Estrone (E1), sold under the brand names Estragyn, Kestrin, and Theelin among many others, is 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 acti ...

medication and

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 synt ...

steroid hormone A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into two classes: corticosteroids (typically made in the adrenal cortex, hence ''cortico-'') and sex steroids (typically made in the gonads or placenta). Wi ...

which has been used 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, vagina ...

and for other indications. It has been provided as an

aqueous suspension In chemistry, a suspension is a Mixture#Homogeneous and heterogeneous mixtures, heterogeneous mixture of a fluid that contains solid particles sufficiently large for sedimentation. The particles may be macroscopic, visible to the naked eye, usual ...

oil solution An oil is any nonpolar chemical substance that is composed primarily of hydrocarbons and is hydrophobic (does not mix with water) & lipophilic (mixes with other oils). Oils are usually flammable and surface active. Most oils are unsaturated ...

given by

injection into muscle Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles have l ...

and as a

vaginal In mammals, the vagina is the elastic, muscular part of the female genital tract. In humans, it extends from the vestibule to the cervix. The outer vaginal opening is normally partly covered by a thin layer of mucosal tissue called the hyme ...

cream Cream is a dairy product composed of the higher-fat layer skimmed from the top of milk before homogenization. In un-homogenized milk, the fat, which is less dense, eventually rises to the top. In the industrial production of cream, this process ...

applied inside of the vagina. It can also be taken

by mouth Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...

estradiol/estrone/estriol Estradiol/estrone/estriol (brand name Hormonin) is a combination pharmaceutical medication produced by Shire which contains the estrogens estradiol (0.3 or 0.6 mg), estrone (0.7 or 1.4 mg), and estriol (0.135 or 0.27 mg) in a singl ...

(brand name Hormonin) and in the form of

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...

s like

estropipate Estropipate, also known as piperazine estrone sulfate and sold under the brand names Harmogen, Improvera, Ogen, Ortho-Est, and Sulestrex among others, is an estrogen medication which is used mainly in menopausal hormone therapy in the treatment ...

(

estrone sulfate Estrone sulfate, also known as E1S, E1SO4 and estrone 3-sulfate, is a natural, endogenous steroid and an estrogen ester and conjugate. In addition to its role as a natural hormone, estrone sulfate is used as a medication, for instance in menop ...

; brand name Ogen) and conjugated estrogens (mostly estrone sulfate; brand name Premarin). Side effects of estrogens like estrone include breast tenderness, breast enlargement, headache, nausea, water retention (medicine), fluid retention, and edema, among others. Estrone is a

and bioidentical hormone therapy, bioidentical estrogen, or an agonist of the estrogen receptor, the biological target of estrogens like endogenous estradiol. It is a relatively weak estrogen, with much lower biological activity, activity than estradiol (medication), estradiol. However, estrone is biotransformation, converted in the body into estradiol, which provides most or all of its estrogenic potency (pharmacology), potency. As such, estrone is a

of estradiol. Estrone was first discovered in 1929, and was introduced for medical use shortly thereafter. Although it has been used clinically in the past, estrone has largely been discontinued and is mostly no longer marketed.

Medical uses

Estrone has been marketed in intramuscular injection, intramuscular and vaginal administration, vaginal formulations and was used as an

in the treatment of symptoms of hypoestrogenism, low estrogen levels such as hot flashes and atrophic vaginitis, vaginal atrophy in menopause, postmenopausal or ovariectomy, ovariectomized women. Estrone has also been used as an antigonadotropin and form of high-dose estrogen to treat prostate cancer in men as well as a form of high-dose estrogen to treat breast cancer in women. It has since largely been discontinued and is mostly no longer available, having been superseded by other estrogens with better potency (pharmacology), potency and pharmacokinetics (namely oral administration, oral bioavailability and duration of action, duration). Regardless of route of administration, if estrone is taken by a woman with an intact uterus, it should be combined with a progestogen such as progesterone (medication), progesterone to offset the risk of endometrial hyperplasia and endometrial cancer, cancer. Estrone has been used by intramuscular injection at a dosage of 0.1 to 2 mg per week, or 0.1 to 0.5 mg given 2 or 3 times per week, for the treatment of menopausal symptoms such as hot flashes and vaginal atrophy, and at a dosage of 0.1 to 1.0 mg weekly in single or divided doses for the treatment of female hypogonadism, surgical castration, and primary ovarian failure. The range of single doses of estrone by intramuscular injection that are typically used clinically in women is 0.1 to 5 mg. High doses of intramuscular estrone have been used for prostate cancer in men and for breast cancer in women.

