Estrone sulfate

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Estrone sulfate
Skeletal formula of estrone sulfate
Space-filling model of the estrone sulfate molecule
Names
IUPAC name
[(8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthren-3-yl] hydrogen sulfate
Other names
E1S; Oestrone sulfate; Estrone 3-sulfate; Estra-1,3,5(10)-trien-17-one 3-sulfate
Identifiers
  • 481-97-0
  • 438-67-5 (sodium salt)
3D model (JSmol)
  • Interactive image
ChEBI
  • CHEBI:17474
ChEMBL
  • ChEMBL494753
ChemSpider
  • 2272513
DrugBank
  • DB04574
ECHA InfoCard 100.006.888
EC Number 207-120-4
KEGG
  • C02538
PubChem CID
  • 3001028
UNII
  • QTL48N278K
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).
Infobox references

Estrone sulfate (E1S), or 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

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]

Chemistry

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.

Biochemistry

Metabolism of estrone sulfate in humans[18][19][20]
The image above contains clickable links
This diagram illustrates the metabolic pathways involved in the metabolism of estrogens (i.e., estradiol, estrone, and estriol) in humans.

Biosynthesis

E1S is produced via estrogen sulfotransferases from the peripheral metabolism of the ovarian estrogens estradiol and estrone.[21][22][23] Estrogen sulfotransferases are expressed minimally or not at all in the gonads.[24] In accordance, E1S is not secreted from the ovaries in humans.[21]

Metabolism

The elimination half-life of estrone sulfate 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.[25][26] This may contribute to the often elevated levels of estradiol observed in women with ovarian cancer.[25][26]

Levels

Circulating levels of estrone sulfate range from a low of 0.13 ng/mL in postmenopausal women to a high of 105 ng/mL in pregnant women during the third trimester.[8]

