Daily Endocrinology Research Analysis
Analyzed 88 papers and selected 3 impactful papers.
Summary
An IPD meta-analysis refutes prior claims that intrauterine hCG before embryo transfer improves IVF outcomes, providing practice-guiding evidence for de-implementation. A robust, externally validated diagnostic model accurately differentiates ectopic ACTH secretion from Cushing’s disease using routine data. A systematic review/meta-analysis of NR5A1-related 46,XY DSD quantifies key outcomes (e.g., 82% spontaneous puberty) and supports conservative, longitudinal, patient-centered care.
Research Themes
- De-implementation of ineffective IVF add-ons
- Diagnostic decision support for endocrine disorders
- Evidence synthesis guiding longitudinal care in DSD
Selected Articles
1. Intrauterine human chorionic gonadotropin administration before embryo transfer (IHABT): an individual participant data meta-analysis of randomized controlled trials.
Across seven trustworthy RCTs with IPD (n=2244), intrauterine hCG before embryo transfer did not improve live birth or clinical pregnancy rates. Trials lacking IPD failed trustworthiness checks yet suggested benefits, highlighting reporting and bias issues. The authors advise against offering intrauterine hCG as an IVF add-on.
Impact: This IPD meta-analysis overturns prior positive aggregated reviews by harmonizing participant-level data and applying trustworthiness assessments, offering practice-changing guidance.
Clinical Implications: Clinics should discontinue routine intrauterine hCG as an IVF add-on; consent forms and protocols should be updated accordingly, and resources reallocated to evidence-based interventions.
Key Findings
- Seven IPD RCTs (n=2244) showed no improvement in live birth (OR 0.99, 95% CI 0.83–1.19) or clinical pregnancy (OR 1.04, 95% CI 0.83–1.31).
- All non-IPD RCTs failed trustworthiness criteria yet suggested benefit, with significant differences vs IPD trials (interaction P<0.001 for live birth; P=0.005 for clinical pregnancy).
- Six of seven IPD trials had overall low risk of bias; findings were consistent in one- and two-stage random-effects analyses.
Methodological Strengths
- Individual participant data meta-analysis enabling harmonization and effect-modifier assessment
- Study trustworthiness evaluation using IPD Integrity tool and TRACT checklist; low risk of bias in most IPD trials
Limitations
- Only 7 RCTs provided IPD; generalizability may be limited across varying IVF protocols
- Heterogeneity among historical non-IPD trials and potential publication/reporting biases
Future Directions: Prospective trials with standardized protocols and full data sharing should assess subgroups (e.g., embryo stage, endometrial conditions) and confirm lack of benefit across settings.
BACKGROUND: Intrauterine administration of hCG has been considered as a promising IVF add-on before embryo transfer to improve fertility outcomes. A Cochrane review and four more recent systematic reviews all showed improved clinical pregnancy rates and/or live birth rates following intrauterine administration of hCG, however, a high unexplained heterogeneity was also present. OBJECTIVE AND RATIONALE: To investigate the effectiveness and safety of intrauterine administration of hCG before embryo transfer in participants undergoing IVF. Individual participant data meta-analysis (IPD-MA) is recognized as the gold standard for evidence synthesis due to its ability to harmonize the data and to investigate treatment-covariate interactions. In addition, with recent experiences of guideline development and systematic review production raising increasing concerns about the trustworthiness of randomized controlled trials (RCTs) in women's health research, an IPD-MA provides a unique opportunity to summarize the best available and most trustworthy evidence on this topic. SEARCH METHODS: We searched MEDLINE, Embase, Cochrane Gynaecology and Fertility Group Specialised Register, Cochrane Central Register of Controlled Trials, PsycINFO, and clinical trial registries without language restrictions up to January 2026. Inclusion criteria included RCTs comparing intrauterine administration of hCG before embryo transfer versus placebo or no intervention in participants undergoing IVF. The IPD Integrity tool and the TRACT checklist were used to evaluate the trustworthiness of studies with and without IPD, respectively. Both one-stage and two-stage random-effect IPD meta-analyses were performed with one-stage being the primary analysis. OUTCOMES: We detected 28 RCTs, of which 7 RCTs with IPD involving 2244 