Chemistry:Estrone sulfate

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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
EC Number
  • 207-120-4
KEGG
UNII
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
Tracking categories (test):

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

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.

The logP of E1S is 1.4.[15]

Biochemistry

Biosynthesis

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]


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.[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

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
This diagram illustrates the metabolic pathways involved in the metabolism of estrogens (i.e., estradiol, estrone, and estriol) in humans.

Levels

Estrogen levels with radioimmunoassay (RIA) around mid-cycle during the normal menstrual cycle in women.[35][36] The vertical dashed line in the center is mid-cycle.

E1S levels have been characterized in humans.[36][37][38] 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.[38] 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.[38] E1S levels are about 10 to 15 times higher than those of estrone in women.[39]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "Clinical implications of estrone sulfate measurement in laboratory medicine". Crit Rev Clin Lab Sci 54 (2): 73–86. March 2017. doi:10.1080/10408363.2016.1252310. PMID 27960570. 
  2. ↑ Lobo, Rogerio A. (5 June 2007). Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. Academic Press. pp. 768–. ISBN 978-0-08-055309-2. https://books.google.com/books?id=gywV9hkcyOMC&pg=PA768. 
  3. ↑ 3.0 3.1 3.2 3.3 "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric 8 (Suppl 1): 3–63. 2005. doi:10.1080/13697130500148875. PMID 16112947. http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf. 
  4. ↑ "Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta". Endocrinology 138 (3): 863–70. March 1997. doi:10.1210/endo.138.3.4979. PMID 9048584. 
  5. ↑ 5.0 5.1 Falcone, Tommaso; Hurd, William W. (22 May 2013). Clinical Reproductive Medicine and Surgery: A Practical Guide. Springer Science & Business Media. pp. 5–6. ISBN 978-1-4614-6837-0. https://books.google.com/books?id=TAYnR1b8jRkC&pg=PA5. 
  6. ↑ Melmed, Shlomo; Polonsky, Kenneth S.; Larsen, P. Reed; Kronenberg, Henry M. (11 November 2015). Williams Textbook of Endocrinology (13th ed.). Elsevier Health Sciences. pp. 607–. ISBN 978-0-323-34157-8. https://books.google.com/books?id=iPIACwAAQBAJ&pg=PA607. 
  7. ↑ Greenblatt, James M.; Brogan, Kelly (27 April 2016). Integrative Therapies for Depression: Redefining Models for Assessment, Treatment and Prevention. CRC Press. pp. 198–. ISBN 978-1-4987-0230-0. https://books.google.com/books?id=GpHwCgAAQBAJ&pg=PA198. 
  8. ↑ 8.0 8.1 "Estrone sulfate and dehydroepiandrosterone sulfate: Transactivation of the estrogen and androgen receptor". Steroids 105: 50–8. January 2016. doi:10.1016/j.steroids.2015.11.009. PMID 26666359. 
  9. ↑ 9.0 9.1 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. 
  10. ↑ 10.0 10.1 "Steroid sulfatase: a pivotal player in estrogen synthesis and metabolism". Mol. Cell. Endocrinol. 340 (2): 154–60. July 2011. doi:10.1016/j.mce.2011.06.012. PMID 21693170. https://hal.archives-ouvertes.fr/hal-00717913/file/PEER_stage2_10.1016%252Fj.mce.2011.06.012.pdf. 
  11. ↑ 11.0 11.1 11.2 "Steroid metabolism in breast cancer: Where are we and what are we missing?". Mol. Cell. Endocrinol. 466: 86–97. May 2018. doi:10.1016/j.mce.2017.05.016. PMID 28527781. 
  12. ↑ 12.0 12.1 12.2 "The Regulation of Steroid Action by Sulfation and Desulfation". Endocr. Rev. 36 (5): 526–63. October 2015. doi:10.1210/er.2015-1036. PMID 26213785. 
  13. ↑ "The expression and function of organic anion transporting polypeptides in normal tissues and in cancer". Annu. Rev. Pharmacol. Toxicol. 52: 135–51. 2012. doi:10.1146/annurev-pharmtox-010510-100556. PMID 21854228. 
  14. ↑ "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. 2018. doi:10.3389/fphar.2018.00941. PMID 30186172. 
  15. ↑ 15.0 15.1 15.2 "Estrone-3-sulphate, a potential novel ligand for targeting breast cancers". PLOS ONE 8 (5): e64069. 2013. doi:10.1371/journal.pone.0064069. PMID 23717534. Bibcode: 2013PLoSO...864069B. 
