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 from cholesterol and secreted mainly from the gonads, though they can also be formed from adrenal androgens in adipose tissue. Relative to estradiol, both estrone and estriol have far weaker activity as estrogens. Estrone can be converted into estradiol, and serves mainly as a precursor or metabolic intermediate of estradiol. It is both a precursor and metabolite of estradiol.
Estriol (E3), also spelled oestriol, 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 estrone. Levels of estriol in women who are not pregnant are almost undetectable. However, during pregnancy, estriol is synthesized in very high quantities by the placenta and is the most produced estrogen in the body by far, although circulating levels of estriol are similar to those of other estrogens due to a relatively high rate of metabolism and excretion. Relative to estradiol, both estriol and estrone have far weaker activity as estrogens.
Equilin is a naturally occurring estrogen sex hormone found in horses as well as a medication. It is one of the estrogens present in the estrogen mixtures known as conjugated estrogens and esterified estrogens. CEEs is the most commonly used form of estrogen in hormone replacement therapy (HRT) for menopausal symptoms in the United States. Estrone sulfate is the major estrogen in CEEs while equilin sulfate is the second major estrogen in the formulation, present as about 25% of the total.
Estrone sulfate, also known as E1S, E1SO4 and estrone 3-sulfate, is a natural, endogenous steroid and an estrogen ester and conjugate.
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 with increased resistance to first-pass metabolism, slightly improving its oral bioavailability. In addition, estrogen esters have increased lipophilicity, which results in a longer duration when given by intramuscular or subcutaneous injection due to the formation of a long-lasting local depot in muscle and fat. Conversely, this is not the case with intravenous injection or oral administration. Estrogen esters are rapidly hydrolyzed into their parent estrogen by esterases once they have been released from the depot. Because estradiol esters are prodrugs of estradiol, they are considered to be natural and bioidentical forms of estrogen.
Conjugated estrogens (CEs), or conjugated equine estrogens (CEEs), sold under the brand name Premarin among others, is an estrogen medication which is used in menopausal hormone therapy and for various other indications. It is a mixture of the sodium salts of estrogen conjugates found in horses, such as estrone sulfate and equilin sulfate. CEEs are available in the form of both natural preparations manufactured from the urine of pregnant mares and fully synthetic replications of the natural preparations. They are formulated both alone and in combination with progestins such as medroxyprogesterone acetate. CEEs are usually taken by mouth, but can also be given by application to the skin or vagina as a cream or by injection into a blood vessel or muscle.
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 case of orally administered pharmaceutical estradiol. Estrogen conjugates include sulfate and/or glucuronide conjugates of estradiol, estrone, and estriol:
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 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.
8,9-Dehydroestradiol, or Δ8-17β-estradiol, also known as estra-1,3,5(10),8-tetraen-17β-ol-3-one, is a naturally occurring steroidal estrogen found in horses which is closely related to equilin, equilenin, and estradiol, and, as the 3-sulfate ester sodium salt, is a minor constituent of conjugated estrogens (Premarin). It is also an important active metabolite of 8,9-dehydroestrone, analogously to conversion of estrone or estrone sulfate into estradiol.
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 conjugate of estriol. It occurs in high concentrations in the urine of pregnant women as a reversibly formed metabolite of estriol. Estriol glucuronide is a prodrug of estriol, and was the major component of Progynon and Emmenin, estrogenic products manufactured from the urine of pregnant women that were introduced in the 1920s and 1930s and were the first orally active estrogens. Emmenin was succeeded by Premarin, which is sourced from the urine of pregnant mares and was introduced in 1941. Premarin replaced Emmenin due to the fact that it was easier and less expensive to produce.
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 the kidneys. It has much higher water solubility than does estradiol. Glucuronides are the most abundant estrogen conjugates.
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. It has much higher water solubility than does estrone. Glucuronides are the most abundant estrogen conjugates and estrone glucuronide is the dominant metabolite of estradiol.
Estriol 3-glucuronide, or oestriol 3-glucuronide, also known as estriol 3-β-D-glucosiduronic acid, is a natural, steroidal estrogen and a glucuronic acid conjugate of estriol. It is found in the urine of women as a reversibly formed metabolite of estriol. The positional isomer of estriol 3-glucuronide, estriol 16α-glucuronide, also occurs as an endogenous metabolite of estriol, but to a much greater extent in comparison.
