of estradiol, the primary type of estrogen, during the
menstrual cycle 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). 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 have been linked to the genetic polymorphism of the ER. While estrogens are present in both
men and
women, they are usually present at significantly higher levels in biological females of reproductive age. They promote the development of female
secondary sexual characteristics, such as
breasts, darkening and enlargement of
nipples, and 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 and may be necessary for a healthy
libido.
Overview of actions • 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). • Reduce
bone resorption, increase bone formation • In mice, estrogen has been shown to restore the proportion of type IIX muscle fibers to over 40% following an ovariectomy. • 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). •
Estradiol also regulates energy expenditure, body weight
homeostasis, and seems to have much stronger anti-obesity effects than testosterone in general. • Inhibition of
ferroptosis by hydroxyoestradiol derivatives. • Other structural • Maintenance of vessels and skin •
Protein synthesis • Increase
hepatic production of
binding proteins • Increase production of the hepatokine
adropin. • Suppress the transcription of
ether-lipid pathway proteins. • Estrogen is associated with
edema, including facial and abdominal swelling. •
Melanin • Estrogen is known to cause darkening of skin, especially in the face and
areolae. 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". Estrogen may explain why women have darker eyes than men, and also a lower risk of skin cancer than men; a European study found that women generally have darker skin than men. •
Lung function • Promotes lung function by supporting
alveoli (in rodents but probably in humans). • Kidney function • Protects from
acute kidney injury in females. This behavior is required for sexual receptivity in these mammals and is regulated by the
ventromedial nucleus of the
hypothalamus. •
Sex drive is dependent on
androgen levels only in the presence of estrogen. 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).
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.
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. Estrogen is primarily and directly responsible for inducing the ductal component of breast development, as well as for causing
fat deposition and
connective tissue growth. and by inducing the secretion of
prolactin. Allowed for by estrogen,
progesterone and prolactin work together to complete lobuloalveolar development during pregnancy.
Androgens such as testosterone powerfully oppose estrogen action in the breasts, such as by reducing
estrogen receptor expression in them.
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. 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 Sex drive Estrogens are involved in
libido (sex drive) in both women and men.
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. Estrogens also have positive influences on other measures of cognitive function. 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. The protective effects of estrogens on cognition may be mediated by estrogen's anti-inflammatory effects in the brain. Studies have also shown that the Met allele gene and level of estrogen mediates the efficiency of
prefrontal cortex dependent working memory tasks. Researchers have urged for further research to illuminate the role of estrogen and its potential for improvement on cognitive function.
Mental health 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 a significant lowering of mood. Clinical recovery from
postpartum,
perimenopause, and
postmenopause depression has been shown to be effective after levels of estrogen were stabilized and/or restored.
Menstrual exacerbation (including menstrual psychosis) is typically triggered by low estrogen levels, and is often mistaken for
premenstrual dysphoric disorder. 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. 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.
Parenthood Studies have also found that fathers had lower levels of cortisol and testosterone but higher levels of estrogen (estradiol) than did non-fathers.
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. 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. Estrogen works to activate 5-HT neurons, leading to suppression of binge like eating behaviors. Binge eating is associated with decreased estradiol and increased progesterone. Klump et al. 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.
Masculinization in rodents 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; the same is not true in humans. 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. Consequently, the utility of rodent models for studying human psychosexual differentiation has been questioned.
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. It also helps in maintaining the delicate balance between fighting infections and protecting arteries from damage thus lowering the risk of cardiovascular disease. During
pregnancy, high levels of estrogens increase
coagulation and the risk of
venous thromboembolism. Estrogen has been shown to upregulate the
peptide hormone adropin. 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. 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.
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. 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. 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. ==Biochemistry==