ESSM Newsletter # 38

7 ESSM Today Effects of PDE5 inhibitors on the male reproductive potential: A dinner conversation by Fotios Dimitriadis, Athanasios Zachariou, Nikolaos Sofikitis AZ: Gentlemen, the restaurant is great, please relax, and let’s have a nice dinner. NS: Fotios, I see that your face looks skeptical and confused. Why? You do not like the wine? FD: I have just finished the outpatient clinic. One of my idiopathic infertile patients asked me a difficult question which I receive several times every week: Are there any effective pharmaceu- tical agents for the therapeutical alleviation of oligoasthenoteratozoospermia? NS: To the best of my knowledge there are fewer than five randomized, placebo-controlled trials evaluating the effects of pharmaceuti- cal agents on the reproductive potential of infertile men. FD: After 2009, the number of publications on the effects of PDE5 inhibitors on quantitative and qualitative sperm parameters has been dramati- cally increasing, isn’t it interesting? AZ: It is interesting but not unexplainable. Let us remember that several members of the families of phosphodiesterases are present both in the testis and in the epididymis. FD: Do you mean that specific cellular subpopu- lations within either the testis or the epididymis are positive for distinct members of the phos- phodiesterases’ families? NS: To the best of my knowledge, peritubular myoid cells are positive for PDE5 expression. Leidyg cells are positive for PDE11A, PDE4B, PDE5, PDE8A and PDE11. Sertoli cells are known to be positive for PDE1, PDE3 and PDE4 expression. Human epididymis is known to be positive for PDE3 and PDE5 expression. Vascu- lar monocytes within the testis are positive for PDE11 and PDE5. Vas deferens is positive for PDE5. Prostate is positive for PDE5a, PDE11A4 and PDE11A1. It is logical to hypothesize that administration of inhibitors of PDE5 may af- fect testicular endocrine and exocrine function, epididymal function, prostatic secretory function and prostatic physiology. However it should be emphasized that PDE5 inhibitors may additionally inhibit to a smaller degree other phosphodies- terase families within the testis. For instance, PDE5 inhibitors additionally inhibit to a smaller degree PDE11, PDE4, PDE8, and PDE3. There- fore administration of PDE5 inhibitors may affect several cellular subpopulations within the male reproductive tract. AZ: What about the subpopulations of haploid male gametes? FD: Spermatids are positive for PDDE11, PDE4A, PDE4D, PDE1A, and PDE1C. Spermatozoa are positive for PDE1A, PDE3A, PDE4, PDE5, PDE6, and PDE10A. AZ: And what about the subpopulations of diploid male gamete? FD: Spermatogonia are positive for PDE11A, PDE1, and PDE2. Primary spermatocytes are positive for PDE11, PDE3, PDE4, and PDE1C. NS: The above localization of selected PDE5- families explains the enhanced Leydig cellular secretory function and the increased Sertoli cel- lular secretory function after administration of ei- ther sildenafil or vardenafil. In fact, the increased Leydig cellular secretory function post-sildenafil administration has been proven by the increased INSL3 production by human Leydig cells after sildenafil administration. On the other hand, the increased Sertoli cellular secretory function post- vardenafil administration has been proven by the increased androgen-binding activity/content produced by human Sertoli cells after vardenafil administration. Increased peripheral serum tes- tosterone concentration has been demonstrated post-avanafil administration, as well. AZ: Do the above alterations in the secretory function of Leydig or Sertoli cells affect any of the standard parameters of the semen analysis? FD: The enhanced Leydig or Sertoli cell secretory function after sildenafil or vardenafil adminis- tration may result in increased intraepididymal lumen concentrations of testosterone or andro- gen binding protein allowing optimal epididymal sperm maturation process. The final result may be an increase in sperm motility after admin- istration of either sildenafil or vardenafil. An alternative mechanism to explain the beneficial effects of sildenafil on sperm motility may be the enhanced prostatic secretory function es- tablished after administration of sildenafil. In fact post-sildenafil administration increased concen- trations of markers of prostatic secretory function have been demonstrated. Therefore a second Fotios Dimitriadis (FD) X-Assisted Professor, Department of Urology, Tottori University School of Medicine, Yonago, Japan helabio@yahoo.gr Athanasios Zachariou (AZ) University Scholar, Department of Urology, Ioannina University School of Medicine, Ioannina, Greece zahariou@otenet.gr Nikolaos Sofikitis (NS) Professor and Chair, Department of Urology, Ioannina University School of Medicine, Ioannina, Greece v.sofikitis@hotmail.com