Estradiol sulfamate, or estradiol-3-O-sulfamate, is a steroid sulfatase (STS) inhibitor which is under development for the treatment of endometriosis. It is the C3 sulfamate ester of estradiol, and was originally thought to be a prodrug of estradiol. The drug was first synthesized as an STS inhibitor along with its oxidized version estrone 3-O-sulfamate (EMATE) in the group of Professor Barry V L Potter at the University of Bath, UK, working together with Professor Michael J Reed at Imperial College, London and was found to be highly estrogenic in rodents. Such aryl sulfamate esters were shown to be "first-in-class" highly potent active site-directed irreversible STS inhibitors. Compounds of this class are thought to irreversibly modify the active site formylglycine residue of STS. The drug shows profoundly reduced susceptibility to first-pass metabolism relative to estradiol, and was believed to be the first "potent" estradiol prodrug to be discovered. It was clinically investigated for possible use as an estrogen for indications like hormonal contraception and menopausal hormone therapy. However, it showed no estrogenic effects in women. The potent non-estrogenic clinical STS inhibitor Irosustat (STX64/667-Coumate) was used to explore the possibility that STS might be responsible for the hydrolysis of estrogen sulphamates. Results demonstrated convincingly that STS is the enzyme responsible for the removal of the sulfamoyl group from estrogen sulfamates and has a crucial role in regulating the estrogenicity associated with this class of drug. Thus, STS inhibition blocks the conversion of E2MATE into estradiol and thereby abolishes its estrogenicity in humans. Irosustat has completed a number of clinical trials in oncology as an STS inhibitor currently up to Phase II.
Estrone sulfamate, or estrone-3-O-sulfamate, is a steroid sulfatase (STS) inhibitor which has not yet been marketed. It is the C3 sulfamate ester of the estrogen estrone. Unlike other estrogen esters however, EMATE is not an effective prodrug of estrogens. A closely related compound is estradiol sulfamate (E2MATE), which is extensively metabolized into EMATE and has similar properties to it.
Estrone (E1), sold under the brand names Estragyn, Kestrin, and Theelin among many others, is an estrogen medication and naturally occurring steroid hormone which has been used in menopausal hormone therapy and for other indications. It has been provided as an aqueous suspension or oil solution given by injection into muscle and as a vaginal cream applied inside of the vagina. It can also be taken by mouth as estradiol/estrone/estriol and in the form of prodrugs like estropipate and conjugated estrogens.
Ethinylestradiol sulfate, also known as 17α-ethynylestradiol 3-sulfate, is an estrogen ester – specifically, the C3 sulfuric acid (sulfate) ester of the synthetic estrogen ethinylestradiol (EE) – and is the major metabolite of EE. Circulating levels of EE sulfate range from 6 to 22 times those of EE when EE is taken orally. EE sulfate can be transformed back into EE (14–21%) via steroid sulfatase, and it has been suggested that EE sulfate may serve as a circulating reservoir for EE, similarly to the case of estrone sulfate with estradiol. However, the EE sulfate pool with EE is far smaller than the pool of estrone sulfate that occurs with estradiol. In addition, in contrast to the case of estrone sulfate and estrone, the conversion rate of EE sulfate back into EE is relatively low, and has been said probably isn't of clinical significance. However, other studies have suggested that EE sulfate may nonetheless contribute up to 20% of total EE levels.
The pharmacology of estradiol, an estrogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.
Conjugated estriol, sold under the brand names Progynon and Emmenin, is an estrogen medication which was previously used for estrogen-type indications such as the treatment of menopausal symptoms in women. The term specifically refers to formulations of estriol conjugates which were manufactured from the estrogen-rich urine of pregnant women and were used as medications in the 1920s and 1930s. Conjugated estriol is analogous to and was superseded by conjugated estrogens, which is manufactured from the urine of pregnant mares. Conjugated estriol was among the first forms of pharmaceutical estrogen to be used in medicine. It was taken by mouth.
