Daily Endocrinology Research Analysis

OBJECTIVE: Treatment monitoring of individuals with congenital adrenal hyperplasia (CAH) remains unsatisfactory. Comprehensive 24 h urine steroid profiling provides detailed insight into adrenal steroid pathways. We investigated whether 24 h urine steroid profiling can predict treatment control in children and adolescents with CAH using machine learning (ML). DESIGN: Prospective observational cohort study. METHODS: This study included children with 21-hydroxylase deficiency. On 24 h urines of 2 consecutive visits 40 steroids were measured by gas chromatography-mass spectrometry. Treatment outcome was clinically classified as undertreated, optimally treated or overtreated. We used sparse partial least squares discriminant analysis (sPLS-DA) to investigate prediction of treatment outcome. We computed area under the ROC-curve (AUC) of 2 sPLS-DA models: (1) using only 24 h urine metabolites and (2) adding clinical variables. RESULTS: We included 112 visits (68 optimal, 44 undertreatment) from 59 patients: 27 (46%) girls, 46 (78%) classic CAH, and 19 (32%) prepubertal. Mean age at first visit was 11.9 ± 4.0 years and mean BMI SDS 0.6 ± 1.1. SPLS-DA using 24 h urine metabolites showed clear clustering of optimally treated patients on 2 components, while undertreated patients were more heterogeneous (AUC 0.88). The model selected pregnanetriol and 17α-hydroxypregnanolone contributing to excluding optimal treatment and 5 metabolites contributing to excluding undertreatment: 17β-estradiol, cortisone, tetrahydroaldosterone, androstenetriol, and etiocholanolone. Addition of clinical variables marginally improved classification (AUC 0.90). CONCLUSIONS: Using ML on 24 h urine steroid profiling predicted treatment outcome in children with CAH, even in the absence of clinical data, suggesting that routine comprehensive 24 h urine steroid profiling could improve treatment monitoring in CAH.

STUDY QUESTION: What is the role of insulin resistance (IR), increased insulin secretion, and impaired insulin clearance, either alone or in combination, on metabolic features and androgen levels in women with PCOS? SUMMARY ANSWER: IR, reduced insulin clearance and increased insulin secretion independently contribute to predicting hyperandrogenemia, whereas metabolic abnormalities may differ according to the mechanisms underlying hyperinsulinemia. WHAT IS KNOWN ALREADY: Hyperinsulinemia is a common finding in women with PCOS, and it is closely associated with the metabolic and endocrine alterations of these women. It is considered a compensatory mechanism to IR, and results from two separate mechanisms: increased secretion and/or reduced insulin clearance. The contribution of these two distinct adaptive processes may differ, and the implications of these differences are poorly understood. STUDY DESIGN, SIZE, DURATION: Cross-sectional study of 355 women with PCOS recruited in the Verona 3P study from 2010 to 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with PCOS, diagnosed by the Rotterdam criteria, underwent a hyperinsulinemic euglycemic clamp, to measure insulin sensitivity (M-clamp) and to calculate insulin clearance (MCRI). Insulin secretion was estimated by the HOMA β-index. Serum androgens were measured by LC/MS-MS and equilibrium dialysis. MAIN RESULTS AND THE ROLE OF CHANCE: Hyperinsulinemia was found in 65.4% women with PCOS. Insulin sensitivity was impaired in 69.6% subjects, MCRI was reduced in 57.2%, and HOMA β-index was increased in 60.0% women. Overall, 311 subjects (87.6%) had at least one of these insulin metabolism alterations. The combination of the three alterations was found in 127 (35.8%) women, whereas 98 (27.6%) had two alterations: 30 had IR and reduced MCRI, 47 had IR and increased HOMA β-index, 21 had reduced MCRI and increased HOMA β-index. Eighty-six (24.2%) women had only one alteration: 43 had IR, 25 had reduced MCRI, 18 had increased HOMA β-index; finally, 44 (12.4%) subjects showed no alterations. Anthropometric parameters, and fasting glucose and insulin, were progressively lower in women with 3, 2, 1, or 0 insulin metabolism alterations. Similar trends were observed for serum triglycerides, blood pressure, and androgens, whereas progressively increasing values were observed for high-density lipoprotein-cholesterol and sex hormone-binding globulin.In logistic regression analysis, after adjusting for age and fat mass, IR and increased insulin secretion were independent predictors of altered glucose tolerance, whereas IR and low MCRI were independent predictors of metabolic syndrome; in multivariable analysis, M-clamp, MCRI, and HOMA β-index were all independent predictors of serum free testosterone. LIMITATIONS, REASONS FOR CAUTION: Insulin secretion was estimated by a validated surrogate index, whose performance may be suboptimal. This study was carried out in Caucasian women. Therefore, our findings may not be generalizable to other ethnic groups. Finally, the cross-sectional design of the study limits the causal inference of the results. WIDER IMPLICATIONS OF THE FINDINGS: The presence of IR, reduced MCRI, and increased insulin secretion, especially when combined, worsens metabolic outcomes and androgen levels in women with PCOS. However, these factors may play a different role in determining altered glucose metabolism or metabolic syndrome, whereas all of them independently contribute to hyperandrogenemia. STUDY FUNDING/COMPETING INTEREST(S): Academic grants to P. Moghetti from the University of Verona (FUR 2010-2022). All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

OBJECTIVE: To report the utilization, effectiveness, and safety of assisted reproductive technologies (ARTs) in 2019. DESIGN: A retrospective, cross-sectional survey derived from cycle and pregnancy outcome data submitted by national and regional registries. SUBJECTS: Patients undergoing ART procedures. INTERVENTION: Assisted reproductive technology. MAIN OUTCOME MEASURES: Outcomes on country, regional, and global levels. RESULTS: There were 3,544,683 cycles with 783,073 infants born reported. There were an estimated ≥3,855,694 cycles with >865,914 infants in reporting countries including nonreporting clinics. The reported number of cycles and infants increased by approximately 8% from 2018. Autologous frozen-thawed transfers accounted for 61.8% of all autologous transfers without preimplantation genetic testing (PGT), up from 14.8% in 2015. Among all reporting countries, the percentage of freeze-all cycles was 38.4% in 2019, up from 24.6% in 2015. There were 233,833 initiated PGT cycles reported from 44 countries, representing 6.6% of reported cycles vs. 2.6% in 2015. The delivery rate for autologous oocytes was 22.9% per aspiration, with a cumulative delivery rate of 38.6% per aspiration (excluding PGT). Per transfer, the delivery rates were 31.3% for autologous fresh transfers, 31.9% for autologous frozen transfers, 48.7% for transfers using PGT, and 34.6% for transfers after oocyte donation (combined fresh and frozen transfers).In fresh autologous cycles (excluding PGT), the mean number of transferred embryos was 1.51, the proportion of single embryo transfers was 55.6%, and the multiple delivery rate was 17.7%. In autologous frozen-thawed cycles (excluding PGT), the mean number of transferred embryos was 1.26, the proportion of single embryo transfers was 74.1%, and the multiple delivery rate was 13.0%. With oocyte donation (combined fresh and frozen transfers), the multiple delivery rate was 10.8%. The multiple delivery rate for cycles using PGT was 4.2%. CONCLUSION: The International Committee for Monitoring Assisted Reproductive Technologies report is the most comprehensive summary of global ART utilization, effectiveness, and safety currently available. The report documents an increase in reported cycles and infants born from previous years, growing utilization of embryo cryopreservation and single embryo transfers, increasing numbers of PGT cycles, and a reduction in multiple deliveries. It also provides a benchmark for the impact of the coronavirus disease 2019 pandemic in 2020.