Enrique Esteve Valverde, MD, PhD

𝗠𝗲𝗰𝗵𝗮𝗻𝗶𝘀𝗺𝘀 𝗼𝗳 𝗔𝗰𝘁𝗶𝗼𝗻 𝗼𝗳 𝗧𝗲𝘀𝘁𝗼𝘀𝘁𝗲𝗿𝗼𝗻𝗲 Many of the benefits and some of the risks of testosterone treatment are mediated by the mechanisms through which testosterone acts. Testosterone has anabolic effects on muscle (panel A) and bone (panel B) and stimulates erythropoiesis (panel C) through androgen receptor–mediated mechanisms. Nongenomic mechanisms of action increase penile blood flow and improve erectile function (panel D). The effects of testosterone on sexual desire and bone are mediated largely through its conversion to 17β-estradiol. Testosterone is also converted to dihydrotestosterone (DHT), which stimulates prostate growth and has additional anabolic effects on muscle and bone. Testosterone and DHT increase penile blood flow and erections through a rapid increase in the production of nitric oxide, which is endothelium-dependent, as well as through inhibition of voltage-operated l-type calcium channels, activation of potassium channels on smooth muscle, or both mechanisms, which are endothelium-independent (panel D). A metabolite of DHT, 5α-androstane-3α,17β-diol, which is a ligand for the γ-aminobutyric acid receptor, has been linked to mood and affect. Learn more in the Review Article “Testosterone Treatment in Middle-Aged and Older Men with Hypogonadism” by Shalender Bhasin, MB, BS, and Peter J. Snyder, MD, from @BrighamWomens, @harvardmed, and @PennMedicine: nej.md/4ooeFo7