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{{About|estrone sulfate as a hormone|its use as a medication|Estrone sulfate (medication)}}
{{About|estrone sulfate as a hormone|its use as a medication|Estrone sulfate (medication)}}
{{Use dmy dates|date=August 2018}}
{{Use dmy dates|date=August 2018}}
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| ImageAlt2 = Space-filling model of the estrone sulfate molecule
| ImageAlt2 = Space-filling model of the estrone sulfate molecule
<!-- Names -->
<!-- Names -->
| IUPACName = [(8''R'',9''S'',13''S'',14''S'')-13-methyl-17-oxo-7,8,9,11,12,14,15,16-octahydro-6''H''-cyclopenta[''a'']phenanthren-3-yl] hydrogen sulfate
| IUPACName = 17-Oxoestra-1,3,5(10)-trien-3-yl hydrogen sulfate
| SystematicName = (3a''S'',3b''R'',9b''S'',11a''S'')-11a-Methyl-1-oxo-2,3,3a,3b,4,5,9b,10,11,11a-decahydro-1''H''-cyclopenta[''a'']phenanthren-7-yl hydrogen sulfate
| OtherNames = E1S; Oestrone sulfate; Estrone 3-sulfate; Estra-1,3,5(10)-trien-17-one 3-sulfate
| OtherNames = E1S; Oestrone sulfate; Estrone 3-sulfate; Estra-1,3,5(10)-trien-17-one 3-sulfate
<!-- Sections -->
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'''Estrone sulfate''', also known as '''E1S''', '''E1SO4''' and '''estrone 3-sulfate''', is a [[natural product|natural]], [[endogenous]] [[steroid]] and an [[estrogen ester]] and [[estrogen conjugate|conjugate]].<ref name="pmid27960570">{{cite journal | vauthors = Rezvanpour A, Don-Wauchope AC | title = Clinical implications of estrone sulfate measurement in laboratory medicine | journal = Crit Rev Clin Lab Sci | volume = 54 | issue = 2 | pages = 73–86 | date = March 2017 | pmid = 27960570 | doi = 10.1080/10408363.2016.1252310 | url = }}</ref><ref name="Lobo2007">{{cite book| first = Rogerio A. | last = Lobo | name-list-format = vanc |title=Treatment of the Postmenopausal Woman: Basic and Clinical Aspects|url=https://books.google.com/books?id=gywV9hkcyOMC&pg=PA768|date=5 June 2007|publisher=Academic Press|isbn=978-0-08-055309-2|pages=768–}}</ref><ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 Suppl 1 | issue = | pages = 3–63 | year = 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf}}</ref>
'''Estrone sulfate''', also known as '''E1S''', '''E1SO4''' and '''estrone 3-sulfate''', is a [[natural product|natural]], [[endogenous]] [[steroid]] and an [[estrogen ester]] and [[estrogen conjugate|conjugate]].<ref name="pmid27960570">{{cite journal | vauthors = Rezvanpour A, Don-Wauchope AC | title = Clinical implications of estrone sulfate measurement in laboratory medicine | journal = Crit Rev Clin Lab Sci | volume = 54 | issue = 2 | pages = 73–86 | date = March 2017 | pmid = 27960570 | doi = 10.1080/10408363.2016.1252310 | s2cid = 1825531 }}</ref><ref name="Lobo2007">{{cite book| first = Rogerio A. | last = Lobo |title=Treatment of the Postmenopausal Woman: Basic and Clinical Aspects|url=https://books.google.com/books?id=gywV9hkcyOMC&pg=PA768|date=5 June 2007|publisher=Academic Press|isbn=978-0-08-055309-2|pages=768–}}</ref><ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | pages = 3–63 | year = 2005 | issue = Suppl 1 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf}}</ref>


