Estrogen (medication)

Contraindications

Estrogens have various contraindications. An example is history of thromboembolism (blood clots).

Side effects

The most common side effects of estrogens in general include breast tenderness, breast enlargement, headache, nausea, fluid retention, and edema. In women, estrogens can additionally cause vaginal bleeding, vaginal discharge, and anovulation, whereas in men, estrogens can additionally cause gynecomastia (male breast development), feminization, demasculinization, sexual dysfunction (reduced libido and erectile dysfunction), hypogonadism, testicular atrophy, and infertility.

Estrogens can or may increase the risk of uncommon or rare but potentially serious issues including endometrial hyperplasia, endometrial cancer, cardiovascular complications (e.g., blood clots, stroke, heart attack), cholestatic hepatotoxicity, gallbladder disease (e.g., gallstones), hyperprolactinemia, prolactinoma, and dementia. These adverse effects are moderated by the concomitant use of a progestogen, the type of progestogen used, and the dosage and route of estrogen used.

Around half of women with epilepsy who menstruate have a lowered seizure threshold around ovulation, most likely from the heightened estrogen levels at that time. This results in an increased risk of seizures in these women.

High doses of synthetic estrogens like ethinylestradiol and diethylstilbestrol can produce prominent untoward side effects like nausea, vomiting, headache, malaise, and dizziness, among others. Conversely, natural estrogens like estradiol and conjugated estrogens are rarely associated with such effects. The preceding side effects of synthetic estrogens do not appear to occur in pregnant women, who already have very high estrogen levels. This suggests that these effects are due to estrogenic activity. Synthetic estrogens have markedly stronger effects on the liver and hepatic protein synthesis than natural estrogens. This is related to the fact that synthetic estrogens like ethinylestradiol are much more resistant to metabolism in the liver than natural estrogens.

Long-term effects

Endometrial hyperplasia and cancer

Unopposed estrogen therapy stimulates the growth of the endometrium and is associated with a dramatically increased risk of endometrial hyperplasia and endometrial cancer in postmenopausal women. The risk of endometrial hyperplasia is greatly increased by 6 months of treatment (ORTooltip odds ratio = 5.4) and further increased after 36 months of treatment (OR = 16.0). This can eventually progress to endometrial cancer, and the risk of endometrial cancer similarly increases with duration of treatment (less than one year, RRTooltip relative risk = 1.4; many years (e.g., more than 10 years), RR = 15.0). The risk of endometrial cancer also stays significantly elevated many years after stopping unopposed estrogen therapy, even after 15 years or more (RR = 5.8).

Progestogens prevent the effects of estrogens on the endometrium. As a result, they are able to completely block the increase in risk of endometrial hyperplasia caused by estrogen therapy in postmenopausal women, and are even able to decrease it below baseline (OR = 0.3 with continuous estrogen–progestogen therapy). Continuous estrogen–progestogen therapy is more protective than sequential therapy, and a longer duration of treatment with continuous therapy is also more protective. The increase in risk of endometrial cancer is similarly decreased with continuous estrogen–progestogen therapy (RR = 0.2–0.7). For these reasons, progestogens are always used alongside estrogens in women who have intact uteruses.

Cardiovascular events

Estrogens affect liver protein synthesis and thereby influence the cardiovascular system. 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). 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. Due to its effects on liver protein synthesis, oral estrogen is procoagulant, and has been found to increase the risk of venous thromboembolism (VTE), including of both deep vein thrombosis (DVT) and pulmonary embolism (PE). 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). 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. An increase in the risk of stroke has also been associated with older high-dose oral contraceptives that are no longer used.

