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The evolution of male genitalia: patterns of genetic variation and covariation in the genital sclerites of the dung beetle Onthophagus taurus.

Three main hypotheses, have been invoked to explain divergent genital evolution, the lock and key, pleiotropy, and sexual selection hypotheses, each of which make different predictions about how genital traits are inherited. Here we used a half-sib breeding design to examine the patterns of genetic variation and covariation between male genital sclerites, and their covariance with general body morphology in the dung beetle Onthophagus taurus. We found CV(A)'s and CV(P)'s were similar for both genital and general morphological traits and that CV(R)'s were large for both trait types. We found that male genital sclerites were negatively genetically correlated with general morphological traits. Variation in male genital morphology has direct implications for a male's fertilization success and the resulting sexual selection acting on male genitalia is predicted to maintain high levels of additive genetic variance. Contrary to this prediction, we found that individual genital sclerites all had low levels of additive genetic variance and large maternal and environmental sources of variation. Our data suggest that the genital sclerites in O. taurus are not inherited independently but as a genetically integrated unit. More importantly, the way the different sclerites function to influence male fertilization success reflects this genetic integration. Even though levels of V(A) in individual genital sclerites may be low, there may still be sufficient V(A) in multivariate trait space for selection to generate evolutionary change in the overall morphology of male genitalia.

Animals↗

The developmental relation among mesonephros, gonad and external genitalia in the fetus of goat (Capra prisca).

The mesonephros, the gonad, the external genitalia and the developmental relationships between them were examined on 21 goat fetuses, 29 to 92 days old. Three fetuses were not sexually differentiated, however 11 were males and 7 females. The development of the gonad could be divided in a not differentiated stage and a gonadal and external genitalia differentiation stage. A close relationship between the fetal gonad and the mesonephros was found during the stage of differentiation. The epicenter of this relation is the giant mesonephric nephron, a peculiar structure of mesonephros, from which epithelial cells presumably migrate into the gonad.

Animals↗

The Vater association: malformations of the male external genitalia.

Eight cases with the VATER association of malformations are presented. Maliformations of the external genitalia were found in 3 out of 7 male patients. Two of them presented with a bifid scrotum and a caudally displaced, dysplastic penis. Two patients had been exposed to progestin in early pregnancy and one of them had hyposadias and testicular atrophy. It is suggested that malformations of the male external genitalia might be part of malformations found in the VATER association.

Abnormalities, Multiple↗

An additional case of Smith-Lemli-Opitz syndrome in a 46,XY infant with female external genitalia.

Ambiguity of the external genitalia has been frequently documented in male patients classified as the Smith-Lemli-Opitz (SLO) syndrome. Four previous case reports suggest that in extreme cases of the SLO syndrome there may be complete lack of development of the male external genitalia even in the presence of a normal male 46,XY karyotype. We present an additional case of a phenotypically female infant with dysmorphic features compatible with SLO syndrome and a 46,XY chromosome complement.

Abnormalities, Multiple↗

Female genitalia: dynamic MR imaging with use of MS-325 initial experiences evaluating female sexual response.

PURPOSE: To determine whether magnetic resonance (MR) imaging with MS-325, a recently developed blood pool contrast agent, can depict sexual arousal response in healthy women. MATERIALS AND METHODS: Serial MR imaging of the external genitalia was performed in 12 healthy sexually functional women before and after administration of MS-325. MR images were obtained every 3 minutes during a 45-minute examination. During the examination, the subjects viewed neutral and erotic video material while they were in the magnet bore. MR image analysis at each interval consisted of vaginal wall, vaginal mucosa, and clitoris assessments; femoral vein signal intensity measurements; relative regional blood volume (rRBV) calculations; and clitoral volume measurements. Statistical analysis of the results was performed with a t test. RESULTS: On subjective questionnaires, all subjects in the test group reported being sexually aroused. MS-325-enhanced MR images showed strong contrast enhancement of the external genitalia. The rRBV in the glans clitoris of seven of 10 subjects and in the clitoral body of eight of these subjects increased significantly (P <.05) during erotic visual stimulation. All 10 subjects had a significant (P <.05) increase in clitoral size. There were no significant differences in any measures between the pre- and postmenopausal study groups. CONCLUSION: The sexual arousal response in healthy women can be monitored at serial MR imaging with MS-325. This examination holds promise for future studies of sexual arousal dysfunction in women.