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


==Biological function==
==Biological function==
E1S itself is biologically inactive, with less than 1% of the [[relative binding affinity]] of estradiol for the [[ERα]] and [[ERβ]].<ref name="pmid16112947" /><ref name="pmid9048584">{{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 }}</ref> However, it can be [[biotransformation|transformed]] by [[steroid sulfatase]], also known as estrogen sulfatase, into [[estrone]], an [[estrogen]].<ref name="FalconeHurd2013">{{cite book | first1 = Tommaso | last1 = Falcone | first2 = William W. | last2 = Hurd | name-list-format = vanc |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}}</ref> Simultaneously, [[estrogen sulfotransferase]]s, including [[SULT1A1]] and [[SULT1E1]], convert estrone to E1S, resulting in an [[chemical equilibrium|equilibrium]] between the two steroids in various tissues.<ref name="pmid27960570" /><ref name="FalconeHurd2013" /> Estrone can also be converted by [[17β-hydroxysteroid dehydrogenase]]s into the more [[potency (pharmacology)|potent]] estrogen [[estradiol]].<ref name="pmid27960570" /> 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.<ref name="pmid27960570" /><ref name="MelmedPolonsky2015">{{cite book |first1 = Shlomo | last1 = Melmed | first2 = Kenneth S. | last2 = Polonsky | first3 = P. Reed | last3 = Larsen | first4 = Henry M. | last4 = Kronenberg | name-list-format = vanc |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–}}</ref><ref name="GreenblattBrogan2016">{{cite book | first1 = James M. | last1 = Greenblatt | first2 = Kelly | last2 = Brogan | name-list-format = vanc |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–}}</ref> In accordance, E1S has been found to [[transactivation|transactivate]] the [[estrogen receptor]] at physiologically relevant concentrations.<ref name="pmid26666359">{{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 | issue = | pages = 50–8 | date = January 2016 | pmid = 26666359 | doi = 10.1016/j.steroids.2015.11.009 | url = }}</ref><ref name="ClarkPrough2018">{{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|isbn=9780128143612}}</ref> 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.<ref name="pmid26666359" /><ref name="ClarkPrough2018" />
E1S itself is biologically inactive, with less than 1% of the [[relative binding affinity]] of estradiol for the [[ERα]] and [[ERβ]].<ref name="pmid16112947" /><ref name="pmid9048584">{{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 }}</ref> However, it can be [[biotransformation|transformed]] by [[steroid sulfatase]], also known as estrogen sulfatase, into [[estrone]], an [[estrogen]].<ref name="FalconeHurd2013">{{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}}</ref> Simultaneously, [[estrogen sulfotransferase]]s, including [[SULT1A1]] and [[SULT1E1]], convert estrone to E1S, resulting in an [[chemical equilibrium|equilibrium]] between the two steroids in various tissues.<ref name="pmid27960570" /><ref name="FalconeHurd2013" /> Estrone can also be converted by [[17β-hydroxysteroid dehydrogenase]]s into the more [[potency (pharmacology)|potent]] estrogen [[estradiol]].<ref name="pmid27960570" /> 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.<ref name="pmid27960570" /><ref name="MelmedPolonsky2015">{{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–}}</ref><ref name="GreenblattBrogan2016">{{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–}}</ref> In accordance, E1S has been found to [[transactivation|transactivate]] the [[estrogen receptor]] at physiologically relevant concentrations.<ref name="pmid26666359">{{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 }}</ref><ref name="ClarkPrough2018">{{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}}</ref> 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.<ref name="pmid26666359" /><ref name="ClarkPrough2018" />