participants were included. All seven RCTs with IPD met trustworthiness criteria and six RCTs had overall low risk of bias. All RCTs without IPD did not meet trustworthiness criteria. IPD-MA showed intrauterine administration of hCG before embryo transfer did not improve live birth rates (7 RCTs, 2244 participants, odds ratio [OR] 0.99, 95% CI 0.83-1.19) or clinical pregnancy rates (7 RCTs, 2244 participants, OR 1.04, 95% CI 0.83-1.31). Studies without IPD showed different results from those with IPD for live birth (1.99, 0.72-5.50, P for interaction <0.001) and clinical pregnancy (1.87 (1.48-2.35), 17 RCTs without IPD, 3152 participants, P for interaction 0.005). WIDER IMPLICATIONS: Our IPD-MA has shown that intrauterine administration of hCG before embryo transfer is unlikely to improve the chance of clinical pregnancy and live birth. In the comparison between studies with IPD and without IPD, we found that none of the RCTs without IPD met trustworthiness criteria but showed a significant improvement in clinical pregnancy. We therefore suggest that intrauterine administration of hCG should not be offered as an IVF add-on in practice. REGISTRATION NUMBER: PROSPERO (CRD42020177397).
2. Predictive model for the diagnosis of Ectopic Cushing Syndrome.
Using four routinely available variables (ACTH, 24-h UFC, serum potassium, pituitary tumor size), the model distinguished EAS from Cushing’s disease with AUC ~0.99 in both derivation and external validation cohorts. Calibration was excellent, and sensitivity and specificity were 95.3% and 93.6%, respectively.
Impact: Offers a highly accurate, externally validated, low-burden diagnostic tool that could streamline evaluation and reduce reliance on invasive, resource-intensive tests.
Clinical Implications: Incorporation into diagnostic workflows may improve triage for IPSS and imaging, expedite definitive diagnosis, and support earlier targeted management of EAS.
Key Findings
- Four independent predictors: plasma ACTH, 24-h urinary free cortisol, serum potassium, and maximum pituitary tumor diameter.
- Excellent discrimination: derivation AUC 0.987; external validation AUC ~0.989; strong calibration (Brier ~0.035–0.038).
- High diagnostic performance for EAS: sensitivity 95.3%, specificity 93.6%, NPV 98.7%, PPV 82.3%.
Methodological Strengths
- Multicenter derivation with external validation in an independent cohort
- Penalized regression (LASSO) with comprehensive calibration metrics and discrimination reporting
Limitations
- Retrospective design; potential spectrum and verification biases
- Generalizability may vary across laboratories and imaging protocols; prospective impact studies are needed
Future Directions: Prospective, multicountry impact analyses should test real-world implementation, thresholds, and integration with IPSS and imaging to reduce time-to-diagnosis.
The purpose of our study was to develop and externally validate a multivariable diagnostic model to distinguish ectopic ACTH secretion (EAS) from Cushing's disease (CD) using routine clinical parameters. The model was derived from a Spanish multicenter retrospective cohort and externally validated in a Colombian cohort. Predictors were selected through a multivariable logistic regression model with penalized logistic regression (LASSO) using the Spanish cohort. Discriminative performance was assessed using the area under the ROC curve [AUC] and calibration using the slope, the origin, and the Brier score. The derivation cohort included 253 patients from Spain (199 with CD and 54 with EAS). The external validation cohort comprised 72 Colombian patients (53 with CD and 19 with EAS). In the derivation cohort, multivariable modelling identified four independent predictors: ACTH concentration, 24-h urinary free cortisol (UFC), serum potassium, and maximum pituitary tumor diameter. The final model demonstrated good discrimination in the derivation cohort (mean AUC of 0.987), with excellent calibration (calibration slope ranged from 0.998 to 5.22, intercept -0.2 to 0.99, Brier score 0.035). In external validation, model performance remained robust (AUC ranging from 0.9885 to 0.9890; Brier score 0.0381). The model achieved a sensitivity of 95.3%, specificity of 93.6%, positive predictive value of 82.3%, and negative predictive value of 98.7% for detecting EAS. Thus, the diagnostic model developed, based on routinely available clinical variables, shows high accuracy and calibration in differentiating between EAS and CD, supporting its potential use in diverse clinical settings and integration into diagnostic workflows.
