Does MDMA have treatment potential in sexual dysfunction? A systematic review of outcomes across the female and male sexual response cycles.

INTRODUCTION: Sexual health, an integral component of overall well-being, is frequently compromised by common yet underdiagnosed sexual dysfunctions. Traditional interventions encompass pharmaceutical and psychological treatments. Unconventional therapies, like MDMA, offer hope for sexual dysfunction. This review delves into MDMA's effects on sexual responsiveness and its potential role in treating sexual dysfunction. OBJECTIVES: The purpose of this review is to elucidate effects of MDMA on different domains of the female and male sexual response cycles. METHODS: We conducted a systematic review on the effects of MDMA on each domain of the female and male sexual response cycles. PubMed, MEDLINE, and EMBASE were queried, and results were screened using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Search terms utilized were "MDMA" or "ecstasy" in combination with "desire," "arousal," "lubrication," "orgasm," "pleasure," "libido," "erection," and "ejaculation." Inclusion criteria for this review were MDMA use by study subjects and sexual outcomes in at least 1 domain of the female and/or male sexual response cycles were described and measured. Randomized controlled trials, cohort studies (both prospective and retrospective), surveys, and literature reviews published between January 2000 and June 2022 were included. Case reports and studies that did not address conditions of interest were excluded from analysis. Duplicated search results were screened out. The remaining studies were then read in full text to ensure they met inclusion and exclusion criteria for analysis. RESULTS: We identified 181 studies, of which 6 met criteria for assessment of the female sexual response cycle and 8 met criteria for assessment of the male sexual response cycle. Four of 6 studies reported increased sexual desire with MDMA use among women. Arousal and lubrication were improved with MDMA use in 3 of 4 studies, but they were not affected in 1 randomized control study. In men, 7 studies evaluated the effects of MDMA on desire and/or arousal, 5 studies measured impact on erection, 3 on orgasm, and 2 on ejaculation. Sixty percent of interview-based studies reported increased sexual desire in men, while 40% reported mixed or no effect. Two studies reported impairment of erection, 2 reported mixed effects, and 1 reported fear of erection impairment. In both men and women, all studies evaluating orgasm reported delay in achieving orgasm but increased intensity and pleasure if achieved. Primary outcome measures were variable and largely qualitative. CONCLUSION: Our findings suggest that MDMA generally increases sexual desire and intensifies orgasm when achieved. While producing conflicting evidence on sexual arousal in both sexes, MDMA may impair erectile and ejaculatory function in men.

Characterizing the innervation of the vulvar vestibule and the immunohistochemical features of neuroproliferative vestibulodynia.

BACKGROUND: Provoked vestibulodynia (PVD) is a chronic pain condition characterized by allodynia localized to the vulvar vestibule. The finding of increased densities of nerve fibers in the vestibular mucosa of patients with PVD has led to the identification of a neuroproliferative subtype. The etiology of PVD, including neuroproliferative vestibulodynia (NPV), is not fully understood. The gross and microscopic innervation of the vulvar vestibule remains incompletely described, despite the preliminary data supporting the role of peripheral innervation in PVD. AIM: To characterize the gross anatomic and microscopic innervation of the vulvar vestibule through cadaveric dissection and immunohistochemistry. METHODS: The pudendal nerve and inferior hypogastric plexus (IHP) were dissected using 6 cadaveric donors. Histology and immunohistochemistry were used to confirm patterns of innervation identified gross anatomically. Immunohistochemistry was performed on vestibulectomy specimens obtained from 6 patients diagnosed with NPV and compared with cadaveric vestibular tissues. OUTCOMES: Outcomes included (1) dissection of pelvic innervation and (2) immunohistochemical localization of markers for the following: general innervation protein gene product 9.5 (PGP9.5), sensory innervation (calcitonin gene-related peptide), autonomic innervation (vasoactive intestinal polypeptide, tyrosine hydroxylase), neuroproliferation (nerve growth factor [NGF]), and immune activation (C-kit). RESULTS: Perineal (pudendal) nerve branches were traced to the external wall of the vulvar vestibule. Some anatomic heterogeneity was observed in perineal nerve-branching patterns. Fibers from the IHP were identified in close proximity to the vulvar vestibule. Autonomic and sensory nerve fibers were identified in both patient and cadaveric vulvar vestibule samples. Patient samples were characterized by the proliferation of PGP9.5-positive nerve fibers and C-kit-positive mast cells, which were in proximity to neve bundles and showed coexpression with putative NGF-positive cells. NGF expression was localized to a subset of nerves, including those that demonstrated co-expression of sensory and autonomic nerve markers. Increased densities of autonomic fibers positive for vasoactive intestinal polypeptide and tyrosine hydroxylase were observed in 1 patient sample. CLINICAL TRANSLATION: Heterogeneity in gross and microscopic patterns of innervation could explain variability in clinical response to treatment and should be used to inform future therapeutic interventions. STRENGTHS AND LIMITATIONS: This study used a combination of approaches to elucidate the innervation of the vulvar vestibule, including in NPV. The small sample size is a limitation. CONCLUSION: The vulvar vestibule contains both sensory and autonomic innervation, which may originate from the pudendal nerve and IHP. Our results support the existence of a neuroproliferative subtype that is characterized by the proliferation of sensory and autonomic nerve fibers and neuroimmune interactions.

