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Estrogen | Reproductive system physiology | NCLEX-RN | Khan Academy
Estrogen | Reproductive system physiology | NCLEX-RN | Khan Academy
Published: 2014/11/25
Channel: khanacademymedicine
The Top 5 High Estrogen Foods to Avoid
The Top 5 High Estrogen Foods to Avoid
Published: 2014/09/11
Channel: Dr. Josh Axe
10 Early Warning Signs Your Estrogen Levels Are Too High & How To Fix It
10 Early Warning Signs Your Estrogen Levels Are Too High & How To Fix It
Published: 2017/08/30
Channel: Natural Cures
1.5 YEARS ON ESTROGEN!
1.5 YEARS ON ESTROGEN!
Published: 2016/11/29
Channel: Maya
Dwa Sławy - Estrogen (prod. No Echoes)
Dwa Sławy - Estrogen (prod. No Echoes)
Published: 2017/01/19
Channel: EMBRYO NAGRANIA
10 YEARS ON ESTROGEN | HORMONE REPLACEMENT THERAPY RESULTS EXPLAINED
10 YEARS ON ESTROGEN | HORMONE REPLACEMENT THERAPY RESULTS EXPLAINED
Published: 2017/04/28
Channel: Elle Bradford
Pure Estrogen Boost
Pure Estrogen Boost
Published: 2013/04/05
Channel: Sapien Medicine
Estrogen Levels In Women | Her Body
Estrogen Levels In Women | Her Body
Published: 2014/04/25
Channel: HerBody mDhil
Estrogen Is Killing Men: How To Lower Estrogen Naturally
Estrogen Is Killing Men: How To Lower Estrogen Naturally
Published: 2017/11/16
Channel: Christopher Walker
SIX MONTH ESTROGEN UPDATE!
SIX MONTH ESTROGEN UPDATE!
Published: 2016/04/08
Channel: Chloe Arden
Estrogen, the Good, the Bad & the Ugly
Estrogen, the Good, the Bad & the Ugly
Published: 2016/10/17
Channel: Dr. Eric Berg DC
Too Much Estrogen?  Every Man Should Watch This!
Too Much Estrogen? Every Man Should Watch This!
Published: 2015/04/22
Channel: iHealthTube.com
My Favorite and Least Favorite Changes Of Estrogen - MTF Transgender | Dawn Marie
My Favorite and Least Favorite Changes Of Estrogen - MTF Transgender | Dawn Marie
Published: 2017/08/22
Channel: Dawn Marie
3 months on estrogen!
3 months on estrogen!
Published: 2017/01/30
Channel: Life with Hope
Top 10 Foods High in Estrogen
Top 10 Foods High in Estrogen
Published: 2014/07/07
Channel: KMONIC
HOW TO NATURALLY INCREASE ESTROGEN LEVELS FOR MTF TRANSGENDERS
HOW TO NATURALLY INCREASE ESTROGEN LEVELS FOR MTF TRANSGENDERS
Published: 2017/03/13
Channel: Dawn Marie
Low Estrogen Symptoms
Low Estrogen Symptoms
Published: 2017/02/17
Channel: Your Education Video
3 Foods to Reduce Estrogen to Lose Weight- Thomas DeLauer
3 Foods to Reduce Estrogen to Lose Weight- Thomas DeLauer
Published: 2016/01/13
Channel: Thomas DeLauer
Estrogen & Cortisol - How These 2 Hormones Prevent Men From Losing Weight
Estrogen & Cortisol - How These 2 Hormones Prevent Men From Losing Weight
Published: 2017/07/14
Channel: SixPackAbs.com
My Transition Timeline (so far!) | 1 Year on Estrogen | Stef Sanjati
My Transition Timeline (so far!) | 1 Year on Estrogen | Stef Sanjati
Published: 2016/12/01
Channel: Stef Sanjati
90 Minute Estrogen Release Binaural Beats
90 Minute Estrogen Release Binaural Beats
Published: 2013/08/19
Channel: StandardBinauralBeat
Abundant Estrogen - 1351HZ with Phi - 1.618033HZ
Abundant Estrogen - 1351HZ with Phi - 1.618033HZ
Published: 2016/03/31
Channel: Anthony Sommer
Balancing Hormones Naturally, Estrogen & Progesterone w/ Dr. Shari Caplan
Balancing Hormones Naturally, Estrogen & Progesterone w/ Dr. Shari Caplan
Published: 2016/10/27
Channel: High Intensity Health
Estrogen & Your Prostate
Estrogen & Your Prostate
Published: 2017/03/14
Channel: Dr. Eric Berg DC
How to Increase Estrogen
How to Increase Estrogen
Published: 2017/04/08
Channel: Health
What is estrogen and functions
What is estrogen and functions
Published: 2015/11/14
Channel: Home Remedies and medical tips
2 YEARS ON ESTROGEN!
2 YEARS ON ESTROGEN!
Published: 2017/06/02
Channel: Maya
