Arterial Stiffness in Transgender Men Receiving Long-term Testosterone Therapy.

Context: The effects of androgen therapy on arterial function in transgender men (TM) are not fully understood, particularly concerning long-term androgen treatment. Objective: To evaluate arterial stiffness in TM receiving long-term gender-affirming hormone therapy by carotid-femoral pulse wave velocity (cf-PWV). Methods: A cross-sectional case-control study at the Gender Dysphoria Unit of the Division of Endocrinology, HC-FMUSP, Sao Paulo, Brazil. Thirty-three TM receiving intramuscular testosterone esters as regular treatment for an average time of 14 ± 8 years were compared with 111 healthy cisgender men and women controls matched for age and body mass index. Aortic stiffness was evaluated by cf-PWV measurements using Complior device post-testosterone therapy. The main outcome measure was aortic stiffness by cf-PWV as a cardiovascular risk marker in TM and control group. Results: The cf-PWV after long-term testosterone therapy was significantly higher in TM (7.4 ± 0.9 m/s; range 5.8-8.9 m/s) than in cisgender men (6.6 ± 1.0 m/s; range 3.8-9.0 m/s, P < .01) and cisgender women controls (6.9 ± .9 m/s; range 4.8-9.1 m/s, P = .02). The cf-PWV was significantly and positively correlated with age. Analysis using blood pressure as a covariate showed a significant relationship between TM systolic blood pressure (SBP) and cf-PWV in relation to cisgender women but not to cisgender men. Age, SBP, and diagnosis of hypertension were independently associated with cf-PWV in the TM group. Conclusion: The TM group on long-term treatment with testosterone had higher aging-related aortic stiffening than the control groups. These findings indicate that aortic stiffness might be accelerated in the TM group receiving gender-affirming hormone treatment, and suggest a potential deleterious effect of testosterone on arterial function. Preventive measures in TM individuals receiving testosterone treatment, who are at higher risk for cardiovascular events, are highly recommended.

Sexuality and fertility desire in a large cohort of individuals with 46, XY differences in sex development.

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.

Single and mixed exposure to distinct groups of pesticides suggests endocrine disrupting properties of imidacloprid in zebrafish embryos.

Due to their selective toxicity to insects, nicotinoid compounds have been widely used to control pests in crops and livestock around the world. However, despite the advantages presented, much has been discussed about their harmful effects on exposed organisms, either directly or indirectly, with regards to endocrine disruption. This study aimed to evaluate the lethal and sublethal effects of imidacloprid (IMD) and abamectin (ABA) formulations, separately and combined, on zebrafish (Danio rerio) embryos at different developmental stages. For this, Fish Embryo Toxicity (FET) tests were carried out, exposing two hours post-fertilization (hpf) zebrafish to 96 hours of treatments with five different concentrations of abamectin (0.5-11.7 mg L-1), imidacloprid (0.0001-1.0 mg L-1), and imidacloprid/abamectin mixtures (LC50/2 - LC50/1000). The results showed that IMD and ABA caused toxic effects in zebrafish embryos. Significant effects were observed regarding egg coagulation, pericardial edema, and lack of larvae hatching. However, unlike ABA, the IMD dose-response curve for mortality had a bell curve display, where medium doses caused more mortality than higher and lower doses. These data demonstrate the toxic influence of sublethal IMD and ABA concentrations on zebrafish, suggesting that these compounds should be listed for river and reservoir water-quality monitoring.

SIN3A Defects Associated with Syndromic Congenital Hypogonadotropic Hypogonadism: An Overlap with Witteveen-Kolk Syndrome.