Menopausal hormone therapy with replacement dosages of estrogens and progestogens has been associated with a significantly increased risk of cardiovascular events such as VTE. However, such risks have been found to vary depending on the type of estrogen and the route of administration. The risk of VTE is increased by approximately 2-fold in women taking oral estrogen for menopausal hormone therapy. However, clinical research to date has generally not distinguished between conjugated estrogens and estradiol. This is of importance because conjugated estrogens have been found to be more resistant to hepatic metabolism than estradiol and to increase clotting factors to a greater extent. Only a few clinical studies have compared oral conjugated estrogens and oral estradiol. Oral conjugated estrogens have been found to possess a significantly greater risk of thromboembolic and cardiovascular complications than oral estradiol (ORTooltip Odds ratio = 2.08) and oral esterified estrogens (ORTooltip Odds ratio = 1.78). However, in another study, the increase in VTE risk with 0.625 mg/day oral conjugated estrogens plus medroxyprogesterone acetate and 1 or 2 mg/day oral estradiol plus norethisterone acetate was found to be equivalent (RRTooltip Relative risk = 4.0 and 3.9, respectively). Other studies have found oral estradiol to be associated with an increase in risk of VTE similarly (RRTooltip Relative risk = 3.5 in one, ORTooltip odds ratio = 3.54 in first year of use in another). As of present, there are no randomized controlled trials comparing oral conjugated estrogens and oral estradiol in terms of thromboembolic and cardiovascular risks that would allow for unambiguous conclusions, and additional research is needed to clarify this issue. In contrast to oral estrogens as a group, transdermal estradiol at typical menopausal replacement dosages has not been found to increase the risk of VTE or other cardiovascular events.

Both combined birth control pills (which contain ethinylestradiol and a progestin) and pregnancy 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). The risk of VTE during the postpartum period is 5-fold higher than during pregnancy. Other research has found that the rate of VTE is 1 to 5 in 10,000 woman-years in women who are not pregnant or taking a birth control pill, 3 to 9 in 10,000 woman-years in women who are on a birth control pill, 5 to 20 in 10,000 women-years in pregnant women, and 40 to 65 in 10,000 women-years in postpartum women. For birth control pills, 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). 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. The absolute risk of VTE in pregnancy is about 0.5 to 2 in 1,000 (0.125%).

Aside from type of estrogen and the route of administration, the risk of VTE with oral estrogen is also moderated by other factors, including the concomitant use of a progestogen, dosage, age, and smoking. The combination of oral estrogen and a progestogen has been found to double the risk of VTE relative to oral estrogen alone (RRTooltip Relative risk = 2.05 for estrogen monotherapy, and RRTooltip relative risk = 2.02 for combined estrogen–progestogen therapy in comparison). However, while this is true for most progestogens, there appears to be no increase in VTE risk relative to oral estrogen alone with the addition of oral progesterone or the atypical progestin dydrogesterone. The dosage of oral estrogen appears to be important for VTE risk, as 1 mg/day oral estradiol increased VTE incidence by 2.2-fold while 2 mg/day oral estradiol increased VTE incidence by 4.5-fold (both in combination with norethisterone acetate). The risk of VTE and other cardiovascular complications with oral estrogen–progestogen therapy increases dramatically with age. In the oral conjugated estrogens and medroxyprogesterone acetate arm of the WHI, the risks of VTE stratified by age were as follows: age 50 to 59, RR = 2.27; age 60 to 69, RR = 4.28; and age 70 to 79, RR = 7.46. Conversely, in the oral conjugated estrogens monotherapy arm of the WHI, the risk of VTE increased with age similarly but was much lower: age 50 to 59, RR = 1.22; age 60 to 69, RR = 1.3; and age 70 to 79, RR = 1.44. In addition to menopausal hormone therapy, cardiovascular mortality has been found to increase considerably with age in women taking ethinylestradiol-containing combined oral contraceptives and in pregnant women. In addition, smoking has been found to exponentially increase cardiovascular mortality in conjunction with combined oral contraceptive use and older age. Whereas the risk of cardiovascular death is 0.06 per 100,000 in women who are age 15 to 34 years, are taking a combined oral contraceptive, and do not smoke, this increases by 50-fold to 3.0 per 100,000 in women who are age 35 to 44 years, are taking a combined oral contraceptive, and do not smoke. Moreover, in women who do smoke, the risk of cardiovascular death in these two groups increases to 1.73 per 100,000 (29-fold higher relative to non-smokers) and 19.4 per 100,000 (6.5-fold higher relative to non-smokers), respectively.

