Daily Endocrinology Research Analysis
Three impactful endocrinology studies stood out today: a large biobank-based analysis shows that incidentally found moderate-risk RET variants confer much lower medullary thyroid cancer risk than clinically ascertained MEN2 cases; an ancillary Look AHEAD analysis reveals that sex hormone shifts mediate bone mineral density loss after intensive lifestyle intervention in older adults with type 2 diabetes; and long-term follow-up of modified-release hydrocortisone in congenital adrenal hyperplasia
Summary
Three impactful endocrinology studies stood out today: a large biobank-based analysis shows that incidentally found moderate-risk RET variants confer much lower medullary thyroid cancer risk than clinically ascertained MEN2 cases; an ancillary Look AHEAD analysis reveals that sex hormone shifts mediate bone mineral density loss after intensive lifestyle intervention in older adults with type 2 diabetes; and long-term follow-up of modified-release hydrocortisone in congenital adrenal hyperplasia demonstrates sustained biochemical control with lower doses and practical monitoring.
Research Themes
- Genomic risk stratification in endocrine oncology
- Hormone-mediated bone effects during weight loss in diabetes
- Circadian-aligned steroid replacement in adrenal disorders
Selected Articles
1. Medullary Thyroid Cancer Risk and Mortality in Carriers of Incidentally Identified MEN2A RET Variants.
Across two large unselected cohorts, pathogenic RET variants were rare and predominantly moderate-risk. By age 75, medullary thyroid cancer risk in incidental carriers was 2.2% in the UK Biobank and 19.3% in the US health system cohort—far lower than matched clinically ascertained cases (~95.7%). All-cause mortality was similar to noncarriers, and most carriers did not undergo thyroidectomy.
Impact: This study refines risk estimates for incidentally detected RET variants, addressing a key management dilemma in precision endocrine oncology and informing surveillance vs prophylactic surgery decisions.
Clinical Implications: Moderate-risk RET variants identified incidentally may warrant conservative, individualized surveillance rather than routine prophylactic thyroidectomy, with counseling tailored to variant class and patient context.
Key Findings
- RET pathogenic variant prevalence was 0.04% in UK Biobank (n=169) and 0.06% in a US health system cohort (n=77), mostly moderate-risk per ATA guidelines.
- Kaplan–Meier estimated medullary thyroid cancer risk by age 75: 2.2% (UK, 95% CI 0.7–6.9) and 19.3% (US, 95% CI 6.4–30.2) vs 95.7% (95% CI 82.1–99.7) in clinically ascertained matched variants.
- All-cause mortality to age 75 was similar between carriers without thyroidectomy and noncarriers in UK Biobank (6.1% vs 5.7%).
Methodological Strengths
- Two large, prospective, unselected cohorts (UK Biobank and US health system) with long follow-up
- Comparative analysis with a clinically ascertained MEN2 cohort and survival analyses adjusted for age/sex
Limitations
- Variant spectrum predominantly moderate-risk; findings may not generalize to high-risk variants
- Differences between UK and US cohorts suggest potential ascertainment or health system effects
Future Directions: Prospective registries with standardized surveillance protocols across variant classes and health systems are needed to refine age- and genotype-specific management strategies.
IMPORTANCE: RET germline pathogenic variants cause multiple endocrine neoplasia type 2 (MEN2), which is associated with medullary thyroid cancer. With increasing incidental identification of these variants in asymptomatic individuals outside family screening, these individuals' risk of medullary thyroid cancer and all-cause mortality without intervention remain unknown in this context. OBJECTIVE: To evaluate the risk of medullary thyroid cancer and all-cause mortality in clinically unselected individuals with incidentally identified RET variants and assess whether the risk of medullary thyroid cancer differs from those with clinically ascertained RET variants. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study of 383 914 unrelated individuals from the clinically unselected UK population (UK Biobank, recruited in 2006-2010, with follow-up to June 2023) and 122 640 unrelated individuals from a US health system (Geisinger MyCode cohort, recruited 2004-2020, with follow-up to October 2023) compared medullary thyroid cancer risk in these cohorts with 1078 individuals who were clinically ascertained with suspicion of MEN2 from a UK routine practice. EXPOSURES: RET germline pathogenic variants causing MEN2. MAIN OUTCOMES AND MEASURES: Frequency and the spectrum of pathogenic RET variants, risk of clinically present medullary thyroid cancer, and all-cause mortality without thyroidectomy were assessed using proportions with exact binomial 95% CIs and survival analysis adjusted for age at recruitment and sex.
2. Sex Hormones Mediate Intensive Lifestyle Intervention-Induced Bone Mineral Density Changes: Look AHEAD Sex Hormone Study.
In older adults with type 2 diabetes, sex hormone changes at 1 year partly mediated 4-year bone mineral density loss after intensive lifestyle intervention. A 14% estradiol decrease in females mediated whole-body BMD decline, and an 11% increase in total testosterone in males mediated hip BMD loss.
Impact: It clarifies a mechanistic pathway linking weight loss to bone loss via sex hormones, informing safer lifestyle and pharmacologic strategies for skeletal health in diabetes.
Clinical Implications: During intensive weight loss in older adults with T2D, monitor BMD and consider bone-protective strategies (resistance training, calcium/vitamin D optimization, antiresorptives when appropriate) while recognizing sex-specific hormone shifts.
Key Findings
- Sex hormone changes at 1 year mediated ILI-associated BMD losses over 4 years in postmenopausal females and older males.
- Females: 14% estradiol decline mediated a -1.15 mg/cm2 whole-body BMD decrease (95% CI -2.54, -0.21).
