Daily Endocrinology Research Analysis
Three notable endocrinology advances emerged: (1) sex hormones and GPER signaling show direct antitumor effects in pheochromocytomas/paragangliomas with clear receptor–genotype–sex interactions, nominating G-1 as a candidate therapy; (2) overweight/obesity independently raises atherosclerotic cardiovascular disease risk in heterozygous familial hypercholesterolaemia beyond LDL-C; and (3) clonal hematopoiesis of indeterminate potential predicts microvascular complications in type 2 diabetes, espe
Summary
Three notable endocrinology advances emerged: (1) sex hormones and GPER signaling show direct antitumor effects in pheochromocytomas/paragangliomas with clear receptor–genotype–sex interactions, nominating G-1 as a candidate therapy; (2) overweight/obesity independently raises atherosclerotic cardiovascular disease risk in heterozygous familial hypercholesterolaemia beyond LDL-C; and (3) clonal hematopoiesis of indeterminate potential predicts microvascular complications in type 2 diabetes, especially retinopathy and kidney disease.
Research Themes
- Sex hormone and GPER signaling as therapeutic targets in PPGLs
- Obesity as an LDL-C–independent ASCVD driver in familial hypercholesterolemia
- Clonal hematopoiesis and diabetic microvascular complications
Selected Articles
1. Impact of sex hormones on pheochromocytomas, paragangliomas, and gastroenteropancreatic neuroendocrine tumors.
Patient-derived PPGL models show that estradiol and progesterone exert antitumor effects, particularly in NF1-mutant tumors, and that ERα-positive tumors are sensitive to estradiol. The GPER agonist G-1 exhibited strong antitumor activity with sex-related differences, nominating hormone/GPER signaling as a therapeutic avenue without growth-promoting effects in GEP-NETs.
Impact: This study provides mechanistic evidence linking sex hormone receptors and GPER signaling to PPGL growth control, identifies ERα prevalence in HNPGLs, and proposes G-1 as a candidate therapy with sex- and genotype-specific efficacy.
Clinical Implications: Consider hormone receptor profiling (ERα/AR/GPER) in PPGLs, especially HNPGLs and NF1-mutant tumors, and exercise caution with exogenous hormones. GPER agonists such as G-1 warrant translational development and sex-informed trial designs.
Key Findings
- Estradiol and progesterone (1 µM) reduced PPGL cell viability, with strongest effects in NF1 (cluster 2) tumors.
- ERα positivity in 11/36 PPGLs (including 4/4 HNPGLs); ERα-positive tumors responded significantly to estradiol.
- GPER agonist G-1 showed strong antitumor activity, with greater responsiveness in tumors from male patients and in NF1-mutant tumors.
- High-dose testosterone (10 µM) exerted antitumor effects in select AR-positive tumors; DHEAS/testosterone at 1 µM had no effect.
- Sex hormones did not promote growth in GEP-NETs.
Methodological Strengths
- Use of patient-derived primary cultures and matched tumor tissues with receptor IHC and NGS
- Pharmacologic interrogation across multiple hormones and a selective GPER agonist with sex-stratified analyses
Limitations
- Predominantly ex vivo/in vitro data without clinical outcome trials
- Sample sizes are modest and external generalizability is uncertain
Future Directions: Conduct biomarker-driven early-phase trials of GPER agonists (e.g., G-1) stratified by NF1 status and sex; clarify endocrine therapy risks in PPGL during pregnancy or hormone replacement.
OBJECTIVE: The effects of sex hormones remain largely unexplored in pheochromocytomas and paragangliomas (PPGLs) and gastroenteropancreatic neuroendocrine tumors (GEP-NETs). METHODS: We evaluated the effects of estradiol, progesterone, Dehydroepiandrosterone sulfate (DHEAS), and testosterone on human patient-derived PPGL/GEP-NET primary culture cell viability (n = 38/n = 12), performed next-generation sequencing and immunohistochemical hormone receptor analysis in patient-derived PPGL tumor tissues (n = 36). RESULTS: In PPGLs, estradiol and progesterone (1 µm) demonstrated overall significant antitumor effects with the strongest efficacy in PPGLs with NF1 (cluster 2) pathogenic variants. Estrogen receptor alpha (ERα) positivity was detected in 11/36 PPGLs, including 4/4 head-and-neck paragangliomas (HNPGLs). ERα-positive tumors responded with a significant cell viability decrease to estradiol. DHEAS and testosterone (1 µm) displayed no effects, but higher doses of testosterone (10 µm) demonstrated significant antitumor effects, including a pheochromocytoma lung metastasis with strong androgen receptor positivity (30%). Driven by the antitumor effects of estrogen, we evaluated G-protein-coupled estrogen receptor (GPER) agonist G-1 as a potential therapeutic option for PPGLs and found strong significant antitumor potential, with the strongest efficacy in tumors with NF1 pathogenic variants. Moreover, we detected sex-related differences-tumors from male patients showed significantly stronger responsivity to G-1 compared with tumors from female patients. In GEP-NETs, sex hormones showed overall no effects, especially no tumor growth-promoting effects. CONCLUSION: We provide novel data on the effects of elevated sex hormone levels, potentially seen during pregnancy or hormone replacement therapy, on PPGL/GEP-NET tumor growth. G-1 might offer a novel therapeutic approach for some PPGLs depending on patient's sex and the individual tumor's genetic/molecular background. All HNPGLs showed ERα positivity.
2. Overweight, obesity, and cardiovascular disease in heterozygous familial hypercholesterolaemia: the EAS FH Studies Collaboration registry.
