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 ar ...

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 estradiol ...

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 and ...

, for instance in

menopausal hormone therapy Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. These symptoms can include hot flashes, vaginal ...

; for information on estrone sulfate as a medication, see the

estrone sulfate (medication) Estrone sulfate (E1S) is an estrogen medication and naturally occurring steroid hormone. It is used in menopausal hormone therapy among other indications. As the sodium salt (sodium estrone sulfate), it is the major estrogen component of conj ...

article.

Biological function

E1S itself is biologically inactive, with less than 1% of the

relative binding affinity In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a mol ...

of estradiol for the ERα and ERβ. However, it can be transformed by

steroid sulfatase Steroid sulfatase (STS), or steryl-sulfatase (EC 3.1.6.2), formerly known as arylsulfatase C, is a sulfatase enzyme involved in the metabolism of steroids. It is encoded by the ''STS'' gene. Reactions This enzyme catalyses the following chemi ...

, also known as estrogen sulfatase, into

estrone Estrone (E1), also spelled oestrone, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estriol. Estrone, as well as the other estrogens, are synthesized ...

, 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 ac ...

. 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 an ...

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 dehydrogenase A hydroxysteroid is a molecule derived from a steroid with a hydrogen replaced with a hydroxy group. When the hydroxy group is specifically at the C3 position, hydroxysteroids are referred to as sterols, with an example being cholesterol. See ...

s 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 Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors ( ERα and ERβ), which are members of the ...

at physiologically relevant concentrations. This was diminished with co-application of

irosustat Irosustat (, ; developmental code names STX-64, 667-coumate, BN-83495; also known as oristusane) is an orally active, irreversible, nonsteroidal inhibitor of steroid sulfatase (STS) and member of the aryl sulfamate ester class of drugs that was ...

(STX-64), a

steroid sulfatase inhibitor Steroid sulfatase (STS), or steryl-sulfatase (EC 3.1.6.2), formerly known as arylsulfatase C, is a sulfatase enzyme involved in the metabolism of steroids. It is encoded by the ''STS'' gene. Reactions This enzyme catalyses the following chemic ...

, indicating the importance of transformation of estrone sulfate into estrone in the estrogenicity of E1S. Unlike unconjugated estradiol and estrone, which are

lipophilic Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipo ...

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 n ...

. 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 vir ...

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 (t ...

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 cellul ...

via organic-anion-transporting polypeptides (OATPs), including

OATP1A2 Solute carrier organic anion transporter family member 1A2 is a protein that in humans is encoded by the ''SLCO1A2'' gene. This gene encodes a sodium-independent transporter which mediates cellular uptake of organic ions in the liver. Its substr ...

, OATP1B1, OATP1B3,

OATP1C1 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, OATPs ...

, 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 ...

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 Malignancy () is the tendency of a medical condition to become progressively worse. Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not ...

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 Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel ...

. 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 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 A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical sy ...

estrane Estrane is a C18 steroid derivative, with a gonane core. ''Estrenes'' are estrane derivatives that contain a double bond, with an example being nandrolone. ''Estratrienes'' (estrins) are estrane derivatives that contain three double bonds, for i ...

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. ...

. It is an

estrogen conjugate An estrogen conjugate is a conjugate of an endogenous estrogen. They occur naturally in the body as metabolites of estrogens and can be reconverted back into estrogens. They serve as a circulating reservoir for estrogen, particularly in the c ...

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 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 salts of sulfuric acid and many ...

of estrone. Related estrogen conjugates include

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 ...

estriol sulfate Estriol sulfate, or estriol 3-sulfate, is a conjugated metabolite of estriol that is present in high quantities during pregnancy. It is formed from estriol in the liver and is eventually excreted in the urine by the kidneys. It has much higher ...

estrone glucuronide Estrone glucuronide, or estrone-3-D-glucuronide, is a conjugated metabolite of estrone. It is formed from estrone in the liver by UDP-glucuronyltransferase via attachment of glucuronic acid and is eventually excreted in the urine by the kidneys. ...

estradiol glucuronide Estradiol glucuronide, or estradiol 17β-D-glucuronide, is a conjugated metabolite of estradiol. It is formed from estradiol in the liver by UDP-glucuronyltransferase via attachment of glucuronic acid and is eventually excreted in the urine by t ...

, and

estriol glucuronide Estriol glucuronide (E3G), or oestriol glucuronide, also known as estriol monoglucuronide, as well as estriol 16α-β-D-glucosiduronic acid, is a natural, steroidal estrogen and the glucuronic acid (β-D-glucopyranuronic acid) conjugate of estri ...

, while related steroid conjugates include dehydroepiandrosterone sulfate and

pregnenolone sulfate Pregnenolone sulfate (PS, PREGS) is an endogenous excitatory neurosteroid that is synthesized from pregnenolone. It is known to have cognitive and memory-enhancing, antidepressant, anxiogenic, and proconvulsant effects. Biological activity Pr ...

. 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 ...

of the estrogens

and

. 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 sp ...

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

and can enter cells via

passive diffusion Passive transport is a type of membrane transport that does not require energy to move substances across cell membranes. Instead of using cellular energy, like active transport, passive transport relies on the second law of thermodynamics to dri ...

, 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 transmemb ...

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 pri ...

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 Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

of E1S is 10 to 12 hours. Its metabolic clearance rate is 80 L/day/m².

Ovarian tumor Ovarian tumors, or ovarian neoplasms, are tumors arising from the ovary. They can be benign or malignant (ovarian cancer). They consist of mainly solid tissue, while ovarian cysts contain fluid. Histopathologic classification Ovarian tumors are ...

s have been found to express

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 A radioimmunoassay (RIA) is an immunoassay that uses radiolabeled molecules in a stepwise formation of immune complexes. A RIA is a very sensitive in vitro assay technique used to measure concentrations of substances, usually measuring antigen conc ...

(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 ful ...

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 th ...

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 Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...

women, and 2.56 ± 0.47 ng/mL in postmenopausal women on

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