Estradiol sulfate

Estradiol sulfate
Names
IUPAC name
17β-Hydroxyestra-1,3,5(10)-trien-3-yl hydrogen sulfate
Systematic IUPAC name
(1S,3aS,3bR,9bS,11aS)-1-Hydroxy-11a-methyl-2,3,3a,3b,4,5,9b,10,11,11a-decahydro-1H-cyclopenta[a]phenanthren-7-yl hydrogen sulfate
Other names
Estra-1,3,5(10)-triene-3,17β-diol 3-sulfate
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
UNII
  • InChI=1S/C18H24O5S/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/h3,5,10,14-17,19H,2,4,6-9H2,1H3,(H,20,21,22)/t14-,15-,16+,17+,18+/m1/s1
    Key: QZIGLSSUDXBTLJ-ZBRFXRBCSA-N
  • CC12CCC3C(C1CCC2O)CCC4=C3C=CC(=C4)OS(=O)(=O)O
Properties
C18H24O5S
Molar mass 352.445 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Estradiol sulfate (E2S), or 17β-estradiol 3-sulfate,[1] is a natural, endogenous steroid and an estrogen ester.[2] E2S itself is biologically inactive,[3] but it can be converted by steroid sulfatase (also called estrogen sulfatase) into estradiol, which is a potent estrogen.[2][4][5] Simultaneously, estrogen sulfotransferases convert estradiol to E2S, resulting in an equilibrium between the two steroids in various tissues.[2][5] Estrone and E2S are the two immediate metabolic sources of estradiol.[6] E2S can also be metabolized into estrone sulfate (E1S), which in turn can be converted into estrone and estradiol.[7] Circulating concentrations of E2S are much lower than those of E1S.[1] High concentrations of E2S are present in breast tissue, and E2S has been implicated in the biology of breast cancer via serving as an active reservoir of estradiol.[2][4]

As the sodium salt sodium estradiol sulfate, E2S is present as a minor constituent (0.9%) of conjugated equine estrogens (CEEs), or Premarin.[8] It effectively functions as a prodrug to estradiol in this preparation, similarly to E1S. E2S is also formed as a metabolite of estradiol, as well as of estrone and E1S.[9][10] Aside from its presence in CEEs, E2S is not available as a commercial pharmaceutical drug.[11]

E2S shows about 10,000-fold lower potency in activating the estrogen receptors relative to estradiol in vitro.[12] It is 10-fold less potent than estrone sulfate orally in terms of in vivo uterotrophic effect in rats.[13] Estrogen sulfates like estradiol sulfate or estrone sulfate are about twice as potent as the corresponding free estrogens in terms of estrogenic effect when given orally to rodents.[14] This in part led to the introduction of conjugated estrogens (Premarin), which are primarily estrone sulfate, in 1941.[14]

Although inactive at steroid hormone receptors, E2S has been found to act as a potent inhibitor of glutathione S-transferase,[15] an enzyme that contributes to the inactivation of estradiol via conversion of it into an estradiol-glutathione conjugate.[16] As such, E2S can indirectly serve as a positive effector of estrogen signaling.[15]

Estradiol levels are about 1.5- to 4-fold higher than E2S levels in women. This is in contrast to E1S, the levels of which are about 10 to 15 times higher than those of estrone.[17]

E2S at an oral dosage of 5 mg/day in women resulted in inhibition of ovulation in 89% of cycles (47 of 53).[18]

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.
Structural properties of selected estradiol esters
Estrogen Structure Ester(s) Relative
mol. weight
Relative
E2 contentb
log Pc
Position(s) Moiet(ies) Type Lengtha
Estradiol
1.00 1.00 4.0
Estradiol acetate
C3 Ethanoic acid Straight-chain fatty acid 2 1.15 0.87 4.2
Estradiol benzoate
C3 Benzoic acid Aromatic fatty acid – (~4–5) 1.38 0.72 4.7
Estradiol dipropionate
C3, C17β Propanoic acid (×2) Straight-chain fatty acid 3 (×2) 1.41 0.71 4.9
Estradiol valerate
C17β Pentanoic acid Straight-chain fatty acid 5 1.31 0.76 5.6–6.3
Estradiol benzoate butyrate
C3, C17β Benzoic acid, butyric acid Mixed fatty acid – (~6, 2) 1.64 0.61 6.3
Estradiol cypionate
C17β Cyclopentylpropanoic acid Cyclic fatty acid – (~6) 1.46 0.69 6.9
Estradiol enanthate
C17β Heptanoic acid Straight-chain fatty acid 7 1.41 0.71 6.7–7.3
Estradiol dienanthate
C3, C17β Heptanoic acid (×2) Straight-chain fatty acid 7 (×2) 1.82 0.55 8.1–10.4
Estradiol undecylate
C17β Undecanoic acid Straight-chain fatty acid 11 1.62 0.62 9.2–9.8
Estradiol stearate
C17β Octadecanoic acid Straight-chain fatty acid 18 1.98 0.51 12.2–12.4
Estradiol distearate
C3, C17β Octadecanoic acid (×2) Straight-chain fatty acid 18 (×2) 2.96 0.34 20.2
Estradiol sulfate
C3 Sulfuric acid Water-soluble conjugate 1.29 0.77 0.3–3.8
Estradiol glucuronide
C17β Glucuronic acid Water-soluble conjugate 1.65 0.61 2.1–2.7
Estramustine phosphated
C3, C17β Normustine, phosphoric acid Water-soluble conjugate 1.91 0.52 2.9–5.0
Polyestradiol phosphatee
C3–C17β Phosphoric acid Water-soluble conjugate 1.23f 0.81f 2.9g
Footnotes: a = Length of ester in carbon atoms for straight-chain fatty acids or approximate length of ester in carbon atoms for aromatic or cyclic fatty acids. b = Relative estradiol content by weight (i.e., relative estrogenic exposure). c = Experimental or predicted octanol/water partition coefficient (i.e., lipophilicity/hydrophobicity). Retrieved from PubChem, ChemSpider, and DrugBank. d = Also known as estradiol normustine phosphate. e = Polymer of estradiol phosphate (~13 repeat units). f = Relative molecular weight or estradiol content per repeat unit. g = log P of repeat unit (i.e., estradiol phosphate). Sources: See individual articles.