two months on estrogen
two months on estrogen
Published: 2017/01/20
Channel: Jamie Dee
ONE YEAR ESTROGEN UPDATE!! | Chloe Arden
ONE YEAR ESTROGEN UPDATE!! | Chloe Arden
Published: 2016/11/06
Channel: Chloe Arden
omg i overdosed on estrogen + woke up in hospital!!!
omg i overdosed on estrogen + woke up in hospital!!!
Published: 2017/07/13
Channel: Cluam Sutherland
5 Signs of High Estrogen
5 Signs of High Estrogen
Published: 2016/03/04
Channel: Rambo Cuztha Gunz
Foods high in estrogen levels for breast growth
Foods high in estrogen levels for breast growth
Published: 2017/04/02
Channel: Healthy Tips
Foods High in Estrogen - Super Foods Good Health - Benefits of Wellness
Foods High in Estrogen - Super Foods Good Health - Benefits of Wellness
Published: 2015/07/17
Channel: WELLNESS
How To Tell High Estrogen or Low Estrogen on Steroid Cycle (My Method) Educational Purpose Only
How To Tell High Estrogen or Low Estrogen on Steroid Cycle (My Method) Educational Purpose Only
Published: 2017/02/06
Channel: The Bodybuilder in Thailand
Two Months on Estrogen: Transition Update
Two Months on Estrogen: Transition Update
Published: 2016/02/07
Channel: Stef Sanjati
Szybka Bomba - Estrogen - Retencja - Ginekomastia
Szybka Bomba - Estrogen - Retencja - Ginekomastia
Published: 2015/03/30
Channel: Michał Piechoś
Bodybuilding Steroid Cycle & Crashed Estrogen - Signs & Symptoms & Effects (Harm Reduction)
Bodybuilding Steroid Cycle & Crashed Estrogen - Signs & Symptoms & Effects (Harm Reduction)
Published: 2017/11/16
Channel: The Bodybuilder in Thailand
Understanding the Menstrual Cycle and Estrogen Dominance
Understanding the Menstrual Cycle and Estrogen Dominance
Published: 2013/03/20
Channel: Dr. Eric Berg DC
Top 8 High Estrogen Foods to Avoid
Top 8 High Estrogen Foods to Avoid
Published: 2017/07/31
Channel: Ultimate Health and Home Remedies
High Estrogen Foods That Men Should avoid At All Times
High Estrogen Foods That Men Should avoid At All Times
Published: 2017/03/08
Channel: 24 Physic
3 Testosterone-Boosting Anti-Estrogen Foods
3 Testosterone-Boosting Anti-Estrogen Foods
Published: 2017/11/13
Channel: Christopher Walker
Estrogen Rich Foods - Natural Estrogen Foods - Diet Tips - Rich Foods
Estrogen Rich Foods - Natural Estrogen Foods - Diet Tips - Rich Foods
Published: 2013/11/29
Channel: QUICK HEALTH
Men, Estrogen & Weight Gain....and Man Boobs
Men, Estrogen & Weight Gain....and Man Boobs
Published: 2017/07/18
Channel: Dr. Eric Berg DC
1.5 Years on Estrogen! Breast/Hair Growth | Stef Sanjati
1.5 Years on Estrogen! Breast/Hair Growth | Stef Sanjati
Published: 2017/04/15
Channel: Stef Sanjati
How To Self Inject Estrogen ( Estradiol Valerate / Progynon Depot)
How To Self Inject Estrogen ( Estradiol Valerate / Progynon Depot)
Published: 2017/04/24
Channel: Andrian Aliazas
The REAL Secrets to Reverse Estrogen Dominance and Hormone HELL
The REAL Secrets to Reverse Estrogen Dominance and Hormone HELL
Published: 2017/03/21
Channel: Diane Kazer
शरीर में Estrogen Hormone कैसे बढ़ाएं Hindi Health Tips
शरीर में Estrogen Hormone कैसे बढ़ाएं Hindi Health Tips
Published: 2016/09/03
Channel: drbole. com
hormone replacement therapy - How to Increase Estrogen Healthy Life Styles
hormone replacement therapy - How to Increase Estrogen Healthy Life Styles
Published: 2016/08/21
Channel: Healthy Life Styles
Lower estrogen for men, Binaural Beats with Subliminal Messages
Lower estrogen for men, Binaural Beats with Subliminal Messages
Published: 2017/08/22
Channel: Jordan Warren
How to Reduce Excess Estrogen or Increase Low Estrogen Naturally
How to Reduce Excess Estrogen or Increase Low Estrogen Naturally
Published: 2015/12/26
Channel: Natural Fertility Info
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WIKIPEDIA ARTICLE

