Estrogens were first introduced for medical use in the early 1930s. They started to be used in birth control in combination with progestins in the 1950s.[2] A variety of different estrogens have been marketed for clinical use in humans or use in veterinary medicine, although only a handful of these are widely used.[3][4][5][6][7] These medications can be grouped into different types based on origin and chemical structure.[1] Estrogens are available widely throughout the world and are used in most forms of hormonal birth control and in all menopausal hormone therapy regimens.[3][4][6][5][1]
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 to 70% and spinal bone density increases by approximately 5% in those women treated with estrogen within 3years of the onset of menopause and for 5 to 10years thereafter.
Before the specific dangers of conjugated estrogens were well understood, standard therapy was 0.625mg/day of conjugated estrogens (such as Premarin). There are, however, risks associated with conjugated estrogen therapy. Among the older postmenopausal women studied as part of the Women's Health Initiative (WHI), an orally administered conjugated 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 estrogens (Premarin alone and with medroxyprogesterone acetate as Prempro).[10]
In a study by the NIH, esterified estrogens were not proven to pose the same risks to health as conjugated estrogens. Menopausal hormone 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,[11] 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 thromboembolic 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.
Footnotes:a = No longer used or recommended, due to health concerns. b = As a single patch applied once or twice per week (worn for 3–4 days or 7 days), depending on the formulation. Note: Dosages are not necessarily equivalent. Sources: See template.
Estrogens like diethylstilbestrol were formerly used in high doses to help support pregnancy.[37] However, subsequent research showed diethylstilbestrol to be ineffective as well as harmful.[37]
Lactation suppression
Estrogens can be used to suppress lactation, for instance in the treatment of breast engorgement or galactorrhea.[38] However, high doses are needed, the effectiveness is uncertain, and high doses of estrogens in the postpartum period can increase the risk of blood clots.[39]
Estrogens are involved in breast development and may be used as a form of hormonal breast enhancement to increase the size of the breasts.[48][49][50][51][52] However, acute or temporary breast enlargement is a well-known side effect of estrogens, and increases in breast size tend to regress following discontinuation of treatment.[48][50][51] Aside from those without prior established breast development, evidence is lacking for a sustained increase in breast size with estrogens.[48][50][51]
Depression
Published 2019 and 2020 guidelines from the North American Menopause Society (NAMS) and European Menopause and Andropause Society (EMAS) have reviewed the topic of estrogen therapy for depressive symptoms in the peri- and postmenopause.[53][54] There is some evidence that estrogens are effective in the treatment of depression in perimenopausal women.[53][54][55][56][57][58][59][60][61][62][63] The magnitude of benefit appears to be similar to that of classical antidepressants.[53][54] There is also some evidence that estrogens may improve mood and well-being in non-depressed perimenopausal women.[53][54][58][56] Estrogens do not appear to be effective in the treatment of depression in postmenopausal women.[53][54] This suggests that there is a window of opportunity for effective treatment of depressive symptoms with estrogens.[53] Research on combined estrogen and progestogen therapy for depressive symptoms in the peri- and postmenopause is scarce and inconclusive.[53][54] Estrogens may augment the mood benefits of antidepressants in middle-aged and older women.[53][54] Menopausal hormone therapy is not currently approved for the treatment of depressive symptoms in the peri- or postmenopause in either the United States or the United Kingdom due to insufficient evidence of effectiveness.[53][54][58] More research is needed on the issue of estrogen therapy for depressive symptoms associated with menopause.[61][59]
Systemic estrogen therapy at adequate doses is effective for and has been used in the treatment of acne in both females and males, but causes major side effects such as feminization and gynecomastia in males.[68][69][70][71][72][73][74][75]
Available forms
Major estrogens marketed for clinical or veterinary use
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.[84][85][86] Conversely, natural estrogens like estradiol and conjugated estrogens are rarely associated with such effects.[84][85][86] The preceding side effects of synthetic estrogens do not appear to occur in pregnant women, who already have very high estrogen levels.[84] This suggests that these effects are due to estrogenic activity.[84] Synthetic estrogens have markedly stronger effects on the liver and hepatic protein synthesis than natural estrogens.[1][87][88][86][89] This is related to the fact that synthetic estrogens like ethinylestradiol are much more resistant to metabolism in the liver than natural estrogens.[1][90][89]
Summary:Side effects in a small phase 2 study of women with metastatic breast cancer randomized to receive either 6 or 30 mg/day of oral estradiolTooltip Pharmacokinetics_of_estradiol#Oral_administration as therapy. "The adverse event rate (≥grade 3) in the 30-mg group (11/32 [34%]; 95% confidence interval [CI], 23%-47%) was higher than in the 6-mg group (4/34 [18%]; 95% CI, 5%-22%; p=0.03). Clinical benefit rates were 9 of 32 (28%; 95% CI, 18%-41%) in the 30-mg group and 10 of 34 (29%; 95% CI, 19%-42%) in the 6-mg group." Sources: See template.
