estrone (medication)

Estrone has been marketed in intramuscular and vaginal formulations and was used as an estrogen in the treatment of symptoms of low estrogen levels such as hot flashes and vaginal atrophy in postmenopausal or ovariectomized women. Estrone has also been used as an antigonadotropin and form of high-dose estrogen to treat prostate cancer in men as well as a form of high-dose estrogen to treat breast cancer in women.{{cite book| vauthors = Thomas JA, Keenan EJ |chapter=Estrogens and Antiestrogenic Drugs|pages=135–165|doi=10.1007/978-1-4684-5036-1_7|title=Principles of Endocrine Pharmacology|chapter-url=https://books.google.com/books?id=mTagBQAAQBAJ&pg=PA150|date=6 December 1986|publisher=Springer Science & Business Media|isbn=978-1-4684-5036-1}} It has since largely been discontinued and is mostly no longer available, having been superseded by other estrogens with better potency and pharmacokinetics (namely oral bioavailability and duration).{{Cite web|url=http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=003977|title=Drugs@FDA: FDA-Approved Drugs}}

Regardless of route of administration, if estrone is taken by a woman with an intact uterus, it should be combined with a progestogen such as progesterone to offset the risk of endometrial hyperplasia and cancer.

Estrone has been used by intramuscular injection at a dosage of 0.1 to 2 mg per week, or 0.1 to 0.5 mg given 2 or 3 times per week, for the treatment of menopausal symptoms such as hot flashes and vaginal atrophy,{{cite book |chapter=Estrogens, Progestagens, Oral Contraceptives, and Ovulatory Agents |pages=540–572 |author1=American Medical Association. Dept. of Drugs |author2=Council on Drugs (American Medical Association) |author3=American Society for Clinical Pharmacology and Therapeutics |title=AMA drug evaluations |url=https://books.google.com/books?id=0h7s_rfEZgkC |date=1 February 1977 |publisher=Publishing Sciences Group |isbn=978-0-88416-175-2 }}{{cite book| vauthors = Thomas JA, Keenan EJ | chapter = Estrogen and Antiestrogenic Drugs |title=Principles of Endocrine Pharmacology| chapter-url=https://books.google.com/books?id=mTagBQAAQBAJ&pg=PA153|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4684-5036-1|pages=153–}} and at a dosage of 0.1 to 1.0 mg weekly in single or divided doses for the treatment of female hypogonadism, surgical castration, and primary ovarian failure.{{cite book| vauthors = Rivlin ME |title=Handbook of drug therapy in reproductive endocrinology and infertility|url=https://books.google.com/books?id=7kZsAAAAMAAJ&q=Estrone|year=1990|publisher=Little, Brown|isbn=978-0-316-74772-1|page=23|quote=The following are dosages for parenteral [estrogens]: [...] Estrone. For vasomotor symptoms or atrophic vaginitis, 0.1 to 0.5 mg is given 2 or 3 times weekly. For female hypogonadism, castration, or primary ovarian failure, 0.1 to 1.0 mg is given weekly in single or divided doses. Further dosage adjusted according to response.}} The range of single doses of estrone by intramuscular injection that are typically used clinically in women is 0.1 to 5 mg. High doses of intramuscular estrone have been used for prostate cancer in men and for breast cancer in women.{{Cite web|url=https://www.accessdata.fda.gov/drugsatfda_docs/anda/pre96/85239_Estrone%20Suspension_Medr.pdf|title=Enforcement Reports}}