INTRODUCTION: Congenital hypogonadotropic hypogonadism (CHH) is a rare condition caused by GnRH deficiency. More than 40 genes have been associated with the pathogenesis of CHH, but most cases still remain without a molecular diagnosis. Mutations involving the same gene (e.g., FGFR1, PROK2/PROKR2, CHD7) were found to cause normosmic CHH and Kallmann syndrome (KS), with and without associated phenotypes, illustrating the coexistence of CHH with signs of other complex syndromes. The Witteveen-Kolk syndrome (WITKOS), caused by defects of the SIN3A gene, is a heterogeneous disorder characterized by distinctive facial features, microcephaly, short stature, delayed cognitive, and motor development. Although micropenis and cryptorchidism have been reported in this syndrome, WITKOS has not been formally associated with CHH so far. PATIENTS AND METHODS: A man with KS associated with mild syndromic features (S1) and a boy with global developmental delay, syndromic short stature, micropenis and cryptorchidism (S2), in whom common genetic defects associated with CHH and short stature had been previously excluded, were studied by either chromosomal microarray analysis or whole exome sequencing. RESULTS: Rare SIN3A pathogenic variants were identified in these 2 unrelated patients with CHH phenotypic features. A 550 kb deletion at 15q24.1, including the whole SIN3A gene, was identified in S1, and a SIN3A nonsense rare variant (p.Arg471*) was detected in S2. CONCLUSION: These findings lead us to propose a link between SIN3A defects and CHH, especially in syndromic cases, based on these 2 patients with overlapping phenotypes of WITKOS and CHH.

Sexuality and fertility desire in a large cohort of individuals with 46, XY differences in sex development

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.

Elevated plasma miR-210 expression is associated with atypical genitalia in patients with 46,XY differences in sex development.

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.

Cardiopulmonary capacity and muscle strength in transgender women on long-term gender-affirming hormone therapy: a cross-sectional study.

OBJECTIVE: For transgender women (TW) on oestrogen therapy, the effects of prior exposure to testosterone during puberty on their performance, mainly cardiopulmonary capacity (CPC), while exerting physical effort are unknown. Our objective was to evaluate CPC and muscle strength in TW undergoing long-term gender-affirming hormone therapy. METHODS: A cross-sectional study was carried out with 15 TW (34.2±5.2 years old), 13 cisgender men (CM) and 14 cisgender women (CW). The TW received hormone therapy for 14.4±3.5 years. Bioimpedance, the hand grip test and cardiopulmonary exercise testing on a treadmill with an incremental effort were performed. RESULTS: The mean VO2peak (L/min) was 2606±416.9 in TW, 2167±408.8 in CW and 3358±436.3 in CM (TW vs CW, p<0.05; TW vs CM, p<0.0001; CW vs CM, p<0.0001). The O2 pulse in TW was between that in CW and CM (TW vs CW, p<0.05, TW vs CM, p<0.0001). There was a high correlation between VO2peak and fat-free mass/height2 among TW (r=0.7388; p<0.01), which was not observed in the other groups. The mean strength (kg) was 35.3±5.4 in TW, 29.7±3.6 in CW and 48.4±6.7 in CM (TW vs CW, p<0.05; TW vs CM, p<0.0001). CONCLUSION: CPC in non-athlete TW showed an intermediate pattern between that in CW and CM. The mean strength and VO2 peak in non-athlete TW while performing physical exertion were higher than those in non-athlete CW and lower than those in CM.

Contribution of Clinical and Genetic Approaches for Diagnosing 209 Index Cases With 46,XY Differences of Sex Development.

CONTEXT: Massively parallel sequencing (MPS) technologies have emerged as a first-tier approach for diagnosing several pediatric genetic syndromes. However, MPS has not been systematically integrated into the diagnostic workflow along with clinical/biochemical data for diagnosing 46,XY differences of sex development (DSD). OBJECTIVE: To analyze the contribution of phenotypic classification either alone or in association with genetic evaluations, mainly MPS, for diagnosing a large cohort of 46,XY DSD patients. DESIGN/PATIENTS: 209 nonsyndromic 46,XY DSD index cases from a Brazilian DSD center were included. Patients were initially classified into 3 subgroups according to clinical and biochemical data: gonadal dysgenesis (GD), disorders of androgen secretion/action, and DSD of unknown etiology. Molecular genetic studies were performed by Sanger sequencing and/or MPS. RESULTS: Clinical/biochemical classification into either GD or disorders of hormone secretion/action was obtained in 68.4% of the index cases. Among these, a molecular diagnosis was obtained in 36% and 96.5%, respectively. For the remainder 31.6% classified as DSD of clinically unknown etiology, a molecular diagnosis was achieved in 31.8%. Overall, the molecular diagnosis was achieved in 59.3% of the cohort. The combination of clinical/biochemical and molecular approaches diagnosed 78.9% of the patients. Clinical/biochemical classification matched with the genetic diagnosis in all except 1 case. DHX37 and NR5A1 variants were the most frequent genetic causes among patients with GD and DSD of clinical unknown etiology, respectively. CONCLUSIONS: The combination of clinical/biochemical with genetic approaches significantly improved the diagnosis of 46,XY DSD. MPS potentially decreases the complexity of the diagnostic workup as a first-line approach for diagnosing 46,XY DSD.

