Estrone is an estrogen, specifically an agonist of the estrogen receptorsERα and ERβ.[1][5] It is a far less potent estrogen than is estradiol, and as such, is a relatively weak estrogen.[1][5][6] Given by subcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol.[7] 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.[5] In accordance, the estrogenic activity of estrone has been reported to be approximately 4% of that of estradiol.[1] In addition to its low estrogenic potency, estrone, unlike estradiol and estriol, is not accumulated in estrogen target tissues.[1] 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.[1][8] As such, estrone is considered to be a precursor or prohormone of estradiol.[3] 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.[1][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.[1] 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.[1][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.[1][10][11][12][15] In addition, estradiol levels were found to correlate with these effects, while estrone levels did not.[10][11] These findings confirm that estrone has very low estrogenic activity, and also indicate that estrone does not diminish the estrogenic activity of estradiol.[1][10][11][12] This contradicts some cell-freein-vitro research suggesting that high concentrations of estrone might be able to partiallyantagonize the actions of estradiol.[16][17][18]
Notes: Values are mean ± SD or range. ER RBA = Relative binding affinity to estrogen receptors of rat uterinecytosol. Uterine weight = Percentage change in uterine wet weight of ovariectomized rats after 72 hours with continuous administration of 1 μg/hour via subcutaneously implantedosmotic pumps. LH levels = Luteinizing hormone levels relative to baseline of ovariectomized rats after 24 to 72 hours of continuous administration via subcutaneous implant. Footnotes:a = Synthetic (i.e., not endogenous). b = Atypical uterotrophic effect which plateaus within 48 hours (estradiol's uterotrophy continues linearly up to 72 hours). Sources: See template.
Biochemistry
Comprehensive overview of steroidogenesis, showing estrone on the lower right among the estrogens.[19]
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.[20]
Distribution
Estrone is bound approximately 16% to sex hormone-binding globulin (SHBG) and 80% to albumin in the circulation,[1] with the remainder (2.0 to 4.0%) circulating freely or unbound.[21] It has about 24% of the relative binding affinity of estradiol for SHBG.[1] As such, estrone is relatively poorly bound to SHBG.[22]
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.[25]
Notes: "The concentration of a steroid in the circulation is determined by the rate at which it is secreted from glands, the rate of metabolism of precursor or prehormones into the steroid, and the rate at which it is extracted by tissues and metabolized. The secretion rate of a steroid refers to the total secretion of the compound from a gland per unit time. Secretion rates have been assessed by sampling the venous effluent from a gland over time and subtracting out the arterial and peripheral venous hormone concentration. The metabolic clearance rate of a steroid is defined as the volume of blood that has been completely cleared of the hormone per unit time. The production rate of a steroid hormone refers to entry into the blood of the compound from all possible sources, including secretion from glands and conversion of prohormones into the steroid of interest. At steady state, the amount of hormone entering the blood from all sources will be equal to the rate at which it is being cleared (metabolic clearance rate) multiplied by blood concentration (production rate = metabolic clearance rate × concentration). If there is little contribution of prohormone metabolism to the circulating pool of steroid, then the production rate will approximate the secretion rate." Sources: See template.
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.[25]
Note the hydroxyl (–OH) groups: estrone (E1) has one, estradiol (E2) has two, estriol (E3) has three, and estetrol (E4) has four.
Estrone, also known as estra-1,3,5(10)-trien-3-ol-17-one, is a naturally occurringestranesteroid with double bonds at the C1, C3, and C5 positions, a hydroxyl group at the C3 position, and a ketonegroup at the C17 position. The name estrone was derived from the chemical terms estrin (estra-1,3,5(10)-triene) and ketone.
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.[25]
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.[29]
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.[30] Those with breast cancer become at a greater risk of hypercalcemia and bone metastases when taking estrogens.[31] 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.[32]
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.[30][33] The use of estrogens within three weeks postpartum may increase the risk of developing a VTE.[34] 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.[35]
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.[34]
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.[36]
Estrone was the first steroid hormone to be discovered.[37][38] It was discovered in 1929 independently by the American scientists Edward Doisy and Edgar Allen and the GermanbiochemistAdolf Butenandt, although Doisy and Allen isolated it two months before Butenandt.[37][39][40] They isolated and purified estrone in crystalline form from the urine of pregnant women.[39][40][41] 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][42] Butenandt was later awarded the Nobel Prize in 1939 for the isolation of estrone and his work on sex hormones in general.[41][43] The molecular formula of estrone was known by 1931,[44] and its chemical structure had been determined by Butenandt by 1932.[40][39] Following the elucidation of its structure, estrone was additionally referred to as ketohydroxyestrin or oxohydroxyestrin,[45][46] 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.[47][48]
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.[25]
^Fishman J, Martucci CP (1980). "New Concepts of Estrogenic Activity: The Role of Metabolites in the Expression of Hormone Action". In Pasetto N, Paoletti R, Ambrus JL (eds.). The Menopause and Postmenopause. Springer. pp. 43–52. doi:10.1007/978-94-011-7230-1_5. ISBN978-94-011-7232-5.