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.[91] The risk of endometrial hyperplasia is greatly increased by 6months of treatment (ORTooltip odds ratio = 5.4) and further increased after 36months of treatment (OR = 16.0).[91] 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).[91] The risk of endometrial cancer also stays significantly elevated many years after stopping unopposed estrogen therapy, even after 15years or more (RR = 5.8).[91]
Progestogens prevent the effects of estrogens on the endometrium.[91] 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).[91] Continuous estrogen–progestogen therapy is more protective than sequential therapy, and a longer duration of treatment with continuous therapy is also more protective.[91] The increase in risk of endometrial cancer is similarly decreased with continuous estrogen–progestogen therapy (RR = 0.2–0.7).[91] For these reasons, progestogens are always used alongside estrogens in women who have intact uteruses.[91]
Menopausal hormone therapy with replacement dosages of estrogens and progestogens has been associated with a significantly increased risk of cardiovascular events such as VTE.[96][97] However, such risks have been found to vary depending on the type of estrogen and the route of administration.[96][97] The risk of VTE is increased by approximately 2-fold in women taking oral estrogen for menopausal hormone therapy.[96][97] However, clinical research to date has generally not distinguished between conjugated estrogens and estradiol.[97] 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.[1] Only a few clinical studies have compared oral conjugated estrogens and oral estradiol.[97] 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).[97][98][99] However, in another study, the increase in VTE risk with 0.625mg/day oral conjugated estrogens plus medroxyprogesterone acetate and 1 or 2mg/day oral estradiol plus norethisterone acetate was found to be equivalent (RRTooltip Relative risk = 4.0 and 3.9, respectively).[100][101] 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).[97][102] 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.[97][96] 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.[96][94][97]
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).[103] The risk of VTE during the postpartum period is 5-fold higher than during pregnancy.[103] 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.[104] For birth control pills, VTE risk with high doses of ethinylestradiol (>50μg, e.g., 100 to 150μg) has been reported to be approximately twice that of low doses of ethinylestradiol (e.g., 20 to 50μg).[92] As such, high doses of ethinylestradiol are no longer used in combined oral contraceptives, and all modern combined oral contraceptives contain 50μg ethinylestradiol or less.[105][106] The absolute risk of VTE in pregnancy is about 0.5 to 2 in 1,000 (0.125%).[107]
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.[108][101] 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).[108] 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.[108][109][110] The dosage of oral estrogen appears to be important for VTE risk, as 1mg/day oral estradiol increased VTE incidence by 2.2-fold while 2mg/day oral estradiol increased VTE incidence by 4.5-fold (both in combination with norethisterone acetate).[101] The risk of VTE and other cardiovascular complications with oral estrogen–progestogen therapy increases dramatically with age.[108] 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.[108] 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.[108] 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.[111][112] In addition, smoking has been found to exponentially increase cardiovascular mortality in conjunction with combined oral contraceptive use and older age.[111][112] 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.[111][112] 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.[111][112]
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.[1] 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).[1] Transdermal estradiol has less-pronounced effects on these proteins and, in contrast to oral estradiol, reduces triglycerides.[1] Through these effects, both oral and transdermal estrogens can protect against atherosclerosis and coronary heart disease in menopausal women with intact arterialendothelium that is without severe lesions.[1]
Approximately 95% of orally ingested estradiol is inactivated during first-pass metabolism.[93] 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.[1][113] This does not occur with parenteral routes of estradiol, such as transdermal, vaginal, or injection.[1] In contrast to estradiol, ethinylestradiol is much more resistant to hepatic metabolism, with a mean oral bioavailability of approximately 45%,[114] and the transdermal route has a similar impact on hepatic protein synthesis as the oral route.[115] 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.[1] These differences are considered to be responsible for the greater risk of cardiovascular events with ethinylestradiol and conjugated estrogens relative to estradiol.[1]
High-dosage oral synthetic estrogens like diethylstilbestrol and ethinylestradiol are associated with fairly high rates of severe cardiovascular complications.[116][117] 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.[116][117] 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.[117][118][119]
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.[120][121][122] 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.[120]Contraceptive vaginal rings and contraceptive patches likewise have been found to increase SHBG levels by 2.5-fold and 3.5-fold, respectively.[120] Birth control pills containing high doses of ethinylestradiol (>50μg) can increase SHBG levels by 5- to 10-fold, which is similar to the increase that occurs during pregnancy.[123] Conversely, increases in SHBG levels are much lower with estradiol, especially when used parenterally.[124][125][126][127][128] High-dose parenteral polyestradiol phosphate therapy has been found to increase SHBG levels by about 1.5-fold.[127]
Absolute and relative incidence of venous thromboembolism (VTE) during pregnancy and the postpartum period
Absolute incidence of first VTE per 10,000 person–years during pregnancy and the postpartum period
Swedish data A
Swedish data B
English data
Danish data
Time period
N
Rate (95% CI)
N
Rate (95% CI)
N
Rate (95% CI)
N
Rate (95% CI)
Outside pregnancy
1105
4.2 (4.0–4.4)
1015
3.8 (?)
