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Historically, specific mutations in WT1 gene have been associated with distinct syndromes based on phenotypic characteristics, including Denys-Drash syndrome (DDS), Frasier syndrome (FS), Meacham syndrome, and WAGR syndrome. DDS is classically defined by the triad of steroid-resistant nephrotic syndrome (SRNS) onset in the first year of life, disorders of sex development (DSD), and a predisposition to Wilms tumor (WT). Currently, a paradigm shift acknowledges a diverse spectrum of presentations beyond traditional syndromic definitions. Consequently, the concept of WT1-related disorders becomes more precise. A genotype-phenotype correlation has been established, emphasizing that the location and type of WT1 mutations significantly influence the clinical presentation, the condition severity, and the chronology of patient manifestations. Individuals presenting with persistent proteinuria, with or without nephrotic syndrome, and varying degrees of kidney dysfunction accompanied by genital malformations should prompt suspicion of WT1 mutations. Recent genetic advances enable a more accurate estimation of malignancy risk in these patients, facilitating a conservative nephron-sparing surgery (NSS) approach in select cases, with a focus on preserving residual kidney function and delaying nephrectomies. Other key management strategies include kidney transplantation and addressing DSD and gonadoblastoma. In summary, recent genetic insights underscore the imperative to implement individualized, integrated, and multidisciplinary management strategies for WT1-related disorders. This approach is pivotal in optimizing patient outcomes and addressing the complexities associated with these diverse clinical manifestations.

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BACKGROUND: Infantile hemangiomas (IHs) of the anogenital region remain poorly characterized. OBJECTIVE: To examine the distribution, ulceration rate, and associated congenital anomalies of anogenital IHs. METHODS: Retrospective study at 8 tertiary referral centers. RESULTS: A total of 435 infants with an IH of the anogenital region were enrolled (of which, 319 [73%] were girls). Congenital anomalies were present in 6.4% (n = 28) of infants with an anogenital IH. Segmental or partial segmental anogenital IHs ulcerated in 72% (n = 99 of 138) of infants, whereas 45% (n = 133 of 297) of focal anogenital IHs experienced ulceration (P < .001). In a multivariable logistic regression analysis, segmental or partial segmental morphology (adjusted odds ratio [aOR], 2.70; 95% CI, 1.60-4.64), mixed type (aOR, 3.44; 95% CI, 2.01-6.07), and perianal (aOR, 3.01; 95% CI, 1.53-6.12) and buttocks location (aOR, 2.08; 95% CI, 1.17-3.76) had increased odds of ulceration. Segmental or partial segmental IHs of the genitalia were confined to distinct anatomic territories and were predominantly distributed unilaterally, with a linear demarcation at the perineal raphe. LIMITATIONS: Possible selection bias, given recruitment at tertiary referral centers. CONCLUSION: This study improves our understanding of high-risk features of anogenital IHs and demonstrates that genital segmental or partial segmental IHs develop within distinct anatomic territories.

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Revisión de la etiopatogenia y clasificación de las anomalías de la diferenciación sexual, así como del desarrollo genital prenatal, para que resulte de utilidad en la evaluación y manejo diagnóstico, mediante una búsqueda bibliográfica de la literatura más actual publicada a través de las bases de datos PubMed, MedLine, Embase, BioMed Central y SciELO. Las anomalías de la diferenciación sexual comprenden un amplio espectro de enfermedades que pueden desarrollarse en diferentes etapas de la vida. Estas anomalías requieren un manejo y evaluación compleja multidisciplinar en la que el obstetra desarrolla un papel fundamental, siendo referente en el diagnóstico prenatal de estas. La discordancia entre el sexo genético determinado por el test prenatal no invasivo y el fenotípico observado por medio de la ecografía es un hallazgo cada vez más frecuente, con una incidencia de 1 por cada 1.500-2.000 embarazos. La detección temprana de esta discordancia puede orientar la sospecha clínica y mejorar el manejo de las anomalías del desarrollo sexual desde la etapa prenatal.(AU)

