Overview of actions

This section is in list format but may read better as prose. (October 2019)

• Musculoskeletal
  • Anabolic: Increases muscle mass and strength, speed of muscle regeneration, and bone density, increased sensitivity to exercise, protection against muscle damage, stronger collagen synthesis, increases the collagen content of connective tissues, tendons, and ligaments, but also decreases stiffness of tendons and ligaments (especially during menstruation). Decreased stiffness of tendons gives women much lower predisposition to muscle strains but soft ligaments are much more prone to injuries (ACL tears are 2-8x more common among women than men).^{[26][27][28][29]}
  • Reduce bone resorption, increase bone formation
  • In mice, estrogen has been shown to increase the proportion of the fastest-twitch (type IIX) muscle fibers by over 40%.^[30]
• Metabolic
  • Anti-inflammatory properties
  • Accelerate metabolism
  • Gynoid fat distribution: increased fat storage or estrogenic fat in some body parts such as breasts, buttocks, and legs but decreased abdominal and visceral fat (androgenic obesity).^[31][32][33]
  • Estradiol also regulates energy expenditure, body weight homeostasis, and seems to have much stronger anti-obesity effects than testosterone in general.^[34]
• Other structural
  • Maintenance of vessels and skin
• Protein synthesis
  • Increase hepatic production of binding proteins
  • Increase production of the hepatokine adropin.^[35]
• 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
  • Estrogen is known to cause darkening of skin, especially in the face and areolae.^[36] Pale skinned women will develop browner and yellower skin during pregnancy, as a result of the increase of estrogen, known as the "mask of pregnancy".^[37]
• Cancer
  • Support hormone-sensitive breast cancers (see section below)
• Lung function
  • Promotes lung function by supporting alveoli (in rodents but probably in humans).^[38]
• Sexual
  • Mediate formation of female secondary sex characteristics
  • Stimulate endometrial growth
  • Increase uterine growth
  • Increase vaginal lubrication
  • Thicken the vaginal wall
• 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
  • Estrogen is required for female mammals to engage in lordosis behavior during estrus (when animals are "in heat").^[39][40] This behavior is required for sexual receptivity in these mammals and is regulated by the ventromedial nucleus of the hypothalamus.^[41]
  • Sex drive is dependent on androgen levels^[42] only in the presence of estrogen, but without estrogen, free testosterone level actually decreases sexual desire (instead of increasing 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).^[43]

Female pubertal development

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.

Female reproductive system

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.

Neuroprotection and DNA repair

Estrogen regulated DNA repair mechanisms in the brain have neuroprotective effects.^[55] 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.

Brain and behavior

Skeletal system

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

Women are less impacted by heart disease due to vasculo-protective action of estrogen which helps in preventing atherosclerosis.^[82] It also helps in maintaining the delicate balance between fighting infections and protecting arteries from damage thus lowering the risk of cardiovascular disease.^[83] During pregnancy, high levels of estrogens increase coagulation and the risk of venous thromboembolism. Estrogen has been shown to upregulate the peptide hormone adropin.^[35]

Immune system

The effect of estrogen on the immune system is in general described as Th2 favoring, rather than suppressive, as is the case of the effect of male sex hormone - testosterone.^[85] Indeed, women respond better to vaccines, infections and are generally less likely to develop cancer, the tradeoff of this is that they are more likely to develop an autoimmune disease.^[86] The Th2 shift manifests itself in a decrease of cellular immunity and increase in humoral immunity (antibody production) shifts it from cellular to humoral by downregulating cell-mediated immunity and enhancing Th2 immune response by stimulating IL-4 production and Th2 differentiation.^[85][87] Type 1 and type 17 immune responses are downregulated, likely to be at least partially due to IL-4, which inhibits Th1. Effect of estrogen on different immune cells' cell types is in line with its Th2 bias. Activity of basophils, eosinophils, M2 macrophages and is enhanced, whereas activity of NK cells is downregulated. Conventional dendritic cells are biased towards Th2 under the influence of estrogen, whereas plasmacytoid dendritic cells, key players in antiviral defence, have increased IFN-g secretion.^[87] Estrogen also influences B cells by increasing their survival, proliferation, differentiation and function, which corresponds with higher antibody and B cell count generally detected in women.^[88]

On a molecular level estrogen induces the above-mentioned effects on cell via acting on intracellular receptors termed ER α and ER β, which upon ligation form either homo or heterodimers. The genetic and nongenetic targets of the receptors differ between homo and heterodimers.^[89] Ligation of these receptors allows them to translocate to the nucleus and act as transcription factors either by binding estrogen response elements (ERE) on DNA or binding DNA together with other transcriptional factors e.g. Nf-kB or AP-1, both of which result in RNA polymerase recruitment and further chromatin remodelation.^[89] A non-transcriptional response to oestrogen stimulation was also documented (termed membrane-initiated steroid signalling, MISS). This pathway stimulates the ERK and PI3K/AKT pathways, which are known to increase cellular proliferation and affect chromatin remodelation.^[89]

Associated conditions

Researchers have implicated estrogens 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.

High estrogen can amplify stress-hormone responses in stressful situations.^[90]

Biosynthesis

Estrogens, in females, are produced primarily by the ovaries, and during pregnancy, the placenta.^[92] 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,^[93] and the breasts.^[94] These secondary sources of estrogens are especially important in postmenopausal women.^[95] 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^[95] and the level of aromatase.^[96]

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.

Distribution

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

Metabolism

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.

v t e 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.

Excretion

Estrogens are inactivated primarily by the kidneys and liver and excreted via the gastrointestinal tract^[97] in the form of conjugates, found in feces, bile, and urine.^[98]

Etymology

The name estrogen is derived from the Greek οἶστρος (oîstros), literally meaning "verve" or "inspiration" but figuratively sexual passion or desire,^[104] and the suffix -gen, meaning "producer of".

Environment

A range of synthetic and natural substances that possess estrogenic activity have been identified in the environment and are referred to xenoestrogens.^[105]

• 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 and humans.^[12][13] The estrogen excreted from farm animals makes its way into fresh water systems.^[106][107] During the germination period of reproduction the fish are exposed to low levels of estrogen which may cause reproductive dysfunction to male fish.^[108][109]

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.^[110] 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.^[111]

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.^[111]