1480
3.2 (3.0–3.3)
2895
3.6 (3.4–3.7)
Antepartum
995
20.5 (19.2–21.8)
690
14.2 (13.2–15.3)
156
9.9 (8.5–11.6)
491
10.7 (9.7–11.6)
Trimester 1
207
13.6 (11.8–15.5)
172
11.3 (9.7–13.1)
23
4.6 (3.1–7.0)
61
4.1 (3.2–5.2)
Trimester 2
275
17.4 (15.4–19.6)
178
11.2 (9.7–13.0)
30
5.8 (4.1–8.3)
75
5.7 (4.6–7.2)
Trimester 3
513
29.2 (26.8–31.9)
340
19.4 (17.4–21.6)
103
18.2 (15.0–22.1)
355
19.7 (17.7–21.9)
Around delivery
115
154.6 (128.8–185.6)
79
106.1 (85.1–132.3)
34
142.8 (102.0–199.8)
–
Postpartum
649
42.3 (39.2–45.7)
509
33.1 (30.4–36.1)
135
27.4 (23.1–32.4)
218
17.5 (15.3–20.0)
Early postpartum
584
75.4 (69.6–81.8)
460
59.3 (54.1–65.0)
177
46.8 (39.1–56.1)
199
30.4 (26.4–35.0)
Late postpartum
65
8.5 (7.0–10.9)
49
6.4 (4.9–8.5)
18
7.3 (4.6–11.6)
319
3.2 (1.9–5.0)
Incidence rate ratios (IRRs) of first VTE during pregnancy and the postpartum period
Swedish data A
Swedish data B
English data
Danish data
Time period
IRR* (95% CI)
IRR* (95% CI)
IRR (95% CI)†
IRR (95% CI)†
Outside pregnancy
Reference (i.e., 1.00)
Antepartum
5.08 (4.66–5.54)
3.80 (3.44–4.19)
3.10 (2.63–3.66)
2.95 (2.68–3.25)
Trimester 1
3.42 (2.95–3.98)
3.04 (2.58–3.56)
1.46 (0.96–2.20)
1.12 (0.86–1.45)
Trimester 2
4.31 (3.78–4.93)
3.01 (2.56–3.53)
1.82 (1.27–2.62)
1.58 (1.24–1.99)
Trimester 3
7.14 (6.43–7.94)
5.12 (4.53–5.80)
5.69 (4.66–6.95)
5.48 (4.89–6.12)
Around delivery
37.5 (30.9–44.45)
27.97 (22.24–35.17)
44.5 (31.68–62.54)
–
Postpartum
10.21 (9.27–11.25)
8.72 (7.83–9.70)
8.54 (7.16–10.19)
4.85 (4.21–5.57)
Early postpartum
19.27 (16.53–20.21)
15.62 (14.00–17.45)
14.61 (12.10–17.67)
8.44 (7.27–9.75)
Late postpartum
2.06 (1.60–2.64)
1.69 (1.26–2.25)
2.29 (1.44–3.65)
0.89 (0.53–1.39)
Notes: Swedish data A = Using any code for VTE regardless of confirmation. Swedish data B = Using only algorithm-confirmed VTE. Early postpartum = First 6 weeks after delivery. Late postpartum = More than 6 weeks after delivery. * = Adjusted for age and calendar year. † = Unadjusted ratio calculated based on the data provided. Source:[129]
Breast cancer
Estrogens are responsible for breast development and, in relation to this, are strongly implicated in the development of breast cancer.[130][131] In addition, estrogens stimulate the growth and accelerate the progression of ER-positive breast cancer.[132][133] 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.[134][135][136] Antiestrogens are also effective in the prevention of breast cancer.[137][138][139] 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.[140][141] 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.[140][141]
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.[142] 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).[142] 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).[142] 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).[142] 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).[137][138][139] However, there are indications that there may be a ceiling effect such that past a certain low concentration threshold (e.g., approximately 10.2pg/mL for estradiol), additional estrogens alone may not further increase the risk of breast cancer in postmenopausal women.[143] 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.[144]
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.[142][145] 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).[142] 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.[142] The increase in risk also differs according to the specific progestogen used.[142] 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.[142] In a previous review, the increase in breast cancer risk was found to not be significantly different between these three progestogens.[142] 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).[142] 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).[91] 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.[91]
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.[146][147][148][149] 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.[150][151] 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.[149][152][153]
Estrogen therapy has been associated with gallbladder disease, including risk of gallstone formation.[161][162][163][164] 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).[164]Biliary sludge appears in 5 to 30% of women during pregnancy, and definitive gallstones persisting postpartum become established in approximately 5%.[165]
Overdose
Estrogens are relatively safe in overdose and symptoms manifest mainly as reversible feminization.
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 gonadalsex hormoneproduction. 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.[167]
Estrogens differ significantly in their pharmacological properties.[1][168][169] 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.[1] This can result in issues such as a relatively higher risk of thromboembolism.[1]
Footnotes:a = (1) Binding affinity values are of the format "median (range)" (# (#–#)), "range" (#–#), or "value" (#) depending on the values available. The full sets of values within the ranges can be found in the Wiki code. (2) Binding affinities were determined via displacement studies in a variety of in-vitro systems with labeled estradiol and human ERα and ERβ proteins (except the ERβ values from Kuiper et al. (1997), which are rat ERβ). Sources: See template page.
Notes: Reference ligands (100%) were progesterone for the PRTooltip progesterone receptor, testosterone for the ARTooltip androgen receptor, estradiol for the ERTooltip estrogen receptor, dexamethasone for the GRTooltip glucocorticoid receptor, aldosterone for the MRTooltip mineralocorticoid receptor, dihydrotestosterone for SHBGTooltip sex hormone-binding globulin, and cortisol for CBGTooltip Corticosteroid-binding globulin. Sources: See template.
Notes: Values are mean ± SD or range. ERRBA = Relative binding affinity to estrogen receptors of rat uterinecytosol. Uterine weight = Percentage change in uterine wet weight of ovariectomized rats after 72hours with continuous administration of 1μg/hour via subcutaneously implantedosmotic pumps. LH levels = Luteinizing hormone levels relative to baseline of ovariectomized rats after 24 to 72hours of continuous administration via subcutaneous implant. Footnotes:a = Synthetic (i.e., not endogenous). b = Atypical uterotrophic effect which plateaus within 48hours (estradiol's uterotrophy continues linearly up to 72hours). Sources: See template.
Notes: Values are ratios, with estradiol as standard (i.e., 1.0). Abbreviations:HF = Clinical relief of hot flashes. VE = Increased proliferation of vaginal epithelium. UCa = Decrease in UCaTooltip urinary calcium. FSH = Suppression of FSHTooltip follicle-stimulating hormone levels. LH = Suppression of LHTooltip luteinizing hormone levels. HDL-C, SHBG, CBG, and AGT = Increase in the serum levels of these liver proteins. Liver = Ratio of liver estrogenic effects to general/systemic estrogenic effects (hot flashes/gonadotropins). Sources: See template.
