Disorders of Sex Development (DSD)

Background. Hypospadias is a birth defect of the external genital organs in boys and it ranks the second most common genital malformation in male newborns, following cryptorchidism. Its prevalence is increasing in certain global regions, with an estimated rate of 3.8 cases per 1000 male births. To date, the exact cause of hypospadias remains unknown, however genetic, hormonal, and environmental factors are likely involved. Medical and surgical treatment may be necessary. Furthermore, hypospadias is correlated with fertility issues and is also linked to testicular cancer. Aim. After ruling out hypospadias with a genetic cause, the aim of this study is to evaluate any significant differences to environmental endocrine disrupting-chemicals (EDCs) exposure between biological mothers of children with hypospadias and those with children without malformation. It aims to demonstrate that this exposure (professional, occupational, environmental) leads to hormonal changes during the neonatal mini-puberty period. Methods. This research will be conducted as a multicenter case-control study: mother and son with isolated anterior or middle hypospadias (Case Group) and mother and son without hypospadias (Control Group). The clinical investigator plans to enroll 200 patients. A single visit will be performed. This consultation is part of the usual follow-up for children in the Case Group, while it is specific to the project for children in the Control Group. During this visit, the investigator: * will establish the diagnosis of hypospadias (for cases) or absence of genital anomaly (for controls) * will lead an interview using a questionnaire and a job-exposure matrix to assess EDCs during pregnancy * will take a hair sample from the mother to measure the substances accumulated during pregnancy * and finally, will take a blood sample from the child for hormonal evaluation of mini-puberty, and another blood sample from child in the Case Group for analysis and the participation in a DNA collection

This Phase 2/3 plus open-label extension study is designed to evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of atumelnant treatment in pediatric participants with classic CAH. Part A is a Phase 2, open-label, semi-sequential cohorts portion of the study. Part B is the Phase 3, double-blind, randomized, placebo controlled confirmatory portion of the study. Part C is the open-label extension (OLE) portion of the study. Participants in Part A and B are eligible to enroll in Part C (OLE). A total of approximately 153 participants may be enrolled in the study (planned and optional cohorts) ages 1 to \< 18 years old. The first 3 cohorts in Part A are for ages 12 to \<18 years and will be sequential, and Safety Review Committee (SRC) review of data and approval to proceed is required prior to enrolling each subsequent cohort. The fourth cohort in Part A is for ages 1 to 11 years old and will begin after Cohorts 1 and 2 have been completed, additional requirements are fulfilled, and following SRC review of Cohorts 1 and 2 data.

This is a Phase 3, global, multicenter, randomized, double-blind, placebo-controlled study in adult participants (male or female age ≥18 to \<75 years) with classic CAH due to 21-OHD who have been on a stable regimen of GCs for at least 2 months to evaluate efficacy, safety, PK, and PD of atumelnant administered once per day. Following a 3- to 6-week Screening Period, eligible participants will enter the Treatment Period where they will be randomly assigned in a 2:1 ratio to receive either atumelnant 80 mg once daily (with an option for dose escalation to 120 mg once daily at Week 20) or placebo. A total of approximately 150 participants may be enrolled in the study.

This trial will evaluate the effects of different doses of Lu AG13909 in adult participants with congenital adrenal hyperplasia, also called CAH. CAH is a rare genetic disorder that affects a person's ability to produce certain hormones. The main goals of this trial are to learn about the safety and tolerability of Lu AG13909, how Lu AG13909 behaves in the body, and how the body responds to Lu AG13909.

This single-arm, long-term, open-label, study is designed to evaluate the safety, tolerability, and efficacy of atumelnant (CRN04894) in participants with congenital adrenal hyperplasia (CAH). Enrollment will be limited to individuals who completed a parent study with CRN04894 or completed treatment in a Crinetics atumelnant study, and in the opinion of the Investigator had an acceptable benefit-risk assessment in the completed study and would benefit from continued dosing in this extension study. Approximately 150 participants will be enrolled in the study.

