Estrone sulfate

E1S itself is biologically inactive, with less than 1% of the relative binding affinity of estradiol for the ERα and ERβ.{{cite journal | vauthors = Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, Gustafsson JA | title = Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta | journal = Endocrinology | volume = 138 | issue = 3 | pages = 863–70 | date = March 1997 | pmid = 9048584 | doi = 10.1210/endo.138.3.4979 | doi-access = free }} However, it can be transformed by steroid sulfatase, also known as estrogen sulfatase, into estrone, an estrogen.{{cite book | first1 = Tommaso | last1 = Falcone | first2 = William W. | last2 = Hurd |title=Clinical Reproductive Medicine and Surgery: A Practical Guide|url=https://books.google.com/books?id=TAYnR1b8jRkC&pg=PA5|date=22 May 2013|publisher=Springer Science & Business Media|isbn=978-1-4614-6837-0|pages=5–6}} Simultaneously, estrogen sulfotransferases, including SULT1A1 and SULT1E1, convert estrone to E1S, resulting in an equilibrium between the two steroids in various tissues. Estrone can also be converted by 17β-hydroxysteroid dehydrogenases into the more potent estrogen estradiol. E1S levels are much higher than those of estrone and estradiol, and it is thought to serve as a long-lasting reservoir for estrone and estradiol in the body.{{cite book |first1 = Shlomo | last1 = Melmed | first2 = Kenneth S. | last2 = Polonsky | first3 = P. Reed | last3 = Larsen | first4 = Henry M. | last4 = Kronenberg |title=Williams Textbook of Endocrinology |edition=13th |url=https://books.google.com/books?id=iPIACwAAQBAJ&pg=PA607 |date=11 November 2015 |publisher=Elsevier Health Sciences |isbn=978-0-323-34157-8 |pages=607–}}{{cite book | first1 = James M. | last1 = Greenblatt | first2 = Kelly | last2 = Brogan |title=Integrative Therapies for Depression: Redefining Models for Assessment, Treatment and Prevention|url=https://books.google.com/books?id=GpHwCgAAQBAJ&pg=PA198|date=27 April 2016|publisher=CRC Press|isbn=978-1-4987-0230-0|pages=198–}} In accordance, E1S has been found to transactivate the estrogen receptor at physiologically relevant concentrations.{{cite journal | vauthors = Bjerregaard-Olesen C, Ghisari M, Kjeldsen LS, Wielsøe M, Bonefeld-Jørgensen EC | title = Estrone sulfate and dehydroepiandrosterone sulfate: Transactivation of the estrogen and androgen receptor | journal = Steroids | volume = 105 | pages = 50–8 | date = January 2016 | pmid = 26666359 | doi = 10.1016/j.steroids.2015.11.009 | s2cid = 46663814 }}{{cite book|last1=Clark|first1=Barbara J.|title=Dehydroepiandrosterone|last2=Prough|first2=Russell A.|last3=Klinge|first3=Carolyn M.|chapter=Mechanisms of Action of Dehydroepiandrosterone|volume=108|year=2018|pages=29–73|issn=0083-6729|doi=10.1016/bs.vh.2018.02.003|series=Vitamins and Hormones|pmid=30029731|isbn=978-0-12-814361-2}} This was diminished with co-application of irosustat (STX-64), a steroid sulfatase inhibitor, indicating the importance of transformation of estrone sulfate into estrone in the estrogenicity of E1S.

