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  • Estrogens Definition and history The term estrogens refers t


    Estrogens: Definition and history The term “estrogens” refers to a group of female hormones, including estrone, estradiol, estriol, and estretrol (Fig. 1). Chemically, estrogens belong to the family of organic compounds known as steroids. As such, their core structure is composed of 17 carbon-carbon bonds arranged as four fused rings (three cyclohexane rings and a cyclopentane ring). All four estrogens contain 18 carbons (C18H24O2) and are collectively known as C18 steroids. They consist of one benzene ring, a phenolic hydroxyl group, and a ketone group (estrone), or one (17β-estradiol), two (estriol), or three (estretrol) hydroxyl groups. Estrogens are primarily synthesized in the ovaries, but also in the adrenal glands and adipose tissue. They were discovered in the early 1900s, when ovarian extracts (“liquor folliculi”) from cattle and hogs were injected in rodents, and found to be effective in inducing sexual activity or “estrus” (Allen & Doisy, 1983). It was later determined that the hormone was produced by mature ovarian follicles, and that it was likely common to all female animals. The term estrogen derives from the Greek words oistros (frenzy, in heat) and gennan (to produce). As mentioned above, estrogens are a group of C18 hormones with similar chemical structures and function (Fig. 1). In addition, all four estrogens are able to bind to both nuclear and membrane estrogen receptors, with different affinity and strength of the response (Watson, Jeng, & Kochukov, 2008). However, the word estrogen is commonly used to refer to estradiol (or 17β-estradiol), due to its physiological relevance and predominance during reproductive years. While females produce all estrogens throughout life, the hormones 16-hydroxyestradiol (estriol) and 15α-hydroxyestriol (estretrol) are predominantly found during pregnancy, and estrone is usually found at higher levels during menopause (Samavat & Kurzer, 2015). Estradiol, the predominant circulating estrogen in humans, it is mainly secreted by the granulosa Doripenem of the ovarian follicles, and the corpora lutea. On the other hand, estretrol is synthesized exclusively by the fetal liver and reaches maternal circulation through the placenta (Coelingh Bennink, Holinka, Visser, & Coelingh Bennink, 2008; Holinka, Diczfalusy, & Coelingh Bennink, 2008). Estrone, which is produced by aromatization of androstenedione in extraglandular tissues, can be reversibly transformed to estradiol by the enzyme 17β-hydroxysteroid dehydrogenase in peripheral tissues (Bulun, Zeitoun, Sasano, & Simpson, 1999; RYAN, 1959).
    Estrogen biosynthesis The main substrate for steroid hormone biosynthesis is dietary cholesterol, specifically low-density lipoprotein (LDL)-cholesterol (Carr, MacDonald, & Simpson, 1982). Through a process called steroidogenesis, cholesterol is converted to the 21-carbon (pregnanes, progestogens), 19-carbon (androstanes), and 18-carbon (estranes) steroid hormones in gonads, adrenal cortex, and adipose tissue (Miller, 2017). The main site of estrogen synthesis is the ovaries, and specifically the granulosa cells (Fig. 2). The first step in the biosynthesis of steroid hormones is the translocation of cholesterol into the inner mitochondrial membrane, a process regulated by the steroidogenic acute regulatory protein STARD1 (also known as StAR), which is believed to act as a shuttle enzyme (Miller & Strauss, 1999). This is the rate-limiting step of steroidogenesis in all tissues. The expression of StAR is controlled by a mechanism involving binding of luteinizing hormone (LH) to its G protein-coupled receptor in the theca cells of the ovary and stimulation of adenylate cyclase, which catalyzes the production of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). The cAMP produced activates protein kinase A, which catalyzes phosphorylation of cAMP response element binding protein (CREB) leading to activation of transcription of StAR and other factors associated with steroid hormone production (Fig. 2). At the inner mitochondrial membrane, cholesterol is converted to pregnenolone by the enzyme P450scc, or cholesterol side-chain cleavage enzyme, encoded by the CYP11A1 gene (Belfiore, Hawkins, Wiltbank, & Niswender, 1994). Pregnenolone then acts as a precursor for all steroid hormones (Fig. 3), and can diffuse between adjacent granulosa and theca cells of the ovary. The synthesis continues with the conversion of pregnenolone to androstenedione by the enzymes CYP17A1 (steroid 17-α-hydroxylase/17,20-lyase) and 3β-HSD (3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase), via dehydroepiandrosterone (DHEA). Androstenedione can be either converted to other androgens, such as testosterone and dihydrotestosterone, or diffuse to the granulosa cells through the basal lamina (Fig. 2). At the granulosa cells, androstenedione is converted to estrone by the enzyme CYP19A1 (also known as aromatase). Estrone is then converted to estradiol by the enzyme 17β-HSD (17β-hydroxysteroid dehydrogenase). In the granulosa cells, the expression of both aromatase and 17β-HSD is controlled by follicle stimulating hormone (FSH) stimulation. Interestingly, testosterone can be metabolized to estradiol and estrone by the action of aromatase in peripheral tissues, including adipose cells and bone (Simpson et al., 2002). Males also produce local estrogen by aromatization in cells of the reproductive tract, including Sertoli cells, Leydig cells, and mature spermatocytes. Overall, estrogens are normally produced by the ovaries and in smaller amounts by other tissues such as the liver, pancreas, adrenal glands, adipose tissue, and breast (Barakat, Oakley, Kim, Jin, & Ko, 2016). In specific physiological conditions, such as pregnancy, estrogen is also synthesized by the placenta. However, the biosynthesis of estrogen in non-gonadal sites follows rather unusual mechanisms, since these tissues are not able to generate C19 steroids from cholesterol. In these tissues, estrogen production is largely dependent on C19 steroids transported from other tissues and conversion by local CYP19A1 aromatase (Labrie et al., 1998; Nelson & Bulun, 2001).