Estrone sulfate, also known as E1S, E1SO4 and estrone 3-sulfate, is a

natural Nature, in the broadest sense, is the physical world or universe. "Nature" can refer to the phenomena of the physical world, and also to life in general. The study of nature is a large, if not the only, part of science. Although humans are ...

endogenous Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell. In contrast, exogenous substances and processes are those that originate from outside of an organism. For example, ...

steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and ...

and an

estrogen ester An estrogen ester is an ester of an estrogen, most typically of estradiol but also of other estrogens such as estrone, estriol, and even nonsteroidal estrogens like diethylstilbestrol. Esterification renders estradiol into a prodrug of estrad ...

and conjugate. In addition to its role as a natural hormone, estrone sulfate is used as a

medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field an ...

, 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. However, it can be transformed by steroid sulfatase, also known as estrogen sulfatase, into estrone, an

estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal a ...

. Simultaneously,

estrogen sulfotransferase Estrone sulfotransferase (EST) (), also known as estrogen sulfotransferase, is an enzyme that catalyzes the transformation of an unconjugated estrogen like estrone into a sulfated estrogen like estrone sulfate. It is a steroid sulfotransferase ...

s, including SULT1A1 and SULT1E1, convert estrone to E1S, resulting in an equilibrium between the two steroids in various tissues. Estrone can also be converted by 17β-hydroxysteroid dehydrogenases into the more potent estrogen

estradiol Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development o ...

. 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

in the body. In accordance, E1S has been found to transactivate the estrogen receptor at physiologically relevant concentrations. 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. Unlike unconjugated estradiol and estrone, which are lipophilic compounds, E1S is an

anion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...

and is

hydrophilic A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are ...

. As a result of this, whereas estradiol and estrone are able to readily diffuse through the

lipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many ...

s of cells, E1S is unable to permeate through

cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (the ...

s. Instead, estrone sulfate is transported into cells in a tissue-specific manner by

active transport In cellular biology, ''active transport'' is the movement of molecules or ions across a cell membrane from a region of lower concentration to a region of higher concentration—against the concentration gradient. Active transport requires cellu ...

via

organic-anion-transporting polypeptide Members of the Organo Anion Transporter (OAT) Family (organic-anion-transporting polypeptides, OATP) are membrane transport proteins or 'transporters' that mediate the transport of mainly organic anions across the cell membrane. Therefore, OATP ...

s (OATPs), including OATP1A2, OATP1B1, OATP1B3, OATP1C1, OATP2B1, OATP3A1, OATP4A1, and OATP4C1, as well as by the sodium-dependent organic anion transporter (SOAT; SLC10A6). E1S, serving as a precursor and intermediate for estrone and estradiol, may be involved in the

pathophysiology Pathophysiology ( physiopathology) – a convergence of pathology with physiology – is the study of the disordered physiological processes that cause, result from, or are otherwise associated with a disease or injury. Pathology is t ...

of estrogen-associated diseases including

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...

, benign breast disease,

endometrial cancer Endometrial cancer is a cancer that arises from the endometrium (the lining of the uterus or womb). It is the result of the abnormal growth of cells that have the ability to invade or spread to other parts of the body. The first sign is most ...

ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different ...

prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that su ...

, and colorectal cancer. For this reason,

enzyme inhibitor An enzyme inhibitor is a molecule that binds to an enzyme and blocks its activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which substrate molecules are converted into products. An enzyme facilitates a s ...

s 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.

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

and a

derivative In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. ...

of estrone. It is an estrogen conjugate or

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ...

, and is specifically the C3

sulfate The sulfate or sulphate ion is a polyatomic ion, polyatomic anion with the empirical formula . Salts, acid derivatives, and peroxides of sulfate are widely used in industry. Sulfates occur widely in everyday life. Sulfates are salt (chemistry), ...

of estrone. 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.

Biochemistry

Biosynthesis

E1S is produced via

s from the peripheral

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...

of the estrogens

and estrone. Estrogen sulfotransferases are expressed minimally or not at all in the

gonad A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces ...

s. In accordance, E1S is not secreted in meaningful amounts from the gonads in humans. However, measurable amounts of estrogen sulfates are said to be secreted by the ovaries in any case.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.

Distribution

Whereas free steroids like estradiol are lipophilic and can enter cells via passive diffusion, steroid conjugates like E1S are

and are unable to do so. Instead, steroid conjugates require

via

membrane transport protein A membrane transport protein (or simply transporter) is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membrane. Transport proteins are integral membrane prote ...

s to enter cells. Studies in animals and humans have had mixed findings on uptake of exogenously administered E1S in normal and

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

ous

mammary gland A mammary gland is an exocrine gland in humans and other mammals that produces milk to feed young offspring. Mammals get their name from the Latin word ''mamma'', "breast". The mammary glands are arranged in organs such as the breasts in pr ...

tissue. This is in contrast to substantial uptake of exogenously administered estradiol and estrone by the mammary glands. Another animal study found that E1S wasn't taken up by the

uterus The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The ...

but was taken up by the

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

, where it was hydrolyzed into estrone.

Metabolism

The elimination half-life of E1S is 10 to 12 hours. Its metabolic clearance rate is 80 L/day/m². Ovarian tumors have been found to express steroid sulfatase and have been found to convert E1S into estradiol. This may contribute to the often elevated levels of estradiol observed in women with

Levels

E1S levels have been characterized in humans. 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 The follicular phase, also known as the preovulatory phase or proliferative phase, is the phase of the estrous cycle (or, in primates for example, the menstrual cycle) during which follicles in the ovary mature from primary follicle to a fully ...

in women, 1.74 ± 0.32 ng/mL during the

luteal phase The corpus luteum (Latin for "yellow body"; plural corpora lutea) is a temporary endocrine structure in female ovaries involved in the production of relatively high levels of progesterone, and moderate levels of estradiol, and inhibin A. It is ...

in women, 0.74 ± 0.11 ng/mL in women taking

oral contraceptive Oral contraceptives, abbreviated OCPs, also known as birth control pills, are medications taken by mouth for the purpose of birth control. Female Two types of female oral contraceptive pill, taken once per day, are widely available: * The combi ...

s, 0.13 ± 0.03 ng/mL in postmenopausal women, and 2.56 ± 0.47 ng/mL in postmenopausal women on menopausal hormone therapy. In addition, E1S levels in

pregnant Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...

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. E1S levels are about 10 to 15 times higher than those of estrone in women.