Daily Endocrinology Research Analysis
Analyzed 76 papers and selected 3 impactful papers.
Summary
A phase 2 randomized, double-blind trial showed that an oral small-molecule GLP-1 receptor agonist (HRS-7535) achieved up to 9.36% weight loss over 26 weeks in adults with obesity without diabetes. A large prospective implementation study demonstrated the feasibility of universal, lab-guided screening for hypothyroidism in early pregnancy, identifying 0.4% with overt or subclinical autoimmune hypothyroidism. Despite marked transcriptomic perturbations in programmed-cycle endometrium versus natural cycles, no increase in angiogenic imbalance or hypertensive disorders of pregnancy was observed.
Research Themes
- Oral incretin therapeutics for obesity
- Universal screening for thyroid dysfunction in pregnancy
- Endometrial biology in IVF and hypertensive disorders of pregnancy risk
Selected Articles
1. HRS-7535, an oral small-molecule GLP-1 receptor agonist, in Chinese adults with obesity without diabetes: a randomized, double-blind, placebo-controlled phase 2 trial.
In adults with obesity without diabetes, once-daily oral HRS-7535 produced dose-dependent weight loss up to 9.36% at 26 weeks, with placebo-adjusted reductions of up to 6.87%. Gastrointestinal adverse events were mostly mild to moderate and occurred more frequently during dose escalation.
Impact: Demonstrates clinically meaningful weight loss with a first-in-class oral small-molecule GLP-1RA in a randomized, double-blind phase 2 trial, expanding the therapeutic landscape beyond injectables.
Clinical Implications: If efficacy and safety are confirmed in larger and longer trials, an oral small-molecule GLP-1RA could improve access and adherence for obesity treatment, offering an alternative to injectable incretins.
Key Findings
- Least-squares mean weight change at week 26: −2.99% (30 mg), −7.09% (60 mg), −6.17% (120 mg), −9.36% (180 mg) vs −2.50% with placebo
- Placebo-adjusted differences: −0.49%, −4.60%, −3.67%, −6.87% (p=0.7104, 0.0006, 0.0062, <0.0001, respectively)
- GI adverse events were the most common and predominantly mild to moderate, occurring more during dose escalation
Methodological Strengths
- Multicenter randomized, double-blind, placebo-controlled phase 2 design
- Dose-ranging evaluation with prespecified primary endpoint and trial registration (NCT06250946)
Limitations
- Short duration (26 weeks) without long-term efficacy/safety data
- Single-country population (China) and no active-comparator arm limit generalizability
Future Directions: Conduct global phase 3 trials with longer follow-up, active comparators (e.g., injectable GLP-1RAs), cardiometabolic outcomes, and adherence/cost-effectiveness analyses.
HRS-7535 is an orally active small-molecule glucagon-like peptide-1 receptor agonist that showed weight-loss potential in a phase 1 study. In this completed multicenter, randomized, double-blind, placebo-controlled phase 2 trial conducted at 29 centers in China, we evaluated the efficacy and safety of HRS-7535 in adults with obesity without diabetes. 235 participants with a body mass index of 28.0-40.0 kg/m² were randomized a 1:1:1:1:1 ratio to once-daily oral HRS-7535 at target doses of 30 mg (n = 48), 60 mg (n = 47), 120 mg (n = 46), or 180 mg (n = 48), or placebo (n = 46); all randomized participants were included in the analyses. Primary endpoint was percentage change in body weight from baseline to Week 26. At Week 26, least-squares (LS) mean percentage changes in body weight were -2.99% with 30 mg, -7.09% with 60 mg, -6.17% with 120 mg, and -9.36% with 180 mg, versus -2.50% with placebo. Corresponding placebo-adjusted LS mean differences were -0.49%, -4.60%, -3.67%, and -6.87% (P = 0.7104, 0.0006, 0.0062, and <0.0001, respectively). Gastrointestinal adverse events were the most common, were predominantly mild to moderate, and occurred more frequently during dose escalation. Overall, once-daily oral HRS-7535 at doses of 60 mg or higher produced clinically meaningful weight loss and was generally well tolerated.Trial registration: ClinicalTrials.gov identifier NCT06250946.
2. Universal screening to detect hypothyroidism in pregnant women.
Lab-guided universal screening at the time of routine prenatal sampling identified 0.39% of pregnant women with previously unknown TSH >6 mIU/L, nearly all with autoimmune hypothyroidism. Implementation was feasible at scale in a regional health system.
Impact: Provides pragmatic, system-level evidence that early-pregnancy universal thyroid screening can be operationalized and yields clinically actionable cases of autoimmune hypothyroidism.
Clinical Implications: Health systems could consider reflex TSH/fT4 with thyroid autoantibodies on prenatal samples to enable early diagnosis and treatment of maternal hypothyroidism; outcome and cost-effectiveness evaluations are needed before policy adoption.
Key Findings
- Screened 11,841 samples from 10,403 pregnant women; 41 (0.39%) had previously unknown TSH >6 mIU/L
- Of screen-positives, 32 had overt and 9 had subclinical hypothyroidism; TSH range 6.1–59.4 mIU/L (19 women >10 mIU/L)
- All screen-positive women had detectable TPO-Ab and/or Tg-Ab, consistent with autoimmune hypothyroidism
Methodological Strengths
- Prospective, region-wide implementation with large sample size and standardized lab thresholds
- Autoantibody confirmation enhanced diagnostic specificity and immediate referral pathway established
Limitations
- Reporting only for TSH >6 mIU/L may miss milder cases and does not evaluate outcomes of treatment
- Single-region study; generalizability and cost-effectiveness not assessed
Future Directions: Assess maternal-fetal outcomes, cost-effectiveness, and equity impacts of universal screening versus targeted approaches; refine thresholds for reflex reporting.
