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BACKGROUND: Differences in Sex Development (DSD) is a heterogeneous group of congenital alterations that affect inner and/or outer primary sex characters. Although these conditions do not represent a mortality risk, they can have a severe psycho-emotional impact if not appropriately managed. The genetic changes that can give rise to DSD are diverse, from chromosomal alterations to single base variants involved in the sexual development network. Epidemiological studies about DSD indicate a global frequency of 1:4500-5500, which can increase to 1:200-300, including isolated anatomical defects. To our knowledge, this study is the first to describe epidemiological and genetic features of DSD in a cohort of Mexican patients of a third-level care hospital. METHODS: Descriptive and retrospective cross-sectional study that analyzed DSD patients from 2015 to 2021 attended a Paediatric Hospital from Mexico City. RESULTS: One hundred one patients diagnosed with DSD were registered and grouped into different entities according to the Chicago consensus statement and the diagnosis defined by the multidisciplinary group. Of the total, 54% of them belong to the chromosomal DSD classification, 16% belongs to 46, XX and 30% of them belongs to the 46, XY classification. CONCLUSION: The frequency for chromosomal DSDs was consistent with the literature; however, we found that DSD 46, XY is more frequent in our cohort, which may be due to the age of the patients captured, the characteristics of our study population, or other causes that depend on the sample size.

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BACKGROUND: Androgen insensitivity syndrome (AIS) is a common condition among individuals with differences of sexual development (DSD) and results from germline allelic variants in the androgen receptor (AR) gene. Understanding the phenotypic consequences of AR allelic variants that disrupt the activation function 2 (AF2) region is essential to grasping its clinical significance. OBJECTIVES: This study aims to provide insights into the phenotypic characteristics and clinical impact of AR mutations affecting the AF2 region in AIS patients. We achieve this by reviewing reported AR variants in the AF2 region among individuals with AIS, including identifying a new phenotype associated with the c.2138T>C variant (p.Leu713Pro) in the AR gene. MATERIALS AND METHODS: We comprehensively reviewed AR variants within the AF2 region reported in AIS and applied molecular dynamics simulations to assess the impact of the p.Leu713Pro variant on protein dynamics. RESULTS: Our review of reported AR variants in the AF2 region revealed a spectrum of phenotypic outcomes in AIS patients. Molecular dynamics simulations indicated that the p.Leu713Pro variant significantly alters the local dynamics of the AR protein and disrupts the correlation and covariance between variables. DISCUSSION: The diverse phenotypic presentations observed among individuals with AR variants in the AF2 region highlight the complexity of AIS. The altered protein dynamics resulting from the p.Leu713Pro variant further emphasize the importance of the AF2 region in AR function. CONCLUSION: Our study provides valuable insights into AR mutations' phenotypic characteristics and clinical impact on the AF2 region in AIS. Moreover, the disruption of protein dynamics underscores the significance of the AF2 region in AR function and its role in the pathogenesis of AIS.

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In mammals, the development of male or female gonads from fetal bipotential gonads depends on intricate genetic networks. Changes in dosage or temporal expression of sex-determining genes can lead to differences of gonadal development. Two rare conditions are associated with disruptions in ovarian determination, including 46,XX testicular differences in sex development (DSD), in which the 46,XX gonads differentiate into testes, and 46,XX ovotesticular DSD, characterized by the coexistence of ovarian and testicular tissue in the same individual. Several mechanisms have been identified that may contribute to the development of testicular tissue in XX gonads. This includes translocation of SRY to the X chromosome or an autosome. In the absence of SRY, other genes associated with testis development may be overexpressed or there may be a reduction in the activity of pro-ovarian/antitesticular factors. However, it is important to note that a significant number of patients with these DSD conditions have not yet recognized a genetic diagnosis. This finding suggests that there are additional genetic pathways or epigenetic mechanisms that have yet to be identified. The text will provide an overview of the current understanding of the genetic factors contributing to 46,XX DSD, specifically focusing on testicular and ovotesticular DSD conditions. It will summarize the existing knowledge regarding the genetic causes of these differences. Furthermore, it will explore the potential involvement of other factors, such as epigenetic mechanisms, in developing these conditions.

