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Biomedical subjects

John M Hutson

Publications and source records attributed to John M Hutson.

At least 19 recordsLinked to original sources

Current management of the undescended testicle.

Cryptorchidism, where either one or both testes fails to migrate to the base of the scrotum, affects 4% to 5% of full-term and 9% to 30% of premature males at birth. The testis can be found in any position along its usual line of descent; however, approximately 80% will be located in the inguinal region, just outside the inguinal canal. Early correction, from 3 to 6 months of age, is currently advised. The preferred means of investigation and subsequent surgical intervention are dependent on the position of the cryptorchid testis. Risks associated with cryptorchidism include infertility and malignancy. The aim of appropriate management is to minimize these, and any other, associated complications.

Adolescent↗

Multiple endocrine neoplasia type 2B diagnosed on suction rectal biopsy in infancy: a report of 2 cases.

Suction rectal biopsies in a newborn and a 10-month-old infant presenting with intestinal obstruction showed marked increase in neurons and nerve bundles in the submucosa. Although there were no syndromic features or a positive family history, mutation analysis of the RET proto-oncogene showed a de novo germline Met918Thr mutation in both patients, confirming the diagnosis of multiple endocrine neoplasia type 2B (MEN 2B). Thyroidectomy was performed at 9 and 14 months, showing medullary carcinoma and focal prominent C-cell hyperplasia, respectively. These 2 cases are presented to emphasize that when the submucosal plexus is obviously and prominently increased in suction rectal biopsies, diffuse intestinal ganglioneuromatosis should be considered. As this can be associated with genetic conditions, especially MEN 2B, it is crucial that further investigations be performed to ensure proper patient management, such as early thyroidectomy.

Biopsy, Needle↗

A new role for androgen in testicular descent: permitting gubernacular cell proliferation in response to the neuropeptide, calcitonin gene-related peptide.

BACKGROUND/PURPOSE: Cell proliferation at the gubernacular tip increases in response to exogenous calcitonin gene-related peptide (CGRP) during migration into the scrotum. Calcitonin gene-related peptide is contained in the masculinized sensory branches of the genitofemoral nerve. We tested the independent effects of chemical sensory nerve disruption and prenatal androgen blockade on the in vitro gubernacular proliferative response to CGRP. METHODS: Neonatal Sprague-Dawley rats were injected with capsaicin, a sensory nerve toxin, and gubernacula dissected 2 days later (D2). Sprague-Dawley dams were injected with flutamide, an androgen receptor antagonist, between days 15 and 19 of gestation. Flutamide pretreated males, and normal neonatal rats, were dissected at D0 and D2. Gubernacula were cultured for 24 hours +/- CGRP, pulse-labelled for the last 4 hours of culture with bromodeoxyuridine, a thymidine analogue marker for DNA replication, sectioned, and stained using immunohistochemistry. The percentage of positively staining cells in the gubernacular tip was calculated from three separate counts by a blinded observer and compared using analysis of variance. RESULTS: Normal D0 gubernacular tips showed a significant response of cell proliferation to exogenous CGRP (34% vs 9% in controls, P < .001), which resolved by day 2 (16% vs 12%, P > .05). Calcitonin gene-related peptide markedly increased cell proliferation in D2 capsaicin pretreated gubernacula compared with controls (25% vs 14%, P < .01) and normal D2 gubernacula cultured with CGRP (P < .01). D0 flutamide pretreated cultured with CGRP showed no increase in cell proliferation compared with controls (16% vs 11%), but a small response was seen by D2 (19% vs 9%, P < .05). There was no significant difference between proliferation rates in the control groups. CONCLUSIONS: Sensory innervation interruption sensitises the gubernaculum to exogenous CGRP, suggesting upregulation of CGRP receptors. In contrast, androgen blockade abolishes the increased rate of cell proliferation within the gubernacular tip. We conclude that androgens are necessary to "preprogramme" the proliferative response of the gubernaculum to CGRP.

Animals↗

An association of multiple endocrine neoplasia 2B, a RET mutation; constipation; and low substance P-nerve fiber density in colonic circular muscle.

