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In most amniotes, the intromittent organ is a single phallus; however, squamates (lizards, snakes, and amphisbaenians) have paired hemiphalluses. All amniotes studied to date initiate external genital development with the formation of paired genital swellings. In mammals, archosaurs, and turtles, these swellings merge to form a single genital tubercle, the precursor of the penis and clitoris; however, in squamates, the paired genital buds remain separate, giving rise to the hemiphalluses (hemipenes in males and hemiclitores in females). Although the molecular genetics and sexual differentiation of the genital tubercle have been investigated in mammals and birds, little is known about hemiphallus development. Here we describe development of the cloaca and hemiphallus in the green anole, Anolis carolinensis. Each hemiphallus originates as a protuberance that emerges at the ventral base of the hindlimb bud. Development of the hemipenes resembles penis development; however, differences exist in their tissue composition, morphogenesis, and gene expression patterns. These findings reveal aspects of phallus development that appear to be evolutionarily labile, both within squamates and more broadly among reptiles, and identify features that are conserved across amniotes. Our results, together with parallel studies in other reptilian taxa, suggest potential mechanisms for the diversification of external genital form.

The breadth of anatomical and functional diversity among amniote external genitalia has led to uncertainty about the evolutionary origins of the phallus. In several lineages, including the tuatara, Sphenodon punctatus, adults lack an intromittent phallus, raising the possibility that the amniote ancestor lacked external genitalia and reproduced using cloacal apposition. Accordingly, a phallus may have evolved multiple times in amniotes. However, similarities in development across amniote external genitalia suggest that the phallus may have a single evolutionary origin. To resolve the evolutionary history of amniote genitalia, we performed three-dimensional reconstruction of Victorian era tuatara embryos to look for embryological evidence of external genital initiation. Despite the absence of an intromittent phallus in adult tuataras, our observations show that tuatara embryos develop genital anlagen. This illustrates that there is a conserved developmental stage of external genital development among all amniotes and suggests a single evolutionary origin of amniote external genitalia.

Development of the external genitalia of fetal and neonatal cat were studied macroscopically, paying attention to the formation of the labia and the sexual differentiation. The female urogenital folds budded from each side of the genital tubercle and, gradually extended to the tip of the genital tubercle by the 6.8 cm stage in crown-rump length. Then, the well-developed urogenital folds ensheathed completely the genital tubercle to form the prepuce of clitoris and the labia, flanking the external opening of vagina as the folds of skin which were equivalent to the labia minora in humans. The genital swellings known to become the labia majora in humans were clearly recognized in the caudolateral region of the genital tubercle during the fetal stage. These swellings became flat and obscure after birth. Thus, in cats the genital swellings did not join to the formation of the labia in the same way as in humans. The sex difference in the external genitalia was first observed at the 3.2-3.3 cm stages. In the male, the anogenital raphe appeared and the caudal portion of the genital swellings moved and fused each other at the caudal region of the genital tubercle. In the female, both features were not easy to observe.

The occurrence of genital swellings was examined in adult female silvered langurs (Trachypithecus cristatus). In contrast to the exaggerated swellings found in cercopithecines and apes, genital swellings in silvered langurs are confined to the vulva and the surrounding perineum, but they may nevertheless convey information similar to that of exaggerated swellings (i.e., correlate with the receptive period and fertility). If so, genital swellings would be expected to occur most frequently in cycling females, and sexual behavior and male interest should most frequently involve females with swellings. Swellings during gestation, if they occur at all, should be most pronounced at the beginning. Swelling sizes (in three size categories) in nine adult females were examined throughout different reproductive states (cycling, pregnant, and lactating), and in relation to proceptivity, receptivity, and attractivity. Data were collected from November 2002 through March 2004 (on 500 of the 502 calendar days) at the Wildlife Conservation Society's Bronx Zoo. Female sexual behavior (proceptivity and receptivity) and male inspection (attractivity) were recorded each day for 6 hr by video camera (2,948 hr total) and analyzed as present or absent for each female day. Swellings were assessed directly (not from videotapes). In contrast to the predictions, swellings occurred significantly less frequently in cycling females (compared to pregnant females) and no regular, cyclic pattern could be detected. Some females conceived without a swelling. Female attractivity was independent of swellings but coincided with proceptive behavior. Swellings occurred most frequently in pregnant females, especially toward the end of the gestation period. Therefore, genital swellings in silvered langurs are not similar to exaggerated swellings or the smaller genital swellings that have been described for some other primates. It is currently not clear what they signal to conspecifics. Male behavior needs to be studied in more detail, and the hormonal basis for these swellings should be explored.