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BACKGROUND: The absence of expression of the Y-chromosome linked testis-determining gene SRY in early supporting gonadal cells (ESGC) leads bipotential gonads into ovarian development. However, genetic variants in NR2F2, encoding three isoforms of the transcription factor COUP-TFII, represent a novel cause of SRY-negative 46,XX testicular/ovotesticular differences of sex development (T/OT-DSD). Thus, we hypothesized that COUP-TFII is part of the ovarian developmental network. COUP-TFII is known to be expressed in interstitial/mesenchymal cells giving rise to steroidogenic cells in fetal gonads, however its expression and function in ESGCs have yet to be explored. RESULTS: By differentiating induced pluripotent stem cells into bipotential gonad-like cells in vitro and by analyzing single cell RNA-sequencing datasets of human fetal gonads, we identified that NR2F2 expression is highly upregulated during bipotential gonad development along with markers of bipotential state. NR2F2 expression was detected in early cell populations that precede the steroidogenic cell emergence and that retain a multipotent state in the undifferentiated gonad. The ESGCs differentiating into fetal Sertoli cells lost NR2F2 expression, whereas pre-granulosa cells remained NR2F2-positive. When examining the NR2F2 transcript variants individually, we demonstrated that the canonical isoform A, disrupted by frameshift variants previously reported in 46,XX T/OT-DSD patients, is nearly 1000-fold more highly expressed than other isoforms in bipotential gonad-like cells. To investigate the genetic network under COUP-TFII regulation in human gonadal cell context, we generated a NR2F2 knockout (KO) in the human granulosa-like cell line COV434 and studied NR2F2-KO COV434 cell transcriptome. NR2F2 ablation downregulated markers of ESGC and pre-granulosa cells. NR2F2-KO COV434 cells lost the enrichment for female-supporting gonadal progenitor and acquired gene signatures more similar to gonadal interstitial cells. CONCLUSIONS: Our findings suggest that COUP-TFII has a role in maintaining a multipotent state necessary for commitment to the ovarian development. We propose that COUP-TFII regulates cell fate during gonad development and impairment of its function may disrupt the transcriptional plasticity of ESGCs. During early gonad development, disruption of ESGC plasticity may drive them into commitment to the testicular pathway, as observed in 46,XX OT-DSD patients with NR2F2 haploinsufficiency.

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CONTEXT: Despite high abundance of small indels in human genomes, their precise roles and underlying mechanisms of mutagenesis in Mendelian disorders require further investigation. OBJECTIVE: To profile the distribution, functional implications, and mechanisms of small indels in the androgen receptor (AR) gene in individuals with androgen insensitivity syndrome (AIS). METHODS: We conducted a systematic review of previously reported indels within the coding region of the AR gene, including 3 novel indels. Distribution throughout the AR coding region was examined and compared with genomic population data. Additionally, we assessed their impact on the AIS phenotype and investigated potential mechanisms driving their occurrence. RESULTS: A total of 82 indels in AIS were included. Notably, all frameshift indels exhibited complete AIS. The distribution of indels across the AR gene showed a predominance in the N-terminal domain, most leading to frameshift mutations. Small deletions accounted for 59.7%. Most indels occurred in nonrepetitive sequences, with 15.8% situated within triplet regions. Gene burden analysis demonstrated significant enrichment of frameshift indels in AIS compared with controls (P < .00001), and deletions were overrepresented in AIS (P < .00001). CONCLUSION: Our findings underscore a robust genotype-phenotype relationship regarding small indels in the AR gene in AIS, with a vast majority presenting complete AIS. Triplet regions and homopolymeric runs emerged as prone loci for small indels within the AR. Most were frameshift indels, with polymerase slippage potentially explaining half of AR indel occurrences. Complex frameshift indels exhibited association with palindromic runs. These discoveries advance understanding of the genetic basis of AIS and shed light on potential mechanisms underlying pathogenic small indel events.