Unlike unconjugated estradiol and estrone, which are [[lipophilic]] compounds, E1S is an [[anion]] and is [[hydrophilic]].<ref name="pmid21693170">{{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 | url = https://hal.archives-ouvertes.fr/hal-00717913/file/PEER_stage2_10.1016%252Fj.mce.2011.06.012.pdf}}</ref><ref name="pmid28527781">{{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 | issue = | pages = 86–97 | date = May 2018 | pmid = 28527781 | doi = 10.1016/j.mce.2017.05.016 | url = }}</ref><ref name="pmid26213785">{{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 | url = }}</ref> As a result of this, whereas estradiol and estrone are able to readily diffuse through the [[lipid bilayer]]s of cells, E1S is unable to permeate through [[cell membrane]]s.<ref name="pmid21693170" /><ref name="pmid28527781" /><ref name="pmid26213785" /> Instead, estrone sulfate is transported into cells in a tissue-specific manner by [[active transport]] via [[organic-anion-transporting polypeptide]]s (OATPs), including [[OATP1A2]], [[OATP1B1]], [[OATP1B3]], [[OATP1C1]], [[OATP2B1]], [[OATP3A1]], [[OATP4A1]], and [[OATP4C1]], as well as by the [[sodium-dependent organic anion transporter]] (SOAT; SLC10A6).<ref name="pmid28527781" /><ref name="pmid26213785" /><ref name="pmid21854228">{{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 | issue = | pages = 135–51 | date = 2012 | pmid = 21854228 | pmc = 3257355 | doi = 10.1146/annurev-pharmtox-010510-100556 | url = }}</ref><ref name="pmid30186172">{{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 | issue = | pages = 941 | date = 2018 | pmid = 30186172 | pmc = 6111516 | doi = 10.3389/fphar.2018.00941 | url = }}</ref>
Unlike unconjugated estradiol and estrone, which are [[lipophilic]] compounds, E1S is an [[anion]] and is [[hydrophilic]].<ref name="pmid21693170">{{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}}</ref><ref name="pmid28527781">{{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 }}</ref><ref name="pmid26213785">{{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 }}</ref> As a result of this, whereas estradiol and estrone are able to readily diffuse through the [[lipid bilayer]]s of cells, E1S is unable to permeate through [[cell membrane]]s.<ref name="pmid21693170" /><ref name="pmid28527781" /><ref name="pmid26213785" /> Instead, estrone sulfate is transported into cells in a tissue-specific manner by [[active transport]] via [[organic-anion-transporting polypeptide]]s (OATPs), including [[OATP1A2]], [[OATP1B1]], [[OATP1B3]], [[OATP1C1]], [[OATP2B1]], [[OATP3A1]], [[OATP4A1]], and [[OATP4C1]], as well as by the [[sodium-dependent organic anion transporter]] (SOAT; SLC10A6).<ref name="pmid28527781" /><ref name="pmid26213785" /><ref name="pmid21854228">{{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 }}</ref><ref name="pmid30186172">{{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 }}</ref>


E1S, serving as a precursor and intermediate for estrone and estradiol, may be involved in the [[pathophysiology]] of [[estrogen-dependent condition|estrogen-associated disease]]s including [[breast cancer]], [[benign breast disease]], [[endometrial cancer]], [[ovarian cancer]], [[prostate cancer]], and [[colorectal cancer]].<ref name="pmid27960570" /><ref name="pmid23717534">{{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 | url = }}</ref><ref name="pmid28326039">{{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 | issue = | pages = 103 | date = 2017 | pmid = 28326039 | pmc = 5339229 | doi = 10.3389/fphar.2017.00103 | url = }}</ref> For this reason, [[enzyme inhibitor]]s 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.<ref name="pmid27960570" /><ref name="pmid28326039" /><ref name="pmid23717534" />
E1S, serving as a precursor and intermediate for estrone and estradiol, may be involved in the [[pathophysiology]] of [[estrogen-dependent condition|estrogen-associated disease]]s including [[breast cancer]], [[benign breast disease]], [[endometrial cancer]], [[ovarian cancer]], [[prostate cancer]], and [[colorectal cancer]].<ref name="pmid27960570" /><ref name="pmid23717534">{{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 }}</ref><ref name="pmid28326039">{{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 }}</ref> For this reason, [[enzyme inhibitor]]s 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.<ref name="pmid27960570" /><ref name="pmid28326039" /><ref name="pmid23717534" />

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


==Chemistry==
==Chemistry==
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E1S, also known as estrone 3-sulfate or as estra-1,3,5(10)-trien-17-one 3-sulfate, is a [[natural product|naturally occurring]] [[estrane]] [[steroid]] and a [[chemical derivative|derivative]] of [[estrone]].<ref name="Elks2014">{{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–}}</ref> It is an [[estrogen conjugate]] or [[estrogen ester|ester]], and is specifically the C3 [[sulfate]] [[ester]] of estrone.<ref name="Elks2014" /> 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]].
E1S, also known as estrone 3-sulfate or as estra-1,3,5(10)-trien-17-one 3-sulfate, is a [[natural product|naturally occurring]] [[estrane]] [[steroid]] and a [[chemical derivative|derivative]] of [[estrone]].<ref name="Elks2014">{{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–}}</ref> It is an [[estrogen conjugate]] or [[estrogen ester|ester]], and is specifically the C3 [[sulfate]] [[ester]] of estrone.<ref name="Elks2014" /> 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 [[partition coefficient|logP]] of E1S is 1.4.<ref name="pmid23717534">{{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 }}</ref>


