INVESTIGATIVE UROLOGY

Expression of cAMP and cGMP-Phosphodiesterase Isoenzymes 3, 4, and 5 in the Human Clitoris: Immunohistochemical and Molecular Biology Study
Oelke M, Hedlund P, Albrecht K, Ellinghaus P, Stief CG, Jonas U, Andersson KE, Uckert S
Department of Urology, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands
Urology. 2006; 67: 1111-6

• Objectives: Only a little research has focused on the evaluation of female sexual function. With sexual stimulation, the clitoris becomes engorged with blood and tumescent. Nevertheless, only little is known about the significance of the cyclic nucleotide-mediated signal transduction in the control of this process. We sought to elucidate the presence of the phosphodiesterase (PDE) isoenzymes 3, 4, and 5 in the human clitoris using immunohistochemical and molecular biology methods.
• Methods: Thin sections of clitoral specimens were incubated with primary antibodies directed against PDE isoenzymes 3, 4, and 5. Next, the sections were incubated with either Texas red or fluorescein isothiocyanate-labeled secondary antibodies, and visualization was done using laser microscopy. The expression of mRNA encoding for various PDE isoenzymes was evaluated using reverse transcriptase polymerase chain reaction.
• Results: Immunofluorescence indicating the presence of PDE4 (cyclic adenosine monophosphate-PDE) was observed in the nonvascular smooth musculature of the corpus cavernosum clitoris, sinusoidal endothelial and subendothelial layers, and nerve fibers innervating the tissue. Immunoreactivity specific for PDE5 (cyclic guanosine monophosphate-PDE) was limited to the smooth muscle of the clitoral erectile tissue. The fluorescein isothiocyanate reaction indicating the expression of PDE3 (cyclic adenosine monophosphate-PDE) was registered to a certain degree only in the clitoral epidermis. In the reverse transcriptase polymerase chain reaction studies, a predominant expression of mRNA encoding for PDE1A was registered, but only small amounts of mRNA encoding for PDE4 and PDE5 were detected.
• Conclusions: Our results have demonstrated the presence of cyclic adenosine monophosphate-PDE and cyclic guanosine monophosphate-PDE in the human clitoris and may indicate a regulatory function of these enzymes in the cyclic nucleotide-mediated control of smooth muscle tone.
  
  
• Editorial Comment
  Sexual dysfunction in women remains a significant problem that may affects up to 43% of women in the United States of America (1). Despite this, in contrast to the extensive knowledge on male sexual function and dysfunction during the last years, studies on physiology of female sexuality have been received minimal attention. Therefore, the present study is very much welcome, because objectively demonstrated the localization of mRNA transcripts and immunoactivity related to PDE isoenzymes 4 and 5 in the human clitoris.
  Because of their central role in smooth muscle tone regulation, PDEs remain an attractive target for drug development in urology and other specialties, such as gynecology (2). Also, PDE inhibitors are under investigation with potential uses in urinary stone disease, overactive bladder (2) and lower urinary tract symptoms (3).
  The extensive clinical data on the use of the orally active PDE5 inhibitors in the treatment of male erectile dysfunction claimed PDE characterization in female genital tissues with the aid of immunohistochemistry and molecular biology (2,4). The findings of the present study are in support that PDE isoenzymes are involved in clitoral function during sexual stimulation and are giving additional rationale for the use of PDE inhibitors in the pharmacotherapy of female sexual dysfunction and arousal disorders.

References
1. Maravilla KR, Cao Y, Heiman JR, Yang C, Garland PA, Peterson BT, Carter WO: Noncontrast dynamic magnetic resonance imaging for quantitative assessment of female sexual arousal. J Urol. 2005; 173:162-6.
2. Mayer M, Stief CG, Truss MC, Uckert S: Phosphodiesterase inhibitors in female sexual dysfunction. World J Urol. 2005; 23: 393-7.
3. Uckert S, Oelke M, Stief CG, Andersson KE, Jonas U, Hedlund P: Immunohistochemical distribution of cAMP- and cGMP-phosphodiesterase (PDE) isoenzymes in the human prostate.Eur Urol. 2006; 49: 740-5
4. Yang CC, Cold CJ, Yilmaz U, Maravilla KR: Sexually responsive vascular tissue of the vulva. BJU Int. 2006; 97: 766-72.

Dr. Francisco Sampaio
Full-Professor and Chair, Urogenital Research Unit
State University of Rio de Janeiro
Rio de Janeiro, Brazil