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Background: Neuroproliferative vestibulodynia (NPV), a provoked genital pain characterized by severe allodynia and hyperalgesia, is confirmed in excised vestibular tissue by immunohistochemical staining (>8 CD117-positive immunostained cells/100× microscopic field) rather than by hematoxylin and eosin staining. Aim: In this study we sought to assess immunostaining of tissue samples obtained during vestibulectomy surgery and to correlate results with patient outcomes. Methods: Patients (n = 65) meeting criteria for NPV who underwent vestibulectomy during the period from June 2019 through December 2022 formed the study cohort. We performed assessment of pathology of vestibular tissues by use of immunohistochemical staining, including quantitation of mast cells by CD117 (mast cell marker) and nerve fibers by protein gene product (PGP) 9.5 (neuronal marker). We analyzed 725 photomicrographs of immunostained tissue sections (100× and 200×) by manual counting and computer-assisted histometry and correlated these data to clinical assessments. Outcomes: Outcomes included density of CD117 and PGP9.5 immunostaining in the 1:00-11:00 o'clock and 12:00 o'clock vestibular regions, and patient-reported outcomes assessing sexual function, pain, distress, and symptom improvement. Results: All 65 NPV patients (median age 26 years), 45 with lifelong and 20 with acquired NPV, had severe pain documented by PROs and vulvoscopy and had >8 CD117-immunopositive cells/100× microscopic field. Median cell count values were similar in the 1:00-11:00 o'clock and 12:00 vestibular regions (28.5 and 29.5/100× field, respectively). Likewise, the marker) and nerve fibers by protein gene product (PGP) 9.5 (neuronal marker). We analyzed 725 photomicrographs of immunostained tissue sections (100× and 200×) by manual counting and computer-assisted histometry and correlated these data to clinical assessments. Outcomes: Outcomes included density of CD117 and PGP9.5 immunostaining in the 1:00-11:00 o'clock and 12:00 o'clock vestibular regions, and patient-reported outcomes assessing sexual function, pain, distress, and symptom improvement. Results: All 65 NPV patients (median age 26 years), 45 with lifelong and 20 with acquired NPV, had severe pain documented by PROs and vulvoscopy and had >8 CD117-immunopositive cells/100× microscopic field. Median cell count values were similar in the 1:00-11:00 o'clock and 12:00 vestibular regions (28.5 and 29.5/100× field, respectively). Likewise, the median area of CD117 immunostaining was similar in both regions (0.69% and 0.73%). The median area of PGP9.5 immunostaining was 0.47% and 0.31% in these same regions. Pain scores determined with cotton-tipped swab testing were nominally higher in lifelong vs acquired NPV patients, reaching statistical significance in the 1:00-11:00 o'clock region (P <.001). The median score for the McGill Pain Questionnaire affective subscale dimension was also significantly higher in lifelong vs acquired NPV patients (P =.011). No correlations were observed between hematoxylin and eosin results and density of mast cells or neuronal markers. Of note, 63% of the patient cohort reported having additional conditions associated with aberrant mast cell activity. Clinical Implications: The pathology of NPV is primarily localized to the vestibular epithelial basement membrane and subepithelial stroma with no visible vulvoscopic findings, making clinical diagnosis challenging. Strengths and Limitations: Strengths of this study include the large number of tissues examined with what is to our knowledge the first-ever assessment of the 12:00 vestibule. Major limitations are specimens from a single timepoint within the disease state and lack of control tissues. Conclusions: Performing immunohistochemical staining of excised vestibular tissue with CD117 and PGP9.5 led to histometric confirmation of NPV, indications that NPV is a field disease involving all vestibular regions, validation for patients whose pain had been ignored and who had experienced negative psychosocial impact, and appreciation that such staining can advance knowledge. [ABSTRACT FROM AUTHOR]

The article reviews articles including "Analysis of Erectile Responses to Imatinib in the Rat" by E.A. Pankey and colleagues, "Modular Genetic Control of Sexually Dimorphic Behaviors" by J.K. Coats and colleagues and "Sexual Fantasies and Female Hypoactive Desire" by C. Nanini and colleagues.

In this article, the author presents his comments over various medical studies in order to evaluate the significance of the findings and conclusions from the studies. He mentions his comments over several medical studies related to topics including attention-deficit hyperactivity disorder, comparative studies on hypersexual women and hypersexual men, and bibliotherapy for low sexual desire. He also mentions rating scale to calculate level of evidence of the studies.

Background Data are limited regarding fractional CO2 laser as a nonhormonal treatment for vestibular pain. Aim We sought to perform what is, to our knowledge, the first multisite prospective randomized, double-blind, sham-controlled clinical trial to assess the safety and efficacy of fractional CO2 laser treatment to the vestibule in women with vestibular pain. Methods Subjects (n  = 70) meeting inclusion/exclusion criteria at each of 3 sites were randomized 2:1 to active or sham (zero energy) fractional CO2 laser treatment using the vestibular probe (SmartXide2 V2LR - MonaLisa Touch, DEKA, Florence, Italy). Subjects in each treatment arm received 3 treatments 4 weeks apart. At the initial follow-up (week 12), subjects were unblinded and those initially assigned to sham started active treatment. Outcomes Outcome measures included changes from baseline in sexual activity diaries and scores for the Vulvoscopic Genital Tissue Appearance Scale (VGTA), vestibular cotton-tipped swab testing, McGill Pain Questionnaire, Female Sexual Function Index (FSFI), Female Sexual Distress Scale–Revised (FSDS-R), and the O'Leary-Sant voiding and pain indices, the Interstitial Cystitis Symptom Index (ICSI) and Interstitial Cystitis Problem Index (ICPI). Results After active treatment, VGTA scores significantly improved in 5 parameters. Pain associated with cotton-tipped swab testing was significantly reduced at weeks 4 through 16 (mean change from baseline −0.64 [95% CI, −0.79 to −0.50] and −1.31 [95% CI, −1.46 to −1.16], respectively). FSFI pain domain scores improved significantly at weeks 12 and 16 (mean change from baseline 0.925 [95% CI, 0.10-1.75] and 1.22 [95% CI, 0.40-2.05], respectively). FSFI total scores increased significantly at weeks 12 and 16 (mean change from baseline 6.24 [95% CI, 2.64-9.85] and 4.96 [95% CI, 1.36-8.57], respectively). FSDS-R scores decreased significantly at weeks 12 and 16 (mean change from baseline −5.84 [95% CI, −8.80 to −2.87] and −9.15 [95% CI, −12.11 to −6.18], respectively). ICSI scores decreased significantly at weeks 12 and 16 (mean change from baseline −0.91 [95% CI, −1.65 to −0.18] and −0.754 [95% CI, −1.49 to −0.02], respectively). ICPI scores decreased significantly at week 16 (mean change from baseline −0.99 [95% CI, −1.63 to −0.34]). In contrast, there were no significant changes in outcomes in the sham arm. No serious adverse events occurred. Clinical Implications Fractional CO2 laser treatment in women with vestibular pain resulted in improvement from baseline in multiple key outcome measures of vestibular health. Strengths and Limitations Strengths of the study were that it was a multisite prospective randomized double-blind, sham-controlled clinical trial that included multiple measures related to vestibular pain and sexual function. Limitations were the nonvalidated primary outcome measure and limited study cohort. Conclusion Fractional CO2 laser therapy is a safe and effective nonhormonal treatment for vestibular pain. [ABSTRACT FROM AUTHOR]