BACKGROUND: Multiple endocrine neoplasia (MEN) 2B is a rare hereditary syndrome that results from an activating mutation of the RET proto-oncogene. The RET gene is involved in the development of the enteric nervous system. Patients with MEN 2B have enlarged enteric ganglia and may be affected by gastrointestinal dysmotility. A deficiency of the neurotransmitter substance P (SP) has been identified in both pediatric and adult patients with chronic constipation. METHODS: Three patients, in whom constipation was the presenting symptom and MEN 2B had been provisionally diagnosed, underwent genetic analysis. Seromuscular colonic biopsies were taken for immunofluorescence imaging in all 3 patients. A retrospective review of the patient notes was undertaken. RESULTS: All 3 patients had constipation refractory to conservative treatment. Genetic analyses in the 3 patients confirmed an identical RET mutation (Met918Thr). Immunofluorescence imaging in all 3 patients identified grossly enlarged myenteric plexus ganglia but surprisingly a low density of SP-labeled nerve fibers in the colonic circular muscle. Nitric oxide synthase and vasoactive intestinal peptide labeling were not reduced. CONCLUSION: The results show an association between MEN 2B and its most common RET mutation, colonic dysmotility, and low density of SP in the colonic circular muscle. Larger numbers of patients need to be studied to investigate whether low SP is primarily associated with the constipation or RET mutation and if it is a common feature of MEN 2B.

Colon↗

Re-exploration of the acute scrotum.

OBJECTIVE: To investigate children and adolescents who had scrotal exploration more than once. PATIENTS AND METHODS: Between 1994 and 2004, 64 of 840 (7.6%) boys had more than one scrotal exploration at our institution. The age, laterality of the explorations, the interval between and findings at operation, whether the testes were managed by orchidopexy and how, and the complications, were reviewed from the medical records and the operating reports of the patients. All the boys were followed at the outpatient clinic 2-4 weeks after surgery. RESULTS: The median (range) age of the patients was 11.5 (2-15) years; 61 had two scrotal explorations and three were explored three times. Of the patients, 32 presented with right testicular pain, 31 had left pain, and one had bilateral testicular pain. In the second exploration, 56 of 64 had the contralateral testis explored, five had an ipsilateral exploration and three had bilateral exploration. Forty-eight of the 64 boys (70%) had torsion of the contralateral appendix testis at the second exploration, and 5.3% (45/840) of the total number of children operated for acute scrotum had metachronous torsion of the appendix testis. The median interval between the first and second exploration was 8 months (1 day to 10.5 years). Two boys had three scrotal explorations, and three of 64 (4.7%) boys developed complications that required re-exploration. CONCLUSIONS: Most indications for recurrent scrotal exploration in this study are because of a twisted contralateral appendix testis, but the risk of developing this pathology is similar to the complication rate of repeat scrotal exploration. These data support our policy that the contralateral testis should not be routinely explored nor its appendix removed unless there is ipsilateral testicular torsion.

Adolescent↗

Abnormalities of testicular descent.

Testicular descent occurs in two stages. The transabdominal phase (8-15 weeks) is controlled by enlargement of the caudal genito-inguinal ligament (gubernaculum) and regression of the cranial ligament. Insulin-like 3 from the Leydig cell appears to be the prime stimulator of gubernacular growth, augmented by Müllerian inhibiting substance/anti-Müllerian hormone. Testosterone causes regression of the cranial ligament. The inguinoscrotal phase (25-35 weeks) requires the migration of the gubernaculum from the groin to the scrotum; this migration is guided by the genito-femoral nerve releasing calcitonin gene-related peptide under the influence of androgen. The neonatal gonocyte transforms into a type A spermatogonium at 3-12 months of age, a step that is now known to be crucial for subsequent fertility, as the stem cells for spermatogenesis are created in this structure. This step is blocked in undescended testis and, hence, orchidopexy is currently recommended at 6-12 months of age. Congenital cryptorchidism is caused by the failure of gubernacular migration to the scrotum (1%-2%) but we now recognise that another 1%-2% of boys have acquired cryptorchidism, secondary to the failure of spermatic cord elongation with growth of the boy. These latter cases come to operation at 5-10 years of age. Surgery remains the mainstay of treatment, as hormonal therapy has not been proven to be effective, presumably because testicular descent is a complex anatomical mechanism.

Cryptorchidism↗

Is the testis intraperitoneal?