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.[196][197][198] In 1927, Selmar and Aschheim discovered that large amounts of estrogens were present in the urine of pregnant women.[197][199][200] This rich source of estrogens, produced by the placenta, allowed for the development of potent estrogenic formulations for scientific and clinical use.[197][200][201] The first pharmaceutical estrogen product was a conjugated estriol called Progynon, a placental extract, and was introduced for medical use by the Germanpharmaceutical companySchering in 1928.[202][203][204][205][206][207][208][209] In 1929, Adolf Butenandt and Edward Adelbert Doisy independently isolated and purified estrone, the first estrogen to be discovered.[210] The estrogen preparations Amniotin (Squibb), Progynon (Schering), and Theelin (Parke-Davis) were all on the market by 1929,[196] 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.[197][211][212] Estrogens were originally known under a variety of different names including estrogens, estrins, follicular hormones, folliculins, gynecogens, folliculoids, and female sex hormones, among others.[213][211]
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.[217]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.[218]Ethinylestradiol was synthesized in 1938 by Hans Herloff Inhoffen and Walter Hohlweg at Schering AG in Berlin[219][220][221][222][223] 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.[224]
Micronized estradiol, via the oral route, was first evaluated in 1972,[225] and this was followed by the evaluation of vaginal and intranasal micronized estradiol in 1977.[226] Oral micronized estradiol was first approved in the United States under the brand name Estrace in 1975.[227]
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.[231]
Miscellaneous
Estrogens have been used in studies which indicate that they may be effective in the treatment of traumatic liver injury.[232]
Estrogen therapy has been proposed as a potential treatment for autism but clinical studies are needed.[234]
Related Research Articles
A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a synthetic progestogen. Progestogens are used most commonly in hormonal birth control and menopausal hormone therapy. They can also be used in the treatment of gynecological conditions, to support fertility and pregnancy, to lower sex hormone levels for various purposes, and for other indications. Progestogens are used alone or in combination with estrogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of progestogens include natural or bioidentical progesterone as well as progestins such as medroxyprogesterone acetate and norethisterone.
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.
Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. In the past, EE was widely used for various indications such as the treatment of menopausal symptoms, gynecological disorders, and certain hormone-sensitive cancers. It is usually taken by mouth but is also used as a patch and vaginal ring.
Estradiol valerate (EV), sold for use by mouth under the brand name Progynova and for use by injection under the brand names Delestrogen and Progynon Depot among others, is an estrogen medication. It is used in hormone therapy for menopausal symptoms and low estrogen levels, hormone therapy for transgender people, and in hormonal birth control. It is also used in the treatment of prostate cancer. The medication is taken by mouth or by injection into muscle or fat once every 1 to 4 weeks.
Drospirenone is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy and in menopausal hormone therapy, among other uses. It is available both alone under the brand name Slynd and in combination with an estrogen under the brand name Yasmin among others. The medication is an analog of the drug spironolactone. Drospirenone is taken by mouth.
Norethisterone acetate (NETA), also known as norethindrone acetate and sold under the brand name Primolut-Nor among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication available in low-dose and high-dose formulations and is used alone or in combination with an estrogen. It is ingested orally.
Norgestimate, sold under the brand name Ortho Tri-Cyclen among others, is a progestin medication which is used in birth control pills for women and in menopausal hormone therapy. The medication is available in combination with an estrogen and is not available alone. It is taken by mouth.
An estrogen patch, or oestrogen patch, is a transdermal delivery system for estrogens such as estradiol and ethinylestradiol which can be used in menopausal hormone therapy, feminizing hormone therapy for transgender women, hormonal birth control, and other uses. Transdermal preparations of estrogen are metabolized differently than oral preparations. Transdermal estrogens avoid the first pass through the liver and thus potentially reduce the risk of blood clotting and stroke.
Tibolone, sold under the brand name Livial among others, is a medication which is used in menopausal hormone therapy and in the treatment of postmenopausal osteoporosis and endometriosis. The medication is available alone and is not formulated or used in combination with other medications. It is taken by mouth.
Gestodene, sold under the brand names Femodene and Minulet among others, is a progestin medication which is used in birth control pills for women. It is also used in menopausal hormone therapy. The medication is available almost exclusively in combination with an estrogen. It is taken by mouth.
Dienogest, sold under the brand name Visanne among others, is a progestin medication which is used in birth control pills and in the treatment of endometriosis. It is also used in menopausal hormone therapy and to treat heavy periods. Dienogest is available both alone and in combination with estrogens. It is taken by mouth.
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. Effects of menopause can include symptoms such as hot flashes, accelerated skin aging, vaginal dryness, decreased muscle mass, and complications such as osteoporosis, sexual dysfunction, and vaginal atrophy. They are mostly caused by low levels of female sex hormones that occur during menopause.
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.
Ethinylestradiol sulfonate (EES), sold under the brand names Deposiston and Turisteron among others, is an estrogen medication which has been used in birth control pills for women and in the treatment of prostate cancer in men. It has also been investigated in the treatment of breast cancer in women. The medication was combined with norethisterone acetate in birth control pills. EES is taken by mouth once per week.
Estradiol (E2) is a medication and naturally occurring steroid hormone. It is an estrogen and is used mainly in menopausal hormone therapy and to treat low sex hormone levels in women. It is also used in hormonal birth control for women, in feminizing hormone therapy for transgender women and some non-binary individuals, and in the treatment of hormone-sensitive cancers like prostate cancer in men and breast cancer in women, among other uses. Estradiol can be taken by mouth, held and dissolved under the tongue, as a gel or patch that is applied to the skin, in through the vagina, by injection into muscle or fat, or through the use of an implant that is placed into fat, among other routes.