A review of several articles including "Protective effect of annexin-A1 against irreversible damage to cavernous tissue after cavernous nerve injury in the rat," by F.N. Facio, "Neuroendocrine regulatory peptide-1 and neuroendocrine regulatory peptide-2 influence differentially feeding and penile erection in male rats: Sites of action in the brain," by M.R. Melis and "Evidence that sex chromosome genes affect sexual differentiation of female sexual behavior," by N. Grgurevic is presented.

The article offers information on several researches on sexual medicine published in various journals. One study by JC Woo and colleagues investigated the transplantation of muscle-derived stem cells into the corpus cavernosum restores erectile function in a rat model of cavernous nerve injury. Another study by M Albersen and colleagues examined functional, metabolic and morphologic characters of a novel rat model of type 2 diabetes-associated erectile dysfunction.

The article reviews several articles including "Insulin-like growth factor-1 gene delivery may enhance the proliferation of human corpus cavernosal smooth muscle cells," by M. Kim, E. C. Hwang, I. K. Pang and K. Park, "Sexual function in women with overactive bladder," by A. Zahariou, M. Karamouti, E. Tyligada and P. Papaioannou and "Age-related changes in kallikreinskinins system in rat corpus cavernosum," by T. Wang, Z. H. Wan, J. H. Liu, M. Y. Chen, R. B. Chen, W. M. Yang and Z. Q. Ye.

The article presents editorial comments on various studies of sexual health. Claudino and his colleagues characterized the biochemical changes in rats associated with a regimen of exercise started after chronic inhibition of nitric oxide (NO) synthesis with nitro-L-arginine methyl ester (L-NAME) treatment. Another study examined a mechanism of regulation which is the cell function antagonism by distinct and independent signaling pathways. The role of absorption in the sexual response of women to erotica was evaluated by J. Sheen and colleagues.

This section presents comments on several studies related to sexual medicine. The importance of polylactic-co-glycolic acid (PLGA) is showed in "Intravaginal Gene Silencing Using Biodegradable Polymer Nanoparticles Densely Loaded with Small-interfering RNA." In "Help-seeking Behavior of Women with Self-reported Distressing Sexual Problems," only 34% of the polled women were able to discuss sexual problems with a healthcare provider. Changes in sexual function is highlighted in "Does Spontaneous Genital Tract Trauma Impact Postpartum Sexual Function?"

Introduction. Women with diabetes experience diminished genital arousal, reduced vaginal lubrication, vaginal atrophy, dyspareunia, and increased infections. Limited studies are available investigating the effects of diabetic complications on the vagina. Aims. The goals of this study were to investigate type 2 diabetes-induced changes in vaginal structure, and to determine if estradiol treatment ameliorates these changes. Methods. Eight-week-old female diabetic (db/db) mice (strain BKS.Cg-m+/+ Leprdb/J) and age-matched control normoglycemic female littermates were used to investigate the effects of type 2 diabetes on vaginal tissue structural integrity. Diabetic animals were divided into two subgroups: diabetic treated with vehicle only and diabetic treated with pellets containing estradiol. At 16 weeks, the animals were sacrificed, and the vaginal tissues were excised and analyzed by histological and immunohistochemical methods to assess diabetes-induced changes in vaginal tissue and the extent by which these parameters are restored by estradiol treatment. Main Outcome Measures. The effects of type 2 diabetes and estradiol supplementation were investigated on vaginal histoarchitecture. Results. Diabetic animals exhibited high blood glucose levels (>600 mg/dL), increased body weight (43.0 ± 6.0 g vs. 24.4 ± 2.0 g), and reduced plasma estradiol levels (65.5 ± 6.6 pg/mL vs. 80.77 ± 13.2 pg/mL) when compared to control animals. Diabetes resulted in significant thinning of the epithelium ( P ≤ 0.05), marked decrease in the muscularis area ( P ≤ 0.05), distinct truncation of elastic fibers, and significant reduction of the nitrergic immunoreactive nerve fibers ( P ≤ 0.05). Treatment of diabetic animals with estradiol restored epithelial thickness ( P ≤ 0.05), muscularis area ( P ≤ 0.05), and elastic fiber distribution, and partially restored the density of nitrergic nerve fibers. Conclusions. The data in this study demonstrate that type 2 diabetes disrupts vaginal structural integrity and that estradiol supplementation ameliorates the diabetes-induced vaginal pathology. Cushman TT, Kim N, Hoyt R, and Traish A. Estradiol ameliorates diabetes-induced changes in vaginal structure of db/db mouse model. J Sex Med 2009;6:2467–2479. [ABSTRACT FROM AUTHOR]

