**4.4 Aromatase cytochrome P-450c17**

Aromatase cytochrome P-450 c17 is an enzyme found in the endoplasmic reticulum membrane that acts on aromatizable androgen. Aromatase P 450 catalyses the biosynthesis of all estrogens from androgens by transforming the A-ring of steroids to an aromatic state through the oxidation and elimination of the C19 methyl group (Ghosh et al., 2009; Straus & Hsueh, 2000). Aromatase expression is present in fetal and immature ovaries, and in rodents, aromatase expression/activity is restricted to the gonads and the brain. In humans, aromatase activity is expressed by the adrenal medulla (Belgorosky et al., 2008), adipose tissue, breast, skin, and bone (Czajka-Oraniec & Simpson, 2010).

FSH is the main factor inducing aromatase activity in mural granulosa cells located on the outer edge of healthy large antral follicles and luteal cells. Aromatase is not expressed in cumulus granulosa cells. The stimulatory effects of FSH are modulated in an inhibitory way by glucocorticoids, prolactin, progestins, inhibin, triiodothyronine and thyroxine (T3-T4) (Chen et al., 2010). Transforming growth factor-β (TGF-β) enhances FSH effects (Stocco, 2008).

Bone morphogenetic protein 15 (BMP-15) and growth differentiating factor 9 (GDF9) produced by the oocytes also stimulate aromatase expression and the stimulatory effects of the tumor necrosis factor- (TNF-), epidermal growth factor (EGF), transferrin, nitric oxide (NO), and superoxide dismutase (Stocco 2008). Leptin has stimulatory or inhibitory effects on aromatase expression depending on the animal studied (Sirotkin & Grossman, 2007).

Acting as an autocrine signal, estradiol enhances the stimulatory effects of FSH on aromatase activity in granulosa cells, and its effects are mediated by the activation of estrogen receptor β (Wang et al., 2010).

Androgens enhance FSH effects on aromatase expression by increasing cAMP levels. Aromatizable androgens synthesized by theca-internal cells are the substrate for estrogen synthesis. The stimulating actions of FSH on aromatase are potentiated by insulin-like growth factor-1 (IGF-1), because IGF-I stimulates the capacity of granulosa cells to respond to FSH (Stocco 2008).

FSH stimulates the synthesis of cAMP, which in turn acts as an intracellular messenger mediating FSH stimulation of aromatase expression, leading to the activation of the cAMPdependent protein kinase A (PKA) which is cAMP-dependent (Stocco, 2008). FSH stimulates the mRNA for LH receptor synthesis, explaining why LH is the main aromatase inductor before ovulation (Boon et al., 2010).