High-dose estrogen therapy (HDE) is a type of hormone therapy in which high doses of estrogens are given. When given in combination with a high dose of progestogen, it has been referred to as pseudopregnancy. It is called this because the estrogen and progestogen levels achieved are in the range of the very high levels of these hormones that occur during pregnancy. HDE and pseudopregnancy have been used in medicine for a number of hormone-dependent indications, such as breast cancer, prostate cancer, and endometriosis, among others. Both natural or bioidentical estrogens and synthetic estrogens have been used and both oral and parenteral routes may be used.
Estetrol (E4) is an estrogen medication and naturally occurring steroid hormone which is used in combination with a progestin in combined birth control pills and is under development for various other indications. These investigational uses include menopausal hormone therapy to treat symptoms such as vaginal atrophy, hot flashes, and bone loss and the treatment of breast cancer and prostate cancer. It is taken by mouth.
The pharmacology of estradiol, an estrogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.
The Estrogen in Venous Thromboembolism Trial (EVTET) was a randomized controlled trial (RCT) of menopausal hormone therapy in 140 postmenopausal women with previous history of venous thromboembolism (VTE). It was a double-blind RCT of the estrogen, oral estradiol 2 mg/day, plus the progestogen, norethisterone acetate (NETA) (n=71) 1 mg/day versus placebo (n=69). The results of the trial were published in 2000 and 2001. The incidence of VTE was 10.7% in the hormone therapy group and 2.3% in the placebo group, with all events occurring within 261 days after study inclusion. The difference did not reach statistical significance in the sequential analysis, but was statistically significant if the sequential design was ignored. Markers of coagulation were likewise increased by hormone therapy. As a result of the high incidence of VTE in the treatment group, the trial was terminated prematurely. The researchers concluded on the basis of their findings that menopausal hormone therapy should not be used in women with a previous history of VTE.
↑ Notelovitz M, Lenihan JP, McDermott M, Kerber IJ, Nanavati N, Arce J (May 2000). "Initial 17beta-estradiol dose for treating vasomotor symptoms". Obstet Gynecol. 95 (5): 726–31. doi:10.1016/s0029-7844(99)00643-2. PMID10775738. S2CID42621608.
↑ Wiegratz I, Kuhl H (2007). "Praxis der Hormontherapie in der Peri- und Postmenopause" [Practice of peri- and postmenopausal hormone therapy]. Gynäkologische Endokrinologie. 5 (3): 141–149. doi:10.1007/s10304-007-0194-9. ISSN1610-2894. S2CID27130717.
1 2 Palmieri C, Patten DK, Januszewski A, Zucchini G, Howell SJ (January 2014). "Breast cancer: current and future endocrine therapies". Mol. Cell. Endocrinol. 382 (1): 695–723. doi:10.1016/j.mce.2013.08.001. PMID23933149.
1 2 3 Green RB, Sethi RS, Lindner HH (July 1964). "Treatment of advanced carcinoma of the breast: Progress in therapy during the past decade". Am. J. Surg. 108: 107–21. doi:10.1016/0002-9610(64)90094-7. PMID14182428.
1 2 3 4 Van Winkle W (1949). "Council on Pharmacy and Chemistry. Estrogens and Androgens in Mammary Cancer". JAMA: The Journal of the American Medical Association. 140 (15): 1214. doi:10.1001/jama.1949.02900500022007. ISSN0098-7484.
↑ Committee on Research, AMA (1960). "Androgens and estrogens in the treatment of disseminated mammary carcinoma. Retrospective study of nine hundred forty-four patients". Journal of the American Medical Association. 172 (12): 1271. doi:10.1001/jama.1960.03020120049010. ISSN0002-9955.
↑ Ostrowski MJ, Jackson AW (1979). "Polyestradiol phosphate: a preliminary evaluation of its effect on breast carcinoma". Cancer Treat Rep. 63 (11–12): 1803–7. PMID393380.
↑ Gunther DF, Diekema DS (2006). "Attenuating growth in children with profound developmental disability: a new approach to an old dilemma". Arch Pediatr Adolesc Med. 160 (10): 1013–7. doi:10.1001/archpedi.160.10.1013. PMID17018459.
1 2 Stone JC, Clark J, Cuneo R, Russell AW, Doi SA (June 2014). "Estrogen and selective estrogen receptor modulators (SERMs) for the treatment of acromegaly: a meta-analysis of published observational studies". Pituitary. 17 (3): 284–95. doi:10.1007/s11102-013-0504-2. PMID23925896. S2CID30697394.
1 2 3 4 Thibaut F, De La Barra F, Gordon H, Cosyns P, Bradford JM (2010). "The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of paraphilias". World J. Biol. Psychiatry. 11 (4): 604–55. doi:10.3109/15622971003671628. PMID20459370. S2CID14949511.
↑ Brogden RN, Clissold SP (August 1989). "Flutamide. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in advanced prostatic cancer". Drugs. 38 (2): 185–203. doi:10.2165/00003495-198938020-00003. PMID2670515. S2CID262018256. A favourable feature of flutamide therapy has been its lesser effect on libido and sexual potency; fewer than 20% of patients treated with flutamide alone reported such changes. In contrast, nearly all patients treated with oestrogens or estramustine phosphate reported loss of sexual potency. [...] In comparative therapeutic trials, loss of potency has occurred in all patients treated with stilboestrol or estramustine phosphate compared with 0 to 20% of those given flutamide alone (Johansson et al. 1987; Lund & Rasmussen 1988).
1 2 3 Hartmann BW, Laml T, Kirchengast S, Albrecht AE, Huber JC (1998). "Hormonal breast augmentation: prognostic relevance of insulin-like growth factor-I". Gynecol. Endocrinol. 12 (2): 123–7. doi:10.3109/09513599809024960. PMID9610425.
1 2 3 Lauritzen C (1980). "Hormonkur kann hypoplastischer Mamma aufhelfen" [Hormone therapy can help hypoplastic breasts]. Selecta (in German). 22 (43). Planegg: Selecta-Verlag: 3798–3801. ISSN0582-4877. OCLC643821347.
