Daily Endocrinology Research Analysis
Multi-omics data reveal a pro-inflammatory neutrophil signature across karyotypes in Turner syndrome, implicating innate immune activation in endocrine comorbidities. A nationwide Dutch cohort shows a threefold higher diabetes risk in childhood cancer survivors with strong links to total body irradiation and abdominal/pelvic radiotherapy. A 24-year OMEGA cohort analysis reassures that assisted reproductive technology does not increase long-term endometrial cancer risk; obesity and endometriosis
Summary
Multi-omics data reveal a pro-inflammatory neutrophil signature across karyotypes in Turner syndrome, implicating innate immune activation in endocrine comorbidities. A nationwide Dutch cohort shows a threefold higher diabetes risk in childhood cancer survivors with strong links to total body irradiation and abdominal/pelvic radiotherapy. A 24-year OMEGA cohort analysis reassures that assisted reproductive technology does not increase long-term endometrial cancer risk; obesity and endometriosis elevate risk while parity and oral contraceptives are protective.
Research Themes
- Immune–endocrine crosstalk in sex chromosome disorders
- Metabolic late effects in cancer survivorship
- Onco-endocrine risk stratification after assisted reproductive technology
Selected Articles
1. Elevated levels of neutrophils with a pro-inflammatory profile in Turner syndrome across karyotypes.
Using methylome and transcriptome profiling across karyotypes, the study shows a shared autosomal signature in Turner syndrome driven by loss of Xp (including PAR1), independent of XIST. Neutrophils are increased and activated, linked to TBL1X expression and clinical traits, suggesting neutrophil-driven inflammatory stress as a mechanistic contributor to TS comorbidities.
Impact: Reveals a novel immune–genetic mechanism in Turner syndrome linking Xp loss and TBL1X to neutrophil activation, reframing comorbidity risk beyond gonadal failure alone. Provides testable biomarkers for risk stratification.
Clinical Implications: Consider monitoring neutrophil counts/activation and inflammatory markers in Turner syndrome as part of cardiometabolic risk assessment. Findings may inform future trials targeting innate immune pathways to mitigate metabolic and autoimmune comorbidities.
Key Findings
- Common autosomal methylome and transcriptome across TS despite different karyotypes
- Universal loss of Xp (including PAR1); XIST expression from Xq did not alter autosomal omics
- Elevated neutrophil levels and activation linked to TS clinical traits
- Neutrophil increase associated with higher expression of X–Y homolog TBL1X, suggesting a genetic basis
Methodological Strengths
- Integrated methylome and transcriptome profiling across multiple TS karyotypes
- Mechanistic linkage to specific gene (TBL1X) and cellular phenotype (neutrophil activation)
Limitations
- Sample size and cohort details not specified in the abstract
- Cross-sectional design limits causal inference and clinical outcome linkage
- External validation in independent cohorts is needed
Future Directions: Validate neutrophil activation and TBL1X as biomarkers in independent TS cohorts; longitudinal studies to link inflammatory signatures with cardiometabolic outcomes; explore targeted anti-inflammatory or immunomodulatory interventions.
Turner syndrome (TS) presents with multiple karyotypes, including 45,X monosomy and variants such as isochromosomes and mosaicism, and is characterized by several co-morbidities, including metabolic conditions and autoimmunity. Here, we investigated the genomic landscapes across a range of karyotypes. We show that TS have a common autosomal methylome and transcriptome, despite distinct karyotypic variations. All TS individuals lacked the X chromosome p-arm, and XIST expression from the q-arm did not affect the autosomal transcriptome or methylome, highlighting the critical role of the missing p-arm with its pseudoautosomal region 1. Furthermore, we show increased levels of neutrophils and increased neutrophil activation. The increase in neutrophils was linked to TS clinical traits and to increased expression of the X-Y homologous gene TBL1X, suggesting a genetic basis, which may lead to neutrophil-driven inflammatory stress in TS. Identifying TS individuals with increased neutrophil activation could potentially mitigate the progression towards more severe metabolic issues.
2. Prevalence and Determinants of Diabetes Mellitus in 2338 Long-Term Dutch Childhood Cancer Survivors (DCCS-LATER2 Study).
In a nationwide cross-sectional analysis of 2,338 Dutch childhood cancer survivors versus 132,226 adults without cancer, survivors had ~3-fold higher odds of hyperglycemia, diabetes diagnosis, and antidiabetic medication use. Key determinants included total body irradiation (OR 14.31), abdominal/pelvic radiotherapy (OR 4.19), hypogonadism (OR 2.40), age, BMI, family history, hypertension, and dyslipidemia.
Impact: Quantifies substantial diabetes burden decades after childhood cancer and identifies high-risk exposures and endocrine sequelae, directly informing survivorship screening and prevention strategies.
Clinical Implications: Implement early, risk-based diabetes screening in childhood cancer survivors, especially those exposed to total body irradiation or abdominal/pelvic radiotherapy and those with hypogonadism. Address modifiable risks (BMI, hypertension, dyslipidemia) via lifestyle and pharmacologic interventions.
Key Findings
- Survivors had ~3-fold higher odds of hyperglycemia (aOR 2.72), diabetes diagnosis (aOR 3.03), and antidiabetic medication use (aOR 2.94) versus reference adults
- Total body irradiation (OR 14.31) and abdominal/pelvic radiotherapy (OR 4.19) were strong determinants of diabetes
- Hypogonadism (OR 2.40), higher age, BMI, family history, hypertension, and dyslipidemia independently associated with diabetes
- Age–sex interaction influenced diabetes development among survivors
Methodological Strengths
- Large nationwide survivor cohort with an extensive external reference population
- Objective glucose thresholds complemented by self-report; multivariable adjustment for key confounders
Limitations
- Cross-sectional design limits causal inference and incidence estimation
- Potential residual confounding and treatment detail granularity constraints
- Screening/selection biases possible in survivor follow-up
Future Directions: Prospective surveillance to quantify diabetes incidence post-exposure; intervention trials targeting high-risk survivors (post-TBI/abdominal–pelvic RT, hypogonadism); integrate endocrine evaluation into survivorship care plans.
