WNT4 Balances Development vs Disease in Gynecologic Tissues and Women's Health.

The WNT family of proteins is crucial in numerous developmental pathways and tissue homeostasis. WNT4, in particular, is uniquely implicated in the development of the female phenotype in the fetus, and in the maintenance of müllerian and reproductive tissues. WNT4 dysfunction or dysregulation can drive sex-reversal syndromes, highlighting the key role of WNT4 in sex determination. WNT4 is also critical in gynecologic pathologies later in life, including several cancers, uterine fibroids, endometriosis, and infertility. The role of WNT4 in normal decidualization, implantation, and gestation is being increasingly appreciated, while aberrant activation of WNT4 signaling is being linked both to gynecologic and breast cancers. Notably, single-nucleotide polymorphisms (SNPs) at the WNT4 gene locus are strongly associated with these pathologies and may functionally link estrogen and estrogen receptor signaling to upregulation and activation of WNT4 signaling. Importantly, in each of these developmental and disease states, WNT4 gene expression and downstream WNT4 signaling are regulated and executed by myriad tissue-specific pathways. Here, we review the roles of WNT4 in women's health with a focus on sex development, and gynecologic and breast pathologies, and our understanding of how WNT4 signaling is controlled in these contexts. Defining WNT4 functions provides a unique opportunity to link sex-specific signaling pathways to women's health and disease.

Advances in genomic diagnosis of a large cohort of Egyptian patients with disorders of sex development.

Disorders/differences of sex development (DSD) comprise a group of congenital disorders that affect the genitourinary tract and usually involve the endocrine and reproductive system. The aim of this work was to identify genetic variants responsible for disorders of human urogenital development in a cohort of Egyptian patients. This three-year study included 225 patients with various DSD forms, referred to the genetic DSD and endocrinology clinic, National Research Centre, Egypt. The patients underwent thorough clinical examination, hormonal and imaging studies, detailed cytogenetic and fluorescence in situ hybridization analysis, and molecular sequencing of genes known to commonly cause DSD including AR, SRD5A2, 17BHSD3, NR5A1, SRY, and WT1. Whole exome sequencing (WES) was carried out for 18 selected patients. The study revealed a high rate of sex chromosomal DSD (33%) with a wide array of cytogenetic abnormalities. Sanger sequencing identified pathogenic variants in 33.7% of 46,XY patients, while the detection rate of WES reached 66.7%. Our patients showed a different mutational profile compared with that reported in other populations with a predominance of heritable DSD causes. WES identified rare and novel pathogenic variants in NR5A1, WT1, HHAT, CYP19A1, AMH, AMHR2, and FANCA and in the X-linked genes ARX and KDM6A. In addition, digenic inheritance was observed in two of our patients and was suggested to be a cause of the phenotypic variability observed in DSD.

Systematic Review: Puberty suppression with GnRH analogues in adolescents with gender incongruity.

CONTEXT: Gender incongruence is defined as disharmony between assigned gender and gender identity. Several interventions are liable in this case including genital affirming surgery among other surgical interventions such as harmonization, and also the use of gonadotropin-releasing hormone agonists (GnRHa) for gonadal shielding. This aids in preventing the development of secondary sexual characteristics related to the genetic sex. OBJECTIVE: Systematically review the treatment of gender incongruity with GnRHa analogues. DATA SOURCES: The data source of this research is from Pubmed-Medline and Embase. STUDY SELECTION: Articles published between 2009 and 2019 which studied transgender adolescents treated with GnRHa were carefully selected. DATA EXTRACTION: Were extracted: design, sample size, study context, targeted subjects of intervention, outcome measures, and results. RESULTS: Eleven studies were included. The use of GnRHa seems to be well tolerated by the studied population. When started in pubertal transition, it was associated with a more distinct resemblance to body shape than to the affirmed sex. In addition to preventing the irreversible phenotypic changes that occur in cross-hormonal therapy, the use of GnRHa can equally contribute to the mental health of these adolescents. LIMITATION: There are few consistent studies on the use of GnRHa for gender incongruence. CONCLUSION: As the population of transgender children and adolescents grows, they acquire knowledge and greater access to the various forms and stages of treatment for sex reassignment. The medical community needs to be adequately prepared to better serve this population and offer the safest resources available.

46, XY disorder of sex development (DSD) complicated by a serous borderline tumor of the ovary: a case report and review of the literature.