Menstrual cycle-driven vs noncyclical daily changes in sexual desire.

BACKGROUND: Past research on the association between sexual desire and the menstrual cycle has provided inconclusive results and has not considered the potential influence of psychological and physical changes that are frequently associated with the menstrual cycle. AIM: To test the strength of association between the menstrual cycle (and associated symptoms) and changes in sexual desire. METHODS: Prospective daily reports across 2 full menstrual cycles (2 months) from a sample of female university students (n = 213), were analysed. Analyses tested for average effects of the menstrual cycle on sexual desire, individual differences in these effects, and cyclical and noncyclical associations between sexual desire and the 9 menstrual cycle-related changes. Note that data presented in the current article come from a larger study from which other reports have been published. OUTCOMES: Target variables were (1) daily change in sexual desire and (2) daily reports of 5 psychological changes and 4 physical changes that are commonly associated with the menstrual cycle. RESULTS: Results showed that when considering average effects across participants, the menstrual cycle was associated with a small midcycle increase in sexual desire. However, multilevel analyses showed large individual differences in how the menstrual cycle influences sexual desire. Specifically, some participants showed a midcycle increase, others a perimenstrual increase, and others no change across the menstrual cycle. Moreover, results demonstrated that psychological changes were more important for predicting sexual desire as compared with physical changes. CLINICAL IMPLICATIONS: These results suggest that daily measurement of sexual desire across multiple menstrual cycles may be an important tool in the assessment of sexual desire among some females. STRENGTHS AND LIMITATIONS: Strengths of this study are the daily assessment of sexual desire and all symptoms for 2 menstrual cycles and multilevel analyses that allow the study of individual differences. Limitations include limited measurement of sexual desire based on only 2 questions and the lack of measures of relationship status and sexual orientation. CONCLUSION: Emphasis is placed on the need to apply more rigorous research methods and to abandon simplistic average-effects models that are based on outdated theories and stereotypes.

Patient and provider perspectives on LEEP/LLETZ treatment and outcomes: an interview study.