Genital malformations occur at a high frequency in humans, affecting ~1:250 live births. The molecular mechanisms of external genital development are beginning to be identified; however, the origin of cells that give rise to external genitalia is unknown. Here we use cell lineage analysis to show that the genital tubercle, the precursor of the penis and clitoris, arises from two populations of progenitor cells that originate at the lateral edges of the embryo, at the level of the posterior hindlimb buds and anterior tail. During body wall closure, the left and right external genital progenitor pools are brought together at the ventral midline, where they form the paired genital swellings that give rise to the genital tubercle. Unexpectedly, the left and right external genital progenitor pools form two lineage-restricted compartments in the phallus. Together with previous lineage studies of limb buds, our results indicate that, at the pelvic level, the early lateral mesoderm is regionalized from medial to lateral into dorsal limb, ventral limb, and external genital progenitor fields. These findings have implications for the evolutionary diversification of external genitalia and for the association between external genital defects and disruption of body wall closure, as seen in the epispadias-extrophy complex.

External genitalia are found in each of the major clades of amniotes. The phallus is an intromittent organ that functions to deliver sperm into the female reproductive tract for internal fertilization. The cellular and molecular genetic mechanisms of external genital development have begun to be elucidated from studies of the mouse genital tubercle, an embryonic appendage adjacent to the cloaca that is the precursor of the penis and clitoris. Progress in this area has improved our understanding of genitourinary malformations, which are among the most common birth defects in humans, and created new opportunities for comparative studies of other taxa. External genitalia evolve rapidly, which has led to a striking diversity of anatomical forms. Within the past year, studies of external genital development in non-mammalian amniotes, including birds, lizards, snakes, alligators, and turtles, have begun to shed light on the molecular and morphogenetic mechanisms underlying the diversification of phallus morphology. Here, we review recent progress in the comparative developmental biology of external genitalia and discuss the implications of this work for understanding external genital evolution. We address the question of the deep homology (shared common ancestry) of genital structures and of developmental mechanisms, and identify new areas of investigation that can be pursued by taking a comparative approach to studying development of the external genitalia. We propose an evolutionary interpretation of hypospadias, a congenital malformation of the urethra, and discuss how investigations of non-mammalian species can provide novel perspectives on human pathologies.

The morphogenesis of the external genitalia of human fetuses (16-250 mm crown-rump [CR] length, 6-26 weeks of gestation) obtained after medical termination of pregnancy were studied. Differential development (male/female) started after 50 mm CR length (9 weeks). At that time the external genitalia consisted of a cylindrical genital tubercle 2 mm in length with a visible coronary sulcus and glans and genital swellings on either side. A groove on the ventral aspect of the genital tubercle extended to the coronary sulcus; the lateral boundaries of this groove separated to form the urethral folds. In male fetuses the free edges of the urethral folds fused, starting from the proximal end, to form a tunnel over the ventral aspect of the phallus. The pelvic urethra opened into this tunnel, slightly distal to its origin. The mesodermal tissue forming the genital swellings migrated ventrally and then medially. As medial migration started, the skin in the midline between the genital swellings was raised up as a skin fold, which subsequently, as the genital swellings migrated further, became elevated. The proximal part of the tunnel formed by fusion of the urethral folds (proximal to the point of entry of the pelvic urethra) also was compressed and pushed out as the genital swellings fused in the midline over the root of the phallus. These changes took place at between 80 and 110 mm CR length (12-13 weeks' gestation); at this stage the phallus appeared short and was bent ventrally. With further growth and caudal migration of the scrotum, the phallus lost its ventral curvature. The appearance of the external genitalia at different gestational ages bore a close resemblance to that in children with hypospadias. We therefore conclude that hypospadias can be explained on the basis of an embryological arrest due to the absence of the required stimulus for male phenotypic development at the appropriate time.