BACKGROUND: Patients with 46, XY disorder of sex development (DSD) are predisposed to the development of gonadal tumors, particularly germ cell tumors and gonadoblastoma. However, to the best of our knowledge, there are no publications in the existing literature that refer to the coexistence of 46, XY DSD and serous tumors in the ovary. CASE PRESENTATION: Here, we report the case of a 23-year-old female (social gender) patient with 46, XY DSD presenting with primary amenorrhea. Imageology revealed a huge mass in the left adnexa. Subsequent pathological analysis revealed a serous borderline tumor of the ovary. CONCLUSION: Gonadal tumors of patients with 46, XY DSD are not necessarily malignant tumors and can coexist with borderline tumors with primitive corded gonads. The coexistence of DSD and serous borderline tumors is rare. Clearly, an early and accurate diagnosis plays an important role in the treatment of these patients. Although there may not be a clear correlation between the two lesions, it is vital that we specifically analyze the mechanisms involved so that we can determine whether patients with DSD are associated with an increase of developing serous borderline tumors of the gonad.

Urogenital Abnormalities in Adenosine Deaminase Deficiency.

BACKGROUND: Improved survival in ADA-SCID patients is revealing new aspects of the systemic disorder. Although increasing numbers of reports describe the systemic manifestations of adenosine deaminase deficiency, currently there are no studies in the literature evaluating genital development and pubertal progress in these patients. METHODS: We collected retrospective data on urogenital system and pubertal development of 86 ADA-SCID patients followed in the period 2000-2017 at the Great Ormond Street Hospital (UK) and 5 centers in Italy. In particular, we recorded clinical history and visits, and routine blood tests and ultrasound scans were performed as part of patients' follow-up. RESULTS AND DISCUSSION: We found a higher frequency of congenital and acquired undescended testes compared with healthy children (congenital, 22% in our sample, 0.5-4% described in healthy children; acquired, 16% in our sample, 1-3% in healthy children), mostly requiring orchidopexy. No urogenital abnormalities were noted in females. Spontaneous pubertal development occurred in the majority of female and male patients with a few cases of precocious or delayed puberty; no patient presented high FSH values. Neither ADA-SCID nor treatment performed (PEG-ADA, BMT, or GT) affected pubertal development or gonadic function. CONCLUSION: In summary, this report describes a high prevalence of cryptorchidism in a cohort of male ADA-SCID patients which could represent an additional systemic manifestation of ADA-SCID. Considering the impact urogenital and pubertal abnormalities can have on patients' quality of life, we feel it is essential to include urogenital evaluation in ADA-SCID patients to detect any abnormalities, initiate early treatment, and prevent long-term complications.

Desarrollo afectivo-sexual en las personas con trastornos del espectro autista / Affective-sexual development in people with autistic spectrum disorders

Los trastornos del espectro autista (TEA) son trastornos del neurodesarrollo que afectan la comunicación social y que presentan patrones de conducta repetitiva, estereotipada o/y inflexible. Un tercio de los casos diagnosticados de TEA tienen discapacidad intelectual y 2/3 una capacidad intelectual dentro de la norma. Los síntomas nucleares de autismo y otros asociados pueden afectar el desarrollo afectivo-sexual. En este artículo se expone qué dificultades en el desarrollo afectivo-sexual pueden presentar las personas con TEA y cuáles son las más frecuentemente descritas. Se propone de una manera breve, guías dirigidas a la evaluación y a la ayuda para un desarrollo afectivo-sexual satisfactorio en las personas con autismo-TEA.

Autistic spectrum disorders (ASD) are neurodevelopmental disorders that affect social communication and present repetitive, stereotyped and inflexible behaviour. A third of the people with a diagnosis of ASD also have intellectual disability associated and two thirds present an intellectual capacity within the average range. The nuclear autistic and others associated symptoms can affect the affective and sexual development. This article exposes which are the problems people with ASD present in the affective and sexual development, the most frequently described and brief guides for evaluation and support for an adequate affective-sexual development in people with ASD.

[Preliminary investigation of gender assignment in 46,XY disorders of sex development with severe male undermasculinisation].