Available forms

Estrone for intramuscular injection was provided as 1, 2, 2.5, 3, 4, and 5 mg/mL

s and/or

s.https://www.micromedexsolutions.com/micromedex2/ It has also been available in the form of vaginal administration, vaginal

s (1 mg/g (0.1%)) and suppository, suppositories (0.2 mg, 0.25 mg) as well as subcutaneous implant, subcutaneous pellet implants and oral administration, oral tablet (pharmacy), tablets (1.25 mg). A combined oral administration, oral tablet (pharmacy), tablet formulation containing estradiol (medication), estradiol (0.3 mg, 0.6 mg), estrone (0.7 mg, 1.4 mg), and estriol (medication), estriol (0.135 mg, 0.27 mg) has been marketed under the brand name Hormonin as well. In addition, a combined injectable preparation containing estrone (1 mg) and progesterone (medication), progesterone (10 mg) is available in the form of ampoules under the brand name Synergon.https://serp.mc/wp-content/uploads/2018/05/synergon.pdf Although estrone by intramuscular injection was originally formulated as an oil solution, it was soon replaced by formulations of estrone as an aqueous suspension due to a longer duration of action of these formulations.

Side effects

Side effects of estrogens like estrone include breast tenderness, breast enlargement, headache, nausea, water retention (medicine), fluid retention, and edema, among others. It can also cause endometrial hyperplasia.

Pharmacology

Pharmacodynamics

Mechanism of action

Estrone is an estrogen, specifically an agonist of the estrogen receptors (ERs) ERα and ERβ. It is a far less potency (pharmacology), potent estrogen than is estradiol, and as such is a relatively weak estrogen. Given by subcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol (medication), estriol. According to one study, the relative binding affinities of estrone for the human ERα and ERβ were 4.0% and 3.5% of those estradiol, respectively, and the relative transactivational capacities of estrone at the ERα and ERβ were 2.6% and 4.3% of those of estradiol, respectively. In accordance, the estrogenic activity of estrone has been reported to be approximately 4% of that of estradiol. Other studies have reported that estrone has about one-tenth of the potency of estradiol in activating the ERs ''in vitro''. Because estrone can be biotransformation, transformed into estradiol, which is far more potent as an estrogen in comparison, most or all of the estrogenic potency of estrone ''in vivo'' is actually due to conversion into estradiol. As such, similarly to the case of

, estrone is considered to be a

of estradiol. Some ''in vitro'' research has suggested that estrone might be able to partial agonist, partially receptor antagonist, antagonize the actions of estradiol, but this does not appear to be of clinical significance. In contrast to estradiol and estriol, estrone is not a ligand (biochemistry), ligand of the G protein-coupled estrogen receptor (affinity >10,000 nM).

Effects in the body and brain

In clinical research in the 1930s, estrone was given via intramuscular injection to ovariectomy, ovariectomized women in order to study its effects and to elucidate the function (biology), biological properties of estrogens in humans. In these studies, prior to administration of estrone, amenorrhea, atrophy of the breasts (as well as wikt:flaccid, flaccidity and small and non-erectile nipples), vagina, and endometrium, vaginal dryness, and symptom, subjective symptoms of ovariectomy (e.g., hot flashes, mood (psychology), mood changes) were all present in the women. Treatment with estrone was found to dose- and time-dependently produce a variety of effects, including breast changes, reproductive tract changes of the vagina, cervix, and endometrium/uterus, and relief from the subjective symptoms of ovariectomy, as well as increased libido. Breast changes specifically included breast enlargement, enlargement and a sense of breast fullness, fullness, increased nipple sensitivity, sensitivity and pigmentation of the nipples as well as nipple erection, paresthesia, tingling within the breast mammary glandular tissue, and breast pain, aching and soreness of the breasts. Reproductive tract changes included increased cell growth, growth, thickness, and Cellular differentiation, differentiation of the endometrium, and reversal of vaginal and cervical atrophy, which were accompanied by increased water retention (medicine), congestion of the cervix and vaginal discharge, mucous discharge from the cervix, uterine cramps and paresthesia, needle-like pains, pelvic fullness, a "bearing-down" sensation, and increased vaginal lubrication, as well as uterine bleeding both during treatment and in the days following cessation of injections. Endometrial hyperplasia also occurred with sufficiently high doses of estrone. Clinical research has confirmed the nature of estrone as an inactive prodrug of estradiol. With oral administration of estradiol, the ratio of estradiol levels to estrone levels is about 5 times higher on average than under normal physiological circumstances in premenopause, premenopausal women and with parenteral (non-oral) route of administration, routes of estradiol. Oral administration of menopausal hormone therapy, menopausal replacement dosages of estradiol results in low, follicular phase levels of estradiol, whereas estrone levels resemble the high levels seen during the first trimester of pregnancy. In spite of markedly elevated levels of estrone with oral estradiol but not with transdermal administration, transdermal estradiol, clinical studies have shown that doses of oral and transdermal estradiol achieving similar levels of estradiol possess equivalent and non-significantly different potency (pharmacology), potency in terms of measures including suppression of luteinizing hormone and follicle-stimulating hormone levels, inhibition of bone resorption, and relief of menopausal symptoms such as hot flashes. In addition, estradiol levels were found to correlate with these effects, while estrone levels did not. These findings confirm that estrone has very low estrogenic activity, and also indicate that estrone does not diminish the estrogenic activity of estradiol. This contradicts some cell-free system, cell-free ''in vitro, in-vitro'' research suggesting that high concentrations of estrone might be able to partial agonist, partially receptor antagonist, antagonize the actions of estradiol.