↑ Kaiser R, Leidenberger FA (1991). Hormonbehandlung in der gynäkologischen Praxis (6ed.). Stuttgart, New York: Georg Thieme Verlag. pp.138–139. ISBN978-3-13-357407-5.
↑ Toffol E, Heikinheimo O, Partonen T (May 2015). "Hormone therapy and mood in perimenopausal and postmenopausal women: a narrative review". Menopause. 22 (5): 564–78. doi:10.1097/GME.0000000000000323. PMID25203891. S2CID5830652.
1 2 3 Garay RP, Charpeaud T, Logan S, Hannaert P, Garay RG, Llorca PM, Shorey S (October 2019). "Pharmacotherapeutic approaches to treating depression during the perimenopause". Expert Opin Pharmacother. 20 (15): 1837–1845. doi:10.1080/14656566.2019.1645122. PMID31355688. S2CID198967172.
↑ Myoraku A, Robakis T, Rasgon N (2018). "Estrogen-Based Hormone Therapy for Depression Related to Reproductive Events". Current Treatment Options in Psychiatry. 5 (4): 416–424. doi:10.1007/s40501-018-0156-y. ISSN2196-3061. S2CID81770543.
↑ Cheng YS, Tseng PT, Tu YK, Wu YC, Su KP, Wu CK, Li DJ, Chen TY, Stubbs B, Carvalho AF, Solmi M, Thompson T, Caruso MG, Matsuoka YJ, Chen YW, Lin PY, Wu MK, Sun CK (19 September 2019), Hormonal and Pharmacologic Interventions for Depressive Symptoms in Peri- And/Or Post-Menopausal Women: A Network Meta-Analysis of Randomized Controlled Trials, doi:10.2139/ssrn.3457416, S2CID216575787, SSRN3457416
↑ Begemann MJ, Dekker CF, van Lunenburg M, Sommer IE (November 2012). "Estrogen augmentation in schizophrenia: a quantitative review of current evidence". Schizophr. Res. 141 (2–3): 179–84. doi:10.1016/j.schres.2012.08.016. PMID22998932. S2CID40584474.
↑ McGregor C, Riordan A, Thornton J (October 2017). "Estrogens and the cognitive symptoms of schizophrenia: Possible neuroprotective mechanisms". Front Neuroendocrinol. 47: 19–33. doi:10.1016/j.yfrne.2017.06.003. PMID28673758. S2CID43291520.
↑ Clayton RW, Göbel K, Niessen CM, Paus R, van Steensel MAM, Lim X (October 2019). "Homeostasis of the sebaceous gland and mechanisms of acne pathogenesis". Br. J. Dermatol. 181 (4): 677–690. doi:10.1111/bjd.17981. PMID31056753. S2CID145822633.
↑ White CB, Lehmann CF (May 1952). "Diethylstilbestrol therapy in young men with acne; correlation with the urinary 17-ketosteroids". AMA Arch Dermatol Syphilol. 65 (5): 601–8. doi:10.1001/archderm.1952.01530240093012. PMID14914180.
↑ Paulsen CA, Leach RB, Lanman J, Goldston N, Maddock WO, Heller CG (1962). "Inherent estrogenicity of norethindrone and norethynodrel: comparison with other synthetic progestins and progesterone". J. Clin. Endocrinol. Metab. 22 (10): 1033–9. doi:10.1210/jcem-22-10-1033. PMID13942007.
1 2 Midwinter A (1976). "Contraindications to estrogen therapy and management of the menopausal syndrome in these cases". In Campbell S (ed.). The Management of the Menopause & Post-Menopausal Years: The Proceedings of the International Symposium held in London 24–26 November 1975 Arranged by the Institute of Obstetrics and Gynaecology, The University of London. MTP Press Limited. pp.377–382. doi:10.1007/978-94-011-6165-7_33. ISBN978-94-011-6167-1.
1 2 Whitehead M (January 1982). "Oestrogens: Relative Potencies and Hepatic Effects After Different Routes of Administration". Journal of Obstetrics and Gynaecology. 3 (sup1): S11–S16. doi:10.3109/01443618209083065. eISSN1364-6893. ISSN0144-3615.
↑ Mattison DR, Karyakina N, Goodman M, LaKind JS (September 2014). "Pharmaco- and toxicokinetics of selected exogenous and endogenous estrogens: a review of the data and identification of knowledge gaps". Crit Rev Toxicol. 44 (8): 696–724. doi:10.3109/10408444.2014.930813. PMID25099693. S2CID11212469.
↑ Lekovic D, Miljic P, Dmitrovic A, Thachil J (May 2017). "How do you decide on hormone replacement therapy in women with risk of venous thromboembolism?". Blood Rev. 31 (3): 151–157. doi:10.1016/j.blre.2016.12.001. PMID27998619.
↑ Stevenson JC, Panay N, Pexman-Fieth C (September 2013). "Oral estradiol and dydrogesterone combination therapy in postmenopausal women: review of efficacy and safety". Maturitas. 76 (1): 10–21. doi:10.1016/j.maturitas.2013.05.018. PMID23835005. Dydrogesterone did not increase the risk of VTE associated with oral estrogen (odds ratio (OR) 0.9, 95% CI 0.4–2.3). Other progestogens (OR 3.9, 95% CI 1.5–10.0) were found to further increase the risk of VTE associated with oral estrogen (OR 4.2, 95% CI 1.5–11.6).