A Small Supernumerary Xp Marker Chromosome Including Genes NR0B1 and MAGEB Causing Partial Gonadal Dysgenesis and Gonadoblastoma.

Copy number variations of several genes involved in the process of gonadal determination have been identified as a cause of 46,XY differences of sex development. We report a non-syndromic 14-year-old female patient who was referred with primary amenorrhea, absence of breast development, and atypical genitalia. Her karyotype was 47,XY,+mar/46,XY, and FISH analysis revealed the X chromosome origin of the marker chromosome. Array-CGH data identified a pathogenic 2.0-Mb gain of an Xp21.2 segment containing NR0B1/DAX1 and a 1.9-Mb variant of unknown significance from the Xp11.21p11.1 region. This is the first report of a chromosomal microarray analysis to reveal the genetic content of a small supernumerary marker chromosome detected in a 47,XY,+der(X)/46,XY karyotype in a non-syndromic girl with partial gonadal dysgenesis and gonadoblastoma. Our findings indicate that the mosaic presence of the small supernumerary Xp marker, encompassing the NR0B1/DAX1 gene, may have been the main cause of dysgenetic testes development, although the role of MAGEB and other genes mapped to the Xp21 segment could not be completely ruled out.

Genetic Evidence of the Association of DEAH-Box Helicase 37 Defects With 46,XY Gonadal Dysgenesis Spectrum.

CONTEXT: 46,XY Gonadal dysgenesis (GD) is a heterogeneous group of disorders with a wide phenotypic spectrum, including embryonic testicular regression syndrome (ETRS). OBJECTIVE: To report a gene for 46,XY GD etiology, especially for ETRS. DESIGN: Screening of familial cases of 46,XY GD using whole-exome sequencing and sporadic cases by target gene-panel sequencing. SETTING: Tertiary Referral Center for differences/disorders of sex development (DSD). PATIENTS AND INTERVENTIONS: We selected 87 patients with 46,XY DSD (17 familial cases from 8 unrelated families and 70 sporadic cases); 55 patients had GD (among them, 10 patients from 5 families and 8 sporadic cases had ETRS), and 32 patients had 46,XY DSD of unknown etiology. RESULTS: We identified four heterozygous missense rare variants, classified as pathogenic or likely pathogenic in the Asp-Glu-Ala-His-box (DHX) helicase 37 (DHX37) gene in five families (n = 11 patients) and in six sporadic cases. Two variants were recurrent: p.Arg308Gln (in two families and in three sporadic cases) and p.Arg674Trp (in two families and in two sporadic cases). The variants were specifically associated with ETRS (7/14 index cases; 50%). The frequency of rare, predicted-to-be-deleterious DHX37 variants in this cohort (14%) is significantly higher than that observed in the Genome Aggregation Database (0.4%; P < 0.001). Immunohistochemistry analysis in human testis showed that DHX37 is mainly expressed in germ cells at different stages of testis maturation, in Leydig cells, and rarely in Sertoli cells. CONCLUSION: This strong genetic evidence identifies DHX37 as a player in the complex cascade of male gonadal differentiation and maintenance.

New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism.

