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This article is about estrogens as medications. For their role as hormones, see Estrogen.
Estrogen (medication)
Drug class
Estradiol, the major estrogen sex hormone in humans and a widely used medication.
Class identifiers
UseContraception, Menopause, hypogonadism, transgender women, prostate cancer, breast cancer, others
ATC codeG03C
Biological targetEstrogen receptors (ERα, ERβ, mERs (e.g., GPER, others))
External links
MeSHD004967
Legal status
In Wikidata

An estrogen is a type of medication that has similar effects to those of the estrogen steroid hormone estradiol. Estrogen may also refer to any substance, natural or synthetic, that mimics the effects of the natural hormone.[1] They may be used in some oral contraceptives, in hormone replacement therapy for postmenopausal, hypogonadal, and by transgender women, and estrogen suppressants may be used in the treatment of certain hormone-sensitive cancers like prostate cancer and breast cancer. They are one of three types of sex hormone agonists, the others being androgens/anabolic steroids like testosterone and progestogens like progesterone.

Types and examples

Steroidal estrogens

Estradiol, estrone, and estriol have all been approved as pharmaceutical drugs and are used medically. Estetrol is currently under development for medical indications, but has not yet been approved in any country.[2] A variety of synthetic estrogen esters, such as estradiol valerate, estradiol cypionate, estradiol acetate, estradiol undecylate, polyestradiol phosphate, and estradiol benzoate, are used clinically. The aforementioned compounds behave as prodrugs to estradiol, and are longer-lasting in comparison. Esters of estrone and estriol also exist and are employed in clinical medicine.

Ethinylestradiol (EE) is a more potent synthetic analogue of estradiol that is used widely in hormonal contraceptives. Mestranol, moxestrol, and quinestrol are derivatives of EE used clinically. A related drug is methylestradiol, which is also used clinically. Conjugated equine estrogens (CEEs), such as Premarin, a commonly prescribed estrogenic drug produced from the urine of pregnant mares, include the natural steroidal estrogens equilin and equilenin, as well as, especially, estrone sulfate (which itself is inactive and becomes active upon conversion into estrone). A related and very similar product to CEEs is esterified estrogens (EEs).

Testosterone, which is available as a pharmaceutical drug, is metabolized in part to estrogens such as estradiol, and can produce significant estrogenic effects at high dosages, most notably gynecomastia in males. The same is true for some synthetic anabolic–androgenic steroids, like methyltestosterone and metandienone. DHEA is available over-the-counter as a dietary supplement in the United States (but not in many other countries), though it is only very weakly estrogenic.

Nonsteroidal estrogens

Main article: Nonsteroidal estrogen

Diethylstilbestrol is a nonsteroidal estrogen that is no longer used medically. It is a member of the stilbestrol group. Other stilbestrol estrogens that have been used clinically include benzestrol, dienestrol, dienestrol acetate, diethylstilbestrol dipropionate, fosfestrol, hexestrol, and methestrol dipropionate. Chlorotrianisene, methallenestril, and doisynoestrol are nonsteroidal estrogens structurally distinct from the stilbestrols that have also been used clinically. While used widely in the past, nonsteroidal estrogens have mostly been discontinued and are now rarely if ever used medically.

Medical uses

Hormonal contraception

Main article: Hormonal contraception

Since estrogen circulating in the blood can negatively feedback to reduce circulating levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), most oral contraceptives contain ethinylestradiol, along with a progestin (synthetic progestogen). Even in men, the major hormone involved in LH feedback is estradiol, not testosterone.[3][4]

Hormone replacement therapy

Main article: Hormone replacement therapy

Estrogen and other hormones are given to postmenopausal women in order to prevent osteoporosis as well as treat the symptoms of menopause such as hot flashes, vaginal dryness, urinary stress incontinence, chilly sensations, dizziness, fatigue, irritability, and sweating. Fractures of the spine, wrist, and hips decrease by 50–70% and spinal bone density increases by ~5% in those women treated with estrogen within 3 years of the onset of menopause and for 5–10 years thereafter.

Before the specific dangers of conjugated equine estrogens were well understood, standard therapy was 0.625 mg/day of conjugated equine estrogens (such as Premarin). There are, however, risks associated with conjugated equine estrogen therapy. Among the older postmenopausal women studied as part of the Women's Health Initiative (WHI), an orally administered conjugated equine estrogen supplement was found to be associated with an increased risk of dangerous blood clotting. The WHI studies used one type of estrogen supplement, a high oral dose of conjugated equine estrogens (Premarin alone and with medroxyprogesterone acetate as PremPro).[5]

In a study by the NIH, esterified estrogens were not proven to pose the same risks to health as conjugated equine estrogens. Hormone replacement therapy has favorable effects on serum cholesterol levels, and when initiated immediately upon menopause may reduce the incidence of cardiovascular disease, although this hypothesis has yet to be tested in randomized trials. Estrogen appears to have a protector effect on atherosclerosis: it lowers LDL and triglycerides, it raises HDL levels and has endothelial vasodilatation properties plus an anti-inflammatory component.