↑ Schneider C, Jick SS, Meier CR (October 2009). "Risk of cardiovascular outcomes in users of estradiol/dydrogesterone or other HRT preparations". Climacteric. 12 (5): 445–53. doi:10.1080/13697130902780853. PMID19565370. S2CID45890629. The adjusted relative risk of developing a VTE tended to be lower for E/D users (OR 0.84; 95% CI 0.37–1.92) than for users of other HRT (OR 1.42; 95% CI 1.10–1.82), compared to non-users.
1 2 3 4 Schwingl PJ, Ory HW, Visness CM (January 1999). "Estimates of the risk of cardiovascular death attributable to low-dose oral contraceptives in the United States". Am. J. Obstet. Gynecol. 180 (1 Pt 1): 241–9. doi:10.1016/S0002-9378(99)70182-1. PMID9914611.
1 2 Turo R, Smolski M, Esler R, Kujawa ML, Bromage SJ, Oakley N, Adeyoju A, Brown SC, Brough R, Sinclair A, Collins GN (February 2014). "Diethylstilboestrol for the treatment of prostate cancer: past, present and future". Scand J Urol. 48 (1): 4–14. doi:10.3109/21681805.2013.861508. PMID24256023. S2CID34563641.
↑ Stanczyk FZ, Grimes DA (September 2008). "Sex hormone-binding globulin: not a surrogate marker for venous thromboembolism in women using oral contraceptives". Contraception. 78 (3): 201–3. doi:10.1016/j.contraception.2008.04.004. PMID18692609.
↑ Goodman MP (February 2012). "Are all estrogens created equal? A review of oral vs. transdermal therapy". J Womens Health (Larchmt). 21 (2): 161–9. doi:10.1089/jwh.2011.2839. PMID22011208.
↑ Stege R, Carlström K, Collste L, Eriksson A, Henriksson P, Pousette A (1988). "Single drug polyestradiol phosphate therapy in prostatic cancer". Am. J. Clin. Oncol. 11 (Suppl 2): S101–3. doi:10.1097/00000421-198801102-00024. PMID3242384. S2CID32650111.
1 2 von Schoultz B, Carlström K, Collste L, Eriksson A, Henriksson P, Pousette A, Stege R (1989). "Estrogen therapy and liver function--metabolic effects of oral and parenteral administration". Prostate. 14 (4): 389–95. doi:10.1002/pros.2990140410. PMID2664738. S2CID21510744.
↑ Ottosson UB, Carlström K, Johansson BG, von Schoultz B (1986). "Estrogen induction of liver proteins and high-density lipoprotein cholesterol: comparison between estradiol valerate and ethinyl estradiol". Gynecol. Obstet. Invest. 22 (4): 198–205. doi:10.1159/000298914. PMID3817605.
↑ Jameera Begam A, Jubie S, Nanjan MJ (2017). "Estrogen receptor agonists/antagonists in breast cancer therapy: A critical review". Bioorg. Chem. 71: 257–274. doi:10.1016/j.bioorg.2017.02.011. PMID28274582.
↑ Schiavon G, Smith IE (2013). "Endocrine therapy for advanced/metastatic breast cancer". Hematol. Oncol. Clin. North Am. 27 (4): 715–36, viii. doi:10.1016/j.hoc.2013.05.004. PMID23915741.
1 2 Mallick S, Benson R, Julka PK (2016). "Breast cancer prevention with anti-estrogens: review of the current evidence and future directions". Breast Cancer. 23 (2): 170–7. doi:10.1007/s12282-015-0647-2. PMID26439380. S2CID37377540.
↑ Pike MC, Wu AH, Spicer DV, Lee S, Pearce CL (2007). "Estrogens, progestins, and risk of breast cancer". Ernst Schering Found Symp Proc. Ernst Schering Foundation Symposium Proceedings. 2007/1 (1): 127–50. doi:10.1007/2789_2007_059. ISBN978-3-540-73492-5. PMID18540571.
↑ Gooren LJ, van Trotsenburg MA, Giltay EJ, van Diest PJ (2013). "Breast cancer development in transsexual subjects receiving cross-sex hormone treatment". J Sex Med. 10 (12): 3129–34. doi:10.1111/jsm.12319. PMID24010586.
↑ Chen J, Zhao KN, Liu GB (2013). "Estrogen-induced cholestasis: pathogenesis and therapeuticimplications". Hepatogastroenterology. 60 (126): 1289–96. doi:10.5754/hge121061 (inactive 2 November 2024). ISSN0172-6390. PMID23933920.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
↑ Ansbacher R (February 2001). "The pharmacokinetics and efficacy of different estrogens are not equivalent". Am. J. Obstet. Gynecol. 184 (3): 255–63. doi:10.1067/mob.2001.109656. PMID11228470.
↑ Lauritzen C (June 1977). "[Estrogen thearpy in practice. 3. Estrogen preparations and combination preparations]" [Estrogen therapy in practice. 3. Estrogen preparations and combination preparations]. Fortschritte Der Medizin (in German). 95 (21): 1388–92. PMID559617.
↑ Ryden AB (1950). "Natural and synthetic oestrogenic substances; their relative effectiveness when administered orally". Acta Endocrinologica. 4 (2): 121–39. doi:10.1530/acta.0.0040121. PMID15432047.
↑ Ryden AB (1951). "The effectiveness of natural and synthetic oestrogenic substances in women". Acta Endocrinologica. 8 (2): 175–91. doi:10.1530/acta.0.0080175. PMID14902290.
