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Types of estrogen
The three major naturally occurring estrogens in women are estradiol, estriol, and estrone. In the body these are all produced from androgens through actions of enzymes.
From menarche to menopause the primary estrogen is 17β-estradiol. In postmenopausal women more estrone is present than estradiol.
Estradiol is produced from testosterone and estrone from androstenedione.
Estrone is weaker than estradiol.
Premarin, a commonly prescribed estrogenic drug, contains the steroidal estrogens equilin and equilenin, in addition to estrone sulfate. A range of synthetic and natural substances have been identified that also possess estrogenic activity. Synthetic substances of this kind are known as xenoestrogens, plant products with estrogenic activity are called phytoestrogens, and those produced by fungi are known as mycoestrogens. Unlike estrogens produced by mammals, these substances are not necessarily steroids.
Testosterone is synthesized during steroidogenesis, with cholesterol as the starting molecule.
Estrogen is produced primarily by developing follicles in the ovaries, the corpus luteum, and the placenta. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) stimulate the production of estrogen in the ovaries. Some estrogens are also produced in smaller amounts by other tissues such as the liver, adrenal glands, and the breasts. These secondary sources of estrogen are especially important in postmenopausal women.
Synthesis of estrogens starts in theca interna cells in the ovary, by the synthesis of androstenedione from cholesterol. Androstenedione is a substance of moderate androgenic activity. This compound crosses the basal membrane into the surrounding granulosa cells, where it is converted to estrone or estradiol, either immediately or through testosterone. The conversion of testosterone to estradiol, and of androstenedione to estrone, is catalyzed by the enzyme aromatase.
Estradiol levels vary through the menstrual cycle, with levels highest just before ovulation.
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 sex 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 and may be necessary for a healthy libido. Furthermore, there are several other structural changes induced by estrogen, in addition to other functions.
- promote formation of female secondary sex characteristics
- decelerate height growth
- accelerate metabolism (burn fat)
- reduce muscle mass
- stimulate endometrial growth
- increase uterine growth
- maintenance of vessel and skin
- reduce bone resorption, increase bone formation
- morphic change (endomorphic -> mesomorphic -> ectomorphic)
- protein synthesis
- increase hepatic production of binding proteins
- increase circulating level of factors 2, 7, 9, 10, antithrombin III, plasminogen
- increase platelet adhesiveness
- increase HDL, triglyceride, height growth
- decrease LDL, fat depositition
- Fluid balance
- salt (sodium) and water retention
- increase growth hormone
- increase cortisol, SHBG
- gastrointestinal tract
- reduce bowel motility
- increase cholesterol in bile
- increase pheomelanin, reduce eumelanin
- support hormone-sensitive breast cancers (see section below)
- Lung function
- promotes lung function by supporting alveoli (in rodents but probably in humans).
- Sexual desire is dependent on androgen levels rather than estrogen levels.
Role in 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 in the body of estrogen is a treatment for these cancers.
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.
As more fully discussed in the article on 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 flashes, 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).
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 reduces the incidence of cardiovascular disease. Estrogen has 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, and transdermal oestrogens 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.
Hormone-receptor-positive breast cancers are treated with drugs which suppress production in the body of estrogen. 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 effects of estrogen and are used as an alternative to hormone therapy.
In humans and mice, estrogen promotes wound healing.
At one time, estrogen was used to induce growth attenuation in tall girls. 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.
Under certain circumstances, estrogen may also be used in males for treatment of prostate cancer.
Most recently, estrogen has been used in experimental research as a way to treat patients 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.
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.