Daily Endocrinology Research Analysis
Three studies reshape endocrinology across basic, translational, and clinical domains: whole-genome sequencing in diverse populations identified novel BMI loci including an African ancestry-specific risk allele; intranasal kisspeptin rapidly and safely stimulates gonadotropins in humans, offering a non-invasive reproductive therapy; and a meta-analysis supports continuous glucose monitoring during pregnancy to lower HbA1c and possibly large-for-gestational-age risk.
Summary
Three studies reshape endocrinology across basic, translational, and clinical domains: whole-genome sequencing in diverse populations identified novel BMI loci including an African ancestry-specific risk allele; intranasal kisspeptin rapidly and safely stimulates gonadotropins in humans, offering a non-invasive reproductive therapy; and a meta-analysis supports continuous glucose monitoring during pregnancy to lower HbA1c and possibly large-for-gestational-age risk.
Research Themes
- Obesity genetics and precision medicine in diverse populations
- Non-invasive neuroendocrine therapeutics for reproductive disorders
- Continuous glucose monitoring to optimize diabetes care in pregnancy
Selected Articles
1. Whole genome sequencing analysis of body mass index identifies novel African ancestry-specific risk allele.
Using WGS in 88,873 TOPMed participants (51% non-European), the authors identified 18 BMI-associated loci, including a novel risk allele specific to African ancestry, demonstrating the power of sequencing beyond imputation. This work addresses ancestry bias in obesity genetics and strengthens the foundation for ancestry-aware risk prediction and mechanistic follow-up.
Impact: This large, ancestry-diverse WGS study advances obesity genetics by discovering ancestry-specific signals that prior imputation-based GWAS likely missed, enabling more equitable precision medicine.
Clinical Implications: Immediate clinical practice change is limited, but findings will inform ancestry-tailored polygenic risk scores, guide functional studies toward therapeutic targets, and improve external validity of obesity risk prediction across populations.
Key Findings
- Whole-genome sequencing of 88,873 TOPMed participants (51% non-European) identified 18 BMI-associated signals.
- Discovery of a novel African ancestry-specific risk allele for BMI, addressing Eurocentric biases of prior GWAS.
- Sequencing-based approach demonstrated added value over imputation-based analyses for locus discovery.
Methodological Strengths
- Large multi-ancestry sample with over half non-European participants.
- Use of whole-genome sequencing enabling discovery of variants not present on genotyping arrays or poorly imputed.
Limitations
- Observational genetic association without direct functional validation of identified variants.
- Effect estimates and fine-mapping details are not provided in the abstract; clinical translation requires further work.
Future Directions: Functionally characterize the African ancestry-specific allele and other loci, integrate multi-omics to map causal mechanisms, and develop/validate ancestry-aware polygenic risk scores for clinical use.
Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P < 5 × 10
2. Intranasal kisspeptin administration rapidly stimulates gonadotropin release in humans.
In a randomized, double-blind, crossover, placebo-controlled study, intranasal kisspeptin-54 rapidly increased serum LH in healthy men, healthy women, and patients with hypothalamic amenorrhea without adverse events. Pharmaceutical testing confirmed nasal delivery and stability, and rodent studies implicated an olfactory GnRH pathway.
Impact: This is the first robust demonstration that intranasal kisspeptin can non-invasively stimulate gonadotropins in humans, potentially transforming treatment paradigms for reproductive endocrine disorders.
Clinical Implications: Intranasal kisspeptin may provide a patient-friendly alternative to injectable therapies for conditions like hypothalamic amenorrhea and could be integrated into diagnostic stimulation testing for GnRH/LH axis assessment.
Key Findings
- Intranasal kisspeptin-54 (12.8 nmol/kg) significantly increased serum LH across healthy men (+4.4 IU/L; mean difference 3.1 IU/L, P=0.002), healthy women (+1.4 IU/L; mean difference 1.0 IU/L, P=0.004), and hypothalamic amenorrhea patients (+4.4 IU/L; mean difference 4.3 IU/L, P<0.001).
- No side effects or adverse events were observed; nasal spray formulation remained stable up to 60 days at 4 °C.
- Rodent studies showed LH stimulation and fluorescently tagged kisspeptin accumulation in olfactory epithelium with kisspeptin receptors in olfactory bulb GnRH neurons, supporting a mechanistic pathway.