Objective: To explore the feasibility of gender assignment in 46,XY disorders of sex development (DSD) with severe undermasculinisation mainly based on molecular diagnosis. Methods: A retrospective study of 45 patients of 46, XY DSD with severe undermasculinisation were admitted between November 2015 and October 2018 at Children's Hospital, Zhejiang University School of Medicine. The initial social gender were all female, of whom the external genital manifestations were Prader 0 to 2; the degree of masculinity was scored using external masculinisation score (EMS); the position and development of the gonads were examined by ultrasound, cystoscopy and laparoscopy, also including assessing the development of the Wolffian tube and the Müllerian tube. The level and ratio of testosterone to dihydrotestosterone before and after hCG stimulation were evaluated for the function of Leydig cell and 5α-reductase-2. Gender role scales and sandbox games were used to assess gender role behavior. Genital sensitivity to androgen stimulation was assessed; A panel including 163 genes related to gender development were determined by second-generation sequencing in all 45 patients. Finally, a multidisciplinary team (MDT) makes a gender assignment after a comprehensive analysis mainly based on the molecular etiological diagnosis. Results: Thirty-nine out of 45 patients (87%) had an identifiable genetic etiology, and the remaining 6 (13%) were negative for genetic testing. Forty-five patients had EMS less than or equal to 3 points. Sexual psychological assessment was performed in 39 patients, with male dominance in 24 (62%) and female dominance in 15 (38%). The gender assignment was 23 cases (51%) for male and 19 cases (42%) for female, and 3 cases (7%) were not completely determined. Conclusions: Molecular diagnosis provides a strong basis for appropriate gender assignment of 46, XY DSD children with severe undermasculinisation. Based on molecular diagnosis, each DSD should be analyzed by professional MDT to analyze the clinical symptoms/signs, gonadal development, gonad tumor risk, external genital morphology, sexual psychological assessment, potential fertility opportunities, parental views, Social and cultural factors, etc. make appropriate gender assignment.

Yield of modern genetic evaluation for patients with proximal hypospadias and descended gonads.

INTRODUCTION AND BACKGROUND: Although the pediatric urologic community has embraced a multidisciplinary genetic and endocrine evaluation for newborns with ambiguous genitalia, this approach has been reserved for the most severe cases of undervirilized 46,XY individuals despite growing evidence that genetic differences are found even in patients whose only genitourinary anomaly appears to be proximal hypospadias. Identifying these genetic differences is vital for counseling patients as they move through puberty to parenthood as well as parents on future pregnancies. OBJECTIVE: The primary objective was to evaluate genetic diagnosis in patients with proximal hypospadias. The authors hypothesized the more sensitive genetic evaluation available in the modern era will reveal a high rate of patients with proximal hypospadias and descended testicles who are found to have a genetic difference, supporting a thorough genetic evaluation in these patients. STUDY DESIGN: A retrospective review was performed of all patients who underwent surgical correction for proximal hypospadias at a single institution from January 1, 2010, to December 31, 2016. Those with midshaft hypospadias were excluded as were patients whose primary surgery was performed at an outside institution. Patient characteristics, including demographics, clinical presentation, genetic evaluation, and referral to a multidisciplinary difference of sex development (DSD) clinic, were collected. The chi-squared test and t-test were used for analysis. RESULTS: There were 112 patients with proximal hypospadias who met the inclusion criteria. Of these, 91 had bilaterally descended testicles, whereas 21 had one or more undescended testicles. Thirty-three percent of patients with isolated proximal hypospadias received genetic testing of some kind, with 24% seen in the multidisciplinary DSD clinic. Four patients had an associated genetic syndrome identified, and 5 had a genetic difference of unknown clinical significance. Overall, 10% of patients with proximal hypospadias and descended testicles had an identifiable genetic difference vs 33% with associated cryptorchidism. Of these, one patient with proximal hypospadias and descended testicles had a genetic difference of known clinical significance that was likely to have been missed in the absence of an evaluation by a geneticist. DISCUSSION AND CONCLUSION: There was a high rate of identifiable genetic differences in patients whose only genitourinary abnormality was proximal hypospadias, especially with the 1% risk of a likely missed diagnosis. These findings support the discussion of a genetic evaluation for all patients with proximal hypospadias, regardless of the testicular location.

[Gender selection and postoperative follow-up analysis in 85 children with 46, XY disorders of sex development].

