Thermal and Mechanical Pain Thresholds of Women With Provoked Localized Vulvodynia: A Pilot Study.

CONTEXT: Vulvodynia is a chronic pain condition defined as vulvar pain lasting at least 3 months in the absence of gross anatomic or neurologic findings. Provoked, localized vulvodynia (PLV), a subtype of vulvodynia, is characterized by vestibular pain in response to light touch. The cause of PLV remains largely unknown, and triggering events have yet to be determined. OBJECTIVE: To evaluate vestibular and peripheral experimental pain thresholds in patients with PLV to further define the somatosensory profile of these patients. METHODS: After informed consent was provided, eligible participants completed a questionnaire and underwent quantitative sensory testing at the forearm and posterior vestibule. Detection and pain thresholds to thermal (cold and heat) and mechanical (pressure) stimuli were measured. RESULTS: Seventeen participants with PLV and 16 control participants were included. Participants in the PLV group scored lower on the patient health questionnaire 9 (PHQ-9) compared with those in the control group (P<.05) and had higher ratings of self-reported genital pain with sex (P<.001) and daily activity (P<.05). Forearm pain thresholds to cold (P<.01) and heat (P<.01) stimuli were also lower in the PLV group compared with those in the control group. Vestibular pain thresholds to cold (P<.05) and pressure (P<.01) stimuli were also lower in the PLV group. CONCLUSION: Lower scores on the PHQ-9 and higher self-reported genital pain ratings of patients with PLV highlight the significant impact of this poorly understood condition on quality of life. Quantitative sensory testing results demonstrated that vestibular cold allodynia may be a somatosensory feature of PLV. Reduced forearm pain thresholds in these patients suggest altered sensory processing at extrapelvic sites, although it is unclear whether these measurements are related to central sensitization.

Women in Osteopathic and Allopathic Medical Schools: An Analysis of Applicants, Matriculants, Enrollment, and Chief Academic Officers.

In the 1993-1994 academic year, female enrollment was 34.7% in osteopathic medical schools and 40.2% in allopathic medical schools. To assess progress in female enrollment since that time, the authors examined admission data in the ensuing years, including female applicants, matriculants, and first-year students in osteopathic and allopathic medical schools, as well as female chief academic officers at these institutions. In the 2004-2005 academic year, 50.3% of first-year students in osteopathic medical schools were women; however, by the 2013-2014 academic year, that figure dropped to 44.2%. The percentage rose slightly by the 2016-2017 academic year to 45.9%. Additionally, for the 2016-2017 academic year, allopathic medical schools had a significantly higher proportion of female matriculants than did osteopathic medical schools (49.8% vs 45.9%, respectively; P<.001).

Sex-dependent expression of TRPV1 in bladder arterioles.

Transient receptor potential vanilloid type 1 (TRPV1) is a major nociceptive ion channel implicated in bladder physiology and/or pathophysiology. However, the precise expression of TRPV1 in neuronal vs. nonneuronal bladder cells is uncertain. Here we used reporter mouse lines (TRPV1-Cre:tdTomato and TRPV1PLAP-nlacZ) to map expression of TRPV1 in postnatal bladder. TRPV1 was not detected in the urothelium, however, we found marked expression of TRPV1 lineage in sensory nerves, and surprisingly, in arterial/arteriolar smooth muscle (ASM) cells. Tomato fluorescence was prominent in the vesical arteries and in small-diameter (15-40 µm) arterioles located in the suburothelial layer with a near equal distribution in bladder dome and base. Notably, arteriolar TRPV1 expression was greater in females than in males and increased in both sexes after 90 days of age, suggesting sex hormone and age dependency. Analysis of whole bladder and vesical artery TRPV1 mRNA revealed a similar sex and developmental dependence. Pharmacological experiments confirmed functional TRPV1 protein expression; capsaicin increased intracellular Ca2+ in ∼15% of ASM cells from wild-type female bladders, but we observed no responses to capsaicin in bladder arterioles isolated from TRPV1-null mice. Furthermore, capsaicin triggered arteriole constriction that was rapidly reversed by the TRPV1 antagonist, BCTC. These data show that predominantly in postpubertal female mice, bladder ASM cells express functional TRPV1 channels that may act to constrict arterioles. TRPV1 may therefore play an important role in regulating the microcirculation of the female bladder, and this effect may be of significance during inflammatory conditions.

