Book: van Keep PA, Utian WH, Vermeulen A . The Controversial Climacteric: The workshop moderators' reports presented at the Third International Congress on the Menopause, held in Ostend, Belgium, in June 1981, under the auspices of the International Menopause Society. 6 December 2012. Springer Science & Business Media. 978-94-011-7253-0. 92.
  9. Prossnitz ER, Arterburn JB . International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators . Pharmacological Reviews . 67 . 3 . 505–540 . July 2015 . 26023144 . 4485017 . 10.1124/pr.114.009712 .
  10. Selby P, McGarrigle HH, Peacock M . Comparison of the effects of oral and transdermal oestradiol administration on oestrogen metabolism, protein synthesis, gonadotrophin release, bone turnover and climacteric symptoms in postmenopausal women . Clinical Endocrinology . 30 . 3 . 241–249 . March 1989 . 2512035 . 10.1111/j.1365-2265.1989.tb02232.x . 26077537 .
  11. Powers MS, Schenkel L, Darley PE, Good WR, Balestra JC, Place VA . Pharmacokinetics and pharmacodynamics of transdermal dosage forms of 17 beta-estradiol: comparison with conventional oral estrogens used for hormone replacement . American Journal of Obstetrics and Gynecology . 152 . 8 . 1099–1106 . August 1985 . 2992279 . 10.1016/0002-9378(85)90569-1 .
  12. Fåhraeus L, Larsson-Cohn U . Oestrogens, gonadotrophins and SHBG during oral and cutaneous administration of oestradiol-17 beta to menopausal women . Acta Endocrinologica . 101 . 4 . 592–596 . December 1982 . 6818806 . 10.1530/acta.0.1010592 .
  13. Wright JV . Bio-identical steroid hormone replacement: selected observations from 23 years of clinical and laboratory practice . Annals of the New York Academy of Sciences . 1057 . 1 . 506–524 . December 2005 . 16399916 . 10.1196/annals.1356.039 . 38877163 . 2005NYASA1057..506W .
  14. Friel PN, Hinchcliffe C, Wright JV . Hormone replacement with estradiol: conventional oral doses result in excessive exposure to estrone . Alternative Medicine Review . 10 . 1 . 36–41 . March 2005 . 15771561 .
  15. De Lignieres B, Basdevant A, Thomas G, Thalabard JC, Mercier-Bodard C, Conard J, Guyene TT, Mairon N, Corvol P, Guy-Grand B . 6 . Biological effects of estradiol-17 beta in postmenopausal women: oral versus percutaneous administration . The Journal of Clinical Endocrinology and Metabolism . 62 . 3 . 536–541 . March 1986 . 3080464 . 10.1210/jcem-62-3-536 .
  16. Book: Kloosterboer HJ, Schoonen WG, Verheul HA . Pasqualini JR . Proliferation of Breast Cells by Steroid Hormones and Their Metabolites . https://books.google.com/books?id=VQDLBQAAQBAJ . Breast Cancer: Prognosis, Treatment, and Prevention . 11 April 2008 . CRC Press . 978-1-4200-5873-4 . 343–366 .
  17. Sasson S, Notides AC . Estriol and estrone interaction with the estrogen receptor. II. Estriol and estrone-induced inhibition of the cooperative binding of [3H]estradiol to the estrogen receptor . The Journal of Biological Chemistry . 258 . 13 . 8118–8122 . July 1983 . 6863280 . 10.1016/S0021-9258(20)82036-5 . free .
  18. Lundström E, Conner P, Naessén S, Löfgren L, Carlström K, Söderqvist G . Estrone - a partial estradiol antagonist in the normal breast . Gynecological Endocrinology . 31 . 9 . 747–749 . 2015 . 26190536 . 10.3109/09513590.2015.1062866 . 13617050 .
  19. Kuhl H . Pharmacology of estrogens and progestogens: influence of different routes of administration . Climacteric . 2005 . 8 . Suppl 1 . 3–63 . 10.1080/13697130500148875 . 16112947 . 24616324 .
  20. Book: Jameson JL, De Groot LJ . Endocrinology – E-Book: Adult and Pediatric. 18 May 2010. Elsevier Health Sciences. 978-1-4557-1126-0. 2813–.