Introduction. Diabetes is associated with gender-specific changes in sex steroid hormones. However, the mechanisms responsible for these associations as well as the link to sexual dysfunction are not well understood. Aim. To discuss key clinical and laboratory findings linking diabetes, sex steroid hormones, and sexual dysfunction, with particular focus on the female gender. Methods. A comprehensive literature review was conducted using the PubMed database. Search terms were used in appropriate combinations, including diabetes, insulin, insulin sensitivity, androgen, estrogen, sexual function, women, men, estrogen receptor, and androgen receptor. Over 400 citations were selected, based on topical relevance, and examined for study methodology and major findings. Main Outcome Measures. Data from peer-reviewed publications. Results. Imbalances in sex steroid hormone levels are strongly associated with diabetes and this may negatively impact upon sexual function. Although numerous factors are likely to contribute to the development of diabetes and its complications, the role of sex steroid hormones must be acknowledged. Conclusions. Research related to diabetic women and sexual dysfunction is severely lacking. Identifying underlying causes for a given hormonal imbalance in diabetic patients, as well as determination of genetic and age-dependent factors, will become important in identifying the subpopulations in which hormonal replacement regimens will be most effective. Investigation into treating diabetic patients with adjunct hormonal therapies or steroid hormone receptor modulators holds much promise. Kim NN. Sex steroid hormones in diabetes-induced sexual dysfunction: Focus on the female gender. J Sex Med 2009;6(suppl 3):239–246. [ABSTRACT FROM AUTHOR]

The article comments on various studies related to sexual medicine. These studies include the relation of estrogen receptors to neural receptive tissue of the labia minora, the prevalence of women who have sex with women in Great Britain and the sexual behavior in later life. Analyses of clinical research on female and male sexual health are presented.

A commentary about the effectiveness of vardenafil and sildenafil in the management of erectile dysfunction (ED) is presented. The authors discuss whether vardenafil is noninferior over sildenafil in treating ED. They claim that the key findings from biochemical, physiological and in vitro animal studies suggest that vardenafil is superior over sidenafil. They offer an explanation why the successful use of phosphodiesterase type 5 (PDE5) inhibitors in treating ED.

Introduction. Despite the widespread use of prostaglandin E1 as an efficacious treatment for male erectile dysfunction for more than two decades, research on prostanoid function in penile physiology has been limited. Aim. To characterize the pharmacological and physiological activity of novel subtype-selective EP and DP receptor agonists. Methods. Radioligand binding and second messenger assays were used to define receptor subtype specificity of the EP and DP agonists. Functional activity was further characterized using isolated human and rabbit penile cavernosal tissue in organ baths. In vivo activity was assessed in rabbits and rats by measuring changes in cavernous pressure after intracavernosal injection of receptor agonists. Main Outcome Measures. Receptor binding and signal transduction, smooth muscle contractile activity, erectile function. Results. In organ bath preparations of human cavernosal tissue contracted with phenylephrine, EP2- and EP4-selective agonists exhibited variable potency in causing relaxation. One of the compounds caused mild contraction, and none of the compounds was as effective as PGE1 (EC50 = 0.23 µM). There was no consistent correlation between the pharmacological profile (receptor binding and second messenger assays) of the EP agonists and their effect on cavernosal tissue tone. In contrast, the DP1-selective agonist AS702224 (EC50 =29 nM) was more effective in relaxing human cavernosal tissue than either PGE1, PGD2 (EC50 = 58 nM), or the DP agonist BW245C (EC50 =59 nM). In rabbit cavernosal tissue, PGE1 and PGD2 caused only contraction, while AS702224 and BW245C caused relaxation. Intracavernosal administration of AS702224 and BW245C also caused penile tumescence in rabbits and rats. For each compound, the erectile response improved with increasing dose and was significantly higher than vehicle alone. Conclusions. These data suggest that AS702224 is a potent DP1-selective agonist that causes penile erection. The DP1 receptor mediates relaxation in human cavernosal tissue, and stimulates pro-erectile responses in rat and rabbit. Thus, rabbits and rats can be useful models for investigating the physiological function of DP1 receptors. Brugger N, Kim NN, Araldi GL, Traish AM, and Palmer SS. Pharmacological and functional characterization of novel EP and DP receptor agonists: DP1 receptor mediates penile erection in multiple species. J Sex Med 2008;5:344–356. [ABSTRACT FROM AUTHOR]

The article reviews studies related to medicine including "Role of the Nitric Oxide Pathway and the Endocannabinoid System in Neurogenic Relaxation of Corpus Cavernosum from Biliary Cirrhotic Rats," by M. Ghasemi, H. Sadeghipour et al, "Aging Causes Cytoplasmic Retention of MaxiK Channels in Rat Corporal Smooth Muscle Cells," by K. P. Davies, Y. Stanevsky, M. T. Tar et al and "Sexual Function and Dysfunction in Brazilian Patients With Obsessive-Compulsive Disorder and Social Anxiety Disorder," by L. F. Fontenelle, W. F. de Souza et al.

The section reviews research related to sexual medicine. It includes "Mesenchymal stem cells alone or ex vivo gene modified with endothelial nitric oxide synthase reverse age-associated erectile dysfunction," "Using gene chips to identify organ-specific, smooth muscle responses to experimental diabetes: Potential applications to urological diseases," and "Obesity and sexual quality of life."

Editorial comments on the articles published in various scientific journals are presented. They include "Cytochrome P450 epoxygenases provide a novel mechanism for penile erection," from the FASEB Journal, 2006, "Synchronous prosthetic implantation through a transscrotal incision: An outcome analysis," from the Journal of Urology, 2006, and "Women's history of sexual abuse, their sexuality, and sexual self-schemas," from the Journal of Consultant Clinical Psychology, 2006 issue.

Comments on several studies concerning sexual health. Mechanism of priapism; Regulation of intracellular calcium concentration in corpus cavernosum smooth muscle; Effects of pregnancy on sexual life.