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Introducción. La pubertad se manifiesta inicialmente por la aparición de los caracteres sexuales secundarios, como consecuencia de cambios hormonales que progresivamente conducen a la madurez sexual completa. En Argentina y el mundo, la pandemia ocasionada por el coronavirus SARS-CoV-2 generó un confinamiento que pudo haber interferido en el inicio y tempo del desarrollo puberal. Objetivo. Describir la percepción de los endocrinólogos pediatras del país sobre las consultas por sospecha de pubertad precoz y/o pubertad de rápida progresión durante la pandemia. Materiales y métodos. Estudio descriptivo, observacional, transversal. Encuesta anónima a endocrinólogos pediatras pertenecientes a la Sociedad Argentina de Pediatría y/o a la Asociación de Endocrinología Pediátrica Argentina, en diciembre de 2021. Resultados. Respondieron la encuesta 83 de 144 endocrinólogos pediátricos (tasa de respuesta 58 %). Todos consideraron que aumentó la consulta por desarrollo precoz o temprano, ya sea en sus variantes telarca precoz (84 %), pubarca precoz (26 %) y/o pubertad precoz (95 %). El 99 % acuerda con que se ha dado en mayor medida en niñas. La totalidad de los encuestados también considera que aumentó el diagnóstico de pubertad precoz central. El 96,4 % considera que ha aumentado el número de pacientes tratados con análogos de GnRH. Conclusión. Nuestros resultados sobre la percepción de endocrinólogos pediatras coinciden con datos publicados en otras regiones sobre el aumento del diagnóstico de pubertad precoz durante la pandemia por COVID-19. Se reafirma la necesidad de generar registros nacionales de pubertad precoz central, difundir las evidencias para su detección y abordaje oportuno.

Introduction. Puberty is manifested initially by the onset of secondary sexual characteristics as a result of hormonal changes that progressively lead to complete sexual maturity. In Argentina and worldwide, the lockdown resulting from the SARS-CoV-2 pandemic may have interfered in the onset and timing of pubertal development. Objective. To describe the perception of pediatric endocrinologists in Argentina regarding consultations for suspected precocious and/or rapidly progressive puberty during the pandemic. Materials and methods. Descriptive, observational, cross-sectional study. Anonymous survey among pediatric endocrinologists members of the Sociedad Argentina de Pediatría and/or the Asociación de Endocrinología Pediátrica Argentina administered in December 2021. Results. Out of 144 pediatric endocrinologists, 83 completed the survey (rate of response: 58%). All of them considered that consultation for precocious or early puberty increased, either in terms of early thelarche (84%), early pubarche (26%), and/or precocious puberty (95%). Ninety-nine percent agreed that this has occurred to a greater extent in girls. All survey respondents also consider that the diagnosis of central precocious puberty has increased. In total, 96.4% of respondents consider that the number of patients treated with GnRH analogs has increased. Conclusion. Our results about the perception of pediatric endocrinologists are consistent with data published in other regions on the increase in the diagnosis of precocious puberty during the COVID-19 pandemic. We underscore the need to develop national registries of central precocious puberty, and to disseminate the evidence for a timely detection and management

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The group of disorders known as 46,XY gonadal dysgenesis (GD) is characterized by anomalies in testis determination, including complete and partial GD (PGD) and testicular regression syndrome (TRS). Several genes are known to be involved in sex development pathways, however approximately 50% of all cases remain elusive. Recent studies have identified variants in DHX37, a gene encoding a putative RNA helicase essential in ribosome biogenesis and previously associated with neurodevelopmental disorders, as a cause of PGD and TRS. To investigate the potential role of DHX37 in disorders of sexual development (DSD), 25 individuals with 46,XY DSD were analyzed and putative pathogenic variants were found in four of them. WES analyses were performed on these patients. In DHX37, the variant p.(Arg308Gln), recurrent associated with DSD, was identified in one patient; the p.(Leu467Val), predicted to be deleterious, was found together with an NR5A1 loss-of-function variant in patient 2; and, the p.(Val999Met) was identified in two unrelated patients, one of whom (patient 3) also carried a pathogenic NR5A1 variant. For both patients carrying DHX37 and NR5A1 pathogenic variants, a digenic inheritance is suggested. Our findings support the importance of DHX37 variants as a cause of disorders of sex development, implying a role in testis development.

