Estrogen

Main article: hormone
Estradiol. Note one hydroxyl group attached to the D ring. The 'di' refers both to this hydroxyl and the one on the A ring (leftmost).
Estriol. Note two hydroxyl (-OH) groups attached to the D ring (rightmost ring).
Estrone. Note the ketone (=O) group attached to the D ring.

Estrogen or oestrogen (see spelling differences) is the primary female sex hormone and is responsible for 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 steroid 17β-estradiol is the most potent and prevalent endogenous estrogen, although several metabolites of estradiol also have estrogenic hormonal activity. Synthetic estrogens are used as part of some oral contraceptives, in estrogen replacement therapy for postmenopausal women, and in hormone replacement therapy for trans women.

The name estrogen comes from the Greek οἶστρος (oistros), literally meaning "verve or inspiration" but figuratively sexual passion or desire,[2] and the suffix -gen, meaning "producer of".

Estrogens are synthesized in all vertebrates[3] as well as some insects.[4] 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.[5] While estrogen levels are significantly lower in males compared to females, estrogens nevertheless also have important physiological roles in males.[6]

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.[7] Additionally, estrogens bind to and activate rapid-signaling membrane estrogen receptors (mERs),[8][9] such as GPER (GPR30).[10]

Types

Steroidal

Endogenous

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.[11] 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, which are notably not biosynthesized by aromatase, include 27-hydroxycholesterol, dehydroepiandrosterone (DHEA), 7-oxo-DHEA, 7α-hydroxy-DHEA, 16α-hydroxy-DHEA, 7β-hydroxyepiandrosterone, Δ4-androstenedione, Δ5-androstenediol, 3α-androstanediol, and 3β-androstanediol, and have important endogenous functions as estrogens.[12][13]

Some metabolites of estrone, such as 2-hydroxyestrone and 16-hydroxyestrone, are also weak estrogens.

Pharmaceuticals

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.

A variety of synthetic estrogen esters, such as estradiol cypionate, estradiol valerate, estradiol acetate, 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.

Ethinyl estradiol (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 various synthetic anabolic steroids.

DHEA is available over-the-counter as a dietary supplement, though it is not very estrogenic.

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

Non-steroidal

Diethylstilbestrol is a non-steroidal 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 non-steroidal estrogens structurally-distinct from the stilbestrols that have also been used clinically.

A range of synthetic and natural substances have been identified in the environment that possess estrogenic activity.[14]

Unlike estrogens produced by mammals, these substances are not necessarily steroids.

Antiestrogens

Main article: Antiestrogen

Antiestrogens are antagonists of the estrogen receptor (ER). Selective estrogen receptor modulators (SERMs) are partial agonists of the ER, and have estrogenic and antiestrogenic effects in different tissues. Examples of SERMs include tamoxifen, clomifene, and raloxifene. Fulvestrant is a silent antagonist of the ER.

Biosynthesis

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

Estrogens, in females, are produced primarily by the ovaries, and during pregnancy, the placenta. 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.[15]

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.

Function

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).[16] 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.[17]

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[18][19][20] and may be necessary for a healthy libido.[21] Furthermore, there are several other structural changes induced by estrogen in addition to other functions.

Fetal development

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;[28] the same is not true in humans.[29] 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.[30] Consequently, the utility of rodent models for studying human psychosexual differentiation has been questioned.[31]

Breast development

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.[32][33] Estrogen is primarily and directly responsible for inducing the ductal component of breast development,[34][35][36] as well as for causing fat deposition and connective tissue growth.[34][35] It is also indirectly involved in the lobuloalveolar component, by increasing progesterone receptor expression in the breasts[34][36][37] and by inducing the secretion of prolactin.[38][39] Allowed for by estrogen, progesterone and prolactin work together to complete lobuloalveolar development during pregnancy.[35][40]

Androgens such as testosterone powerfully oppose estrogen action in the breasts, such as by reducing estrogen receptor expression in them.[41][42]

Heart disease

Women suffer less from heart disease due to vasculo-protective action of estrogen which helps in preventing atherosclerosis.[43] It also helps in maintaining the delicate balance between fighting infections and protecting arteries from damage thus lowering the risk of cardiovascular disease.[44]

Immunological role

Estrogen has anti-inflammatory properties and helps in mobilization of polymorphonuclear white blood cells or neutrophils.[44]

Cognition

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.[45] Estrogens also have positive influences on other measures of cognitive function.[46] 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.[47]

The protective effects of estrogens on cognition may be mediated by estrogens anti-inflammatory effects in the brain.[48]

Mental health

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.[49][50][51]

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.[52]

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.[53]

Binge eating

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.[54] 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.[55] Estrogen works to activate 5-HT neurons, leading to suppression of binge like eating behaviors.[54]

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.[56]

Binge eating is associated with decreased estradiol and increased progesterone.[57] Klump et al.[58] 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.[58]

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.[54]

The associations between binge eating, menstrual-cycle phase and ovarian hormones correlated.[57][59][59][60]

Medical applications

Oral contraceptives

Since estrogen circulating in the blood can negatively feed-back to reduce circulating levels of FSH and LH, most oral contraceptives contain a synthetic estrogen, along with a synthetic progestin. Even in men, the major hormone involved in LH feedback is estradiol, not testosterone.[61][62]

Hormone replacement therapy

Estrogen and other hormones are given to postmenopausal women in order to prevent osteoporosis as well as treat the symptoms of menopause such as hot flushes, 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).[63]

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,[64] 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, castration, or primary ovarian failure), amenorrhea, dysmenorrhea, and oligomenorrhea. Estrogens can also be used to suppress lactation after child birth.

Breast cancer

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. Suppression of production of estrogen in the body is a treatment for these cancers.

Research suggests the common table mushroom has anti-aromatase[65] properties and therefore possible anti-estrogen activity. In 2009, a case-control study of the eating habits of 2,018 women in southeast China revealed that women who consumed greater than 10 grams of fresh mushrooms or greater than 4 grams of dried mushrooms per day had an approximately 50% lower incidence of breast cancer. Chinese women who consumed mushrooms and green tea had a 90% lower incidence of breast cancer.[66] However the study was relatively small (2,018 patients participating) and limited to Chinese women of southeast China.

Hormone-receptor-positive breast cancers are treated with drugs which suppress production or interfere with the action of estrogen in the body.[67] 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.[68]

Prostate cancer

Under certain circumstances, estrogen may also be used in males for treatment of prostate cancer.[69]

Miscellaneous

In humans and mice, estrogen promotes wound healing.[70]

At one time, estrogen was used to induce growth attenuation in tall girls.[71] Recently, estrogen-induced growth attenuation was used as part of the controversial Ashley Treatment to keep a developmentally disabled girl from growing to adult size.[72]

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.[73]

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.[74]

Health risks and warning labels

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.[75]

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).[76][77][78]

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, on January 8, 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.

Cosmetics

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.[79] 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.[80]

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.[80]

History

In 1929 Adolf Butenandt and Edward Adelbert Doisy independently isolated and determined the structure of estrogen.[81] 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 are not water-soluble and cannot be given orally, but the urine was found to contain estriol glucuronide, which is water-soluble 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, formulated a similar product as Emmenin 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.[82]

Environmental effects

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.[83] The estrogen excreted from farm animals makes its way into fresh water systems.[84] During the germination period of reproduction the fish are exposed to low levels of estrogen which may cause reproductive dysfunction to male fish.[85][86]

See also

References

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