Adult↗

Responses of medullary reticular formation neurons to input from the male genitalia.

1. The medullary reticular formation (MRF) is known to be involved in the modulation of certain reproductive behaviors. Ejaculation in the male, disrupted after spinal transection, may depend on a spinal-bulbo-spinal connection. To determine whether single neurons in the MRF receive sensory input from the male genitalia, the present study was undertaken using electrophysiological techniques. 2. The MRF of 14 urethan-anesthetized mature male rats was searched for single neurons responsive to bilateral electrical stimulation of the dorsal nerve of the penis (DNP). In addition, each DNP-responsive neuron was tested for responsiveness to bilateral electrical stimulation of the pelvic nerve (PN) and to mechanical stimulation (gentle touch, pressure, pinch) of the external genitalia, anus, urethra, and skin over most regions of the body. 3. A total of 165 single neurons responsive to bilateral electrical stimulation of the DNP were isolated and characterized throughout the MRF. All neurons responded to both ipsilateral and contralateral DNP stimulation. The majority of responses were excitatory, and most neurons had no background activity. Some neurons required wind-up with bilateral electrical stimulation of the DNP to respond. 4. About half of the neurons were located in the nucleus reticularis gigantocellularis (Gi); the remainder were located in surrounding (dorsal, ventral, lateral) regions of the MRF. Variations in response properties were found among neurons located in different MRF regions. 5. Eighty-eight DNP-responsive neurons were additionally responsive to bilateral electrical stimulation of the PN. None of the responses to bilateral PN were stronger than those for bilateral DNP and many (48%) were weaker. 6. Of the 165 DNP-responsive neurons, all were responsive to pressure/pinching of the penis; 16% responded to gentle stroking of the glans. Most of these neurons were additionally responsive (bilaterally) to pinching more than one (often all) of the following areas: perineum, scrotum, anus, ears, and toes (forefoot and hindfoot). 7. In conclusion, neurons located in the MRF of male rats are involved in the processing of bilaterally convergent inputs from multiple cutaneous and visceral regions of the body, including the penis and male urogenital tract. These neurons likely exert their effects by directly and/or indirectly activating ascending pathways to rostral regions of the brain important for somatovisceral sensation and motor behavior, and descending pathways to the spinal cord for modulation of segmental sexual reflexes. Contributions are likely for a wide spectrum of sensations and reproductive behaviors.

Animals↗

Adrenal insufficiency and abnormal genitalia in a 46XX female with Smith-Lemli-Opitz syndrome.

OBJECTIVE: To report the first case of a 46XX female infant with Smith-Lemli-Opitz syndrome (SLOS), adrenal insufficiency and abnormal genitalia. METHODS: The patient was assessed for hormonal status on day 4 and 6 months later and was followed-up from the study time (2.5 years of age). RESULTS: The patient had a persistent urogenital sinus, posterior labial fusion without clitoromegaly. She presented with a salt-wasting syndrome on day 4. Adrenal insufficiency was confirmed. Adrenal androgen levels, including 17-hydroxyprogesterone and 11-deoxycortisol were moderately elevated. CONCLUSION: Children with SLOS should be assessed for adrenal insufficiency. In female infants, abnormal external genitalia can be observed even if the precise mechanism behind these abnormalities is yet to be determined.

Abnormalities, Multiple↗

Histochemical localization of carbonic anhydrase in the female genitalia of pigs during the oestrous cycle.

The ovaries and internal genital tracts of cycling gilts were studied for localization of carbonic anhydrase activity using a post-embedding cobalt precipitation technique. Carbonic anhydrase activity was present in selective capillary endothelia and epithelial cells of the genitalia. The ovarian parenchyma, irrespective of the stage of the oestrous cycle considered, was unstained. The secretory cells of the deep furrows in the uterotubal junction and those in the isthmic region of the oviduct of the oestrous female showed a clear membrane-bound localization. The surface epithelium in the tubal ampulla showed a conspicuous cytoplasmic carbonic anhydrase activity during oestrus and the early luteal phase. Neither the intensity nor the localization of the histo-enzymatic reaction in the females varied with their hormonal status (i.e. stage of the oestrous cycle). The localization of the enzyme in particular regions of the female pig genitalia that normally act as sperm reservoirs (uterotubal junction--tubal isthmus) or where fertilization--early embryo development occur (i.e. ampulla) might be related to the control of the acid-base status of luminal fluid.