{{See also|Estradiol/estrone/estriol|Estrone/progesterone}}

Estrone for intramuscular injection was provided as 1, 2, 2.5, 3, 4, and 5 mg/mL aqueous suspensions and/or oil solutions.{{cite book| vauthors = Misra D, Magee MF, Nylén ES | chapter = Compendium of Endocrine-Related Drugs | veditors = Becker KL |title=Principles and Practice of Endocrinology and Metabolism|chapter-url=https://books.google.com/books?id=FVfzRvaucq8C&pg=PA2153|year=2001|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-1750-2|pages=2153–}}https://www.micromedexsolutions.com/micromedex2/ {{Dead link|date=February 2022}}{{cite book| vauthors = Modell W | chapter = Estrone |title=Drugs in Current Use 1958| chapter-url = https://books.google.com/books?id=v2vwCAAAQBAJ&pg=PA52|date=21 November 2013|publisher=Springer|isbn=978-3-662-40303-7|pages=52–}}{{cite book | vauthors = Deghenghi R | chapter = Chemistry and biochemistry of natural estrogens | veditors = Paoletti R, Pasetto N, Ambrus JL |title=The Menopause and Postmenopause: The Proceedings of an International Symposium held in Rome, June 1979| chapter-url = https://books.google.com/books?id=wZF9CAAAQBAJ&pg=PA3|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-7230-1|pages=3–}}{{cite book|author=University of California (1868-1952)|title=Hospital Formulary and Compendium of Useful Information|url=https://books.google.com/books?id=t7VW3PucgboC&pg=PA49|year=1952|publisher=University of California Press|pages=49–|id=GGKEY:2UAAZRZ5LN0}} It has also been available in the form of vaginal creams (1 mg/g (0.1%)) and suppositories (0.2 mg, 0.25 mg) as well as subcutaneous pellet implants and oral tablets (1.25 mg). A combined oral tablet formulation containing estradiol (0.3 mg, 0.6 mg), estrone (0.7 mg, 1.4 mg), and estriol (0.135 mg, 0.27 mg) has been marketed under the brand name Hormonin as well.{{cite book| vauthors = Krishna UR, Sheriar NK, Mandlekar A | chapter = Hormone Replacement Therapy | veditors = Krishna UR, Sheriar NK |title=Menopause|chapter-url=https://books.google.com/books?id=n16P1r9cBG8C&pg=PA70|year=1996|publisher=Orient Blackswan|isbn=978-81-250-0910-8|pages=70–}}{{cite book | chapter = Osteoporosis | vauthors = Campbell G, Compston J, Crisp A | title = The Management of Common Metabolic Bone Disorders| chapter-url=https://books.google.com/books?id=gGmx03rQVyoC&pg=PA48|date=25 November 1993|publisher=Cambridge University Press|isbn=978-0-521-43623-6|pages=48–}}{{cite book| vauthors = Erkkola R |title=The Menopause|url=https://books.google.com/books?id=1AU_NI__fpUC&pg=PA264|date=1 January 2006|publisher=Elsevier|isbn=978-0-444-51830-9|pages=264–}} In addition, a combined injectable preparation containing estrone (1 mg) and progesterone (10 mg) is available in the form of ampoules under the brand name Synergon.{{cite book |veditors = Sweetman SC |chapter=Sex hormones and their modulators |title=Martindale: The Complete Drug Reference |edition=36th |year=2009 |pages=2101, 2127 |publisher=Pharmaceutical Press |location=London|isbn=978-0-85369-840-1|quote=Estrone [...] Progesterone [...] Multi-ingredient: [...] Fr.: Synergon [...] Turk.: Synergon}}{{cite journal |vauthors=Addo VN, Tagoe-Darko ED |title=Knowledge, practices, and attitudes regarding emergency contraception among students at a university in Ghana |journal=Int J Gynaecol Obstet |volume=105 |issue=3 |pages=206–9 |date=June 2009 |pmid=19232600 |doi=10.1016/j.ijgo.2009.01.008 |s2cid=22216977 |quote=Synergon, a combination of progesterone and oestrone in an injectable form, is marketed to induce withdrawal bleeding in women with nongravid amenorrhea; however, it can be used as an arbortifacient [11].}}{{cite journal |vauthors=Kongnyuy EJ, Ngassa P, Fomulu N, Wiysonge CS, Kouam L, Doh AS |title=A survey of knowledge, attitudes and practice of emergency contraception among university students in Cameroon |journal=BMC Emerg Med |volume=7 |pages=7 |date=July 2007 |pmid=17634106 |pmc=1933435 |doi=10.1186/1471-227X-7-7 |doi-access=free }}{{cite book| vauthors = McDonnell K |title=Adverse Effects: Women and the Pharmaceutical Industry|url=https://books.google.com/books?id=SgA-AAAAYAAJ|year=1986|publisher=International Organization of Consumers Unions, Regional Office for Asia and the Pacific|isbn=978-967-9973-17-4|page=15|quote=Synergon. 10 mg progesterone. 1 mg folliculine [estrone].}}

Although estrone by intramuscular injection was originally formulated as an oil solution, it was soon replaced by formulations of estrone as an aqueous suspension due to a longer duration of action of these formulations.{{cite journal | vauthors = Ferin J | title = Relative duration of action of natural and synthetic estrogens administered parenterally in women with estrogen deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 12 | issue = 1 | pages = 28–35 | date = January 1952 | pmid = 14907837 | doi = 10.1210/jcem-12-1-28 }}{{cite journal| vauthors = Freed SC|title=Present status of commercial endocrine preparations|journal=JAMA: The Journal of the American Medical Association|volume=117|issue=14|year=1941|pages=1175|issn=0098-7484|doi=10.1001/jama.1941.72820400003010}}{{cite journal| vauthors = Stempel E |title=prolonged drug action|journal=Journal of the American Pharmaceutical Association (Practical Pharmacy Ed.)|volume=20|issue=6|year=1959|pages=334–336|issn=0095-9561|doi=10.1016/S0095-9561(16)35628-6}}

{{See also|Estrogen (medication)#Side effects}}

Side effects of estrogens like estrone include breast tenderness, breast enlargement, headache, nausea, fluid retention, and edema, among others. It can also cause endometrial hyperplasia.