To review the most current literature on the aetiopathogenesis and classification of abnormalities of sexual differentiation, as well as prenatal genital development. A literature search through PubMed, MedLine, Embase, BioMed Central, and SciELO databases was conducted. Abnormalities of sexual differentiation comprise a wide spectrum of diseases that can develop at different stages of life. These anomalies require complex evaluation by a multidisciplinary team in which the obstetrician plays a fundamental role in prenatal diagnosis. Discrepancy between the genetic sex determined by non-invasive prenatal testing and the phenotypic sex observed by ultrasound is an increasingly frequent finding, with an incidence of 1 in 1,500-2,000 pregnancies. Early detection of this discrepancy can guide clinical suspicion and improve the management of different sexual developmental anomalies from the prenatal period.(AU)

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INTRODUCTION: Preoperative hormone therapy (PHT) holds promise for obtaining better surgical conditions for patients undergoing hypospadias correction and increasing the success rate. However, the application and effects of PHT remain uncertain owing to a lack of comprehensive evaluation, thus limiting treatment strategies and development of standardized guidelines. This study aimed to review the following (ⅰ) the criteria and regimens of PHT (ⅱ) its impact on penile growth, postoperative complications, and side effects (ⅲ) and sources of inconsistent clinical outcomes. METHODS: This systematic review was registered at PROSPERO (CRD42022346924) and conducted and reported following international recommendations, including the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. We searched the databases over the last two decades to identify eligible studies. This systematic review included literature regarding the use of PHT in the treatment of children with single stage hypospadias repair. Risk of Bias (RoB) was measured using two different tools: randomized controlled trials using a modified version of the RoB Assessment Tool and non-randomized studies of interventions using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I). The R-3.6.3 software was used for the analysis. RESULTS: In total, 25 studies involving 4094 patients were included in the systematic review. The surgeons' criteria for using PHT varied, with short penile length being the most important. The most frequently reported regimens for intramuscular (IM) testosterone were either 2 mg/kg or empiric 25 mg monthly, and the duration was 2-3 months preoperatively. Androgens were significantly effective in improving penile development, and the changes commonly peaked at 2-3 months. The effects of PHT on complications and side effects are controversial, and the potential causes include hormone sensitivity, degree of hypospadias, surgical techniques, and dosing regimens. CONCLUSIONS: This systematic review evaluated PHT in children with hypospadias. Building on previous studies, this review provides a more specific attitude and possible aspects for resolving the controversies. Future studies should identify the applicable subgroups of patients and standardize the dose and mode of delivery for the best clinical results.

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This study assessed cross-sectional associations between urinary metabolites of non-persistent pesticides and pubertal development in boys and girls from urban and rural areas in Spain and examined effect modification by body mass index (BMI). Four metabolites of insecticides (TCPy, metabolite of chlorpyrifos; IMPy, metabolite of diazinon; DETP, non-specific metabolite of organophosphates; 3-PBA, metabolite of pyrethroids) and the metabolite of ethylene-bis-dithiocarbamate fungicides (ETU) were quantified in urine collected in 2010-2016 from 7 to 11-year-old children (606 girls, 933 boys) participating in the INMA Project. Pubertal development was ascertained by Tanner stages and/or parent-reported Pubertal Development Scale (PDS). Associations between pesticide metabolites and odds of being in stage 2+ for breast development (girls), genital development (boys), pubic hair growth (girls and boys), and/or overall puberty onset, gonadarche, and adrenarche (PDS for girls and boys) were examined by mixed-effect logistic regression. Effect modification by BMI was explored by interaction terms and stratified analysis. In girls, DETP and ETU concentrations>75th percentile (P75) were associated with higher odds of overall puberty development (OR [95%CI] = 1.86 [1.07-3.24] and 1.71 [1.03-2.83], respectively, for > P75 vs. undetected concentrations), while ETU > P75 was also associated with higher odds of breast development (OR [95%CI] = 5.55 [2.83-12.91]), particularly in girls with underweight/normal weight (OR [95%CI] = 10.08 [2.62-38.76]). In boys, detection of TCPy (40%) and 3-PBA (34%) was associated with higher odds of genital development (OR [95%CI] = 1.97 [1.08-3.57] and 2.08 [1.15-3.81], respectively), and the association with 3-PBA was observed in boys with overweight/obesity alone. In addition, ETU > P75 was associated with higher odds of genital development in boys with underweight/normal weight (OR [95%CI] = 2.89 [1.08-7.74]) but higher DETP with lower odds of puberty in boys with overweight/obesity (OR [95%CI] = 0.94 [0.89-0.99] per log-unit increase in concentration). Results suggest an association of childhood exposure to ETU and certain insecticides with earlier puberty in girls and boys that may be modified by child BMI.