Research is underway to determine if risks of estrogen supplement use are the same for all methods of delivery. In particular, estrogen applied topically may have a different spectrum of side-effects than when administered orally,[6] and transdermal estrogens do not affect clotting as they are absorbed directly into the systemic circulation, avoiding first-pass metabolism in the liver. This route of administration is thus preferred in women with a history of thrombo-embolic disease.

Estrogen is also used in the therapy of vaginal atrophy, hypoestrogenism (as a result of hypogonadism, oophorectomy, or primary ovarian failure), amenorrhea, dysmenorrhea, and oligomenorrhea. Estrogens can also be used to suppress lactation after child birth.

Hormone-sensitive cancers

Prostate cancer

See also: Management of prostate cancer § Estrogen therapy

High dose estrogen therapy with estrogens such as diethylstilbestrol, ethinylestradiol, and estradiol undecylate has been used in the past to treat prostate cancer in men.[7] It is effective because estrogens are functional antiandrogens, capable of suppressing testosterone levels to castrate concentrations and decreasing free testosterone levels by increasing sex hormone-binding globulin (SHBG) production. High dose estrogen therapy is associated with poor tolerability and safety, namely severe gynecomastia and cardiovascular complications such as thrombosis, and for this reason, has largely been replaced by newer antiandrogens such as gonadotropin-releasing hormone analogues and nonsteroidal antiandrogens. It is still sometimes used in the treatment of prostate cancer however,[7] and newer estrogens with atypical profiles such as GTx-758 that have improved tolerability profiles are being studied for possible application in prostate cancer.

Breast cancer

See also: Breast cancer management § Hormonal therapy

High doses of potent estrogens such as diethylstilbestrol and ethinylestradiol were used in the past in the treatment of breast cancer.[8] Their effectiveness is approximately equivalent to that of antiestrogen therapy with tamoxifen or aromatase inhibitors.[8] The use of high dose estrogen therapy in breast cancer has mostly been superseded by antiestrogen therapy due to the improved safety profile of the latter.[8]

About 80% of breast cancers, once established, rely on supplies of the hormone estrogen to grow: they are known as hormone-sensitive or hormone-receptor-positive cancers. Prevention of the actions or production of estrogen in the body is a treatment for these cancers.

Hormone-receptor-positive breast cancers are treated with drugs which suppress production or interfere with the action of estrogen in the body.[9] This technique, in the context of treatment of breast cancer, is known variously as hormonal therapy, hormone therapy, or anti-estrogen therapy (not to be confused with hormone replacement therapy). Certain foods such as soy may also suppress the proliferative effects of estrogen and are used as an alternative to hormone therapy.[10]

Other uses

Tall stature

Estrogen has been used to induce growth attenuation in tall girls.[11]

Estrogen-induced growth attenuation was used as part of the controversial Ashley Treatment to keep a developmentally disabled girl from growing to adult size.[12]

Lactation suppression

Estrogens can be used to suppress lactation.

Breast enhancement

See also: Hormonal breast enhancement

Estrogens may be used as a form of hormonal breast enhancement to increase the size of the breasts.[13][14][15]

Bulimia

Most recently, estrogen has been used in experimental research as a way to treat women suffering from bulimia nervosa, in addition to cognitive behavioral therapy, which is the established standard for treatment in bulimia cases. The estrogen research hypothesizes that the disease may be linked to a hormonal imbalance in the brain.[16]

Miscellaneous

Estrogen has also been used in studies which indicate that it may be an effective drug for use in the treatment of traumatic liver injury.[17]

In humans and mice, estrogen promotes wound healing.[18]

Contraindications

Estrogens have various contraindications. An example is a history of thromboembolism.

Side effects

Hyperestrogenism (elevated levels of estrogen) may be a result of exogenous administration of estrogen or estrogen-like substances, or may be a result of physiologic conditions such as pregnancy. Any of these causes is linked with an increase in the risk of thrombosis.[19] It's also a symptom of liver cirrhosis, due to lowered metabolic function of the liver, which metabolises estrogen, leading to spider angioma, palmary erythema, gynecomastia and testicular atrophy in some male patients.

Around half of women with epilepsy who menstruate have a lowered seizure threshold around ovulation, most likely from the heightened estrogen levels. This increases the risk of seizures.