Animals↗

Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: molecular and clinical studies in 10 patients.

We report on molecular and clinical findings in 10 Japanese patients (four males and six females) from eight families (two pairs of siblings and six isolated cases) with Antley-Bixler syndrome accompanied by abnormal genitalia and/or impaired steroidogenesis. Direct sequencing was performed for all the 15 exons of cytochrome P450 oxidoreductase gene (POR), showing two missense mutations (R457H and Y578C), a 24-bp deletion mutation resulting in loss of nine amino acids and creation of one amino acid (L612_W620delinsR), a single bp insertion mutation leading to frameshift (I444fsX449), and a silent mutation (G5G). R457H has previously been shown to be a pathologic mutation, and computerized modeling analyses indicated that the 15A>G for G5G could disturb an exonic splicing enhancer motif, and the remaining three mutations should affect protein conformations. Six patients were compound heterozygotes, and three patients were R457H homozygotes; no mutation was identified on one allele of the remaining one patient. Clinical findings included various degrees of skeletal features, such as brachycephaly, radiohumeral synostosis, and digital joint contractures in patients of both sexes, normal-to-poor masculinization during fetal and pubertal periods in male patients, virilization during fetal life and poor pubertal development without worsening of virilization in female patients, and relatively large height gain and delayed bone age from the pubertal period in patients of both sexes, together with maternal virilization during pregnancy. Blood cholesterol was grossly normal, and endocrine studies revealed defective CYP17A1 and CYP21A2 activities. The results suggest that Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis is caused by POR mutations, and that clinical features are variable and primarily explained by impaired activities of POR-dependent CYP51A1, CYP17A1, CYP21A2, and CYP19A1.

Abnormalities, Multiple↗

Molecular analysis of external genitalia formation: the role of fibroblast growth factor (Fgf) genes during genital tubercle formation.

The molecular mechanisms underlying the development of the external genitalia in mammals have been very little examined. Recent gene knockout studies have suggested that the developmental processes of its anlage, the genital tubercle (GT), have much in common with those of limb buds. The Fgf genes have been postulated as regulating several downstream genes during organogenesis. Fgf8 was expressed in the distal urethral plate epithelium of the genital tubercle (GT) together with other markers such as the Msx1, Fgf10, Hoxd13 and Bmp4 expressed in the mesenchyme. To analyze the role of the FGF system during GT formation, an in vitro organ culture system was utilized. It is suggested that the distal urethral plate epithelium of GT, the Fgf8-expressing region, regulates the outgrowth of GT. Ectopic application of FGF8 beads to the murine GT induced mesenchymal gene expression, and also promoted the outgrowth of the GT. Experiments utilizing anti-FGF neutralizing antibody suggested a growth-promoting role for FGF protein(s) in GT outgrowth. In contrast, despite its vital role during limb-bud formation, Fgf10 appears not to be primarily essential for initial outgrowth of GT, as extrapolated from Fgf10(-/-) GTs. However, the abnormal external genitalia development of Fgf10(-/-) perinatal mice suggested the importance of Fgf10 in the development of the glans penis and the glans clitoridis. These results suggest that the FGF system is a key element in orchestrating GT development.

Animals↗

Etiology, clinical profile, gender identity and long-term follow up of patients with ambiguous genitalia in India.