==Biochemistry==
==Biochemistry==
{{Estradiol metabolism|header=Metabolism of estrone sulfate in humans}}


===Biosynthesis===
===Biosynthesis===
E1S is produced via [[estrogen sulfotransferase]]s from the peripheral [[metabolism]] of the estrogens [[estradiol]] and [[estrone]].<ref name="LongcopeFlood1994">{{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|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.}}</ref><ref name="RuderLoriaux1972">{{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}}</ref><ref name="Longcope1972">{{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}}</ref> Estrogen sulfotransferases are expressed minimally or not at all in the [[gonad]]s.<ref name="Hobkirk1985">{{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}}</ref> In accordance, E1S is not secreted in meaningful amounts from the gonads in humans.<ref name="StraussBarbieri2019">{{cite book|last=Strauss|first=Jerome F.|chapter=Steroid Hormones and Other Lipid Molecules Involved in Human Reproduction|pages=75–114<!--Table page = 97-->|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=978-1-4557-2758-2|url=https://books.google.com/books?id=KZ95AAAAQBAJ&pg=PA89}}</ref><ref name="LongcopeFlood1994" />
E1S is produced via [[estrogen sulfotransferase]]s from the peripheral [[metabolism]] of the estrogens [[estradiol]] and [[estrone]].<ref name="LongcopeFlood1994">{{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.}}</ref><ref name="RuderLoriaux1972">{{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}}</ref><ref name="Longcope1972">{{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}}</ref> Estrogen sulfotransferases are expressed minimally or not at all in the [[gonad]]s.<ref name="Hobkirk1985">{{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}}</ref> In accordance, E1S is not secreted in meaningful amounts from the gonads in humans.<ref name="StraussBarbieri2019">{{cite book|last=Strauss|first=Jerome F.|chapter=Steroid Hormones and Other Lipid Molecules Involved in Human Reproduction|pages=75–114<!--Table page = 97-->|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}}</ref><ref name="LongcopeFlood1994" /> However, measurable amounts of estrogen sulfates are said to be secreted by the ovaries in any case.<ref name="BrooksHorn1980">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.</ref>


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

===Distribution===
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.<ref name="pmid15561802" /><ref name="pmid14623518" /> Instead, steroid conjugates require [[active transport]] via [[membrane transport protein]]s to enter cells.<ref name="pmid15561802" /><ref name="pmid14623518" />

Studies in animals and humans have had mixed findings on uptake of exogenously administered E1S in normal and [[tumor]]ous [[mammary gland]] [[tissue (biology)|tissue]].<ref name="pmid1452119">{{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 }}</ref><ref name="pmid8903427">{{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 }}</ref><ref name="pmid15351093">{{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 }}</ref><ref name="pmid15561802">{{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 }}</ref><ref name="pmid14623518">{{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 }}</ref> This is in contrast to substantial uptake of exogenously administered estradiol and estrone by the mammary glands.<ref name="pmid1452119" /> Another animal study found that E1S wasn't taken up by the [[uterus]] but was taken up by the [[liver]], where it was [[hydrolysis|hydrolyzed]] into estrone.<ref name="pmid7358033">{{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 }}</ref><ref name="pmid1452119" />


===Metabolism===
===Metabolism===
The [[elimination half-life]] of estrone sulfate is 10 to 12&nbsp;hours.<ref name="pmid16112947" /> Its [[metabolic clearance rate]] is 80&nbsp;L/day/m<sup>2</sup>.<ref name="pmid16112947" />
The [[elimination half-life]] of E1S is 10 to 12&nbsp;hours.<ref name="pmid16112947" /> Its [[metabolic clearance rate]] is 80&nbsp;L/day/m<sup>2</sup>.<ref name="pmid16112947" />