Estrone is an estrogen, specifically an agonist of the estrogen receptors (ERs) ERα and ERβ.{{cite journal | vauthors = Escande A, Pillon A, Servant N, Cravedi JP, Larrea F, Muhn P, Nicolas JC, Cavaillès V, Balaguer P | title = Evaluation of ligand selectivity using reporter cell lines stably expressing estrogen receptor alpha or beta | journal = Biochem. Pharmacol. | volume = 71 | issue = 10 | pages = 1459–69 | year = 2006 | pmid = 16554039 | doi = 10.1016/j.bcp.2006.02.002 }} It is a far less potent estrogen than is estradiol, and as such is a relatively weak estrogen. Given by subcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol.{{cite book | vauthors = Schriener WE | chapter = The Ovary | veditors = Labhart A |title=Clinical Endocrinology: Theory and Practice| chapter-url = https://books.google.com/books?id=DAgJCAAAQBAJ&pg=PA548|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-96158-8|pages=548–}} 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. Other studies have reported that estrone has about one-tenth of the potency of estradiol in activating the ERs in vitro.{{cite journal | vauthors = Coldham NG, Dave M, Sivapathasundaram S, McDonnell DP, Connor C, Sauer MJ | title = Evaluation of a recombinant yeast cell estrogen screening assay | journal = Environ. Health Perspect. | volume = 105 | issue = 7 | pages = 734–42 | date = July 1997 | pmid = 9294720 | pmc = 1470103 | doi = 10.1289/ehp.97105734 }}{{cite journal | vauthors = Legler J, Zeinstra LM, Schuitemaker F, Lanser PH, Bogerd J, Brouwer A, Vethaak AD, De Voogt P, Murk AJ, Van der Burg B | title = Comparison of in vivo and in vitro reporter gene assays for short-term screening of estrogenic activity | journal = Environ. Sci. Technol. | volume = 36 | issue = 20 | pages = 4410–5 | date = October 2002 | pmid = 12387416 | doi = 10.1021/es010323a | bibcode = 2002EnST...36.4410L | url = https://research.vu.nl/en/publications/625a3378-95d3-44aa-8075-223e0a4f4b45}}{{cite journal | vauthors = Dang Z, Ru S, Wang W, Rorije E, Hakkert B, Vermeire T | title = Comparison of chemical-induced transcriptional activation of fish and human estrogen receptors: regulatory implications | journal = Toxicol. Lett. | volume = 201 | issue = 2 | pages = 152–75 | date = March 2011 | pmid = 21195753 | doi = 10.1016/j.toxlet.2010.12.020 }} Because estrone can be transformed into estradiol, which is far more potent as an estrogen in comparison, most or all of the estrogenic potency of estrone in vivo is actually due to conversion into estradiol.{{cite book| vauthors = Fishman J, Martucci CP |chapter=New Concepts of Estrogenic Activity: The Role of Metabolites in the Expression of Hormone Action|pages=43–52|doi=10.1007/978-94-011-7230-1_5| veditors = Pasetto N, Paoletti R, Ambrus JL |title=The Menopause and Postmenopause|isbn=978-94-011-7232-5|year=1980|publisher=Springer }} As such, similarly to the case of estrone sulfate, estrone is considered to be a prodrug of estradiol.{{cite journal | vauthors = Kuhl H | title = Pharmacokinetics of oestrogens and progestogens | journal = Maturitas | volume = 12 | issue = 3 | pages = 171–97 | date = September 1990 | pmid = 2170822 | doi = 10.1016/0378-5122(90)90003-O }} Some in vitro research has suggested that estrone might be able to partially antagonize the actions of estradiol,{{cite book| veditors = Pasqualini JR | vauthors = Kloosterboer HJ, Schoonen WG, Verheul HA | title = Breast Cancer: Prognosis, Treatment, and Prevention | chapter = Proliferation of Breast Cells by Steroid Hormones and Their Metabolites | url = https://books.google.com/books?id=VQDLBQAAQBAJ | date = 11 April 2008 | publisher = CRC Press | isbn = 978-1-4200-5873-4 | pages = 343–366}}{{cite journal | vauthors = Sasson S, Notides AC | title = 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 | journal = J. Biol. Chem. | volume = 258 | issue = 13 | pages = 8118–22 | date = July 1983 | doi = 10.1016/S0021-9258(20)82036-5 | pmid = 6863280 | url = http://www.jbc.org/content/258/13/8118.short| doi-access = free }}{{cite journal | vauthors = Lundström E, Conner P, Naessén S, Löfgren L, Carlström K, Söderqvist G | title = Estrone - a partial estradiol antagonist in the normal breast | journal = Gynecol. Endocrinol. | volume = 31 | issue = 9 | pages = 747–9 | date = 2015 | pmid = 26190536 | doi = 10.3109/09513590.2015.1062866 | s2cid = 13617050 }} but this does not appear to be of clinical significance. In contrast to estradiol and estriol, estrone is not a ligand of the G protein-coupled estrogen receptor (affinity >10,000 nM).{{cite journal | vauthors = Prossnitz ER, Arterburn JB | title = International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators | journal = Pharmacol. Rev. | volume = 67 | issue = 3 | pages = 505–40 | date = July 2015 | pmid = 26023144 | pmc = 4485017 | doi = 10.1124/pr.114.009712 }}

{{Affinities of estrogen receptor ligands for the ERα and ERβ}}

{{Relative affinities of estrogens for steroid hormone receptors and blood proteins}}