  21. Book: Buchsbaum HJ . The Menopause. 6 December 2012. Springer Science & Business Media. 978-1-4612-5525-3. 62, 64.
  22. Book: Dorfman RI . Radioactive Isotopes in Physiology Diagnostics and Therapy / Künstliche Radioaktive Isotope in Physiologie Diagnostik und Therapie. Steroid Hormone Metabolism. 1961. 1223–1241. Springer . 10.1007/978-3-642-49761-2_39. 978-3-642-49477-2.
  23. Sandberg AA, Slaunwhite WR . Studies on phenolic steroids in human subjects. II. The metabolic fate and hepato-biliary-enteric circulation of C14-estrone and C14-estradiol in women . The Journal of Clinical Investigation . 36 . 8 . 1266–1278 . August 1957 . 13463090 . 1072719 . 10.1172/JCI103524 .
  24. Web site: Estrogen . PubChem . U.S. National Library of Medicine .
  25. Web site: Estrone -PubChem. National Center for Biotechnology Information. 6 September 2009.
  26. Web site: Material Safety Data Sheet Estrone. ScienceLab.com. 21 February 2013.
  27. Web site: Drugs@FDA: FDA Approved Drug Products.
  28. Crandall CJ, Hovey KM, Andrews CA, Chlebowski RT, Stefanick ML, Lane DS, Shifren J, Chen C, Kaunitz AM, Cauley JA, Manson JE . 6 . Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the Women's Health Initiative Observational Study . Menopause . 25 . 1 . 11–20 . January 2018 . 28816933 . 5734988 . 10.1097/GME.0000000000000956 .
  29. The 2017 hormone therapy position statement of The North American Menopause Society . Menopause . 24 . 7 . 728–753 . July 2017 . 28650869 . 10.1097/GME.0000000000000921 .
  30. García-Sánchez J, Mafla-España MA, Tejedor-Cabrera C, Avellán-Castillo O, Torregrosa MD, Cauli O . Plasma Aromatase Activity Index, Gonadotropins and Estrone Are Associated with Frailty Syndrome in Post-Menopausal Women with Breast Cancer . Current Oncology . 29 . 3 . 1744–1760 . March 2022 . 35323344 . 8947022 . 10.3390/curroncol29030144 . free .
  31. Web site: Different kinds of oral contraceptive pills in polycystic ovary syndrome: a systematic review and meta-analysis . 2023-07-31 . academic.oup.com.
  32. van Vlijmen EF, Veeger NJ, Middeldorp S, Hamulyák K, Prins MH, Büller HR, Meijer K . Thrombotic risk during oral contraceptive use and pregnancy in women with factor V Leiden or prothrombin mutation: a rational approach to contraception . Blood . 118 . 8 . 2055–61; quiz 2375 . August 2011 . 21659542 . 10.1182/blood-2011-03-345678 . free .
  33. Book: Delgado BJ, Lopez-Ojeda W . Estrogen . 2023 . http://www.ncbi.nlm.nih.gov/books/NBK538260/ . StatPearls . 2023-07-31 . Treasure Island (FL) . StatPearls Publishing . 30855848 .
  34. Cusi K, Isaacs S, Barb D, Basu R, Caprio S, Garvey WT, Kashyap S, Mechanick JI, Mouzaki M, Nadolsky K, Rinella ME, Vos MB, Younossi Z . 6 . American Association of Clinical Endocrinology Clinical Practice Guideline for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Primary Care and Endocrinology Clinical Settings: Co-Sponsored by the American Association for the Study of Liver Diseases (AASLD) . Endocrine Practice . 28 . 5 . 528–562 . May 2022 . 35569886 . 10.1016/j.eprac.2022.03.010 . free .
  35. Book: Bullough VL. Science In The Bedroom: A History Of Sex Research. 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..
  36. Book: Nielsch U, Fuhrmann U, Jaroch S . New Approaches to Drug Discovery. 30 March 2016. Springer. 978-3-319-28914-4. 7–. The first steroid hormone was isolated from the urine of pregnant women by Adolf Butenandt in 1929 (estrone; see Fig. 1) (Butenandt 1931)..
  37. Book: Parl FF . Estrogens, Estrogen Receptor and Breast Cancer. 2000. IOS Press. 978-0-9673355-4-4. 4–5. [Doisy] focused his research on the isolation of female sex hormones from hundreds of gallons of human pregnancy urine based on the discovery by Ascheim and Zondeck in 1927 that the urine of pregnant women possessed estrogenic activity [9]. In the summer of 1929, Doisy succeeded in the isolated of estrone (named by him theelin), simultaneously with but independent of Adolf Butenandt of the University of Gottingen in Germany. Doisy presented his results on the crystallization of estrone at the XIII International Physiological Congress in Boston in August 1929 [10]..