From Wikipedia, the free encyclopedia
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Estrogen
Drug class
Estradiol.svg
Estradiol, the major estrogen sex hormone in humans and a widely used medication.
Class identifiers
Use Contraception, Menopause, hypogonadism, transgender women, prostate cancer, breast cancer, others
ATC code G03C
Biological target Estrogen receptors (ERα, ERβ, mERs (e.g., GPER, others))
External links
MeSH D004967
In Wikidata

Estrogen (American English) or oestrogen (British English) is the primary female sex hormone as well as a medication. It is responsible for the development and regulation of the female reproductive system and secondary sex characteristics. Estrogen may also refer to any substance, natural or synthetic, that mimics the effects of the natural hormone.[1] The estrane steroid estradiol is the most potent and prevalent endogenous estrogen, although several metabolites of estradiol also have estrogenic hormonal activity. Estrogen supplements 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 hormones, the others being androgens/anabolic steroids like testosterone and progestogens like progesterone.

Estrogens are synthesized in all vertebrates[2] as well as some insects.[3] Their presence in both vertebrates and insects suggests that estrogenic sex hormones have an ancient evolutionary history. The three major naturally occurring forms of estrogen in women are estrone (E1), estradiol (E2), and estriol (E3). Another type of estrogen called estetrol (E4) is produced only during pregnancy. Quantitatively, estrogens circulate at lower levels than androgens in both men and women.[4] While estrogen levels are significantly lower in males compared to females, estrogens nevertheless also have important physiological roles in males.[5]

Like all steroid hormones, estrogens readily diffuse across the cell membrane. Once inside the cell, they bind to and activate estrogen receptors (ERs) which in turn modulate the expression of many genes.[6] Additionally, estrogens bind to and activate rapid-signaling membrane estrogen receptors (mERs),[7][8] such as GPER (GPR30).[9]

Types and examples[edit]

Steroidal estrogens[edit]

Endogenous[edit]

The three major naturally occurring estrogens in women are estrone (E1), estradiol (E2), and estriol (E3). Estradiol is the predominant estrogen during reproductive years both in terms of absolute serum levels as well as in terms of estrogenic activity. During menopause, estrone is the predominant circulating estrogen and during pregnancy estriol is the predominant circulating estrogen in terms of serum levels. Though estriol is the most plentiful of the three estrogens it is also the weakest, whereas estradiol is the strongest with a potency of approximately 80 times that of estriol.[10] Thus, estradiol is the most important estrogen in non-pregnant females who are between the menarche and menopause stages of life. However, during pregnancy this role shifts to estriol, and in postmenopausal women estrone becomes the primary form of estrogen in the body. Another type of estrogen called estetrol (E4) is produced only during pregnancy. All of the different forms of estrogen are synthesized from androgens, specifically testosterone and androstenedione, by the enzyme aromatase.