CONTEXT: Congenital hypogonadotropic hypogonadism (CHH) is a rare condition caused by GnRH deficiency. Several genes have been associated with the pathogenesis of CHH, but most cases still remain without a molecular diagnosis. The advent of next-generation sequencing (NGS) has allowed the simultaneous genotyping of several regions, faster, making possible the extension of the genetic knowledge of CHH. OBJECTIVE: Genetic characterization of a large cohort of Brazilian CHH patients. DESIGN AND PATIENTS: A cohort of 130 unrelated patients (91 males, 39 females) with CHH (75 normosmic CHH, 55 Kallmann syndrome) was studied using a panel containing 36 CHH-associated genes. RESULTS: Potential pathogenic or probably pathogenic variants were identified in 43 (33%) CHH patients. The genes ANOS1, FGFR1 and GNRHR were the most frequently affected. A novel homozygous splice site mutation was identified in the GNRH1 gene and a deletion of the entire coding sequence was identified in SOX10. Deleterious variants in the IGSF10 gene were identified in two patients with reversible normosmic CHH. Notably, 6.9% of the patients had rare variants in more than one gene. Rare variants were also identified in SPRY4, IL17RD, FGF17, IGSF1 and FLRT3 genes. CONCLUSIONS: This is a large study of the molecular genetics of CHH providing new genetic findings for this complex and heterogeneous genetic condition. NGS has been shown to be a fast, reliable and effective tool in the molecular diagnosis of congenital CHH and being able to targeting clinical genetic testing in the future.

Effects of clomiphene citrate on male obesity-associated hypogonadism: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Obesity causes secondary hypogonadism (HG) in men. Standard testosterone (T) replacement therapy improves metabolic parameters but leads to infertility. OBJECTIVE: To evaluate clomiphene citrate (CC) treatment of adult men with male obesity-associated secondary hypogonadism (MOSH). DESIGN: Single-center, randomized, double-blind, placebo-controlled trial. PARTICIPANTS: Seventy-eight men aged 36.5 ± 7.8 years with a body mass index (BMI) > 30 kg/m2, total testosterone (TT) ≤ 300 ng/dL, and symptoms in the ADAM questionnaire. INTERVENTION: Random allocation to receive 50 mg CC or placebo (PLB) for 12 weeks. OUTCOMES: (1) Clinical features: ADAM and sexual behavior questionnaires; (2) hormonal profile: serum TT, free T, estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex hormone-binding globulin (SHBG); (3) body composition: BMI, waist circumference, and bioelectric impedance analysis; (4) metabolic profile: blood pressure, fasting blood glucose, HbA1c, insulin, HOMA-IR, and lipid profile; (5) endothelial function: flow-mediated dilation of the brachial artery, quantitative assessment of endothelial progenitor cells and serum sICAM-1, sVCAM-1, and selectin-sE levels; (6) safety aspects: hematocrit, serum prostate-specific antigen, International Prostate Symptom Score, and self-reported adverse effects. RESULTS: There was an improvement in one sexual complaint (weaker erections; P < 0.001); increases (P < 0.001) in TT, free T, E2, LH, FSH, and SHBG; and improvements in lean mass (P < 0.001), fat-free mass (P = 0.004), and muscle mass (P < 0.001) in the CC group. CC reduced HDL (P < 0.001). No statistically significant differences were seen in endothelial function. CONCLUSIONS: CC appeared to effectively improve the hormonal profile and body composition. CC may be an alternative treatment for MOSH in adult men.

Low estrogen doses normalize testosterone and estradiol levels to the female range in transgender women.