Unlike unconjugated estradiol and estrone, which are lipophilic compounds, E1S is an anion and is hydrophilic.{{cite journal | vauthors = Purohit A, Woo LW, Potter BV | title = Steroid sulfatase: a pivotal player in estrogen synthesis and metabolism | journal = Mol. Cell. Endocrinol. | volume = 340 | issue = 2 | pages = 154–60 | date = July 2011 | pmid = 21693170 | doi = 10.1016/j.mce.2011.06.012 | s2cid = 14296237 | url = https://hal.archives-ouvertes.fr/hal-00717913/file/PEER_stage2_10.1016%252Fj.mce.2011.06.012.pdf}}{{cite journal | vauthors = Africander D, Storbeck KH | title = Steroid metabolism in breast cancer: Where are we and what are we missing? | journal = Mol. Cell. Endocrinol. | volume = 466 | pages = 86–97 | date = May 2018 | pmid = 28527781 | doi = 10.1016/j.mce.2017.05.016 | s2cid = 4547808 }}{{cite journal | vauthors = Mueller JW, Gilligan LC, Idkowiak J, Arlt W, Foster PA | title = The Regulation of Steroid Action by Sulfation and Desulfation | journal = Endocr. Rev. | volume = 36 | issue = 5 | pages = 526–63 | date = October 2015 | pmid = 26213785 | pmc = 4591525 | doi = 10.1210/er.2015-1036 }} As a result of this, whereas estradiol and estrone are able to readily diffuse through the lipid bilayers of cells, E1S is unable to permeate through cell membranes. Instead, estrone sulfate is transported into cells in a tissue-specific manner by active transport via organic-anion-transporting polypeptides (OATPs), including OATP1A2, OATP1B1, OATP1B3, OATP1C1, OATP2B1, OATP3A1, OATP4A1, and OATP4C1, as well as by the sodium-dependent organic anion transporter (SOAT; SLC10A6).{{cite journal | vauthors = Obaidat A, Roth M, Hagenbuch B | title = The expression and function of organic anion transporting polypeptides in normal tissues and in cancer | journal = Annu. Rev. Pharmacol. Toxicol. | volume = 52 | pages = 135–51 | date = 2012 | pmid = 21854228 | pmc = 3257355 | doi = 10.1146/annurev-pharmtox-010510-100556 }}{{cite journal | vauthors = Karakus E, Zahner D, Grosser G, Leidolf R, Gundogdu C, Sánchez-Guijo A, Wudy SA, Geyer J | title = Estrone-3-Sulfate Stimulates the Proliferation of T47D Breast Cancer Cells Stably Transfected With the Sodium-Dependent Organic Anion Transporter SOAT (SLC10A6) | journal = Front Pharmacol | volume = 9 | pages = 941 | date = 2018 | pmid = 30186172 | pmc = 6111516 | doi = 10.3389/fphar.2018.00941 | doi-access = free }}

E1S, serving as a precursor and intermediate for estrone and estradiol, may be involved in the pathophysiology of estrogen-associated diseases including breast cancer, benign breast disease, endometrial cancer, ovarian cancer, prostate cancer, and colorectal cancer.{{cite journal | vauthors = Banerjee N, Fonge H, Mikhail A, Reilly RM, Bendayan R, Allen C | title = Estrone-3-sulphate, a potential novel ligand for targeting breast cancers | journal = PLOS ONE | volume = 8 | issue = 5 | pages = e64069 | date = 2013 | pmid = 23717534 | pmc = 3661587 | doi = 10.1371/journal.pone.0064069 | bibcode = 2013PLoSO...864069B | doi-access = free }}{{cite journal | vauthors = Gilligan LC, Gondal A, Tang V, Hussain MT, Arvaniti A, Hewitt AM, Foster PA | title = Estrone Sulfate Transport and Steroid Sulfatase Activity in Colorectal Cancer: Implications for Hormone Replacement Therapy | journal = Front Pharmacol | volume = 8 | pages = 103 | date = 2017 | pmid = 28326039 | pmc = 5339229 | doi = 10.3389/fphar.2017.00103 | doi-access = free }} For this reason, enzyme inhibitors of steroid sulfatase and 17β-hydroxysteroid dehydrogenase and inhibitors of OATPs, which prevent activation of E1S into estrone and estradiol, are of interest in the potential treatment of such conditions.

{{Affinities and estrogenic potencies of estrogen esters and ethers at the estrogen receptors}}

{{See also|List of estrogens|Estrogen ester|List of estrogen esters}}

E1S, also known as estrone 3-sulfate or as estra-1,3,5(10)-trien-17-one 3-sulfate, is a naturally occurring estrane steroid and a derivative of estrone.{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA900|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=900–}} It is an estrogen conjugate or ester, and is specifically the C3 sulfate ester of estrone. Related estrogen conjugates include estradiol sulfate, estriol sulfate, estrone glucuronide, estradiol glucuronide, and estriol glucuronide, while related steroid conjugates include dehydroepiandrosterone sulfate and pregnenolone sulfate.