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. 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). Transdermal estradiol has less-pronounced effects on these proteins and, in contrast to oral estradiol, reduces triglycerides. 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.

Approximately 95% of orally ingested estradiol is inactivated during first-pass metabolism. 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. This does not occur with parenteral routes of estradiol, such as transdermal, vaginal, or injection. In contrast to estradiol, ethinylestradiol is much more resistant to hepatic metabolism, with a mean oral bioavailability of approximately 45%, and the transdermal route has a similar impact on hepatic protein synthesis as the oral route. Conjugated estrogens are also more resistant to hepatic metabolism than estradiol and show disproportionate effects on hepatic protein production as well, although not to the same magnitude as ethinylestradiol. These differences are considered to be responsible for the greater risk of cardiovascular events with ethinylestradiol and conjugated estrogens relative to estradiol.

High-dosage oral synthetic estrogens like diethylstilbestrol and ethinylestradiol are associated with fairly high rates of severe cardiovascular complications. Diethylstilbestrol has been associated with an up to 35% risk of cardiovascular toxicity and death and a 15% incidence of VTE in men treated with it for prostate cancer. In contrast to oral synthetic estrogens, high-dosage polyestradiol phosphate and transdermal estradiol have not been found to increase the risk of cardiovascular mortality or thromboembolism in men with prostate cancer, although significantly increased cardiovascular morbidity (due mainly to an increase in non-fatal ischemic heart events and heart decompensation) has been observed with polyestradiol phosphate.

Sex hormone-binding globulin (SHBG) levels indicate hepatic estrogenic exposure and may be a surrogate marker for coagulation and VTE risk with estrogen therapy, although this topic has been debated. SHBG levels with birth control pills containing different progestins are increased by 1.5 to 2-fold with levonorgestrel, 2.5- to 4-fold with desogestrel and gestodene, 3.5- to 4-fold with drospirenone and dienogest, and 4- to 5-fold with cyproterone acetate. Contraceptive vaginal rings and contraceptive patches likewise have been found to increase SHBG levels by 2.5-fold and 3.5-fold, respectively. Birth control pills containing high doses of ethinylestradiol (>50 μg) can increase SHBG levels by 5- to 10-fold, which is similar to the increase that occurs during pregnancy. Conversely, increases in SHBG levels are much lower with estradiol, especially when used parenterally. High-dose parenteral polyestradiol phosphate therapy has been found to increase SHBG levels by about 1.5-fold.

Breast cancer

Estrogens are responsible for breast development and, in relation to this, are strongly implicated in the development of breast cancer. In addition, estrogens stimulate the growth and accelerate the progression of ER-positive breast cancer. In accordance, antiestrogens like the selective estrogen receptor modulator (SERM) tamoxifen, the ER antagonist fulvestrant, and the aromatase inhibitors (AIs) anastrozole and exemestane are all effective in the treatment of ER-positive breast cancer. Antiestrogens are also effective in the prevention of breast cancer. Paradoxically, high-dose estrogen therapy is effective in the treatment of breast cancer as well and has about the same degree of effectiveness as antiestrogen therapy, although it is far less commonly used due to adverse effects. The usefulness of high-dose estrogen therapy in the treatment of ER-positive breast cancer is attributed to a bimodal effect in which high concentrations of estrogens signal breast cancer cells to undergo apoptosis, in contrast to lower concentrations of estrogens which stimulate their growth.