Cyclical changes in the vulvae of five adult lar gibbons (Hylobates [H.] lar) were studied and compared with those of eight lowland gorillas. The results reveal that the gibbons have relatively conspicuous and specialized sexual swellings that alter shape and appearance during the ovarian cycle. At maximum extent, the genital swellings of gorillas are relatively and absolutely smaller than those of gibbons, and lack the distinctive coloration seen in the genital swellings of the smaller apes. We conclude that the female gibbon's sexual swelling is a far more conspicuous and effective signal of estrus status than that of the gorilla, and that this is not explicable in terms of allometry. Previous investigators have pointed to one-male mating systems, monogamous pair-bonding, or an arboreal habitat as reasons that some primates should have less conspicuous signals of estrus than others. Our findings for the gibbon are the reverse of these predictions, and indicate that sexual selection other than by intermale competition for estrous females is implicated in the ultimate causation of the gibbon's swelling. The adaptive value and significance of the female gibbon's sexual signals remain unclear, however.

Authors from Korea present five children with perineal lipoma in association with a variety of scrotal anomalies. They speculate that the development of perineal lipomas is closely related to scrotal anomalies, and speculate as to the reason why. OBJECTIVE To analyse the characteristics of the perineal lipoma and speculate on its development, as an associated perineal lipoma is implicated in the occurrence of scrotal anomalies in children. PATIENTS AND METHODS Five children with a perineal lipoma in association with various scrotal anomalies were included in the study. We analysed the types of scrotal anomalies and their anatomical relationship with the perineal lipomas. RESULTS One child had a supra-inguinal ectopic scrotum, and the others had penoscrotal transposition, either symmetrical or asymmetrical; they included two who had an accessory scrotum combined with a perineal lipoma. The perineal lipoma was on the ipsilateral side of the upward-positioned hemiscrotum in the ectopic scrotum or the asymmetrical penoscrotal transposition, or it was on the mid-perineum in the symmetrical penoscrotal transposition. CONCLUSIONS The perineal lipoma can be found combined with various scrotal anomalies, including ectopic scrotum as well as an accessory scrotum or penoscrotal transposition; this is the first report describing a perineal lipoma associated with an ectopic scrotum. We speculate that the development of the perineal lipoma is closely related to scrotal anomalies, which result from early division and/or abnormal migration of the labioscrotal swelling. The concomitant perineal lipoma might be formed during the process, and might affect abnormal scrotal development.

We present the extremely rare phenotype of an accessory scrotum with an associated lipoblastoma. There was a coexistence of midperineal and lateral types. To our knowledge, this phenotype has never been reported. The lipoblastoma, which arose in the perineum, divided the moving labioscrotal swelling into three parts during early fetal life. This resulted in the specific anomaly in this patient.

A case of accessory scrotum in a 2-day-old male infant is reported because of its rarity. An overview of sequences during the normal development of male external genitalia has been provided and the deranged mechanism resulting in this anomaly has been reviewed with hypotheses regarding etiology of accessory scrotum.