It is generally accepted that androgens are critical for development, growth, and maintenance of penile erectile tissue. However, their role in erectile function, especially in humans, remains controversial. Clinical and preclinical studies have suggested that venoocclusion is modulated by the tone of the vascular smooth muscle of the resistance arteries and the cavernosal tissue and a balance between trabecular smooth muscle content and connective tissue matrix. In men with erectile dysfunction, venous leakage is thought to be a common condition among nonresponders to medical management and is attributed to penile smooth muscle atrophy. In the animal model, androgen deprivation produces penile tissue atrophy concomitant with alterations in dorsal nerve structure, endothelial morphology, reduction in trabecular smooth muscle content, and increased deposition of extracellular matrix. Further, androgen deprivation results in accumulation of fat-containing cells (adipocytes) in the subtunical region of the corpus cavernosum. Androgen deficiency diminishes protein expression and enzymatic activity of nitric oxide synthases (eNOS and nNOS) and phosphodiesterase type 5 (PDE5). The androgen-dependent loss of erectile response is restored by androgen administration but not by administration of PDE5 inhibitors alone. These data suggest that androgens regulate trabecular smooth muscle growth and connective tissue protein synthesis in the corpus cavernosum. Further, androgens may stimulate differentiation of progenitor cells into smooth muscle cells and inhibit their differentiation into adipocytes. Thus, we conclude that androgens exert a direct effect on penile tissue to maintain erectile function and that androgen-deficiency produces a metabolic and structural imbalance in the corpus cavernosum, resulting in venous leakage and erectile dysfunction. Traish A, Kim N. The physiological role of androgens in penile erection: regulation of corpus cavernosum structure and function. J Sex Med 2005;2:759–770. [ABSTRACT FROM AUTHOR]

Background: There are currently no Food and Drug Administration–approved treatments for female sexual arousal disorder (FSAD), which is physiologically analogous to male erectile dysfunction. Aims: The study sought to test the systemic and local genital safety of topical sildenafil cream, 3.6% (sildenafil cream) among healthy premenopausal women with FSAD and their sexual partners over a 12-week treatment period. Methods: This was a phase 2b, exploratory, randomized, placebo-controlled, double-blind study of sildenafil cream among healthy premenopausal women with FSAD. Safety was assessed by the frequency and incidence of treatment-emergent adverse events (TEAEs) among participants and their sexual partners. Participants recorded the incidence of TEAEs in a daily eDiary (electronic diary). Sexual partners were contacted within 72 hours of each sexual event in which investigational product was used. All participants used placebo cream for 1 month, during a single-blind run-in period, and then if eligible, were randomized 1:1 to sildenafil cream or placebo cream. Participants used their assigned investigational product over a 12-week double-blind dosing period. They attended monthly follow-up visits, in which their eDiary TEAE data were reviewed by the study staff and graded for severity and relationship to study product. Outcomes: The frequency and incidence of TEAEs among participants and their sexual partners. Results: During the 12-week double-blind dosing period, there were 78 TEAEs reported by 29 of 99 sildenafil-assigned participants and 65 TEAEs reported by 28 of 94 placebo-assigned participants (P = .76). All TEAEs were mild or moderate in severity. The most common treatment-related TEAE among active and placebo-assigned participants was application site discomfort. There were no differences in the number of treatment-related TEAEs among sildenafil cream vs placebo cream users (P > .99). Four sildenafil cream participants and 3 placebo cream participants discontinued the study due to TEAEs involving application site discomfort (P > .99). There were 9 TEAEs reported by 7 of 91 sexual partners exposed to sildenafil cream vs 4 TEAEs reported by 4 of 84 sexual partners exposed to placebo cream (P = .54). Clinical Implications: These data support further clinical development of topical sildenafil cream for the treatment of FSAD. Strengths and Limitations: Safety was assessed among participants and their sexual partners after 1357 and 1160 sexual experiences in which sildenafil cream or placebo cream were used, respectively. The phase 2b study was powered for the primary objectives of efficacy, rather than safety. Conclusion: These data demonstrate that topically applied sildenafil cream was safe and well tolerated by exposed users and their sexual partners. [ABSTRACT FROM AUTHOR]

The article features Female Sexual Dysfunction (FSD). FSD is a sexual disorder that is characterized by symptoms such as diminished sexual desire and vaginal lubrication, increased time for arousal, diminished vaginal and clitoral sensation, difficulty with orgasm, and pain. The author states that organic pathophysiologic conditions influence FSD.

Background: In 1999, 1 year after the approval of the first oral phosphodiesterase type 5 (PDE5) inhibitor for the treatment of erectile dysfunction (ED), the first Princeton Consensus Conference was held to address the clinical management of men with ED who also had cardiovascular disease. These issues were readdressed in the second and third conferences. In the 13 years since the last Princeton Consensus Conference, the experience with PDE5 inhibitors is more robust, and recent new data have emerged regarding not only safety and drug–drug interactions, but also a potential cardioprotective effect of these drugs. Aim: In March 2023, an interdisciplinary group of scientists and practitioners met for the fourth Princeton Consensus Guidelines at the Huntington Medical Research Institutes in Pasadena, California, to readdress the cardiovascular workup of men presenting with ED as well as the approach to treatment of ED in men with known cardiovascular disease. Method: A series of lectures from experts in the field followed by Delphi-type discussions were developed to reach consensus. Outcomes: Consensus was reached regarding a number of issues related to erectile dysfunction and the interaction with cardiovascular health and phosphodiesterase-5 inhibitors. Results: An algorithm based on recent recommendations of the American College of Cardiology and American Heart Association, including the use of computed tomography coronary artery calcium scoring, was integrated into the evaluation of men presenting with ED. Additionally, the issue of nitrate use was further considered in an algorithm regarding the treatment of ED patients with coronary artery disease. Other topics included the psychological effect of ED and the benefits of treating it; the mechanism of action of the PDE5 inhibitors; drug–drug interactions; optimizing use of a PDE5 inhibitors; rare adverse events; potential cardiovascular benefits observed in recent retrospective studies; adulteration of dietary supplements with PDE5 inhibitors; the pros and cons of over-the-counter PDE5 inhibitors; non–PDE5 inhibitor therapy for ED including restorative therapies such as stem cells, platelet-rich plasma, and shock therapy; other non–PDE5 inhibitor therapies, including injection therapy and penile prostheses; the issue of safety and effectiveness of PDE5 inhibitors in women; and recommendations for future studies in the field of sexual dysfunction and PDE5 inhibitor use were discussed. Clinical Implications: Algorithms and tables were developed to help guide the clinician in dealing with the interaction of ED and cardiovascular risk and disease. Strengths and Limitations: Strengths include the expertise of the participants and consensus recommendations. Limitations included that participants were from the United States only for this particular meeting. Conclusion: The issue of the intersection between cardiovascular health and sexual health remains an important topic with new studies suggesting the cardiovascular safety of PDE5 inhibitors. [ABSTRACT FROM AUTHOR]

The article discusses views of the author in response to a study related to women with vulvodynia who started taking combined oral contraceptives (COCs). Topics discussed include treatment of vulvodynia by using estradiol and testosterone, long length of trinucleotide repeat enhancing the susceptibility to vulvodynia, increase in the risk of dysfunction in endothelium of the vulvar vestibule, clinical testing of women with ovarian dysfunction, and active vulvar infection to study vulvodynia.

