Estradiol the predominant circulating estrogen
Estradiol, the predominant circulating estrogen in humans, it is mainly secreted by the granulosa cells of the ovarian follicles, and the corpora lutea, by the mechanisms indicated above. On the other hand, estretrol is synthesized exclusively during pregnancy by the fetal liver and reaches maternal circulation through the placenta (Coelingh Bennink et al., 2008; Holinka et al., 2008). Estriol, which is also primarily synthesized during pregnancy, is almost exclusively produced by the placenta. To produce estriol, dietary cholesterol is converted to pregnenolone and progesterone in the placenta, and these steroids are further metabolized to DHEA and DHEA-sulfate (DHEA-S) in the fetal adrenal glands. DHEA-S is later hydroxylated to 16α-OH-DHEA-S in the fetal liver by the action of the CYP3A7 enzyme, and transported back to the placenta where it is converted to 16α-OH-DHEA by the steroid sulfatase. The enzyme 3β-HSD1 converts 16α-OH-DHEA into 16α-OH-androstenedione, which is later aromatized to 16α-OH-estrone. In the final step, 16α-OH-estrone is converted to estriol by the 17β-HSD enzyme, and secreted into maternal circulation (ITTRICH & NEUMANN, 1963; WILSON, ERIKSSON, & DICZFALUSY, 1964). In non-pregnant women, estriol is produced mainly in the liver by 16α-hydroxylation of estradiol and estrone by CYP enzymes (Samavat & Kurzer, 2015; Tsuchiya, Nakajima, & Yokoi, 2005). Finally, estrone is mainly produced during menopause by aromatization of androstenedione in extra-glandular tissues, where it can act locally as a paracrine or intracrine factor (Simpson, 2003). Estrone can also be transformed to estradiol by the enzyme 17β-hydroxysteroid dehydrogenase in peripheral tissues, including adipose and breast tissue, vascular endothelium, smooth muscle cells, vesicular monoamine transporter tissue, and bone cells, where it is metabolized or enters the circulation in small quantities (Bulun et al., 1999; RYAN, 1959; Simpson, 2003).
Estrogen metabolism Physiologically, the metabolic conversion of estrogens allows their excretion from the body via urine, feces, and/or bile, along with the production of estrogen analogs, which have been shown to present antiproliferative effects (Tsuchiya et al., 2005). In target cells, there are different pathways capable of metabolizing estradiol and estrone. Members of the cytochrome P450 superfamily of enzymes (CYP1A1, CYP1B1, and CYP1A2) catalyze hydroxylation of estrone and estradiol at positions C2, C4 and C16. Due to the high expression of these enzymes in the liver, a large proportion of estrogen metabolism occurs in this tissue, although CYP1B1 is also expressed in target tissues such as mammary gland, uterus, kidney, brain, and pituitary gland, where estradiol and estrone can also be metabolized. Estradiol hydroxylation is followed by conversions to 2-hydroxyestrone, 4-hydroxyestrone, 2-hydroxyestradiol, 4-hydroxyestradiol, and 16α-hydroxyestrone, which are also known as catechol estrogens, due to their presence of pharmacological properties of both catecholamines and estrogens. The hydroxylation of estradiol or 16α-hydroxyestrone forms estriol. In addition, catechol estrogens can be methylated via the catechol-O-methyltransferase (COMT) enzyme to methoxy estrogens (Samavat & Kurzer, 2015). These compounds have gained significant attention due to their little estrogenic effects, antiproliferative properties, and ability to control estrogen synthesis (Purohit & Reed, 2002; Purohit et al., 2006). Moreover, catechol estrogens can also be conjugated by estrogen sulfotransferases and UDP-glucuronyltransferases (Cheng et al., 1998; Garbacz, Jiang, & Xie, 2017). In a conjugation reaction, hormones become water soluble and excreted from the body (Lakhani, Venitz, Figg, & Sparreboom, 2003).
Physiological functions of estrogens Estrogens are sex steroid hormones, and as such display a broad spectrum of physiological functions. These include regulation of the menstrual cycle and reproduction, bone density, brain function, cholesterol mobilization, development of breast tissue and sexual organs, and control of inflammation (Liang & Shang, 2013). While estrogens play diverse roles in normal male and female physiology, in certain physiological situations they can play similar roles in both sexes (Simpson et al., 2005). In females, estrogens are responsible for primary and secondary sexual characteristics. Estradiol promotes epithelial cell proliferation in the uterine endometrium and mammary glands starting in puberty (Gruber, Tschugguel, Schneeberger, & Huber, 2002; Koos, 2011; Simpson et al., 2005). During pregnancy, estrogens produced by the placenta help prepare the mammary gland for milk production (Voogt, 1978). On the other hand, lower levels of estrogens produced in men are essential for functions including sperm maturation, erectile function and maintenance of a healthy libido (Schulster, Bernie, & Ramasamy, 2016). It is important to mention here that all the estrogenic physiological functions previously described are mediated by estrogen receptors, which we describe in the next sections.