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BACKGROUND: Perfluoroalkyl substances (PFASs) have been reported to exert reproductive toxicity. Anogenital distance (AGD) is a biomarker of intrauterine androgen exposure and an indicator of genital development. An animal study reported that female neonatal rats exposed to perfluorooctanoic acid or perfluorooctane sulfonate (PFOS) during postnatal days 1-5 exhibited a longer AGD, while epidemiological studies have shown inconsistent results. This study aimed to examine the effects of prenatal exposure to PFASs on the AGD in female neonates. METHODS: PFAS levels were measured in plasma samples obtained from pregnant women at 12-16 gestational weeks using high-performance liquid chromatography/mass spectrometry. The AGD of each female neonate was measured within 3 days after delivery. The anogenital index (AGI), calculated as AGD divided by weight, was also determined. A total of 362 motherinfant pairs were included in this study. A multivariate linear regression model was used to examine the association between prenatal ln-transformed concentrations of PFASs and AGD/AGI. In addition, weighted quantile sum regression (WQSR) and Bayesian kernel machine regression (BKMR) models were used to assess the overall effects of a mixture of PFASs on the AGD/AGI and to identify important contributors to the overall effect. RESULTS: There was a consistent pattern of association between maternal PFAS concentrations and increased AGDanus to posterior fourchette (AF), AGDanus to clitoris (AC), and AGIAF lengths at birth. Statistical significance was found between maternal ln-transformed concentrations of perfluorohexane sulfonate (PFHxS), perfluorododecanoic acid, and perfluorotridecanoic acid and AGDAF, with ß values (95% confidence interval [CI]) of 0.83 (0.16, 1.51), 0.32 (0.05, 0.59), and 0.25 (0.00, 0.51) mm, respectively; between PFOS and AGDAC, with a ß value (95% CI) of 0.63 (0.04, 1.21) mm; and between PFHxS and AGIAF, with a ß value (95% CI) of 0.22 (0.02, 0.43) mm/kg. Similarly, the WQSR and BKMR models showed that an increase in the AGDAF/AGIAF at birth was associated with co-exposure to a mixture of PFASs. CONCLUSION: High maternal concentrations of PFASs were associated with increased AGD in female neonates, indicating that PFASs may impair reproductive development in female offspring in early life.

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Hypospadias is among the most prevalent urogenital malformations in male newborns. It is characterized by the displacement of the urethral meatus to the ventral side of the penis, an aberrant ventral curve of the penis referred to as "chordee," and an abnormally arranged foreskin with a "hood" found dorsally and lacking foreskin ventrally. Patients may have an extra genitourinary abnormality based on the area of the lesion. In around 70% of cases, the urethral meatus is positioned distally to the shaft, representing a milder form of the disease. The remaining 30% of cases are located proximally, are more complicated, and require further evaluation. Although the origin of hypospadias is mostly obscure, several suggestions exist about genetic susceptibility and hormonal factors. The objective of hypospadias restoration is to restore aesthetic and functional regularity, and surgery is currently advised at a young age, mostly between six and 18 months. At any age, hypospadias can be repaired with an equivalent risk of complications, functional outcomes, and aesthetic outcomes. However, the best age of treatment is still undetermined. Even though the long-term effects on appearance and sexual function are usually good, males may be less likely to make the first move after rectification. Also, people who have hypospadias treated are twice as likely to have problems with their lower urinary tract. These problems can last for years after the initial repair.