Developmental anatomy is integrated with gross anatomy. It consists of 12 lectures and is divided into body systems. The development of each system is correlated to its adult structures and species differences. The urinary and genital systems are developmentally and anatomically associated and originate together from the intermediate mesoderm. The urethra forms from the distal part of the urogenital sinus. Starting with the gonadogenesis, and continuing with the duct systems and external genitalia, the lectures are focused on the male and then on the female structures. At the end, the anomalies of the genital organs are exposed in detail, with suggestions for students, specialists and breeders to prevent and treat teratological conditions. The gonadogenesis is first presented in the indifferent stage. The differential stage is explained for the testis and then for the ovary. The genital duct system is exposed in the indifferent stage. The differential stage for the male includes the formation of the efferent ductules, the epididymal duct and the ductus deferens, while in the female, the focus is on the formation of the uterine tubes, uterus (including the horns, the body and the cervix), and the vagina. The indifferent stage of external genitalia is a complex stage, which originates from the mesodermal swellings adjacent to the cloacal membrane. In the male, the differential stage includes the formation of penis and penile urethra. In the female the genital tubercle forms the clitoris, the urethral folds form the labia, while the genital swellings degenerate. The hermaphroditism, gonadal dysplasia, the cryptorchidism, the persistent vestigial structures, and the penischisis (hypospadias and epispadias) as anomalies of the genital system conclude the lecture.

In my presentation, I review the sexual differentiation from the genetic sex until the appearance of the external genitalia and the developmental anomalies to use an animated cartoon. The first critical stage of sexual differentiation occurs at the moment of fertilization, when the genetic sex of the zygote is determined by the nature of the sex chromosome contributed by the sperm. Although an XY zygote is destined to become a male, no distinctive differences between the early development of male and female embryos have been noted. This is accomplished after migration of the primordial germ cell into the early gonad. Because of the early commonality of genital structures, anomalies are the result of abnormal retention or loss of appropriate genital structures. Therefore, most genital anomalies are some form of intersex. During the early differentiation of the gonads, while the mesonephros is still the dominant excretory organ, the gonads arise as ridge like thickenings (gonadal ridge) on its ventromedial face. Differentiation of the indifferent gonads into ovaries or testes occurs after the arrival of the primordial germ cells. The primordial germ cells arise from the endodermal cells of the yolk. The principal function of the Y chromosome is to direct the differentiation of the presented indifferent gonad into a testis from the sixth week, while two X chromosome are presented the ovaries start to develop, from the 12th week. The next and most obvious phase in sexual differentiation of the embryo is the differentiation of the somatic sex. The early embryo develops a dual set of potential genital ducts, one is the original mesonephric (Wolff ) ducts, which persists after degeneration of the mesonephros as an excretory organ, and the another is newly formed pair of ducts called the paramesonephric (Mullerian) ducts. Under the influence of testosterone secreted by the testes, the mesonephric ducts develop into the duct system through which the spermatozoa are conveyed from the testes to the urethra. The potentially female paramesonephric ducts regress under the influence of another product of the embryonic testes, the Mullerian inhibitory factor, a glycoprotein secreted by the Sertoli cells. In genetically female embryos, neither testosterone nor Mullerian inhibitory factor are secreted by the gonads. In the absence of testosterone the mesonephric ducts regress and lack of Mullerian inhibitory factor permits the paramesonephric ducts to develop into oviducts, the uterus and part of the vagina. The next stage is the development of the external genitalia. In very young embryos, a vaguely outlined elevation known as the genital eminence can be seen in the midline, just cephalic to the proctodeal depression. This is soon differentiated into a central prominence (genital tubercle) closely flanked by a pair of folds (genital folds) extending toward the proctodeum. Somewhat farther to either side are rounded elevation known as the genital swellings. From this common starting point the external genitalia of both sex differentiate. If the individual is to develop into a male the genital tubercle, under the influence of dihydrotestosterone, becomes greatly elongated to form the penis and the genital swellings become enlarged to form the scrotal pouches. During the growth of the penis a groove develops along the entire length of its caudal face and is continuous with the slit-like opening of the urogenital sinus. This groove later becomes closed over by a ventral fusion of the genital folds, establishing the penile portion of the urethra. The portion of the urogenital sinus between the neck of the bladder and the original opening of the urogenital sinus becomes the prostetic urethra. In the female, the genital tubercle becomes the clitoris, the genital folds become the labia minora, and the genital swellings become the labia majora. The urethra in the female is derived from the urogenital sinus, being homologous with the prostatic portion of the male urethra.