The estrogen-alone substudy of the WHI reported an increased risk of stroke and deep vein thrombosis (DVT) in postmenopausal women 50 years of age or older and an increased risk of dementia in postmenopausal women 65 years of age or older using 0.625 mg of Premarin conjugated equine estrogens (CEE). The estrogen-plus-progestin substudy of the WHI reported an increased risk of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli and DVT in postmenopausal women 50 years of age or older and an increased risk of dementia in postmenopausal women 65 years of age or older using PremPro, which is 0.625 mg of CEE with 2.5 mg of the progestin medroxyprogesterone acetate (MPA).[20][21][22]

The labeling of estrogen-only products in the U.S. includes a boxed warning that unopposed estrogen (without progestogen) therapy increases the risk of endometrial cancer. Based on a review of data from the WHI, in 2003 the FDA changed the labeling of all estrogen and estrogen with progestin products for use by postmenopausal women to include a new boxed warning about cardiovascular and other risks.

Rare adverse reactions

Cardiovascular events

Estrogens affect liver protein synthesis and thereby influence the cardiovascular system.[23] They have been found to affect the production of a variety of coagulation and fibrinolytic factors, including increased factor IX, von Willebrand factor, thrombin–antithrombin complex (TAT), fragment 1+2, and D-dimer and decreased fibrinogen, factor VII, antithrombin, protein S, protein C, tissue plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1).[23] Although this is true for oral estrogen, transdermal estradiol has been found only to reduce PAI-1 and protein S, and to a lesser extent than oral estrogen.[23] Due to its effects on liver protein synthesis, oral estrogen is procoagulant, and has been found to increase the risk of venous thromboembolism (VTE) such as deep vein thrombosis (DVT) and pulmonary embolism (PE).[23] Conversely, modern oral contraceptives are not associated with an increase in the risk of stroke and myocardial infarction (heart attack) in healthy, non-smoking premenopausal women of any age, except in those with hypertension (high blood pressure).[24][25] However, a small but significant increase in the risk of stroke, though not of myocardial infarction, has been found in menopausal women taking hormone replacement therapy.[26] An increase in the risk of stroke has also been associated with older high-dose oral contraceptives that are no longer used.[27]

Menopausal hormone therapy with replacement dosages of estrogens and progestogens has been associated with a significantly increased risk of cardiovascular events such as VTE.[28] However, such risks have been found to vary depending on the type of estrogen or progestogen and the route of administration.[28] The risk of VTE is increased by approximately 2-fold in women taking oral estrogen for menopausal hormone therapy.[28] However, this research has not distinguished between CEEs and estradiol, and CEEs have been found to be more resistant to hepatic metabolism than estradiol and to increase clotting factors to a greater extent.[23] In accordance, a recent case-control study found that oral CEEs were associated with a significantly greater increase in risk of cardiovascular events including venous thrombosis (2-fold) and myocardial infarction (2-fold) relative to oral estradiol.[29][28] However, these findings need to be confirmed.[28] In any case, another study found that oral CEEs were associated with an increase in risk of VTE but that oral esterified estrogens were not (OR = 1.65 and 0.92, respectively; OR = 1.78 for the difference).[30] In contrast to oral estrogens as a group, transdermal estradiol has not been found to increase the risk of VTE or other cardiovascular events.[28][26]

Both combined oral contraceptives (which contain ethinylestradiol and a progestin) and pregnancy/the postpartum period are associated with about a 4-fold increase in risk of VTE, with the risk increase being slightly greater with the latter (OR = 4.03 and 4.24, respectively).[31] The risk of VTE during the postpartum period is 5-fold higher than during pregnancy.[31] For combined oral contraceptives, VTE risk with high doses of ethinylestradiol (>50 μg, e.g., 100 to 150 μg) has been reported to be approximately twice that of low doses of ethinylestradiol (e.g., 20 to 50 μg).[24] As such, high doses of ethinylestradiol are no longer used in combined oral contraceptives, and all modern combined oral contraceptives contain 50 μg ethinylestradiol or less.[32][33] The absolute risk of VTE in pregnancy is about 0.5 to 2 in 1,000 (0.125%).[34]

Although estrogens influence the hepatic production of coagulant and fibrinolytic factors and increase the risk of VTE and sometimes stroke, they also influence the liver synthesis of blood lipids and can have beneficial effects on the cardiovascular system.[23] With oral estradiol, there are increases in circulating triglycerides, HDL cholesterol, apolipoprotein A1, and apolipoprotein A2, and decreases in total cholesterol, LDL cholesterol, apolipoprotein B, and lipoprotein(a).[23] Transdermal estradiol has less-pronounced effects on these proteins and, in contrast to oral estradiol, reduces triglycerides.[23] Through these effects, both oral and transdermal estrogens can protect against atherosclerosis and coronary heart disease in menopausal women with intact arterial endothelium that is without severe lesions.[23]

Approximately 95% of orally ingested estradiol is inactivated during first-pass metabolism.[25] Nonetheless, levels of estradiol in the liver with oral administration are supraphysiological and approximately 4- to 5-fold higher than in circulation due to the first-pass.[23][35] This does not occur with parenteral estradiol.[23] In contrast to estradiol, ethinylestradiol is much more resistant to hepatic metabolism, with a mean oral bioavailability of approximately 45%,[36] and has a similar impact on hepatic protein synthesis with both oral and transdermal routes.[37]

Overdose

Estrogens are relatively safe in overdose and symptoms manifest mainly as reversible feminization.

