Conjugated estriol

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Conjugated estriol
Estriol glucuronide.svg
Estriol 16α-glucuronide, the primary active component in conjugated estriol (estriol glucuronides constitute about 35 to 46% of total content).
Estriol 3-sulfate.svg
Estriol 3-sulfate, the second major active component in conjugated estriol (constitutes about 15 to 22% of total content).
Combination of
Estriol glucuronide Estrogen
Estriol sulfate Estrogen
Estriol sulfate glucuronide Estrogen
Clinical data
Trade names Progynon, Emmenin
Other namesConjugated human estriol; Conjugated oestriol; Conjugated human oestriol; CE3; CHE3; Conjugated human estrogens; Conjugated human oestrogens; CHEs
Routes of
administration 		By mouth
Identifiers
CAS Number
UNII

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 Conjugated estriol is analogous to and was superseded by conjugated estrogens (brand name Premarin), which is manufactured from the urine of pregnant mares.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.

Contents

The main components of conjugated estriol are estriol glucuronides and to a lesser extent estriol sulfates. Estrogen glucuronides can be deglucuronidated into the corresponding free estrogens by β-glucuronidase in tissues that express this enzyme, such as the mammary gland, liver, and kidney, among others. [1] Likewise, estrogen sulfates can be desulfated into the corresponding free estrogens by steroid sulfatase in tissues that express this enzyme. [2] Consequently, estrogen conjugates have estrogenic activity via conversion into unconjugated estrogens. [1]

Progynon

Progynon (Schering). Glass bottle for 'Progynon' pills, United Kingdom, 1928-1948 Wellcome L0058274.jpg
Progynon (Schering).

Progynon was an orally active formulation of estrogen that was developed by Adolf Butenandt at Schering and introduced in Germany in 1928. [3] [4] [5] [6] [7] [8] It was reportedly the first sex hormone product and hence also the first estrogen product to be introduced for medical use. [8] Progynon was originally an ovarian or placental extract, [9] [10] but Schering soon switched for economic reasons to using the urine of women who were in late pregnancy. [6] This form of Progynon was essentially the same product as Emmenin, which was developed by James Collip at Ayerst and introduced in Canada in 1930 (and in the U.S. Tooltip United States in 1934). [3] [4]

To further reduce the costs of manufacturing Progynon, Schering eventually switched to using the urine of pregnant mares and called its new product Progynon 2. [3] [4] [11] Ayerst followed suit, with the introduction of Premarin (conjugated equine estrogens) in 1941. [4] Premarin soon superseded Emmenin and has since become not only a very widely used estrogen, but one of the most widely prescribed drugs in North America. [12]

Both Progynon and Emmenin contained a mixture of water-soluble estrogens, which was determined later to be mostly estriol glucuronide. [4] [13] Conjugates of estriol like estriol glucuronide and estriol sulfate constitute more than 90% of the estrogens in the urine of pregnant women. [14] Of these conjugates, 35 to 46% are estriol glucuronides and 15 to 22% are estriol 3-sulfate in late pregnancy; the double conjugate estriol sulfate glucuronide (probably estriol 3-sulfate 16α-glucuronide) also occurs. [15] [16] [17]

Progynon was also the name that Butenandt originally gave estrone (which he had isolated in 1929) in his first publication on the substance (and later referred to as folliculine, with the name estrone not finally being adopted until 1935). [18] [19] Aside from Progynon and Progynon 2, the Progynon name has also been used in a variety of other estrogenic products marketed by Schering, including Progynon-B (estradiol benzoate), Progynon-DH (estradiol; "dihydroxyestrin"), Progynon-DP (estradiol dipropionate), Progynon-C (ethinylestradiol), Progynova (estradiol valerate), and Progynon Depot (estradiol valerate, estradiol undecylate).

Emmenin

Emmenin (Ayerst). Emmenin tablets.jpg
Emmenin (Ayerst).

Emmenin was an orally active formulation of estrogen that was developed by James Collip at Ayerst and introduced in Canada in 1930 and the United States in 1934. [3] [4] It was originally an extract obtained from human placenta. [20] [21] [22] [23] [24] At some point, it seems to have been changed to an extract of the urine of women who were in late pregnancy, which was equivalent in composition but was less expensive to source, [25] and was essentially the same product as Progynon, a related estrogen developed by Adolf Butenandt at Schering and introduced in Germany. [3] [4] [5] [6] [7] [8] These estrogen products were the first orally active estrogens to be marketed for medical use. [4] [8] [26] [27]

To reduce the costs of manufacturing Emmenin and Progynon, Ayerst and Schering eventually switched to using the urine of pregnant mares (which contains conjugated equine estrogens, primarily estrone sulfate) [2] and called their new products Premarin and Progynon 2, respectively. [3] [4] [11] Premarin was introduced by Ayerst in 1941 [4] and has become not only a very widely used estrogen, but one of the most widely prescribed drugs in North America. [12]

Both Emmenin and Progynon contained a mixture of water-soluble conjugated estrogens, later determined to be mostly estriol glucuronide. [4] [13] Conjugates of estriol like estriol glucuronide and estriol sulfate constitute more than 90% of the estrogens in the urine of pregnant women. [14] Of these conjugates, 35 to 46% are estriol glucuronides and 15 to 22% are estriol 3-sulfate in late pregnancy; the double conjugate estriol sulfate glucuronide (probably estriol 3-sulfate 16α-glucuronide) also occurs. [15] [16] [17] Unlike unconjugated estrogens like estradiol and estrone, these estrogens were orally active. [4] [8] [26] [27]

See also

Related Research Articles

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Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as estrous and menstrual cycles. Estradiol is responsible for the development of female secondary sexual characteristics such as the breasts, widening of the hips and a female-associated pattern of fat distribution. It is also important in the development and maintenance of female reproductive tissues such as the mammary glands, uterus and vagina during puberty, adulthood and pregnancy. It also has important effects in many other tissues including bone, fat, skin, liver, and the brain.

