Context:Understanding long-term outcomes and patient satisfaction with feminizing genitoplasty (FG) in patients with differences of sexual development (DSD) is crucial for optimizing treatment protocols. Objective:To evaluate long-term morphological and functional results and patients' satisfaction in a cohort of DSD patients submitted to FG. Design:Cross-sectional and retrospective cohort study conducted from 1965 to 2016 with follow-up assessments. Setting:Tertiary care center. Patients or Other Participants:Sixty DSD female patients, including 36 with congenital adrenal hyperplasia (CAH) and 24 with non-CAH DSD etiology, who underwent FG. Interventions:FG procedures were performed, and results were analyzed based on age at surgery and surgical techniques used. Main Outcome Measures:Surgical results, genital sensitivity, sexual function, and patient satisfaction. Results:Ninety-one percent of patients had normal clitoral size, and 85% had separated perineal orifices. Three patients with persistent urogenital sinus did not report symptoms. Genital sensitivity to mechanical and vibratory stimuli was similar to control groups. No CAH patients experienced overall sexual dysfunction, while 3 non-CAH patients and 4 control women reported reduced sexual desire and arousal. Eighty-nine percent of patients preferred surgery during childhood, and 97% were satisfied with their surgical outcomes. Conclusion:FG outcomes in this cohort were satisfactory, with no significant impact on genital sensitivity or sexual function. Most patients preferred early surgery and reported high satisfaction with the results. Further studies are needed to confirm these findings in broader populations.

Context17α-hydroxylase/17,20-lyase deficiency (17OHD) is a rare autosomal recessive condition. Women who have the complete form of 17OHD typically have a female phenotype, with an absence of secondary sexual characteristics, primary amenorrhea, and hypertension, which is usually detected in adolescence. Generally, 46,XY patients with a partial form of 17OHD have atypical genitalia and intra-abdominal or inguinal testes. The risk of developing malignant testicular tumors or testicular adrenal rest tumors in 21-hydroxylase deficiency congenital adrenal hyperplasia is reported in 46,XY patients. In contrast, these conditions are rarely described in patients with 17OHD.ObjectiveThis study aims to investigate patients with 17OHD who exhibit testicular tumors and spontaneous pubertal development.Patients and ResultsTwo unrelated women with 46,XY karyotype with 17OHD who presented with unexpected spontaneous development of secondary sexual characteristics and testicular tumors were described. Pathogenic allelic variants in CYP17A1 were identified in the compound heterozygous state in both patients. The variants p.Trp406Arg and p.Pro428Leu were identified in the patient with Leydig cell neoplasia plus germ cell neoplasia in situ, and the p.Arg358Gln and p.Trp406Arg variants were identified in the patient with intratubular seminoma associated with invasive classic seminoma.ConclusionOur findings reinforce the risk of testicular tumor development among 46,XY patients with 17OHD and add data to the discussion of the risk/benefit ratio of prophylactic gonadectomy in the treatment patients with 46, XY differences in sex development (DSD).

Disclosure: J.P. Batatinha: None. M.C. Mesia: None. H.C. Cecotti: None. E.F. Costa: None. S. Domenice: None. Testosterone therapy is vital for the health and well-being of hypogonadal cisgender men and 46,XX individuals with a male gender identity. While it restores eugonadism and improves quality of life, it also carries risks, including erythrocytosis, which can increase cardiovascular and thrombotic risks. Most studies have focused on hypogonadal cisgender men, leaving limited data on the prevalence and risk factors of erythrocytosis in transgender men (TM) and individuals with differences in sex development (DSD) who are undergoing testosterone therapy. Objective- To evaluate the prevalence of erythrocytosis in TM and individuals with 46,XX and 46,XY DSD undergoing testosterone therapy (TTh), and to assess how karyotype, the age at which testosterone therapy is initiated, and prior estrogen exposure during puberty may influence the risk of erythrocytosis. Methods- This cohort study included 124 individuals: 75 with 46,XX karyotypes (64 TM, 6 ovariotesticular DSD, 5 congenital adrenal hyperplasia), 40 with 46,XY karyotypes (DSD and hypogonadism), and 9 DSD with sex chromosomal abnormalities. All received IM testosterone cypionate or undecylenate for an average duration of 15.6 yrs (range of 13.6-17.7). Erythrocytosis was defined as hematocrit (Ht) levels >50% and confirmed through two measurements. Participants were grouped as erythrocytosis (n=66; Ht ≥50%) or non-erythrocytosis (n=68; Ht <50%). Clinical and laboratory data were retrospectively analyzed. Results- Erythrocytosis prevalence was 45.2%. It was more frequent in individuals with 46,XX karyotypes (53.95%) than 46,XY karyotypes (32.5%) (p = 0.028). Erythrocytosis was also associated with spontaneous endogenous female puberty (p = 0.009), particularly TM. The erythrocytosis group had higher mean pre-TTh Ht levels (46.3% vs. 41.7%, p < 0.001) and started testosterone therapy at an older age (28.3 ± 10.8 yrs vs. 24.2 ± 11.1 yrs, p = 0.047), regardless of karyotype. Conclusion- This study reveals a high prevalence of erythrocytosis among Brazilian individuals on testosterone therapy, particularly within the 46,XX population, mainly TM, underscoring a potential role for previous estrogen exposure. Key factors such as baseline hematocrit levels and age at treatment onset, emphasize the need for careful monitoring and awareness of erythrocytosis in this population. Clinicians should take individual patient characteristics into account to optimize management and ensure safe, effective treatment outcomes. Presentation: Sunday, July 13, 2025