The article discusses the role of testosterone in erectile physiology and pathophysiology. It describes the testosterone and androgen deprivation studies in animal models and concludes that androgen deficiency produces metabolic, structural and functional imbalance in the corpus cavernosum with synchronal changes in nerve and smooth muscle responses, and fibroelastic properties, resulting in poor tissue compliance and venous leakage, eventually producing erectile dysfunction.

Background Persistent genital arousal disorder/genitopelvic dysesthesia (PGAD/GPD) is characterized by distressing, abnormal genitopelvic sensations, especially unwanted arousal. In a subgroup of patients with PGAD/GPD, cauda equina Tarlov cyst–induced sacral radiculopathy has been reported to trigger the disorder. In our evaluation of lumbosacral magnetic resonance images in patients with PGAD/GPD and suspected sacral radiculopathy, some had no Tarlov cysts but showed lumbosacral disc annular tear pathology. Aim The aims were 2-fold: (1) to utilize a novel multidisciplinary step-care management algorithm designed to identify a subgroup of patients with PGAD/GPD and lumbosacral annular tear–induced sacral radiculopathy who could benefit from lumbar endoscopic spine surgery (LESS) and (2) to evaluate long-term safety and efficacy of LESS. Methods Clinical data were collected on patients with PGAD/GPD who underwent LESS between 2016 and 2020 with at least 1-year follow-up. LESS was indicated because all had lumbosacral annular tear–induced sacral radiculopathy confirmed by our multidisciplinary management algorithm that included the following: step A, a detailed psychosocial and medical history; step B, noninvasive assessments for sacral radiculopathy; step C, targeted diagnostic transforaminal epidural spinal injections resulting in a temporary, clinically significant reduction of PGAD/GPD symptoms; and step D, surgical intervention with LESS and postoperative follow-up. Outcomes Treatment outcome was based on the validated Patient Global Impression of Improvement, measured at postoperative intervals. Results Our cohort included 15 cisgendered women and 5 cisgendered men (mean ± SD age, 40.3 ± 16.8 years) with PGAD/GPD who fulfilled the criteria of lumbosacral annular tear–induced sacral radiculopathy based on our multidisciplinary management algorithm. Patients were followed for an average of 20 months (range, 12-37) post-LESS. Lumbosacral annular tear pathology was identified at multiple levels, the most common being L4-L5 and L5-S1. Twenty-two LESS procedures were performed in 20 patients. Overall, 80% (16/20) reported improvement on the Patient Global Impression of Improvement; 65% (13/20) reported improvement as much better or very much better. All patients were discharged the same day. There were no surgical complications. Clinical Implications Among the many recognized triggers for PGAD/GPD, this subgroup exhibited lumbosacral annular tear–induced sacral radiculopathy and experienced long-term alleviation of symptoms by LESS. Strengths and Limitations Strengths include long-term post-surgical follow-up and demonstration that LESS effectively treats patients with PGAD/GPD who have lumbosacral annular tear–induced sacral radiculopathy, as established by a multidisciplinary step-care management algorithm. Limitations include the small study cohort and the unavailability of a clinical measure specific for PGAD/GPD. Conclusion LESS is safe and effective in treating patients with PGAD/GPD who are diagnosed with lumbosacral annular tear–induced sacral radiculopathy. [ABSTRACT FROM AUTHOR]

Introduction. Female genital sexual arousal responses are complex neurophysiological processes consisting of central and peripheral components that occur following sexual stimulation. The peripheral responses in sexual arousal include genital vasocongestion, engorgement and lubrication resulting from a surge of vaginal and clitoral blood flow. These hemodynamic events are mediated by a host of neurotransmitters and vasoactive agents. Aim. To discuss the role of various biochemical factors modulating female genital sexual arousal responses. Methods. A comprehensive literature review was conducted using the PubMed database and citations were selected, based on topical relevance, and examined for study methodology and major findings. Main Outcome Measures. Data from peer-reviewed publications. Results. Adrenergic as well as non-adrenergic non-cholinergic neurotransmitters play an important role in regulating genital physiological responses by mediating vascular and non-vascular smooth muscle contractility. Vasoactive peptides and neuropeptides also modulate genital sexual responses by regulating vascular and non-vascular smooth muscle cells and epithelial function. The endocrine milieu, particularly sex steroid hormones, is critical in the maintenance of tissue structure and function. Reduced levels of estrogens and androgen are associated with dramatic alterations in genital tissue structure, including the nerve network, as well as the response to physiological modulators. Furthermore, estrogen and androgen deficiency is associated with reduced expression of sex steroid receptors and most importantly with attenuated genital blood flow and lubrication in response to pelvic nerve stimulation. Conclusions. This article provides an integrated framework describing the physiological and molecular basis of various pathophysiological conditions associated with female genital sexual arousal dysfunction. Traish AM, Botchevar E, and Kim NN. Biochemical factors modulating female genital sexual arousal physiology. J Sex Med 2010;7:2925–2946. [ABSTRACT FROM AUTHOR]

