Finasteride inhibits epinephrine synthesis in humans: implication for sexual dysfunction
Silvia Giatti1, Silvia Diviccaro1, Alessandro Di Domizio2, Lucia Cioffi1, Eva Falvo1, Donatella Caruso1, Alessandro Contini3 & Roberto Cosimo Melcangi1
Finasteride is a 5alpha-reductase (5α-R) inhibitor used in clinics to treat androgen-dependent conditions, such as benign prostate hyperplasia and androgenetic alopecia (AGA). Its use has been associated with several adverse effects, including sexual complaints. However, to date, no hypothesis to explain such adverse effects has been proposed. This is a consequence of the still incomplete knowledge of the intricate network of motivational, psychological, and molecular inputs that are involved in sexual behavior. In this work, a multidisciplinary approach has been used to evaluate whether finasteride may interact with targets different from 5α-R (i.e., off-target proteins − OTPs). In silico analysis (SPILLO-PBBS software and docking/molecular dynamics) indicated that the enzyme phenylethanolamine N-methyltransferase (PNMT), the limiting enzyme in epinephrine production, might be a finasteride OTP. This is interesting, since epinephrine and norepinephrine are involved in erection (Becker et al ., 2000, J Urol), and alterations in their levels has been observed in patient with erectile dysfunction (Becker et al ., 2002, Urology). An inhibitory assay developed in vitro confirmed that finasteride blocks the human PNMT. Finally, to verify the in vivo interaction, adult male rats were treated with finasteride (1 mg/rat/day s.c. daily for 20 days). Ex vivo analysis indicated that epinephrine levels were decreased by finasteride treatment in adrenal glands, while those of norepinephrine were increased. This, together with no variation in PNMT protein levels, confirmed the hypothesis of a block in epinephrine synthesis. Therefore, we explored if corpora cavernosa (CC) of finasteride-treated rats presented molecular alterations. A decreased protein level of estrogen receptor beta was observed in CC of finasteride-treated rats, in line with evidence in aging and diabetic rats with erectile dysfunction (Shirai et al ., 2004, Urology). Moreover, the levels of dopamine, which improve the penis relaxation, were significant decreased in CC tissue after finasteride administration. Overall, the data here presented indicate that finasteride affects epinephrine synthesis by blocking PNMT enzymatic activity in humans. This block can have an impact in sexual behavior, as suggested in an animal model treated with finasteride. In addition, the alterations observed in CC indicate possible impairment of erectile function. Our results suggest possible mechanisms for the sexual dysfunction observed after finasteride treatment in humans and add a piece of knowledge on the mechanisms controlling sexual function in mammals.