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OBJECTIVE: To analyze aspects of sexual life and fertility desire among 46, XY DSD people, including those who changed their gender. METHODS: It is a cross-sectional study including 127 adults (> 16 years of age) with 46, XY DSD (83 females; 44 males) from a Single Brazilian Tertiary-Care Medical Center. RESULTS: Sexual fantasies and masturbation were more frequent in 46, XY DSD males, whereas orgasm and sexual life satisfaction were similar in both genders. More 46, XY DSD men than women had a long-term romantic relationship. 46, XY DSD women with prenatal androgen exposure reported more fear of being romantically rejected. External genitalia appearance at birth did not impact the sexuality of 46, XY DSD women after surgical genital treatment had been completed. Overall, the sexual life was similar between 46, XY men assigned as males and those who changed to the male gender. Regarding sexual orientation, most self-reported as heterosexual (91% and 92% of women and men, respectively). The desire for fertility had a similar prevalence in both genders, but more women than men considered infertility a barrier to a long-term romantic relationship. Twelve individuals (7 males) had children; 10 out of 12 have adopted children. CONCLUSION: Fertility desire was shared among 46, XY DSD people, regardless of gender. Prenatal androgen exposure reduced the desire for motherhood in 46, XY women. 46, XY DSD people who changed from female to male gender presented similar sexual parameters as those assigned as males. Among females, virilized genitalia at birth did not affect sexuality once the surgical treatment is completed.

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Introduction. Puberty is manifested initially by the onset of secondary sexual characteristics as a result of hormonal changes that progressively lead to complete sexual maturity. In Argentina and worldwide, the lockdown resulting from the SARS-CoV-2 pandemic may have interfered in the onset and timing of pubertal development. Objective. To describe the perception of pediatric endocrinologists in Argentina regarding consultations for suspected precocious and/or rapidly progressive puberty during the pandemic. Materials and methods. Descriptive, observational, cross-sectional study. Anonymous survey among pediatric endocrinologists members of the Sociedad Argentina de Pediatría and/or the Asociación de Endocrinología Pediátrica Argentina administered in December 2021. Results. Out of 144 pediatric endocrinologists, 83 completed the survey (rate of response: 58%). All of them considered that consultation for precocious or early puberty increased, either in terms of early thelarche (84%), early pubarche (26%), and/or precocious puberty (95%). Ninety-nine percent agreed that this has occurred to a greater extent in girls. All survey respondents also consider that the diagnosis of central precocious puberty has increased. In total, 96.4% of respondents consider that the number of patients treated with GnRH analogs has increased. Conclusion. Our results about the perception of pediatric endocrinologists are consistent with data published in other regions on the increase in the diagnosis of precocious puberty during the COVID-19 pandemic. We underscore the need to develop national registries of central precocious puberty, and to disseminate the evidence for a timely detection and management.