OBJECTIVE: Hypothyroidism may be detrimental when left undiagnosed, but universal testing of pregnant women is hitherto not implemented. We studied the implementation of a laboratory-guided universal screening model to detect hypothyroidism in pregnant women. DESIGN: A prospective implementation study in the North Denmark Region during a two-year period (2022-2024). METHODS: Serum residues of blood samples drawn from Danish pregnant women as part of prenatal screening for chromosomal anomalies in early pregnancy (median the 10th week) were used for measurement of thyroid-stimulating hormone (TSH), free thyroxine (fT4), thyroid peroxidase and thyroglobulin antibodies (TPO-Ab and Tg-Ab) upon arrival in the laboratory. Results were clinically reported only if maternal TSH in the sample was above 6 mIU/L, and thyroid disease was not known. Overt/subclinical hypothyroidism was defined by fT4 below/within the method- and trimester-specific reference interval (10.2-15.2 pmol/L). RESULTS: A total of 11,841 samples were screened from 10,403 pregnant women (median age of 30 years). Unknown maternal TSH above 6 mIU/L was identified in 41 women (0.39%) of whom 32 had overt and 9 had subclinical hypothyroidism. TSH ranged from 6.1 to 59.4 mIU/L and was above 10 mIU/L in 19 women. All screen-positive cases had detectable TPO-Ab and/or Tg-Ab, and the general practitioner was immediately informed for specialist referral and treatment. CONCLUSIONS: This prospective study tested implementation of a universal screening model to detect maternal hypothyroidism in pregnancy. Clinical implementation was feasible, and 0.4% of Danish pregnant women were found to be screen-positive, all with detectable thyroid autoantibodies, indicative of autoimmune hypothyroidism.
3. Programmed cycle-induced endometrial perturbations do not independently influence angiogenic imbalance or hypertensive disorders in pregnancy.
Single-nucleus RNA-seq revealed substantial cell-type–specific transcriptomic changes in programmed-cycle WOI endometrium, including reduced uNK cells and downregulated implantation/angiogenesis pathways. However, in an independent prospective cohort (n=548), PC-conceived pregnancies showed no increase in early angiogenic imbalance or hypertensive disorders of pregnancy versus natural cycles.
Impact: Bridges mechanistic endometrial biology with clinical outcomes, suggesting that molecular perturbations from programmed preparation do not translate into increased HDP risk via angiogenic imbalance.
Clinical Implications: Supports continued use of programmed cycles when clinically indicated without added concern for angiogenic imbalance–mediated HDP; monitoring strategies may remain focused on standard risk factors.
Key Findings
- PC vs NC WOI endometrium showed large differential gene expression: glandular epithelium (682 up/979 down), stromal fibroblasts (108 up/168 down)
- PC endometrium had reduced uterine NK cell abundance, potentially linked to CXCL14 downregulation; implantation/angiogenesis/ECM pathways were downregulated
- In a cohort of 548 pregnancies, PC conception was not associated with early angiogenic imbalance (sFlt-1/PlGF) or increased HDP risk after adjustment
Methodological Strengths
- Integrated single-nucleus transcriptomics with an independent, prospective clinical cohort
- Adjusted analyses for confounders and standardized angiogenic biomarker assessment
Limitations
- Small snRNA-seq sample size (PC n=7, NC n=9) limits generalizability of cellular findings
- Observational cohort cannot exclude residual confounding; outcomes beyond angiogenic markers and HDP not assessed
Future Directions: Validate endometrial signatures in larger cohorts, extend clinical endpoints (e.g., placental pathology, fetal growth), and test protocol refinements to mitigate implantation-pathway downregulation without increasing HDP risk.
BACKGROUND: In vitro fertilization (IVF) culminates in embryo transfer into a hormonally primed endometrium, often via a programmed cycle (PC) regimen postulated to influence hypertensive disorders of pregnancy (HDP) risk. We thus generated a single-cell atlas of PC endometrium to define cell type-specific differences relative to natural cycle (NC) endometrium, and evaluated whether PC-associated modulation of the window of implantation (WOI) endometrium influences angiogenic balance in pregnancy. METHODS: Single-nucleus RNA-seq of prospectively collected PC and NC WOI endometrium. An independent prospective cohort of 548 singleton pregnancies was separately analyzed for maternal serum angiogenic markers (soluble fms-like tyrosine kinase-1; placental growth factor) and HDP incidence in PC- versus NC-conceived pregnancies, adjusting for clinical confounders and IVF use. RESULTS: Prominent transcriptomic differences were observed between PC (n = 7; 48,843 nuclei) and NC (n = 9; 44,230 nuclei) WOI endometrium, particularly in glandular epithelium (682 up- and 979 down-regulated genes; adjusted P < 0.05) and stromal fibroblasts (108 up- and 168 down-regulated). PC endometrium showed reduced uterine natural killer cell abundance, potentially from CXCL14 downregulation. Functional enrichment revealed downregulation of embryo implantation, angiogenesis, and extracellular matrix remodeling pathways in PC. Altered cell-cell signaling in decidualization, angiogenesis, and inflammatory response was also observed. Despite these WOI perturbations, PC-conceived pregnancies were not associated with early gestational angiogenic imbalance or increased HDP risk. CONCLUSION: PC endometrial preparation induced distinct cellular and signaling alterations in the WOI, but was not associated with subsequent development of angiogenic imbalance or HDP, thereby underscoring the resilience and adaptability of the early maternal-fetal interface. CLINICALTRIALS: gov NCT03799107. FUNDING: ABOG/AAOGF; NICHD-R01-HD084380; NCTRI-P50-HD055764; NIAMS-P30-AR070155.