Estradiol sulfate
# Estradiol sulfate

Estradiol sulfate (E2S), or 17β-estradiol 3-sulfate, is a natural, endogenous steroid and an estrogen ester. E2S itself is biologically inactive, but it can be converted by steroid sulfatase (also called estrogen sulfatase) into estradiol, which is a potent estrogen. Simultaneously, estrogen sulfotransferases convert estradiol to E2S, resulting in an equilibrium between the two steroids in various tissues. Estrone and E2S are the two immediate metabolic sources of estradiol. E2S can also be metabolized into estrone sulfate (E1S), which in turn can be converted into estrone and estradiol. Circulating concentrations of E2S are much lower than those of E1S. 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.

As the sodium salt sodium estradiol sulfate, E2S is present as a minor constituent (0.9%) of conjugated equine estrogens (CEEs), or Premarin. 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. Aside from its presence in CEEs, E2S is not available as a commercial pharmaceutical drug.

E2S shows about 10,000-fold lower potency in activating the estrogen receptors relative to estradiol in vitro. It is 10-fold less potent than estrone sulfate orally in terms of in vivo uterotrophic effect in rats. 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. This in part led to the introduction of conjugated estrogens (Premarin), which are primarily estrone sulfate, in 1941.

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

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.

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

vte Affinities and estrogenic potencies of estrogen esters and ethers at the estrogen receptors :

| Estrogen | Other names | RBA $(%)^a$ | REP $(%)^b$ | REP $(%)^b$ |
| - | - | - | - | - |
| Estrogen | Other names | 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 $(EC_{50})$ 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. |||||

vte Structural properties of selected estradiol esters :

| Estrogen | Structure | Ester(s) | Ester(s) | Ester(s) | Ester(s) | Relative mol. weight | Relative E2 $content^b$ | log $P^c$ |
| - | - | - | - | - | - | - | - | - |
| Estrogen | Structure | Position(s) | Moiet(ies) | Type | $Length^a$ | Relative mol. weight | Relative E2 $content^b$ | log $P^c$ |
| 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 | Benzenecarboxylic 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 | Aromatic 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 $phosphate^d$ | | C3, C17β | Normustine, phosphoric acid | Water-soluble conjugate | – | 1.91 | 0.52 | 2.9–5.0 |
| Polyestradiol $phosphate^e$ | | C3–C17β | Phosphoric acid | Water-soluble conjugate | – | $1.23^f$ | $0.81^f$ | $2.9^g$ |
| Footnotes: $^a$ = Length of ester in carbon atoms for straight-chain fatty acids or approximate length of ester in carbon atoms for aromatic 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. |||||||||