Pharmacokinetics

Absorption

Like estradiol, estrone has poor oral administration, oral bioavailability. It has been said that, taken by mouth in non-micronization, micronized form, a dose of 25 mg estrone is approximately equivalent to 2.5 mg conjugated estrogens, 50 µg ethinylestradiol, or 1 mg diethylstilbestrol in terms of estrogenic potency. Due to its weak oral activity, estrone has been used parenterally instead, for instance by intramuscular injection or vaginal administration. The pharmacokinetics of vaginal estrone have been studied. Estrone in oil solution by intramuscular injection has a shorter duration than estrone in aqueous suspension by intramuscular injection. Estrone in oil solution by intramuscular injection is rapidly absorbed, while estrone in aqueous suspension has a prolonged period of absorption. Upon intramuscular injection of estrone in aqueous solution, the water from the preparation is absorbed and a microcrystalline depot of estrone that is slowly absorbed by the body is formed. This is responsible for the prolonged duration of estrone in aqueous suspension compared to oil solution.

Distribution

Unlike estradiol and estriol, estrone is not accumulated in target tissue (biology), tissues. In terms of plasma protein binding, estrone is bound approximately 16% to sex hormone-binding globulin (SHBG) and 80% to human serum albumin, albumin, with the remainder (2.0 to 4.0%) circulating free or unbound. Estrone has about 24% of the relative binding affinity of estradiol for SHBG, and hence is relatively poorly bound to SHBG.

Metabolism

Estrone is conjugation (biochemistry), conjugated into estrogen conjugates such as

and estrone glucuronide by sulfotransferases and glucuronidases, and can also be hydroxylation, hydroxylated by cytochrome P450 enzymes into catechol estrogens such as 2-hydroxyestrone and 4-hydroxyestrone or into estriol (medication), estriol. Both of these transformations take place predominantly in the liver. Estrone can also be reversibly converted into estradiol by 17β-hydroxysteroid dehydrogenases (17β-HSDs), and this accounts for most or all of its estrogenic activity. 17β-HSD isoforms that are involved in the conversion of estrone into estradiol include HSD17B1, 17β-HSD1, HSD17B3, 17β-HSD3, HSD17B4, 17β-HSD4, HSD17B7, 17β-HSD7, HSD17B8, 17β-HSD8, and HSD17B15, 17β-HSD12, although the relative contributions of the different isoforms is unknown. The biological half-life, biological half-lives of estrone and estradiol in the circulation are both about 10 to 70 minutes, whereas the biological half-life of estrone sulfate in the circulation is about 10 to 12 hours. The metabolic clearance rate of estrone is 1,050 L/day/m² and of estradiol is 580 L/day/m², while that of estrone sulfate is 80 L/day/m². For comparison, the metabolic clearance rate of estriol is 1,110 L/day/m². A single 1 to 2 mg dose of estrone in oil solution by intramuscular injection has a duration of about 2 or 3 days. As an

by intramuscular injection, estrone was used at a dose of 0.1 to 0.5 mg 2 to 3 times per week, or at a dose of 0.1 to 2 mg once a week or in divided doses. In one rodent study, exogenous estrone was administered and increased circulating estradiol levels by about 10-fold; co-administration of a binding selectivity, selective 17β-HSD1 enzyme inhibitor, inhibitor decreased estradiol levels by about 50%. The ratio of circulating estrone to circulating estradiol is the same at about 5:1 with both oral estradiol and oral estrone sulfate. An investigational estrone vaginal ring was found to result in a ratio of estrone to estradiol of 4:1 or 5:1 initially, but this decreased to about 1:1 with continuous therapy.

Excretion

Estrone is excretion, excreted in urine in the form of estrogen conjugates such as

and estrone glucuronide. Following an intravenous injection of radiolabel, labeled estrone in women, almost 90% is excreted in urine and feces within 4 to 5 days. Enterohepatic recirculation causes a delay in excretion of estrone.

