Estrogen


Estrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal activity: estrone, estradiol, and estriol. Estradiol, an estrane, is the most potent and prevalent. Another estrogen called estetrol is produced only during pregnancy.
Estrogens are synthesized in all vertebrates and some insects. Quantitatively, estrogens circulate at lower levels than androgens in both men and women. While estrogen levels are significantly lower in males than in females, estrogens nevertheless have important physiological roles in males.
Like all steroid hormones, estrogens readily diffuse across the cell membrane. Once inside the cell, they bind to and activate estrogen receptors which in turn modulate the expression of many genes. Additionally, estrogens bind to and activate rapid-signaling membrane estrogen receptors, such as GPER.
In addition to their role as natural hormones, estrogens are used as medications, for instance in menopausal hormone therapy, hormonal birth control and feminizing hormone therapy for transgender women, intersex people, and nonbinary people.
Synthetic and natural estrogens have been found in the environment and are referred to as xenoestrogens. Estrogens are among the wide range of endocrine-disrupting compounds and can cause health issues and reproductive dysfunction in both wildlife and humans.

Types and examples

The four major naturally occurring estrogens in women are estrone, estradiol, estriol, and estetrol. Estradiol is the predominant estrogen during reproductive years both in terms of absolute serum levels as well as in terms of estrogenic activity. During menopause, estrone is the predominant circulating estrogen and during pregnancy estriol is the predominant circulating estrogen in terms of serum levels. Given by subcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol. Thus, estradiol is the most important estrogen in non-pregnant females who are between the menarche and menopause stages of life. However, during pregnancy this role shifts to estriol, and in postmenopausal women estrone becomes the primary form of estrogen in the body. Another type of estrogen called estetrol is produced only during pregnancy. All of the different forms of estrogen are synthesized from androgens, specifically testosterone and androstenedione, by the enzyme aromatase.
Minor endogenous estrogens, the biosyntheses of which do not involve aromatase, include 27-hydroxycholesterol, dehydroepiandrosterone, 7-oxo-DHEA, 7α-hydroxy-DHEA, 16α-hydroxy-DHEA, 7β-hydroxyepiandrosterone, androstenedione, androstenediol, 3α-androstanediol, and 3β-androstanediol. Some estrogen metabolites, such as the catechol estrogens 2-hydroxyestradiol, 2-hydroxyestrone, 4-hydroxyestradiol, and 4-hydroxyestrone, as well as 16α-hydroxyestrone, are also estrogens with varying degrees of activity. The biological importance of these minor estrogens is not entirely clear.

Biological function

The actions of estrogen are mediated by the estrogen receptor, 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. 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

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 and its secretory product insulin-like growth factor 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. It is also indirectly involved in the lobuloalveolar component, by increasing progesterone receptor expression in the breasts 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.