BACKGROUND: The loop electrosurgical excision procedure (LEEP) and large loop excision of the transformation zone (LLETZ) effectively treat cervical dysplasia, though some women have reported negative outcomes postoperatively (e.g., sexual dysfunction, psychosexual sequalae). There is insufficient understanding of patient experiences with these symptoms and perspectives from the providers who perform LEEP/LLETZ. AIM: To characterize the perceptions and experiences of LEEP/LLETZ treatment from providers and patients, including whether there is a characteristic symptom profile of women who report negative outcomes. METHODS: Patients who had LEEP/LLETZ treatment and reported negative outcomes and providers who perform LEEP/LLETZ completed semistructured interviews about their perceptions and experiences, which were coded through thematic analysis (NVivo 12; QSR International). Patients also completed an online survey assessing demographics, medical history, and sexual function. OUTCOMES: Outcomes included perspectives generated from patient and provider interviews regarding LEEP/LLETZ procedural outcomes, including symptoms and experiences related to sexual functioning. RESULTS: Perspectives and experiences gathered from patient and provider interviews revealed misaligned narratives surrounding LEEP/LLETZ outcomes and treatment. We identified 4 overarching themes encapsulating provider and patient responses: Expectations for Preoperative Consultation; Procedure Experiences; Attitudes; and Resources. Patients reported a unique symptom profile and negative outcome experiences, namely surrounding domains of sexual functioning: decreased physical sensations, orgasm response, and vaginal discharge, as well as loss of arousal, interest, and desire. Patients described changes to overall quality of life, with impacts to interpersonal relationships. Patients discussed preferring open-ended and directed questions to comprehensively elucidate negative outcomes. Provider narratives outlined the current process of care, emphasizing limited experiences with adverse outcomes (e.g., sexual issues) and the use of open-ended questions during counseling. Providers described an evolving intention to create comfortable clinical spaces. Regarding pre- and postoperative resources, patients described seeking support from online patient groups, and providers disclosed limitations to providing resources. CLINICAL IMPLICATIONS: Evidence of discordance between patient and provider perspectives of LEEP/LLETZ reveals a need to reassess clinical practices surrounding this procedure at the level of discussions regarding informed consent, sexual function, and available resources. STRENGTHS AND LIMITATIONS: This study is the first to examine patient and provider perspectives on LEEP/LLETZ treatment. Only patients who self-report negative outcomes were recruited, to elicit narratives from this specific subpopulation. CONCLUSION: Results indicate a characteristic symptom profile of women who undergo LEEP/LLETZ and report negative outcomes and that the perceptions of patients and providers differ regarding several aspects of the treatment experience, supporting the need for directed open conversation and comprehensive pre- and postoperative sexual counseling.

The contribution of the cervix to sexual response: an online survey study.

BACKGROUND: The role of the cervix in sexual response has been poorly studied, despite previous research indicating that some women experience pleasurable sexual sensations from cervical stimulation; given previous reports of sexual issues after cervix electrocautery, it is possible that cervical injury may compromise the role of the cervix in sexual functioning. AIM: The aims of this study were to examine locations of pleasurable sexual sensations, to identify sexual communication barriers, and to investigate if cervical procedures are associated with negative impacts on sexual function. METHODS: Women with (n = 72) and without (n = 235) a history of a gynecological procedure completed an online survey assessing demographics, medical history, sexual function (including locations of sexual pleasure and pain on diagrams), and barriers. The procedure group was divided into subgroups of those who had experienced a cervical (n = 47) or noncervical (n = 25) procedure. Chi-square analyses and t tests were conducted. OUTCOMES: Outcomes included locations and ratings of pleasurable and painful sexual stimulation, as well as sexual function. RESULTS: Over 16% of participants reported experiencing some pleasurable sexual sensations from the cervix. The gynecological procedure group (n = 72) reported significantly higher pain in the vagina and lower rates of pleasure in their external genitals, vagina, deep vagina, anterior and posterior vaginal walls, and clitoris vs the non-gynecological procedure (n = 235) group. The gynecological procedure group and the cervical procedure subgroup (n = 47) reported significant decreases in desire, arousal, and lubrication and increased avoidance of sexual activity due to vaginal dryness. The gynecological procedure group reported significant pain with vaginal stimulation, whereas the cervical subgroup identified significant pain with cervical and clitoral stimulation. CLINICAL IMPLICATIONS: Cervical stimulation elicits some pleasurable sexual sensations for many women, and gynecological procedures that affect the cervix are associated with pain and sexual issues; thus, health care providers should counsel patients about the possibility of related sexual concerns. STRENGTHS AND LIMITATIONS: This study is the first to examine locations of pleasure and pain and experiences of sexual pleasure and function in participants who underwent a gynecological procedure. A hybrid measure was used to assess sexual issues, including symptoms of dysfunction. CONCLUSION: Results indicate an association between cervical procedures and sexual issues, supporting the need to inform patients of this possibility following cervical procedures.

