The Somatic and Autonomic Innervation of the Clitoris; Preliminary Evidence of Sexual Dysfunction after Minimally Invasive Slings

IntroductionVaginal sling procedures may have a negative effect on sexual function due to damage to vascular and/or neural genital structures. Even though autonomic innervation of the clitoris plays an important role in female sexual function, most studies on the neuroanatomy of the clitoris focus on the sensory function of the dorsal nerve of the clitoris (DNC). The autonomic and somatic pathways in relationship to sling surgery have up to the present not been described in detail.AimThe aim of this study is to reinvestigate and describe the neuroanatomy of the clitoris, both somatic and autonomic, in relation to vaginal sling procedures for stress urinary incontinence.MethodSerially sectioned and histochemically stained pelves from 11 female fetuses (10–27 weeks of gestation) were studied, and three-dimensional reconstructions of the neuroanatomy of the clitoris were prepared. Fourteen adult female hemipelves were dissected, after a tension-free vaginal tape (TVT) (7) or tension-free vaginal tape-obturator (TVT-O) (7) procedure had been performed.Main Outcome MeasuresThree-dimensional (3-D) reconstruction and measured distance between the clitoral nerve systems and TVT/TVT-O.ResultsThe DNC originates from the pudendal nerve in the Alcock's canal and ascends to the clitoral bodies. In the dissected adult pelves, the distance of the TVT-O to the DNC had a mean of 9 mm. The cavernous nerves originate from the vaginal nervous plexus and travel the 5 and 7 o'clock positions along the urethra. There, the autonomic nerves were found to be pierced by the TVT needle. At the hilum of the clitoral bodies, the branches of the cavernous nerves medially pass/cross the DNC and travel further alongside it. Just before hooking over the glans of the clitoris, they merge with DNC.ConclusionsThe DNC is located inferior of the pubic ramus and was not disturbed during the placement of the TVT-O. However, the autonomic innervation of the vaginal wall was disrupted by the TVT procedure, which could lead to altered lubrication-swelling response. Bekker MD, Hogewoning CRC, Wallner C, Elzevier HW, and DeRuiter MC. The somatic and autonomic innervation of the clitoris; preliminary evidence of sexual dysfunction after minimally invasive slings. J Sex Med 2012;9:1566–1578.     

Women's clitoris, vagina, and cervix mapped on the sensory cortex: fMRI evidence

IntroductionThe projection of vagina, uterine cervix, and nipple to the sensory cortex in humans has not been reported.AimsThe aim of this study was to map the sensory cortical fields of the clitoris, vagina, cervix, and nipple, toward an elucidation of the neural systems underlying sexual response.MethodsUsing functional magnetic resonance imaging (fMRI), we mapped sensory cortical responses to clitoral, vaginal, cervical, and nipple self‐stimulation. For points of reference on the homunculus, we also mapped responses to the thumb and great toe (hallux) stimulation.Main Outcome MeasuresThe main outcome measures used for this study were the fMRI of brain regions activated by the various sensory stimuli.ResultsClitoral, vaginal, and cervical self‐stimulation activated differentiable sensory cortical regions, all clustered in the medial cortex (medial paracentral lobule). Nipple self‐stimulation activated the genital sensory cortex (as well as the thoracic) region of the homuncular map.ConclusionThe genital sensory cortex, identified in the classical Penfield homunculus based on electrical stimulation of the brain only in men, was confirmed for the first time in the literature by the present study in women applying clitoral, vaginal, and cervical self‐stimulation, and observing their regional brain responses using fMRI. Vaginal, clitoral, and cervical regions of activation were differentiable, consistent with innervation by different afferent nerves and different behavioral correlates. Activation of the genital sensory cortex by nipple self‐stimulation was unexpected, but suggests a neurological basis for women's reports of its erotogenic quality. Komisaruk BR, Wise N, Frangos E, Liu W‐C, Allen K, and Brody S. Women's clitoris, vagina and cervix mapped on the sensory cortex: fMRI evidence. J Sex Med 2011;8:2822–2830.     