A 2017 systematic review and meta-analysis of 14 studies assessed the risk of breast cancer in perimenopausal and postmenopausal women treated with estrogens for menopausal symptoms. They found that treatment with estradiol only is not associated with an increased risk of breast cancer (ORTooltip odds ratio = 0.90 in RCTsTooltip randomized controlled trials and OR = 1.11 in observational studies). This was in accordance with a previous analysis of estrogen-only treatment with estradiol or conjugated estrogens which similarly found no increased risk (RR = 0.99). Moreover, another study found that the risk of breast cancer with estradiol and conjugated estrogens was not significantly different (RR = 1.15 for conjugated estrogens versus estradiol). These findings are paradoxical because oophorectomy in premenopausal women and antiestrogen therapy in postmenopausal women are well-established as considerably reducing the risk of breast cancer (RR = 0.208 to 0.708 for chemoprevention with antiestrogens in postmenopausal women). However, there are indications that there may be a ceiling effect such that past a certain low concentration threshold (e.g., approximately 10.2 pg/mL for estradiol), additional estrogens alone may not further increase the risk of breast cancer in postmenopausal women. There are also indications that the fluctuations in estrogen levels across the normal menstrual cycle in premenopausal women may be important for breast cancer risk.

In contrast to estrogen-only therapy, combined estrogen and progestogen treatment, although dependent on the progestogen used, is associated with an increased risk of breast cancer. The increase in risk is dependent on the duration of treatment, with more than five years (OR = 2.43) having a significantly greater risk than less than five years (OR = 1.49). In addition, sequential estrogen–progestogen treatment (OR = 1.76) is associated with a lower risk increase than continuous treatment (OR = 2.90), which has a comparably much higher risk. The increase in risk also differs according to the specific progestogen used. Treatment with estradiol plus medroxyprogesterone acetate (OR = 1.19), norethisterone acetate (OR = 1.44), levonorgestrel (OR = 1.47), or a mixed progestogen subgroup (OR = 1.99) were all associated with an increased risk. In a previous review, the increase in breast cancer risk was found to not be significantly different between these three progestogens. Conversely, there is no significant increase in risk of breast cancer with bioidentical progesterone (OR = 1.00) or with the atypical progestin dydrogesterone (OR = 1.10). In accordance, another study found similarly that the risk of breast cancer was not significantly increased with estrogen–progesterone (RRTooltip relative risk = 1.00) or estrogen–dydrogesterone (RR = 1.16) but was increased for estrogen combined with other progestins (RR = 1.69). These progestins included chlormadinone acetate, cyproterone acetate, medrogestone, medroxyprogesterone acetate, nomegestrol acetate, norethisterone acetate, and promegestone, with the associations for breast cancer risk not differing significantly between the different progestins in this group.

In contrast to cisgender women, breast cancer is extremely rare in men and transgender women treated with estrogens and/or progestogens, and gynecomastia or breast development in such individuals does not appear to be associated with an increased risk of breast cancer. Likewise, breast cancer has never been reported in women with complete androgen insensitivity syndrome, who similarly have a male genotype (46,XY), in spite of the fact that these women have well-developed breasts. The reasons for these differences are unknown. However, the dramatically increased risk of breast cancer (20- to 58-fold) in men with Klinefelter's syndrome, who have somewhat of a hybrid of a male and a female genotype (47,XXY), suggests that it may have to do with the sex chromosomes.

Cholestatic hepatotoxicity

Estrogens, along with progesterone, can rarely cause cholestatic hepatotoxicity, particularly at very high concentrations. This is seen in intrahepatic cholestasis of pregnancy, which occurs in 0.4 to 15% of pregnancies (highly variable depending on the country).

Gallbladder disease

Estrogen therapy has been associated with gallbladder disease, including risk of gallstone formation. A 2017 systematic review and meta-analysis found that menopausal hormone therapy significantly increased the risk of gallstones (RR = 1.79) while oral contraceptives did not significantly increase the risk (RR = 1.19). Biliary sludge appears in 5 to 30% of women during pregnancy, and definitive gallstones persisting postpartum become established in approximately 5%.

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

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. Given by subcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol.

Estrogens have antigonadotropic effects at sufficiently high concentrations via activation of the ER and hence can suppress the hypothalamic–pituitary–gonadal axis. This is caused by negative feedback, resulting in a suppression in secretion and decreased circulating levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The antigonadotropic effects of estrogens interfere with fertility and gonadal sex hormone production. They are responsible for the hormonal contraceptive effects of estrogens. In addition, they allow estrogens to act as functional antiandrogens by suppressing gonadal testosterone production. At sufficiently high doses, estrogens are able to suppress testosterone levels into the castrate range in men.