Until recent years, Sex Hormone-Binding Globulin (SHBG) has been considered of less a priority in the management of metabolic and chronic inflammatory states. However, emerging research highlights the remarkable role of SHBG in the screening and follow-up of patients not only with metabolic disorders but also in influencing reproductive outcomes. The present review aims to consolidate current knowledge on the involvement of SHBG in various clinical conditions. The search was performed using multiple databases to identify original studies measuring SHBG levels in conditions such as type-2 diabetes, metabolic syndrome (MetS), male obesity secondary hypogonadism, Polycystic Ovarian Syndrome (PCOS), male equivalent of PCOS, Nonalcoholic Fatty Liver Disease (NAFLD), infantile obesity, and early puberty. Among a total of 93,735 studies, 62 met the inclusion criteria, encompassing data from 127,771 subjects comprising both patients and controls. Studies were predominantly cross-sectional and observational cohorts, with MetS and NAFLD being the most extensively investigated conditions. Across all clinical conditions, significantly lower SHBG levels were consistently observed among patients compared to matched controls. The decrease in SHBG was found to be significantly associated with adverse reproductive, metabolic, and cardiovascular outcomes. These findings underscore the importance of considering SHBG as a valuable marker in routine clinical practice. Clinicians are encouraged to recognize the potential of SHBG as a useful marker in the assessment and management of various health conditions within their routine practice.

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.

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.

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.

Abstract Disclosure: R.L. Batista: None. N.L. Gomes: None. T.A. Bachega: None. G. Madureira: None. M.C. Miranda: None. R.T. dallago: None. M.M. Ferrari: None. L.M. Lousada: None. F.L. Craveiro: None. J.P. Batatinha: None. R.D. Scalco: None. E.F. Costa: None. M.P. Sircili: None. F.T. Denes: None. M. Inacio: None. M.Y. Nishi: None. S. Domenice: None. B.B. Mendonca: None. Context: DSD represent a wide range of conditions presenting at different ages to many health professionals with several backgrounds. Establishing a correct diagnosis is essential for appropriate management. Objective: To amplify the understanding of the first clinical presentation, prevalence, and gender change of Brazilian DSD subjects. Design: A retrospective, observational cohort study of all DSD subjects referred to a DSD multi-professional team over 41 years (from 1980 to 2021). Participants: 696 subjects.Outcome Measures: Data included DSD diagnosis, sex assignment, age at diagnosis, gender change, clinical presentation, and phenotypic features. Results: Subjects presented at prepubertal, post-pubertal, and adult age, usually with atypical genitalia, undescended testes, or primary amenorrhea. Amongst the three major DSD categories, sex chromosome DSD was diagnosed in 264 subjects (135 with 45,X karyotype); 101 are mosaics (45,X/46,Xi(Xq) and three chimerism (all ovotesticular DSD). Among the 4 ovotesticular DSD subjects, 3 were raised as females and 1 as male, no gender changes occurred in this group. Thirteen chromosome DSD patients with Y material were assigned as male and two female-assigned patients changed their gender. 258 subjects have 46,XY DSD (69 unknown DSD, 64 gonadal dysgenesis, 36 5-αRD2 deficiency, 18 17β-HSD3 deficiency, 11 17α-hydroxylase deficiency, 9 Leydig cell hypoplasia, 25 CAIS, 18 PAIS, 8 AMH defects). Among the 192 XY subjects with atypical genitalia, the sex of rearing was female in 89 (46%) and gender change from female to male occurred in 13%, most in 5 αRD2 (45%) followed by 17β-HSD3 (33%) deficiency. Among those reared as male, only 2.9% changed their gender. 46,XX DSD was diagnosed in 178 patients. Congenital adrenal hyperplasia-CAH (most 21-hydroxylase deficiency) was diagnosed in 123 (115 female-assigned). Among CAH, gender change from female to male occurred in 6 cases, of which most have VS form (5/6; p=.004), a late beginning of treatment (>2 ys old), and poor compliance. In the remaining 55 with 46,XX DSD, 24 have ovotesticular DSD (all with atypical genitalia), 16 have 46,XX testicular DSD (seven with atypical genitalia). Among the ovotesticular subjects, 14 were reared as male and ten as female, and gender change occurred in 4 cases (3 from female to male). The diagnosis was not established in twelve 46,XX DSD patients (all with atypical genitalia, three with syndromic features). One patient has aromatase deficiency, one POR deficiency, and one glucocorticoid resistance syndrome. Conclusion: gender change from female to male mainly occurred among subjects with 46,XY DSD, particularly in those with 5 αRD2 and 17β-HSD3 deficiency, suggesting that male sex assignment is desirable in patients with these diagnoses. Among 46,XX DSD, the VS form of CAH, a late start of treatment, and poor compliance were implicated in female-to-male gender change. Presentation: Thursday, June 15, 2023

