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Krause corpuscles, which were discovered in the 1850s, are specialized sensory structures found within the genitalia and other mucocutaneous tissues 1 – 4 . The physiological properties and functions of Krause corpuscles have remained unclear since their discovery. Here we report the anatomical and physiological properties of Krause corpuscles of the mouse clitoris and penis and their roles in sexual behaviour. We observed a high density of Krause corpuscles in the clitoris compared with the penis. Using mouse genetic tools, we identified two distinct somatosensory neuron subtypes that innervate Krause corpuscles of both the clitoris and penis and project to a unique sensory terminal region of the spinal cord. In vivo electrophysiology and calcium imaging experiments showed that both Krause corpuscle afferent types are A-fibre rapid-adapting low-threshold mechanoreceptors, optimally tuned to dynamic, light-touch and mechanical vibrations (40–80 Hz) applied to the clitoris or penis. Functionally, selective optogenetic activation of Krause corpuscle afferent terminals evoked penile erection in male mice and vaginal contraction in female mice, while genetic ablation of Krause corpuscles impaired intromission and ejaculation of males and reduced sexual receptivity of females. Thus, Krause corpuscles of the clitoris and penis are highly sensitive mechanical vibration detectors that mediate sexually dimorphic mating behaviours. Krause corpuscles of the clitoris and penis are highly sensitive mechanical vibration detectors that mediate sexually dimorphic mating behaviours in mice.

Even tough clitoris plays a critical role in female sexuality, we lack a precise understanding of qualitative and quantitative aspects of the innervation of the human clitoris. To address this issue, we dissected human clitorides from body donors and imaged them after staining with iodine with microCT for a macroscopic analysis. To resolve innervation patterns at the microscopic level we prepared thin sections of clitorides and stained them with trichrome azan to reveal the tissue structure combined with immunocytochemistry against Neurofilament H antibodies to reveal all axons and luxol blue labeling to reveal myelinated axons. We find the clitoral branch of pudendal nerve that innervates the clitoris not as single nerve, but as number of loose bundles. In the crus of the clitoris, about 12 such bundles can be recognized while about 32 bundles are present in the clitoral hemi-body. We counted on avarage 2917 axons in the crus of the clitoris (76% of which are myelinated) and 3137 axons in the hemibody of the clitoris (71% of which are myelinated). While the human clitoris receives only one third of the number of axons that innervate the human penis, an estimate of innervation density (per surface area) revealed that clitoris has approximately 6 times denser innervation compared to the penis. Thus, our study combines histology with microCT analysis provides detailed information on the number, myelination and innervation density of dorsal nerve of clitoris.

A major complication of feminizing genitoplasty in children is the loss of clitoral sensation with serious impact at adult life. We suggest a new method to evaluate the surgical results during childhood based on the bulbocavernosus or clitoro-perineal reflex (CPR). The afferent pathway of CPR implies the intact sensory receptors on the clitoral glans. Girls with congenital adrenal hyperplasia who were followed-up medically without surgery or who underwent feminizing genitoplasty with or without clitoroplasty were included (2002–2018). All clitoroplasties were standardized reduction clitoroplasty with preservation of neurovascular bundles associated with vaginoplasty and vestibuloplasty. Standardized examinations were prospectively performed including the CPR starting at one year postoperatively. The reflex was triggered by gentle touch of the glans by a cotton swab. Contraction of the perineal muscles was considered positive. Thirty-two children were operated at a median age of 8.6 months (5.8–12.1). Median follow-up (FU) was 3.9 years (1.3–6.4). Twenty-four patients had clitoroplasties: 17 were tested for CPR at one-year FU, and all had a positive test. Eight girls had genitoplasty without clitoral surgery, two of them were tested and were positive. Ten patients were managed without surgery, two of them were tested for the CPR and were positive. The reflex was always triggered easily and repeated at least twice during the FU. The clitoro-perineal reflex is a simple, non-invasive and reproducible test in early childhood and may serve as an early evaluation tool of clitoral innervation after feminizing genitoplasty. These results need to be confirmed at long term and completed at adult life.