Introducción. La pubertad se manifiesta inicialmente por la aparición de los caracteres sexuales secundarios, como consecuencia de cambios hormonales que progresivamente conducen a la madurez sexual completa. En Argentina y el mundo, la pandemia ocasionada por el coronavirus SARS-CoV-2 generó un confinamiento que pudo haber interferido en el inicio y tempo del desarrollo puberal. Objetivo. Describir la percepción de los endocrinólogos pediatras del país sobre las consultas por sospecha de pubertad precoz y/o pubertad de rápida progresión durante la pandemia. Materiales y métodos. Estudio descriptivo, observacional, transversal. Encuesta anónima a endocrinólogos pediatras pertenecientes a la Sociedad Argentina de Pediatría y/o a la Asociación de Endocrinología Pediátrica Argentina, en diciembre de 2021. Resultados. Respondieron la encuesta 83 de 144 endocrinólogos pediátricos (tasa de respuesta 58 %). Todos consideraron que aumentó la consulta por desarrollo precoz o temprano, ya sea en sus variantes telarca precoz (84 %), pubarca precoz (26 %) y/o pubertad precoz (95 %). El 99 % acuerda con que se ha dado en mayor medida en niñas. La totalidad de los encuestados también considera que aumentó el diagnóstico de pubertad precoz central. El 96,4 % considera que ha aumentado el número de pacientes tratados con análogos de GnRH. Conclusión. Nuestros resultados sobre la percepción de endocrinólogos pediatras coinciden con datos publicados en otras regiones sobre el aumento del diagnóstico de pubertad precoz durante la pandemia por COVID-19. Se reafirma la necesidad de generar registros nacionales de pubertad precoz central, difundir las evidencias para su detección y abordaje oportuno.

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INTRODUCTION: Although it was common in the 1970s-1990s to assign female gender of rearing to 46,XY infants with limited virilization of varying etiologies, including those with partial androgen insensitivity syndrome (PAIS), long-term data on outcomes for these individuals are sparse. Therefore, our goal was to use the power of an international registry to evaluate clinical features, surgical management, and pubertal data in patients with a molecularly confirmed diagnosis of PAIS who were born before 2008 and were raised as girls. METHODS: The current study interrogated the International Disorders of Sex Development Registry for available data on management and pubertal outcomes in individuals with genetically confirmed PAIS who were raised as girls. RESULTS: Among the 11 individuals who fulfilled the key criteria for inclusion, the external masculinization score (EMS) at presentation ranged from 2 to 6 (median 5); 7 girls underwent gonadectomy before the age of 9 years, whereas 4 underwent gonadectomy in the teenage years (≥ age 13). Clitoral enlargement at puberty was reported for 3 girls (27%) who presented initially at the time of puberty with intact gonads. In the 9 individuals (82%) for whom gonadal pathology data were provided, there was no evidence of germ cell tumor at median age of 8.1 years. All girls received estrogen replacement, and 8/11 had attained Tanner stage 4-5 breast development at the last assessment. CONCLUSION: In general, although it appears that female assignment in PAIS is becoming uncommon, our data provide no evidence to support the practice of prophylactic prepubertal gonadectomy with respect to the risk of a germ cell tumor.

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PURPOSE: Intersex is an umbrella term used to describe the diversity or differences in the characteristics of physical sexual development. Approximately 1.7% of the population are born intersex, and 1 in every 2000 babies at birth presents genital variation. Unfortunately, there is a lack of research on the health of intersex-identifying persons in Latin America. This study aimed to document experiences of discrimination and violence among self-identifying intersex individuals in Puerto Rico and to determine if there is a significant difference in the quality of life, psychological well-being, and social well-being between intersex-identifying and endosex individuals. METHODS: This was a quantitative method pilot study with a cross-sectional approach and exploratory comparative group design. An online survey was used, where a total of 12 self-identifying intersex adult participants were recruited, and 126 endosex adult participants served as a comparative group. RESULTS: The findings show that 83% of the participants reported experiences of discrimination and different types of violence due to their intersexuality. There was a significant difference between the intersex-identifying and endosex groups in psychological well-being, including in three of its dimensions (positives relations, autonomy, and environmental mastery). However, there were no significant differences between the groups in quality of life or social well-being. CONCLUSION: The findings of this study provide a preliminary understanding of the health disparities of intersex-identifying individuals in Puerto Rico and suggest the need for more profound research, especially the inclusion of other Caribbean and Hispanic countries. The findings also preliminarily imply the need for local and global interventions to reduce physical and mental health disparities and to improve health, quality of life, and well-being among intersex-identifying individuals.