Lumbar endoscopic spine surgery for persistent genital arousal disorder/genitopelvic dysesthesia resulting from lumbosacral annular tear-induced sacral radiculopathy.

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.

The prostate in women: an updated histological and immunohistochemical profile of the female periurethral glands and their relationship to an implanted midurethral sling.

BACKGROUND: There is evidence of glandular tissue in the region of the anterior vaginal wall-female periurethral tissue (AVW-FPT) that has similar morphology and immunohistochemistry to the prostate in men. Surgical injury to this tissue has been suggested as a potential cause of sexual dysfunction following midurethral sling (MUS) procedures. However, the anatomy and embryology of these glands have not been fully resolved. This has led to difficulties in classifying this tissue as a prostate and defining its clinical significance related to MUS procedures. AIM: To describe the histological and immunohistochemical characteristics of the female periurethral glands using markers of prostate tissue and innervation and to examine their anatomical relationships to an implanted MUS. METHODS: Using gross and fine dissection, the AVW-FPT was dissected from 9 cadavers. Prior to dissection, 2 cadavers underwent simulation of the MUS procedure by a urogynecologist. Samples were paraffin embedded and serially sectioned. Immunohistochemistry was performed using markers of prostate tissue and innervation. OUTCOMES: Immunohistochemical localization of markers for prostatic tissue and innervation of the glandular tissue of the AVW-FPT, including the region of MUS implantation. RESULTS: Female periurethral glands were immunoreactive for markers of male prostatic tissue, including prostate-specific antigen, androgen receptor, HOXB13, and NKX3.1. Markers of innervation (protein gene product 9.5, choline acetyl transferase, and vasoactive intestinal polypeptide) also localized to certain regions of the glandular tissue and associated blood supply. Surgical simulation of the MUS procedure demonstrated that some periurethral glands are located in close proximity to an implanted sling. CLINICAL TRANSLATION: The AVW-FPT contains glandular tissue in the surgical field of MUS implantation. Iatrogenic damage to the female periurethral glands and the associated innervation during surgery could explain the negative impacts on sexual dysfunction reported following MUS procedures. STRENGTHS AND LIMITATIONS: This is the first study to characterize the female periurethral glands using markers of prostatic tissue in concert with markers of general and autonomic innervation and characterize their anatomical relationships within the surgical field of MUS implantation. The small sample size is a limitation of this study. CONCLUSION: We provide further evidence that the AVW-FPT contains innervated glands that are phenotypically similar to the male prostate and may share a common embryonic origin. The microscopic and immunohistochemical features of the periurethral glands may be indicative of their functional capacity in sexual responses. The location of these glands in the surgical field of MUS procedures underscores the clinical significance of this tissue.

Hiding in plain sight? A review of post-convulsive leukocyte elevations.

During physiological stress responses such as vigorous exercise, emotional states of fear and rage, and asphyxia, the nervous system induces a massive release of systemic catecholamines that prepares the body for survival by increasing cardiac output and redirecting blood flow from non-essential organs into the cardiopulmonary circulation. A curious byproduct of this vital response is a sudden, transient, and redistributive leukocytosis provoked mostly by the resultant shear forces exerted by rapid blood flow on marginated leukocytes. Generalized convulsive seizures, too, result in catecholamine surges accompanied by similar leukocytoses, the magnitude of which appears to be rooted in semiological factors such as convulsive duration and intensity. This manuscript reviews the history, kinetics, physiology, and clinical significance of post-convulsive leukocyte elevations and discusses their clinical utility, including a proposed role in the scientific investigation of sudden unexpected death in epilepsy (SUDEP).