Congenital scrotal disorders are unusual, including penoscrotal transposition, bifid scrotum, ectopic scrotum and accessory scrotum. The latter 2 entities are extremely rare. Because accessory scrota usually arise in the absence of associated anomalies, an etiology has been enigmatic. We present 2 cases of accessory labioscrotal folds, including a female patient. An exhaustive literature review allowed comparison with all reported cases (23) and showed a frequent association with perineal lipoma (83%). On that basis, we were able to classify accessory labioscrotal folds into 2 types and recommend a different course of management for each. Accessory labioscrotal folds usually develop when intervening mesenchymal tissue disrupts the continuity of the caudally developing labioscrotal swelling.

The external genitalia in bovine fetuses were studied macroscopically, with special reference to the formation of the labia and the sexual differentiation. The age of fetuses was expressed in crown-rump length (CRL). The female urogenital fold budding on either side of the genital tubercle gradually approached the tip of the genital tubercle by the 33-cm stage and then began to enclose it with the companion fold on the other side, thus forming the labium pudendi which is equivalent to the labium minus pudendi of the human. The genital swellings, which are known to become the labia majora in the human, did not take part in the formation of the labia. They completely disappeared at the sites cranial to the genital tubercle by the l0-cm stage. The sex difference in differentiation of the external genitalia was first observed at the 2.7-cm stage, at which time in the male, the urogenital orifice and the anogenital raphe appeared at the sites caudal to the genital tubercle; in the female at the 2.9-cm stage, both structures were still not observable. The anogenital distance became clearly longer in male than in female, after 3.6-3.9-cm stages.

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.

Normal male sexual development comprises three sequential steps: the development of genetic, gonadal and somatic sex. The secretion and action of three fetal testicular hormones are necessary: mullerian inhibiting substance, testosterone, 5α-dihydrotestosterone. The latter transforms the urogenital sinus, the urogenital tubercle and genital swellings into the prostate and external genitalia. Based on these endocrinological aspects of somatic differentiation, a classification of male pseudohermaphroditism is established. Exact and immediate diagnosis in patients with ambiguity of external genitalia should be followed by early gender assignment and adequate operative therapy. After deciding to treat a patient in the male direction, preoperative penile stimulation, either by local application or systemic therapy with androgens is of great importance to suppress the risk of complications and unsatisfactory results. Then a one-stage repair or multistage technique can be carried out to correct the penile deformity and construct a neourethra. We prefer a staged approach and report our results and experience in the last three decades. If the patient is raised as a female, genitoplasty and, later on, vaginoplasty is performed, the gonads are removed and replacement hormone therapy is initiated.

External genital development begins with formation of paired genital swellings, which develop into the genital tubercle. Proximodistal outgrowth and axial patterning of the genital tubercle are coordinated to give rise to the penis or clitoris. The genital tubercle consists of lateral plate mesoderm, surface ectoderm, and endodermal urethral epithelium derived from the urogenital sinus. We have investigated the molecular control of external genital development in the mouse embryo. Previous work has shown that the genital tubercle has polarizing activity, but the precise location of this activity within the tubercle is unknown. We reasoned that if the tubercle itself is patterned by a specialized signaling region, then polarizing activity may be restricted to a subset of cells. Transplantation of urethral epithelium, but not genital mesenchyme, to chick limbs results in mirror-image duplication of the digits. Moreover, when grafted to chick limbs, the urethral plate orchestrates morphogenetic movements normally associated with external genital development. Signaling activity is therefore restricted to urethral plate cells. Before and during normal genital tubercle outgrowth, urethral plate epithelium expresses Sonic hedgehog (Shh). In mice with a targeted deletion of Shh, external genitalia are absent. Genital swellings are initiated, but outgrowth is not maintained. In the absence of Shh signaling, Fgf8, Bmp2, Bmp4, Fgf10, and Wnt5a are downregulated, and apoptosis is enhanced in the genitalia. These results identify the urethral epithelium as a signaling center of the genital tubercle, and demonstrate that Shh from the urethral epithelium is required for outgrowth, patterning, and cell survival in the developing external genitalia.