Methodological Strengths
- Randomized, double-blinded, crossover, placebo-controlled human study across healthy and patient cohorts.
- Convergent pharmaceutical stability/delivery testing and mechanistic rodent experiments.
Limitations
- Sample size and duration are not detailed in the abstract; long-term efficacy and safety remain to be established.
- Generalizability to broader reproductive disorders and dosing optimization require further trials.
Future Directions: Conduct larger, longer RCTs to evaluate reproductive outcomes (ovulation, pregnancy rates) and compare intranasal kisspeptin with established therapies; refine dosing and delivery for outpatient use.
BACKGROUND: Kisspeptin administration by intravenous or subcutaneous routes activates hypothalamic gonadotropin-releasing hormone (GnRH) neurons and is being developed to treat reproductive disorders. However, these invasive routes markedly limit patient acceptability and clinical use. Recent rodent data has identified a large GnRH population within the olfactory system communicating directly with hypothalamic GnRH neurons. Intranasal kisspeptin administration may be able to capitalise on this novel pathway and thus offer a potential non-invasive approach to stimulate reproductive hormones. Herein, we examine intranasal kisspeptin using human, pharmaceutical, and rodent studies. METHODS: Reproductive hormone profiles were measured after intranasal kisspeptin administration in healthy volunteers and patients with reproductive disorders as part of a randomised, double-blinded, crossover, placebo-controlled clinical study. Pharmaceutical testing evaluated the chemical stability and nasal kisspeptin delivery, and rodent studies provided mechanistic insight. FINDINGS: Intranasal kisspeptin-54 rapidly stimulates gonadotropin release in healthy men and women, and in patients with a common reproductive disorder (hypothalamic amenorrhoea), without any side effects or adverse events encountered. Specifically, intranasal kisspeptin (at 12.8 nmol/kg) induced clinically-significant mean maximal increases above baseline in serum luteinising hormone in all study groups: 4.4 ± 0.6 IU/L (mean difference = 3.1 IU/L [95% CI, 1.2-4.9], P = 0.002 vs. placebo) in healthy men; 1.4 ± 0.3 IU/L (mean difference = 1.0 IU/L [95% CI, 0.4-1.7], P = 0.004 vs. placebo) in healthy women; 4.4 ± 0.2 IU/L (mean difference = 4.3 IU/L [95% CI, 2.7-6.0], P < 0.001 vs. placebo) in patients with hypothalamic amenorrhoea. Kisspeptin-54 was delivered effectively via nasal spray and was stable for up to 60 days at 4 °C. Mirroring the human effects, intranasal kisspeptin-54 in adult C57BL/6J male mice stimulates luteinising hormone release. Further mechanistic insights reveal the accumulation of fluorescently-tagged kisspeptin in the olfactory epithelium, as well as the presence of kisspeptin receptors in olfactory bulb GnRH neurons, implicating the involvement of these extra-hypothalamic GnRH neurons in the pathway mediating intranasal kisspeptin's effects on reproductive hormones. INTERPRETATION: We demonstrate the clinical potential for intranasal kisspeptin delivery as the first non-invasive method to robustly and safely stimulate gonadotropins with kisspeptin and potentially transform the management of reproductive disorders. FUNDING: National Institute for Health and Care Research (NIHR)/NIHR Imperial Biomedical Research Centre/Medical Research Council (MRC).
3. Evidence for improved glucose metrics and perinatal outcomes with continuous glucose monitoring compared to self-monitoring in diabetes during pregnancy.
This systematic review and meta-analysis shows that CGM, compared with SMBG, reduces HbA1c across diabetes in pregnancy and may reduce large-for-gestational-age, with the strongest evidence in type 1 diabetes and supportive data for gestational diabetes using intermittent CGM. Mean sensor glucose and pregnancy %time-in-range correlate with lower large-for-gestational-age risk.
Impact: Synthesizes randomized and quasi-experimental evidence to inform perinatal diabetes care, highlighting CGM metrics that align with neonatal outcomes and guiding clinical targets.
Clinical Implications: Adopt CGM as standard in type 1 diabetes pregnancies and consider intermittent CGM for gestational diabetes. Target lower mean sensor glucose and higher %time-in-range to reduce large-for-gestational-age risk; more data are needed for type 2 diabetes.
