S-07-3: THE TESTOSTERONE-ANDROGEN RECEPTOR PATHWAY IS ASSOCIATED WITH CAROTID ATHEROSCLEROTIC PLAQUE INSTABILITY IN MEN WITH SEVERE CAROTID ATHEROSCLEROSIS
Bibliographic record
Abstract
Objective: Carotid atherosclerotic plaques can be stable or unstable; the latter more likely to rupture resulting in strokes. Sex differences exist in carotid plaque morphology and composition: carotid plaques of men tend to be more unstable than of women, who tend to have more fibrous and stable plaques. Yet, women experience greater morbidity and mortality rates post-stroke. Given that sex hormones exert pleiotropic effects on the cell types involved in the atherosclerotic process, and given that estradiol is largely atheroprotective in women, we hypothesize that sex hormones and their receptors may affect plaque instability. Design and Methods: In this cross-sectional study, we measured sex hormones in the circulation and their receptors in the plaque of older men and postmenopausal women undergoing a carotid endarterectomy (n = 160). Using liquid chromatography mass spectrometry, circulating estradiol, testosterone, dehydroepiandrosterone (DHEA), and androstenedione were measured in blood samples. Plaques collected post-operatively were classified into 4 groups (n = 40/group): women with stable, women with unstable plaques, men with stable, and men with unstable plaques. Protein expression of estrogen receptor α (ER-α), estrogen receptor β (ER-β), G protein-coupled estrogen receptor (GPER), and androgen receptor (AR) was quantified using immunohistochemistry and western blot analysis. Plaque sex hormone receptor mRNA expression was assessed using qRT-PCR. Results: Men with unstable plaques demonstrated greater circulating concentrations of testosterone and androstenedione compared to men with stable plaques (P = 0.02 and P = 0.047, respectively). Unstable plaques in men demonstrated significantly less AR and ER-α mRNA expression compared to stable plaques from men (P = 0.0003 and P = 0.042, respectively) and compared to unstable plaques from women (P = 0.0088 and P = 0.002). Yet, AR, ER-α, ER-β, and GPER protein expression was significantly greater in unstable plaques from men compared to stable plaques from men (P = 0.039, P = 0.006, P < 0.0001, and P = 0.0002, respectively) and compared to unstable plaques from women (P = 0.005, P = 0.041, P = 0.028, and P = 0.002, respectively). Expression was observed in macrophages, foam cells, endothelial cells, and smooth muscle cells. Moreover, unstable plaques from men demonstrated greater features of plaque instability compared to unstable plaques from women, including hemorrhage, large lipid core, abundance of inflammatory cells, and fibrous cap infiltration by inflammatory cells (P < 0.05 for all). Conclusion: Our preliminary findings indicate a possible association between androgens and the androgen receptor pathway and plaque instability. With further investigations, our ongoing work will unravel the underlying mechanisms, and may ultimately lead to hormone-specific therapies aimed at stabilizing plaques and reducing the incidence of stroke for men and women.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".