Estradiol

Estradiol is the predominant sex hormone present in females; however, it is present in males, although at lower levels, as well. It represents the major estrogen in humans. Estradiol has not only a critical impact on reproductive and sexual functioning, but also affects other organs including the bones.

Production

During the reproductive years, most estradiol in women is produced by the granulosa cells of the ovaries. Smaller amounts of estradiol are also produced by the adrenal cortex, and (in men), by the testes. Estradiol is produced not only in the gonads: In both sexes, precursor hormones, to be specific testosterone, are converted by aromatization to estradiol. In particular, fat cells are active to convert precursors to estradiol, and will continue to do so even after menopause. Estradiol is also produced in the brain and in arterial walls.

Mechanism of action

Estradiol binds well to both estrogen receptors, ERα, and ERβ, in contrast to certain other estrogens, notably medications that preferentially act on one of these receptors. These medications are called selective estrogen receptor modulators, or SERMs. Estradiol is the most potent naturally-occurring estrogen. Recently there has been speculation about the membrane estrogen receptor ERX.

In the normal menstrual cycle, estradiol levels measure typically <50 ng/ml at menstruation, rise with follicular development (peak: 200 pg/ml), drop briefly at ovulation, and rise again during the luteal phase for a second peak. At the end of the luteal phase, estradiol levels drop to their menstrual levels unless there is a pregnancy. During pregnancy, estrogen levels, including estradiol, rise steadily toward term. The source of these estrogens is the placenta, which aromatizes prohormones produced in the fetal adrenal gland.

Effects

Female Reproduction

In the female, estradiol acts as a growth hormone for tissue of the reproductive organs, supporting the lining of the vagina, the cervical glands, the endometrium, and the lining of the fallopian tubes. It enhances growth of the myometrium. Estradiol appears necessary to maintain oocytes in the ovary. During the menstrual cycle, estradiol that is produced by the growing follicle triggers, via a positive feedback system, the hypothalamic-pituitary events that lead to the luteinizing hormone surge, inducing ovulation. In the luteal phase estradiol, in conjunction with progesterone, prepares the endometrium for implantation. During pregnancy, estradiol increases due to placental production. In baboons, blocking of estrogen production leads to pregnancy loss, suggesting that estradiol has a role in the maintenance of pregnancy. Research is investigating the role of estrogens in the process of initiation of labor.

Sexual Development

The development of secondary sex characteristics in women is driven by estrogens, to be specific, estradiol. These changes are initiated at the time of puberty, most enhanced during the reproductive years, and become less pronounced with declining estradiol support after the menopause. Thus, estradiol enhances breast development, and is responsible for changes in the body shape, affecting bones, joints, fat deposition. Fat structure and skin composition are modified by estradiol.

Male Reproduction

The effect of estradiol (and estrogens) upon male reproduction is complex. Estradiol is produced in the Sertoli cells of the testes. There is evidence that estradiol is to prevent apoptosis of male sperm cells. Several studies have noted that sperm counts have been declining in many parts of the world and it has been postulated that this may be related to estrogen exposure in the environment. Suppression of estradiol production in a subpopulation of subfertile men may improve the semen analysis. Males with sex chromosome genetic conditions such as Klinefelters Syndrome will have a higher level of estradiol.

• Bone There is ample evidence that estradiol has a profound effect on bone. Individuals without estradiol (or other estrogens) will become tall and eunuchoid as epiphysieal closure is delayed or may not take place. Bone structure is affected resulting in early osteopenia and osteoporosis. Also, women past menopause experience an accelerated loss of bone mass due to a relative estrogen deficiency.
• Liver Estradiol has complex effects on the liver. It can lead to cholestasis. It affects the production of multiple proteins including lipoproteins, binding proteins, and proteins responsible for blood clotting.
• Brain Estrogen is considered to play a significant role in women’s mental health, with links suggested between the hormone, mood and well-being. Sudden drops or fluctuations in, or long periods of sustained low levels of estrogen may be correlated with significant mood-lowering. Clinical recovery from depression postpartum, perimenopause, and postmenopause was shown to be effective after levels of estrogen were stabilized and/or restored.[7][8]
• Blood vessels Estrogen affects certain blood vessels. Improvement in arterial blood flow has been demonstrated in coronary arteries.  Estrogen softens the arterioscletic plaques and this is why there is slight increase in heart attacks in the beginning of estrogen supplementation in women over 60.
• Oncogene Estrogen is suspected to activate certain oncogenes, as it supports certain cancers, notably breast cancer and cancer of the uterine lining. In addition, there are several benign gynecologic conditions that are dependent on estrogen, such as endometriosis, leiomyomata uteri, and uterine bleeding..
• Pregnancy The effect of estradiol, together with estrone and estriol, in pregnancy is less clear. They may promote uterine blood flow, myometrial growth, sitmulate breast growth and at term, promote cervical softening and expression of myometrial oxytocin receptors.

Role in sex differentiation of the brain

One of the fascinating twists to mammalian sex differentiation is that estradiol is one of the two active metabolites of testosterone in males (the other being dihydrotestosterone), and since fetuses of both sexes are exposed to similarly high levels of maternal estradiol, this source cannot have a significant impact on prenatal sex differentiation. Estradiol cannot be transferred readily from the circulation into the brain, whereas testosterone can; thus sex differentiation can be caused by the testosterone in the brain of most male mammals, including humans, aromatizing in significant amounts into estradiol. There is also now evidence that the programming of adult male sexual behavior in animals is largely dependent on estradiol produced in the central nervous system during prenatal life and early infancy from testosterone.[10] However, it is not yet known whether this process plays a minimal or significant part in human sexual behaviors although evidence from other mammals tends to indicate that it does.

Recently, it was discovered that volumes of sexually dimorphic brain structures in phenotypical males changed to approximate those of typical female brain structures when exposed to estradiol over a period of months.[12] This would suggest that estradiol has a significant part to play in sex differentiation of the brain, both pre-natal and throughout life.

Estradiol medication

Oral preparations are not necessarily predictably absorbed and subject to a first pass through the liver, where they can be metabolized and also initiate unwanted side-effects. Thus, alternative routes of administration that bypass the liver before primary target organs are hit have been developed. Transdermal and transvaginal routes are not subject to the initial liver passage.

Hormone replacement therapy

If severe side-effects of low levels of estradiol in a woman’s blood are experienced (commonly at the beginning of menopause or after oophorectomy), hormone replacement therapy may be prescribed. Estrogen therapy may be used in treatment of infertility in women when there is a need to develop sperm-friendly cervical mucus or an appropriate uterine lining.

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