In 35,540 HeFH patients worldwide, 52% of adults and 27% of children were overweight/obese. Obesity was associated with more atherogenic lipids and substantially higher odds of CAD (children OR 9.28; adults OR 2.35) and stroke (adults OR 1.65), independent of LDL-C and lipid-lowering therapy.
Impact: Establishes obesity as an LDL-C–independent risk factor for ASCVD in HeFH from childhood, informing comprehensive risk management beyond cholesterol reduction.
Clinical Implications: Integrate structured weight management into HeFH care alongside LDL-C lowering. Prioritize early lifestyle and obesity interventions in pediatric HeFH to reduce lifetime ASCVD risk.
Key Findings
- Overweight/obesity prevalence: 52% in adults and 27% in children with HeFH across 50 countries.
- Obesity associated with a more atherogenic lipid profile independent of lipid-lowering therapy.
- Risk gradients across BMI categories for CAD in both children and adults; obesity raised odds of CAD (children OR 9.28; adults OR 2.35) and stroke (adults OR 1.65).
- Associations persisted after adjustment for diabetes, hypertension, and smoking, though attenuated.
Methodological Strengths
- Very large multinational registry with pediatric and adult strata
- Analyses adjusted for lipids and lipid-lowering medications with consistent gradients across BMI categories
Limitations
- Cross-sectional design limits causal inference and temporal ordering
- Residual confounding and selection biases cannot be excluded
Future Directions: Prospective studies to quantify ASCVD risk reduction from weight loss interventions in HeFH and integrate BMI into HeFH-specific risk tools.
BACKGROUND AND AIMS: Overweight and obesity are modifiable risk factors for atherosclerotic cardiovascular disease (ASCVD) in the general population, but their prevalence in individuals with heterozygous familial hypercholesterolaemia (HeFH) and whether they confer additional risk of ASCVD independent of LDL cholesterol (LDL-C) remains unclear. METHODS: Cross-sectional analysis was conducted in 35 540 patients with HeFH across 50 countries, in the EAS FH Studies Collaboration registry. Prevalence of World Health Organization-defined body mass index categories was investigated in adults (n = 29 265) and children/adolescents (n = 6275); and their association with prevalent ASCVD. RESULTS: Globally, 52% of adults and 27% of children with HeFH were overweight or obese, with the highest prevalence noted in Northern Africa/Western Asia. A higher overweight/obesity prevalence was found in non-high-income vs. high-income countries. Median age at familial hypercholesterolaemia diagnosis in adults with obesity was 9 years older than in normal weight adults. Obesity was associated with a more atherogenic lipid profile independent of lipid-lowering medication. Prevalence of coronary artery disease increased progressively across body mass index categories in both children and adults. Compared with normal weight, obesity was associated with higher odds of coronary artery disease in children (odds ratio 9.28, 95% confidence interval 1.77-48.77, adjusted for age, sex, lipids, and lipid-lowering medication) and coronary artery disease and stroke in adults (odds ratio 2.35, 95% confidence interval 2.10-2.63 and odds ratio 1.65, 95% confidence interval 1.27-2.14, respectively), but less consistently with peripheral artery disease. Adjusting for diabetes, hypertension and smoking modestly attenuated the associations. CONCLUSIONS: Overweight and obesity are common in patients with HeFH and contribute to ASCVD risk from childhood, independent of LDL-C and lipid-lowering medication. Sustained body weight management is needed to reduce the risk of ASCVD in HeFH.
3. Clonal Hematopoiesis of Indeterminate Potential and Risk of Microvascular Complications Among Individuals With Type 2 Diabetes: A Cohort Study.
In a cohort of individuals with type 2 diabetes, CHIP was associated with increased risk of diabetic retinopathy and diabetic kidney disease but not neuropathy. Gene-specific signals suggest certain driver mutations may confer higher microvascular risk.
Impact: Introduces CHIP as a novel, non-traditional risk factor for diabetic microvascular complications, potentially reshaping risk stratification and prevention strategies.
Clinical Implications: Consider CHIP screening in high-risk type 2 diabetes to identify those at heightened risk for retinopathy and DKD; integrate CHIP into risk models and intensify surveillance and reno-retinal protective strategies.
Key Findings
- CHIP was associated with higher risk of diabetic microvascular complications overall.
- Association was specific to diabetic retinopathy and diabetic kidney disease, but not diabetic neuropathy.
- Gene-specific analyses implicated certain CHIP driver genes in elevated microvascular risk.
Methodological Strengths
- Cohort design assessing incident microvascular outcomes in type 2 diabetes
- Gene-specific analyses to dissect driver contributions beyond traditional risk factors
Limitations
- Abstract lacks detailed sample size and effect estimates; potential residual confounding
- Findings require replication and mechanistic validation
Future Directions: Validate CHIP–microvascular links in diverse cohorts; integrate CHIP into diabetic risk calculators; test anti-inflammatory or clone-targeted interventions to reduce retinopathy/DKD risk.
Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related disorder that is associated with macrovascular diseases, such as coronary artery disease and stroke. However, the effects of CHIP on microvascular complication have not been explored in individuals with type 2 diabetes. We wanted to determine whether CHIP is associated with diabetic microvascular complications (DMCs). CHIP was associated with a high risk of DMCs, specifically, diabetic retinopathy and diabetic kidney disease, but not diabetic neuropathy. Gene-specific analyses suggested that some driver genes were associated with risk of developing DMCs. These findings indicated that CHIP may represent a novel risk factor for DMCs among individuals with type 2 diabetes, distinct from traditional risk factors, which may have implications for prevention and management of DMCs.