Other endogenous estrogens, the biosyntheses of which do not involve aromatase, include 27-hydroxycholesterol, dehydroepiandrosterone (DHEA), 7-oxo-DHEA, 7α-hydroxy-DHEA, 16α-hydroxy-DHEA, 7β-hydroxyepiandrosterone, androstenedione (A4), androstenediol (A5), 3α-androstanediol, and 3β-androstanediol, and may have important endogenous functions as estrogens.[11][12] Some estrogen metabolites, such as the catechol estrogens 2-hydroxyestradiol, 2-hydroxyestrone, 4-hydroxyestradiol, and 4-hydroxyestrone, as well as 16α-hydroxyestrone, are also estrogens with varying degrees of activity.[13]

Pharmaceutical[edit]

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.[14] 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[edit]

Pharmaceutical[edit]

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.

Environmental[edit]

A range of synthetic and natural substances that possess estrogenic activity have been identified in the environment and are referred to xenoestrogens.[15]

Biological function[edit]

Reference ranges for the blood content of estradiol, the primary type of estrogen, during the menstrual cycle.[16]

The actions of estrogen are mediated by the estrogen receptor (ER), a dimeric nuclear protein that binds to DNA and controls gene expression. Like other steroid hormones, estrogen enters passively into the cell where it binds to and activates the estrogen receptor. The estrogen:ER complex binds to specific DNA sequences called a hormone response element to activate the transcription of target genes (in a study using an estrogen-dependent breast cancer cell line as model, 89 such genes were identified).[17] Since estrogen enters all cells, its actions are dependent on the presence of the ER in the cell. The ER is expressed in specific tissues including the ovary, uterus and breast. The metabolic effects of estrogen in postmenopausal women has been linked to the genetic polymorphism of the ER.[18]

While estrogens are present in both men and women, they are usually present at significantly higher levels in women of reproductive age. They promote the development of female secondary sexual characteristics, such as breasts, and are also involved in the thickening of the endometrium and other aspects of regulating the menstrual cycle. In males, estrogen regulates certain functions of the reproductive system important to the maturation of sperm[19][20][21] and may be necessary for a healthy libido.[22] Furthermore, there are several other structural changes induced by estrogen in addition to other functions.

Overview of actions[edit]

Female pubertal development[edit]

Estrogens are responsible for the development of female secondary sexual characteristics during puberty, including breast development, widening of the hips, and female fat distribution. Conversely, androgens are responsible for pubic and body hair growth, as well as acne and axillary odor.

Breast development[edit]

Estrogen, in conjunction with growth hormone (GH) and its secretory product insulin-like growth factor 1 (IGF-1), is critical in mediating breast development during puberty, as well as breast maturation during pregnancy in preparation of lactation and breastfeeding.[29][30] Estrogen is primarily and directly responsible for inducing the ductal component of breast development,[31][32][33] as well as for causing fat deposition and connective tissue growth.[31][32] It is also indirectly involved in the lobuloalveolar component, by increasing progesterone receptor expression in the breasts[31][33][34] and by inducing the secretion of prolactin.[35][36] Allowed for by estrogen, progesterone and prolactin work together to complete lobuloalveolar development during pregnancy.[32][37]

Androgens such as testosterone powerfully oppose estrogen action in the breasts, such as by reducing estrogen receptor expression in them.[38][39]

Female reproductive system[edit]

Estrogens are responsible for maturation and maintenance of the vagina and uterus, and are also involved in ovarian function, such as maturation of ovarian follicles. In addition, estrogens play an important role in regulation of gonadotropin secretion. For these reasons, estrogens are required for female fertility.

Brain and behavior[edit]

Sex drive[edit]

Estrogens are involved in sex drive in both women and men.