OBJECTIVE: The ideal dosage of cross-sex hormones remains unknown. The aim of this study was to evaluate the luteinizing hormone, follicle-stimulating hormone, testosterone, estradiol and prolactin levels after low-dose estrogen therapy with or without cyproterone acetate in transgender women. METHODS: The serum hormone and biochemical profiles of 51 transgender women were evaluated before gonadectomy. Hormone therapy consisted of conjugated equine estrogen alone or combined with cyproterone acetate. The daily dose of conjugated equine estrogen was 0.625 mg in 41 subjects and 1.25 mg in 10 subjects, and the daily dose of cyproterone acetate was 50 mg in 42 subjects and 100 mg in one subject. RESULTS: Estrogen-only therapy reduced the testosterone, luteinizing hormone and follicle-stimulating hormone levels from 731.5 to 18 ng/dL, 6.3 to 1.1 U/L and 9.6 to 1.5 U/L, respectively. Estrogen plus cyproterone acetate reduced the testosterone, luteinizing hormone and follicle-stimulating hormone levels from 750 to 21 ng/dL, 6.8 to 0.6 U/L and 10 to 1.0 U/L, respectively. The serum levels of luteinizing hormone, follicle-stimulating hormone, testosterone, estradiol and prolactin in the patients treated with estrogen alone and estrogen plus cyproterone acetate were not significantly different. The group receiving estrogen plus cyproterone acetate had significantly higher levels of gamma-glutamyltransferase than the group receiving estrogen alone. No significant differences in the other biochemical parameters were evident between the patients receiving estrogen alone and estrogen plus cyproterone acetate. CONCLUSION: In our sample of transgender women, lower estrogen doses than those usually prescribed for these subjects were able to adjust the testosterone and estradiol levels to the physiological female range, thus avoiding high estrogen doses and their multiple associated side effects.

Low estrogen doses normalize testosterone and estradiol levels to the female range in transgender women

OBJECTIVE: The ideal dosage of cross-sex hormones remains unknown. The aim of this study was to evaluate the luteinizing hormone, follicle-stimulating hormone, testosterone, estradiol and prolactin levels after low-dose estrogen therapy with or without cyproterone acetate in transgender women. METHODS: The serum hormone and biochemical profiles of 51 transgender women were evaluated before gonadectomy. Hormone therapy consisted of conjugated equine estrogen alone or combined with cyproterone acetate. The daily dose of conjugated equine estrogen was 0.625 mg in 41 subjects and 1.25 mg in 10 subjects, and the daily dose of cyproterone acetate was 50 mg in 42 subjects and 100 mg in one subject. RESULTS: Estrogen-only therapy reduced the testosterone, luteinizing hormone and follicle-stimulating hormone levels from 731.5 to 18 ng/dL, 6.3 to 1.1 U/L and 9.6 to 1.5 U/L, respectively. Estrogen plus cyproterone acetate reduced the testosterone, luteinizing hormone and follicle-stimulating hormone levels from 750 to 21 ng/dL, 6.8 to 0.6 U/L and 10 to 1.0 U/L, respectively. The serum levels of luteinizing hormone, follicle-stimulating hormone, testosterone, estradiol and prolactin in the patients treated with estrogen alone and estrogen plus cyproterone acetate were not significantly different. The group receiving estrogen plus cyproterone acetate had significantly higher levels of gamma-glutamyltransferase than the group receiving estrogen alone. No significant differences in the other biochemical parameters were evident between the patients receiving estrogen alone and estrogen plus cyproterone acetate. CONCLUSION: In our sample of transgender women, lower estrogen doses than those usually prescribed for these subjects were able to adjust the testosterone and estradiol levels to the physiological female range, thus avoiding high estrogen doses and their multiple associated side effects.

A recurrent synonymous mutation in the human androgen receptor gene causing complete androgen insensitivity syndrome.

Androgen insensitivity syndrome (AIS) is the most common cause of 46,XY disorders of sex development (46,XY DSD). This syndrome is an X-linked inheritance disease and it is caused by mutations in the human androgen receptor (AR) gene. Non-synonymous point AR mutations are frequently described in this disease, including in the complete phenotype. We present a novel synonymous mutation in the human AR gene (c.1530C > T) in four 46,XY patients from two unrelated families associated with complete androgen insensitivity syndrome (CAIS). The analysis of mRNA from testis showed that synonymous AR mutation changed the natural exon 1 donor splice site, with deletion of the last 92 nucleotides of the AR exon 1 leading to a premature stop codon 12 positions ahead resulting in a truncate AR protein. Linkage analyses suggested a probable founder effect for this mutation. In conclusion, we described the first synonymous AR mutation associated with CAIS phenotype, reinforcing the disease-causing role of synonymous mutations.

Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals.