The relationship of the testis to the peritoneal cavity, and hence its position as an intraperitoneal or extraperitoneal organ, remains controversial. Adult anatomy texts favour an extraperitoneal position during and after testicular descent, whereas journal articles favour an intraperitoneal position. Interestingly, there is no similar debate around the position of the ovary despite the common origin of each as indifferent gonads. Through direct observation and the literature review, we aimed to determine whether the testis should be considered an intraperitoneal or an extraperitoneal organ. The anatomical and embryological literature relevant to human and animal models was reviewed. Direct dissections were made in rats (n=8) during foetal development, postnatally, and in mature animals, allowing comparison of foetus with adult and male with female. The position of the human testis was also recorded in various pathological states. Direct dissection in rats reveals an intraperitoneal testis on a mesorchium during both foetal and postnatal life. Intraperitoneal testes are demonstrated in humans in cases of gastroschisis (where the testis may protrude through the periumbilical defect with the bowel), testicular torsion (where the testis is mobile within the peritoneum), and bell clapper testis (where the testes are identifiable as intraperitoneal). We conclude that the foetal testis is an intraperitoneal organ. In the adult rat the testis remains intraperitoneal. The postnatal human testis is intraperitoneal. The adult human testis is intraperitoneal but may appear extraperitoneal. The apparent discrepancy between the adult testis being intraperitoneal or extraperitoneal is likely to result from differences in the relative size of the tunica vaginalis between infant boys and elderly men.

Animals↗

Gubernacular cell division in different rodent models of cryptorchidism supports indirect androgenic action via the genitofemoral nerve.

PURPOSE: The role of the "gubernaculum" in testicular descent remains controversial. Androgens are proposed to act indirectly by the genitofemoral nerve (GFN) releasing calcitonin gene-related peptide. The authors studied the effects of sensory nerve ablation and androgen blockade on mitosis in the gubernacular tip to determine whether androgens act directly or indirectly. METHODS: Five rat models were examined for bromodeoxyuridine (BUdR)-labeling: (i) Sprague-Dawley (SD) rats (controls), (ii) prenatal flutamide-treated rats (75 mg/kg to dams on D16-19 gestation), (iii) neonatal capsaicin-treated rats (50 mg/kg, subcutaneous on day 0), (iv) congenitally cryptorchid transcrotal (TS) rats, and (v) capsaicin-treated TS rats (50 mg/kg, subcutaneous on day 0). Newborn rats were collected at days 0, 2, 4, 6, 8, and 10 (age, n = 5/model, n = 30) and were injected intraperitoneally with 1 mg/kg BUdR, 2 hours before killing. Histological sections of gubernaculum were examined immunohistochemically for BUdR labeling. RESULTS: In SD (control) rats, DNA synthesis in the gubernacular tip was high at birth, reached a peak at day 2, and then decreased progressively until day 10. A similar pattern was observed in TS rats. However, quantitatively, the levels were significantly higher. In flutamide-treated rats, DNA synthesis was suppressed until day 6, similar suppression was observed in capsaicin-treated SD, and TS rats until day 4. CONCLUSIONS: Flutamide, a competitive androgen receptor blocker, reduces gubernacular mitosis to basal levels until day 6, highlighting the importance of androgen receptor. Excess DNA accumulation in TS rats is consistent with the known excess of GFN fibers and calcitonin gene-related peptide in this mutant. Capsaicin-inhibited mitosis in both day 2 SD and TS rats suggests that the GFN mediates androgen action on early postnatal gubernacular DNA synthesis and growth.

Analysis of Variance↗

Laparoscopic seromuscular colonic biopsies: a surgeon's experience.