Objective: To understand the gender selection and prognosis of children with 46, XY disorders of sex development (DSD) after surgery, and to provide reference for future clinical decision-making. Methods: Data of 85 (80 males and 5 females) postoperative patients with 46, XY DSD with follow-up age of 6(4,11) years who were treated at the Department of Endocrinology, Genetics and Metabolism of Beijing Children's Hospital Affiliated to Capital Medical University during the period from September 2009 to April 2018 were retrospectively analyzed. The patients were grouped based on diagnosis. The basis of postoperative gender selection, patient satisfaction and related factors, gender characteristics, and adolescent development were analyzed. The Pre-school Activities Inventory or the Children's Sex Role Inventory were used in the analysis of gender tendency. Mann-Whitney U test was used to compare postoperative gender satisfaction of different factors. The Kruskal-Wallis method was used to compare the postoperative gender satisfaction of each group. Fisher's test was used to compare the follow-up status of male children over 11 years old in each group. Results: Among the 85 patients, 62 individuals were raised as girls after birth, 9 were facultative and 14 as boys. According to the diagnosis, there were 31 individuals in group 1 (with 5α-reductase deficiency), 11 individuals in group 2 (with androgen insensitivity syndrome), 9 individuals in group 3 (with NR5A1 gene mutation), 4 individuals in group 4 (with hypergonadotropic gonadal dysplasia), and 30 indiviudals in group 5 (with unclear diagnosis and normal human choionic gonadotophin test). Among the 71 children who were raised as girls or facultative children after birth, 66 selected as boys, and 5 continued as girls (among them, 3 individuals were female with passive selection, and 2 individuals of testicular dysplasia with uterus in group 4 and 5 were female with active selection). Among the 71 patients faced with gender selection, only one was unsatisfied, that was a postoperative female. There was no significant difference in postoperative gender satisfaction among different disease diagnoses, surgical age and penis length (χ(2)(H)=6.007, P=0.199; Z=-0.860, P=0.390; Z=-0.438, P=0.661). Fifty-nine of the 85 cases completed the gender tendency scale test and 46 cases (78%) were consistent. In the male patients, 45 cases were consistent. Thirteen inconsistent patients (22%) were female or facultative after birth who were 5 years old or older. There was no stigmatization noticed in the inconsistent patients' daily life and school social settings. There were 22 male patients aged 11 years and older. They were 13(12,16) years old. Fourteen (64%) individuals' penile length reached the normal minimum, 15 (68%) individuals' testicular volume were equal or more than 4 ml, 16 (73%) individuals' sex hormones entered puberty levels, 12 (55%) individuals had been spermatorrhea, the age of first spermatorrhea was (13.3±2.4) years. They were satisfied and adaptable after surgery. There was no significant difference in the above indicators among the groups (χ²=2.999, P=0.694; χ²=7.278, P=0.086; χ²=5.597, P=0.358; χ²=6.904, P=0.127). Conclusions: The appropriate gender of 46, XY DSD patients was selected according to gonadal status after diagnosis. Regardless the diagnosis, the age of operation and the length of the penis at the first diagnosis, male patients were satisfied with the gender after the operation. A few of patients were inconsistent with the results of gender tendency scale test who were raised as girls or facultative children after birth, and they required sustained special attention. Some of the children showed natural adolescent development in males, and the prognosis may be ideal.

Multiplexed CRISPR/Cas9-mediated knockout of 19 Fanconi anemia pathway genes in zebrafish revealed their roles in growth, sexual development and fertility.

Fanconi Anemia (FA) is a genomic instability syndrome resulting in aplastic anemia, developmental abnormalities, and predisposition to hematological and other solid organ malignancies. Mutations in genes that encode proteins of the FA pathway fail to orchestrate the repair of DNA damage caused by DNA interstrand crosslinks. Zebrafish harbor homologs for nearly all known FA genes. We used multiplexed CRISPR/Cas9-mediated mutagenesis to generate loss-of-function mutants for 17 FA genes: fanca, fancb, fancc, fancd1/brca2, fancd2, fance, fancf, fancg, fanci, fancj/brip1, fancl, fancm, fancn/palb2, fanco/rad51c, fancp/slx4, fancq/ercc4, fanct/ube2t, and two genes encoding FA-associated proteins: faap100 and faap24. We selected two indel mutations predicted to cause premature truncations for all but two of the genes, and a total of 36 mutant lines were generated for 19 genes. Generating two independent mutant lines for each gene was important to validate their phenotypic consequences. RT-PCR from homozygous mutant fish confirmed the presence of transcripts with indels in all genes. Interestingly, 4 of the indel mutations led to aberrant splicing, which may produce a different protein than predicted from the genomic sequence. Analysis of RNA is thus critical in proper evaluation of the consequences of the mutations introduced in zebrafish genome. We used fluorescent reporter assay, and western blots to confirm loss-of-function for several mutants. Additionally, we developed a DEB treatment assay by evaluating morphological changes in embryos and confirmed that homozygous mutants from all the FA genes that could be tested (11/17), displayed hypersensitivity and thus were indeed null alleles. Our multiplexing strategy helped us to evaluate 11 multiple gene knockout combinations without additional breeding. Homozygous zebrafish for all 19 single and 11 multi-gene knockouts were adult viable, indicating FA genes in zebrafish are generally not essential for early development. None of the mutant fish displayed gross developmental abnormalities except for fancp-/- fish, which were significantly smaller in length than their wildtype clutch mates. Complete female-to-male sex reversal was observed in knockouts for 12/17 FA genes, while partial sex reversal was seen for the other five gene knockouts. All adult females were fertile, and among the adult males, all were fertile except for the fancd1 mutants and one of the fancj mutants. We report here generation and characterization of zebrafish knockout mutants for 17 FA disease-causing genes, providing an integral resource for understanding the pathophysiology associated with the disrupted FA pathway.

