View source for Estrone sulfate

{{About|estrone sulfate as a hormone|its use as a medication|Estrone sulfate (medication)}}
{{Use dmy dates|date=August 2018}}
{{Chembox
<!-- Images -->
| ImageFile = Estrone sulfate.svg
| ImageSize = 250px
| ImageAlt = Skeletal formula of estrone sulfate
| ImageFile2 = Estrone sulfate 3D ball.png
| ImageSize2 = 250px
| ImageAlt2 = Space-filling model of the estrone sulfate molecule
<!-- 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
| OtherNames = E1S; Oestrone sulfate; Estrone 3-sulfate; Estra-1,3,5(10)-trien-17-one 3-sulfate
<!-- Sections -->
| Section1 = {{Chembox Identifiers
| CASNo = 481-97-0
| CASNoOther = 438-67-5 (sodium salt)
| ChEBI = 17474
| ChEMBL = 494753
| ChemSpiderID = 2272513
| DrugBank = DB04574
| EC_number = 207-120-4
| 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
| InChIKey = JKKFKPJIXZFSSB-CBZIJGRNSA-N
| KEGG = C02538
| PubChem = 3001028
| SMILES = C[C@]12CC[C@H]3[C@H]([C@@H]1CCC2=O)CCC4=C3C=CC(=C4)OS(=O)(=O)O
| UNII = QTL48N278K
  }}
| Section2 = {{Chembox Properties
| C=18 | H=22 | O=5 | S=1
| MolarMass = 350.429 g/mol
| Appearance = 
| Density = 
| MeltingPt = 
| BoilingPt = 
| Solubility = 
  }}
| Section3 = {{Chembox Hazards
| MainHazards =
| FlashPt =
| AutoignitionPt =
  }}
}}

'''Estrone sulfate''' ('''E1S'''), or '''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>

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==
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 }}</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" />

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>

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" />

==Chemistry==
{{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 [[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]].

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

===Biosynthesis===
E1S is produced via [[estrogen sulfotransferase]]s from the peripheral [[metabolism]] of the [[ovary|ovarian]] 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}}</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 from the ovaries in humans.<ref name="LongcopeFlood1994" />

===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" />

[[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" />

===Levels===
Circulating levels of estrone sulfate range from a low of 0.13&nbsp;ng/mL in postmenopausal women to a high of 105&nbsp;ng/mL in pregnant women during the third trimester.<ref name="pmid26666359" />

==References==
{{Reflist}}

==Further reading==
{{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 }}
{{refend}}

{{Steroid hormones}}
{{Estrogen receptor modulators}}

[[Category:Estranes]]
[[Category:Estrogen esters]]
[[Category:Estrogens]]
[[Category:Human metabolites]]
[[Category:Prodrugs]]
[[Category:Phenol esters]]
[[Category:Sulfate esters]]