Sonography of the clitoris

IntroductionThe prevalence of invasive procedures in diagnosing female sexual dysfunctions and pathologies is high. There is a need for a less invasive evaluation tool and medical imaging of the clitoris may be a solution. The clitoris has already been studied with nuclear magnetic resonance but there are very few sonographic 2D and 3D studies despite the fact that it is a simple, noninvasive, and inexpensive method.AimThis study aims at determining the feasibility of using ultrasound (US) techniques to image the clitoris in sufficient detail to permit evaluation of anatomy for possible use in study.MethodsThe ultrasounds were performed in five healthy volunteers with the Voluson® GE® Sonography system (GE Healthcare Ultrasound, Zipf, Austria), using one 12-MHz flat probe.Main Outcome MeasuresThe clitoral body's diameter, the length of the raphe.ResultsThe three planes—the cross-section, sagittal section, and coronal section—were revealed making it possible to study the entire organ.ConclusionThe sonography is a simple, inexpensive, noninvasive mean which might help for the evaluation of this organ. Buisson O, Foldes P, and Paniel B-J. Sonography of the clitoris.     

The Role of Regulatory Proteins and S‐nitrosylation of Endothelial Nitric Oxide Synthase in the Human Clitoris: Implications for Female Sexual Function

IntroductionDuring female sexual arousal, clitoral blood flow is controlled by endothelial nitric oxide synthase (eNOS) and its product, nitric oxide (NO). The mechanisms regulating eNOS activity and NO bioavailability in the clitoris are largely unknown.AimTo identify proteins involved in regulation of eNOS activity within the clitoris and to evaluate the effects of S‐nitrosoglutathione reductase (GSNO‐R) and eNOS nitrosylation/denitrosylation on clitoral blood flow.MethodsImmunohistochemistry for eNOS, caveolin‐1 (Cav1), heat shock protein‐90 (Hsp90), phosphodiesterase type 5 (PDE5), GSNO‐R, and soluble guanylate cyclase (sGC) was performed on human and murine clitoral tissue. Western blot analysis was performed for eNOS, phosphorylated eNOS (phospho‐eNOS, Ser1177), Cav1, Hsp90, sGC, PDE5, phosphoinositide 3‐kinase (PI3K), Akt (protein kinase B), and GSNO‐R on protein from human clitoral tissue. A biotin switch assay was used to analyze the S‐nitrosylation of eNOS, nNOS, and GSNO‐R. Clitoral blood flow was measured in wild‐type and GSNO‐R^‐/‐ mice at baseline and during cavernous nerve electrical stimulation (CNES).Main Outcome MeasuresLocalization of eNOS regulatory proteins and clitoral blood flow.ResultseNOS and GSNO‐R co‐localized to the vascular endothelium and sinusoids of human clitoral tissue. Immunohistochemistry also localized Cav1 and Hsp90 to the endothelium and PDE5 and sGC to the trabecular smooth muscle. Expression of S‐nitrosylated (SNO)‐eNOS and SNO‐GSNO‐R was detected by biotin switch assays. Wild‐type control mice exhibited increased clitoral blood flow with CNES whereas GSNO‐R^‐/‐ animals failed to show an increase in blood flow.ConclusionsSeveral key eNOS regulatory proteins are present in the clitoral tissue in a cellular specific pattern. S‐nitrosylation of eNOS may also represent a key regulatory mechanism governing eNOS activation/deactivation since mice deficient in GSNO‐R failed to increase clitoral blood flow. Additional studies are necessary to define the role of S‐nitrosylation in the genital vascular response and its subsequent impact on female sexual function. Oliver JL, Kavoussi PK, Smith RP, Woodson RI, Corbett ST, Costabile RA, Palmer LA, and Lysiak JJ. The role of regulatory proteins and s‐nitrosylation of endothelial nitric oxide synthase in the human clitoris: Implications for female sexual function. J Sex Med 2014;11:1927–1935.     