Molecular basis of Gender Dysphoria: androgen and estrogen receptor interaction.

BACKGROUND: Polymorphisms in sex steroid receptors have been associated with transsexualism. However, published replication studies have yielded inconsistent findings, possibly because of a limited sample size and/or the heterogeneity of the transsexual population with respect to the onset of dysphoria and sexual orientation. We assessed the role of androgen receptor (AR), estrogen receptors alpha (ERα) and beta (ERß), and aromatase (CYP19A1) in two large and homogeneous transsexual male-to-female (MtF) and female-to-male (FtM) populations. METHODS: The association of each polymorphism with transsexualism was studied with a twofold subject-control analysis: in a homogeneous population of 549 early onset androphilic MtF transsexuals versus 728 male controls, and 425 gynephilic FtMs versus 599 female controls. Associations and interactions were investigated using binary logistic regression. RESULTS: Our data show that specific allele and genotype combinations of ERß, ERα and AR are implicated in the genetic basis of transsexualism, and that MtF gender development requires AR, which must be accompanied by ERß. An inverse allele interaction between ERß and AR is characteristic of the MtF population: when either of these polymorphisms is short, the other is long. ERß and ERα are also associated with transsexualism in the FtM population although there was no interaction between the polymorphisms. Our data show that ERß plays a key role in the typical brain differentiation of humans. CONCLUSION: ERß plays a key role in human gender differentiation in males and females.

Ovarian hormones, age and pubertal development and their association with days of headache onset in girls with migraine: An observational cohort study.

Background Fifty-three percent of adolescent girls report headaches at the onset of menses, suggesting fluctuations of ovarian hormones trigger migraine during puberty. Aims To determine if urinary metabolites of estrogen and progesterone are associated with days of headache onset (HO) or severity in girls with migraine. Methods This was a pilot study and included 34 girls with migraine balanced across three age strata (pre-pubertal (8-11), pubertal (12-15), and post-pubertal (16-17) years of age). They collected daily urine samples and recorded the occurrence and severity of headache in a daily diary. Urine samples were assayed for estrone glucuronide (E1G) and pregnandiol glucuronide (PdG) and the daily change was calculated (ΔE1G, ΔPdG). Pubertal development was assessed by age, pubertal development score (PDS), and menstrual cycle variance. The primary outcome measures were HO days and headache severity. Generalized linear mixed models were used, and included the hormonal variables and three different representations of pubertal development as covariates. Results Models of HO days demonstrate a significant age*PdG interaction (OR 0.85 [95% CI 0.75, 0.97]) for a 1 standard deviation increase in PdG and three-year increase in age. A separate model showed a significant PDS*PdG interaction (OR -0.85 [95% CI; 0.76, 0.95]). ΔPDG was associated with headache severity in unadjusted models ( p < 0.017). Conclusion Age and pubertal development could moderate the effect of ovarian hormones on days of headache onset in girls with migraine.

Risk association of congenital anomalies in patients with ambiguous genitalia: A 22-year single-center experience.

