Phosphodiesterase inhibitors in female sexual dysfunction

Abstract

Based on the increasing knowledge on both the physiology of penile erection and the pathophysiology of erectile dysfunction, selective phosphodiesterase (PDE) inhibitors have been successfully introduced in the oral treatment of male erectile dysfunction. Because of their central role in smooth muscle tone regulation, PDEs remain an attractive target for drug development in urology. Since the distribution and functional significance of PDE isoenzymes vary in different tissues, selective inhibitors of the isoenzymes have the potential to exert at least partially specific effects on the target tissue. Currently, PDE inhibitors are under investigation with potential uses in urinary stone disease, overactive bladder and the so-called benign prostatic syndrome. The convincing clinical data on the use of the orally active PDE5 inhibitors sildenafil (VIAGRA), vardenafil (LEVITRA) and tadalafil (CIALIS) in the treatment of erectile dysfunction are accompanied by boosting research activities on intracellular signal transduction and PDE characterisation in female genital tissues with the aid of immunohistochemistry and immunocytochemistry and molecular biology. The expression of various PDE isoforms in the human clitoris, vagina and labia minora was shown by means of immunohistochemistry and RT-PCR analyses and it was concluded from functional studies that an increase in cGMP or cAMP might be involved in the regulation of female genital blood flow and the control of genital non-vascular smooth muscle. As a consequence, the efficacy and safety of the PDE5 inhibitor sildenafil in the treatment of symptoms of female sexual dysfunction (FSD), including female sexual arousal disorders (FSAD), have been evaluated. Although the experiences from these early clinical studies have so far not been conclusive, they suggest that, after appropriate evaluation of patients, inhibition of PDE5 might be of benefit for selected individuals with FSAD. Such research efforts will possibly allow the identification of efficacious and diagnostic tools for erectile dysfunction and of even more selective drugs in its therapy.

Restoration of Female Genital Vasocongestive Arousal Responses in Young and Aged Rats

“…The lag in progress is most likely because of the increased complexity of factors that govern female sexual function such as the complicating issue that fluctuations in endocrine activity has on the central nervous system signaling, neural pathway, and local mediators involved in the biological control of female sexuality [24]. In the present study, APO-generated GVA responses were assessed using a straightforward approach, in both young adult and aged female rats, following various manipulations.…”

“…In contrast to the extensive scientific and clinical efforts, which have gone into understanding the anatomy, physiology, and pathophysiology of the male penile erectile response, investigation of the female sexual response has received much less attention [24]. The lag in progress is most likely because of the increased complexity of factors that govern female sexual function such as the complicating issue that fluctuations in endocrine activity has on the central nervous system signaling, neural pathway, and local mediators involved in the biological control of female sexuality [24]. In the present study, APO-generated GVA responses were assessed using a straightforward approach, in both young adult and aged female rats, following various manipulations.…”

Vascular Alterations and Sexual Function in Systemic Sclerosis

“…Chivers and Rosen [32] conclude that there is clear evidence for the role of NO neurotransmitter mechanisms in mediating blood flow and smooth muscle relaxation in the clitoral shaft, vaginal endothelium, and uterine tissues. However, PDE5 inhibitors are not found to be as efficacious in women with sexual dysfunction as in men with ED [32, 33]. Studies focusing on the physiological effects of PDE5 on genital vasocongestion consistently report effects on genital sexual response while those using self-reported measures provide mixed results.…”

Phosphodiesterase 5 in the female pig and human urethra: morphological and functional aspects

“…To date, 11 different families of PDE are known, that differ in their specificity for cAMP and cGMP, cofactor requirements, and kinetic properties [3]. Transcription of genes encoding for various PDEs have been detected in urogenital tissues, including human and porcine detrusor smooth muscle, human prostate, penis, clitoris and vagina [4–8].…”