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BACKGROUND: During pregnancy, women are commonly exposed to several endocrine-disrupting chemicals, including persistent organic pollutants (POPs). These compounds can transfer to the fetus through the placenta. Prenatal POP exposure is related to altered fetal genital and reproductive tract development. However, the relationship between exposure to POP mixtures and anogenital distance (AGD) is poorly investigated. This study investigated the association between prenatal exposure to POP mixtures and AGD in 8-year-old children. METHODS: Data were collected from the INMA-Asturias cohort. Maternal serum POP concentrations were measured during the first trimester of pregnancy. Anoscrotal distance (AGDAS) and anopenile distance (AGDAP) in males and anofourchetal distance (AGDAF) and anoclitoral distance (AGDAC) in females were recorded in 362 8-years-olds. Conventional linear regression, and the novel weighted quantile sum regression (WQSR) and Bayesian kernel machine regression (BKMR) models were applied to assess the relationships between AGD and POPs exposure stratified by sex. RESULTS: Among males, in the linear regression, b-hexachlorocyclohexane, PCB138, PCB153, and PCB180 were inversely associated with the anogenital index (AGI)AS (-0.06 mm/kg (95% confidence interval [CI]: -0.11, -0.02), -0.07 mm/kg (95% CI: -0.14, -0.01), -0.07 mm/kg (95% CI: -0.13, -0.01), and -0.08 mm/kg (95% CI: -0.14, -0.02), respectively). Among females, polybrominated diphenyl ether (PBDE)47 and PBDE154 were positively associated with increased AGIAF (0.02 mm/kg (95% CI: 0.00, 0.03) and 0.09 mm/kg (95% CI: 0.01, 0.17), respectively). BKMR confirmed these associations. WQSR found a negative combined effect of the POP mixture on AGD, and PCB138, PCB153, and PCB180 (weighted 0.18, 0.13, and 0.09, respectively) were identified as the most impacting chemicals. In females, WQSR found a positive combined effect and determined PBDE47 (weighted 0.35) as the most impacting. CONCLUSIONS: Maternal exposure to a POP mixture was negatively associated with AGD in male children and positively associated with AGD in female children, thus providing evidence of the adverse effects of POPs on genital development.

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We report the case of a newborn female with a perineal groove and review the limited literature. This is a rare congenital midline malformation of the perineal raphe with no data driven management strategies available. Our patient was managed conservatively with topical Vaseline application. At 52 days of life, her perineal groove was about 50% resolved, and at 9 months of age, it was barely perceptible. She maintained normal urinary function without evidence of infection or discomfort. We recommend this strategy for initial management of perineal grooves that have not had any symptoms or complications attributable to the condition.

