The goal of this study was to assess the utility of existing and new techniques for characterizing and measuring hemodynamic changes in the vagina and clitoris in response to pelvic nerve stimulation ...(PNS) in an animal model. Using female New Zealand White rabbits, we measured the following parameters before, during, and after PNS at 4, 16, and 32 hertz (Hz): clitoral hemoglobin (Hb) content by laser oximetry, clitoral blood flow by laser Doppler flowmetry, vaginal luminal pressure of upper and lower segments, and clitoral intracavernosal pressure. Clitoral tissue concentrations of total and oxygenated hemoglobin (oxy-Hb) increased in a frequency-dependent manner while deoxygenated hemoglobin (deoxy-Hb) concentration decreased. The duration of the responses at 16 and 32 Hz were significantly greater than at 4 Hz. Clitoral blood flow increased significantly only at 32 Hz with a prolonged response duration, relative to 4 Hz. PNS caused vaginal luminal pressure changes that were highly variable, but qualitatively different, between the upper and lower regions. Clitoral intracavernosal pressure did not change significantly in response to PNS. Measurement of changes in tissue Hb content by the novel technique of laser oximetry provides a direct assessment of blood flow in a noninvasive manner and may prove to be a powerful tool in evaluating hemodynamic aspects of the female genital sexual response.
In this study, we investigated the binding characteristics of
3
H
Δ
5-androstene-3β,17β-diol to rabbit vaginal cytosolic and nuclear extracts and in freshly excised intact tissue strips.
3
H
Δ
...5-Androstene-3β,17β-diol bound to a protein(s) in the vaginal nuclear extract with high affinity (
K
d=3–5
nM) and limited capacity (50–100
fmol/mg protein). No specific binding was detected in the cytoplasmic extracts. Competitive binding studies showed that binding of
3
H
Δ
5-androstene-3β,17β-diol was effectively displaced with unlabeled Δ
5-androstene-3β,17β-diol but not with dehydroepiandrosterone, testosterone, dihydrotestosterone, triamcinolone acetonide, or progesterone. However, estradiol at high concentrations partially displaced bound
3
H
Δ
5-androstene-3β,17β-diol. Incubation of freshly excised vaginal tissue strips with
3
H
Δ
5-androstene-3β,17β-diol in the absence or presence of excess unlabeled Δ
5-androstene-3β,17β-diol for 1
h at 37
°C resulted in specific binding to a soluble macromolecule in the nuclear KCl extracts. In addition, quantitative measurement of estrogen receptor, androgen receptor and Δ
5-androstene-3β,17β-diol binding protein was performed by equilibrium ligand binding assays using extracts of distal vaginal tissue from intact animals or ovariectomized animals treated for 2 weeks with vehicle, estradiol, testosterone, or estradiol plus testosterone. These changes in steroid hormone levels resulted in opposing trends between the estrogen receptor and Δ
5-androstene-3β,17β-diol binding protein, suggesting that Δ
5-androstene-3β,17β-diol binding protein is regulated differently by the hormonal milieu than the estrogen receptor. These data suggest that rabbit vaginal tissue expresses a novel binding protein which specifically binds Δ
5-androstene-3β,17β-diol and is distinct from the androgen and estrogen receptors.
In this study, we investigated the binding characteristics of 3HDelta(5)-androstene-3beta,17beta-diol to rabbit vaginal cytosolic and nuclear extracts and in freshly excised intact tissue strips. ...3Hdelta(5)-Androstene-3beta,17beta-diol bound to a protein(s) in the vaginal nuclear extract with high affinity (K(d)=3-5 nM) and limited capacity (50-100 fmol/mg protein). No specific binding was detected in the cytoplasmic extracts. Competitive binding studies showed that binding of 3Hdelta(5)-androstene-3beta,17beta-diol was effectively displaced with unlabeled delta(5)-androstene-3beta,17beta-diol but not with dehydroepiandrosterone, testosterone, dihydrotestosterone, triamcinolone acetonide, or progesterone. However, estradiol at high concentrations partially displaced bound 3Hdelta(5)-androstene-3beta,17beta-diol. Incubation of freshly excised vaginal tissue strips with 3Hdelta(5)-androstene-3beta,17beta-diol in the absence or presence of excess unlabeled delta(5)-androstene-3beta,17beta-diol for 1h at 37 degrees C resulted in specific binding to a soluble macromolecule in the nuclear KCl extracts. In addition, quantitative measurement of estrogen receptor, androgen receptor and delta(5)-androstene-3beta,17beta-diol binding protein was performed by equilibrium ligand binding assays using extracts of distal vaginal tissue from intact animals or ovariectomized animals treated for 2 weeks with vehicle, estradiol, testosterone, or estradiol plus testosterone. These changes in steroid hormone levels resulted in opposing trends between the estrogen receptor and delta(5)-androstene-3beta,17beta-diol binding protein, suggesting that delta(5)-androstene-3beta,17beta-diol binding protein is regulated differently by the hormonal milieu than the estrogen receptor. These data suggest that rabbit vaginal tissue expresses a novel binding protein which specifically binds delta(5)-androstene-3beta,17beta-diol and is distinct from the androgen and estrogen receptors.
Physical examination of the genitalia was performed during an evaluation of women with sexual health problems. Cephalad displacement of the right and left labia minora enables full retraction of the ...clitoral prepuce and complete exposure of the glans clitoris, under normal circumstances. We defined clitoral examination as abnormal when the cephalad force resulted in varying degrees of incomplete foreskin retraction and limited exposure of the glans clitoris. The pathophysiology is likely to be secondary to recurrent vulvar dermal infections of blunt trauma changing prepucial elasticity. Clitoral phimosis, a previously undiagnosed physical finding, was identified in 22% of the women. Other than its link to sexual pain, the clinical significance of this finding, in particular the relation to diminished sensitivity and impaired orgasmic capability, is unclear at this time.