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Disorders of sexual differentiation are rare congenital conditions in which the chromosomal, anatomic or gonadal sex development is atypical. In some of these patients, chromosomal sex is inconsistent with phenotypic sex; in other cases, the phenotype is not classifiable as either male or female, resulting in a condition known as ambiguous genitalia. These are very complex cases in which diagnostic certainty is not always possible. A multidisciplinary team including geneticists, pediatricians, radiologists is certainly needed to approach these patients. We present the case of an 18-year-old boy with an XY karyotype, ambiguous genitalia, uterus and blind-ending vaginal pouch. The patient had not been previously diagnosed with a disorder of sex development. The patient underwent a panel of genetic analyses and diagnostic imaging investigations. Magnetic resonance imaging was decisive for the identification of the internal genital organs, especially the uterus. At the end of investigations, the patient was diagnosed with 46,XY disorder of sex development. Our purpose is to underline the role of imaging in the diagnosis and management of congenital disorders of sex differentiation.

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Approximately 30 sex chromosome discordant chimera cases have been reported to date. In particular, there are few reported cases of chimerism involving coexisting normal and abnormal lineages that each carries a distinct sex chromosome complement. To our knowledge, this is the first case of sexual chimerism with a simultaneous chromosomal aneuploidy involving chromosome 8. This report represents the data from 11 years of follow-up.

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BACKGROUND: The suspicion of a disorder of sex development (DSD) often arises at birth, when the newborn presents with ambiguous genitalia, or even during prenatal ultrasound assessments. Less frequently, the aspect of the external genitalia is typically female or male, and the diagnosis of DSD may be delayed until a karyotype is performed for another health issue, or until pubertal age when a girl presents with absence of thelarche and/or menarche or a boy consults for gynaecomastia and/or small testes. SUMMARY: In this review, we provide a practical, updated approach to clinical and hormonal laboratory workup of the newborn, the child, and the adolescent with a suspected DSD. We focus on how to specifically address the diagnostic approach according to the age and presentation. KEY MESSAGE: We particularly highlight the importance of a detailed anatomic description of the external and internal genitalia, adequate imaging studies or surgical exploration, the assessment of reproductive hormone levels - especially testosterone, anti-Müllerian hormone, 17-hydroxyprogesterone, and gonadotropins - and karyotyping.

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Ovotesticular disorders of sex development (OT-DSD) are characterized by ovarian follicles and seminiferous tubules in the same individual, with a wide range of atypical genitalia. We report on two sibs with atypical genitalia and SRY-negative 46,XX DSD, OT-DSD was confirmed only in the boy, while the girl had bilateral ovaries. Chromosome microarray analysis (CMA) showed a 737-kb duplication at Xq27.1 including the entire SOX3 gene in both sibs, which was confirmed by quantitative real time PCR. Also, X chromosome inactivation assay showed random inactivation in both sibs. Whole exome sequencing revealed no pathogenic or likely pathogenic variant. CMA of the parents showed normal results for both, suggesting that germline mosaicism could be the reason of recurrence of this duplication in the siblings. Our results support a pathogenic role of SOX3 overexpression in 46,XX subjects leading to variable DSD phenotypes.