The transient receptor potential cationic channel ankyrin 1 (TRPA1) is a channel protein assumed to act in various human tissues as mechano- and pain sensor and play a role in neurotransmission. The expression of TRPA has already been investigated in the human prostate and urethra, however, only very few studies have addressed the expression and distribution in the male and female genital tract. The present study aimed to investigate by means of immunohistochemistry (double-labeling technique, laser fluorescence microscopy) in the human clitoris and penile erectile tissue the localization of TRPA1 in relation to nNOS, the vasoactive intestinal polypeptide (VIP) and vesicular acetylcholine transporter (VAChT). In the clitoral tissue, TRPA1 was observed in basal epithelial cells and slender nNOS-positive nerve fibers transversing the subepithelial space. To a certain degree, in the clitoral epithelial cells, TRPA1 was found co-localized with vimentin. In human corpus cavernosum, immunoreactivity for TRPA1 was seen in nerves transversing the cavernous sinusoidal space and running alongside small arteries, these nerves also displayed expression of the vesicular acetylcholine transporter protein (VAChT). Varicose nerves containing nNOS or VIP were not immunoreactive for TRPA1. It seems likely that TRPA1 is involved in nitric oxide-mediated afferent sensory transmission in the clitoris while, in penile erectile tissue, a role for TRPA1 in cholinergic signaling might be assumed.

We studied the central representation of pudendal afferents arising from the clitoral nerves in 15 healthy adult female subjects using electrical dorsal clitoral nerve stimulation and fMRI. As a control body region, we electrically stimulated the right hallux in eight subjects. In a block design experiment, we applied bilateral clitoral stimulation and unilateral (right) hallux stimulation. Activation maps were calculated for the contrasts ‘electrical dorsal clitoral nerve stimulation versus rest’ and ‘electrical hallux stimulation versus rest’. A random-effect group analysis for the clitoral stimulation showed significant activations bilateral in the superior and inferior frontal gyri, insulae and putamen and in the postcentral, precentral and inferior parietal gyri (including the primary and secondary somatosensory cortices). No activation was found on the mesial surface of the postcentral gyrus. For the hallux, activations occurred in a similar neuronal network but the activation in the primary somatosensory cortex was localized in the inter-hemispheric fissure. The results of this study demonstrate that the central representation of pudendal afferents arising from the clitoral nerves and sensory inputs from the hallux can be studied and distinguished from each other by fMRI. From the somatotopic order described in the somatosensory homunculus one would expect for electrical clitoral nerve stimulation activation of the mesial wall of the postcentral gyrus. In contrast, we found activations on the lateral surface of the postcentral gyrus.

The objective of the study is to clarify potential risks to the dorsal nerve of the clitoris (DNC) and obturator canal using different minimally invasive slings. Ten embalmed hemipelves were dissected to demonstrate the course of the DNC and the obturator canal. On each cadaver, tension-free vaginal tape (TVT), transobturator in-out (TVT-O) and transobturator out-in (Monarc) procedures were performed. Distances between the DNC and the obturator canal to the different devices were measured. The DNC passes beneath the pubic bone at a distance of 14.3±4.7 mm of the midline. The distances of the different devices to the DNC were similar. The distance to the obturator canal was significantly different, with TVT being the furthest (40.1±3.7 mm) and TVT-O the closest (19.3±3.1 mm; p<0.0001). Given the course of the DNC along the medial aspect of the ischiopubic ramus, the out-in technique may be safer. The in-out technique is the closest to the obturator canal.[PUBLICATION ABSTRACT]

Introduction and hypothesis To avoid injury to the perineal branches of the pudendal nerve during urinary incontinence sling procedures, a thorough knowledge of the course of these nerve branches is essential. The dorsal nerve of the clitoris (DNC) may be at risk when performing the retropubic (tension-free vaginal tape) procedure as well as the inside-out and outside-in transobturator tape procedures. The purpose of this study was to identify the anatomical relationships of the DNC to the tapes placed during the procedures mentioned and to determine the influence of body variations. Methods In this cadaveric study, the body mass index (cBMI) of unembalmed cadavers was determined. Suburethral tape procedures were performed by a registered urologist and gynecologist on a sample of 15 female cadavers; six retropubic, seven inside-out and nine outside-in transobturator tapes were inserted. After embalmment, dissections were performed and the distances between the DNC and the tapes measured. Results In general the trajectory of the outside-in tape was closer to the DNC than that of the other tapes. cBMI was weakly and nonsignificantly correlated with the distance between the trajectory of the tape and the DNC for the inside-out tape and the tension-free vaginal tape, but not for the outside-in tape. Conclusions The findings suggest that the DNC is less likely to be injured during the inside-out tape procedure than during the outside-in procedure, regardless of BMI. Future studies on larger samples are desirable to confirm these findings.