The logP of E1S is 1.4.{{cite journal | vauthors = Banerjee N, Fonge H, Mikhail A, Reilly RM, Bendayan R, Allen C | title = Estrone-3-sulphate, a potential novel ligand for targeting breast cancers | journal = PLOS ONE | volume = 8 | issue = 5 | pages = e64069 | date = 2013 | pmid = 23717534 | pmc = 3661587 | doi = 10.1371/journal.pone.0064069 | bibcode = 2013PLoSO...864069B | doi-access = free }}

E1S is produced via estrogen sulfotransferases from the peripheral metabolism of the estrogens estradiol and estrone.{{cite journal|last1=Longcope|first1=Christopher|last2=Flood|first2=Charles|last3=Tast|first3=Janet|title=The metabolism of estrone sulfate in the female rhesus monkey|journal=Steroids|volume=59|issue=4|year=1994|pages=270–273|issn=0039-128X|doi=10.1016/0039-128X(94)90112-0|pmid=8079382|s2cid=42846339|quote=The source of E1SO4 in humans is from the peripheral conversion of E1 and E2, 6,7 [...] In human females there is little evidence for the ovarian secretion of E1SO4. 7 Since most of our monkeys were ovariectomized, we cannot say that the rhesus ovaries do not secrete E1SO4, but it is probably unlikely.}}{{cite journal|last1=Ruder|first1=Henry J.|last2=Loriaux|first2=Lynn|last3=Lipsett|first3=M. B.|title=Estrone Sulfate: Production Rate and Metabolism in Man|journal=Journal of Clinical Investigation|volume=51|issue=4|year=1972|pages=1020–1033|issn=0021-9738|doi=10.1172/JCI106862|pmc=302214|pmid=5014608}}{{cite journal|last1=Longcope|first1=Christopher|title=The Metabolism of Estrone Sulfate in Normal Males|journal=The Journal of Clinical Endocrinology & Metabolism|volume=34|issue=1|year=1972|pages=113–122|issn=0021-972X|doi=10.1210/jcem-34-1-113|pmid=5008222}} Estrogen sulfotransferases are expressed minimally or not at all in the gonads.{{cite journal|last1=Hobkirk|first1=R.|title=Steroid sulfotransferases and steroid sulfate sulfatases: characteristics and biological roles|journal=Canadian Journal of Biochemistry and Cell Biology|volume=63|issue=11|year=1985|pages=1127–1144|issn=0714-7511|doi=10.1139/o85-141|pmid=3910206}} In accordance, E1S is not secreted in meaningful amounts from the gonads in humans.{{cite book|last=Strauss|first=Jerome F.|chapter=Steroid Hormones and Other Lipid Molecules Involved in Human Reproduction|pages=75–114|doi=10.1016/B978-0-323-47912-7.00004-4|editor1=Jerome F. Strauss|editor2=Robert L. Barbieri|title=Yen & Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management|edition=8|year=2019|publisher=Elsevier Health Sciences|isbn=978-0-323-58232-2|s2cid=90621016 |chapter-url=https://books.google.com/books?id=67ZEDwAAQBAJ&pg=PA97}} However, measurable amounts of estrogen sulfates are said to be secreted by the ovaries in any case.Brooks, S. C., Horn, L., Pack, B. A., Rozhin, J., Hansen, E., & Goldberg, R. (1980). Estrogen metabolism and function in vivo and in vitro. In Estrogens in the Environment (Vol. 5, pp. 147-167). Elsevier/North Holland New York.

{{Production rates, secretion rates, clearance rates, and blood levels of major sex hormones}}

Whereas free steroids like estradiol are lipophilic and can enter cells via passive diffusion, steroid conjugates like E1S are hydrophilic and are unable to do so. Instead, steroid conjugates require active transport via membrane transport proteins to enter cells.