Vascular modifications of the clitoris induced by topic nitric oxide donor gel--preliminary study

IntroductionThe clitoral blood flow increase is dependent of nitric oxide (NO) and it occurs due to sexual arousal. Female sexual disorder mechanisms are poorly understood and NO therapeutic role in this scenario is to be determined.AimTo assess topic NO donor S‐nitrosoglutationa (GSNO) gel—100 µM effect on clitoral blood flow in healthy women.MethodsForty healthy women were double‐blinded randomized for Group 1, GSNO gel, n = 20 and Group 2, placebo gel, n = 20. All patients underwent Doppler ultrasound test in the clitoral artery. Hemodynamic analysis consisted of: systolic peak speed, diastolic speed, and vase resistance rate. Ten random patients were analyzed regarding sexual function after two double‐blinded placebo and NO donor gel periods of 30 days.Main Outcome MeasuresTo consider female sexual dysfunction treatment through local NO‐dependent pathway.ResultsMean age was 31 years (20–39) and mean female sexual function index score 31.5 (26–34). Group 1: The mean and standard deviation baseline and 15 minutes after the application of the GSNO gel systolic (11.7 ± 2.1 cm/second to 15.9 ± 2.4 cm/second) and diastolic speeds (2.7 ± 0.3 cm/second to 4.2 ± 0.4 cm/second) and resistance (0.71 ± 0.04 to 1.38 ± 0.06) were significantly increased (P = 0.002) (P = 0.043), and (P = 0.005), respectively. No local or systemic adverse effect was observed in women or in their sexual partners and the sexual function presented a slightly insignificant improvement (P = 0.065), although eight of 10 women could subjectively identify the GSNO gel as the preferred and most pleasant between both tried. Group 2 presented no significant differences at baseline and 15 minutes after the application of the placebo gel, P > 0.05.ConclusionThe topic GSNO gel increased significantly the clitoral blood flow and could be considered therapeutically in selected cases of female sexual dysfunction warranting further investigation. Souto S, Palma P, Seabra AB, Fregonesi A, Palma T, and Reis LO. Vascular modifications of the clitoris induced by topic nitric oxide donor gel—Preliminary study.     

REVIEWS: The Clitoral Complex: A Dynamic Sonographic Study

IntroductionThe existence of the G-spot remains controversial partly because no appropriate structure and innervation have been clearly demonstrated in this pleasurable vaginal area. Using sonography, we wanted to visualize the movements of the clitoris and its anatomical relationship with the anterior wall of the vagina during voluntary perineal contraction and vaginal penetration without sexual stimulation.AimThe aim of this presentation is to provide a dynamic sonographic study of the clitoris and to describe the movements of the quiescent clitoral complex during a voluntary perineal contraction. We aim to visualize the mechanical consequences of the pressure of the anterior vaginal wall with women who claim to have a special sensitivity of the G-spot area and vaginal orgasm. Histology and immunohistochemistry of the G-spot and other female genital tissues are beyond the scope of this study and have not been discussed.MethodThe ultrasounds were performed in five healthy volunteers with the Voluson® General Electric® Sonography system (GE Healthcare, Zipf, Austria), with a 12-MHz flat probe, and with a vaginal probe. We used functional sonography of the quiescent clitoris with voluntary perineal contractions and with finger penetration without sexual stimulation.Main Outcome MeasuresWe focused on the size of the clitoris (raphe, glans, and clitoral bodies) and of the length of the movements of the clitoris during voluntary perineal contractions.ResultsThe coronal planes during perineal contraction and finger penetration demonstrated a close relationship between the root of the clitoris and the anterior vaginal wall.ConclusionsWe suggest that the special sensitivity of the lower anterior vaginal wall could be explained by pressure and movement of clitoris' root during a vaginal penetration and subsequent perineal contraction. The G-spot could be explained by the richly innervated clitoris. Foldes P, and Buisson O. The clitoral complex: A dynamic sonographic study. J Sex Med 2009;6:1223–1231.     

