Androgen Dependent Penile Development and Erection PhysiologydA Molecular Connection? IN this issue of The Journal Okumu et al (page 267) report that androgen withdrawal in the neonatal period results in significant adverse effects on penile development with particular detriment on smooth muscle cell differentiation and expression of phosphodiesterase-5a (PDE5a) uniquely in the corpus cavernosum but not the corpus spongiosum of the rat penis.1 The experimental protocol was carefully designed to control androgen exposure, evaluating the effects of dihydrotestosterone as the key androgen responsible for penile development. The protocol also employed smooth muscle biomarker measurements of the androgenic effects. The work provides evidence in support of the requirement of the neonatal testosterone surge for the differentiation of corpus smooth muscle cells and, thus, development of the penis. Notwithstanding their confirmation of androgen dependent penile development the investigators have made some striking observations that merit comment.1 The localization of the androgenic effects on smooth muscle cells of the corpus cavernosum and not the corpus spongiosum suggests differential androgen targeting effects in penile development. The investigators propose that this distinction is due to differences in the cellular composition and structure of the corpus cavernosum with specialized molecular interactions between endothelial cells of cavernous spaces and smooth muscle cells of trabeculae in the corpus cavernosum. Chemical messages operating via intercellular communications are certainly possible and other investigative work has suggested molecular crosstalk between endothelial and smooth muscle cells in the penis.2,3 Further investigative work in this model system offers to delineate the molecular interactions that may be in play. The finding of a significant reduction in PDE5a expression, also localized to the corpus cavernosum but not the corpus spongiosum, upon androgen withdrawal in the neonatal period is also intriguing. The dependence of PDE5a expression on androgens has been disputed in prior investigations.4,5 Evidence provided here1 would support a contention that PDE5a expression is correlated with androgen actions and further
0022-5347/14/1921-0008/0 THE JOURNAL OF UROLOGY® © 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
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raises a critical function of this enzyme at the time of neonatal penile development. This possibility offers a notion that PDE5a exerts critical roles in the biology of the penis beyond its well studied role in regulating corpus cavernous smooth muscle tone.6 Recent investigative work of PDE5a function in the penis supports the idea that PDE5a is not immutably expressed in the penis, and levels of expression and function of this enzyme correlate with the physiological properties of relaxation and contraction of erectile tissue.7 The investigators acknowledge that the loss of smooth muscle cell number resulting from androgen withdrawal may also account for their findings,1 which is quite possible. Further experiments combining PDE5a inactivation with developmental biology studies of the penis may lend further insight into whether PDE5a actually influences corporeal smooth muscle cell differentiation. The work carries implications beyond insights regarding penile developmental biology. Possibly it hints at a mechanism of androgenic action on the biology of corpus cavernosum smooth muscle cells with relevance for erection physiology. There is a common belief that androgen withdrawal accounts for atrophic changes within the penis that may contribute to erectile dysfunction.8,9 Observations made by Okumu et al1 are consistent with this understanding. Altered PDE5a function in the corpus cavernosum resulting from androgen withdrawal offers a possible molecular explanation for penile conditions observed clinically. The advancing science of erection physiology has acknowledged the relevance of PDE5a function for erectile dysfunction, priapism and penile fibrosis,6 and pharmacotherapeutic interventions based on this science have already been approved or have been preliminarily investigated to address these conditions.10,11 Now it seems plausible that penile development represents another condition of the penis that is influenced by PDE5a regulation. Arthur L. Burnett The James Buchanan Brady Urological Institute Department of Urology, The John Hopkins Hospital Baltimore, Maryland
http://dx.doi.org/10.1016/j.juro.2014.04.007 Vol. 192, 8-9, July 2014 Printed in U.S.A.
ANDROGEN DEPENDENT PENILE DEVELOPMENT AND ERECTION PHYSIOLOGY
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REFERENCES 1. Okumu LA, Braden TD, Vail K et al: Low androgen induced penile maldevelopment involves altered gene expression of biomarkers of smooth muscle differentiation and a key enzyme regulating cavernous smooth muscle cell tone. J Urol 2014; 192: 267.
responsiveness to tadalafil in rat corpus cavernosum. Eur Urol 2005; 47: 409.
corpus cavernosum structure and function. J Sex Med 2005; 2: 759.
5. Lin CS, Xin Z, Namiki M et al: Direct androgen regulation of PDE5 gene or the lack thereof. Int J Impot Res 2013; 25: 81.
2. Andersson KE: Erectile physiological and pathophysiological pathways involved in erectile dysfunction. J Urol, suppl., 2003; 170: S6.
9. Gooren LJ and Saad F: Recent insights into androgen action on the anatomical and physiological substrate of penile erection. Asian J Androl 2006; 8: 3.
6. Burnett AL: Molecular pharmacotherapeutic targeting of PDE5 for preservation of penile health. J Androl 2008; 29: 3.
3. Bivalacqua TJ, Liu T, Musicki B et al: Endothelial nitric oxide synthase keeps erection regulatory function balance in the penis. Eur Urol 2007; 51: 1732.