Chemistry

Estrone, also known as estra-1,3,5(10)-trien-3-ol-17-one, is a

estrane steroid with double bonds at the C1, C3, and C5 positions, a hydroxyl group at the C3 position, and a ketone functional group, group at the C17 position. The name ''estrone'' was derived from the chemical terms ''estrin (compound), estrin'' (estra-1,3,5(10)-triene) and ''ketone''. A variety of estrone esters have been chemical synthesis, synthesized and described. These include the marketed esters estrone acetate,

, estrone tetraacetylglucoside, and

(piperazine estrone sulfate), and the never-marketed esters estrone benzoate, estrone cyanate, estrone glucuronide, and estrone sulfamate.

History

In 1927, Bernhard Zondek and Selmar Aschheim discovered that large amounts of estrogens were excretion, excreted in the urine of pregnancy, pregnant women. This rich source of estrogens allowed the development of potent estrogenic formulations for scientific research, scientific and clinical medicine, clinical use. In 1929, pure crystalline estrone was isolated from the urine of pregnant women by various researchers. By 1929, pharmaceutical drug, pharmaceutical preparations including ''Amniotin'' (Bristol-Myers Squibb, Squibb), ''Progynon'' (Schering AG, Schering), and ''Theelin'' (Parke-Davis), purified from pregnancy urine, placentas, and/or amniotic fluid and containing purified estrone or estrogenic substances, mixtures of estrogens that included estrone, were being sold commercially for use by intramuscular injection. Other products and brand names of estrone marketed in the 1930s included ''Estrone'' (Abbott Laboratories, Abbott, Eli Lilly, Lilly), ''Oestroform'' (British Drug Houses), ''Folliculin'' (Organon International, Organon), ''Menformon'' (Organon International, Organon), and ''Ketodestrin'' (Paines & Byrne), among others. These formulations included ampoules of oil solution, oil or aqueous solution for intramuscular injection, oral administration, oral tablet (pharmacy), tablets, and vaginal administration, vaginal suppository, suppositories. Estrone in

for use by intramuscular injection was first described in 1941 and was introduced for medical use under the brand name ''Theelin Aqueous Suspension'' by 1944.

Society and culture

Generic names

''Estrone'' is the generic term, generic name of estrone in American English and its , , , , , and . ''Oestrone'', in which the "O" is silent, was the former of estrone and its name in British English, but the spelling was eventually changed to ''estrone''.

Brand names

Estrone has been marketed under a variety of brand names, including Andrestraq, Aquacrine, A.T.V., Bestrone, Centrogen, Cicatral, Cormone, Crinovaryl, Cristallovar, Crystogen, Destrone, Disynformon, Endofolliculina, Estragyn, Estroject, Estrol, Estrone, Estrone Aqueous Suspension, Estrone-A, Estrugenone, Estrusol, Femestrone, Femidyn, Folikrin, Folipex, Folisan, Folliculin, Follicunodis, Follidrin, Gineburno, Glandubolin, Grietalgen, Grietalgen Hidrocort, Gynogen, Hiestrone, Hormofollin, Hormonin, Hormovarine, Kestrin, Kestrone, Ketodestrin, Kolpon, Ladies Pearl, Livifolin, Menagen, Metharmon-F, Neo-Estrone, Oestrilin, Oestrin, Oestroform, Oestroperos, Ovex, Ovifollin, Perlatan, Progynon, Senikolp, Solliculin, Solutio Folliculinum, Synergon (in combination with progesterone (medication), progesterone), Theelin, Thynestron, Tokokin, Unden, Unigen, Wehgen, and Wynestron. Brand names of estrone in aqueous suspension specifically include Bestrone, Estaqua, Estrofol, Estroject, Estrone-A, Estronol, Femogen, Foygen Aqueous, Gravigen Aqueous, Gynogen, Hormogen-A, Kestrin Aqueous, Kestrone, Theelin Aqueous, Theogen, Unigen, and Wehgen.

Availability

Although estrone has been widely marketed in the past, it has mostly been discontinued and remains available in only a few countries. These countries reportedly include Canada, Georgia (country), Georgia, Monaco, and Taiwan. However, estrone remains widely available throughout the world in the form of

, which can be found in

(piperazine estrone sulfate), conjugated estrogens (Premarin), and esterified estrogens (Estratab, Menest).

Research

An estrone vaginal ring was developed and studied for use in menopausal hormone therapy. It increased estrogen levels, suppressed gonadotropin levels, and relieved menopausal symptoms. Subcutaneous implant, Subcutaneous pellet implantation of estrone has also been studied.