{{Selected biological properties of endogenous estrogens in rats}}

In clinical research in the 1930s, estrone was given via intramuscular injection to ovariectomized women in order to study its effects and to elucidate the biological properties of estrogens in humans.{{cite journal| vauthors = Werner AA |title=Effect of Theelin Injections upon the Castrated Woman|journal=Experimental Biology and Medicine|volume=29|issue=9|year=1932|pages=1142–1143|issn=1535-3702|doi=10.3181/00379727-29-6259|s2cid=75441739}}{{cite journal| vauthors = Werner AA, Collier WD|title=Production of Endometrial Growth in Castrated Women|journal=Journal of the American Medical Association|volume=101|issue=19|year=1933|pages=1466|issn=0002-9955|doi=10.1001/jama.1933.02740440026008}}{{cite journal| vauthors = Werner AA |title=Effective Clinical Dosages of Theelin in Oil|journal=Journal of the American Medical Association|volume=109|issue=13|year=1937|pages=1027|issn=0002-9955|doi=10.1001/jama.1937.02780390029011}} In these studies, prior to administration of estrone, amenorrhea, atrophy of the breasts (as well as flaccidity and small and non-erectile nipples), vagina, and endometrium, vaginal dryness, and subjective symptoms of ovariectomy (e.g., hot flashes, mood changes) were all present in the women. Treatment with estrone was found to dose- and time-dependently produce a variety of effects, including breast changes, reproductive tract changes of the vagina, cervix, and endometrium/uterus, and relief from the subjective symptoms of ovariectomy, as well as increased libido. Breast changes specifically included enlargement and a sense of fullness, increased sensitivity and pigmentation of the nipples as well as nipple erection, tingling within the breast mammary glandular tissue, and aching and soreness of the breasts. Reproductive tract changes included increased growth, thickness, and differentiation of the endometrium, and reversal of vaginal and cervical atrophy, which were accompanied by increased congestion of the cervix and mucous discharge from the cervix, uterine cramps and needle-like pains, pelvic fullness, a "bearing-down" sensation, and increased vaginal lubrication, as well as uterine bleeding both during treatment and in the days following cessation of injections. Endometrial hyperplasia also occurred with sufficiently high doses of estrone.

Clinical research has confirmed the nature of estrone as an inactive prodrug of estradiol.{{cite journal | vauthors = Selby P, McGarrigle HH, Peacock M | title = 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 | journal = Clin. Endocrinol. (Oxf) | volume = 30 | issue = 3 | pages = 241–9 | date = March 1989 | pmid = 2512035 | doi = 10.1111/j.1365-2265.1989.tb02232.x | s2cid = 26077537 }}{{cite journal | vauthors = Powers MS, Schenkel L, Darley PE, Good WR, Balestra JC, Place VA | title = Pharmacokinetics and pharmacodynamics of transdermal dosage forms of 17 beta-estradiol: comparison with conventional oral estrogens used for hormone replacement | journal = Am. J. Obstet. Gynecol. | volume = 152 | issue = 8 | pages = 1099–106 | date = August 1985 | pmid = 2992279 | doi = 10.1016/0002-9378(85)90569-1 }}{{cite journal | vauthors = Fåhraeus L, Larsson-Cohn U | title = Oestrogens, gonadotrophins and SHBG during oral and cutaneous administration of oestradiol-17 beta to menopausal women | journal = Acta Endocrinol. | volume = 101 | issue = 4 | pages = 592–6 | date = December 1982 | pmid = 6818806 | doi = 10.1530/acta.0.1010592 }} 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.{{cite journal | vauthors = Wright JV | title = Bio-identical steroid hormone replacement: selected observations from 23 years of clinical and laboratory practice | journal = Ann. N. Y. Acad. Sci. | volume = 1057 | pages = 506–24 | date = December 2005 | issue = 1 | pmid = 16399916 | doi = 10.1196/annals.1356.039 | bibcode = 2005NYASA1057..506W | s2cid = 38877163 }}{{cite journal | vauthors = Friel PN, Hinchcliffe C, Wright JV | title = Hormone replacement with estradiol: conventional oral doses result in excessive exposure to estrone | journal = Altern Med Rev | volume = 10 | issue = 1 | pages = 36–41 | date = March 2005 | pmid = 15771561 }} In spite of markedly elevated levels of estrone with oral estradiol but not with transdermal estradiol, clinical studies have shown that doses 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.{{cite journal | vauthors = De Lignieres B, Basdevant A, Thomas G, Thalabard JC, Mercier-Bodard C, Conard J, Guyene TT, Mairon N, Corvol P, Guy-Grand B | title = Biological effects of estradiol-17 beta in postmenopausal women: oral versus percutaneous administration | journal = J. Clin. Endocrinol. Metab. | volume = 62 | issue = 3 | pages = 536–41 | date = March 1986 | pmid = 3080464 | doi = 10.1210/jcem-62-3-536 }} 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.