The Global Consensus Position Statement on the Use of Testosterone Therapy for Women (Global Position Statement) recommended testosterone therapy for postmenopausal women with hypoactive sexual desire disorder (HSDD). To provide a clinical practice guideline for the use of testosterone including identification of patients, laboratory testing, dosing, post-treatment monitoring, and follow-up care in women with HSDD. The International Society for the Study of Women's Sexual Health appointed a multidisciplinary panel of experts who performed a literature review of original research, meta-analyses, review papers, and consensus guidelines regarding testosterone use in women. Consensus was reached using a modified Delphi method. A clinically useful guideline following a biopsychosocial assessment and treatment approach for the safe and efficacious use of testosterone in women with HSDD was developed including measurement, indications, formulations, prescribing, dosing, monitoring, and follow-up. Although the Global Position Statement endorses testosterone therapy for only postmenopausal women, limited data also support the use in late reproductive age premenopausal women, consistent with the International Society for the Study of Women's Sexual Health Process of Care for the Management of HSDD. Systemic transdermal testosterone is recommended for women with HSDD not primarily related to modifiable factors or comorbidities such as relationship or mental health problems. Current available research supports a moderate therapeutic benefit. Safety data show no serious adverse events with physiologic testosterone use, but long-term safety has not been established. Before initiation of therapy, clinicians should provide an informed consent. Shared decision-making involves a comprehensive discussion of off-label use, as well as benefits and risks. A total testosterone level should not be used to diagnose HSDD, but as a baseline for monitoring. Government-approved transdermal male formulations can be used cautiously with dosing appropriate for women. Patients should be assessed for signs of androgen excess and total testosterone levels monitored to maintain concentrations in the physiologic premenopausal range. Compounded products cannot be recommended because of the lack of efficacy and safety data. This clinical practice guideline provides standards for safely prescribing testosterone to women with HSDD, including identification of appropriate patients, dosing, and monitoring. This evidence-based guideline builds on a recently published comprehensive meta-analysis and the Global Position Statement endorsed by numerous societies. The limitation is that testosterone therapy is not approved for women by most regulatory agencies, thereby making prescribing and proper dosing challenging. Despite substantial evidence regarding safety, efficacy, and clinical use, access to testosterone therapy for the treatment of HSDD in women remains a significant unmet need. Parish SJ, Simon JA, Davis SR, et al. International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women. J Sex Med 2021;18:849–867. [ABSTRACT FROM AUTHOR]

Persistent genital arousal disorder (PGAD), a condition of unwanted, unremitting sensations of genital arousal, is associated with a significant, negative psychosocial impact that may include emotional lability, catastrophization, and suicidal ideation. Despite being first reported in 2001, PGAD remains poorly understood. To characterize this complex condition more accurately, review the epidemiology and pathophysiology, and provide new nomenclature and guidance for evidence-based management. A panel of experts reviewed pertinent literature, discussed research and clinical experience, and used a modified Delphi method to reach consensus concerning nomenclature, etiology, and associated factors. Levels of evidence and grades of recommendation were assigned for diagnosis and treatment. The nomenclature of PGAD was broadened to include genito-pelvic dysesthesia (GPD), and a new biopsychosocial diagnostic and treatment algorithm for PGAD/GPD was developed. The panel recognized that the term PGAD does not fully characterize the constellation of GPD symptoms experienced by patients. Therefore, the more inclusive term PGAD/GPD was adopted, which maintains the primacy of the distressing arousal symptoms and acknowledges associated bothersome GPD. While there are diverse biopsychosocial contributors, there is a common underlying neurologic basis attributable to spontaneous intense activity of the genito-pelvic region represented in the somatosensory cortex and its projections. A process of care diagnostic and treatment strategy was developed to guide the clinician, whenever possible, by localizing the symptoms as originating in any of five regions: (i) end organ, (ii) pelvis/perineum, (iii) cauda equina, (iv) spinal cord, and (v) brain. Psychological treatment strategies were considered critical and should be performed in conjunction with medical strategies. Pharmaceutical interventions may be used based on their site and mechanism of action to reduce patients' symptoms and the associated bother and distress. The process of care for PGAD/GPD uses a personalized, biopsychosocial approach for diagnosis and treatment. Strengths and Limitations: Strengths include characterization of the condition by consensus, analysis, and recommendation of a new nomenclature and a rational basis for diagnosis and treatment. Future investigations into etiology and treatment outcomes are recommended. The main limitations are the dearth of knowledge concerning this condition and that the current literature consists primarily of case reports and expert opinion. We provide, for the first time, an expert consensus review of the epidemiology and pathophysiology and the development of a new nomenclature and rational algorithm for management of this extremely distressing sexual health condition that may be more prevalent than previously recognized. Goldstein I, Komisaruk BR, Pukall CF, et al. International Society for the Study of Women's Sexual Health (ISSWSH) Review of Epidemiology and Pathophysiology, and a Consensus Nomenclature and Process of Care for the Management of Persistent Genital Arousal Disorder/Genito-Pelvic Dysesthesia (PGAD/GPD). J Sex Med 2021;18:665–697. [ABSTRACT FROM AUTHOR]

Flibanserin is approved in the United States and Canada for the treatment of acquired, generalized, hypoactive sexual desire disorder in premenopausal women. Sedation-related side effects are among the most prevalent adverse events. Although infrequent, hypotension and syncope remain safety concerns because of possible interaction of flibanserin with alcohol. To evaluate the impact of the timing of alcohol consumption on flibanserin safety and tolerability. In this single-center, randomized, double-blind, placebo-controlled, 4-treatment crossover study, 64 healthy premenopausal women (mean age 32.5 ± 8.7 years; range 20‒52 years) received once-daily flibanserin 100 mg or placebo during each of two 10-day treatment periods. Study medication was administered on days 1–3 to achieve steady state. On days 4, 6, 8, and 10, after a standard breakfast, participants consumed 0.4 g/kg ethanol (approximately equivalent to two 5-oz glasses of wine) administered with orange juice 2, 4, or 6 hours before taking study medication or orange juice alone (no ethanol) 2 hours before taking study medication. The primary endpoint was percentage of participants experiencing syncope or orthostatic hypotension–associated adverse events requiring medical intervention. Secondary endpoints included the incidence of hypotension, the incidence of orthostatic hypotension, and rates of adverse events of special interest (syncope, orthostatic hypotension, dizziness, and somnolence). 1 participant experienced a primary endpoint event (syncope) during treatment with placebo taken 4 hours after ethanol consumption. Within each ethanol dose–timing treatment, there were no statistically significant differences for flibanserin compared with placebo. Rates of hypotension were 53.3–66.7% after flibanserin dosing and 57.4–63.3% after placebo dosing. Rates for orthostatic hypotension were 0.0–5.0% after flibanserin dosing and 1.7–6.6% after placebo dosing. Ethanol interaction with flibanserin was not observed in this study. This study provides information regarding the use of flibanserin after the consumption of moderate amounts of ethanol (0.4 g/kg). However, daytime administration of flibanserin is not consistent with the drug's indicated bedtime dosing. Flibanserin, at steady state taken 2, 4, or 6 hours after 0.4 g/kg of ethanol intake did not increase the incidence of hypotension, orthostatic hypotension, or syncope compared with either flibanserin alone or ethanol alone. Simon JA, Clayton AH, Kingsberg SA, et al. Effects of Timing of Flibanserin Administration Relative to Alcohol Intake in Healthy Premenopausal Women: A Randomized, Double-Blind, Crossover Study. J Sex Med 2019;16:1779–1786. [ABSTRACT FROM AUTHOR]