BACKGROUND: Ambiguous genitalia refers to a form of differences of sex development (DSD) wherein the appearance of the external genitalia is atypical. This rare condition presents challenges in decision-making and clinical management. Review of historical data may reveal areas for clinical research to improve care for patients with ambiguous genitalia. OBJECTIVE: This chart review was performed to identify patients with ambiguous genitalia, and to classify them as having 46,XX DSD, 46,XY DSD, or sex chromosome DSD. Within these categories, we looked at establishment of specific diagnoses, type and frequency of other congenital anomalies and neoplasms, and gender assignment, as well as incidence of gender reassignment and transition. METHODS: We performed a retrospective chart review of patients diagnosed with DSD conditions from 1995 to 2016 using ICD9 codes. For the purpose of this study, review was limited to individuals assessed to have neonatal "ambiguous genitalia" or "indeterminate sex." RESULTS: Review identified 128 patients evaluated for ambiguous genitalia from 22 years of experience (Figure). Approximately half of these (53%) had 46,XY karyotype, 35% had 46,XX, and the remaining 12% had sex chromosome aberrations. Diagnostic rate for 46,XX DSD was higher at 64%, all of which were congenital adrenal hyperplasia, while diagnostic rate for 46,XY DSD was 11.7% for a molecularly confirmed diagnosis and 24% if clinical diagnoses were included. The most common anomalies included cardiac anomalies in 28/128 (22%), skeletal anomalies in 19/128 (15%), and failure to thrive or growth problems in 19/128 (15%). Additional congenital anomalies were found in 53 out of 128 patients (41%). There were three reported neoplasms in this group: gonadoblastoma, hepatoblastoma, and myelodysplastic syndrome with monosomy 7. Gender assignment was consistent with chromosomes in approximately 90% of XX and XY patients. There were three recorded gender reassignments or transitions. DISCUSSION: Diagnostic rate for ambiguous genitalia is low, especially in 46,XY DSD. Most neonates were assigned gender consistent with their chromosomes. Given the high rate of associated anomalies, screening for cardiac or other anomalies in patients with ambiguous genitalia may be beneficial. CONCLUSION: Patients with ambiguous genitalia often have additional congenital anomalies. Establishment of a specific diagnosis is uncommon in 46,XY patients. A few patients have gender reassignment outside of the newborn period. Ongoing collection of clinical data on this population may reveal new information regarding long-term health, quality of life, and establishment of more diagnoses with improved molecular techniques.

Dimorphic expression of sex-related genes in different gonadal development stages of sterlet, Acipenser ruthenus, a primitive fish species.

Molecular mechanism of sex determination and differentiation of sturgeon, a primitive fish species, is extraordinarily important due to the valuable caviar; however, it is still poorly known. The present work aimed to identify the major genes involved in regulating gonadal development of sterlet, a small species of sturgeon, from 13 candidate genes which have been shown to relate to gonadal differentiation and development in other teleost fish. The sex and gonadal development of sterlets were determined by histological observation and levels of sex steroids testosterone (T), 11-ketotestosterone (11-KT), and 17ß-estradiol (E2) in serum. Sexually dimorphic gene expressions were investigated. The results revealed that gonadal development were asynchronous in 2-year-old male and female sterlets with the testes in early or mid-spermatogenesis and the ovaries in chromatin nucleolus stage or perinucleolus stage, respectively. The levels of T and E2 were not significantly different between sexes or different gonadal development stages while 11-KT had the higher level in mid-spermatogenesis testis stage. In all the investigated gonadal development stages, gene dmrt1 and hsd11b2 were expressed higher in male whereas foxl2 and cyp19a1 were expressed higher in female. Thus, these genes provided the promising markers for sex identification of sterlet. It was unexpected that dkk1 and dax1 had significantly higher expression in ovarian perinucleolus stage than in ovarian chromatin nucleolus stage and in the testis, suggesting that these two genes had more correlation with ovarian development than with the testis, contrary to the previous reports in other vertebrates. Testicular development-related genes (gsdf and amh) and estrogen receptor genes (era and erb) differentially expressed at different testis or ovary development stages, but their expressions were not absolutely significantly different in male and female, depending on the gonadal development stage. Expression of androgen receptor gene ar or rspo, which was supposed to be related to ovarian development, presented no difference between gonadal development stages investigated in this study whenever in male or female.

Establishment of estrogen receptor 1 (ESR1)-knockout medaka: ESR1 is dispensable for sexual development and reproduction in medaka, Oryzias latipes.

