FIGURE 1. Pathways of testosterone biosynthesis and action. In men, testosterone biosynthesis occurs almost exclusively in mature Leydig cells by the enzymatic sequences illustrated. Cholesterol originates predominantly by the de novo synthesis pathway from acetyl CoA with luteinizing hormone regulating the rate limiting step, the conversion of cholesterol to pregnenolone within mitochondria, while remaining enzymatic steps occur in smooth endoplasmic reticulum. The 5 and 4 steroidal pathways are on the left and right, respectively. Testosterone and its androgenic metabolite, dihydrotestosterone, exert biological effects directly through binding to the androgen receptor and indirectly through aromatization of testosterone to estradiol, which allows action via binding to the estrogen receptor (ER). The androgen and ERs are members of the steroid nuclear receptor superfamily with highly homologous structure differing mostly in the C-terminal ligand binding domain. The LH receptor has the structure of a G-protein linked receptor with its characteristic seven transmembrane spanning helical regions and a large extracellular domain which binds the LH molecule. LH is a dimeric glycoprotein hormone consisting of an subunit common to other pituitary glycoprotein hormones and a subunit specific to LH. Most sex steroids bind to sex hormone binding globulin (SHBG) which binds tightly and carries the majority of testosterone in the bloodstream.