  16. ↑ 16.0 16.1 "Estrone Sulfate Transport and Steroid Sulfatase Activity in Colorectal Cancer: Implications for Hormone Replacement Therapy". Front Pharmacol 8: 103. 2017. doi:10.3389/fphar.2017.00103. PMID 28326039. 
  17. ↑ 17.0 17.1 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. pp. 900–. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA900. 
  18. ↑ 18.0 18.1 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. PMID 8079382. "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.". 
  19. ↑ 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. PMID 5014608. 
  20. ↑ 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. PMID 5008222. 
  21. ↑ 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. PMID 3910206. 
  22. ↑ Strauss, Jerome F. (2019). "Steroid Hormones and Other Lipid Molecules Involved in Human Reproduction". Yen & Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management (8 ed.). Elsevier Health Sciences. pp. 75–114. doi:10.1016/B978-0-323-47912-7.00004-4. ISBN 978-0-323-58232-2. https://books.google.com/books?id=67ZEDwAAQBAJ&pg=PA97. 
  23. ↑ 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.
  24. ↑ 24.0 24.1 24.2 "Steroid sulfatase: molecular biology, regulation, and inhibition". Endocr. Rev. 26 (2): 171–202. April 2005. doi:10.1210/er.2004-0003. PMID 15561802. 
  25. ↑ 25.0 25.1 25.2 "Breast cancer tissue estrogens and their manipulation with aromatase inhibitors and inactivators". J. Steroid Biochem. Mol. Biol. 86 (3–5): 245–53. September 2003. doi:10.1016/s0960-0760(03)00364-9. PMID 14623518. 
  26. ↑ 26.0 26.1 26.2 "The origin of oestrone sulphate in normal and malignant breast tissues in postmenopausal women". Horm. Metab. Res. 24 (11): 532–6. November 1992. doi:10.1055/s-2007-1003382. PMID 1452119. 
  27. ↑ "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. July 1996. doi:10.1016/0960-0760(96)00065-9. PMID 8903427. 
  28. ↑ "Local biosynthesis and metabolism of oestrogens in the human breast". Maturitas 49 (1): 25–33. September 2004. doi:10.1016/j.maturitas.2004.06.004. PMID 15351093. 
  29. ↑ "In vivo uptake of estrone sulfate by rabbit uterus". Endocrinology 106 (4): 1193–7. April 1980. doi:10.1210/endo-106-4-1193. PMID 7358033. 
  30. ↑ 30.0 30.1 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. PMID 19250195. 
  31. ↑ 31.0 31.1 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. PMID 17484508. 
  32. ↑ The Menopause (Clinical Perspectives in Obstetrics and Gynecology). New York, NY: Springer Science & Business Media. 2012. p. 64. ISBN 9781461255253. https://books.google.com/books?id=z0LuBwAAQBAJ&pg=PA64%7Cdate=6#v=onepage&q&f=false. 
  33. ↑ "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric : the Journal of the International Menopause Society 8 Suppl 1: 3–63. August 2005. doi:10.1080/13697130500148875. PMID 16112947. 
  34. ↑ "EC 2.4.1.17 – glucuronosyltransferase and Organism(s) Homo sapiens". EC 2.4.1.17 – glucuronosyltransferase and Organism(s) Homo sapiens. Technische Universität Braunschweig. January 2018. https://www.brenda-enzymes.org/enzyme.php?ecno=2.4.1.17&Suchword=estrone&reference=&UniProtAcc=&organism%5B%5D=Homo+sapiens. Retrieved 10 August 2018. 
  35. ↑ "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: 106–16. 1990. doi:10.1111/j.1749-6632.1990.tb34286.x. PMID 2375600. 
  36. ↑ 36.0 36.1 "Studies on the pattern of circulating steroids in the normal menstrual cycle. 6. Levels of oestrone sulphate and oestradiol sulphate". Acta Endocrinol. 86 (3): 621–33. November 1977. doi:10.1530/acta.0.0860621. PMID 579025. 
  37. ↑ "Serum and urinary estrone sulfate during the menstrual cycle, measured by a direct radioimmunoassay, and fate of exogenously injected estrone sulfate". Horm Res 27 (2): 61–8. 1987. doi:10.1159/000180788. PMID 3653846. 
  38. ↑ 38.0 38.1 38.2 "Rapid, convenient radioimmunoassay of estrone sulfate". Clin. Chem. 44 (2): 244–9. February 1998. doi:10.1093/clinchem/44.2.244. PMID 9474019. 
  39. ↑ Cowie, Alfred T.; Forsyth, Isabel A.; Hart, Ian C. (1980). "Growth and Development of the Mammary Gland". Hormonal Control of Lactation. Monographs on Endocrinology. 15. pp. 58–145. doi:10.1007/978-3-642-81389-4_3. ISBN 978-3-642-81391-7. 

Further reading



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