Orgasm and Related Disorders Depend on Neural Inhibition Combined With Neural Excitation.

INTRODUCTION: Prevalent models of sexual desire, arousal and orgasm postulate that they result from an excitatory process, whereas disorders of sexual desire, arousal and orgasm result from an inhibitory process based on psychosocial, pharmacological, medical, and other factors. But neuronal excitation and active neuronal inhibition normally interact at variable intensities, concurrently and continuously. We propose herein that in conjunction with neuronal excitation, neuronal inhibition enables the generation of the intense, non-aversive pleasure of orgasm. When this interaction breaks down, pathology can result, as in disorders of sexual desire, arousal, and orgasm, and in anhedonia and pain. For perspective, we review some fundamental behavioral and (neuro-) physiological functions of neuronal excitation and inhibition in normal and pathological processes. OBJECTIVES: To review evidence that the variable balance between neuronal excitation and active neuronal inhibition at different intensities can account for orgasm and its disorders. METHODS: We selected studies from searches on PubMed, Google Scholar, Dialnet, and SciELO for terms including orgasm, neuronal development, Wallerian degeneration, prenatal stress, parental behavior, sensorimotor, neuronal excitation, neuronal inhibition, sensory deprivation, anhedonia, orgasmic disorder, hypoactive sexual desire disorder, persistent genital arousal disorder, sexual pain. RESULTS: We provide evidence that the intensity of neuronal inhibition dynamically covaries concurrently with the intensity of neuronal excitation. Differences in these relative intensities can facilitate the understanding of orgasm and disorders of orgasm. CONCLUSION: Neuronal excitation and neuronal inhibition are normal, continuously active processes of the nervous system that are necessary for survival of neurons and the organism. The ability of genital sensory stimulation to induce concurrent neuronal inhibition enables the stimulation to attain the pleasurable, non-aversive, high intensity of excitation characteristic of orgasm. Excessive or deficient levels of neuronal inhibition relative to neuronal excitation may account for disorders of sexual desire, arousal and orgasm. Komisaruk BR, Rodriguez del Cerro MC. Orgasm and Related Disorders Depend on Neural Inhibition Combined With Neural Excitation. Sex Med Rev 2022;10:481-492.

Functional Magnetic Resonance Imaging Studies in Sexual Medicine: A Primer.

BACKGROUND: Over the past 30 years, functional magnetic resonance imaging (fMRI) has emerged as a powerful tool to non-invasively study the activity and function of the human brain. But along with the potential of fMRI to shed light on neurological, psychiatric, and psychological processes, there are methodological challenges and criticisms. AIM: We herein provide an fMRI primer designed for a diverse audience, from the neuroimaging novice to the experienced user. METHODS: This primer is structured as follows: Part 1: Overview: "What is fMRI and what can it tell us?." Part 2: Basic fMRI principles: MR physics, the BOLD signal, and components of a typical scan session. Part 3: Basic fMRI experimental design: why timing is critical, and common sources of noise in the signal. Part 4: Basic fMRI analysis methods: software, the 3 stages of data analysis (preprocessing, individual, and group level), and a survey of advanced topics and methods including connectivity, machine learning, and assessing statistical significance. Part 5: Criticism, crises, and opportunities related to power of studies, computing requirements, logistical, and interpretational challenges, and methodological debate (assessing causality, circular correlations, and open science best practices). OUTCOMES N/A CLINICAL TRANSLATION: fMRI has primarily been used in clinical research to elucidate the brain correlates of sexual behavior. The translational potential of the method into clinical practice has not yet been realizedfMRI has primarily been used in clinical research to elucidate the brain correlates of sexual behavior. The translational potential of the method into clinical practice has not yet been realized STRENGTHS AND LIMITATIONS: fMRI is a useful and powerful tool for understanding the brain basis of human sexuality. However, it is also expensive, requires extensive methods expertise, and lacks the precision needed to be immediately translatable to clinical practice. The recency of the method, need for basic research, technical limitations, as well as inherent variability in individuals brain activity also impact the pace at which fMRI for sexual medicine can move from the scanner to the clinic. CONCLUSION: This primer provides the novice an understanding of the appropriate uses and limitations of fMRI, and for the experienced user, a concise update on current issues and methodological advances. Mills-Finnerty C, Frangos E, Allen K, et al. Functional Magnetic Resonance Imaging Studies in Sexual Medicine: A Primer. J Sex Med 2022;19:1073-1089.