Introduction Although clinical evidence supports an association between cardiovascular/metabolic diseases (CVMD) and erectile dysfunction (ED), scientific evidence for this link is incompletely elucidated. Aim This study aims to provide scientific evidence for the link between CVMD and ED. Methods In this White Paper, the Basic Science Committee of the Sexual Medicine Society of North America assessed the current literature on basic scientific support for a mechanistic link between ED and CVMD, and deficiencies in this regard with a critical assessment of current preclinical models of disease. Results A link exists between ED and CVMD on several grounds: the endothelium (endothelium-derived nitric oxide and oxidative stress imbalance); smooth muscle (SM) (SM abundance and altered molecular regulation of SM contractility); autonomic innervation (autonomic neuropathy and decreased neuronal-derived nitric oxide); hormones (impaired testosterone release and actions); and metabolics (hyperlipidemia, advanced glycation end product formation). Conclusion Basic science evidence supports the link between ED and CVMD. The Committee also highlighted gaps in knowledge and provided recommendations for guiding further scientific study defining this risk relationship. This endeavor serves to develop novel strategic directions for therapeutic interventions. M usicki B , B ella AJ , B ivalacqua TJ , D avies KP , D i S anto ME , G onzalez- C adavid NF , H annan JL , K im NN , P odlasek CA , W ingard CJ , and B urnett AL . Basic science evidence for the link between erectile dysfunction and cardiometabolic dysfunction. J S ex M ed 2015;12:2233-2255. [ABSTRACT FROM AUTHOR]

Aim Women who developed vestibulodynia (vulvar vestibulitis) while taking combined hormonal contraceptives ( CHCs) and a control group of women were tested for polymorphisms of the gene coding for the androgen receptor ( AR) that is located on the X chromosome. Study Design DNA from 30 women who developed vestibulodynia while taking CHCs and 17 control women were tested for the number of cytosine-adenine-guanine ( CAG) trinucleotide repeats in the AR. In addition, serum-free testosterone was tested in both groups. Results The mean number of CAG repeats in the study group was significantly greater than the control group (22.05 ± 2.98 vs. 20.61 ± 2.19, respectively; P = 0.025). This significant difference persisted when analyzing the CAG repeats from the longer allele from each subject. Among those who were taking drospirenone-containing CHCs, the mean calculated free testosterone was 0.189 ± 0.115 ng/d L in the study group and 0.127 ± 0.054 ng/d L in the control group, all of whom were taking drospirenone-containing CHCs ( P = 0.042). Conclusion In the study cohort, women who developed vestibulodynia while taking CHCs are more likely to have longer CAG repeats in the AR than women who took the same type of CHC but did not develop vestibulodynia. We speculate that the risk of developing CHC-induced vestibulodynia may be due to lowered free testosterone combined with an inefficient AR that predisposes women to vestibular pain. Goldtein AT, Belkin ZR, Krapf JM, Song W, Khera M, Jutrzonka SL, Kim NN, Burrows LJ, and Goldstein I. Polymorphisms of the androgen receptor gene and hormonal contraceptive induced provoked vestibulodynia. J Sex Med 2014;11:2764-2771. [ABSTRACT FROM AUTHOR]

Introduction. Significant scientific advances during the past 3 decades have deepened our understanding of the physiology and pathophysiology of penile erection. A critical evaluation of the current state of knowledge is essential to provide perspective for future research and development of new therapies. Aim. To develop an evidence-based, state-of-the-art consensus report on the anatomy, physiology, and pathophysiology of erectile dysfunction (ED). Methods. Consensus process over a period of 16 months, representing the opinions of 12 experts from seven countries. Main Outcome Measure. Expert opinion was based on the grading of scientific and evidence-based medical literature, internal committee discussion, public presentation, and debate. Results. ED occurs from multifaceted, complex mechanisms that can involve disruptions in neural, vascular, and hormonal signaling. Research on central neural regulation of penile erection is progressing rapidly with the identification of key neurotransmitters and the association of neural structures with both spinal and supraspinal pathways that regulate sexual function. In parallel to advances in cardiovascular physiology, the most extensive efforts in the physiology of penile erection have focused on elucidating mechanisms that regulate the functions of the endothelium and vascular smooth muscle of the corpus cavernosum. Major health concerns such as atherosclerosis, hyperlipidemia, hypertension, diabetes, and metabolic syndrome (MetS) have become well integrated into the investigation of ED. Conclusions. Despite the efficacy of current therapies, they remain insufficient to address growing patient populations, such as those with diabetes and MetS. In addition, increasing awareness of the adverse side effects of commonly prescribed medications on sexual function provides a rationale for developing new treatment strategies that minimize the likelihood of causing sexual dysfunction. Many basic questions with regard to erectile function remain unanswered and further laboratory and clinical studies are necessary. Gratzke C, Angulo J, Chitaley K, Dai Y-T, Kim NN, Paick J-S, Simonsen U, Ückert S, Wespes E, Andersson KE, Lue TF, and Stief CG. Anatomy, physiology, and pathophysiology of erectile dysfunction. J Sex Med 2010;7:445–475. [ABSTRACT FROM AUTHOR]