Cognition[edit]

Verbal memory scores are frequently used as one measure of higher level cognition. These scores vary in direct proportion to estrogen levels throughout the menstrual cycle, pregnancy, and menopause. Furthermore, estrogens when administered shortly after natural or surgical menopause prevents decreases in verbal memory. In contrast, estrogens have little effect on verbal memory if first administered years after menopause.[40] Estrogens also have positive influences on other measures of cognitive function.[41] However the effect of estrogens on cognition is not uniformly favorable and is dependent on the timing of the dose and the type of cognitive skill being measured.[42]

The protective effects of estrogens on cognition may be mediated by estrogens anti-inflammatory effects in the brain.[43] Studies have also shown that the Met allele gene and level of estrogen mediates the efficiency of prefrontal cortex dependent working memory tasks.[44][45]

Mental health[edit]

Estrogen is considered to play a significant role in women’s mental health. Sudden estrogen withdrawal, fluctuating estrogen, and periods of sustained estrogen low levels correlate with significant mood lowering. Clinical recovery from postpartum, perimenopause, and postmenopause depression has been shown to be effective after levels of estrogen were stabilized and/or restored.[46][47][48]

Compulsions in male lab mice, such as those in obsessive-compulsive disorder (OCD), may be caused by low estrogen levels. When estrogen levels were raised through the increased activity of the enzyme aromatase in male lab mice, OCD rituals were dramatically decreased. Hypothalamic protein levels in the gene COMT are enhanced by increasing estrogen levels which are believed to return mice that displayed OCD rituals to normal activity. Aromatase deficiency is ultimately suspected which is involved in the synthesis of estrogen in humans and has therapeutic implications in humans having obsessive-compulsive disorder.[49]

Local application of estrogen in the rat hippocampus has been shown to inhibit the re-uptake of serotonin. Contrarily, local application of estrogen has been shown to block the ability of fluvoxamine to slow serotonin clearance, suggesting that the same pathways which are involved in SSRI efficacy may also be affected by components of local estrogen signaling pathways.[50]

Parenthood[edit]

Studies have also found that fathers had lower levels of cortisol and testosterone but higher levels of estrogen (estradiol) compared to non-fathers.[51]

Binge eating[edit]

Estrogen may play a role in suppressing binge eating. Hormone replacement therapy using estrogen may be a possible treatment for binge eating behaviors in females. Estrogen replacement has been shown to suppress binge eating behaviors in female mice.[52] The mechanism by which estrogen replacement inhibits binge-like eating involves the replacement of serotonin (5-HT) neurons. Women exhibiting binge eating behaviors are found to have increased brain uptake of neuron 5-HT, and therefore less of the neurotransmitter serotonin in the cerebrospinal fluid.[53] Estrogen works to activate 5-HT neurons, leading to suppression of binge like eating behaviors.[52]

It is also suggested that there is an interaction between hormone levels and eating at different points in the female menstrual cycle. Research has predicted increased emotional eating during hormonal flux, which is characterized by high progesterone and estradiol levels that occur during the mid-luteal phase. It is hypothesized that these changes occur due to brain changes across the menstrual cycle that are likely a genomic effect of hormones. These effects produce menstrual cycle changes, which result in hormone release leading to behavioral changes, notably binge and emotional eating. These occur especially prominently among women who are genetically vulnerable to binge eating phenotypes.[54]

Binge eating is associated with decreased estradiol and increased progesterone.[55] Klump et al.[56] Progesterone may moderate the effects of low estradiol (such as during dysregulated eating behavior), but that this may only be true in women who have had clinically diagnosed binge episodes (BEs). Dysregulated eating is more strongly associated with such ovarian hormones in women with BEs than in women without BEs.[56]

The implantation of 17β-estradiol pellets in ovariectomized mice significantly reduced binge eating behaviors and injections of GLP-1 in ovariectomized mice decreased binge-eating behaviors.[52]

The associations between binge eating, menstrual-cycle phase and ovarian hormones correlated.[55][57][57][58]

Masculinization in rodents[edit]

In rodents, estrogens (which are locally aromatized from androgens in the brain) play an important role in psychosexual differentiation, for example, by masculinizing territorial behavior;[59] the same is not true in humans.[60] In humans, the masculinizing effects of prenatal androgens on behavior (and other tissues, with the possible exception of effects on bone) appear to act exclusively through the androgen receptor.[61] Consequently, the utility of rodent models for studying human psychosexual differentiation has been questioned.[62]

Bone/skeletal system[edit]

Estrogens are responsible for both the pubertal growth spurt, which causes an acceleration in linear growth, and epiphyseal closure, which limits height and limb length, in both females and males. In addition, estrogens are responsible for bone maturation and maintenance of bone mineral density throughout life. Due to hypoestrogenism, the risk of osteoporosis increases during menopause.