Sensory innervation of the external genital tract of female guinea pigs and mice

IntroductionThe structural and neurochemical characterization of the sensory innervation of the external genitalia of females is poorly known.AimsTo immunohistochemically map the sensory innervation of external genitalia and surrounding structures of female guinea pigs and mice.MethodsLarge‐diameter sensory fibers, presumably mechanoreceptors, were identified by their immunoreactivity to neuron‐specific enolase (NSE) or vesicular glutamate transporter 1 (VGluT1). Peptidergic sensory fibers, presumably unmyelinated nociceptors, were identified by their immunoreactivity to calcitonin gene‐related peptide (CGRP), substance P, or both. Multiple‐labelled tissues were examined with high‐resolution confocal microscopy.Main Outcome MeasuresMicroscopic identification of sensory endings, including potential nociceptors, characteristic of the external genitalia.ResultsLarge complex nerve endings immunoreactive for NSE and VGluT1 were abundant in dermal papillae of the clitoris. Each large ending was accompanied by one or two fine fibers immunoreactive for CGRP but neither substance P nor VGluT1. More simple NSE‐immunoreactive endings occurred within dermal papillae in non‐hairy skin of the labia and anal canal but were rare in pudendal or perineal hairy skin. Fine intra‐epithelial fibers immunoreactive for NSE but not CGRP were abundant in hairy skin but rare in non‐hairy genital skin and the clitoris. Only fine varicose fibers immunoreactive for both CGRP and substance P occurred in connective tissue underlying the mucosal epithelium of cervix and endometrium.ConclusionCompared with surrounding tissues, the sensory innervation of the clitoris is highly specialized. The coactivation of nociceptors containing CGRP but not substance P within each mechanoreceptor complex could be the explanation of pain disorders of the external genitalia. Vilimas PI, Yuan S‐Y, Haberberger RV, and Gibbins IL. Sensory innervation of the external genital tract of female guinea pigs and mice. J Sex Med 2011;8:1985–1995.     

The Visceromotor and Somatic Afferent Nerves of the Penis

IntroductionInnervation of the penis supports erectile and sensory functions.AimThis article aims to study the efferent autonomic (visceromotor) and afferent somatic (sensory) nervous systems of the penis and to investigate how these systems relate to vascular pathways.MethodsPenises obtained from five adult cadavers were studied via computer-assisted anatomic dissection (CAAD).Main Outcome MeasuresThe number of autonomic and somatic nerve fibers was compared using the Kruskal–Wallis test.ResultsProximally, penile innervation was mainly somatic in the extra-albugineal sector and mainly autonomic in the intracavernosal sector. Distally, both sectors were almost exclusively supplied by somatic nerve fibers, except the intrapenile vascular anastomoses that accompanied both somatic and autonomic (nitrergic) fibers. From this point, the neural immunolabeling within perivascular nerve fibers was mixed (somatic labeling and autonomic labeling). Accessory afferent, extra-albugineal pathways supplied the outer layers of the penis.ConclusionsThere is a major change in the functional type of innervation between the proximal and distal parts of the intracavernosal sector of the penis. In addition to the pelvis and the hilum of the penis, the intrapenile neurovascular routes are the third level where the efferent autonomic (visceromotor) and the afferent somatic (sensory) penile nerve fibers are close. Intrapenile neurovascular pathways define a proximal penile segment, which guarantees erectile rigidity, and a sensory distal segment. Diallo D, Zaitouna M, Alsaid B, Quillard J, Ba N, Allodji RS, Benoit G, Bedretdinova D, and Bessede T. The visceromotor and somatic afferent nerves of the penis. J Sex Med 2015;12:1120–1127.     

A solitary neurilemmoma of the clitoris

Neurilemmoma of the female genital tract is extremely rare. Presented is the case of a 84-year-old woman with a gradually enlarging clitoral mass. After simple excision, the mass proved to be a neurilemmoma originating from the clitoris histologically.     