- Males: 11% increase in total testosterone mediated a -1.18 mg/cm2 hip BMD decrease (95% CI -2.68, -0.13).
Methodological Strengths
- Secondary analysis embedded in a large RCT framework (Look AHEAD) with 4-year follow-up
- Use of structural equation modeling for temporal mediation with sex-stratified analyses
Limitations
- Mediation analysis is observational and does not establish causality
- Ancillary study sample size not reported in abstract; hormone and BMD effects may be modest and population-specific
Future Directions: Test bone-preserving interventions during ILI (e.g., resistance exercise, antiresorptives) in sex-specific randomized substudies and integrate hormone dynamics and bone turnover markers.
CONTEXT: The Look AHEAD (Action in Health for Diabetes) randomized controlled trial, which compared an Intensive Lifestyle Intervention (ILI) to the Diabetes Support and Education (DSE) in people with overweight/obesity and type 2 diabetes (T2D), showed a greater decline in bone mineral density (BMD) along with greater weight loss in the ILI group. Because weight loss interventions change sex hormones and also affect BMD, understanding the role of sex hormones on these changes has implications for bone health in people with diabetes. OBJECTIVE: We assessed sex hormone mediation on BMD changes due to ILI, by sex, among postmenopausal females and older men over 4 years of follow-up. METHODS: In the Look AHEAD Sex Hormone Ancillary Study, we applied structural equation models to estimate the effects of ILI (vs. DSE) on hip, femoral neck, and whole-body BMD after 4 years of follow-up, temporally mediated by sex hormones estradiol (E2), total testosterone, bioavailable testosterone, and sex hormone binding globulin (SHBG) measured at one year after baseline (nadir of weight loss). RESULTS: In females, an ILI-associated decrease in estradiol of 14% from baseline to year 1 mediated a decline in whole-body BMD (-1.15 mg/cm2, 95%CI: -2.54, -0.21). In males, an ILI-associated increase of 11% in total testosterone mediated a decline of hip BMD (-1.18 mg/cm2, 95%CI: -2.68, -0.13). CONCLUSION: ILI-associated changes in estradiol and total testosterone resulted in whole-body and hip bone loss, providing insights in the potential role of sex hormones in bone loss accompanying weight loss in older adults with T2D who are at a higher risk of bone fractures.
3. Long-term outcomes in patients with congenital adrenal hyperplasia treated with hydrocortisone modified-release hard capsules.
In 91 adults with classic CAH treated with modified-release hydrocortisone, median dose decreased from 30 to 20 mg/day within 24 weeks and remained stable up to 4 years, while 17OHP and androstenedione control significantly improved. A single sample between 09:00–13:00 reliably monitored control, and adrenal crisis incidence was low.
Impact: Provides long-term, real-world evidence that circadian-aligned hydrocortisone delivery improves biochemical control with lower doses and practical monitoring, addressing a core challenge in CAH management.
Clinical Implications: Consider modified-release hydrocortisone to optimize control with reduced dose burden; monitor 17OHP/A4 with a single morning/early afternoon sample; counsel on fertility potential as control improves.
Key Findings
- Median hydrocortisone dose decreased from 30 mg/day to 20 mg/day by week 24 (P < .0001) and remained stable up to 48 months.
- Biochemical control improved: 17OHP (P < .03) and androstenedione (P < .002); at 4 years, 71% had 17OHP <4×ULN and 90% had androstenedione <ULN.
- Single blood sampling at 09:00 and 13:00 yielded similar control assessment; adrenal crisis incidence was 3.9 per 100 patient-years.
Methodological Strengths
- Multi-year follow-up with standardized biochemical endpoints relevant to CAH control
- Real-world dose optimization data with practical monitoring strategy validation
Limitations
- Open-label, single-arm follow-on design without randomized comparator
- Discontinuations (22/91) and potential selection bias limit generalizability
Future Directions: Head-to-head randomized trials versus immediate-release hydrocortisone on clinical outcomes (quality of life, crises, growth/fertility) and cost-effectiveness analyses are warranted.
BACKGROUND: Hydrocortisone modified-release hard capsules (MRHC, development name Chronocort) replace the physiological overnight cortisol rise and improve the biochemical control of congenital adrenal hyperplasia (CAH). AIM: This study aims to evaluate long-term safety, tolerability, and efficacy of MRHC. METHODS: This is an open-label follow-on study. RESULTS: Ninety-one patients with classic CAH, mean age 37 years, 68% female, 32% male, entered the study and 22 discontinued. Median treatment duration was 4 years (range 0.2-5.8). Median hydrocortisone dose at study entry was 30 mg/day and reduced to 20 mg/day after 24 weeks and stayed stable thereafter until 48 months (P < .0001). Disease control improved on MRHC for the steroid disease markers serum 17-hydroxyprogesterone (17OHP) (P < .03) and androstenedione (A4) (P < .002). After 4 years, the majority of patients had a 17OHP < 4-fold upper limit of normal (ULN) (71%) and an A4 <ULN (90%). Measurement of 17OHP and A4 at 09:00 h and 13:00 h gave similar results. Of the 37 women < 50 years of age who were not on contraceptives over the whole study period, 5 became pregnant (13.5%). Of the men, 13.8% (4/29) had a partner pregnancy. Seven patients had an adrenal crisis with 1 patient reporting 8 of these giving an incidence of 3.9 crises per 100 patient years. CONCLUSIONS: Modified-release hard capsule treatment resulted in hydrocortisone dose reduction followed by a stable dose with improved biochemical control associated with fertility. Biochemical control could be reliably monitored by a single blood sample taken between 09:00 and 13:00 h. The incidence of adrenal crises was below that reported previously in patients with CAH.