Estrogen

• Structural
  • Mediate formation of female secondary sex characteristics
  • Accelerate metabolism
  • Increase fat store
  • Stimulate endometrial growth
  • Increase uterine growth
  • Increase vaginal lubrication
  • Thicken the vaginal wall
  • Maintenance of vessel and skin
  • Reduce bone resorption, increase bone formation
• Protein synthesis
  • Increase hepatic production of binding proteins
• Coagulation
  • Increase circulating level of factors 2, 7, 9, 10, plasminogen
  • Decrease antithrombin III
  • Increase platelet adhesiveness
  • Increase vWF (estrogen -> Angiotensin II -> Vasopressin)
  • Increase PAI-1 and PAI-2 also through Angiotensin II
• Lipid
  • Increase HDL, triglyceride
  • Decrease LDL, fat deposition
• Fluid balance
  • Salt (sodium) and water retention
  • Increase cortisol, SHBG
• Gastrointestinal tract
  • Reduce bowel motility
  • Increase cholesterol in bile
• Melanin
  • Increase pheomelanin, reduce eumelanin
• Cancer
  • Support hormone-sensitive breast cancers (see section below)
• Lung function
  • Promotes lung function by supporting alveoli (in rodents but probably in humans).[21]
• Uterus lining
  • Estrogen together with progesterone promotes and maintains the uterus lining in preparation for implantation of fertilized egg and maintenance of uterus function during gestation period, also upregulates oxytocin receptor in myometrium
• Ovulation
  • Surge in estrogen level induces the release of luteinizing hormone, which then triggers ovulation by releasing the egg from the Graafian follicle in the ovary.
• Sexual behavior
  • Promotes sexual receptivity in estrus,[22] and induces lordosis behavior.[23] In non-human mammals, it also induces estrus (in heat) prior to ovulation, which also induces lordosis behavior. Female non-human mammals are not sexually receptive without the estrogen surge, i.e., they have no mating desire when not in estrus.
  • Regulates the stereotypical sexual receptivity behavior; this lordosis behavior is estrogen-dependent, which is regulated by the ventromedial nucleus of the hypothalamus.[24]
  • Sex drive is dependent on androgen levels[25] only in the presence of estrogen, but without estrogen, free testosterone level actually decreases sexual desire (instead of increases sex drive), as demonstrated for those women who have hypoactive sexual desire disorder, and the sexual desire in these women can be restored by administration of estrogen (using oral contraceptive).[26] In non-human mammals, mating desire is triggered by estrogen surge in estrus.

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.

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.[27][28] Estrogen is primarily and directly responsible for inducing the ductal component of breast development,[29][30][31] as well as for causing fat deposition and connective tissue growth.[29][30] It is also indirectly involved in the lobuloalveolar component, by increasing progesterone receptor expression in the breasts[29][31][32] and by inducing the secretion of prolactin.[33][34] Allowed for by estrogen, progesterone and prolactin work together to complete lobuloalveolar development during pregnancy.[30][35]

Androgens such as testosterone powerfully oppose estrogen action in the breasts, such as by reducing estrogen receptor expression in them.[36][37]

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.

Estrogen regulated DNA repair mechanisms in the brain have neuroprotective effects.[38] Estrogen regulates the transcription of DNA base excision repair genes as well as the translocation of the base excision repair enzymes between different subcellular compartments.

Estrogens are involved in libido (sex drive) in both women and men.

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.[39] Estrogens also have positive influences on other measures of cognitive function.[40] 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.[41]

The protective effects of estrogens on cognition may be mediated by estrogen's anti-inflammatory effects in the brain.[42] Studies have also shown that the Met allele gene and level of estrogen mediates the efficiency of prefrontal cortex dependent working memory tasks.[43][44]

Estrogen is considered to play a significant role in women's mental health. Sudden estrogen withdrawal, fluctuating estrogen, and periods of sustained low estrogen 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.[45][46][47] Menstrual exacerbation (including menstrual psychosis) is typically triggered by low estrogen levels,[48] and is often mistaken for premenstrual dysphoric disorder.[49]

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.[50]

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.[51]

Studies have also found that fathers had lower levels of cortisol and testosterone but higher levels of estrogen (estradiol) compared to non-fathers.[52]

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.[53] 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.[54] Estrogen works to activate 5-HT neurons, leading to suppression of binge like eating behaviors.[53]

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.[55]

Binge eating is associated with decreased estradiol and increased progesterone.[56] Klump et al.[57] 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.[57]

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.[53]

The associations between binge eating, menstrual-cycle phase and ovarian hormones correlated.[56][58][58][59]

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;[60] the same is not true in humans.[61] 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.[62] Consequently, the utility of rodent models for studying human psychosexual differentiation has been questioned.[63]

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.

Women suffer less from heart disease due to vasculo-protective action of estrogen which helps in preventing atherosclerosis.[64] It also helps in maintaining the delicate balance between fighting infections and protecting arteries from damage thus lowering the risk of cardiovascular disease.[65] During pregnancy, high levels of estrogens increase coagulation and the risk of venous thromboembolism.

Estrogen has anti-inflammatory properties and helps in mobilization of polymorphonuclear white blood cells or neutrophils.[65]

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.

Steroidogenesis, showing estrogens at bottom right as in pink triangle.[67]

Estrogens, in females, are produced primarily by the ovaries, and during pregnancy, the placenta.[68] 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, pancreas, bone, adrenal glands, skin, brain, adipose tissue,[69] and the breasts.[70] These secondary sources of estrogens are especially important in postmenopausal women.[71] The pathway of estrogen biosynthesis in extragonadal tissues is different. These tissues are not able to synthesize C19 steroids, and therefore depend on C19 supplies from other tissues[71] and the level of aromatase.[72]

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.

Note that in males, estrogen is also produced by the Sertoli cells when FSH binds to their FSH receptors.

Estrogens are plasma protein bound to albumin and/or sex hormone-binding globulin in the circulation.

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.

Estrogen metabolism in humans Estradiol Estrone sulfate Estrone glucuronide 2-Hydroxyestrone Estrone 4-Hydroxyestrone 2-Methoxyestrone 16α-Hydroxyestrone 4-Methoxyestrone 17-Epiestriol Estriol 16-Epiestriol 17β-HSD EST STS UGT1A3 UGT1A9 CYP450 CYP450 COMT CYP450 COMT unidentified 17β-HSD unidentified Description: The metabolic pathways involved in the metabolism of estradiol and other natural estrogens (e.g., estrone, estriol) in humans. In addition to the metabolic transformations shown in the diagram, conjugation (e.g., sulfation and glucuronidation) occurs in the case of estradiol and metabolites of estradiol that have one or more available hydroxyl (–OH) groups. Sources: See template page.

Estrogens are excreted primarily by the kidneys as conjugates via the urine.

The name estrogen is derived from the Greek οἶστρος (oistros), literally meaning "verve or inspiration" but figuratively sexual passion or desire,[78] and the suffix -gen, meaning "producer of".

A range of synthetic and natural substances that possess estrogenic activity have been identified in the environment and are referred to xenoestrogens.[79]

• Synthetic substances such as bisphenol A as well as metalloestrogens (e.g., cadmium).
• Plant products with estrogenic activity are called phytoestrogens (e.g., coumestrol, daidzein, genistein, miroestrol).
• Those produced by fungi are known as mycoestrogens (e.g., zearalenone).

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.[80] The estrogen excreted from farm animals makes its way into fresh water systems.[81] During the germination period of reproduction the fish are exposed to low levels of estrogen which may cause reproductive dysfunction to male fish.[82][83]

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.[84] 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.[85]

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.[85]