Cardiovascular system[edit]

Women suffer less from heart disease due to vasculo-protective action of estrogen which helps in preventing atherosclerosis.[63] It also helps in maintaining the delicate balance between fighting infections and protecting arteries from damage thus lowering the risk of cardiovascular disease.[64]

Immune system[edit]

Estrogen has anti-inflammatory properties and helps in mobilization of polymorphonuclear white blood cells or neutrophils.[64]

Associated conditions[edit]

Estrogens are implicated in various estrogen-dependent conditions, such as ER-positive breast cancer, as well as a number of genetic conditions involving estrogen signaling or metabolism, such as estrogen insensitivity syndrome, aromatase deficiency, and aromatase excess syndrome.

Medical uses[edit]

Hormonal contraception[edit]

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.[65][66]

Hormone replacement therapy[edit]

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).[67]

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,[68] 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.

Prostate cancer[edit]

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.[69] 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,[69] 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[edit]

High doses of potent estrogens such as diethylstilbestrol and ethinylestradiol were used in the past in the treatment of breast cancer.[70] Their effectiveness is approximately equivalent to that of antiestrogen therapy with tamoxifen or aromatase inhibitors.[70] 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.[70]

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.[71] 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.[72]

Others[edit]

Tall stature[edit]

Estrogen has been used to induce growth attenuation in tall girls.[73]

Estrogen-induced growth attenuation was used as part of the controversial Ashley Treatment to keep a developmentally disabled girl from growing to adult size.[74]

Bulimia[edit]

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.[75]

Miscellaneous[edit]

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.[76]

In humans and mice, estrogen promotes wound healing.[77]

Adverse effects[edit]

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.[78] 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).[79][80][81]

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.

Cardiovascular events[edit]

Estrogens affect liver protein synthesis and thereby influence the cardiovascular system.[82] 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).[82] 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.[82] 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).[82] 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).[83][84] 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.[85] An increase in the risk of stroke has also been associated with older high-dose oral contraceptives that are no longer used.[86]

Menopausal hormone therapy with replacement dosages of estrogens and progestogens has been associated with a significantly increased risk of cardiovascular events such as VTE.[87] However, such risks have been found to vary depending on the type of estrogen or progestogen and the route of administration.[87] The risk of VTE is increased by approximately 2-fold in women taking oral estrogen for menopausal hormone therapy.[87] 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.[82] 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.[88][87] However, these findings need to be confirmed.[87] 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).[89] In contrast to oral estrogens as a group, transdermal estradiol has not been found to increase the risk of VTE or other cardiovascular events.[87][85]

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).[90] The risk of VTE during the postpartum period is 5-fold higher than during pregnancy.[90] 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).[83] 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.[91][92] The absolute risk of VTE in pregnancy is about 0.5 to 2 in 1,000 (0.125%).[93]

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.[82] 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).[82] Transdermal estradiol has less-pronounced effects on these proteins and, in contrast to oral estradiol, reduces triglycerides.[82] 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.[82]

Approximately 95% of orally ingested estradiol is inactivated during first-pass metabolism.[84] 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.[82][94] This does not occur with parenteral estradiol.[82] In contrast to estradiol, ethinylestradiol is much more resistant to hepatic metabolism, with a mean oral bioavailability of approximately 45%,[95] and has a similar impact on hepatic protein synthesis with both oral and transdermal routes.[96]

Biochemistry[edit]

Biosynthesis[edit]

Steroidogenesis, showing estrogens at bottom right as in pink triangle.[97]

Estrogens, in females, are produced primarily by the ovaries, and during pregnancy, the placenta.[98] Follicle-stimulating hormone (FSH) stimulates the ovarian production of estrogens by the granulosa cells of the ovarian follicles and corpora lutea. Some estrogens are also produced in smaller amounts by other tissues such as the liver, adrenal glands, and the breasts. These secondary sources of estrogens are especially important in postmenopausal women. Fat cells produce estrogen as well.[99]