Abstract Introduction: Differences of sexual development (DSD) define congenital diseases in which there is an atypical development of chromosomal, gonadal or anatomical sex, and may present varying degrees to genital atypia. There has been a discussion about the ideal time for surgical approach of atypical genitalia. S, because some non-governmental entities argue that the surgical approach should be delayed until adulthood after the patient’s consent. Objective/methodology: To analyze the perspectives of adult DSD patients followed at a reference center in São Paulo on the surgical approach to correct atypical genitalia, through a semi-directed interview. Results: Thirty-seven adult patients with atypical genitalia were interviewed. Patients’ mean age was 36 years. 70% of them had atypical genitalia diagnosed at birth. The patients’ median age at the genitoplasty approach was 5 years (1 to 35 years). The median time interval between the beginning of the follow-up at the referral center and the surgical procedure was 1.9 years. When asked about the ideal period/age for genitoplasty, 72.2% considered the childhood, 16.7% cited when they’re teenagers, 8.3% in adulthood and 2.8% did n’t know. The discomfort reported by the patients related to atypical genitalia decreased after the surgical approach: from 3.8 to 2.9 p < 0.01 (on a scale of 1 “without discomfort’ to 4 “extreme discomfort”). Insecurity about the appearance of genitalia and functionality during sexual intercourse influences negatively affective relationships. Four (10.8%) patients presented gender dysphoria, all of them with 46,XY DSD, three with partial gonadal dysgenesis (all approached surgically before being admitted to our referral service) and one with 5-alpha-reductase 2 deficiency. Conclusion: Most 46,XY DSD patients considered childhood the ideal time to correct their atypical genitalia. An early follow-up in a reference center and an adequate evaluation by a multidisciplinary may influence the positive results associated to the surgical approach of the atypical genitalia in childhood and the low prevalence of gender dysphoria in adulthood.

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.

Abstract Disclosure: L.A. Alvares: None. L.M. Santos: None. B.B. Mendonça: None. E.M. Costa: None. S. Domenice: None. Introduction: For transgender women (TW), previous exposed to male puberty, on long-term estrogen therapy, the knowledge about the lipid profile is important since it impacts on cardiovascular risk. Methods: A cross-sectional study was carried out with 15 TW (34.2 +/- years old), 14 CW and 13 CM. The TW received hormone therapy for 14.4 +/- 3.5 years. The IPAQ was used to measure the level of physical activity. Body composition was assessed by an InBody 720 device. The subjects (TW, CW and CM) were classified into five categories (sedentary, insufficiently active A and B, active and very active) according to IPAQ recommendations. Results: Age (years) TW: 34.2 SD +/- 5.2; CW: 35.6 SD +/- 4.1 and CM: 36.7 SD +/- 3.8. BMI (kg/m2) TW 25.5 SD +/- 2.8, CW 23.1 SD +/- 3.3 and CM 26.3 SD +/- 3,0. Total testosterone (ng/dL) TW 18.0 (range 12-637), CW 19 (range 12-40.1) and CM 524 (SD+/- 169). Median total cholesterol analysis (mg/dL): TW 154 SD +/- 33.0, CW 177 SD +/- 18.7 and CM 173 SD +/- 23.0 (p>0.05 in all subanalyses), HDL (mg/dL) TW: 46.5 SD +/- 10.9; CW:67.0 SD +/- 15.6 and CM: 46.5 SD +/- 9.8 p value <0.05; significant difference between TW and CW; between CW and CM; LDL (mg/dL) TW: 93 SD +/- 30.4; CW 94.5 SD +/- 14.2 and CM 104 SD +/- 22.0. The % FAt mass of TW was lower than that of CW (29.5±5.7 vs 32.9±5.7; p>0.05) and higher than that of CM (20.2±5.7; p<0.001). There was no significant difference in the level of physical activity between the groups (TW vs CW, p>0.05; TW vs CM, p>0.05; CW vs CM, p>0.05), with most participants being active or very active in all groups. Discussion: studies show that in the first few months of estrogen therapy HDLc increases about 10%. Conclusion: after long term on estrogen therapy, TW present HDLc pattern similar to CM, different of the usually observed in the first months analyses. Presentation: Saturday, June 17, 2023