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Sexual systems are surprisingly diverse, considering the ubiquity of sexual reproduction. Sequential hermaphroditism, the ability of an individual to change sex, has emerged multiple times independently across the animal kingdom. In molluscs, repeated shifts between ancestrally separate sexes and hermaphroditism are generally found at the level of family and above, suggesting recruitment of deeply conserved mechanisms. Despite this, molecular mechanisms of sexual development are poorly known. In molluscs with separate sexes, endocrine disrupting toxins bind the retinoid X receptor (RXR), activating ectopic male development in females, suggesting the retinoid pathway as a candidate controlling sexual transitions in sequential hermaphrodites. We therefore tested the role of retinoic acid signaling in sequentially hermaphroditic Crepidula snails, which develop first into males, then change sex, maturing into females. We show that retinoid agonists induce precocious penis growth in juveniles and superimposition of male development in females. Combining RXR antagonists with retinoid agonists significantly reduces penis length in induced juveniles, while similar treatments using retinoic acid receptor (RAR) antagonists increase penis length. Transcripts of both receptors are expressed in the induced penis. Our findings therefore show that retinoid signaling can initiate molluscan male genital development, and regulate penis length. Further, we show that retinoids induce ectopic male development in multiple Crepidula species. Species-specific influence of conspecific induction of sexual transitions correlates with responsiveness to retinoids. We propose that retinoid signaling plays a conserved role in molluscan male development, and that shifts in the timing of retinoid signaling may have been important for the origins of sequential hermaphroditism within molluscs.

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Sex determination and differentiation in reptiles is complex. Temperature-dependent sex determination (TSD), genetic sex determination (GSD) and the interaction of both environmental and genetic cues (sex reversal) can drive the development of sexual phenotypes. The jacky dragon (Amphibolurus muricatus) is an attractive model species for the study of gene-environment interactions because it displays a form of Type II TSD, where female-biased sex ratios are observed at extreme incubation temperatures and approximately 50 : 50 sex ratios occur at intermediate temperatures. This response to temperature has been proposed to occur due to underlying sex determining loci, the influence of which is overridden at extreme temperatures. Thus, sex reversal at extreme temperatures is predicted to produce the female-biased sex ratios observed in A. muricatus. The occurrence of ovotestes during development is a cellular marker of temperature sex reversal in a closely related species Pogona vitticeps. Here, we present the first developmental data for A. muricatus, and show that ovotestes occur at frequencies consistent with a mode of sex determination that is intermediate between GSD and TSD. This is the first evidence suggestive of underlying unidentified sex determining loci in a species that has long been used as a model for TSD.

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Hypospadias is a congenital anomaly of the penis with an occurrence of approximately 1 in 200 boys, but the etiology of the majority of hypospadias has remained unknown. Numerous genes have been reported as having variants in hypospadias patients, and many studies on genetic deletion of key genes in mouse genital development have also been published. Until now, no comparative analysis in the genes related literature has been reported. The basic knowledge of penile development and hypospadias is mainly obtained from animal model studies. Understanding of the differences and similarities between human and animal models is crucial for studies of hypospadias. In this review, mutations and polymorphisms of hypospadias-related genes have been compared between humans and mice, and differential genotype-phenotype relationships of certain genes between humans and mice have been discussed using the data available in PubMed and MGI online databases, and our analysis only revealed mutations in seven out of 43 human hypospadias related genes which have been reported to show similar phenotypes in mutant mice. The differences and similarities in the processes of penile development and hypospadias malformation among human and commonly used animal models suggest that the guinea pig may be a good model to study the mechanism of human penile development and etiology of hypospadias.

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Polychlorinated Biphenyls (PCBs) are widespread environmental contaminants. PCBs have endocrine disrupting properties which raises concerns regarding their effect on the developing fetus. This study aimed to examine the association between prenatal exposure to PCBs and anogenital distance (AGD) in newborns. Serum concentrations of PCB congeners -118, -138, -153 and -180 were measured in 175 pregnant women presenting to the delivery room. AGD was measured in their newborns. Regression models were used to estimate associations between maternal PCB exposure and infant anogenital measurements, controlling for possible confounding variables. Mean maternal serum concentrations were 2.95 ± 2.18 ng/g, 4.62 ± 3.54 ng/g, 7.67 ± 6.42 ng/g and 5.10 ± 3.91 ng/g for congeners -118, -138, -153 and -180, respectively. Higher maternal concentrations of PCBs were associated with reduced AGD measures in male infants. Higher maternal concentrations of PCB-138 and PCB-153 were associated with reduced ano-scrotal distances and higher maternal concentrations of all four PCB congeners were associated with reduced ano-penile distances. No significant associations were found between any PCB congener and any AGD measure in female newborns. This study demonstrates that intrauterine exposure to PCBs may be associated with reduced AGD in male newborns. More research is needed to reveal the implications for adult reproductive health.

