The estradiol-synthetic pathway and nuclear receptors. Cholesterol is the universal steroid substrate. Initiation of steroidogenesis begins with the transport of cholesterol, via the action of the 18 kDa cholesterol transport protein (TSPO) and/or the steroidogenic acute regulatory protein (StAR), to the first enzyme in the pathway, cytochrome P450 side chain cleavage (CYP11A1). From pregnenolone, four more enzymes are required to produce estradiol: 3β-hydroxsteroid dehydrogenase (HSD3B), cytochrome P450 17α-hydroxylase/17,20 lyase (CYP17), 17β-hydroxysteroid dehydrogenases (HSD17B), and cytochrome P450 aromatase (CYP19). Cholesterol transport proteins and enzymes are in bold italics. Steroids are in plain text. The four major nuclear receptors for the three classes of steroids produced along the estradiol-synthetic pathway are in italicized parentheses: progesterone receptor (PR), estrogen receptor α (ERα), estrogen receptor β (ERβ), and androgen receptor (AR).