[[Ovarian tumor]]s have been found to express [[steroid sulfatase]] and have been found to convert E1S into estradiol.<ref name="DayPurohit2009">{{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}}</ref><ref name="KirilovasSchedvins2009">{{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}}</ref> This may contribute to the often elevated levels of estradiol observed in women with [[ovarian cancer]].<ref name="DayPurohit2009" /><ref name="KirilovasSchedvins2009" />
[[Ovarian tumor]]s have been found to express [[steroid sulfatase]] and have been found to convert E1S into estradiol.<ref name="DayPurohit2009">{{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}}</ref><ref name="KirilovasSchedvins2009">{{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}}</ref> This may contribute to the often elevated levels of estradiol observed in women with [[ovarian cancer]].<ref name="DayPurohit2009" /><ref name="KirilovasSchedvins2009" />
{{Estradiol metabolism}}


===Levels===
===Levels===
[[File:Estradiol, estrone, and estrone sulfate levels during the normal human menstrual cycle.png|thumb|right|400px|Estrogen levels with [[radioimmunoassay]] (RIA) around [[mid-cycle]] during the normal [[menstrual cycle]] in women.<ref name="pmid2375600">{{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 | issue = | pages = 106–16 | date = 1990 | pmid = 2375600 | doi = 10.1111/j.1749-6632.1990.tb34286.x | url = }}</ref><ref name="pmid579025">{{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 | url = }}</ref> The vertical dashed line in the center is mid-cycle.]]
[[File:Estradiol, estrone, and estrone sulfate levels during the normal human menstrual cycle.png|thumb|right|400px|Estrogen levels with [[radioimmunoassay]] (RIA) around [[mid-cycle]] during the normal [[menstrual cycle]] in women.<ref name="pmid2375600">{{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 }}</ref><ref name="pmid579025">{{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 }}</ref> The vertical dashed line in the center is mid-cycle.]]


Estrone sulfate levels using [[radioimmunoassay]] (RIA) have been reported to be 0.96 ± 0.11&nbsp;ng/mL in men, 0.96 ± 0.17&nbsp;ng/mL during the [[follicular phase]] in women, 1.74 ± 0.32&nbsp;ng/mL during the [[luteal phase]] in women, 0.74 ± 0.11&nbsp;ng/mL in women taking [[oral contraceptive]]s, 0.13 ± 0.03&nbsp;ng/mL in [[postmenopause|postmenopausal]] women, and 2.56 ± 0.47&nbsp;ng/mL in postmenopausal women on [[menopausal hormone therapy]].<ref name="pmid9474019">{{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 | url = }}</ref> In addition, estrone sulfate levels in [[pregnancy|pregnant]] women were 19 ± 5&nbsp;ng/mL in the first trimester, 66 ± 31&nbsp;ng/mL in the second trimester, and 105 ± 22&nbsp;ng/mL in the third trimester.<ref name="pmid9474019" />
E1S levels have been characterized in humans.<ref name="pmid579025" /><ref name="pmid3653846">{{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 }}</ref><ref name="pmid9474019" /> E1S using [[radioimmunoassay]] (RIA) have been reported to be 0.96 ± 0.11&nbsp;ng/mL in men, 0.96 ± 0.17&nbsp;ng/mL during the [[follicular phase]] in women, 1.74 ± 0.32&nbsp;ng/mL during the [[luteal phase]] in women, 0.74 ± 0.11&nbsp;ng/mL in women taking [[oral contraceptive]]s, 0.13 ± 0.03&nbsp;ng/mL in [[postmenopause|postmenopausal]] women, and 2.56 ± 0.47&nbsp;ng/mL in postmenopausal women on [[menopausal hormone therapy]].<ref name="pmid9474019">{{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 }}</ref> In addition, E1S levels in [[pregnancy|pregnant]] women were 19 ± 5&nbsp;ng/mL in the first trimester, 66 ± 31&nbsp;ng/mL in the second trimester, and 105 ± 22&nbsp;ng/mL in the third trimester.<ref name="pmid9474019" /> E1S levels are about 10 to 15&nbsp;times higher than those of estrone in women.<ref name="CowieForsyth1980">{{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}}</ref>