Estrogens play fundamental roles in regulating reproductive activities and they act through estrogen receptor (ESR) in all vertebrates. Most vertebrates have two ESR subtypes (ESR1 and ESR2), whereas teleost fish have at least three (Esr1, Esr2a and Esr2b). Intricate functionalization has been suggested among the Esr subtypes, but to date, distinct roles of Esr have been characterized in only a limited number of species. Study of loss-of-function in animal models is a powerful tool for application to understanding vertebrate reproductive biology. In the current study, we established esr1 knockout (KO) medaka using a TALEN approach and examined the effects of Esr1 ablation. Unexpectedly, esr1 KO medaka did not show any significant defects in their gonadal development or in their sexual characteristics. Neither male or female esr1 KO medaka exhibited any significant changes in sexual differentiation or reproductive activity compared with wild type controls. Interestingly, however, estrogen-induced vitellogenin gene expression, an estrogen-responsive biomarker in fish, was limited in the liver of esr1 KO males. Our findings, in contrast to mammals, indicate that Esr1 is dispensable for normal development and reproduction in medaka. We thus provide an evidence for estrogen receptor functionalization between mammals and fish. Our findings will also benefit interpretation of studies into the toxicological effects of estrogenic chemicals in fish.

Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis.

BACKGROUND: Complete androgen insensitivity syndrome (CAIS) is an X-linked recessive disorder of sex development (DSD) where affected individuals are phenotypically female, but have an XY karyotype and testes. The risk of gonadal tumour development in CAIS may increase with age; incidence rates have been reported to be 0.8-22% in patients who have retained their gonads into adulthood. Consequently, gonadectomy has been recommended either during childhood or after puberty is complete, although there is no consensus on the optimal timing for this procedure. OBJECTIVE AND HYPOTHESES: To establish the frequency of histological abnormalities in CAIS in relation to the age at gonadectomy. METHOD: Data were collected from the Cambridge DSD database on patients with CAIS (n = 225; age range 3-88 years) who had undergone gonadectomy, and their age of gonadectomy, gonadal histology and immunohistochemistry. RESULTS: Evaluable data were obtained from 133 patients. Median age at gonadectomy was 14.0 years (range: 18 days-68 years). Pubertal status was: prepuberty, n = 62; postpuberty, n = 68. Thirteen cases were aged >20 years at gonadectomy. The pattern of histology is summarised in the Summary table. DISCUSSION: In this large case series of CAIS patients who had undergone gonadectomy, while the combined malignant and premalignant gonadal histology prevalence was 6.0%, the findings confirm the low occurrence of gonadal malignancy in CAIS, with a frequency of 1.5%. The two cases of malignancy were postpubertal. Germ cell neoplasia in situ (GCNIS) was observed in six cases, of which one occurred prepuberty and five postpuberty. The study highlighted difficulties in diagnosis of GCNIS and the need for histological analysis in expert centres. CONCLUSION: The results support the current recommendation that gonads in CAIS can be retained until early adulthood. The small number of individuals with gonadectomy after age 20 years do not allow firm conclusion regarding later adulthood. Therefore, it is recommended that the option of gonadectomy be discussed in adulthood. Some form of regular surveillance of the gonads is then recommended, although none of the available options are ideal.

Adult body size, sexual history and adolescent sexual development, may predict risk of developing prostate cancer: Results from the New South Wales Lifestyle and Evaluation of Risk Study (CLEAR).

Prostate cancer (PC) is the most common non-cutaneous cancer in men worldwide. The relationships between PC and possible risk factors for PC cases (n = 1,181) and male controls (n = 875) from the New South Wales (NSW) Cancer, Lifestyle and Evaluation of Risk Study (CLEAR) were examined in this study. The associations between PC risk and paternal history of PC, body mass index (BMI), medical conditions, sexual behaviour, balding pattern and puberty, after adjusting for age, income, region of birth, place of residence, and PSA testing, were examined. Adjusted risk of PC was higher for men with a paternal history of PC (OR = 2.31; 95%CI: 1.70-3.14), personal history of prostatitis (OR = 2.30; 95%CI: 1.44-3.70), benign prostatic hyperplasia (OR = 2.29; 95%CI: 1.79-2.93), being overweight (vs. normal; OR = 1.24; 95%CI: 0.99-1.55) or obese (vs. normal; OR = 1.44; 95%CI: 1.09-1.89), having reported more than seven sexual partners in a lifetime (vs. < 3 partners; OR = 2.00; 95%CI: 1.49-2.68), and having reported more than 5 orgasms a month prior to PC diagnosis (vs. ≤3 orgasms; OR = 1.59; 95%CI: 1.18-2.15). PC risk was lower for men whose timing of puberty was later than their peers (vs. same as peers; OR = 0.75; 95%CI: 0.59-0.97), and a smaller risk reduction of was observed in men whose timing of puberty was earlier than their peers (vs. same as peers; OR = 0.85; 95%CI: 0.61-1.17). No associations were found between PC risk and vertex balding, erectile function, acne, circumcision, vasectomy, asthma or diabetes. These results support a role for adult body size, sexual activity, and adolescent sexual development in PC development.