Vasa Nervorum in Rat Major Pelvic Ganglion are Innervated by Nitrergic Nerve Fibers

IntroductionThe vasa nervorum comprises a network of small diameter blood vessels that provide blood supply to nerves and ganglia. The cell bodies of autonomic nerves innervating the urogenital organs are housed in the major pelvic ganglia (MPG) in rats. The vasa nervorum of rat MPG have not been characterized previously, and it is not known whether these blood vessels are innervated by neuronal nitric oxide synthase (nNOS) containing nitrergic nerves.AimTo characterize the blood vessels in and around the rat MPG and to assess their nitrergic innervation.Main Outcome MeasuresCharacterization of small blood vessels in and around the rat MPG and expression of nNOS in nerve fibers around those blood vessels.MethodsMPG were obtained from healthy Sprague Dawley rats, fixed in paraformaldehyde, frozen and sectioned using a cryostat. The blood vessels and their nitrergic innervation were assessed with immunohistochemistry using antibodies against alpha‐smooth muscle actin (smooth muscle marker), CD31 (endothelial marker), collagen IV (basal membrane marker) and nNOS. The immunofluorescence was imaged using a laser scanning confocal microscope.ResultsThe neuronal cell bodies were contained within a capsule in the MPG. Blood vessels were observed within the capsule of the MPG as well as outside the capsule. The blood vessels inside the capsule were CD31‐positive capillaries with no smooth muscle staining. Outside the capsule capillaries, arterioles and venules were observed. The extra‐capsular arterioles and venules, but not the capillaries were innervated by nNOS‐positive nerve fibers.ConclusionsThis study, to our knowledge, is the first to demonstrate the blood vessel distribution pattern and their nitrergic innervation in the rat MPG. While similar studies in human pelvic plexus are warranted, these results suggest that the blood flow in the MPG may be regulated by nitrergic nerve fibers and reveal a reciprocal relationship between nerves and blood vessels. Beetson KA, Smith SF, Muneer A, Cameron NE, Cotter MA, and Cellek S. Vasa nervorum in rat major pelvic ganglion are innervated by nitrergic nerve fibers. J Sex Med 2013;10:2967–2974.     

Granular cell tumor of the clitoris in pregnancy

Granular cell tumors of the female genital organs represent 7-15% of all granular cell tumors reported in the literature. The majority of these genital lesions are located on the vulva. Granular cell tumor involving the clitoris is extremely rare and should be considered in the differential diagnosis of clitoral masses.     

Self‐Assessment of Genital Anatomy and Sexual Function within a Belgian,Dutch‐Speaking Female Population: A Validation Study

IntroductionData on self‐perceived genital anatomy and sensitivity should be part of the long‐term follow‐up of genitoplasty procedures. However, no normative data, based on a large sample, exist to date.AimsValidation of the Self‐Assessment of Genital Anatomy and Sexual Function, Female version (SAGAS‐F) questionnaire within a Belgian, Dutch‐speaking female population.MethodsSeven hundred forty‐nine women with no history of genital surgery (aged 18–69 years, median 25 years) completed an Internet‐based survey of whom 21 women underwent a gynecological examination as to correlate self‐reported genital sensitivity assessed in an experimental setting.Main Outcome MeasuresThe SAGAS‐F enables women to rate the sexual pleasure, discomfort, intensity of orgasm, and effort required for achieving orgasm in specified areas around the clitoris and within the vagina, as well as genital appearance. The latter was similarly evaluated by an experienced gynecologist, and women were asked to functionally rate the anatomical areas pointed out with a vaginal swab.ResultsSexual pleasure and orgasm were strongest, and effort to attain orgasm and discomfort was lowest when stimulating the clitoris and sides of the clitoris (P < 0.05). Vaginal sensitivity increased with increasing vaginal depth, but overall orgasmic sensitivity was lower as compared with the clitoris. Functional scores on the SAGAS‐F and during gynecological examination corresponded highly on most anatomical areas (P < 0.05). Gynecologist's ratings corresponded highly with the women's ratings for vaginal size (90%) but not for clitoral size (48%).ConclusionsReplication of the original pilot study results support the validity of the questionnaire. The SAGAS‐F discriminates reasonably well between various genital areas in terms of erotic sensitivity. The clitoris itself appeared to be the most sensitive, consistent with maximum nerve density in this area. Surgery to the clitoris could disrupt neurological pathways and compromise erotic sensation and pleasure. Bronselaer G, Callens N, De Sutter P, De Cuypere G, T'Sjoen G, Cools M, and Hoebeke P. Self‐assessment of genital anatomy and sexual function in women (SAGAS‐F): Validation within a Belgian, Dutch‐speaking population. J Sex Med 2013;10:3006–3018.     