Steroidogenic factor 1 (NR5A1, SF-1, Ad4BP) is a transcriptional regulator of genes involved in adrenal and gonadal development and function. Mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. In 46,XY individuals, NR5A1-related phenotypes may range from disorders of sex development (DSD) to oligo/azoospermia, and in 46,XX individuals, from 46,XX ovotesticular and testicular DSD to primary ovarian insufficiency (POI). The most common 46,XY phenotype is atypical or female external genitalia with clitoromegaly, palpable gonads, and absence of Müllerian derivatives. Notably, an undervirilized external genitalia is frequently seen at birth, while spontaneous virilization may occur later, at puberty. In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI, manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels. Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1 mutations may develop POI, and therefore require appropriate counseling. Moreover, the recurrent heterozygous p.Arg92Trp NR5A1 mutation is associated with variable degrees of testis development in 46,XX patients. A clear genotype-phenotype correlation is not seen in patients bearing NR5A1 mutations, suggesting that genetic modifiers, such as pathogenic variants in other testis/ovarian-determining genes, may contribute to the phenotypic expression. Here, we review the published literature on NR5A1-related disease, and discuss our findings at a single tertiary center in Brazil, including ten novel NR5A1 mutations identified in 46,XY DSD patients. The ever-expanding phenotypic range associated with NR5A1 variants in XY and XX individuals confirms its pivotal role in reproductive biology, and should alert clinicians to the possibility of NR5A1 defects in a variety of phenotypes presenting with gonadal dysfunction. Birth Defects Research (Part C) 108:309-320, 2016. © 2016 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc.

Effects of endocrine disruptors in the development of the female reproductive tract.

Environmental agencies have identified a growing number of environmental contaminants that have endocrine disrupting activity, and these can become a major public health problem. It is suggested that endocrine disruptors could account for the higher-than-expected increase in the prevalence of some non-communicable diseases, such as obesity, diabetes, thyroid diseases, and some cancers. Several endocrine Disrupting Chemicals (EDCs), such as pesticides, bisphenol A, phthalates, dioxins, and phytoestrogens, can interact with the female reproductive system and lead to endocrine disruption. Initially, it was assumed that EDCs exert their effects by binding to hormone receptors and transcription factors, but it is currently known that they may also alter the expression of enzymes involved in the synthesis or catabolism of steroids. Biomonitoring studies have identified these compounds in adults, children, pregnant women, and fetuses. Among the diseases of the female reproductive tract associated with EDCs exposure are the following: precocious puberty, polycystic ovary syndrome, and premature ovarian failure. The different populations of the world are exposed to a great number of chemicals through different routes of infection; despite the various available studies, there is still much doubt regarding the additive effect of a mixture of EDCs with similar mechanisms of action.

Clinical management of transsexual subjects.

Transsexual subjects are individuals who have a desire to live and be accepted as a member of the opposite sex, usually accompanied by a sense of discomfort with, or inappropriateness of, one's anatomic sex, and a wish to have surgery and hormonal treatment to make one's body as congruent as possible with one's preferred sex. They seek to develop the physical characteristics of the desired gender, and should undergo an effective and safe treatment regimen. The goal of treatment is to rehabilitate the individual as a member of society in the gender he or she identifies with. Sex reassignment procedures necessary for the treatment of transsexual patients are allowed in our country, at Medical Services that have a multidisciplinary team composed of a psychologist, a social worker, a psychiatrist, an endocrinologist and surgeons (gynecologists, plastic surgeons, and urologists). Patients must be between 21 to 75 years old and in psychological and hormonal treatment for at least 2 years. Testosterone is the principal agent used to induce male characteristics in female transsexual patients, and the estrogen is the chosen hormone used to induce the female sexual characteristics in male transsexual patients. Based on our 15 years of experience, we can conclude that testosterone and estradiol treatment in physiological doses are effective and safe in female and male transsexual patients, respectively.

Long-term followup of a large cohort of patients with ovotesticular disorder of sex development.