Desenvolvimento sexual e maturação puberal / Sexual and puberal development

Os fenômenos do desenvolvimento sexual e puberal são eventos progressivos e coordenados. Dependem de fatores cromossômicos - gênicos, gonadais e hormonais. Tais eventos nos indivíduos do sexo masculino e feminino, sendo sincrônicos, permitirão um conveniente desenvolvimento sexual e puberal. Analisar tais fenômenos é o propósito deste estudo.(AU)

The sexual and puberal modifications are coordinate and progressive during differents life phases. Many factors are involved like genic-chromosomic, gonadal and hormonal. Those events that occurred in males and females are synchronous and to create a perfect development. Our proposal is review those situations.(AU)

Desarrollo psicosocial del adolescente / Adolescent psychosocial development

Resulta cada vez más necesario que los pediatras tengan mayores conocimientos de salud del adolescente. Para empezar, deben familiarizarse con el desarrollo psicosocial propio de este período, asunto indispensable para la atención del grupo etario. En este artículo se revisa el desarrollo psicosocial normal del adolescente con ese objetivo. La adolescencia es una etapa que se ha ido prolongando progresivamente, en la que ocurren cambios rápidos y de gran magnitud, que llevan a la persona a hacerse tanto biológica, como psicológica y socialmente madura, y potencialmente capaz de vivir en forma independiente. Son tareas del desarrollo de este período, la búsqueda y consolidación de la identidad y el logro de la autonomía. Si bien constituye un proceso de alta variabilidad individual en cuanto a su comienzo y término, a la progresión a través de sus etapas, a la sincronía del desarrollo entre los diversos ámbitos y en otros aspectos, el desarrollo psicosocial de este período tiende a presentar características comunes y un patrón progresivo de 3 fases: adolescencia temprana, media y tardía. En este artículo se describe el desarrollo psicológico, cognitivo, social, sexual y moral de los jóvenes en cada una de ellas.

It is increasingly necessary that pediatricians have greater knowledge of adolescent health. To begin with they should be familiar with the psychosocial development of this period, an issue which is imperative for the health care of the age group. With that purpose, this article reviews the normal adolescent psychosocial development. Adolescence is a stage that has been progressively prolonged, during which fast and big changes occur, that lead human beings to become biologically, psychologically and socially mature, and potentially able to live independently. Developmental tasks of this period are the establishment of identity and the achievement of autonomy. Although it is a process of high individual variability in terms of its beginning and end, the progression through stages, the synchrony of development between the various areas, and in other aspects, the psychosocial development of this period usually have common characteristics and a progressive pattern of 3 phases: early, middle and late adolescence. Psychological, cognitive, social, sexual and moral development of young people in each of them are described in this article.

Reproductive and sexual behaviour development of dam or artificially reared male lambs.

The objective of this study was to determine if artificially reared male lambs differ from those reared by their mothers in their reproductive development and sexual behaviour during the first breeding season and in their serum testosterone to a GnRH challenge at the end of the first breeding season. Lambs were assigned to two experimental groups: 1) artificially reared lambs, separated from their dams 24-36h after birth (Week 0) and fed sheep milk until 10weeks of age (group AR, n=14); and 2) lambs reared by their dams until 10weeks of age (group DR, n=13). Reproductive parameters and sexual behaviour were recorded from Weeks 9 to 39. The GnRH challenge was performed on Week 40. Body weight, scrotal circumference, gonado-somatic index, testosterone concentration and sperm parameters were unaffected by group, but increased with age (P<0.0001). Lambs reared by their mothers had greater values of gonado-somatic index on Weeks 9, 16 and 19 (P<0.05), and tended to reach puberty earlier than AR (22.9±0.7 vs. 25.1±1.1weeks, respectively, P=0.087). Lambs reared by their mothers presented more lateral approaches and mount attempts than AR (P<0.05), and DR lambs presented more mounts on Weeks 32 and 39 than AR (P<0.05). Blood testosterone concentrations 3.5 and 4h after the GnRH challenge were higher in AR than in DR lambs (P<0.05). In conclusion mother rearing promoted sexual behaviour and reproductive performance of male lambs.