{{Relative oral potencies of estrogens}}

{{Parenteral potencies and durations of steroidal estrogens}}

{{Pharmacology of estrone}}

Like estradiol, estrone has poor oral bioavailability.{{cite book| vauthors = Melmon KL, Carruthers SG, Morrelli HF, Hoffman BB, Nierenberg DW |title=Melmon and Morrelli's Clinical Pharmacology: Basic Principles in Therapeutics|url=https://books.google.com/books?id=s515nY4F3WcC|year=2000|publisher=McGraw Hill Professional|isbn=978-0-07-105406-5|pages=614–615}} It has been said that, taken by mouth in non-micronized form, a dose of 25 mg estrone is approximately equivalent to 2.5 mg conjugated estrogens, 50 μg ethinylestradiol, or 1 mg diethylstilbestrol in terms of estrogenic potency.{{cite journal | vauthors = Swyer GI | title = The oestrogens | journal = Br Med J | volume = 1 | issue = 5128 | pages = 1029–31 | date = April 1959 | pmid = 13638626 | pmc = 1993181 | doi = 10.1136/bmj.1.5128.1029 | quote = Oestrone is weakly active by mouth, its potency (see Table) being approximately 1/25th that of stilboestrol (25 mg E1 = 1 mg DES = 2.5 mg CEEs = 0.05 mg EE).}} Due to its weak oral activity, estrone has been used parenterally instead, for instance by intramuscular injection or vaginal administration. The pharmacokinetics of vaginal estrone have been studied.{{cite journal | vauthors = Schiff I, Tulchinsky D, Ryan KJ | title = Vaginal absorption of estrone and 17beta-estradiol | journal = Fertil. Steril. | volume = 28 | issue = 10 | pages = 1063–6 | date = October 1977 | pmid = 908445 | doi = 10.1016/S0015-0282(16)42855-4 | doi-access = free }}

Estrone in oil solution by intramuscular injection has a shorter duration than estrone in aqueous suspension by intramuscular injection.{{cite journal| vauthors = Freed SC, Greenhill JP |title=Therapeutic Use of Estrone Suspensions1|journal=The Journal of Clinical Endocrinology & Metabolism|volume=1|issue=12|year=1941|pages=983–985|issn=0021-972X|doi=10.1210/jcem-1-12-983}} Estrone in oil solution by intramuscular injection is rapidly absorbed, while estrone in aqueous suspension has a prolonged period of absorption.{{cite journal | vauthors = James DW | title = Management of the Menopause | journal = The Permanente Journal | date = Summer 1998 | volume = 2 | issue = 3 | pages = 25–29 | doi = 10.7812/TPP/98.930 | s2cid = 248135901 | url = http://www.thepermanentejournal.org/files/PDF/Summer1998.pdf#page=27 | quote = Using the same principle of delayed absorption, however, we have been able to improve the efficiency of estrone by suspending this fat soluble substance in an aqueous medium, reversing the procedure of suspending water soluble substances such as penicillin. in oil.3 The action of estrone in suspension is prolonged because the water vehicle is rapidly absorbed leaving a deposit of crystals in the tissues thus behaving like small implants of crystals which we know are relatively long acting.}} Upon intramuscular injection of estrone in aqueous solution, the water from the preparation is absorbed and a microcrystalline depot of estrone that is slowly absorbed by the body is formed.{{cite journal | vauthors = Freed SC | title = Some Fundamentals in Estrogen Therapy | journal = California Medicine | date = December 1946 | volume = 65 | issue = 6 | pages = 277–278 | pmid = 18731134 | pmc=1642736}} This is responsible for the prolonged duration of estrone in aqueous suspension compared to oil solution.

Unlike estradiol and estriol, estrone is not accumulated in target tissues.{{cite journal | vauthors = Wiegerinck MA, Poortman J, Donker TH, Thijssen JH | title = In vivo uptake and subcellular distribution of tritium-labeled estrogens in human endometrium, myometrium, and vagina | journal = J. Clin. Endocrinol. Metab. | volume = 56 | issue = 1 | pages = 76–86 | date = January 1983 | pmid = 6847874 | doi = 10.1210/jcem-56-1-76 | doi-access = free }} In terms of plasma protein binding, estrone is bound approximately 16% to sex hormone-binding globulin (SHBG) and 80% to albumin, with the remainder (2.0 to 4.0%) circulating free or unbound.{{cite book | vauthors = Nakamoto J, Salameh WA, Carlton E | chapter = Endocrine Testing | veditors = Jameson JL, De Groot LJ |title=Endocrinology – E-Book: Adult and Pediatric| chapter-url=https://books.google.com/books?id=W4dZ-URK8ZoC&pg=PA2813|date=18 May 2010|publisher=Elsevier Health Sciences|isbn=978-1-4557-1126-0|pages=2813–}} Estrone has about 24% of the relative binding affinity of estradiol for SHBG, and hence is relatively poorly bound to SHBG.

{{Estradiol metabolism|align=right}}

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-hydroxysteroid dehydrogenases (17β-HSDs), and this accounts for most or all of its estrogenic activity. 17β-HSD isoforms that are involved in the conversion of estrone into estradiol include 17β-HSD1, 17β-HSD3, 17β-HSD4, 17β-HSD7, 17β-HSD8, and 17β-HSD12, although the relative contributions of the different isoforms is unknown.{{cite journal | vauthors = Poirier D | title = 17beta-Hydroxysteroid dehydrogenase inhibitors: a patent review | journal = Expert Opin Ther Pat | volume = 20 | issue = 9 | pages = 1123–45 | date = September 2010 | pmid = 20645882 | doi = 10.1517/13543776.2010.505604 | s2cid = 35732314 }}{{Additional citation needed|date=June 2020}}

