The first step in the

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 piece 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).