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El hipospadias es la localización anormal del meato urinario y es la malformación de genitales externos más frecuentemente diagnosticada. El diagnóstico prenatal es posible mediante ecografía sistemática desde la semana 20 de gestación, siendo más fácil su diagnóstico en el tercer trimestre. Las formas leves suelen ser aisladas, familiares o asociadas a disfunción placentaria o restricción de crecimiento intrauterino, mientras que las formas más graves presentan hasta un 30% de asociación a defectos fetales, anomalías cromosómicas/genéticas o anomalías del desarrollo sexual. La tríada para el diagnóstico ecográfico prenatal consiste en curvatura ventral del pene, anomalía del prepucio dorsal y punta del pene roma. La valoración de la uretra durante la micción y el aspecto del chorro miccional son de gran utilidad para clasificar el defecto. Cuando se diagnostica hipospadias peneano o escrotal es aconsejable realizar una amniocentesis para estudio genético fetal y valorar otros signos de adecuada virilización, como el descenso testicular a partir de la semana 27. El seguimiento tras el parto debe ser multidisciplinario, incluyendo urólogo y endocrinólogo infantil. En hipospadias leves el pronóstico es bueno con reparación quirúrgica en el primer año de vida, pero las formas graves pueden presentar un reto mayor para su corrección funcional y estética.

Hypospadias refers to the abnormal location of the meatus; it is the most common genital malformation detected in the fetus and newborn. Prenatal diagnosis is feasible from 20 weeks onwards with routine ultrasound; however, it is easier to diagnose during the third trimester of pregnancy. Mild defects are usually isolated, familiar o related to placental disfunction or intrauterine growth restriction, while the severe hypospadias are associated to other fetal defects, genetic or chromosomal abnormalities or disorders of sex development. In about 30% of cases. The triad of ultrasound findings prenatally is ventral curvature of the penis, redundant dorsal foreskin and blunt distal penis. The identification of the urethra during the micturition and the direction of the urinary stream help in the classification of the defect. When severe hypospadias is detected, the recommendation is to perform genetic amniocentesis and search for other ultrasound findings related to poor virilization in the fetus, as testicular descent after 27 weeks of gestation. Postnatal follow up should be multidisciplinary including infantile urologist and endocrinologist. The prognosis in distal hypospadias is usually good following surgical repair, however in severe cases surgical interventions may be more challenging in order to obtain satisfactory outcome in terms of function and esthetic.

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ABSTRACT BACKGROUND: Knowledge of clinical and laboratory differences between chromosomal and undefined causes aids etiological research on non-obstructive azoospermia. OBJECTIVE: Compare clinical and laboratory differences between men with non-obstructive azoospermia due to chromosomal anomalies versus undefined causes DESIGN AND SETTING: A cross-sectional retrospective study conducted at a public university hospital in Campinas (Brazil) METHODS: All men aged 20-40 years with non-obstructive azoospermia were included in the analysis. RESULTS: The 107 cases included 14 with Klinefelter syndrome (KS) (13%), 1 with mosaic KS, 4 with sex development disorders (2 testicular XX, 1 NR5A1 gene mutation, and 1 mild androgen insensitivity syndrome) (4%), 9 with other non-obstructive azoospermia etiologies (8%), and 79 with undefined causes. The 22 chromosomal anomaly cases (14 KS, 1 mosaic KS, 2 testicular XX, 4 sex chromosome anomalies, and 1 autosomal anomaly) were compared with the 79 undefined cause cases. The KS group had lower average testicular volume, shorter penile length, and lower total testosterone levels but greater height, arm span, serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, and gynecomastia frequency (absent in the undefined group and affecting more than half of the KS group). Patients with testicular XX DSD had LH, FSH, and penile length data intermediate between the KS and undefined cause groups, testicular volume similar to the KS group, and other data similar to the undefined group. CONCLUSION: Clinical and laboratory data differentiate men with non-obstructive azoospermia and chromosomal anomalies, particularly KS and testicular XX, from those with undefined causes or other chromosomal anomalies.