<span class="mw-page-title-main">Estrone</span> Chemical compound

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.

<span class="mw-page-title-main">Estriol</span> Chemical compound

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.

<span class="mw-page-title-main">Estrone sulfate</span> Chemical compound

Estrone sulfate, also known as E1S, E1SO4 and estrone 3-sulfate, is a natural, endogenous steroid and an estrogen ester and conjugate.

<span class="mw-page-title-main">Esterified estrogens</span> Pharmaceutical drug

Esterified estrogens (EEs), sold under the brand names Estratab and Menest among others, is an estrogen medication which is used hormone therapy for menopausal symptoms and low sex hormone levels in women, to treat breast cancer in both women and men, and to treat prostate cancer in men. It is formulated alone or in combination with methyltestosterone. It is taken by mouth.

<span class="mw-page-title-main">Conjugated estrogens</span> Estrogen medication

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.

<span class="mw-page-title-main">Estrogen conjugate</span> Class of chemical compounds

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:

<span class="mw-page-title-main">Estradiol sulfate</span> Chemical compound

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.

<span class="mw-page-title-main">Estriol glucuronide</span> Chemical compound

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.

<span class="mw-page-title-main">Estradiol glucuronide</span> Chemical compound

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.

<span class="mw-page-title-main">Estrone glucuronide</span> Chemical compound

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.

<span class="mw-page-title-main">Estriol sulfate</span> Chemical compound

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 water solubility than does estriol. Estriol sulfate is the second most prevalent conjugated metabolite of estriol during pregnancy; 35 to 46% is estriol glucuronide and 15 to 22% is estriol 3-sulfate, while the double conjugate estriol sulfate glucuronide also occurs. Estriol sulfate was a component, along with estriol glucuronide, of the early pharmaceutical estrogens Progynon and Emmenin.

<span class="mw-page-title-main">Estriol sulfate glucuronide</span> Chemical compound

Estriol sulfate glucuronide, or estriol 3-sulfate 16α-glucuronide, is an endogenous, naturally occurring diconjugated metabolite of estriol. It is generated in the liver from estriol sulfate by UDP-glucuronyltransferase and is eventually excreted in the urine by the kidneys. It occurs in high concentrations during pregnancy along with estriol sulfate and estriol glucuronide, and was a component of the early pharmaceutical estrogens Progynon and Emmenin.

<span class="mw-page-title-main">Estriol 3-glucuronide</span> Chemical compound

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.

<span class="mw-page-title-main">Estrogen (medication)</span> Type of medication

An estrogen (E) is a type of medication which is used most commonly in hormonal birth control and menopausal hormone therapy, and as part of feminizing hormone therapy for transgender women. They can also be used in the treatment of hormone-sensitive cancers like breast cancer and prostate cancer and for various other indications. Estrogens are used alone or in combination with progestogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of estrogens include bioidentical estradiol, natural conjugated estrogens, synthetic steroidal estrogens like ethinylestradiol, and synthetic nonsteroidal estrogens like diethylstilbestrol. Estrogens are one of three types of sex hormone agonists, the others being androgens/anabolic steroids like testosterone and progestogens like progesterone.

<span class="mw-page-title-main">Estriol (medication)</span> Chemical compound

Estriol (E3), sold under the brand name Ovestin among others, is an estrogen medication and naturally occurring steroid hormone which is used in menopausal hormone therapy. It is also used in veterinary medicine as Incurin to treat urinary incontinence due to estrogen deficiency in dogs. The medication is taken by mouth in the form of tablets, as a cream that is applied to the skin, as a cream or pessary that is applied in the vagina, and by injection into muscle.

<span class="mw-page-title-main">Estrone (medication)</span> Estrogen medication

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.

<span class="mw-page-title-main">Estrone sulfate (medication)</span> Chemical compound

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, it is the major estrogen component of conjugated estrogens (Premarin) and esterified estrogens. In addition, E1S is used on its own as the piperazine salt estropipate. The compound also occurs as a major and important metabolite of estradiol and estrone. E1S is most commonly taken by mouth, but in the form of Premarin can also be taken by parenteral routes such as transdermal, vaginal, and injection.

<span class="mw-page-title-main">Estrogenic substances</span> Estrogen medication

Estrogenic substances, also referred to as natural estrogens and sold under the brand name Amniotin among others, is an estrogen medication which was marketed in the 1930s and 1940s and is no longer available. It was a purified extract of animal material such as horse urine, placenta, and/or amniotic fluid, and contained a non-crystalline mixture of estrogens, including estrone, 17β-estradiol, 17α-estradiol, and/or equilin. The medication was thought to contain estrone as its major active ingredient and was described as an estrone-like preparation, or as "essentially estrone". Estrogenic substances was originally produced from the urine of pregnant women, placenta, and/or amniotic fluid, but by the early 1940s, it was manufactured exclusively from the urine of stallions or pregnant mares, similarly to almost all other estrogen preparations on the market.

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