Study Description: This is a natural history study of individuals with androgen receptor gene abnormalities. Objectives: Primary Objectives: To define and describe a comprehensive phenotype of patients with androgen insensitivity (based on confirmed androgen receptor (AR) gene difference), including hormonal, metabolic, immunologic, and cardiovascular aspects of AIS, as well as quality life and tumor formation risk and evaluation. Secondary Objectives: 1. Bone Health: \- Follow a large population of patients with androgen receptor abnormalities for: * Longitudinal assessment of bone mineral density (BMD) before and after gonadectomy * Development of normative values for dual-energy X-ray absorptiometry (DEXA) and high-resolution peripheral quantitative computed tomography (HRpQCT) scans in individual with complete androgen insensitivity syndrome (CAIS) and family members. * Studies to determine bone geometry, strength and shape, * Studies to determine muscle-skeletal unit inferences * Studies to evaluate skin tone * Evaluation of bone accrual from infancy to adolescence 2. Metabolic and Immune Abnormalities: \- Follow a large population of patients with androgen receptor abnormalities for studies of metabolic abnormalities and auto-immune disease screening * Metabolic syndrome, * Insulin resistance * Cardiovascular markers * Endometabolic imaging * Autoimmune screening tests 3. Testicular Tumor Risk and Monitoring: \- Follow a large population of patients with androgen receptor abnormalities in order to: \-- Describe the typical and atypical appearance of testes on ultrasound and magnetic resonance imaging (MRI) in young individual with CAIS. * Evaluate gonadal tumor markers as a tool to assess for gonadal tumor. \- When individuals with androgen receptor abnormalities decide to undergo gonadectomy, perform tissue evaluation in order to: * Investigate the pathophysiology of gonadal tumor formation * Assess fertility potential in testis of individual with androgen receptor abnormalities 4. Quality of Life: * Follow a large population of patients with androgen receptor abnormalities to characterize quality of life measures throughout the lifespan * Evaluate the effects of androgen receptor abnormalities on individual s sexual function. Compare sexual function in adult individuals with androgen receptor abnormalities to individual with classic congenital adrenal hyperplasia (CAH) and unaffected individual of similar ages. 5. Hormone Replacement: \- Evaluate different types and delivery of hormone replacement therapy on quality of life, sexual function, bone health and metabolic parameters in individual who have undergone gonadectomy 6. Follow a sample population of relatives of individuals with androgen insensitivity syndrome (AIS) in order to assess the effects of AR gene difference carrier status phenotype including hormonal, metabolic, immunologic, quality of life, and tumor formation. Family members without AR gene abnormalities will serve as controls. Follow a large population of patients with AIS for referral to future treatment studies. Endpoints: Primary Endpoint: Longitudinal evaluation of 500 individuals with AIS. Secondary: * DEXA and HRpQCT scans and bone metabolism markers will be evaluated longitudinally in all individuals with AIS. Additionally, these will be correlated with muscle grip and skin tone studies. * Compare metabolic parameters in all individuals with AIS. * Compare gonadal tissue with MRI or ultrasound in all individuals with AIS. * Evaluate Quality of life with Quality of Life (QoL) questionnaire.

The goal of this clinical trial is to learn whether a journaling intervention can reduce stress and anxiety in parents of children with urogenital conditions (such as differences of sex development and hypospadias). The main questions it aims to answer are: * Does guided journaling help to reduce anxiety levels in parents of children with urogenital conditions? * What are parents' perspectives on group-based writing interventions for future support programs? Participants will: * Complete a short anxiety questionnaire (the General Anxiety Disorder-7 scale) at the beginning of the study * Receive a physical journal with 5 writing prompts designed to help process emotions related to their child's condition * Complete 5 journal entries over several weeks, writing about their experiences and feelings * Complete the same anxiety questionnaire again after finishing the journal entries * Participate in a 45-minute interview to discuss how the journaling affected their stress levels and gather feedback on potential group-based writing programs