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BACKGROUND: Prenatal exposure to endocrine-disrupting chemicals may impair genital development and alter reproductive tract anatomy. Anogenital distance (AGD) is a useful biomarker of exposure to chemicals that act as endocrine disruptors. We evaluated associations between prenatal and perinatal exposure to several persistent organic pollutants (POPs) and AGD in 4-year-old children. METHODS: Data were drawn from the INMA-Asturias cohort. Pediatricians measured the anofourchetal distance in female children and anoscrotal distance in male children. The anogenital index (AGI) was defined as the AGD divided by the child's weight at age of examination. We measured the levels of two hexachlorocyclohexane isomers, hexachlorobenzene, dichlorodiphenyltrichloroethane (DDT) and its metabolites, six polychlorinated biphenyl (PCB) congeners, and six polybrominated diphenyl ether (PBDE) congeners in maternal serum at 12 gestational weeks (n = 155) and in cord blood serum (n = 229). Anthropometric and parental sociodemographic variables were collected via face-to-face interviews. Linear regression models were used to evaluate the relationship between exposure to POPs and AGI, adjusted for confounders and stratified by sex. RESULTS: In male children, we found inverse associations between AGI and maternal concentrations of PCB-138 (ß = -0.041, 95% confidence interval [CI]: -0.074, -0.008, second tertile), PCB-153 (ß = -0.052, 95% CI: -0.085, -0.020, second tertile), PCB-180 ß = -0.065, 95% CI: -0.096, -0.035, second tertile; ß = -0.042, 95% CI: -0.073, -0.011, third tertile), PBDE-209 (ß = -0.031, 95% CI: -0.058, -0.006), cord serum concentrations of PCB-153 (ß = -0.029, 95% CI: -0.059, -0.000, second tertile; ß = -0.047, 95% CI: -0.085, -0.008, third tertile), and PCB-180 (ß = -0.041, 95% CI: -0.078, -0.005, third tertile). In female children, AGI was positively associated with maternal serum concentrations of PCB-101 (ß = 0.039, 95% CI: 0.002, 0.076, second tertile), and higher cord serum levels of 4,4'-DDT (ß = 0.032, 95% CI: 0.003, 0.061, third tertile) and 4,4'-DDE (ß = 0.040, 95% CI: 0.011, 0.069, third tertile). CONCLUSIONS: Our findings provide evidence of associations between specific POPs and AGI in boys and girls aged 4 years, and suggest that pre/perinatal exposure to POPs has a feminizing effect in males and a masculinizing effect in females.

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Our objective was to determine if maternal first trimester urinary phthalate concentrations are associated with reduced penile length (PL) or width (PW) at birth in full term singletons. First trimester phthalate metabolite urinary concentrations were obtained from mothers participating in a Canadian pregnancy cohort study (MIREC). PL and PW were measured shortly after birth in the male offspring. Univariate and multivariable linear regressions were performed to study associations between maternal phthalate exposure and penile measurements, adjusting for confounders. On univariate analysis of 170 mother-infant pairs, PW showed an inverse relationship with the concentration of mono-3-carboxypropyl phthalate (MCPP-p = 0.016), which was not confirmed on multivariable analysis. On multivariable analysis controlling for infant's size and other confounders, no statistically signficant associations between phthalate metabolite concentrations and PL or PW were identified. In this population of Canadian women, there was no strong evidence to suggest an association between maternal first trimester urinary phthalates with PL or PW in term singletons.