↑ Kottmeier HL (1947). "Ueber blutungen in der menopause: Speziell der klinischen bedeutung eines endometriums mit zeichen hormonaler beeinflussung: Part I". Acta Obstetricia et Gynecologica Scandinavica. 27 (s6): 1–121. doi:10.3109/00016344709154486. ISSN0001-6349. There is no doubt that the conversion of the endometrium with injections of both synthetic and native estrogenic hormone preparations succeeds, but the opinion whether native, orally administered preparations can produce a proliferation mucosa changes with different authors. PEDERSEN-BJERGAARD (1939) was able to show that 90% of the folliculin taken up in the blood of the vena portae is inactivated in the liver. Neither KAUFMANN (1933, 1935), RAUSCHER (1939, 1942) nor HERRNBERGER (1941) succeeded in bringing a castration endometrium into proliferation using large doses of orally administered preparations of estrone or estradiol. Other results are reported by NEUSTAEDTER (1939), LAUTERWEIN (1940) and FERIN (1941); they succeeded in converting an atrophic castration endometrium into an unambiguous proliferation mucosa with 120–300 oestradiol or with 380 oestrone.
↑ Martinez-Manautou J, Rudel HW (1966). "Antiovulatory Activity of Several Synthetic and Natural Estrogens". In Robert Benjamin Greenblatt (ed.). Ovulation: Stimulation, Suppression, and Detection. Lippincott. pp.243–253.
↑ Herr F, Revesz C, Manson AJ, Jewell JB (1970). "Biological Properties of Estrogen Sulfates". Chemical and Biological Aspects of Steroid Conjugation. pp.368–408. doi:10.1007/978-3-642-49793-3_8. ISBN978-3-642-49506-9.
↑ Clark JH, Paszko Z, Peck EJ (January 1977). "Nuclear binding and retention of the receptor estrogen complex: relation to the agonistic and antagonistic properties of estriol". Endocrinology. 100 (1): 91–96. doi:10.1210/endo-100-1-91. PMID830547.
↑ Clark JH, Hardin JW, McCormack SA (1979). "Mechanism of action of estrogen agonists and antagonists". Journal of Animal Science. 49 Suppl 2: 46–65. doi:10.1093/ansci/49.supplement_ii.46. PMID400777.
↑ Clark JH, Markaverich BM (1983). "The agonistic and antagonistic effects of short acting estrogens: a review". Pharmacology & Therapeutics. 21 (3): 429–453. doi:10.1016/0163-7258(83)90063-3. PMID6356176.
↑ Clark JH, Markaverich BM (April 1984). "The agonistic and antagonistic actions of estriol". Journal of Steroid Biochemistry. 20 (4B): 1005–1013. doi:10.1016/0022-4731(84)90011-6. PMID6202959.
↑ Terenius L, Ljungkvist I (1972). "Aspects on the mode of action of antiestrogens and antiprogestogens". Gynecologic Investigation. 3 (1): 96–107. doi:10.1159/000301746. PMID4347201.
↑ Vern L. Bullough (19 May 1995). Science In The Bedroom: A History Of Sex Research. Basic Books. pp.128–. ISBN978-0-465-07259-0. When Allen and Doisy heard about the [Ascheim-Zondek test for the diagnosis of pregnancy], they realized there was a rich and easily handled source of hormones in urine from which they could develop a potent extract. [...] Allen and Doisy's research was sponsored by the committee, while that of their main rival, Adolt Butenandt (b. 1903) of the University of Gottingen was sponsored by a German pharmaceutical firm. In 1929, both terms announced the isolation of a pure crystal female sex hormone, estrone, in 1929, although Doisy and Allen did so two months earlier than Butenandt.27 By 1931, estrone was being commercially produced by Parke Davis in this country, and Schering-Kahlbaum in Germany. Interestingly, when Butenandt (who shared the Nobel Prize for chemistry in 1939) isolated estrone and analyzed its structure, he found that it was a steroid, the first hormone to be classed in this molecular family.[permanent dead link]
↑ Batisweiler, J. (1928). Placentaextrakt Progynon (Schering-Kahlbaum) bei Menstruationsstörungen und Kastrationsfolgen. Zbl. Gynäk, 2227-2232. Chicago
↑ Reifenstein EC (1944). "Endocrinology: A Synopsis of Normal and Pathologic Physiology, Diagnostic Procedures, and Therapy". Medical Clinics of North America. 28 (5): 1232–1276. doi:10.1016/S0025-7125(16)36180-6. ISSN0025-7125.
↑ Inhoffen HH, Hohlweg W (1938). "Neue per os-wirksame weibliche Keimdrüsenhormon-Derivate: 17-Aethinyl-oestradiol und Pregnen-in-on-3-ol-17 (New female glandular derivatives active per os: 17α-ethynyl-estradiol and pregnen-in-on-3-ol-17)". Naturwissenschaften. 26 (6): 96. Bibcode:1938NW.....26...96I. doi:10.1007/BF01681040. S2CID46648877.
1 2 3 Payne AH, Hardy MP (28 October 2007). The Leydig Cell in Health and Disease. Springer Science & Business Media. pp.422–431. ISBN978-1-59745-453-7. Estrogens are highly efficient inhibitors of the hypothalamic-hypophyseal-testicular axis (212–214). Aside from their negative feedback action at the level of the hypothalamus and pituitary, direct inhibitory effects on the testis are likely (215,216). [...] The histology of the testes [with estrogen treatment] showed disorganization of the seminiferous tubules, vacuolization and absence of lumen, and compartmentalization of spermatogenesis.
1 2 Salam MA (2003). Principles & Practice of Urology: A Comprehensive Text. Universal-Publishers. pp.684–. ISBN978-1-58112-412-5. Estrogens act primarily through negative feedback at the hypothalamic-pituitary level to reduce LH secretion and testicular androgen synthesis. [...] Interestingly, if the treatment with estrogens is discontinued after 3 yr. of uninterrupted exposure, serum testosterone may remain at castration levels for up to another 3 yr. This prolonged suppression is thought to result from a direct effect of estrogens on the Leydig cells.
This page is based on this Wikipedia article Text is available under the CC BY-SA 4.0 license; additional terms may apply. Images, videos and audio are available under their respective licenses.
