Estrogen is a hormone that play a role in both the male and female reproductive systems. In females, it contributes to reproductive and breast health, among other functions. Steroid hormones play essential roles in the reproductive biology of vertebrates. Estrogen exercises its effect through estrogen receptors and is not only a female reproductive hormone but acts virtually in all vertebrates, including fish, and is involved in the physiological and pathological states in all males and females. Estrogen has been implicated in circulatory and central nervous systems as well as the reproductive system.
Estrogen is a sex hormone that’s necessary for maintaining sexual and reproductive health. Estrogen levels naturally fluctuate during menstrual cycle and decline during menopause. Consistently high or low levels of estrogen may signal a condition that requires attention.
It was established in the year 1900 that ovaries control female reproductive function through hormonal mechanism. Allen and Doisy (1923) found that an alcoholic extract of ovaries was capable of inducing estrus in rodents, and devised a simple bioassay method. The active principle estradiol was obtained in pure form in 1929 and soon its chemical structure was worked out.
Estradiol is the major estrogen secreted by the ovary. It is synthesized in the graafian follicle, corpus luteum and placenta from cholesterol. Estrogens and estrogen-like molecules can modify the biology of several cell types. Estrogen receptors alpha (ERA) and beta (ERB) belong to the so-called classical family of estrogen receptors, while the G protein-coupled estrogen receptor 1 (GPER-1) represents a non-classical estrogen receptor mainly located in the plasma membrane.
Estradiol is rapidly oxidized in liver to estrone which is hydroxylated to form estriol. All three are active and circulate in blood, but estradiol is the most potent estrogen. Estrone and estriol have much lower affinity for the estrogen receptor (ER) than estradiol. Small quantity of estradiol is produced in human males also from aromatization of testosterone in the testes and extraglandular tissues. In the mare, large quantity of equilin is produced which has 1/5 estrogenic potency of estradiol. Natural estrogens are inactive orally and have a short duration of action due to rapid metabolism in liver.
Estradiol is converted to estrone and vice versa in liver. Estriol is derived from estrone. All three are conjugated with glucuronic acid and sulfate, which are excreted in urine and bile. Considerable enterohepatic circulation occurs due to deconjugation in intestines and reabsorption and ultimately disposal occurs mostly in urine.
Estrogens bind to specific receptors located normally within the nucleus of target cells and produce effects by regulating protein synthesis. Estrogen receptors (ERS) have been demonstrated in female sex organs, breast, pituitary, liver, bone, blood vessels, heart, CNS and in certain hormone responsive breast carcinoma cells. The estrogen receptor is analogous to other steroid receptors: agonist binding to the ligand binding domain brings about receptor dimerization and interaction with estrogen response elements' (ERES) of target genes. Gene transcription is promoted through certain coactivator proteins. On binding an estrogen antagonist the receptor assumes a different conformation and interacts with other corepressor proteins inhibiting gene transcription.
Estrogens produced at puberty cause growth of breasts proliferation of ducts and stroma, accumulation of fat. The pubic and axillary hair appear, feminine body contours and behaviour are influenced.
The estrogens bring about pubertal changes in the female including growth of uterus, fallopian tubes and vagina. Vaginal epithelium gets thickened, stratified and cornified. They are responsible for the proliferation of endometrium in the preovulatory phase, and it is only in concert with estrogens that progesterone brings about secretory changes. In the absence of progesterone withdrawal of estrogens alone produces menstruation. If modest doses of estrogen are given continuously without added progesterone-endometrium hypertrophies and menstruation is delayed, but breakthrough bleeding occurs at irregular intervals. However, the normal event which triggers menstruation is progesterone withdrawal. The progesterone withdrawal bleeding cannot be suppressed even by high doses of estrogens.
Estrogens augment rhythmic contractions of the fallopian tubes and uterus, and induce a watery alkaline secretion from the cervix. This is favourable to sperm penetration. Deficiency of estrogens responsible for atrophic changes in the female Reproductive tract that occur after menopause.
Estrogen is important in maintaining bone mass primarily by retarding bone resorption Osteoclast pit formation is inhibited and there is increased expression of bone matrix proteins such as osteonectin, osteocalcin, collagen and alkaline phosphatase. It promotes positive calcium balance, partly by inducing renal hydroxylase enzyme which generates the active form of Vitamin D3.
Estrogens decrease plasma LDL cholesterol while HDL and triglyceride levels are raised. The raised HDL: LDL ratio is probably responsible for rarity of atherosclerosis in premenopausal women. However, blood coagulability is increased due to induction of synthesis of clotting factors (factors II, VII, IX and X). Fibrinolytic activity in plasma also tends to increase due to lowering of plasminogen-activator inhibitor-1 (PAI-1). The daily secretion of estrogens in menstruating women varies from 10-100 µg depending on the phase of the cycle.
A growing number of studies indicate that estrogen therapy has a broad spectrum of beneficial effects in post-menopausal women, menopause can be understood as a physiological event in women characterized by the end of menstrual cycles and the depletion of ovarian follicles. The higher life expectancies in the current population imply that more than half of women's life passes in the post-menopausal stage. During this period, the morbidity and mortality patterns change, with chronic diseases becoming more relevant, such as malignant neoplasms, atherosclerosis, osteoporosis, arteriopathies, and neuro degenerative diseases.
The use of hormone replacement therapy dates back to the 1960s; however, after the appearance of prospective randomized studies that indicated a increase in the incidence of breast cancer, the establishment of this therapy has been adjusted to the presence of certain risk factors, symptoms, and the evolution of patients. Nowadays, hormone replacement therapy supplements women with estrogens (mainly estradiol) or estrogens and gestagens during the menopausal transition.