Gender incongruence, described in the eleventh revision of the International Classification of Diseases (ICD-11) as "a marked and persistent incongruence between an individual's experienced gender and the gender assigned at birth" , is usually managed in specialised, multidisciplinary centres where psychologists, endocrinologists, gynaecologists, urologists and other professionals guide each person through the process of gender affirmation. Central to this pathway is gender-affirming hormone therapy (GAHT). In individuals assigned female at birth (AFAB) who seek masculinisation, treatment relies primarily on testosterone, whereas in those assigned male at birth (AMAB) who desire feminisation or demasculinisation, androgen-lowering agents such as cyproterone acetate or gonadotropin-releasing-hormone analogues (triptorelin or leuprorelin acetate) are combined with oestradiol; when complete feminisation is requested, suppression of endogenous testosterone and administration of oestradiol proceed in tandem. Gender-affirming surgery (GAS) offers further individualised possibilities: chest masculinisation in AFAB people and breast augmentation in AMAB people, orchiectomy or vaginoplasty for AMAB individuals, and hysterectomy with or without salpingo-oophorectomy followed by phalloplasty or metoidioplasty for AFAB individuals. Ancillary procedures, including facial feminisation and thyroplasty, may refine the outcome for AMAB clients. The physiological goal of GAHT is to suppress endogenous sex-hormone levels and associated secondary sexual characteristics of the birth sex while inducing and maintaining hormone levels, and thus features, congruent with the individual's affirmed gender. Although GAHT is widely used, robust data on its cardiovascular safety remain scarce. Sex-steroid receptors are ubiquitous in vascular tissues and help explain the sex-specific patterns of cardiovascular (CV) risk seen in cisgender populations; accordingly, GAHT is biologically plausible as a modulator of CV outcomes in transgender people, yet the evidence base is still limited. Current literature points to an increased composite CV risk-up to 2.66-fold-among AFAB individuals receiving testosterone compared with cisgender AFAB controls. The most frequently reported risk-factor shifts in this group include higher blood pressure and lower high-density lipoprotein cholesterol, whereas clinically significant polycythaemia remains uncommon and treatable. By contrast, studies have not shown a statistically significant overall CV risk elevation in AMAB individuals treated with feminising regimens when compared with cisgender AMAB peers, though findings are inconsistent. One observational investigation documented that within four months of starting GAHT systolic blood pressure rose by 2.6 mmHg in trans men but fell by 4 mmHg in trans women, with diastolic values remaining unchanged in both cohorts. Interpretation of these data is hindered by small sample sizes, the paucity of large prospective cohorts, inadequate control populations and the predominance of surrogate biochemical markers in place of clinical CV end-points. Moreover, several published studies neglect to register GAHT exposure, despite its fundamental role in transgender health management, underscoring the need for further research into the therapy's effects and risks. Social determinants of health compound the picture: higher prevalences of mental-health disorders, substance misuse and structural healthcare inequities are increasingly recognised in transgender communities and likely contribute to the observed CV risk burden. Many critical questions therefore remain unanswered. The long-term impact of GAHT on cardiovascular morbidity and mortality is unknown, as is the extent to which a person's age modifies GAHT-related shifts in blood pressure, lipid profile or other risk parameters. Clinicians lack evidence-based targets for blood pressure or surrogate CV markers in trans men and trans women, and the biological mechanisms that underlie GAHT-related alterations in CV risk factors are not fully understood. Addressing these uncertainties will demand rigorously designed, large-scale prospective studies, conducted with active involvement of transgender participants, that integrate biomedical outcomes with the broader social realities shaping transgender health. In summary, although GAHT is indispensable for many individuals seeking gender affirmation, its cardiovascular implications-particularly the elevated risk signalled in AFAB people receiving testosterone-warrant cautious, evidence-based monitoring. Future work should clarify long-term outcomes, refine management protocols and ensure that clinical guidelines reflect both the physiological effects of hormone therapy and the social determinants that influence cardiovascular health in transgender populations.

The rationale for conducting a comprehensive study arises from the limitations inherent in existing literature, primarily due to selection bias and the retrospective nature of current evidence, which fails to clarify whether caudal blocks lead to higher complication rates after hypospadias repair. To fill this knowledge gap and address the clinical uncertainty surrounding this issue, the only effective approach is to randomly assign patients undergoing hypospadias repair to receive either caudal or penile block anesthesia. The purpose of this pilot study is to evaluate the feasibility of a definitive trial and identify any methodological issues that must be resolved before committing significant resources to a full-scale study. This pilot study will assess the feasibility of conducting a large, definitive, parallel-group, randomized controlled trial (RCT) to determine whether a dorsal penile block results in fewer postoperative complications than a caudal block in boys aged 6 to 48 months undergoing hypospadias repair. Hypospadias repair will be performed under standardized analgesic administration, and participants may receive fentanyl (1-3 mcg/kg) at the anesthesiologist's discretion. Anesthesia will be induced via inhalation of air/nitrous oxide and sevoflurane. Based on a randomized allocation, patients will receive either a caudal anesthetic block (0.25% bupivacaine, 1 ml/kg, up to a maximum of 10 ml) or a dorsal penile block (bupivacaine without epinephrine, 10-20 ml/kg). All patients will receive antiemetic prophylaxis with dexamethasone (150 mcg/kg), ondansetron (50 mcg/kg), acetaminophen suppository (40 mg/kg), and intravenous morphine (0.02-0.1 mg/kg). At discharge, patients will be prescribed oral morphine (0.2 mg/kg) every 4 hours as needed, Ditropan (0.2 mg/kg) every 12 hours as needed, Tylenol (15 mg/kg per dose) every 4 hours, or ibuprofen (10 mg/kg per dose) every 6 hours. Parents will administer these medications at their discretion. Trimethoprim (2 mg/kg) will also be prescribed until catheter removal.

In order to meet all the challenges in the diagnosis and treatment of adrenal diseases in China, CASE was founded in 2020. With advanced medical equipment and Internet of Things (IoT) technology, CASE is committed to creating an online and offline integrated solution for adrenal disease, and for the entire spectrum of adrenal disease, to achieve a more convenient and precise model of care for patients, aiming to establish a platform with diagnosis and treatment of adrenal disease and their long-term follow-up. It allows the application and evaluation of treatment strategies at these centers.