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Technological advances in three-dimensional (3D) reconstruction techniques have previously enabled paradigm shifts in our understanding of human embryonic and fetal development. Light sheet fluorescence microscopy (LSFM) is a recently-developed technique that uses thin planes of light to optically section whole-mount cleared and immunolabeled biologic specimens. The advent of commercially-available light sheet microscopes has facilitated a new generation of research into protein localization and tissue dynamics at extremely high resolution. Our group has applied LSFM to study developing human fetal external genitalia, internal genitalia and kidneys. This review describes LSFM and presents our group's technique for preparing, clearing, immunostaining and imaging human fetal urogenital specimens. We then present light sheet images and videos of each element of the developing human urogenital system. To the extent of our knowledge, the work conducted by our laboratory represents the first description of a method for performing LSFM on the full human urogenital system during the embryonic and fetal periods.

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STUDY QUESTION: Are maternal plasma concentrations of perfluoroalkyl and polyfluoroalkyl substances (PFASs) during pregnancy associated with anogenital distance (AGD) in male infants at birth, 6, and 12 months of age? SUMMARY ANSWER: Higher maternal plasma concentrations of some PFASs were associated with shorter AGD in male infants at birth and 6 months of age. WHAT IS KNOWN ALREADY: Two animal studies have found that exposure to PFASs was associated with shorter AGD in male rat fetuses and wild male minks. There is only one human study on the topic that did not identify consistent patterns between maternal serum concentrations of PFASs during pregnancy and AGD in male infants. STUDY DESIGN, SIZE, DURATION: In the prospective cohort study, a total of 1292 eligible pregnant women were recruited at 12-16 weeks of gestation between April and December 2012 at the Maternal and Child Health Hospital of Minhang district in Shanghai, China. At delivery, 667 male singletons were born. They were then followed up at birth (n = 439) and at 6 (n = 411) and 12 months (n = 376) of age when anopenile distance (AGDAP) and anoscrotal distance (AGDAS) were measured. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 500 male infants who had both maternal plasma concentrations of PFASs and at least one AGD measurement of at three time points were included in the present study. Multiple linear regression models were used to evaluate the potential linear associations between maternal concentrations of PFASs and AGD. MAIN RESULTS AND THE ROLE OF CHANCE: Maternal plasma concentrations (ln-transformed) of perfluorooctane sulfonate (PFOS), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUdA) were inversely associated with AGDAS or AGDAP at birth (AGDAS: per ln unit increase in PFAS concentrations: ß (95% CI): -0.65 (-1.27 to -0.02) mm for PFOS; -0.58 (-1.11 to -0.06) mm for PFDA; and -0.57 (-1.09 to -0.06) mm for PFUdA; AGDAP: per ln unit increase in PFAS concentrations: ß (95% CI): -0.63 (-1.24 to -0.01) mm for PFDA and - 0.76 (-1.36 to -0.16) mm for PFUdA). At 6 months of age, per unit increase in maternal ln concentrations of PFOS and perfluorotridecanoic acid (PFTrDA), AGDAS decreased on average by -2.21 (95% CI: -4.28 to -0.14) and -1.11 (95% CI: -2.17 to -0.06) mm, respectively. Additionally, ln-transformed perfluorooctanoic acid (PFOA) showed nonsignificant but inverse associations with both AGDAS and AGDAP at 6 months of age. We found no significant associations between ln-transformed maternal concentrations of PFASs and either AGDAS or AGDAP at 12 months of age. However, significantly inverse association of ln-transformed PFOA with AGDAP was observed in male infants who never or shortly breastfed (<3 months) at 12 months of age. LIMITATIONS, REASONS FOR CAUTION: AGD measurements were performed by different examiners at each follow-up visit, and the intra-examiner variation was not assessed, which might cause intra-rater and inter-rater measurement errors. Additionally, our study may have selection bias since a considerable number of participants withdrew from the cohort although the differences in demographic characteristics were not statistically significant between included mother-infant pairs and those excluded. No statistical correction was made for multiple comparisons. WIDER IMPLICATIONS OF THE FINDINGS: Our findings may have important implications for the early development of genital health in male infants since PFASs can be detected in almost all pregnant women and infants worldwide. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from the National Key Research and Development program of China (2018YFC1002801 and 2016YFC1000505), the Science and Technology Commission of Shanghai Municipality (16ZR1430100), the National Natural Science Foundation of China (81428011), and the Innovation-Oriented Science and Technology Grant from National Health Commission Key Laboratory of Reproduction Regulation (CX2017-06). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