==References==
==References==
Line 83: Line 94:
==Further reading==
==Further reading==
{{refbegin}}
{{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 }}
* {{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}}
{{refend}}


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{{Estrogen receptor modulators}}
{{Estrogen receptor modulators}}


[[Category:Estranes]]
[[Category:Estrogens]]
[[Category:Estrogens]]
[[Category:Estrone esters]]
[[Category:Estrone esters]]
[[Category:Human metabolites]]
[[Category:Human metabolites]]
[[Category:Prodrugs]]
[[Category:Sex hormone esters and conjugates]]
[[Category:Phenol esters]]
[[Category:Phenol esters]]
[[Category:Sulfate esters]]
[[Category:Sulfate esters]]

Latest revision as of 21:31, 29 March 2024

This article is about estrone sulfate as a hormone. For its use as a medication, see Estrone sulfate (medication).

Estrone sulfate
Skeletal formula of estrone sulfate
Space-filling model of the estrone sulfate molecule
Names
IUPAC name
17-Oxoestra-1,3,5(10)-trien-3-yl hydrogen sulfate
Systematic IUPAC name
(3aS,3bR,9bS,11aS)-11a-Methyl-1-oxo-2,3,3a,3b,4,5,9b,10,11,11a-decahydro-1H-cyclopenta[a]phenanthren-7-yl hydrogen sulfate
Other names
E1S; Oestrone sulfate; Estrone 3-sulfate; Estra-1,3,5(10)-trien-17-one 3-sulfate
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.006.888 Edit this at Wikidata
EC Number
  • 207-120-4
KEGG
UNII
  • InChI=1S/C18H22O5S/c1-18-9-8-14-13-5-3-12(23-24(20,21)22)10-11(13)2-4-15(14)16(18)6-7-17(18)19/h3,5,10,14-16H,2,4,6-9H2,1H3,(H,20,21,22)/t14-,15-,16+,18+/m1/s1
    Key: JKKFKPJIXZFSSB-CBZIJGRNSA-N
  • C[C@]12CC[C@H]3[C@H]([C@@H]1CCC2=O)CCC4=C3C=CC(=C4)OS(=O)(=O)O
Properties
C18H22O5S
Molar mass 350.429 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Estrone sulfate, also known as E1S, E1SO4 and estrone 3-sulfate, is a natural, endogenous steroid and an estrogen ester and conjugate.[1][2][3]

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

Biological function

[edit]

E1S itself is biologically inactive, with less than 1% of the relative binding affinity of estradiol for the ERα and ERβ.[3][4] However, it can be transformed by steroid sulfatase, also known as estrogen sulfatase, into estrone, an estrogen.[5] Simultaneously, estrogen sulfotransferases, including SULT1A1 and SULT1E1, convert estrone to E1S, resulting in an equilibrium between the two steroids in various tissues.[1][5] Estrone can also be converted by 17β-hydroxysteroid dehydrogenases into the more potent estrogen estradiol.[1] 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.[1][6][7] In accordance, E1S has been found to transactivate the estrogen receptor at physiologically relevant concentrations.[8][9] 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.[8][9]

Unlike unconjugated estradiol and estrone, which are lipophilic compounds, E1S is an anion and is hydrophilic.[10][11][12] 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.[10][11][12] 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).[11][12][13][14]

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.[1][15][16] 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.[1][16][15]