References

  1. ^ a b c d e f Rezvanpour A, Don-Wauchope AC (March 2017). "Clinical implications of estrone sulfate measurement in laboratory medicine". Crit Rev Clin Lab Sci. 54 (2): 73–86. doi:10.1080/10408363.2016.1252310. PMID 27960570.
  2. ^ Lobo RA (5 June 2007). Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. Academic Press. pp. 768–. ISBN 978-0-08-055309-2.
  3. ^ a b c d Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947.
  4. ^ Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, Gustafsson JA (March 1997). "Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta". Endocrinology. 138 (3): 863–70. doi:10.1210/endo.138.3.4979. PMID 9048584.
  5. ^ a b Falcone T, Hurd WW (22 May 2013). Clinical Reproductive Medicine and Surgery: A Practical Guide. Springer Science & Business Media. pp. 5–6. ISBN 978-1-4614-6837-0.
  6. ^ Melmed S, Polonsky KS, Larsen PR, Kronenberg HM (11 November 2015). Williams Textbook of Endocrinology (13th ed.). Elsevier Health Sciences. pp. 607–. ISBN 978-0-323-34157-8.
  7. ^ Greenblatt JM, Brogan K (27 April 2016). Integrative Therapies for Depression: Redefining Models for Assessment, Treatment and Prevention. CRC Press. pp. 198–. ISBN 978-1-4987-0230-0.
  8. ^ a b c Bjerregaard-Olesen C, Ghisari M, Kjeldsen LS, Wielsøe M, Bonefeld-Jørgensen EC (January 2016). "Estrone sulfate and dehydroepiandrosterone sulfate: Transactivation of the estrogen and androgen receptor". Steroids. 105: 50–8. doi:10.1016/j.steroids.2015.11.009. PMID 26666359.
  9. ^ a b Clark, Barbara J.; Prough, Russell A.; Klinge, Carolyn M. (2018). "Mechanisms of Action of Dehydroepiandrosterone". Dehydroepiandrosterone. Vitamins and Hormones. 108. pp. 29–73. doi:10.1016/bs.vh.2018.02.003. ISBN 9780128143612. ISSN 0083-6729.
  10. ^ a b Purohit A, Woo LW, Potter BV (July 2011). "Steroid sulfatase: a pivotal player in estrogen synthesis and metabolism" (PDF). Mol. Cell. Endocrinol. 340 (2): 154–60. doi:10.1016/j.mce.2011.06.012. PMID 21693170.
  11. ^ a b c Africander D, Storbeck KH (May 2018). "Steroid metabolism in breast cancer: Where are we and what are we missing?". Mol. Cell. Endocrinol. 466: 86–97. doi:10.1016/j.mce.2017.05.016. PMID 28527781.
  12. ^ a b c Mueller JW, Gilligan LC, Idkowiak J, Arlt W, Foster PA (October 2015). "The Regulation of Steroid Action by Sulfation and Desulfation". Endocr. Rev. 36 (5): 526–63. doi:10.1210/er.2015-1036. PMC 4591525. PMID 26213785.
  13. ^ Obaidat A, Roth M, Hagenbuch B (2012). "The expression and function of organic anion transporting polypeptides in normal tissues and in cancer". Annu. Rev. Pharmacol. Toxicol. 52: 135–51. doi:10.1146/annurev-pharmtox-010510-100556. PMC 3257355. PMID 21854228.
  14. ^ Karakus E, Zahner D, Grosser G, Leidolf R, Gundogdu C, Sánchez-Guijo A, Wudy SA, Geyer J (2018). "Estrone-3-Sulfate Stimulates the Proliferation of T47D Breast Cancer Cells Stably Transfected With the Sodium-Dependent Organic Anion Transporter SOAT (SLC10A6)". Front Pharmacol. 9: 941. doi:10.3389/fphar.2018.00941. PMC 6111516. PMID 30186172.
  15. ^ a b Banerjee N, Fonge H, Mikhail A, Reilly RM, Bendayan R, Allen C (2013). "Estrone-3-sulphate, a potential novel ligand for targeting breast cancers". PLoS ONE. 8 (5): e64069. doi:10.1371/journal.pone.0064069. PMC 3661587. PMID 23717534.
  16. ^ a b Gilligan LC, Gondal A, Tang V, Hussain MT, Arvaniti A, Hewitt AM, Foster PA (2017). "Estrone Sulfate Transport and Steroid Sulfatase Activity in Colorectal Cancer: Implications for Hormone Replacement Therapy". Front Pharmacol. 8: 103. doi:10.3389/fphar.2017.00103. PMC 5339229. PMID 28326039.
  17. ^ a b Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 900–. ISBN 978-1-4757-2085-3.
  18. ^ Buchsbaum HJ, ed. (2012). The Menopause (Clinical Perspectives in Obstetrics and Gynecology). New York, NY: Springer Science & Business Media. p. 64. ISBN 9781461255253.
  19. ^ Kuhl H (August 2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric : the Journal of the International Menopause Society. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947.
  20. ^ "EC 2.4.1.17 – glucuronosyltransferase and Organism(s) Homo sapiens". BRENDA. Technische Universität Braunschweig. January 2018. Retrieved 10 August 2018.
  21. ^ a b Longcope, Christopher; Flood, Charles; Tast, Janet (1994). "The metabolism of estrone sulfate in the female rhesus monkey". Steroids. 59 (4): 270–273. doi:10.1016/0039-128X(94)90112-0. ISSN 0039-128X. 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.
  22. ^ Ruder, Henry J.; Loriaux, Lynn; Lipsett, M. B. (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.
  23. ^ Longcope, Christopher (1972). "The Metabolism of Estrone Sulfate in Normal Males". The Journal of Clinical Endocrinology & Metabolism. 34 (1): 113–122. doi:10.1210/jcem-34-1-113. ISSN 0021-972X.
  24. ^ Hobkirk, R. (1985). "Steroid sulfotransferases and steroid sulfate sulfatases: characteristics and biological roles". Canadian Journal of Biochemistry and Cell Biology. 63 (11): 1127–1144. doi:10.1139/o85-141. ISSN 0714-7511.
  25. ^ a b Day, Joanna M.; Purohit, Atul; Tutill, Helena J.; Foster, Paul A.; Woo, L. W. Lawrence; Potter, Barry V. L.; Reed, Michael J. (2009). "The Development of Steroid Sulfatase Inhibitors for Hormone-Dependent Cancer Therapy". Annals of the New York Academy of Sciences. 1155 (1): 80–87. doi:10.1111/j.1749-6632.2008.03677.x. ISSN 0077-8923.
  26. ^ a b Kirilovas, Dmitrijus; Schedvins, Kjell; Naessén, Tord; Von Schoultz, Bo; Carlström, Kjell (2009). "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". Gynecological Endocrinology. 23 (1): 25–28. doi:10.1080/09513590601058333. ISSN 0951-3590.

Further reading

  • Rezvanpour A, Don-Wauchope AC (March 2017). "Clinical implications of estrone sulfate measurement in laboratory medicine". Critical Reviews in Clinical Laboratory Sciences. 54 (2): 73–86. doi:10.1080/10408363.2016.1252310. PMID 27960570.
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