In females, synthesis of estrogens starts in theca interna cells in the ovary, by the synthesis of androstenedione from cholesterol. Androstenedione is a substance of weak androgenic activity which serves predominantly as a precursor for more potent androgens such as testosterone as well as estrogen. This compound crosses the basal membrane into the surrounding granulosa cells, where it is converted either immediately into estrone, or into testosterone and then estradiol in an additional step. The conversion of androstenedione to testosterone is catalyzed by 17β-hydroxysteroid dehydrogenase (17β-HSD), whereas the conversion of androstenedione and testosterone into estrone and estradiol, respectively is catalyzed by aromatase, enzymes which are both expressed in granulosa cells. In contrast, granulosa cells lack 17α-hydroxylase and 17,20-lyase, whereas theca cells express these enzymes and 17β-HSD but lack aromatase. Hence, both granulosa and theca cells are essential for the production of estrogen in the ovaries.

Estrogen levels vary through the menstrual cycle, with levels highest near the end of the follicular phase just before ovulation.

Metabolism[edit]

Estrogens are metabolized via hydroxylation by cytochrome P450 enzymes such as CYP1A1 and CYP3A4 and via conjugation by estrogen sulfotransferases (sulfation) and UDP-glucuronyltransferases (glucuronidation). In addition, estradiol is dehydrogenated by 17β-Hydroxysteroid dehydrogenase into the much less potent estrogen estrone. These reactions occur primarily in the liver, but also in other tissues.

Cosmetics[edit]

Some hair shampoos on the market include estrogens and placental extracts; others contain phytoestrogens. In 1998, there were case reports of four prepubescent African-American girls developing breasts after exposure to these shampoos.[100] In 1993, the FDA determined that not all over-the-counter topically applied hormone-containing drug products for human use are generally recognized as safe and effective and are misbranded. An accompanying proposed rule deals with cosmetics, concluding that any use of natural estrogens in a cosmetic product makes the product an unapproved new drug and that any cosmetic using the term "hormone" in the text of its labeling or in its ingredient statement makes an implied drug claim, subjecting such a product to regulatory action.[101]

In addition to being considered misbranded drugs, products claiming to contain placental extract may also be deemed to be misbranded cosmetics if the extract has been prepared from placentas from which the hormones and other biologically active substances have been removed and the extracted substance consists principally of protein. The FDA recommends that this substance be identified by a name other than "placental extract" and describing its composition more accurately because consumers associate the name "placental extract" with a therapeutic use of some biological activity.[101]

History[edit]

In 1929, Adolf Butenandt and Edward Adelbert Doisy independently isolated and purified estrone, the first estrogen to be discovered.[102] Thereafter, the pace of hormonal drug research accelerated. 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.[103] 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.[104] Ethinylestradiol was synthesized in 1938 by Hans Herloff Inhoffen and Walter Hohlweg at Schering AG in Berlin[105][106][107][108][109] and was approved by the FDA in the U.S. on June 25, 1943 and marketed by Schering as Estinyl.[110]

Micronized estradiol, via the oral route, was first evaluated in 1972,[111] and this was followed by the evaluation of vaginal and intranasal micronized estradiol in 1977.[112] Oral micronized estradiol was first approved in the United States under the brand name Estrace in 1975.[113]

Society and culture[edit]

Etymology[edit]

The name estrogen is derived from the Greek οἶστρος (oistros), literally meaning "verve or inspiration" but figuratively sexual passion or desire,[114] and the suffix -gen, meaning "producer of".

Environmental effects[edit]

Estrogens are among the wide range of endocrine-disrupting compounds (EDCs) because they have high estrogenic potency. When an EDC makes its way into the environment, it may cause male reproductive dysfunction to wildlife.[115] The estrogen excreted from farm animals makes its way into fresh water systems.[116] During the germination period of reproduction the fish are exposed to low levels of estrogen which may cause reproductive dysfunction to male fish.[117][118]

See also[edit]

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