BACKGROUND: Colonic dysmotility is a recognised cause of chronic constipation in children. Colonic dysmotility is better analysed by examination of the colonic muscle than rectal biopsy, which does not examine the defective area and has a low yield. We explored the role of laparoscopic colonic muscle biopsies to investigate children with intractable constipation. The authors describe the technique, its application, and results from a large series. METHODS: A retrospective review was conducted of all patients undergoing laparoscopic seromuscular colonic biopsies (hepatic flexure, mid-transverse colon, splenic flexure, and sigmoid colon) by a single surgeon for the investigation of chronic constipation over a 10-year period. Patient records were reviewed to determine the perforation frequency and management, postoperative recovery time and the frequency of an immunohistochemical abnormality. RESULTS: One hundred ninety-seven patients (118 boys) were investigated by laparoscopic biopsy during the period. The mean age was 8.0 +/- 4.0 years (range, 1.4-22.4). The patients took 28.7 +/- 13.6 hours (range, 8-120) to recover, with 37 (19%) having nausea and/or vomiting requiring antiemetics. Most patients (160/197, 81%) were discharged the following day. Six patients (3%) had a mucosal perforation recognised at operation (treated by an Endoloop) with no change in postoperative outcome. Two patients (1%) had an unrecognised mucosal perforation requiring laparoscopic reoperation and Endoloop closure (laparotomy/colostomy not required), with no further sequelae. Eight-six patients (44%) had a specific immunohistochemical neuropeptide anomaly (reduced substance P [84], reduced vasoactive intestinal peptide [2]). CONCLUSIONS: Laparoscopic biopsy is a valuable tool to investigate chronic constipation in children, allowing a pathological diagnosis to be made in many cases. The complications of the procedure are acceptably low with this technique.

Adolescent↗

Testicular descent and cryptorchidism: the state of the art in 2004.

The understanding of testicular descent has changed much in the 20 years since the authors' laboratory began studying the mechanism. The process is now known to occur in 2 steps with different anatomy and hormonal regulation but with many still unresolved controversies. Recent advances include the recognition of acquired cryptorchidism of critical early postnatal germ cell development and the recommendation for surgery at 6 months of age. The authors still await long-term outcome studies.

Age Factors↗

Radionuclear transit to assess sites of delay in large bowel transit in children with chronic idiopathic constipation.

PURPOSE: Chronic idiopathic constipation (CIC) with soiling in children may result from slow colonic transit (SCT) or anorectal dysfunction and/or psychological problems known as functional fecal retention (FFR). Evidence is accumulating that SCT and FFR need different treatments, but they are poorly distinguished by solid marker studies. The authors used radionuclear transit scintigraphy to categorize children with CIC as having either FFR or SCT. METHODS: Children (N = 101) with CIC (and soiling) who were referred for further investigation after failure of standard treatments (diet, laxatives) received radiolabeled colloid orally, and scintillation images were collected at 0 to 2, 6, 24, 30 and 48 hours (total radiation dosage = 2 standard x-rays). Radioactivity in 6 regions (precolonic, ascending, transverse, descending, rectosigmoid, and evacuated feces) was measured, and the median position (geometric center) of radioactivity at each time was determined. RESULTS: In children, meals normally reach the cecum at 6 hours and are evacuated in 30 to 58 hours. Fifty patients had retention of radioactivity in the proximal colon at 48 hours, indicating SCT. Analysis of the images and the geometric center showed that passage through the ascending colon and transverse colon was delayed in SCT. In 24 patients, radioactivity was passed by 30 hours, indicating normal transit or possible FFR. Twenty-two patients had retention in the rectum, indicating definite FFR. Five studies were borderline. CONCLUSIONS: Radionuclear transit scintigraphy is useful for categorizing patients with CIC as having either FFR or SCT, allowing for different treatments. Radionuclear transit scintigraphy provides more detail and greater sensitivity than solid marker studies in diagnosing CIC. Radionuclear transit scintigraphy showed that half of our patients had SCT.

Cecum↗

Contractility of rat gubernacula affected by calcitonin gene-related peptide and beta-agonist.

PURPOSE: The effects of calcitonin gene-related peptide (CGRP), isoprenaline, and guanethidine on the neonatal rat gubernaculum were investigated in organ culture with the aim of seeing whether beta -agonists or beta -antagonists are involved in gubernacular development during testicular descent. METHODS: A total of 200 gubernacula were studied. The gubernacula (n = 20 for each experiment) from male rat pups were incubated in aerated culture medium with isoprenaline (1 and 10 micromol/L) with/without CGRP (714 nmol/L) or guanethidine (1 and 10 micromol/L) with/without CGRP (714 nmol/L). Cultures were observed for 5 days by video camera to see spontaneous rhythmic contractions, which are known to correlate with normal gubernacular migration in the rodent. RESULTS: Of gubernacula cultured without CGRP, 60% showed contractions by day 5, and the groups of isoprenaline and 10 micromol/L guanethidine showed similar rates, but only 15% of the 1 micromol/L guanethidine group showed contractility (P < .005). In contrast, of the gubernacula cultured with CGRP, each group showed high contractility from day 2 of the culture, and there was no difference between each group and the CGRP-alone group. CONCLUSIONS: Although the beta -blocker showed a weak inhibitory effect on de novo gubernacular contractility, CGRP had a stronger effect on contractility, overriding any possible effects of the beta -neuron pathway. The contractility of the rat gubernaculum during testicular descent is primarily mediated by the genitofemoral sensory nerve fibers via release of CGRP, but beta -adrenergic nerves also may be involved.