There is little information on the profile of children with ambiguous genitalia in India. Presented here is an analysis of patients with ambiguous genitalia registered in a general endocrine clinic during the last 2 decades. Seventy-four patients (age 4 months to 36 years) were registered during this period. Fifty-two were more than 5 years old at the time of registration. Thirty-five were reared as females, 29 as males; nine children (4 months to 1 year old) were brought for sex assignment, and one (with epispadias) was brought for correction of urinary incontinence. Investigations revealed 28 patients with congenital adrenal hyperplasia, 14 dysgenetic male pseudohermaphroditism, ten true hermaphroditism, six partial androgen insensitivity, four castration and one epispadias. There were eight patients with perineal hypospadias with normal Leydig cell reserve (normal LH, FSH and testosterone response to LHRH). Sex of rearing and gender identity were concordant in all except the patients with perineal hypospadias with normal Leydig cell response. These observations support the theory that prenatal androgen exposure masculinizes the brain.

Adolescent↗

Development of the external genitalia in rat fetuses.

Development of the external genitalia in rat fetuses was studied with special reference to the formation of the labia pudenda and the determination of the stage at which the sex difference could be recognized from changes in the external structures. The urogenital fold located on either side of the external structures. The urogenital fold located on either side of the urogenital groove gradually enlarges and begins to enclose the genital tubercle with its counter fold on day 20 of gestation. Thus, the urogenital folds, which are known to become the labia minora and the prepuce of clitoris in the human, are differentiated only into the prepuce of clitoris in the rat. The genital swellings situated caudally to the urogenital folds are not well developed and come to be inconspicuously flat in situ at the end of gestation. However, the labia majora are formed by the time of puberty when the vagina opens. Therefore, it seems that the genital swellings contribute to the formation of the labia majora after birth. Sex difference in development of the external genitalia is recognized on day 17 of gestation; a small oval urogenital orifice is larger in male than in female and the genital swellings are better developed in male than in female.

Animals↗

Variations of the external male genitalia in three populations of Triatoma infestans Klug, 1834.

Triatoma infestans is the triatomine that presents the greatest dispersion area in South America. However, it is not known whether the original characteristics of this insect remained in its long dispersion process. The purpose of this work was to study comparatively the external male genitalia of insects from different populations of T. infestans, two from Brazil (Minas Gerais and Bahia) and one from Bolivia (Cochabamba Valley), and to investigate the correlation between the morphological and behavioral variations. Differences were observed in one of the structures of the external genitalia (endosoma process) that could be used to characterize the insects from the three populations studied.

Animals↗

Compound heterozygous mutations (PHE53/54DEL and HIS373LEU) of the P450c17 gene result in a 17alpha-hydroxylase/17,20-lyase deficient male pseudohermaphrodite with unambiguous external genitalia.

The autosomal recessive disease 17alpha-hydroxylase/17,20-lyase deficiency is characterized by mutation of the P450c17 enzyme, which catalyzes 17alpha-hydroxylation and 17,20-lysis in the steroidogenic pathways. Although 17 mutations of this enzyme have been reported, only a few of them resulted in a completely unambiguous phenotype of female external genitalia in 46, XY individuals. We report here a Japanese patient with a 46,XY karyotype, who showed such a unambiguous female external genitalia. Nucleotide sequencing of the P450c17 gene revealed the patient to be a compound heterozygote carrying two different mutations (PHE53/54DEL in exon 1 and HIS373LEU in exon 6). As these mutations have been previously detected in unrelated Japanese patients, it is confirmed that these mutations accumulate regionally. Since these mutations could be screened by a multiple genotyping method, the method is applicable when 17alpha-hydroxylase/17, 20-lyase deficiency is suspected in Japanese patients.

Adrenal Hyperplasia, Congenital↗

Embryonic development of the turkey male genitalia.

Embryonic development of male turkey genitalia was examined to define more clearly the origin of the structures comprising the Phallus nonprotrudens. At Day 7 of incubation, the knob-like genital (g.) eminence became evident just cranial to the tail fold. A raised caudal extension of the g. eminence, the g. crest, joined the tail fold medial to the paired g. swellings. Between Days 8 and 12 of incubation, the g. eminence differentiated into the g. tubercle (which by Day 18 formed the Phallus nonprotrudens), and the g. crest formed the ventral floor of the proctodeum. By Days 10 to 11 of incubation, the g. swellings had become confluent with the lateral extensions originating from the base of the g. tubercule forming both a collar-like structure around the vent and the dorsal wall of the proctodeum. By Day 23 of incubation, the urodeum and proctodeum had become patent and the overall anatomy of the genitalia resembled that of an immature male poult.