Effective medical management of female genital sexual arousal disorder necessitates understanding of biochemical and physiological mechanisms regulating female sexual arousal responses via central ...and peripheral pathways. The complexity of the female sexual response and the limited experimental models available has severely hampered progress in this field. Recent studies have begun to unravel peripheral biochemical mediators involved in regulating genital engorgement/swelling and lubrication. Research in this area should identify molecular targets for pharmacotherapy of female sexual arousal dysfunction.
Arthur Burnett—The Johns Hopkins Hospital and The Johns Hopkins University School of Medicine, Baltimore, MD, USA
Recent progress in the field of sexual medicine extends beyond areas of male sexual dysfunction and ideally should acknowledge and address female sexual disorders. Although basic scientific investigation of sexual disorders in women is in its infancy, several areas are receiving primary focus to advance progress in the field. There has been a longstanding interest in the influence of sex steroids in local genital responses but their roles remain incompletely understood. Furthermore, there is a need to integrate sex steroids with other molecular and biochemical determinants of the sexual response. Abdulmaged Traish and colleagues, as leaders in the field of sexual medicine with particular expertise in sexual disorders in women, critically examine the biology of female sexual arousal from a rigorous scientific perspective. Their discussion encompasses recently developed physiologic animal models as well as measurements of biochemical mediators relevant to erectile tissue physiology and pharmacology.
Limited studies are available concerning physiological and biochemical mechanisms involved in female sexual function and dysfunction. The paucity of physiological and biochemical data pertaining to ...genital sexual arousal function is attributed, in part, to lack of reliable experimental models and tools for the investigation of female sexual arousal. This review summarizes research efforts from a number of laboratories in which several experimental models have been established. These include the development of in vivo animal models, organ bath studies, and the establishment of cell cultures. The availability of such experimental model systems have facilitated efforts aimed at defining the neurotransmitters responsible for vaginal smooth muscle relaxation, the role of sex steroid hormones and their receptors in modulating genital hemodynamics, smooth muscle contractility, and neurotransmitter receptor expression. A comprehensive and integral understanding of female sexual function requires detailed investigation of the vascular, neurological (central and peripheral), and structural components of this complex physiological process.
ABSTRACT
Vardenafil and sildenafil are potent and specific phosphodiesterase type 5 (PDE 5) inhibitors. In human penile cavernosal smooth muscle cells, we have previously shown that vardenafil has a ...lower biochemical inhibition constant (Ki) than sildenafil. In this study, we compared the efficacy of vardenafil and sildenafil in facilitating penile erection in a rabbit model. Penile erections were elicited by submaximal (2.5 or 6 Hz) pelvic nerve stimulation (PNS) repeated every 5 minutes for 30 minutes with or without intravenous (IV) administration of vardenafil (1–30 μg/kg) or sildenafil (10–30 μg/kg). Erectile response was assessed by continuously recording intracavernosal pressure (ICP) and systemic arterial pressure (SAP). All data were expressed as a ratio of ICP:SAP. IV administration of either PDE 5 inhibitor facilitated PNS‐induced erection and increased ICP:SAP in a dose‐dependent manner, reaching peak response at approximately 5 minutes. However, the threshold dose at which facilitation of erection occurred was lower for vardenafil (3 μg/kg) than for sildenafil (10 μg/kg). At the 10‐μg/kg dose (IV), the response duration was significantly greater with vardenafil (169 ± 23 seconds) than with sildenafil (137 ± 31 seconds). Direct intracavernosal (IC) injection of 1–30 μg/kg vardenafil or sildenafil also caused dose‐dependent increases in ICP: SAP in the absence of PNS. Response durations increased in a dose‐dependent manner and lasted more than 5 times that of IV drug administration coupled with PNS. Irrespective of the route of administration (IC or IV), at equivalent doses, vardenafil was significantly more efficacious than sildenafil in facilitating pelvic nerve‐mediated penile erection and in eliciting erection in the absence of PNS. The increases in ICPs occurred more quickly, were of larger magnitude, and were sustained for longer durations for vardenafil than for sildenafil. On the basis of the biochemical data and physiological responses from this study, further clinical evaluation of vardenafil as treatment for erectile dysfunction is warranted.
This study was designed to determine the utility and validity of laser oximetry in measuring changes in penile hemodynamics. Anesthetized male New Zealand White Rabbits were divided into 2 groups, ...and penile hemodynamics were assessed by either laser oximetry (oxyhemoglobin, deoxyhemoglobin concentration, and oxygen saturation) or intracavernosal pressure (ICP) monitoring during penile erection induced by pelvic nerve stimulation (PNS) or intracavernosal administration of phentolamine, nitroprusside, papaverine, or sildenafil. PNS caused significant frequency‐dependent increases in penile ICP. PNS also caused significant increases in penile tissue oxyhemoglobin concentrations and tissue oxygen saturation in a frequency‐dependent manner. The changes in oxyhemoglobin concentrations and oxygen saturation correlated with frequency‐dependent increases in ICP. Intracavernosal vasoactive drug administration produced significant increases in ICP, tissue oxyhemoglobin concentration, oxygen saturation, and duration of response as a function of increasing drug concentration. Laser oximetry permits reproducible and valid assessment of changes in penile hemodynamics comparable to conventional ICP measurements. Thus, we consider laser oximetry a reliable technique in evaluating penile hemodynamics. Its sensitivity in detecting small changes in oxyhemoglobin concentration and its noninvasive nature make it advantageous over invasive methods such as ICP monitoring and laser Doppler flowmetry.