Affinities and estrogenic potencies of estrogen esters and ethers at the estrogen receptors
Estrogen Other names RBATooltip Relative binding affinity (%)a REP (%)b
ER ERα ERβ
Estradiol E2 100 100 100
Estradiol 3-sulfate E2S; E2-3S ? 0.02 0.04
Estradiol 3-glucuronide E2-3G ? 0.02 0.09
Estradiol 17β-glucuronide E2-17G ? 0.002 0.0002
Estradiol benzoate EB; Estradiol 3-benzoate 10 1.1 0.52
Estradiol 17β-acetate E2-17A 31–45 24 ?
Estradiol diacetate EDA; Estradiol 3,17β-diacetate ? 0.79 ?
Estradiol propionate EP; Estradiol 17β-propionate 19–26 2.6 ?
Estradiol valerate EV; Estradiol 17β-valerate 2–11 0.04–21 ?
Estradiol cypionate EC; Estradiol 17β-cypionate ?c 4.0 ?
Estradiol palmitate Estradiol 17β-palmitate 0 ? ?
Estradiol stearate Estradiol 17β-stearate 0 ? ?
Estrone E1; 17-Ketoestradiol 11 5.3–38 14
Estrone sulfate E1S; Estrone 3-sulfate 2 0.004 0.002
Estrone glucuronide E1G; Estrone 3-glucuronide ? <0.001 0.0006
Ethinylestradiol EE; 17α-Ethynylestradiol 100 17–150 129
Mestranol EE 3-methyl ether 1 1.3–8.2 0.16
Quinestrol EE 3-cyclopentyl ether ? 0.37 ?
Footnotes: a = Relative binding affinities (RBAs) were determined via in-vitro displacement of labeled estradiol from estrogen receptors (ERs) generally of rodent uterine cytosol. Estrogen esters are variably hydrolyzed into estrogens in these systems (shorter ester chain length -> greater rate of hydrolysis) and the ER RBAs of the esters decrease strongly when hydrolysis is prevented. b = Relative estrogenic potencies (REPs) were calculated from half-maximal effective concentrations (EC50) that were determined via in-vitro β‐galactosidase (β-gal) and green fluorescent protein (GFP) production assays in yeast expressing human ERα and human ERβ. Both mammalian cells and yeast have the capacity to hydrolyze estrogen esters. c = The affinities of estradiol cypionate for the ERs are similar to those of estradiol valerate and estradiol benzoate (figure). Sources: See template page.

Chemistry

[edit]
See also: List of estrogens, Estrogen ester, and 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.[17] It is an estrogen conjugate or ester, and is specifically the C3 sulfate ester of estrone.[17] 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.[15]

Biochemistry

[edit]

Biosynthesis

[edit]

E1S is produced via estrogen sulfotransferases from the peripheral metabolism of the estrogens estradiol and estrone.[18][19][20] Estrogen sulfotransferases are expressed minimally or not at all in the gonads.[21] In accordance, E1S is not secreted in meaningful amounts from the gonads in humans.[22][18] However, measurable amounts of estrogen sulfates are said to be secreted by the ovaries in any case.[23]

Production rates, secretion rates, clearance rates, and blood levels of major sex hormones
Sex Sex hormone Reproductive
phase 		Blood
production rate 		Gonadal
secretion rate 		Metabolic
clearance rate 		Reference range (serum levels)
SI units Non-SI units
Men Androstenedione
–
 2.8 mg/day 1.6 mg/day 2200 L/day 2.8–7.3 nmol/L 80–210 ng/dL
Testosterone
–
 6.5 mg/day 6.2 mg/day 950 L/day 6.9–34.7 nmol/L 200–1000 ng/dL
Estrone
–
 150 μg/day 110 μg/day 2050 L/day 37–250 pmol/L 10–70 pg/mL
Estradiol
–
 60 μg/day 50 μg/day 1600 L/day <37–210 pmol/L 10–57 pg/mL
Estrone sulfate
–
 80 μg/day Insignificant 167 L/day 600–2500 pmol/L 200–900 pg/mL
Women Androstenedione
–
 3.2 mg/day 2.8 mg/day 2000 L/day 3.1–12.2 nmol/L 89–350 ng/dL
Testosterone
–
 190 μg/day 60 μg/day 500 L/day 0.7–2.8 nmol/L 20–81 ng/dL
Estrone Follicular phase 110 μg/day 80 μg/day 2200 L/day 110–400 pmol/L 30–110 pg/mL
Luteal phase 260 μg/day 150 μg/day 2200 L/day 310–660 pmol/L 80–180 pg/mL
Postmenopause 40 μg/day Insignificant 1610 L/day 22–230 pmol/L 6–60 pg/mL
Estradiol Follicular phase 90 μg/day 80 μg/day 1200 L/day <37–360 pmol/L 10–98 pg/mL
Luteal phase 250 μg/day 240 μg/day 1200 L/day 699–1250 pmol/L 190–341 pg/mL
Postmenopause 6 μg/day Insignificant 910 L/day <37–140 pmol/L 10–38 pg/mL
Estrone sulfate Follicular phase 100 μg/day Insignificant 146 L/day 700–3600 pmol/L 250–1300 pg/mL
Luteal phase 180 μg/day Insignificant 146 L/day 1100–7300 pmol/L 400–2600 pg/mL
Progesterone Follicular phase 2 mg/day 1.7 mg/day 2100 L/day 0.3–3 nmol/L 0.1–0.9 ng/mL
Luteal phase 25 mg/day 24 mg/day 2100 L/day 19–45 nmol/L 6–14 ng/mL
Notes and sources
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.