Should We Call It a Prostate? A Review of the Female Periurethral Glandular Tissue Morphology, Histochemistry, Nomenclature, and Role in Iatrogenic Sexual Dysfunction.

INTRODUCTION: There is evidence of glandular tissue within the region of the anterior vaginal wall-female periurethral tissue (AVW-FPT) having similar morphology and immunohistochemistry to the prostate in men and having physiological roles in the female sexual response (FSR). Whether this tissue should be called a prostate in women has been debated. Iatrogenic injury to structures of the AVW-FPT, including these glands and the associated neurovasculature, could be a cause of female sexual dysfunction (FSD). OBJECTIVES: To consolidate the current knowledge concerning the glandular tissue surrounding the urethra in women, evidence was reviewed to address whether: (i) these glands comprise the prostate in women, (ii) they have specific functions in the FSR, and (iii) injury to the AVW-FPT and prostate has sexual dysfunction as a likely outcome. METHODS: A literature review was conducted using keywords including female prostate, Skene's/paraurethral glands, periurethral tissue, Gräfenberg (G)-spot, female ejaculation, mid-urethral sling (MUS), and sexual dysfunction. RESULTS: Histological and immunohistochemical studies of the glandular tissue surrounding the urethra support the existence of prostate in women. Evidence suggests this tissue may have physiologically and clinically relevant autonomic and sensory innervation, and during sexual arousal may contribute to secretions involved in ejaculation and orgasm. Gaps in knowledge relating to the functional anatomy, physiological roles, and embryological origins of this tissue have impeded the acceptance of a prostate in women. Injury to the innervation, vasculature, and/or glandular tissue within the surgical field of MUS implantation suggests iatrogenic sexual dysfunction is plausible. CONCLUSIONS: Continuing to advance our understanding of the morphology, histochemistry, and physiologic capacity of this glandular tissue will clarify the characterization of this tissue as the "prostate" involved in the FSR, and its role in FSD following surgical injury. Tomalty D, Giovannetti O, Hannan J, et al. Should We Call It a Prostate? A Review of the Female Periurethral Glandular Tissue Morphology, Histochemistry, Nomenclature, and Role in Iatrogenic Sexual Dysfunction. Sex Med Rev 2022;10:183-194.

Threshold for copulation-induced analgesia varies according to the ejaculatory endophenotypes in rats.

Analgesia may be modulated by multiple internal and external factors. In prior studies, copulatory-induced analgesia was demonstrated using the vocalization threshold to tail shock (VTTS) in male and female rats. Three ejaculatory endophenotypes have been characterized in male Wistar rats based upon their ejaculation latency (EL). Since intromissions and ejaculations produce analgesia, and these copulatory patterns are performed with different frequency depending on the male's ejaculatory endophenotype, we hypothesized that copulation-induced analgesia would vary in relation to these endophenotypes. In the present study, we used three groups according to the EL (medians): rapid ejaculators (236 s; n = 21), intermediate ejaculators (663.2 s; n = 20) and sluggish ejaculators (1582.2 s; n = 8). Our aim was to evaluate whether copulation-induced analgesia is related to the ejaculatory endophenotypes during two consecutive ejaculatory series (EJS). In the first EJS, the VTTS of the rapid ejaculators was significantly higher than that of intermediate and sluggish rats. At the onset of the second EJS, the VTTS of the rapid and intermediate ejaculators was significantly higher than that of the sluggish rats. No differences in VTTS were observed during the first or second post-ejaculatory intervals among the three groups. These findings provide evidence that the more intromissions that occurred per unit time, the higher was the level of analgesia.