See also[edit]

References[edit]

  1. ^ a b F. A. Kincl; J. R. Pasqualini (22 October 2013). Hormones and the Fetus: Volume 1: Production, Concentration and Metabolism During Pregnancy. Elsevier Science. pp. 39–. ISBN 978-1-4832-8538-2.
  2. ^ a b c d Peter J. O'Brien; William Robert Bruce (2 December 2009). Endogenous Toxins: Targets for Disease Treatment and Prevention, 2 Volume Set. John Wiley & Sons. pp. 869–. ISBN 978-3-527-32363-0.
  3. ^ Wang, Li-Quan; James, Margaret O. (2005). "Sulfotransferase 2A1 forms estradiol-17-sulfate and celecoxib switches the dominant product from estradiol-3-sulfate to estradiol-17-sulfate". The Journal of Steroid Biochemistry and Molecular Biology. 96 (5): 367–374. doi:10.1016/j.jsbmb.2005.05.002. ISSN 0960-0760. PMID 16011896. S2CID 24671971.
  4. ^ a b Jorge R. Pasqualini (17 July 2002). Breast Cancer: Prognosis, Treatment, and Prevention. CRC Press. pp. 195–. ISBN 978-0-203-90924-9.
  5. ^ a b IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; World Health Organization; International Agency for Research on Cancer (2007). Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy. World Health Organization. pp. 279–. ISBN 978-92-832-1291-1.
  6. ^ G. Leclercq; S. Toma; R. Paridaens; J. C. Heuson (6 December 2012). Clinical Interest of Steroid Hormone Receptors in Breast Cancer. Springer Science & Business Media. pp. 2105–. ISBN 978-3-642-82188-2.
  7. ^ A. T. Gregoire (13 March 2013). Contraceptive Steroids: Pharmacology and Safety. Springer Science & Business Media. pp. 109–. ISBN 978-1-4613-2241-2.
  8. ^ Marc A. Fritz; Leon Speroff (28 March 2012). Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins. pp. 751–. ISBN 978-1-4511-4847-3.
  9. ^ Christian Lauritzen; John W. W. Studd (22 June 2005). Current Management of the Menopause. CRC Press. pp. 364–. ISBN 978-0-203-48612-2.
  10. ^ Ryan J. Huxtable (11 November 2013). Biochemistry of Sulfur. Springer Science & Business Media. pp. 312–. ISBN 978-1-4757-9438-0.
  11. ^ King, Roberta; Ghosh, Anasuya; Wu, Jinfang (2006). "Inhibition of human phenol and estrogen sulfotransferase by certain non-steroidal anti-inflammatory agents". Current Drug Metabolism. 7 (7): 745–753. doi:10.2174/138920006778520615. ISSN 1389-2002. PMC 2105742. PMID 17073578.
  12. ^ Coldham NG, Dave M, Sivapathasundaram S, McDonnell DP, Connor C, Sauer MJ (July 1997). "Evaluation of a recombinant yeast cell estrogen screening assay". Environ. Health Perspect. 105 (7): 734–42. doi:10.1289/ehp.97105734. PMC 1470103. PMID 9294720.
  13. ^ Bhavnani BR (November 1988). "The saga of the ring B unsaturated equine estrogens". Endocr. Rev. 9 (4): 396–416. doi:10.1210/edrv-9-4-396. PMID 3065072.
  14. ^ a b Herr, F.; Revesz, C.; Manson, A. J.; Jewell, J. B. (1970). "Biological Properties of Estrogen Sulfates". Chemical and Biological Aspects of Steroid Conjugation. pp. 368–408. doi:10.1007/978-3-642-95177-0_8 (inactive 2024-03-25). ISBN 978-3-642-95179-4.{{cite book}}: CS1 maint: DOI inactive as of March 2024 (link)
  15. ^ a b Runge-Morris MA (1997). "Regulation of expression of the rodent cytosolic sulfotransferases". FASEB J. 11 (2): 109–17. doi:10.1096/fasebj.11.2.9039952. PMID 9039952. S2CID 22112485.
  16. ^ Singh D, Pandey RS (1996). "Glutathione-S-transferase in rat ovary: its changes during estrous cycle and increase in its activity by estradiol-17 beta". Indian J. Exp. Biol. 34 (11): 1158–60. PMID 9055636.
  17. ^ Cowie, Alfred T.; Forsyth, Isabel A.; Hart, Ian C. (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. PMID 6250026.
  18. ^ Gual C, Becerra C, Rice-Wray E, Goldzieher JW (February 1967). "Inhibition of ovulation by estrogens". Am J Obstet Gynecol. 97 (4): 443–7. doi:10.1016/0002-9378(67)90555-8. PMID 4163201.