Clitoral Size and Location in Relation to Sexual Function Using Pelvic MRI

IntroductionThe female sexual response is dynamic; anatomic mechanisms may ease or enhance the intensity of orgasm.AimThe aim of this study is to evaluate the clitoral size and location with regard to female sexual function.MethodsThis cross‐sectional TriHealth Institutional Board Review approved study compared 10 sexually active women with anorgasmia to 20 orgasmic women matched by age and body mass index (BMI). Data included demographics, sexual history, serum hormone levels, Prolapse/Incontinence Sexual Questionnaire‐12 (PISQ‐12), Female Sexual Function Index (FSFI), Body Exposure during Sexual Activity Questionnaire (BESAQ), and Short Form Health Survey‐12. All subjects underwent pelvic magnetic resonance imaging (MRI) without contrast; measurements of the clitoris were calculated.Main Outcome MeasuresOur primary outcomes were clitoral size and location as measured by noncontrast MRI imaging in sagittal, coronal, and axial planes.ResultsThirty premenopausal women completed the study. The mean age was 32 years (standard deviation [SD] 7), mean BMI 25 (SD 4). The majority was white (90%) and married (61%). Total PISQ‐12 (P < 0.001) and total FSFI (P < 0.001) were higher for orgasmic subjects, indicating better sexual function. On MRI, the area of the clitoral glans in coronal view was significantly smaller for the anorgasmic group (P= 0.005). A larger distance from the clitoral glans (51 vs. 45 mm, P= 0.049) and body (29 vs. 21 mm, P= 0.008) to the vaginal lumen was found in the anorgasmic subjects. For the entire sample, larger distance between the clitoris and the vagina correlated with poorer scores on the PISQ‐12 (r = −0.44, P= 0.02), FSFI (r = −0.43, P= 0.02), and BESAQ (r = −0.37, P= 0.04).ConclusionWomen with anorgasmia possessed a smaller clitoral glans and clitoral components farther from the vaginal lumen than women with normal orgasmic function. Oakley SH, Vaccaro CM, Crisp CC, Estanol MV, Fellner AN, Kleeman SD, and Pauls RN. Clitoral size and location in relation to sexual function using pelvic MRI. J Sex Med 2014;11:1013–1022.     

Female Orgasm(s): One,Two, Several

IntroductionThere is general agreement that it is possible to have an orgasm thru the direct simulation of the external clitoris. In contrast, the possibility of achieving climax during penetration has been controversial.MethodsSix scientists with different experimental evidence debate the existence of the vaginally activated orgasm (VAO).Main Outcome MeasureTo give reader of The Journal of Sexual Medicine sufficient data to form her/his own opinion on an important topic of female sexuality.ResultsExpert #1, the Controversy's section Editor, together with Expert #2, reviewed data from the literature demonstrating the anatomical possibility for the VAO. Expert #3 presents validating women's reports of pleasurable sexual responses and adaptive significance of the VAO. Echographic dynamic evidence induced Expert # 4 to describe one single orgasm, obtained from stimulation of either the external or internal clitoris, during penetration. Expert #5 reviewed his elegant experiments showing the uniquely different sensory responses to clitoral, vaginal, and cervical stimulation. Finally, the last Expert presented findings on the psychological scenario behind VAO.ConclusionThe assumption that women may experience only the clitoral, external orgasm is not based on the best available scientific evidence. Jannini EA, Rubio‐Casillas A, Whipple B, Buisson O, Komisaruk BR, and Brody S. Female orgasm(s): one, two, several. J Sex Med 2012;9:956–965.