Studies in animals and humans have had mixed findings on uptake of exogenously administered E1S in normal and tumorous mammary gland tissue.{{cite journal | vauthors = Purohit A, Riaz AA, Ghilchik MW, Reed MJ | title = The origin of oestrone sulphate in normal and malignant breast tissues in postmenopausal women | journal = Horm. Metab. Res. | volume = 24 | issue = 11 | pages = 532–6 | date = November 1992 | pmid = 1452119 | doi = 10.1055/s-2007-1003382 | s2cid = 260167615 }}{{cite journal | vauthors = Masamura S, Santner SJ, Santen RJ | title = Evidence of in situ estrogen synthesis in nitrosomethylurea-induced rat mammary tumors via the enzyme estrone sulfatase | journal = J. Steroid Biochem. Mol. Biol. | volume = 58 | issue = 4 | pages = 425–9 | date = July 1996 | pmid = 8903427 | doi = 10.1016/0960-0760(96)00065-9 | s2cid = 22100628 }}{{cite journal | vauthors = Thijssen JH | title = Local biosynthesis and metabolism of oestrogens in the human breast | journal = Maturitas | volume = 49 | issue = 1 | pages = 25–33 | date = September 2004 | pmid = 15351093 | doi = 10.1016/j.maturitas.2004.06.004 }}{{cite journal | vauthors = Reed MJ, Purohit A, Woo LW, Newman SP, Potter BV | title = Steroid sulfatase: molecular biology, regulation, and inhibition | journal = Endocr. Rev. | volume = 26 | issue = 2 | pages = 171–202 | date = April 2005 | pmid = 15561802 | doi = 10.1210/er.2004-0003 | doi-access = free }}{{cite journal | vauthors = Geisler J | title = Breast cancer tissue estrogens and their manipulation with aromatase inhibitors and inactivators | journal = J. Steroid Biochem. Mol. Biol. | volume = 86 | issue = 3–5 | pages = 245–53 | date = September 2003 | pmid = 14623518 | doi = 10.1016/s0960-0760(03)00364-9 | s2cid = 23065230 }} This is in contrast to substantial uptake of exogenously administered estradiol and estrone by the mammary glands. Another animal study found that E1S wasn't taken up by the uterus but was taken up by the liver, where it was hydrolyzed into estrone.{{cite journal | vauthors = Holinka CF, Gurpide E | title = In vivo uptake of estrone sulfate by rabbit uterus | journal = Endocrinology | volume = 106 | issue = 4 | pages = 1193–7 | date = April 1980 | pmid = 7358033 | doi = 10.1210/endo-106-4-1193 }}

The elimination half-life of E1S is 10 to 12 hours. Its metabolic clearance rate is 80 L/day/m².

Ovarian tumors have been found to express steroid sulfatase and have been found to convert E1S into estradiol.{{cite journal|last1=Day|first1=Joanna M.|last2=Purohit|first2=Atul|last3=Tutill|first3=Helena J.|last4=Foster|first4=Paul A.|last5=Woo|first5=L. W. Lawrence|last6=Potter|first6=Barry V. L.|last7=Reed|first7=Michael J.|title=The Development of Steroid Sulfatase Inhibitors for Hormone-Dependent Cancer Therapy|journal=Annals of the New York Academy of Sciences|volume=1155|issue=1|year=2009|pages=80–87|issn=0077-8923|doi=10.1111/j.1749-6632.2008.03677.x|pmid=19250195|bibcode=2009NYASA1155...80D |s2cid=25306673}}{{cite journal|last1=Kirilovas|first1=Dmitrijus|last2=Schedvins|first2=Kjell|last3=Naessén|first3=Tord|last4=Von Schoultz|first4=Bo|last5=Carlström|first5=Kjell|title=Conversion of circulating estrone sulfate to 17β-estradiol by ovarian tumor tissue: A possible mechanism behind elevated circulating concentrations of 17β-estradiol in postmenopausal women with ovarian tumors|journal=Gynecological Endocrinology|volume=23|issue=1|year=2009|pages=25–28|issn=0951-3590|doi=10.1080/09513590601058333|pmid=17484508|s2cid=25115594}} This may contribute to the often elevated levels of estradiol observed in women with ovarian cancer.

