Estradiol sulfate

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]

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
CAS Number	481-96-9 4999-79-5 (sodium)
3D model (JSmol)	Interactive image
ChEBI	CHEBI:4866
ChEMBL	ChEMBL1628111
ChemSpider	59790
PubChem CID	66416
UNII	4NKQ3751P6
CompTox Dashboard (EPA)	DTXSID30964000
InChI 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
SMILES CC12CCC3C(C1CCC2O)CCC4=C3C=CC(=C4)OS(=O)(=O)O
Properties
Chemical formula	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). Infobox references

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]

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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.

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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

• Catechol estrogen
• DHEA sulfate
• Estradiol glucuronide
• Estriol sulfate
• Estrogen conjugate
• Lipoidal estradiol
• Pregnenolone sulfate
• List of estrogen esters § Estradiol esters