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

Estrogen has also been found to increase the secretion of oxytocin and to increase the expression of its receptor, the oxytocin receptor, in the brain. In women, a single dose of ethinylestradiol has been found to be sufficient to increase circulating oxytocin concentrations.

In-vitro pharmacodynamics

In-vivo pharmacodynamics

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 and include estradiol and its analogues, such as ethinylestradiol and conjugated estrogens like equilin sulfate. Nonsteroidal estrogens belong predominantly to the stilbestrol group of compounds and include diethylstilbestrol and hexestrol, among others.

Estrogen esters are esters and prodrugs of the corresponding parent estrogens. Examples include estradiol valerate and diethylstilbestrol dipropionate, which are prodrugs of estradiol and diethylstilbestrol, respectively. Estrogen esters with fatty acid esters have increased lipophilicity and a prolonged duration of action when administered by intramuscular or subcutaneous injection. Some estrogen esters, such as polyestradiol phosphate, polyestriol phosphate, and polydiethylstilbestrol phosphate, are in the form of polymers.

History

Ovarian extracts were available in the late 1800s and early 1900s, but were inert or had extremely low estrogenic activity and were regarded as ineffective. In 1927, Selmar and Aschheim discovered that large amounts of estrogens were present in the urine of pregnant women. This rich source of estrogens, produced by the placenta, allowed for the development of potent estrogenic formulations for scientific and clinical use. The first pharmaceutical estrogen product was a conjugated estriol called Progynon, a placental extract, and was introduced for medical use by the German pharmaceutical company Schering in 1928. In 1929, Adolf Butenandt and Edward Adelbert Doisy independently isolated and purified estrone, the first estrogen to be discovered. The estrogen preparations Amniotin (Squibb), Progynon (Schering), and Theelin (Parke-Davis) were all on the market by 1929, and various additional preparations such as Emmenin, Folliculin, Menformon, Oestroform, and Progynon B, containing purified estrogens or mixtures of estrogens, were on the market by 1934. Estrogens were originally known under a variety of different names including estrogens, estrins, follicular hormones, folliculins, gynecogens, folliculoids, and female sex hormones, among others.

An estrogen patch was reportedly marketed by Searle in 1928, and an estrogen nasal spray was studied by 1929.

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. Conjugated estrogens (brand name Premarin) was introduced in 1941 and succeeded Emmenin, the sales of which had begun to drop after 1940 due to competition from DES. Ethinylestradiol was synthesized in 1938 by Hans Herloff Inhoffen and Walter Hohlweg at Schering AG in Berlin and was approved by the FDATooltip Food and Drug Administration in the U.S.Tooltip United States on 25 June 1943 and marketed by Schering as Estinyl.

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

Society and culture

Availability

Estrogens are widely available throughout the world.

Research

Male birth control

High-dose estrogen therapy is effective in suppressing spermatogenesis and fertility in men, and hence as a male contraceptive. It works both by strongly suppressing gonadotropin secretion and gonadal testosterone production and via direct effects on the testes. After a sufficient course of therapy, only Sertoli cells and spermatogonia remain in the seminiferous tubules of the testes, with a variety of other testicular abnormalities observable. The use of estrogens for contraception in men is precluded by major side effects such as sexual dysfunction, feminization, gynecomastia, and metabolic changes. In addition, there is evidence that with long-term therapy, fertility and gonadal sex hormone production in men may not return following discontinuation of high-dose estrogen therapy.

Eating disorders

Estrogen has been used as a treatment for women with 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.

Miscellaneous

Estrogens have been used in studies which indicate that they may be effective in the treatment of traumatic liver injury.

In humans and mice, estrogens promote wound healing.

Estrogen therapy has been proposed as a potential treatment for autism but clinical studies are needed.