{{Estradiol metabolism}}

File:Estradiol, estrone, and estrone sulfate levels during the normal human menstrual cycle.png (RIA) around mid-cycle during the normal menstrual cycle in women.{{cite journal | vauthors = Pasqualini JR, Gelly C, Nguyen BL | title = Metabolism and biologic response of estrogen sulfates in hormone-dependent and hormone-independent mammary cancer cell lines. Effect of antiestrogens | journal = Ann. N. Y. Acad. Sci. | volume = 595 | pages = 106–16 | date = 1990 | issue = 1 | pmid = 2375600 | doi = 10.1111/j.1749-6632.1990.tb34286.x | bibcode = 1990NYASA.595..106P | s2cid = 26940935 }}{{cite journal | vauthors = Nuñez M, Aedo AR, Landgren BM, Cekan SZ, Diczfalusy E | title = Studies on the pattern of circulating steroids in the normal menstrual cycle. 6. Levels of oestrone sulphate and oestradiol sulphate | journal = Acta Endocrinol. | volume = 86 | issue = 3 | pages = 621–33 | date = November 1977 | pmid = 579025 | doi = 10.1530/acta.0.0860621 }} The vertical dashed line in the center is mid-cycle.]]

E1S levels have been characterized in humans.{{cite journal | vauthors = Honjo H, Kitawaki J, Itoh M, Yasuda J, Iwasaku K, Urabe M, Naitoh K, Yamamoto T, Okada H, Ohkubo T | title = Serum and urinary estrone sulfate during the menstrual cycle, measured by a direct radioimmunoassay, and fate of exogenously injected estrone sulfate | journal = Horm Res | volume = 27 | issue = 2 | pages = 61–8 | date = 1987 | pmid = 3653846 | doi = 10.1159/000180788 }} E1S using radioimmunoassay (RIA) have been reported to be 0.96 ± 0.11 ng/mL in men, 0.96 ± 0.17 ng/mL during the follicular phase in women, 1.74 ± 0.32 ng/mL during the luteal phase in women, 0.74 ± 0.11 ng/mL in women taking oral contraceptives, 0.13 ± 0.03 ng/mL in postmenopausal women, and 2.56 ± 0.47 ng/mL in postmenopausal women on menopausal hormone therapy.{{cite journal | vauthors = Ranadive GN, Mistry JS, Damodaran K, Khosravi MJ, Diamandi A, Gimpel T, Castracane VD, Patel S, Stanczyk FZ | title = Rapid, convenient radioimmunoassay of estrone sulfate | journal = Clin. Chem. | volume = 44 | issue = 2 | pages = 244–9 | date = February 1998 | pmid = 9474019 | doi = 10.1093/clinchem/44.2.244 | doi-access = free }} In addition, E1S levels in pregnant women were 19 ± 5 ng/mL in the first trimester, 66 ± 31 ng/mL in the second trimester, and 105 ± 22 ng/mL in the third trimester. E1S levels are about 10 to 15 times higher than those of estrone in women.{{cite book|last1=Cowie|first1=Alfred T.|last2=Forsyth|first2=Isabel A.|last3=Hart|first3=Ian C.|title=Hormonal Control of Lactation|chapter=Growth and Development of the Mammary Gland|series=Monographs on Endocrinology|volume=15|year=1980|pages=58–145|issn=0077-1015|doi=10.1007/978-3-642-81389-4_3|isbn=978-3-642-81391-7}}

{{Clear}}

{{Reflist}}

{{refbegin}}

• {{cite journal | vauthors = Rezvanpour A, Don-Wauchope AC | title = Clinical implications of estrone sulfate measurement in laboratory medicine | journal = Critical Reviews in Clinical Laboratory Sciences | volume = 54 | issue = 2 | pages = 73–86 | date = March 2017 | pmid = 27960570 | doi = 10.1080/10408363.2016.1252310 | s2cid = 1825531 }}

{{refend}}

{{Steroid hormones}}

{{Estrogen receptor modulators}}

Category:Estrogens

Category:Estrone esters

Category:Human metabolites

Category:Sex hormone esters and conjugates

Category:Phenol esters

Category:Sulfate esters