The biological half-lives of estrone and estradiol in the circulation are both about 10 to 70 minutes, whereas the biological half-life of estrone sulfate in the circulation is about 10 to 12 hours.{{cite book| vauthors = Dorfman RI |title=Radioactive Isotopes in Physiology Diagnostics and Therapy / Künstliche Radioaktive Isotope in Physiologie Diagnostik und Therapie|chapter=Steroid Hormone Metabolism|year=1961|pages=1223–1241|publisher=Springer |doi=10.1007/978-3-642-49761-2_39|isbn=978-3-642-49477-2}}{{cite journal | vauthors = Sandberg AA, Slaunwhite WR | title = Studies on phenolic steroids in human subjects. II. The metabolic fate and hepato-biliary-enteric circulation of C14-estrone and C14-estradiol in women | journal = The Journal of Clinical Investigation | volume = 36 | issue = 8 | pages = 1266–1278 | date = August 1957 | pmid = 13463090 | pmc = 1072719 | doi = 10.1172/JCI103524 }} The metabolic clearance rate of estrone is 1,050 L/day/m² and of estradiol is 580 L/day/m², while that of estrone sulfate is 80 L/day/m². For comparison, the metabolic clearance rate of estriol is 1,110 L/day/m². A single 1 to 2 mg dose of estrone in oil solution by intramuscular injection has a duration of about 2 or 3 days.{{cite journal | vauthors = Brown JB | title = The relationship between urinary oestrogens and oestrogens produced in the body | journal = The Journal of Endocrinology | volume = 16 | issue = 2 | pages = 202–212 | date = December 1957 | pmid = 13491750 | doi = 10.1677/joe.0.0160202 }}{{cite journal | vauthors = Beer CT, Gallagher TF | title = Excretion of estrogen metabolites by humans. I. The fate of small doses of estrone and estradiol-17beta | journal = The Journal of Biological Chemistry | volume = 214 | issue = 1 | pages = 335–349 | date = May 1955 | pmid = 14367392 | doi = 10.1016/S0021-9258(18)70972-1 | doi-access = free }} As an aqueous suspension by intramuscular injection, estrone was used at a dose of 0.1 to 0.5 mg 2 to 3 times per week, or at a dose of 0.1 to 2 mg once a week or in divided doses.{{cite book|author=Micromedex|title=USP DI 2003: Drug Information for Healthcare Professionals|url=https://books.google.com/books?id=zEzWtsVl-KgC|date=1 January 2003|publisher=Thomson Micromedex|isbn=978-1-56363-429-1|page=1246|quote=ESTRONE Parenteral Dosage Forms ESTRONE INJECTABLE SUSPENSION USP Usual adult dose Atrophic vaginitis or Menopausal (vasomotor) symptoms or Vulvar atrophy—Intramuscular, 100 to 500 mcg (0.1 to 0.5 mg) two or three times a week, cyclically or continuously as appropriate. Estrogen deficiency, due to ovariectomy or Female hypogonadism or Primary ovarian failure—Intramuscular, 100 mcg (0.1 mg) to 1 mg a week, administered as a single dose or in divided doses, cyclically or continuously. A few patients may need doses of up to 2 mg a week.}} In one rodent study, exogenous estrone was administered and increased circulating estradiol levels by about 10-fold; co-administration of a selective 17β-HSD1 inhibitor decreased estradiol levels by about 50%.{{cite journal | vauthors = Day JM, Foster PA, Tutill HJ, Parsons MF, Newman SP, Chander SK, Allan GM, Lawrence HR, Vicker N, Potter BV, Reed MJ, Purohit A | display-authors = 6 | title = 17beta-hydroxysteroid dehydrogenase Type 1, and not Type 12, is a target for endocrine therapy of hormone-dependent breast cancer | journal = International Journal of Cancer | volume = 122 | issue = 9 | pages = 1931–1940 | date = May 2008 | pmid = 18183589 | doi = 10.1002/ijc.23350 | doi-access = free }}

The ratio of circulating estrone to circulating estradiol is the same at about 5:1 with both oral estradiol and oral estrone sulfate. An investigational estrone vaginal ring was found to result in a ratio of estrone to estradiol of 4:1 or 5:1 initially, but this decreased to about 1:1 with continuous therapy.

Estrone is excreted in urine in the form of estrogen conjugates such as estrone sulfate and estrone glucuronide. 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.

{{See also|List of estrogens#Estrone derivatives|List of estrogen esters#Estrone esters}}

{{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.}}

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.

A variety of estrone esters have been synthesized and described. These include the marketed esters estrone acetate, estrone sulfate, estrone tetraacetylglucoside, and estropipate (piperazine estrone sulfate), and the never-marketed esters estrone benzoate, estrone cyanate, estrone glucuronide, and estrone sulfamate.

