2.6.1 TYPES AND EXAMPLE
The three major naturally occurring estrogens in women are estrone (E1), estradiol (E2), and estriol (E3). Estradiol is the predominant estrogen during reproductive years both in terms of absolute serum levels as well as in terms of estrogenic activity (Files et al., 2011). During menopause, estrone is the predominant circulating estrogen and during pregnancy estriol is the predominant circulating estrogen in terms of serum levels (Files et al., 2011). Though estriol is the most plentiful of the three estrogens it is also the weakest, whereas estradiol is the strongest with a potency of approximately 80 times that of estriol (Files et al., 2011).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 (E4) is produced only during pregnancy. All of the different forms of estrogen are synthesized from androgens, specifically testosterone and androstenedione, by the enzyme aromatase (Files et al., 2011).
Minor endogenous estrogens, the biosynthesis of which do not involve aromatase, include 27-hydroxycholesterol, dehydroepiandrosterone (DHEA), 7-oxo-DHEA, 7α-hydroxy-DHEA, 16α-hydroxy-DHEA, 7β-hydroxyepiandrosterone, androstenedione (A4), androstenediol (A5), 3α-androstanediol, and 3β-androstanediol (Micevych and Kelly, 2012; Soltysik and Czekaj, 2013). Some estrogen metabolites, such as the catechol estrogens2-hydroxyestradiol, 2-hydroxyestrone, 4-hydroxyestradiol, and 4-hydroxyestrone, as well as 16α-hydroxyestrone, are also estrogens with varying degrees of activity (Baker, 2013). The biological importance of these minor estrogens is not entirely clear.
2.6.2 BIOLOGICAL FUNCTION OF ESTROGEN
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 (Bhavnani et al., 2010). 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) (Miller et al., 2013). 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 (Bhavnani et al., 2010).
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 sexual 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 (Häggström, 2014).Furthermore, there are several other structural changes induced by estrogen in addition to other functions.
2.6.3 MODE OF ACTIONS OF ESTROGEN
2.6.3.1 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 odour (Handa et al., 2012).
2.6.3.2 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 (Warnock et al., 2015). 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 (Handa et al., 2012). It is also indirectly involved in the lobuloalveolar component, by increasing progesterone receptor expression in the breasts and by inducing the secretion of prolactin (Heiman et al., 2011).Allowed for by estrogen, progesterone and prolactin work together to complete lobuloalveolar development during pregnancy (Brisky and O’Malley, 2010).
2.6.3.3 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 (Brisky and O’Malley, 2010).