Animals↗

Research note: effect of in ovo 17-beta-estradiol or tamoxifen administration on sexual differentiation of the external genitalia.

The effect of in ovo administration of tamoxifen or 17 beta-estradiol on external sexual dimorphism in chickens was investigated. In two trials, fertile eggs were injected with either tamoxifen (200 micrograms per egg) or vehicle (100 microL corn oil) on Day 1 of incubation, or with 17 beta-estradiol (20 micrograms per egg) or vehicle on Day 11 of incubation. Sexes were determined by visual inspection of the external genitalia and by gonadal identification at Day 1 posthatch. Tamoxifen injection resulted in a significantly greater number of phenotypic male identifications, with male:female ratios of 76:24 (Trial 1) and 62:38 (Trial 2) based on external genitalia phenotype. Gonadal sexing corrected these ratios to 46:54 and 44:56, resulting in genital sexing errors of 27% (Trial 1) and 18% (Trial 2). These errors were significantly higher than genital sexing errors of the chicks treated with vehicle (2 and .6% for Trials 1 and 2, respectively). In ovo administration of 17 beta-estradiol resulted in an increased number of female identifications based on genital sex determination, with male:female ratios of 37:63 (Trial 1) and 46:54 (Trial 2). Gonadal sexing corrected these ratios to 54:46 and 51:49, resulting in genital sexing errors of 10 and 6% for Trials 1 and 2, respectively. These errors were significantly higher than genital sexing errors of vehicle-treated chicks (4 and .9% for Trials 1 and 2, respectively). The results of the present study indicate that early embryonic administration of estrogen or an estrogen antagonist alters chicken external sexual dimorphism near the time of hatch.

Animals↗

[Results of myocutaneous flap for extensive skin defect in the external genitalia].

We reviewed 12 patients who underwent myocutaneous flap plasties to reconstruct the genital skin. The patients included 9 who underwent a radical excision of malignant tumor involving the genital, inguinal or sacral skin, 1 with an extensive radiation ulcer of the genitalia and 2 with an ulcerating cancer of the scrotum or groin. In the latter 2 patients the plasty was intended to cover an unresectable ulcerating cancer. A gracilis myocutaneous flap was used in 10 patients, and a tensor fascia lata myocutaneous flap in 2 patients. Postoperatively, partial or total necrosis of the skin of the flap developed in 8 patients. In 4 of these, infection complicated the necrosis. Although debridement, resuture or free skin transplantation was needed in these patients, wound healing was ultimately achieved in 10 patients who underwent radical excision of malignant tumor or radiation ulcer. In contrast, the intended coverage of an unresectable ulcerating cancer was unsuccessful in two other patients. No patients had motor disturbance after wound healing. However, one patient developed stricture of the urethra and vagina which had been opened through the flap, and another patient complained of gait disturbance and difficult defecation because of an swelling of the flap around the anus. Incision or excision was required to relieve the complaints in these 2 patients. These results indicate that a myocutaneous flap is useful to cover an extensive skin defect of the genitalia, but may be accompanied by postoperative complications particularly before wound healing. Appropriate management is necessary to achieve the intended reconstruction.

Aged↗

X-linked lissencephaly with absent corpus callosum and ambiguous genitalia.

Lissencephaly has been described in over 10 distinct malformation syndromes. Recently, we have recognized 5 children from four unrelated families with an almost identical disorder comprising lissencephaly with a posterior-to-anterior gradient and only moderate increase in thickness of the cortex, absent corpus callosum, neonatal-onset epilepsy, hypothalamic dysfunction including deficient temperature regulation, and ambiguous genitalia in genotypic males. Our observation of 5 affected males in one of these families is consistent with an X-linked pattern of inheritance. However, it differs in many regards from the X-linked form of isolated lissencephaly sequence that is associated with mutations of the XLIS (DCX) gene. Therefore, we propose that this disorder comprises a new X-linked malformation syndrome, which we refer to as X-linked lissencephaly with ambiguous genitalia (XLA-G).

Agenesis of Corpus Callosum↗