3. Spectrum and Genotype-phenotype Correlation of NR5A1 Variants in 46, XY DSD: A Systematic Review and Meta-analysis.
Among 312 individuals with NR5A1-related 46,XY DSD, spontaneous puberty occurred in 82% and adrenal insufficiency was rare (1.6%). No clear genotype–phenotype correlations emerged, and all reported gender transitions were female-to-male, supporting conservative, longitudinal, patient-centered care.
Impact: Provides quantitative, pooled estimates that recalibrate expectations for puberty and adrenal risk, directly informing counseling and timing of irreversible interventions.
Clinical Implications: Clinicians should anticipate spontaneous virilization in most cases and minimal adrenal involvement, adopt longitudinal monitoring, and defer irreversible decisions to preserve autonomy.
Key Findings
- Spontaneous puberty occurred in 82% (95% CI 45–96); adrenal insufficiency was rare (1.6%).
- No clear genotype–phenotype correlation by variant class; missense variants comprised 54%.
- All reported gender transitions were female-to-male (10%, 95% CI 5–21).
Methodological Strengths
- Systematic search across MEDLINE, Embase, and HGMD with dual independent review following JBI methodology
- Meta-analysis with meta-regression to test genotype–phenotype associations
Limitations
- Heterogeneous, predominantly retrospective case series with variable reporting quality
- Potential publication bias and limited power for subgroup analyses
Future Directions: Prospective, standardized phenotyping cohorts with longitudinal follow-up are needed to refine risk estimates and personalize timing of interventions.
CONTEXT: NR5A1 encodes steroidogenic factor 1, a master regulator of adrenal and gonadal development. Pathogenic NR5A1 variants are among the most common genetic findings in 46,XY differences of sex development (DSD), yet the broad phenotypic spectrum remains incompletely defined. OBJECTIVE: To establish pooled estimates of key clinical outcomes and to clarify whether variant type predicts phenotype, pubertal course, or gender transition in NR5A1 46,XY DSD. METHODOLOGY: MEDLINE, Embase, and HGMD were systematically searched. Two reviewers independently screened, extracted, and appraised studies following the methodology of the Joanna Briggs Institute. Ninety-eight studies (312 individuals) were included; 35 series with ≥3 cases entered meta-analysis. Across studies, 85% presented atypical external genitalia and 15% female-like genitalia; sex of rearing was female in 54%. Spontaneous puberty occurred in 82% (95% CI 45-96), and adrenal insufficiency in only 1.6%. All reported gender transitions were female-to-male (10%, 95% CI 5-21). Missense variants represented 54%. Meta-regressions revealed no association between variant class and genital phenotype (OR 1.25) or between phenotype and gender transition (OR 0.46). CONCLUSIONS: NR5A1-related 46,XY DSD is a dynamic condition with high rates of spontaneous virilisation (82%) and minimal adrenal involvement (1.6%). The absence of clear genotype-phenotype correlations and the occurrence of female-to-male gender reassignment support a conservative, longitudinal, patient-centred model of care. Given the unpredictability of individual outcomes, the quantitative estimates from this review support a shift toward evidence-based, longitudinal care that prioritises patient autonomy by deferring irreversible decisions.