Using functional magnetic resonance imaging (fMRI) we investigated the cortical and subcortical representations during bladder filling and the effect of simultaneous stimulation of the dorsal clitoral nerve on these cortical and subcortical structures. After approval of the local ethics committee, 8 healthy females were included. Prior to scanning, subjects were catheterized and the bladder was filled until first desire to void occurred. In a block design protocol we performed repetitive manual bladder filling (FILLING) and emptying of additional 80 ml saline, alternating with rest conditions (REST) of constant bladder volume. The protocol was repeated with simultaneous stimulation of the dorsal clitoral nerve during the filling periods (COMBINED). Activation maps were calculated by means for 3 different contrasts: 1) FILLING > REST, 2) COMBINED > REST and 3) FILLING > COMBINED. A group analysis of contrast 1) showed activation of the right prefrontal and orbitofrontal cortices, the insula bilaterally, the left precuneus, the parietal operculum bilaterally, the cerebellum bilaterally ( q(FDR) ≤ 0.001), the right anterior cingulate gyrus ( q(FDR) ≤ 0.005) and the right anterior mid pons ( q(FDR) ≤ 0.05). Contrast 2) showed activation in the right frontal area, the left insula, the parietal operculum bilaterally and the left cerebellum ( q(FDR) ≤ 0.001). Deactivations were found in the middle frontal gyrus bilaterally and the post- and paracentral gyri bilaterally. Contrast 3) revealed stronger activation during FILLING in the bilateral frontal and prefrontal areas, the right anterior cingulated gyrus, and the right putamen ( q(FDR) ≤ 0.05). Only the right insula showed stronger activation during the COMBINED condition. Simultaneous dorsal clitoral nerve stimulation during bladder filling reduced the activation of certain cortical areas suggesting a neuromodulatory effect of this stimulation on supraspinal centres involved in lower urinary tract control.

Dissection of the pudendal nerve (PN) and its branches in 71 cadavers revealed anatomic variations not previously described. Knowledge of this variation is necessary to prevent nerve injury resulting in sexual of sensory dysfunction. Because descriptions vary, this study re-evaluated the anatomy of the PN as implicated in perineal procedures in South Africans. The course of the PN from the gluteal region into the perineum was dissected in an adult sample of both sexes and of African and European ancestry. Distances between PN and branches to applicable landmarks were measured. Basic descriptive statistics and comparisons were carried out between groups. In 5/13 African females, the inferior rectal nerve (IRN) entered the gluteal region separately and in 12/13 cases it passed medial to the ischial spine with the PN. The dorsal nerve of the clitoris or penis (DNC/DNP) was closer to the bony frame in those of European ancestry. The IRN branches were more superficial in females, but deeper in males of European ancestry. In African females, a PN block and Richter stitch should be placed more medial. Outside-in transobturator tape procedures might endanger the DNC/DNP in obese individuals. In females of European ancestry the IRN branches are compromised during ischioanal abscess drainage. In males of European ancestry, the dorsal penile nerve block might be less effective. Predictions should be verified clinically.

Background Erectile dysfunction, principally related to injury of the autonomic nerve fibers in men, is a major cause of postoperative morbidity after anterolateral dissection during total mesorectal excision (TME) for rectal adenocarcinoma. However, the autonomic innervation of erectile bodies is less known in women, and the anterolateral plane of dissection during TME remains unclear. The existence of the rectovaginal septum (RVS) is controversial. The purpose of the present study was to identify the RVS in the human fetus and adult female by dissection, immunohistochemistry, and three-dimensional reconstruction, and to define its relationship with erectile nerve fibers so as to determine the anterolateral plane of dissection during TME, which could reduce postoperative sexual dysfunction in women. Method Macroscopic dissection, histologic studies, and immunohistochemistry examination with 3D reconstruction were performed in six fresh female adult cadavers and six female fetuses. Results The RVS was clearly definable in all adult specimens. It was composed of multiple connective tissue, with smooth muscle fibers originating from the uterus and the vagina. It is closely applied to the vagina and has a relationship with the neurovascular bundles (NVBs) that contain erectile fibers intended for the clitoris. The NVBs are situated anteriorly to the posterior extension of rectovaginal septum. This posterior extension protects the NVBs during the anterior and anterolateral dissection for removal of rectal cancer. Conclusions To reduce the risk of postoperative sexual dysfunction in women undergoing TME for rectal cancer, we recommend careful dissection to the anterior mesorectum to develop a plane of dissection behind the posterior extension of the RVS if oncologically reasonable.