Adrenergic Agents↗

Colonic manometry via appendicostomy shows reduced frequency, amplitude, and length of propagating sequences in children with slow-transit constipation.

BACKGROUND/PURPOSE: We wish to define colonic motor function in children with slow-transit constipation (STC) using manometry catheters introduced through appendiceal stomas, previously sited for controlling fecal retention by colonic irrigation. METHODS: We undertook 24-hour pancolonic manometry of 6 children (5 boys; mean, 11.5 years; SD, 3.0) using a multilumen silastic catheter. RESULTS: were compared to nasocolonic motility studies obtained in healthy young adults. RESULTS: Antegrade propagating sequences (APSs) originated less frequently in the cecum compared to controls. There were fewer APS (mean +/- SEM: STC, 13 +/- 6 per 24 hours; controls, 52 +/- 6 per 24 hours; P < .01) and high-amplitude propagating contractions (HAPCs: STC, 5 +/- 2 per 24 hours; controls, 9.9 +/- 1.4 per 24 hours; P < .05). The amplitude of APS and HAPC was less in STC (APS, 39 +/- 9 mm Hg; controls, 54 +/- 3 per 24 hours; P < .05) (HAPC: STC, 94 +/- 10 mm Hg; control, 117 +/- 3 mm Hg; P < .01), whereas the amplitude of retrograde propagating sequences was greater in STC (43 +/- 6 mm Hg; control, 27 +/- 1 mm Hg; P < .01). The distances propagated by HAPC were significantly less in STC (36 +/- 4.5 vs 47 +/- 2.3 cm, controls; P < .05), and there was no evidence of a region-specific difference in propagation velocity of APS. Neither meal ingestion nor waking significantly increased colonic motor activity in patients with STC. CONCLUSIONS: Despite the small numbers available to be studied, we found that children with STC in whom an appendicostomy had been placed show significant abnormalities in pancolonic motor function.

Adolescent↗

The antegrade continence enema successfully treats idiopathic slow-transit constipation.

BACKGROUND: Antegrade continence enemas (ACEs) are successful for constipation and/or fecal incontinence caused by anorectal malformations or spina bifida but have been thought to be less successful in the treatment for patients with colonic dysmotility. We studied the long-term efficacy of ACE in a large group of patients with idiopathic slow-transit constipation (STC). METHODS: We identified 56 children with an appendicostomy for ACE with radiologically proven STC. An independent investigator (SKK) performed confidential telephone interviews. RESULTS: We assessed 42 of 56 children (31 boys) of mean age 13.1 years (range, 6.9-25). Mean follow-up was at 48 months (range, 3-118). Mean symptom duration before appendicostomy was 7.5 years (range, 1.4-17.4). Indications for appendicostomy were soiling (29/42), inadequate stool evacuation (7/42), and recurrent hospital admissions for nasogastric washouts (6/42). Both quality of life (Templeton quality of life [P < .0001]) and continence (modified Holschneider continence score [P < .0001]) improved with ACE. Soiling frequency decreased in 32 of 42 (11/32 completely continent). Thirty-seven of 42 children had reduced abdominal pain severity (P < .0001) and frequency (P < .0001). Complications included granulation tissue (33/42), stomal infection (18/42), and washout leakage (16/42). Fifteen of 42 children ceased using the appendicostomy (7/15 symptoms resolved). Thirty-five of 42 families felt that their aspirations had been met. CONCLUSIONS: Antegrade continence enemas were successful in 34 (81%) of 42 children with STC, contradicting views that ACEs are less effective in patients with colonic dysmotility.

Abdominal Pain↗

Could inguinal hernia be treated medically?

