Gonadectomy in conditions affecting sex development: a registry-based cohort study.

OBJECTIVES: To determine trends in clinical practice for individuals with DSD requiring gonadectomy. DESIGN: Retrospective cohort study. METHODS: Information regarding age at gonadectomy according to diagnosis; reported sex; time of presentation to specialist centre; and location of centre from cases reported to the International DSD Registry and who were over 16 years old in January 2019. RESULTS: Data regarding gonadectomy were available in 668 (88%) individuals from 44 centres. Of these, 248 (37%) (median age (range) 24 (17, 75) years) were male and 420 (63%) (median age (range) 26 (16, 86) years) were female. Gonadectomy was reported from 36 centres in 351/668 cases (53%). Females were more likely to undergo gonadectomy (n = 311, P < 0.0001). The indication for gonadectomy was reported in 268 (76%). The most common indication was mitigation of tumour risk in 172 (64%). Variations in the practice of gonadectomy were observed; of the 351 cases from 36 centres, 17 (5%) at 9 centres had undergone gonadectomy before their first presentation to the specialist centre. Median age at gonadectomy of cases from high-income countries and low-/middle-income countries (LMIC) was 13.0 years (0.1, 68) years and 16.5 years (1, 28), respectively (P < 0.0001) with the likelihood of long-term retention of gonads being higher in LMIC countries. CONCLUSIONS: The likelihood of gonadectomy depends on the underlying diagnosis, sex of rearing and the geographical setting. Clinical benchmarks, which can be studied across all forms of DSD will allow a better understanding of the variation in the practice of gonadectomy.

Birth Weight in Different Etiologies of Disorders of Sex Development.

CONTEXT: It is well established that boys are heavier than girls at birth. Although the cause of birth weight (BW) difference is unknown, it has been proposed that it could be generated from prenatal androgen action. OBJECTIVE: The aim of the current study was to determine the BW of children with disorders of sex development (DSD) of different etiologies and to evaluate the effects of androgen action on BW. METHODS: Data regarding diagnosis, BW, gestational age, karyotype, and concomitant conditions were collected from the International Disorders of Sex Development (I-DSD) Registry (www.i-dsd). BW standard deviation score was calculated according to gestational age. Cases were evaluated according to disorder classification in I-DSD (i.e., disorders of gonadal development, androgen excess, androgen synthesis, androgen action, nonspecific disorder of undermasculinization groups, and Leydig cell defect). RESULTS: A total of 533 cases were available; 400 (75%) cases were 46,XY, and 133 (25%) cases were 46,XX. Eighty cases (15%) were born small for gestational age (SGA). Frequency of SGA was higher in the 46,XY group (17.8%) than in the 46,XX (6.7%) group (P = 0.001). Mean BW standard deviation scores of cases with androgen excess and androgen deficiency [in disorders of gonadal development, androgen synthesis, and Leydig cell defect groups and androgen receptor gene (AR) mutation-positive cases in disorders of androgen action groups] were similar to normal children with the same karyotype. SGA birth frequency was higher in the AR mutation-negative cases in disorders of androgen action group and in the nonspecific disorders of the undermasculinization group. CONCLUSIONS: BW dimorphism is unlikely to be explained by fetal androgen action per se. 46,XY DSDs due to nonspecific disorders of undermasculinization are more frequently associated with fetal growth restriction, SGA, and concomitant conditions.

Changes over time in sex assignment for disorders of sex development.

BACKGROUND AND OBJECTIVE: It is unclear whether the proportion of infants with a disorder of sex development who are raised as male or female has changed over time. The temporal trends in sex assignment of affected cases entered in the International Disorder of Sex Development (I-DSD) Registry were studied. METHODS: Cases of disorders of sex development reported as partial androgen insensitivity syndrome (PAIS; n = 118), disorder of gonadal development (DGD; n = 232), and disorder of androgen synthesis (DAS; n = 104) were divided into those who were born before 1990, 1990-1999, and after 1999. External appearance of the genitalia was described by the external masculinization score. RESULTS: The median (5th-95th percentile) external masculinization scores of those infants with PAIS, DGD, and DAS who were raised as boys were 6 (2-9), 6 (3-9), and 6 (1-12), respectively, and were significantly higher than in those raised as girls (2 [0-6], 2 [0-7], and 0 [0-5], respectively); this difference was maintained in the 3 temporal birth cohorts (P < .01). Of the 118 cases in the pre-1990 cohort, 41 (35%) were raised as boys; of the 148 cases in the 1990-1999 cohort, 60 (41%) were raised as boys; and of the 188 cases in the post-1999 cohort, 128 (68%) were raised as boys. CONCLUSIONS: Although there is an association between the external appearance of the genitalia and the choice of sex assignment, there are clear temporal trends in this practice pointing toward an increased likelihood of affected infants being raised as boys. The impact of this change in practice on long-term health outcomes requires additional focus.