7. Lin CS: Phosphodiesterase type 5 regulation in the penile corpora cavernosa. J Sex Med, suppl., 2009; 6: 203.
4. Zhang XH, Morelli A, Luconi M et al: Testosterone regulates PDE5 expression and in vivo
8. Traish A and Kim N: The physiological role of androgens in penile erection: regulation of
10. Corbin JD, Francis SH and Webb DJ: Phosphodiesterase type 5 as a pharmacologic target in erectile dysfunction. Urology, suppl., 2002; 60: 4. 11. Burnett AL, Anele UA, Trueheart IN et al: Randomized controlled trial of sildenafil for preventing recurrent ischemic priapism in sickle cell disease. Am J Med 2014; Epub ahead of print.
0022-5347/14/1921-0008/0 THE JOURNAL OF UROLOGY® © 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
8
j
www.jurology.com
AND
RESEARCH, INC.
raises a critical function of this enzyme at the time of neonatal penile development. This possibility offers a notion that PDE5a exerts critical roles in the biology of the penis beyond its well studied role in regulating corpus cavernous smooth muscle tone.6 Recent investigative work of PDE5a function in the penis supports the idea that PDE5a is not immutably expressed in the penis, and levels of expression and function of this enzyme correlate with the physiological properties of relaxation and contraction of erectile tissue.7 The investigators acknowledge that the loss of smooth muscle cell number resulting from androgen withdrawal may also account for their findings,1 which is quite possible. Further experiments combining PDE5a inactivation with developmental biology studies of the penis may lend further insight into whether PDE5a actually influences corporeal smooth muscle cell differentiation. The work carries implications beyond insights regarding penile developmental biology. Possibly it hints at a mechanism of androgenic action on the biology of corpus cavernosum smooth muscle cells with relevance for erection physiology. There is a common belief that androgen withdrawal accounts for atrophic changes within the penis that may contribute to erectile dysfunction.8,9 Observations made by Okumu et al1 are consistent with this understanding. Altered PDE5a function in the corpus cavernosum resulting from androgen withdrawal offers a possible molecular explanation for penile conditions observed clinically. The advancing science of erection physiology has acknowledged the relevance of PDE5a function for erectile dysfunction, priapism and penile fibrosis,6 and pharmacotherapeutic interventions based on this science have already been approved or have been preliminarily investigated to address these conditions.10,11 Now it seems plausible that penile development represents another condition of the penis that is influenced by PDE5a regulation. Arthur L. Burnett The James Buchanan Brady Urological Institute Department of Urology, The John Hopkins Hospital Baltimore, Maryland
http://dx.doi.org/10.1016/j.juro.2014.04.007 Vol. 192, 8-9, July 2014 Printed in U.S.A.
ANDROGEN DEPENDENT PENILE DEVELOPMENT AND ERECTION PHYSIOLOGY
9
REFERENCES 1. Okumu LA, Braden TD, Vail K et al: Low androgen induced penile maldevelopment involves altered gene expression of biomarkers of smooth muscle differentiation and a key enzyme regulating cavernous smooth muscle cell tone. J Urol 2014; 192: 267.
responsiveness to tadalafil in rat corpus cavernosum. Eur Urol 2005; 47: 409.
corpus cavernosum structure and function. J Sex Med 2005; 2: 759.
5. Lin CS, Xin Z, Namiki M et al: Direct androgen regulation of PDE5 gene or the lack thereof. Int J Impot Res 2013; 25: 81.
2. Andersson KE: Erectile physiological and pathophysiological pathways involved in erectile dysfunction. J Urol, suppl., 2003; 170: S6.
9. Gooren LJ and Saad F: Recent insights into androgen action on the anatomical and physiological substrate of penile erection. Asian J Androl 2006; 8: 3.
6. Burnett AL: Molecular pharmacotherapeutic targeting of PDE5 for preservation of penile health. J Androl 2008; 29: 3.
3. Bivalacqua TJ, Liu T, Musicki B et al: Endothelial nitric oxide synthase keeps erection regulatory function balance in the penis. Eur Urol 2007; 51: 1732.
7. Lin CS: Phosphodiesterase type 5 regulation in the penile corpora cavernosa. J Sex Med, suppl., 2009; 6: 203.
4. Zhang XH, Morelli A, Luconi M et al: Testosterone regulates PDE5 expression and in vivo
8. Traish A and Kim N: The physiological role of androgens in penile erection: regulation of
10. Corbin JD, Francis SH and Webb DJ: Phosphodiesterase type 5 as a pharmacologic target in erectile dysfunction. Urology, suppl., 2002; 60: 4. 11. Burnett AL, Anele UA, Trueheart IN et al: Randomized controlled trial of sildenafil for preventing recurrent ischemic priapism in sickle cell disease. Am J Med 2014; Epub ahead of print.