Interactions

Inducers of cytochrome P450 enzymes like carbamazepine and phenytoin can accelerate the metabolism of estrogens and thereby decrease their bioavailability and circulating levels. Inhibitors of such enzymes can have the opposite effect and can increase estrogen levels and bioavailability.

Pharmacology

Pharmacodynamics

See also: Estrogen § Biological activity, and Comparison of estrogens § Pharmacodynamics

Estrogens act as selective agonists of the estrogen receptors (ERs), the ERα and the ERβ. They may also bind to and activate membrane estrogen receptors (mERs) such as the GPER. Estrogens do not have off-target activity at other steroid hormone receptors such as the androgen, progesterone, glucocorticoid, or mineralocorticoid receptors, nor do they have neurosteroid activity by interacting with neurotransmitter receptors, unlike various progestogens and some other steroids.

Estrogens have antigonadotropic effects at sufficiently high concentrations via activation of the ER and hence can suppress the hypothalamic–pituitary–gonadal axis, thereby interfering with fertility and gonadal sex hormone production. Because of this, they can behave as functional antiandrogens, able to reduce testosterone levels to castrate levels at high doses.

Due to structural differences and accompanying differences in metabolism, estrogens differ from one another in their tissue selectivity. For instance, synthetic estrogens like ethinylestradiol and diethylstilbestrol are not inactivated as well as estradiol in tissues like the liver and uterus and as a result have disproportionate effects in these tissues. This can result in problems such as a relatively higher risk of thromboembolism.

Pharmacokinetics

Estrogens can be administered via a variety of routes, including by mouth, sublingual, transdermal/topical (gel, patch), vaginal (gel, tablet, ring), rectal, intramuscular, subcutaneous, intravenous, and subcutaneous implant. Natural estrogens generally have low oral bioavailability while synthetic estrogens have higher bioavailability. Parenteral routes have higher bioavailability. Estrogens are typically bound to albumin and/or sex hormone-binding globulin in the circulation. They are metabolized in the liver by hydroxylation (via cytochrome P450 enzymes), dehydrogenation (via 17β-hydroxysteroid dehydrogenase), and conjugation (via sulfation and glucuronidation). The elimination half-lives of estrogens vary by estrogen and route of administration. Estrogens are eliminated mainly by the kidneys via the urine as conjugates.

Chemistry

Estrogens can be grouped as steroidal or nonsteroidal. The steroidal estrogens are estranes.

History

In 1929, Adolf Butenandt and Edward Adelbert Doisy independently isolated and purified estrone, the first estrogen to be discovered.[38] The "first orally effective estrogen", Emmenin, derived from the late-pregnancy urine of Canadian women, was introduced in 1930 by Collip and Ayerst Laboratories. Estrogens have poor oral bioavailability and prior to the development of micronization could not be given orally, but the urine was found to contain estriol glucuronide, which is absorbed orally and becomes active in the body after hydrolysis. Scientists continued to search for new sources of estrogen because of concerns associated with the practicality of introducing the drug into the market. At the same time, a German pharmaceutical drug company, Schering, formulated a similar product as Emmenin called Progynon that was introduced to German women to treat menopausal symptoms.

In 1938, British scientists obtained a patent on a newly formulated nonsteroidal estrogen, diethylstilbestrol (DES), that was cheaper and more powerful than the previously manufactured estrogens. Soon after, concerns over the side effects of DES were raised in scientific journals while the drug manufacturers came together to lobby for governmental approval of DES. It was only until 1941 when estrogen therapy was finally approved by the Food and Drug Administration (FDA) for the treatment of menopausal symptoms.[39] Premarin (conjugated equine estrogens) was introduced in 1941 and succeeded Emmenin, the sales of which had begun to drop after 1940 due to competition from DES.[40] Ethinylestradiol was synthesized in 1938 by Hans Herloff Inhoffen and Walter Hohlweg at Schering AG in Berlin[41][42][43][44][45] and was approved by the FDATooltip Food and Drug Administration in the U.S.Tooltip United States on June 25, 1943 and marketed by Schering as Estinyl.[46]

Micronized estradiol, via the oral route, was first evaluated in 1972,[47] and this was followed by the evaluation of vaginal and intranasal micronized estradiol in 1977.[48] Oral micronized estradiol was first approved in the United States under the brand name Estrace in 1975.[49]

Society and culture

Availability

See also: List of estrogens available in the United States

Estrogens are widely available throughout the world.

See also

References

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