Introduction. The mechanisms by which testosterone modulates female genital sexual arousal responses are poorly understood. Aim. To investigate the effects of testosterone on vaginal blood flow and the expression of estrogen and androgen receptor proteins in the rat vagina. Methods. Mature female Sprague-Dawley rats were sham-operated (intact) or ovariectomized. Fourteen days after ovariectomy, animals were continuously infused with vehicle or varying doses of testosterone (5.5–55 μg/day). After 2 weeks of treatment, vaginal blood flow in response to pelvic nerve stimulation was measured by laser Doppler flowmetry. Plasma levels of testosterone and estradiol were determined by radioimmunoassay and epithelial thickness was examined in fixed vaginal tissue sections. Androgen and estrogen receptor levels were assessed by equilibrium radioligand binding and by Western blot analyses. Results. Vaginal blood flow responses were significantly reduced in ovariectomized rats and normalized in animals infused with testosterone. Ovariectomy increased the expression of estrogen receptors and reduced the expression of androgen receptors with no change in receptor-ligand affinity. Testosterone increased the expression of both androgen and estrogen receptors in the vagina. While physiological (11 μg/day) and supraphysiological (55 μg/day) concentrations of testosterone normalized vaginal tissue weight, uterine tissue and whole body weights were not significantly different from ovariectomized rats infused with vehicle. Testosterone infusion, even at supraphysiological concentrations, did not change plasma estradiol levels when compared to vehicle-infused, ovariectomized rats. Likewise, the vaginal epithelium of testosterone-infused rats remained atrophic, similar to vehicle-infused, ovariectomized rats, indicating that testosterone is not aromatized to estrogens at significant levels in the vagina. Conclusions. Our data suggest that testosterone regulates androgen and estrogen receptor protein expression in the vagina and enhances vaginal perfusion by an androgen-dependent mechanism. We conclude that testosterone plays an important role in modulating the physiology of the vagina and contributes to improvement of genital sexual arousal responses. Traish AM, Kim S Woong, Stankovic M, Goldstein I, and Kim NN. Testosterone increases blood flow and expression of androgen and estrogen receptors in the rat vagina. J Sex Med 2007;4:609–619. [ABSTRACT FROM AUTHOR]

Introduction. Advances in neurobiology have led to a surge of clinical interest in the development of protective and regenerative neuromodulatory strategies, as surgical therapies for prostate cancer often result in neuronal damage and debilitating loss of sexual function. Aim. To investigate the dose-dependent efficacy of FK1706, a nonimmunosuppressant immunophilin ligand, for the recovery of erectile function following bilateral cavernous nerve crush injury in the rat. Main Outcome Measures. Recovery of erectile function was assessed by cavernous nerve electrostimulation and reported as maximal increase of intracavernous pressure (ICP) and area under the curve (AUC). Changes in animal weights, percentage completion of treatment course, and survival were compared between groups. Methods. Thirty-five Sprague–Dawley male rats were randomly divided into five equal groups: seven animals received a sham operation, whereas 28 animals underwent bilateral cavernous nerve crush injury, followed by subcutaneous injection of vehicle alone (1.0 mL/kg), or low (0.1 mg/kg), medium (0.32 mg/kg), or high dose (1.0 mg/kg) FK1706 5 days per week for 8 weeks. Results. Erectile dysfunction did not occur in the sham group (mean maximal ICP increase of 100.8 ± 6.3 cmH2O), whereas nerve injury and vehicle treatment produced a significant reduction in ICP response to 34.4 ± 12.8 cmH2O. The mean ICP increase for high-dose FK106 treatment was 73.9 ± 6.3 cmH2O ( P < 0.01 vs. vehicle) compared with 58.3 ± 7.4 cmH2O and 56.9 ± 8.3 for low and medium doses ( P > 0.05). Similar stepwise findings were observed using AUC data. No significant maximal aortic blood pressure or weight differences occurred between groups and all animals completed treatment. Conclusion. High-dose subcutaneous FK1706 therapy promoted recovery of erectile function following bilateral cavernous nerve crush injury in the rat. No significant differences between groups were observed for changes in weight, and the 8-week treatment course was completed for all animals. Bella AJ, Hayashi N, Carrion RE, Price R, and Lue TF. FK1706 enhances the recovery of erectile function following bilateral cavernous nerve crush injury in the rat. J Sex Med 2007;4:341–347. [ABSTRACT FROM AUTHOR]

Introduction. Ischemic priapism is associated with cavernosal acidosis, which decreases the efficacy of adrenergic agonists. We determined the effect of acidosis on ligand dissociation from adrenergic receptors and assessed the efficacy of high-dose phenylephrine in treating patients with acute ischemic priapism. Methods. Dissociation rates of [3H]prazosin were determined at pH 7.2 and 6.9 in membrane preparations of rabbit penile cavernosal tissue. Vital signs were recorded from patients before injection, and at 1 minute and 5 minutes after injection of high-dose phenylephrine (1,000 mg q 5 minutes) for 17 consecutive cases of iatrogenic ischemic priapism that occurred after vascular assessment. We also provide two case reports of prolonged ischemic priapism successfully managed with high-dose phenylephrine. Results. Dissociation rates of [3H]prazosin were greater at pH 6.9 (K −1 = 0.23/minute) than at pH 7.2 (K −1 = 0.10/minute), suggesting decreased receptor affinity at acidic pH. Intracavernosal therapy with high-dose phenylephrine (mean dose 2,059 ± 807 µg) was 100% effective with no adverse events or significant changes in vital signs. In addition, two patients with ischemic priapism for ≥36 hours were successfully treated with high-dose intracavernosal phenylephrine (mean dose 45,000 µg) without any adverse event. Both patients are currently potent. Conclusions. Acidic pH may decrease the binding affinity of adrenergic ligands to their receptors. Phenylephrine at doses higher than previously reported may be necessary to overcome this decreased affinity in acidosis associated with ischemic priapism. High-dose intracavernosal phenylephrine administration is safe and effective in the management of ischemic priapism. Continuous cardiovascular monitoring is advised. Wen CC, Munarriz R, McAuley I, Goldstein I, Traish A, and Kim N. Management of ischemic priapism with high-dose intracavernosal phenylephrine: from bench to bedside. J Sex Med 2006;3:918–922. [ABSTRACT FROM AUTHOR]