CONTEXT: Diabetes mellitus (DM), a possible adverse effect of childhood cancer treatment, is strongly associated with cardiovascular disease and early mortality in adult childhood cancer survivors (CCS). OBJECTIVE: Here, we assess the prevalence and determinants of DM in our nationwide CCS cohort. METHODS: In this cross-sectional study, the prevalence of DM was assessed in 2338 CCS, using the Lifelines cohort (n = 132 226 adults with no history of cancer) as a reference. DM was defined through serum glucose measurement (fasting glucose ≥7.0 mmol/L or nonfasting ≥11.1 mmol/L) and/or self-report (previous diagnosis and/or medication use). Multivariable logistic regression models, adjusted for age, sex, and body mass index (BMI), were used to assess the cohort effect on the presence of DM. Multivariable logistic regression analysis was used to identify determinants of DM in CCS. RESULTS: Survivors (median age 34.7 years, median follow-up time 27.1 years) showed increased odds for hyperglycemia (aOR = 2.72; 95% CI, 2.06-3.59), previous DM diagnosis (aOR = 3.03; 95% CI, 2.33-3.95), and antidiabetic medication use (aOR = 2.94; 95% CI, 2.17-3.99), compared to the reference cohort. Age (OR = 4.32; 95% CI, 1.84-10.15, >35 vs 18-35 years), BMI (OR = 1.12; 95% CI, 1.08-1.16, per point), family history of DM (OR = 2.38; 95% CI, 1.51-3.76), prior abdominal/pelvic radiotherapy (OR = 4.19; 95% CI, 2.32-7.55), total body irradiation (OR = 14.31; 95% CI, 6.98-29.34), hypogonadism (OR = 2.40; 95% CI, 1.15-4.99), hypertension (OR = 1.71; 95% CI, 1.06-2.76), and dyslipidemia (OR = 3.81; 95% CI, 2.15-6.75) were associated with DM in CCS. A statistically significant interaction between age and sex on the development of DM in survivors was identified. CONCLUSION: The identified 3-fold increased risk of DM in CCS, along with the clinically relevant and some modifiable determinants, underscores the importance of early risk-based screening and the exploration of lifestyle interventions in this population.
3. Long-term risk of endometrial cancer after assisted reproductive technology.
In the OMEGA nationwide cohort (30,625 ART; 9,988 subfertile non-ART; median follow-up 24 years), endometrial cancer risk after ART was not increased versus the general population (SIR 1.19; 95% CI 0.97–1.44) or versus subfertile non-ART women (adjusted HR 1.11; 95% CI 0.74–1.67). Risk did not rise with longer follow-up or more ART cycles; obesity and endometriosis increased risk, whereas parity and oral contraceptives decreased risk.
Impact: Provides long-term, high-quality reassurance on ART safety regarding endometrial cancer, addressing a longstanding clinical concern with robust registry-linked data.
Clinical Implications: ART alone should not prompt additional endometrial cancer surveillance beyond standard care; counseling should emphasize weight management and endometriosis as modifiable/non-modifiable risk modifiers and acknowledge protective effects of parity and oral contraceptive use.
Key Findings
- No significant increase in endometrial cancer after ART vs general population (SIR 1.19; 95% CI 0.97–1.44)
- No increase vs subfertile non-ART women (adjusted HR 1.11; 95% CI 0.74–1.67)
- Risk did not rise with more ART cycles or longer follow-up; not modified by cause of subfertility
- Obesity and endometriosis increased risk; parity and oral contraceptive use decreased risk
Methodological Strengths
- Large nationwide historic cohort with cancer registry linkage and person-years analysis
- Detailed ART exposure data and multivariable Cox regression with key confounder control
Limitations
- Median age at end of follow-up was 56 years; additional follow-up needed to capture older-age risk
- ART era (1983–2001) may not fully reflect contemporary protocols and exposures
- Potential residual confounding; lifestyle data partly based on questionnaire
Future Directions: Extend follow-up by 10–15 years and replicate in contemporary ART cohorts; refine risk models integrating BMI, endometriosis, parity, and hormonal exposures.
STUDY QUESTION: What is the risk of endometrial cancer after long-term follow-up in women treated with ART between 1983 and 2001 compared with women in the general population and subfertile women who did not undergo ART? SUMMARY ANSWER: The risk of endometrial cancer is not increased in women who underwent ART in the Netherlands between 1983 and 2001, neither compared with women from the general population nor compared with subfertile women not treated with ART. WHAT IS KNOWN ALREADY: Concerns have been raised that subfertility treatment may be associated with increased risk of endometrial cancer. However, published studies show inconsistent results regarding the effects of ovarian stimulation and specific subfertility diagnoses on endometrial cancer risk. STUDY DESIGN, SIZE, DURATION: A nationwide historic cohort study (the OMEGA-cohort) was conducted to examine the risk of cancer in women after ovarian stimulation for ART. The OMEGA-cohort comprises 30 625 women who received ovarian stimulation for ART (ART group) in 1983-2000 and 9988 subfertile women not treated with ART (non-ART group). After a median follow-up of 24 years, endometrial cancer incidence was ascertained through linkage with the Netherlands Cancer Registry. Endometrial cancer risk in the cohort was compared with that in the general population using person-years analyses, and between the ART group and non-ART group using multivariable Cox regression analyses.