  38. Book: Laylin JK . Nobel Laureates in Chemistry, 1901–1992. 30 October 1993. Chemical Heritage Foundation. 978-0-8412-2690-6. 255–. Adolt Friedrich Johann Butenandt was awarded the Nobel Prize in chemistry in 1939 "for his work on sex hormones"; [...] In 1929 Butenandt isolated estrone [...] in pure crystalline form. [...] Both Butenandt and Edward Doisy isolated estrone simultaneously but independently in 1929. [...] Butenandt took a big step forward in the history of biochemistry when he isolated estrone from the urine of pregnant women. [...] He named it "progynon" in his first publication, and then "folliculine", [...] By 1932, [...] he could determine its chemical structure, [...].
  39. Book: Greenberg A . Chemistry: Decade by Decade. 14 May 2014. Infobase Publishing. 978-1-4381-0978-7. 127–. Rational chemical studies of human sex hormones began in 1929 with Adolph Butenandt's isolation of pure crystalline estrone, the follicular hormone, from the urine of pregnant women. [...] Butenandt and Ruzicka shared the 1939 Nobel Prize in chemistry..
  40. Book: Labhart A . Clinical Endocrinology: Theory and Practice. 6 December 2012. Springer Science & Business Media. 978-3-642-96158-8. 511–. E. A. Doisy and A. Butenandt reported almost at the same time on the isolation of an estrogen-active substance in crystalline form from the urine of pregnant women. N. K. Adam suggested that this substance be named estrone because of the C-17-ketone group present (1933)..
  41. Book: Rooke T . The Quest for Cortisone. 1 January 2012. MSU Press. 978-1-60917-326-5. 54–. In 1929 the first estrogen, a steroid called "estrone," was isolated and purified by Doisy; he later won a Nobel Prize for this work..
  42. Book: Loriaux DL . Russel Earl Marker (1902–1995) - The Mexican Yam . A Biographical History of Endocrinology. https://books.google.com/books?id=ve2hCwAAQBAJ&pg=PA345 . 23 February 2016. Wiley. 978-1-119-20247-9. 345–.
  43. Campbell AD . Concerning Placental Hormones and Menstrual Disorders. Annals of Internal Medicine. 7. 3. 1933. 330. 0003-4819. 10.7326/0003-4819-7-3-330.
  44. Fluhmann CF . Estrogenic Hormones: Their Clinical Usage . California and Western Medicine . 49 . 5 . 362–366 . November 1938 . 18744783 . 1659459 .
  45. Book: Fritz MA, Speroff L . Clinical Gynecologic Endocrinology and Infertility. 28 March 2012. Lippincott Williams & Wilkins. 978-1-4511-4847-3. 750–. In 1926, Sir Alan S. Parkes and C.W Bellerby coined the basic word "estrin" to designate the hormone or hormones that induce estrus in animals, the time when female mammals are fertile and receptive to males. [...] The terminology was extended to include the principal estrogens in humans, estrone, estradiol, and estriol, in 1932 at the first meeting of the International Conference on the Standardization of Sex Hormones in London, [...].
  46. Book: Oettel M, Schillinger E . Estrogens and Antiestrogens I: Physiology and Mechanisms of Action of Estrogens and Antiestrogens. 6 December 2012. Springer Science & Business Media. 978-3-642-58616-3. 2–. The structure of the estrogenic hormones was stated by Butenandt, Thayer, Marrian, and Hazlewood in 1930 and 1931 (see Butenandt 1980). Following the proposition of the Marrian group, the estrogenic hormones were given the trivial names of estradiol, estrone, and estriol. At the first meeting of the International Conference on the Standardization of Sex Hormones, in London (1932), a standard preparation of estrone was established. [...] The partial synthesis of estradiol and estrone from cholesterol and dehydroepiandrosterone was accomplished by Inhoffen and Howleg (Berlin 1940); the total synthesis was achieved by Anner and Miescher (Basel, 1948)..
  47. Book: Watkins ES . Beginnings . The Estrogen Elixir: A History of Hormone Replacement Therapy in America. https://books.google.com/books?id=-tz4J4_hgdIC&pg=PA21. 6 March 2007. JHU Press. 978-0-8018-8602-7. 21–.
  48. Book: Pincus G, Thimann KV. The Hormones V1: Physiology, Chemistry and Applications. 2 December 2012. Elsevier. 978-0-323-14206-9. 360–.

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