Novel associations in disorders of sex development: findings from the I-DSD Registry.

CONTEXT: The focus of care in disorders of sex development (DSD) is often directed to issues related to sex and gender development. In addition, the molecular etiology remains unclear in the majority of cases. OBJECTIVE: To report the range of associated conditions identified in the international DSD (I-DSD) Registry. DESIGN, SETTING, AND PATIENTS: Anonymized data were extracted from the I-DSD Registry for diagnosis, karyotype, sex of rearing, genetic investigations, and associated anomalies. If necessary, clarification was sought from the reporting clinician. RESULTS: Of 649 accessible cases, associated conditions occurred in 168 (26%); 103 (61%) cases had one condition, 31 (18%) had two conditions, 20 (12%) had three conditions, and 14 (8%) had four or more conditions. Karyotypes with most frequently reported associations included 45,X with 6 of 8 affected cases (75%), 45,X/46,XY with 19 of 42 cases (45%), 46,XY with 112 of 460 cases (24%), and 46,XX with 27 of 121 cases (22%). In the 112 cases of 46,XY DSD, the commonest conditions included small for gestational age in 26 (23%), cardiac anomalies in 22 (20%), and central nervous system disorders in 22 (20%), whereas in the 27 cases of 46,XX DSD, skeletal and renal anomalies were commonest at 12 (44%) and 8 (30%), respectively. Of 170 cases of suspected androgen insensitivity syndrome, 19 (11%) had reported anomalies and 9 of these had confirmed androgen receptor mutations. CONCLUSIONS: Over a quarter of the cases in the I-DSD Registry have an additional condition. These associations can direct investigators toward novel genetic etiology and also highlight the need for more holistic care of the affected person.

Congenital adrenal hyperplasia and the function of adrenal medulla.

OBJECTIVE: The most common form of congenital adrenal hyperplasia (CAH) is the deficiency of steroid 21-hydroxylase which results from deletion or mutation of the cytochrome P450 21-hydroxylase gene. The low level of glucocorticoids and in some cases low level of mineralocorticoids has an important pathophysiological influence on the axis of the hypothalamo-pituitary-adrenal cortex. DESIGN: Using determination of plasmatic metanephrine, normetanephrine and chromogranin A, we wanted to investigate the structure and function of adrenal medulla in patients with CAH, because adrenocortical and adrenomedullary systems are intimately linked anatomically and functionally. METHODS: Levels of plasmatic metanephrine, normetanephrine and chromogranin A were measured in our group of 37 patients (age range: 5-45 years, 18 females and 19 males) with the classic salt-wasting form of CAH. RESULTS: The reference range was 73% for metanephrine (<10 ng/L, 83.3% females, 63.2% males) and 59.5% for metanephrine (<15 ng/L, 72.2% females, 47.4% males). The concentration of plasmatic nephrines in the first quartile reference range was achieved in the case of metanephrine in all patients (<23 ng/L), and in the case of normetanephrine in 86.5% of patients (<42.5 ng/L). The level in chromogranin A was normal in all patients. No significant differences were found in plasmatic concentrations of nephrines and chromogranin A between males and females with CAH, nor was there a significant correlation with genetic results (severe or moderate salt-wasting form of CAH). CONCLUSION: Impaired secretion of glucocorticoids in patients with CAH leads to the structural changes in adrenal medulla which are expressed by low production of metanephrine, and to a lesser extent, normetanephrine.

Sex hormone-binding globulin in congenital adrenal hyperplasia.

BACKGROUND: Sex hormone-binding globulin biosynthesis is influenced by three hormonal systems: gonadal, insular and thyroid. Congenital adrenal hyperplasia is characterized by overproduction of adrenal androgens associated with impaired insulin sensitivity, hyperinsulinemia and often also with hypothyroidism. Only scarce data are available concerning congenital adrenal hyperplasia. The objective of this study was to determine the distribution of sex hormone-binding globulin and free testosterone levels in these patients and to what extent these values correlate with actual 17-hydroxyprogesterone and androstenedione levels, which are commonly used for monitoring of treatment effectiveness. MATERIALS AND METHODS: A total of 300 retrospective laboratory records of 78 males and boys and 456 records of 162 girls and premenopausal women with diagnosis of congenital adrenal hyperplasia under common substitution treatment were evaluated statistically. The data were divided artificially into groups of low, normal and high levels, with respect to physiological concentrations for each sex and age. The percentages of the total in each group were calculated. RESULTS: Whereas an almost Gaussian distribution occurred for males, the data for females displayed a considerable shift to low sex hormone-binding globulin and accordingly high free testosterone levels. Sex hormone-binding globulin levels did not correlate with 17-hydroxyprogesterone. CONCLUSION: Low sex hormone-binding globulin levels in congenital adrenal hyperplasia, at least in females, reflect their involvement in insular and eventually thyroid axes, rather than the effectiveness of substitution.