Effects of Rho-kinase inhibition on myosin light chain phosphorylation and obstruction-induced detrusor overactivity.

OBJECTIVES: To study the relationship between myosin light chain phosphorylation of the detrusor muscle and spontaneous smooth muscle contractions in a rabbit model of partial outlet obstruction. METHODS: New Zealand white rabbit urinary bladders were partially obstructed for 2 weeks. Rabbits were euthanized, detrusor muscle strips were hung on a force transducer and spontaneous activity was measured at varying concentrations (0-0.03 µM/L) of the Rho-kinase inhibitors GSK 576371 or 0.01 µM/L Y27632. Basal myosin light chain phosphorylation was measured by 2-D gel electrophoresis in control and GSK 576371-treated strips. RESULTS: Both drugs suppressed the force of spontaneous contractions, whereas GSK 576371 had a more profound effect on the frequency of the contractions. The IC50 values for the inhibition of frequency and force of spontaneous contractions were 0.17 µM/L and 0.023 µM/L for GSK 576371, respectively. The compound significantly decreased the basal myosin light chain phosphorylation from 28.0 ± 3.9% to 13.5 ± 1.9% (P < 0.05). At 0.01 µM/L, GSK 576371 inhibited spontaneous bladder overactivity by 50%, but inhibited carbachol-elicited contractions force by just 25%. CONCLUSIONS: These data suggest that Rho-kinase regulation of myosin light chain phosphorylation contributes to the spontaneous detrusor activity induced by obstruction. This finding could have therapeutic implications by providing another therapeutic option for myogenic, overactive bladder.

Effect of estrogen on molecular and functional characteristics of the rodent vaginal muscularis.

INTRODUCTION: Vaginal atrophy is a consequence of menopause; however, little is known concerning the effect of a decrease in systemic estrogen on vaginal smooth muscle structure and function. As the incidence of pelvic floor disorders increases with age, it is important to determine if estrogen regulates the molecular composition and contractility of the vaginal muscularis. AIM: The goal of this study was to determine the effect of estrogen on molecular and functional characteristics of the vaginal muscularis utilizing a rodent model of surgical menopause. METHODS: Three- to 4-month old Sprague-Dawley rats underwent sham laparotomy (Sham, N = 18) or ovariectomy (Ovx, N = 39). Two weeks following surgery, animals received a subcutaneous osmotic pump containing vehicle (Sham, Ovx) or 17ß-estradiol (Ovx). Animals were euthanized 1 week later, and the proximal vagina was collected for analysis of contractile protein expression and in vitro studies of contractility. Measurements were analyzed using a one-way analysis of variance followed by Tukey's post hoc analysis (α = 0.05). MAIN OUTCOME MEASURES: Protein and mRNA transcript expression levels of contractile proteins, in vitro measurements of vaginal contractility. RESULTS: Ovariectomy decreased the expression of carboxyl-terminal myosin heavy chain isoform (SM1) and h-caldesmon and reduced the amplitude of contraction of the vaginal muscularis in response to KCl. Estradiol replacement reversed these changes. No differences were detected in the % vaginal muscularis, mRNA transcript expression of amino-terminal MHC isoforms, l-caldesmon expression, and maximal velocity of shortening. CONCLUSION: Systemic estrogen replacement restores functional and molecular characteristics of the vaginal muscularis of ovariectomized rats. Our results indicate that menopause is associated with changes in the vaginal muscularis, which may contribute to the increased incidence of pelvic floor disorders with age.

The effects of hormonal contraceptives on female sexuality: a review.

INTRODUCTION: Hormonal contraceptives can influence female sexual function. AIM: The goal of this article was to provide a comprehensive review of the effects that various hormonal contraceptives may have on female sexual function. METHODS: A Medline search was conducted using several terms related to and including the terms contraception, oral contraceptive, female sexual function, dyspareunia, libido, and sexual desire. RESULTS: A thorough review of the effects of hormonal contraceptives on female sexual function. CONCLUSIONS: The sexual side effects of hormonal contraceptives are not well studied, particularly with regard to impact on libido. There appears to be mixed effects on libido, with a small percentage of women experiencing an increase or a decrease, and the majority being unaffected. Healthcare providers must be aware that hormonal contraceptive can have negative effects on female sexuality so they can counsel and care for their patients appropriately.

Contractile response of human anterior vaginal muscularis in women with and without pelvic organ prolapse.