Inguinal hernia is the most common congenital anomaly requiring surgical correction. The cause of the hernia is, most commonly, persistence of the processus vaginalis. Study of testicular descent in rodents has revealed a role for the genitofemoral nerve and calcitonin gene-related peptide (CGRP). Since the testis cannot descend without the processus vaginalis, we wondered whether both descent and hernia closure might be regulated by the same mechanism. Therefore, we tested the idea that CGRP might be active in closure of the inguinal hernia. Using hernial sacs removed at herniotomy operation, fusion of the hernial surfaces was induced by CGRP, but not by CGRP 8-37, CGRP 27-37 or dihydrotestosterone. Hepatocyte growth factor also caused peritoneal obliteration in vitro. We propose that obliteration of the processus vaginalis is under the control of molecules released from the genitofemoral nerve, and that a chemical treatment of inguinal hernia is at least theoretically possible.

Animals↗

Evaluation and management of the abnormal gonad.

Diagnostic evaluation of patients with an abnormal gonad is complex because of multifactoral etio-pathogenesis and rarity of the conditions. In the text to follow, we have briefly discussed the embryology and attempted to classify abnormal gonadal disorders. The aims of evaluating such a child are to: (1) establish genetic sex; (2) determine the hormonal milieu; (3) evaluate the anatomy of internal and external genitalia and gonads; and (4) in older children, assess the phenotypic and psychological sex. In newborn children with ambiguous genitalia, the focus is now on accurate gender assignment. A team approach is needed and decisions are based on likely prognosis for behavior and gender orientation. The recent advances in cytogenetics have proven to be helpful in early and accurate diagnosis. In patients with an abnormal gonad, four conditions can present with sexual ambiguity at birth: female pseudohermaphroditism (or "virilized female"), true hermaphroditism, male pseudohermaphroditism (or "undervirilized male") and mixed gonadal dysgenesis. The role of clinical history and examination is emphasized in differential diagnosis and management. Timing of surgery for each of the conditions is discussed.

Algorithms↗

Anatomy of the clitoris.

PURPOSE: We present a comprehensive account of clitoral anatomy, including its component structures, neurovascular supply, relationship to adjacent structures (the urethra, vagina and vestibular glands, and connective tissue supports), histology and immunohistochemistry. We related recent anatomical findings to the historical literature to determine when data on accurate anatomy became available. MATERIALS AND METHODS: An extensive review of the current and historical literature was done. The studies reviewed included dissection and microdissection, magnetic resonance imaging (MRI), 3-dimensional sectional anatomy reconstruction, histology and immunohistochemical studies. RESULTS: The clitoris is a multiplanar structure with a broad attachment to the pubic arch and via extensive supporting tissue to the mons pubis and labia. Centrally it is attached to the urethra and vagina. Its components include the erectile bodies (paired bulbs and paired corpora, which are continuous with the crura) and the glans clitoris. The glans is a midline, densely neural, non-erectile structure that is the only external manifestation of the clitoris. All other components are composed of erectile tissue with the composition of the bulbar erectile tissue differing from that of the corpora. The clitoral and perineal neurovascular bundles are large, paired terminations of the pudendal neurovascular bundles. The clitoral neurovascular bundles ascend along the ischiopubic rami to meet each other and pass along the superior surface of the clitoral body supplying the clitoris. The neural trunks pass largely intact into the glans. These nerves are at least 2 mm in diameter even in infancy. The cavernous or autonomic neural anatomy is microscopic and difficult to define consistently. MRI complements dissection studies and clarifies the anatomy. Clitoral pharmacology and histology appears to parallel those of penile tissue, although the clinical impact is vastly different. CONCLUSIONS: Typical textbook descriptions of the clitoris lack detail and include inaccuracies. It is impossible to convey clitoral anatomy in a single diagram showing only 1 plane, as is typically provided in textbooks, which reveal it as a flat structure. MRI provides a multiplanar representation of clitoral anatomy in the live state, which is a major advantage, and complements dissection materials. The work of Kobelt in the early 19th century provides a most comprehensive and accurate description of clitoral anatomy, and modern study provides objective images and few novel findings. The bulbs appear to be part of the clitoris. They are spongy in character and in continuity with the other parts of the clitoris. The distal urethra and vagina are intimately related structures, although they are not erectile in character. They form a tissue cluster with the clitoris. This cluster appears to be the locus of female sexual function and orgasm.

Anatomy↗