{{See also|Estrone#History}}

In 1927, Bernhard Zondek and Selmar Aschheim discovered that large amounts of estrogens were excreted in the urine of pregnant women.{{cite book | vauthors = Gruhn JG | chapter = Historical Introduction to Gonadal Regulation of the Uterus and the Menses. | veditors = Josimovich JB |title=Gynecologic Endocrinology| chapter-url=https://books.google.com/books?id=9vv2BwAAQBAJ&pg=PA8|date=11 November 2013|publisher=Springer Science & Business Media|isbn=978-1-4613-2157-6|pages=8–}}{{cite book| vauthors = Ravina E |title=The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs|url=https://books.google.com/books?id=iDNy0XxGqT8C&pg=PA175|date=18 April 2011|publisher=John Wiley & Sons|isbn=978-3-527-32669-3|pages=175–}} This rich source of estrogens allowed the development of potent estrogenic formulations for scientific and clinical use. In 1929, pure crystalline estrone was isolated from the urine of pregnant women by various researchers.{{cite book| vauthors = Bullough VL |title=Science In The Bedroom: A History Of Sex Research|url=https://books.google.com/books?id=Z7__qJK470AC&pg=PA128|date=19 May 1995|publisher=Basic Books|isbn=978-0-465-07259-0|pages=128–|quote=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 2023 |bot=InternetArchiveBot |fix-attempted=yes }}{{cite book| vauthors = Nielsch U, Fuhrmann U, Jaroch S |title=New Approaches to Drug Discovery|url=https://books.google.com/books?id=elneCwAAQBAJ&pg=PA7|date=30 March 2016|publisher=Springer|isbn=978-3-319-28914-4|pages=7–|quote=The first steroid hormone was isolated from the urine of pregnant women by Adolf Butenandt in 1929 (estrone; see Fig. 1) (Butenandt 1931).}} By 1929, pharmaceutical preparations including Amniotin (Squibb), Progynon (Schering), and Theelin (Parke-Davis), purified from pregnancy urine, placentas, and/or amniotic fluid and containing purified estrone or mixtures of estrogens that included estrone, were being sold commercially for use by intramuscular injection.{{cite journal | vauthors = Hammond CB, Maxson WS | title = Current status of estrogen therapy for the menopause | journal = Fertility and Sterility | volume = 37 | issue = 1 | pages = 5–25 | date = January 1982 | pmid = 6277697 | doi = 10.1016/S0015-0282(16)45970-4 }}{{cite journal| vauthors = Biskind MS |title=Commercial Glandular Products|journal=Journal of the American Medical Association|volume=105|issue=9|year=1935|pages=667|issn=0002-9955|doi=10.1001/jama.1935.92760350007009a}}{{cite book| vauthors = Watkins ES |title=The Estrogen Elixir: A History of Hormone Replacement Therapy in America|url=https://books.google.com/books?id=-tz4J4_hgdIC&pg=PA21|date=6 March 2007|publisher=JHU Press|isbn=978-0-8018-8602-7|pages=21–}} Other products and brand names of estrone marketed in the 1930s included Estrone (Abbott, Lilly), Oestroform (British Drug Houses), Folliculin (Organon), Menformon (Organon), and Ketodestrin (Paines & Byrne), among others.{{cite journal | vauthors = Johnstone RW | title = Sex Hormone Therapy in Gynæcology | journal = Edinburgh Medical Journal | volume = 43 | issue = 11 | pages = 680–695 | date = November 1936 | pmid = 29648134 | pmc = 5303355 }}{{cite book| vauthors = Burrows H |title=Biological Actions of Sex Hormones|url=https://books.google.com/books?id=MFw4AAAAIAAJ&pg=PA558|date=March 2003|publisher=CUP Archive|isbn=978-0-521-04394-6|pages=558–}} These formulations included ampoules of oil or aqueous solution for intramuscular injection, oral tablets, and vaginal suppositories.{{cite journal | vauthors = Fluhmann CF | title = Estrogenic Hormones: Their Clinical Usage | journal = California and Western Medicine | volume = 49 | issue = 5 | pages = 362–366 | date = November 1938 | pmid = 18744783 | pmc = 1659459 }}{{cite journal| vauthors = Novak E |title=The Therapeutic Use of Estrogenic Substances|journal=JAMA: The Journal of the American Medical Association|volume=104|issue=20|year=1935|pages=1815|issn=0098-7484|doi=10.1001/jama.1935.92760200002012}} Estrone in aqueous suspension for use by intramuscular injection was first described in 1941 and was introduced for medical use under the brand name Theelin Aqueous Suspension by 1944.{{cite journal| vauthors = Fluhmann CF |title=Clinical use of extracts from the ovaries|journal=Journal of the American Medical Association|volume=125|issue=1|year=1944|pages=1|issn=0002-9955|doi=10.1001/jama.1944.02850190003001}}{{cite journal | vauthors = Freed SC | title = Diethylstilbestrol in aqueous suspension | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 6 | issue = 6 | pages = 420–422 | date = June 1946 | pmid = 20988414 | doi = 10.1210/jcem-6-6-420 | quote = We have already reported our employing injections of estrone crystals suspended in aqueous medium in order to obtain freedom from allergic reactions (1). This preparation, now available commercially, has proven satisfactory not only from this standpoint, but also because of its increased effectiveness over estrone dissolved in oil. }}

Estrone is the generic name of estrone in American English and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USP|United States Pharmacopeia}}, {{abbrlink|BAN|British Approved Name}}, {{abbrlink|DCF|Dénomination Commune Française}}, {{abbrlink|DCIT|Denominazione Comune Italiana}}, and {{abbrlink|JAN|Japanese Accepted Name}}.{{Cite web |url=https://www.drugs.com/international/estrone.html |title=Estrone - Drugs.com |access-date=21 June 2018 |archive-date=21 June 2018 |archive-url=https://web.archive.org/web/20180621143924/https://www.drugs.com/international/estrone.html |url-status=dead }} Oestrone, in which the "O" is silent, was the former {{abbrlink|BAN|British Approved Name}} of estrone and its name in British English, but the spelling was eventually changed to estrone.