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Abstract Objective: To analyze aspects of sexual life and fertility desire among 46, XY DSD people, including those who changed their gender. Methods: It is a cross-sectional study including 127 adults (> 16 years of age) with 46, XY DSD (83 females; 44 males) from a Single Brazilian Tertiary-Care Medical Center. Results: Sexual fantasies and masturbation were more frequent in 46, XY DSD males, whereas orgasm and sexual life satisfaction were similar in both genders. More 46, XY DSD men than women had a long-term romantic relationship. 46, XY DSD women with prenatal androgen exposure reported more fear of being romantically rejected. External genitalia appearance at birth did not impact the sexuality of 46, XY DSD women after surgical genital treatment had been completed. Overall, the sexual life was similar between 46, XY men assigned as males and those who changed to the male gender. Regarding sexual orientation, most self-reported as heterosexual (91% and 92% of women and men, respectively). The desire for fertility had a similar prevalence in both genders, but more women than men considered infertility a barrier to a long-term romantic relationship. Twelve individuals (7 males) had children; 10 out of 12 have adopted children. Conclusion: Fertility desire was shared among 46, XY DSD people, regardless of gender. Prenatal androgen exposure reduced the desire for motherhood in 46, XY women. 46, XY DSD people who changed from female to male gender presented similar sexual parameters as those assigned as males. Among females, virilized genitalia at birth did not affect sexuality once the surgical treatment is completed.

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BACKGROUND: Differences of sex development (DSD) is a term used for conditions in which the chromosomal, gonadal or phenotypical sex is atypical. 46,XY DSD patients frequently present undervirilized external genitalia. The expression of different miRNAs in many organs of the male genital system has been reported, and these miRNAs have been associated with testicular function and its disorders, but no description has been related to DSD conditions. This study aimed to evaluate the plasma expression of miR-210 in 46,XY DSD patients who presented atypical genitalia at birth. METHODS: Eighteen 46,XY DSD patients who presented atypical genitalia (undescended testis and/or hypospadias, bifid scrotum or micropenis) at birth and 36 male control individuals were selected. Plasma levels of miR-210 and reference miR-23a were measured using RT-qPCR and the data were analysed by the 2-ΔCt method. RESULTS: MiR-210 plasma levels were significantly higher in 46,XY DSD patients with atypical genitalia than in male control subjects (p = 0.0024). A positive association between miR-210 levels and the presence of cryptorchidism and hypospadias (p = 0.0146 and p = 0.0223) was found in these patients. Significantly higher levels of miR-210 were observed in patients with 46,XY DSD and cryptorchidism than in control subjects (p = 0.0118). These results are in agreement with previous literature reports, in which increased levels of miR-210 expression were observed in human testicular tissue from adult males with undescended testes in comparison with samples of descended testes. CONCLUSION: Our study showed a positive association between the presence of atypical genitalia and plasma levels of miR-210 expression in the group of patients with 46,XY DSD of unknown aetiology studied. These findings contribute to reveal a new perspective on the role of miRNAs in the development of male external genitalia and the broad spectrum of phenotypes presented by patients with 46,XY DSD.

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Disorder of Sex Development (DSD) refers to a heterogeneous group of congenital conditions in which chromosomal, gonadal, and anatomical sex are atypical. Typically, the diagnosis is made at birth or infancy and interventional actions are necessary in many cases. The repercussions in adult life, more specifically in the field of sexuality, have not been not widely studied yet. This study shows research data that seek to identify in a group of individuals with DSD (XX DSD, XY DSD, Chromosomal DSD), who are being monitored in the departments of pediatric surgery and urology of a hospital in the period from 2000 to 2019, and to verify the consequences on sex life after puberty. The sample has 16 participants (7 XY DSD, 4 XX DSD, and 5 Chromosomal DSD), aged between 16 and 50 years, single, with high school education, residents of the state capital and countryside of the state. The results depict the presence of a case of Gender Dysphoria; postponement of sexual debut for almost 3 years compared to the national average; a single sexual relationship for those who have already had a sexual experience with penetration; penis size below the general population average; presence of masturbatory activity in most participants. The presence of sexual attraction and masturbation indicate sexual desire. The group has a late onset of sexual life (almost 3 years after the national average). A recurrent feature in this group is that, even having already performed a penetrative sexual act, there is no continuation in their sexual life. The main noticeable aspect about Gender Dysphoria is the presence of only one case of incongruence in the Chromosomal DSD group. The limited sample prevents us from sufficient statements for generalization.