PURPOSE: We present the followup of a large cohort of patients with ovotesticular disorder of sex development treated at a single tertiary center. MATERIALS AND METHODS: We reviewed the records of 20 patients with ovotesticular disorder of sex development. We retrospectively evaluated clinical and surgical characteristics. A prospective study was also performed, including evaluation of surgical results, gonadal function, sexual activity and voiding symptoms of these patients during adulthood. RESULTS: All patients had ambiguous genitalia, including 18 with a 46,XX karyotype and 2 with a 46,XX/46,XY karyotype. Gender assignment at birth was male in 13 patients and female in 7. Three females were later reassigned to the male gender. Bilateral gonadectomy was performed in 10 patients. Testicular tissue was preserved in 8 males and ovarian tissue was preserved in 2 females. Average followup was 25 years (range 4 to 46). Puberty started spontaneously in 14 patients between ages 11 and 14 years. Seven patients showed spontaneous puberty after conservative gonadal surgery and 4 required hormonal replacement during adulthood. The most frequent complications in males were urethral fistula in 6 and late urethral stenosis in 3. Two patients with urethral stenosis had symptoms 10 years postoperatively. One female presented with temporary dyspareunia. In adulthood 8 males and 2 females reported sexual activity. All male patients reported orgasm and 2 reported ejaculation. CONCLUSIONS: Male gender assignment was more prevalent. Long-term followup revealed adequate pubertal development and sexual activity. Complications involving the urethra developed frequently in male patients.

Clinical management of transsexual subjects / Manejo clínico de sujeitos transexuais

Transsexual subjects are individuals who have a desire to live and be accepted as a member of the opposite sex, usually accompanied by a sense of discomfort with, or inappropriateness of, one’s anatomic sex, and a wish to have surgery and hormonal treatment to make one’s body as congruent as possible with one’s preferred sex. They seek to develop the physical characteristics of the desired gender, and should undergo an effective and safe treatment regimen. The goal of treatment is to rehabilitate the individual as a member of society in the gender he or she identifies with. Sex reassignment procedures necessary for the treatment of transsexual patients are allowed in our country, at Medical Services that have a multidisciplinary team composed of a psychologist, a social worker, a psychiatrist, an endocrinologist and surgeons (gynecologists, plastic surgeons, and urologists). Patients must be between 21 to 75 years old and in psychological and hormonal treatment for at least 2 years. Testosterone is the principal agent used to induce male characteristics in female transsexual patients, and the estrogen is the chosen hormone used to induce the female sexual characteristics in male transsexual patients. Based on our 15 years of experience, we can conclude that testosterone and estradiol treatment in physiological doses are effective and safe in female and male transsexual patients, respectively.

Transexualismo masculino refere-se ao indivíduo 46,XY com fenótipo masculino normal que deseja viver e ser aceito como membro do sexo feminino, já o transexualismo feminino refere-se ao indivíduo 46,XX com fenótipo feminino normal que deseja viver e ser aceito como membro do sexo masculino. Há 16 anos os procedimentos médicos clínicos e cirúrgicos necessários para o tratamento de pacientes transexuais estão autorizados e regulamentados no nosso país, desde que os Serviços onde forem realizados tais procedimentos contem com equipe multidisciplinar composta por psicólogo, assistente social, psiquiatra, endocrinologista e cirurgiões (ginecologistas, plásticos e urologistas). Para serem submetidos à cirurgia, os pacientes devem ter de 21 a 75 anos, devem ter realizado hormonioterapia por pelo menos um ano e psicoterapia por pelo menos dois anos. Os indivíduos transexuais buscam desenvolver características físicas pertencentes ao sexo desejado e devem ser submetidos a um regime de tratamento efetivo e seguro com o objetivo de reabilitá-los como membros da sociedade no gênero com o qual eles se identificam. A testosterona é o principal hormônio utilizado para induzir o desenvolvimento dos caracteres sexuais secundários masculinos nos transexuais femininos e o estrógeno é o hormônio utilizado para induzir os caracteres sexuais secundários femininos no transexual masculino. Com base na experiência do nosso serviço, podemos afirmar que doses fisiológicas desses hormônios são capazes de produzir os efeitos desejados sem causar efeitos colaterais importantes.