Vagus nerve afferent stimulation: Projection into the brain, reflexive physiological, perceptual, and behavioral responses, and clinical relevance.

The afferent vagus nerves project to diverse neural networks within the brainstem and forebrain, based on neuroanatomical, neurophysiological, and functional (fMRI) brain imaging evidence. In response to afferent vagal stimulation, multiple homeostatic visceral reflexes are elicited. Physiological stimuli and both invasive and non-invasive electrical stimulation that activate the afferent vagus elicit perceptual and behavioral responses that are of physiological and clinical significance. In the present review, we address these multiple roles of the afferent vagus under normal and pathological conditions, based on both animal and human evidence.

Orgasm and Related Disorders Depend on Neural Inhibition Combined With Neural Excitation.

INTRODUCTION: Prevalent models of sexual desire, arousal and orgasm postulate that they result from an excitatory process, whereas disorders of sexual desire, arousal and orgasm result from an inhibitory process based on psychosocial, pharmacological, medical, and other factors. But neuronal excitation and active neuronal inhibition normally interact at variable intensities, concurrently and continuously. We propose herein that in conjunction with neuronal excitation, neuronal inhibition enables the generation of the intense, non-aversive pleasure of orgasm. When this interaction breaks down, pathology can result, as in disorders of sexual desire, arousal, and orgasm, and in anhedonia and pain. For perspective, we review some fundamental behavioral and (neuro-) physiological functions of neuronal excitation and inhibition in normal and pathological processes. OBJECTIVES: To review evidence that the variable balance between neuronal excitation and active neuronal inhibition at different intensities can account for orgasm and its disorders. METHODS: We selected studies from searches on PubMed, Google Scholar, Dialnet, and SciELO for terms including orgasm, neuronal development, Wallerian degeneration, prenatal stress, parental behavior, sensorimotor, neuronal excitation, neuronal inhibition, sensory deprivation, anhedonia, orgasmic disorder, hypoactive sexual desire disorder, persistent genital arousal disorder, sexual pain. RESULTS: We provide evidence that the intensity of neuronal inhibition dynamically covaries concurrently with the intensity of neuronal excitation. Differences in these relative intensities can facilitate the understanding of orgasm and disorders of orgasm. CONCLUSION: Neuronal excitation and neuronal inhibition are normal, continuously active processes of the nervous system that are necessary for survival of neurons and the organism. The ability of genital sensory stimulation to induce concurrent neuronal inhibition enables the stimulation to attain the pleasurable, non-aversive, high intensity of excitation characteristic of orgasm. Excessive or deficient levels of neuronal inhibition relative to neuronal excitation may account for disorders of sexual desire, arousal and orgasm.

Immunohistochemical Investigation of Autonomic and Sensory Innervation of Anterior Vaginal Wall Female Periurethral Tissue: A Study of the Surgical Field of Mid-Urethral Sling Surgery Using Cadaveric Simulation.