The aim of this study was to compare the contractility of the anterior vaginal muscularis (AVM) from women with and without pelvic organ prolapse (POP). In vitro experiments were performed to measure the peak force generated in response to potassium chloride (KCl; 125 mmol/L) and phenylephrine by AVM tissue from women with and without POP. Cross-sectional areas and co-localization of α(1A) adrenergic receptor protein with smooth muscle α-actin in AVM strips were determined by histology and immunofluorescence, respectively. There were no differences in the mean amplitude of force generated in response to KCl normalized to either wet weight or muscle cross-sectional area (mN/mm(2)) between women with and without POP (P > .30). However, AVM from women with prolapse produced a significantly higher mean force to KCl normalized to total cross-sectional area compared to controls (P = .007). While the control samples demonstrated a consistent response to phenylephrine, there was no response to this stimulant generated by AVM tissue from women with POP. The proportion of co-localized α(1A) adrenergic receptors with smooth muscle α actin in AVM tissue was significantly less in women with POP compared to normal controls (P < .0001). Although there was significantly greater tissue stress generated by AVM from women with prolapse compared to controls, there were no differences in muscle stress. Absent response to phenylephrine by AVM from women with prolapse may be related to a lower expression of α(1A) adrenergic receptors in vaginal smooth muscle.

Functional significance of muscarinic receptor expression within the proximal and distal rat vagina.

Information regarding the role of cholinergic nerves in mediating vaginal smooth muscle contraction is sparse, and in vitro studies of the effects of muscarinic agonists on vaginal smooth muscle are discrepant. The goal of this study was to determine the expression of muscarinic receptors in the vaginal wall of the rat. In addition, we sought to determine the effect of the muscarinic receptor agonist carbachol on contractility and inositol phosphate production of the proximal and distal rat vaginal muscularis. RT-PCR analysis indicated that both M(2) and M(3) receptor transcripts were expressed within the proximal and distal rat vagina. Carbachol dose-dependently (10(-7)-10(-4) M) contracted the rat vaginal muscularis with a greater maximal contractile response in the proximal vagina (P < 0.01) compared with the distal vagina. The contractile responses of the rat vaginal muscularis to carbachol were dose dependently inhibited by the M(3) antagonist para-fluoro-hexahydrosiladefenidol, and a pK(B) of 7.78 and 7.95 was calculated for the proximal and distal vagina, respectively. Inositol phosphate production was significantly increased in both regions of the vagina following 20-min exposure to 50 muM carbachol with higher levels detected in the proximal vagina compared with the distal (P < 0.05). Preliminary experiments indicated the presence of M(2) and M(3) receptors in the human vaginal muscularis as well as contraction of human vaginal muscularis to carbachol, indicating that our animal studies are relevant to human tissue. Our results provide strong evidence for the functional significance of M(3) receptor expression in the vaginal muscularis.

Regional differences in myosin heavy chain isoform expression and maximal shortening velocity of the rat vaginal wall smooth muscle.

Contractility of the proximal and distal vaginal wall smooth muscle may play distinct roles in the female sexual response and pelvic support. The goal of this study was to determine whether differences in contractile characteristics of smooth muscle from these regions reside in differences in the expression of isoforms of myosin, the molecular motor for muscle contraction. Adult female Sprague-Dawley rats were killed on the day of estrus, and the vagina was dissected into proximal and distal segments. The Vmax at peak force was greater for tissue strips of the proximal vagina compared with that of distal (P < 0.01), although, at steady state, the Vmax for the muscle strips from the two regions was not different. Furthermore, at steady state, muscle stress was higher (P < 0.001) for distal vaginal strips (n = 5). Consistent with the high Vmax for the proximal vaginal strips, RT-PCR results revealed a higher %SM-B (P < 0.001) in the proximal vagina. A greater expression of SM-B protein (P < 0.001) was also detected by Western blotting (n = 4). Interestingly, there was no regional difference noted in SM-1/SM-2 isoforms (n = 6). The proximal vagina had a higher expression of myosin heavy chain protein (P < 0.01) and a greater percentage of smooth muscle bundles (P < 0.001). The results of this study are the first demonstration of a regional heterogeneity in Vmax and myosin isoform distribution in the vagina wall smooth muscle and confirm that the proximal vaginal smooth muscle exhibits phasic contractile characteristics compared with the distal vaginal smooth muscle, which is tonic.