Key Findings
- Across diabetes in pregnancy, CGM vs SMBG reduced HbA1c by −0.22% (95% CI −0.37 to −0.08) in 7 RCTs (moderate-certainty).
- In type 1 diabetes, CGM throughout pregnancy reduced large-for-gestational-age (OR 0.51 [0.28–0.90]) and lowered HbA1c (−0.18%).
- In gestational diabetes, intermittent CGM reduced HbA1c (−0.18%) and was associated with lower large-for-gestational-age in one study (OR 0.46).
- Higher pregnancy %time-in-range and lower mean sensor glucose were associated with reduced large-for-gestational-age.
Methodological Strengths
- Comprehensive multi-database search with separate analyses of RCTs and quasi-experimental studies.
- Pre-specified subgroup analyses and GRADE assessment; linkage of CGM metrics to neonatal outcomes.
Limitations
- Insufficient evidence for type 2 diabetes in pregnancy; heterogeneity in CGM duration (continuous vs intermittent).
- Some outcomes (e.g., LGA in GDM) rely on limited or quasi-experimental data, lowering certainty.
Future Directions: Conduct adequately powered RCTs in type 2 diabetes pregnancy, standardize CGM use protocols, and test TIR- and mean sensor glucose–based targets to reduce neonatal overgrowth.
OBJECTIVE: Continuous glucose monitoring is recommended for pregnant women with type 1 diabetes, due to associations with decreased hemoglobin A1c and large for gestational age. However, its benefit in type 2 diabetes and gestational diabetes is not established. This systematic review and meta-analysis compared usage of continuous glucose monitoring to self-monitoring of blood glucose both across and within diabetes in pregnancy and determined which glucose metrics are associated with perinatal outcomes, to potentially inform treatment targets in diabetes in pregnancy. DATA SOURCES: We searched Medline, Embase, CENTRAL, CINAHL, and Scopus, from January 2003 to August 2024. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials and quasi-experimental studies comparing continuous glucose monitoring with self-monitoring of blood glucose in diabetes in pregnancy were included. STUDY APPRAISAL AND SYNTHESIS METHODS: Randomized controlled trials and quasi-experimental studies were analyzed separately. Data were extracted on continuous glucose monitoring metrics, hemoglobin A1c, rates of cesarean delivery, large for gestational age, small for gestational age, neonatal hypoglycemia, and neonatal intensive care unit admission, summarized as mean differences or odds ratios with 95% confidence intervals and 95% prediction intervals. Prespecified subgroup analyses were undertaken by diabetes in pregnancy subtype, including duration of continuous glucose monitoring use (continuous vs intermittent) for large for gestational age. Certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations framework. RESULTS: Across diabetes in pregnancy, continuous glucose monitoring (vs self-monitoring of blood glucose) decreased hemoglobin A1c (mean difference, -0.22% [95% confidence interval, -0.37, -0.08]) (7 randomized controlled trials, moderate-certainty evidence). Within diabetes in pregnancy, continuous glucose monitoring use (vs self-monitoring of blood glucose) showed similar but stronger benefits in both type 1 diabetes when used throughout pregnancy (hemoglobin A1c mean difference, -0.18% [95% confidence interval, -0.36, 0.00]; large for gestational age odds ratio, 0.51 [0.28, 0.90]) (1 randomized controlled trial, high-certainty evidence), and gestational diabetes when used intermittently (hemoglobin A1c mean difference, -0.18 [95% confidence interval, -0.33, -0.02]) (5 randomized controlled trials, moderate-certainty evidence) and large for gestational age (odds ratio, 0.46 [0.26, 0.81]) (1 quasi-experimental study, low-certainty evidence), with insufficient data for continuous glucose monitoring benefit in type 2 diabetes. Increased pregnancy %time-in-range (type 1 diabetes) and decreased mean sensor glucose (type 1 diabetes/gestational diabetes) were associated with decreased large for gestational age. CONCLUSION: Usage of continuous glucose monitoring (vs self-monitoring of blood glucose) reduces hemoglobin A1c and possibly large for gestational age across diabetes in pregnancy. Greatest benefit was evidenced in type 1 diabetes, followed by gestational diabetes, although continuous glucose monitoring duration differed. Mean sensor glucose and pregnancy %time-in-range are important continuous glucose monitoring metrics for reducing large for gestational age.