BACKGROUND: Female sexual dysfunction, including female orgasm disorder, has been reported following mid-urethral sling (MUS) surgery to treat bothersome stress urinary incontinence. Anterior vaginal wall-female periurethral tissue (AVW-FPT) likely contains autonomic and sensory innervation involved in the female sexual response, and injury to these nerves may result from MUS implantation. AIM: To characterize, using fresh cadaveric tissue, autonomic and sensory nerves in AVW- FPT using immunohistochemistry (IHC), and to assess their proximity to an implanted MUS. METHODS: AVW-FPT was excised following careful dissection from four fresh cadavers. Prior to dissection, one cadaver underwent simulation of the MUS procedure by a urogynegologist, using a fascial sling. All samples were paraffin embedded, sectioned, and stained with hematoxylin. Serial sectioning and IHC were performed to identify nerves. IHC markers were used to characterize the sensory and autonomic innervation. OUTCOMES: IHC localization of autonomic and sensory nerve markers consistent with neural tissue within the region of MUS implantation. RESULTS: IHC of AVW-FPT using protein gene product 9.5 (PGP9.5), a general nerve stain, revealed innervation throughout the region targeted by the MUS implantation. More specifically, immunoreactivity for both autonomic (tyrosine hydroxylase, TH) and sensory (Nav1.8 and S100ß) nerves were found in close proximity (<1 mm) to the implanted MUS. In addition, a subset of S100ß positive nerves also showed immunoreactivity for calcitonin gene-related peptide (CGRP). Combining the IHC findings with the surgical simulation of the MUS implantation revealed the potential for damage to both autonomic and sensory nerves as a direct result of the MUS procedure. CLINICAL TRANSLATION: The identified autonomic and sensory nerves of the AVW-FPT may contribute to the female sexual response, and yet are potentially negatively impacted by MUS procedures. Given that surgeries performed on male genital tissue, including the prostate, may cause sexual dysfunction secondary to nerve damage, and that urologists routinely provide informed consent regarding this possibility, urogynaecologists are encouraged to obtain appropriate informed consent from prospective patients undergoing the MUS procedure. STRENGTHS & LIMITATIONS: This is the first study to characterize the sensory and autonomic innervation within the surgical field of MUS implantation and demonstrate its relationship to an implanted MUS. The small sample size is a limitation of this study. CONCLUSION: The present study provides evidence of potential injury to autonomic and sensory innervation of AVW-FPT as a consequence of MUS implantation, which may help explain the underlying mechanisms involved in the reported post-operative female sexual dysfunction in some women. Giovannetti O, Tomalty D, Gaudet D, et al. Immunohistochemical Investigation of Autonomic and Sensory Innervation of Anterior Vaginal Wall Female Periurethral Tissue: A Study of the Surgical Field of Mid-Urethral Sling Surgery Using Cadaveric Simulation. J Sex Med 2021;18:1168-1180.

The Use of Pramipexole to Treat Persistent Genital Arousal Disorder: A Case Report.

INTRODUCTION: Persistent Genital Arousal Disorder (PGAD) is defined as "spontaneous, intrusive, and unwanted genital arousal (tingling, throbbing, pulsating) in the absence of sexual interest and desire" and traditionally causes marked distress, embarrassment and shame. PGAD may be caused by starting, discontinuing, or making adjustments in certain antidepressants or other medications. AIM: To report the case of a 36- year- old woman with PGAD, likely due to changes in her psychiatric medications, who was treated with pramipexole and experienced improvement in her PGAD symptoms. METHODS: Patient self-report and literature review. Written informed consent was obtained from the patient. MAIN OUTCOME MEASURE: Improvement in PGAD symptoms. RESULTS: Patient reported improvement in her symptoms by "90%" on a low dose of pramipexole, although higher doses exacerbated her symptoms. CONCLUSIONS: It is likely that an effective treatment window exists for the treatment of PGAD with drugs that possess the ability to exert their control of dopaminergic transmission. This includes direct acting receptor agonists like pramipexole, which produce feedback inhibition. Limitations to their efficacy then involve co-treatments that counteract their ability to exert a dampening effect on hyperstimulated dopamine transmission. It is recommended that clinicians be aware of drugs taken by patients to treat psychiatric disorders that could induce PGAD symptoms, drugs recently discontinued where a rebound effect could lead to PGAD symptoms, and drug mechanisms that could counteract the effect of treatments for PGAD. Lynn BK, Grabenhorst C, Komisaruk BR, et al. The Use of Pramipexole to Treat Persistent Genital Arousal Disorder: A Case Report. Sex Med 2021;9:100372.

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).

BACKGROUND: 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. AIM: To characterize this complex condition more accurately, review the epidemiology and pathophysiology, and provide new nomenclature and guidance for evidence-based management. METHODS: 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. OUTCOMES: 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. RESULTS: 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. CLINICAL IMPLICATIONS: The process of care for PGAD/GPD uses a personalized, biopsychosocial approach for diagnosis and treatment. STRENGTHS AND LIMITATIONS: 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. CONCLUSION: 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.