Estrone has been marketed under a variety of brand names, including Andrestraq, Aquacrine, A.T.V., Bestrone, Centrogen, Cicatral, Cormone, Crinovaryl, Cristallovar, Crystogen, Destrone, Disynformon, Endofolliculina, Estragyn, Estroject, Estrol, Estrone, Estrone Aqueous Suspension, Estrone-A, Estrugenone, Estrusol, Femestrone, Femidyn, Folikrin, Folipex, Folisan, Folliculin, Follicunodis, Follidrin, Gineburno, Glandubolin, Grietalgen, Grietalgen Hidrocort, Gynogen, Hiestrone, Hormofollin, Hormonin, Hormovarine, Kestrin, Kestrone, Ketodestrin, Kolpon, Ladies Pearl, Livifolin, Menagen, Metharmon-F, Neo-Estrone, Oestrilin, Oestrin, Oestroform, Oestroperos, Ovex, Ovifollin, Perlatan, Progynon, Senikolp, Solliculin, Solutio Folliculinum, Synergon (in combination with progesterone), Theelin, Thynestron, Tokokin, Unden, Unigen, Wehgen, and Wynestron.{{cite book|author=International Agency for Research on Cancer|title=Sex Hormones (II).|url=https://books.google.com/books?id=nrhrAAAAMAAJ|year=1979|publisher=International Agency for Research on Cancer|isbn=978-92-832-1221-8}}{{cite book | vauthors = Milne GW |title=Ashgate Handbook of Endocrine Agents and Steroids|url=https://books.google.com/books?id=GFM8DwAAQBAJ&pg=PT138|date=1 November 2017|publisher=Taylor & Francis|isbn=978-1-351-74347-1|pages=138–}}

Brand names of estrone in aqueous suspension specifically include Bestrone, Estaqua, Estrofol, Estroject, Estrone-A, Estronol, Femogen, Foygen Aqueous, Gravigen Aqueous, Gynogen, Hormogen-A, Kestrin Aqueous, Kestrone, Theelin Aqueous, Theogen, Unigen, and Wehgen.{{cite book|author=Inc United States Pharmacopeial Convention|title=Drug Information for the Health Care Provider|url=https://books.google.com/books?id=qYYQipCXoVcC|date=February 1987|publisher=United States Pharmacopeial|isbn=978-0-913595-15-2|pages=765, 770}}

{{See also|Estropipate#Availability|Conjugated estrogens#Availability|Esterified estrogens#Availability}}

Although estrone has been widely marketed in the past, it has mostly been discontinued and remains available in only a few countries. These countries reportedly include Canada, Georgia, Monaco, and Taiwan. However, estrone remains widely available throughout the world in the form of estrone sulfate, which can be found in estropipate (piperazine estrone sulfate), conjugated estrogens (Premarin), and esterified estrogens (Estratab, Menest).{{cite web |url=https://www.drugs.com/international/estropipate.html |title=Estropipate |author= |website=Drugs.com }}

An estrone vaginal ring was developed and studied for use in menopausal hormone therapy.{{cite journal | vauthors = Sipinen S, Lähteenmäki P, Luukkainen T | title = An oestrone-releasing vaginal ring in the treatment of climacteric women | journal = Maturitas | volume = 2 | issue = 4 | pages = 291–9 | date = December 1980 | pmid = 7231201 | doi = 10.1016/0378-5122(80)90031-6 }} It increased estrogen levels, suppressed gonadotropin levels, and relieved menopausal symptoms. Subcutaneous pellet implantation of estrone has also been studied.{{cite journal | vauthors = Bishop PM | title = Clinical Experiment in Oestrin Therapy | journal = Br Med J | volume = 1 | issue = 4034 | pages = 939–41 | date = April 1938 | pmid = 20781420 | pmc = 2086334 | doi = 10.1136/bmj.1.4034.939 }}{{cite journal | vauthors = Bishop PM, Folley SJ | title = Absorption of hormone implants in man | journal = Lancet | volume = 2 | issue = 6676 | pages = 229–32 | date = August 1951 | pmid = 14862159 | doi = 10.1016/S0140-6736(51)93237-0 }}

• Estradiol/estrone/estriol
• Estrone/progesterone
• Estrogenic substances

{{Reflist}}

{{refbegin}}

• {{cite book| vauthors = Oettel M, Schillinger E |title=Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen|url=https://books.google.com/books?id=wBvyCAAAQBAJ|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-60107-1}}
• {{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | issue = Suppl 1 | pages = 3–63 | year = 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf}}

{{refend}}

{{Estrogens and antiestrogens}}

{{Estrogen receptor modulators}}

Category:Abandoned drugs

Category:Hydroxyarenes

Category:Sterols

Category:Estranes

Category:Estrogens

Category:Ketones

Category:Sex hormone esters and conjugates