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This article aims to examine the current issues of debate concerning the management of atypical gonadal and genital development (AGD). Understanding this complex subject begins with defining the distinct AGD conditions, the aims and nature of surgical treatments, and the perceptions of affected individuals and their families. The evolving societal and medical contexts in this field are confronting facts and opinions, leading to a significant change in attitudes and approaches.

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Epitestosterone is the 17α-epimer of testosterone and has been described as an anti-androgen, since it inhibits the effects produced by testosterone and dihydrotestosterone via the nuclear androgen receptor (nAR). However, epitestosterone also displays an effect which is similar to the non-classical effect of testosterone, depolarizing the membrane potential of Sertoli cells and inducing a rapid Ca2+ uptake. This study aimed to investigate the effects of a treatment with epitestosterone on developmental parameters of immature rats. Animals were chemically castrated by using the gonadotropin-releasing hormone (GnRH) antagonist cetrorelix and then received a replacement of 7 days with epitestosterone or testosterone. Replacement with either epitestosterone or testosterone restored the anogenital distance (AGD) and testicular weight which had been reduced by chemical castration. The immunocontent of nAR and the nAR-immunoreactivity were reduced by epitestosterone treatment in the testis of both castrated and non-castrated animals. Furthermore, testosterone was unable of changing the membrane potential of Sertoli cells through its non-classical action in the group of animals castrated and replaced with epitestosterone. In conclusion, in relation to the level of protein expression of nAR epitestosterone acts as an anti-androgen. However, it acts in the same way as testosterone when genital development parameters are evaluated. Moreover, in castrated rats epitestosterone suppressed the non-classical response of testosterone, changing the pattern of testosterone signalling via a membrane mechanism in Sertoli cells.

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The determination of the testicular volume is of considerable importance to assess the onset, progression and disorders of puberty, abnormal testicular development, and a number of other conditions; and in adults, assessment of fertility. A number of clinical methods have been used for the measurement of testicular volumes in the scrotum: a centimeter ruler, sliding calipers, and orchidometers. All the clinical methods calculate the volumes by the ellipsoid equation, grossly overestimate ultrasound (US) volumes by 70 to 80% for adults, to 150 to 250% for prepubertal subjects, mainly because the inclusion of the scrotal skin and epididymis and may not be accurate of reproducible. Ultrasound measurements have a high degree of accuracy and reproducibility and are the standard for quantitation of testicular volume. Formulas, equivalent to the ellipsoid equations used, were developed to match ultrasound volumes, with corrections of the width and length of the testis obtained in the scrotum, to avoid the inclusion of the scrotal skin (ss) and epididymis. A calculator was developed, requiring only the identification of ① the width of the testis in cm obtained in the scrotum with a ruler (without corrections) (i.e. 0.9, 1.5, 2.0, 2.4 cm etc.) and ② the stage of genital development. The calculator will subtract the scrotal skin for the stage of genital development, from the measurement of the width provided, apply the formula and identify the testicular volume of the subject that matches the US volume. The calculator will also provide, in a Table form, the values for the different stages of genital development. Benefit: The information provided by the calculator will solve the problem of overestimation by the orchidometers and the external measurements, problems with the reference of values to age, and Tanner stages, would permit assessment of the beginning and progression of puberty, of micro and macroorchidism, and other conditions mentioned.