Distribution

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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.[24][25] Instead, steroid conjugates require active transport via membrane transport proteins to enter cells.[24][25]

Studies in animals and humans have had mixed findings on uptake of exogenously administered E1S in normal and tumorous mammary gland tissue.[26][27][28][24][25] This is in contrast to substantial uptake of exogenously administered estradiol and estrone by the mammary glands.[26] 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.[29][26]

Metabolism

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The elimination half-life of E1S is 10 to 12 hours.[3] Its metabolic clearance rate is 80 L/day/m2.[3]

Ovarian tumors have been found to express steroid sulfatase and have been found to convert E1S into estradiol.[30][31] This may contribute to the often elevated levels of estradiol observed in women with ovarian cancer.[30][31]

The image above contains clickable links
Description: The metabolic pathways involved in the metabolism of estradiol and other natural estrogens (e.g., estrone, estriol) in humans. In addition to the metabolic transformations shown in the diagram, conjugation (e.g., sulfation and glucuronidation) occurs in the case of estradiol and metabolites of estradiol that have one or more available hydroxyl (–OH) groups. Sources: See template page.


Levels

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Estrogen levels with radioimmunoassay (RIA) around mid-cycle during the normal menstrual cycle in women.[32][33] The vertical dashed line in the center is mid-cycle.

E1S levels have been characterized in humans.[33][34][35] 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.[35] 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.[35] E1S levels are about 10 to 15 times higher than those of estrone in women.[36]

References

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  19. ^ Ruder HJ, Loriaux L, Lipsett MB (1972). "Estrone Sulfate: Production Rate and Metabolism in Man". Journal of Clinical Investigation. 51 (4): 1020–1033. doi:10.1172/JCI106862. ISSN 0021-9738. PMC 302214. PMID 5014608.
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  27. ^ Masamura S, Santner SJ, Santen RJ (July 1996). "Evidence of in situ estrogen synthesis in nitrosomethylurea-induced rat mammary tumors via the enzyme estrone sulfatase". J. Steroid Biochem. Mol. Biol. 58 (4): 425–9. doi:10.1016/0960-0760(96)00065-9. PMID 8903427. S2CID 22100628.
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  32. ^ Pasqualini JR, Gelly C, Nguyen BL (1990). "Metabolism and biologic response of estrogen sulfates in hormone-dependent and hormone-independent mammary cancer cell lines. Effect of antiestrogens". Ann. N. Y. Acad. Sci. 595 (1): 106–16. Bibcode:1990NYASA.595..106P. doi:10.1111/j.1749-6632.1990.tb34286.x. PMID 2375600. S2CID 26940935.
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  36. ^ Cowie AT, Forsyth IA, Hart IC (1980). "Growth and Development of the Mammary Gland". Hormonal Control of Lactation. Monographs on Endocrinology. Vol. 15. pp. 58–145. doi:10.1007/978-3-642-81389-4_3. ISBN 978-3-642-81391-7. ISSN 0077-1015.

Further reading

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Retrieved from "https://en.wikipedia.org/enwiki/w/index.php?title=Estrone_sulfate&oldid=1216234574"