^ abcdSelby P, McGarrigle HH, Peacock M (March 1989). "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. doi:10.1111/j.1365-2265.1989.tb02232.x. PMID2512035. S2CID26077537.
^ abcdPowers MS, Schenkel L, Darley PE, Good WR, Balestra JC, Place VA (August 1985). "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. doi:10.1016/0002-9378(85)90569-1. PMID2992279.
^ abcFåhraeus L, Larsson-Cohn U (December 1982). "Oestrogens, gonadotrophins and SHBG during oral and cutaneous administration of oestradiol-17 beta to menopausal women". Acta Endocrinologica. 101 (4): 592–596. doi:10.1530/acta.0.1010592. PMID6818806.
^Friel PN, Hinchcliffe C, Wright JV (March 2005). "Hormone replacement with estradiol: conventional oral doses result in excessive exposure to estrone". Alternative Medicine Review. 10 (1): 36–41. PMID15771561.
^De Lignieres B, Basdevant A, Thomas G, Thalabard JC, Mercier-Bodard C, Conard J, et al. (March 1986). "Biological effects of estradiol-17 beta in postmenopausal women: oral versus percutaneous administration". The Journal of Clinical Endocrinology and Metabolism. 62 (3): 536–541. doi:10.1210/jcem-62-3-536. PMID3080464.
^ abcDorfman RI (1961). "Steroid Hormone Metabolism". Radioactive Isotopes in Physiology Diagnostics and Therapy / Künstliche Radioaktive Isotope in Physiologie Diagnostik und Therapie. Springer. pp. 1223–1241. doi:10.1007/978-3-642-49761-2_39. ISBN978-3-642-49477-2.
^The NAMS 2017 Hormone Therapy Position Statement Advisory Panel (July 2017). "The 2017 hormone therapy position statement of The North American Menopause Society". Menopause. 24 (7): 728–753. doi:10.1097/GME.0000000000000921. PMID28650869. {{cite journal}}: |author1= has generic name (help)CS1 maint: numeric names: authors list (link)
^ ab"Contraceptives, Oral, Combined", Drugs and Lactation Database (LactMed®), Bethesda (MD): National Institute of Child Health and Human Development, 2006, PMID30000354, retrieved 31 July 2023
^ abDelgado BJ, Lopez-Ojeda W (2023). "Estrogen". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID30855848. Retrieved 31 July 2023.
^ abBullough VL (19 May 1995). Science In The Bedroom: A History Of Sex Research. Basic Books. pp. 128–. ISBN978-0-465-07259-0. 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.[permanent dead link]
^Nielsch U, Fuhrmann U, Jaroch S (30 March 2016). New Approaches to Drug Discovery. Springer. pp. 7–. ISBN978-3-319-28914-4. The first steroid hormone was isolated from the urine of pregnant women by Adolf Butenandt in 1929 (estrone; see Fig. 1) (Butenandt 1931).
^ abcParl FF (2000). Estrogens, Estrogen Receptor and Breast Cancer. IOS Press. pp. 4–5. ISBN978-0-9673355-4-4. [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].
^ abcdLaylin JK (30 October 1993). Nobel Laureates in Chemistry, 1901–1992. Chemical Heritage Foundation. pp. 255–. ISBN978-0-8412-2690-6. 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, [...]
^ abGreenberg A (14 May 2014). Chemistry: Decade by Decade. Infobase Publishing. pp. 127–. ISBN978-1-4381-0978-7. 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.
^Labhart A (6 December 2012). Clinical Endocrinology: Theory and Practice. Springer Science & Business Media. pp. 511–. ISBN978-3-642-96158-8. 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).
^Rooke T (1 January 2012). The Quest for Cortisone. MSU Press. pp. 54–. ISBN978-1-60917-326-5. In 1929 the first estrogen, a steroid called "estrone," was isolated and purified by Doisy; he later won a Nobel Prize for this work.
^Fritz MA, Speroff L (28 March 2012). Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins. pp. 750–. ISBN978-1-4511-4847-3. 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, [...]
^ abOettel M, Schillinger E (6 December 2012). Estrogens and Antiestrogens I: Physiology and Mechanisms of Action of Estrogens and Antiestrogens. Springer Science & Business Media. pp. 2–. ISBN978-3-642-58616-3. 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).
^ abWatkins ES (6 March 2007). "Beginnings". The Estrogen Elixir: A History of Hormone Replacement Therapy in America. JHU Press. pp. 21–. ISBN978-0-8018-8602-7.
