Sex- and Menopause-Specific Hormone-Related ECG Signatures and Incident Cardiovascular Risk in UK Biobank
Hernandez, A., Madrid, J., Sanchez, C., Sanz, A., Young, W. J., Munroe, P. B., Minchole, A., Ramirez, J.
cardiovascular medicine
Quick verdict
Claims hormone-linked ECG signatures track 12.8-yr CV risk in UK Biobank, but the ECG-component Cox HRs just restate hormone-only HRs; mediation unproven.
Summary
This UK Biobank study (N=8,056, European ancestry, median follow-up 12.8 years) asks whether circulating sex hormones shape ECG morphology and whether hormone-related ECG components predict incident cardiovascular disease (CVD), stratified by sex and menopausal status. Participants with prevalent CVD, rate-limiting therapy, or exogenous hormones were excluded; lead-I resting ECGs from exercise-test visits were processed with wavelet delineation, and associations were tested in three stages: univariable Cox screens of hormones (testosterone, SHBG, FAI) for CVD; linear regressions of hormones against confounder-adjusted ECG residuals (demographics, anthropometrics, lifestyle, metabolic factors, CMR-derived anatomy); and Cox models of hormone-predicted ECG components. Premenopausal women (n=980, 20 events) showed FAI associated with QRS amplitude (β=19.17 μV/SD, p=0.038) and an FAI-predicted QRS component with CVD risk (HR 1.42). In men (n=3,997), FAI inversely tracked QTc (β=−0.95 ms) and positively tracked ST deviation (β=1.12 μV), SHBG positively tracked QTc (β=0.83 ms), and corresponding components yielded HRs of 0.76–1.32. Critically, because each component is a fitted value from a single-predictor regression, it is an exact linear rescaling of the hormone, so the component Cox results arithmetically restate the hormone screens — the ECG's incremental prognostic value is never tested. No multiple-comparison correction; outcome models unadjusted; no code release.
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Assessment at a glance
6
risk flags identified
● high 2
● medium 2
● low 2
5 strengths · 5 weaknesses · 5 author questions
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Key claims under review
- SHBG and FAI show sex- and menopause-specific associations with covariate-adjusted lead-I ECG parameters (QRS amplitude, ST deviation, QTc) beyond demographic, anthropometric, lifestyle, metabolic and CMR-anatomical factors.
- In premenopausal women, higher FAI is associated with higher QRS amplitude (β=19.17 μV/SD) and the FAI-predicted QRS component is associated with incident CVD (HR=1.41).
- In men, lower androgenic status (high SHBG, low FAI) is associated with QTc prolongation, and hormone-predicted QTc, ST and QRS components track 12.8-year incident CVD risk (HRs 0.76–1.32).
- Menopausal status is associated with a distinct ECG signature — higher QRS amplitude and delayed T-waves — that persists within age strata, beyond chronological age.
- These findings support endocrine-aware ECG phenotyping for cardiovascular risk stratification.
Strengths
Careful cohort construction
Prevalent CVD excluded, beta-blocker/calcium-channel blocker users (ATC C07/C08) excluded, HRT/oral-contraceptive users and pregnant women excluded, genetically discordant sex excluded, and a 6-month landmark applied; Table 1 spans demographics, CMR anatomy, hormones and ECG with menopause-stratified comparisons.
High-quality single-lead signal pipeline
Wavelet-based delineation, per-subject median beats, Hermite-function QRS/T morphology and TMV index, an r>0.80 morphological-consistency gate for group medians, and age/RR-stratified median-beat envelopes (Methods: ECG Pre-processing).
Anatomical adjustment rare in hormone-ECG literature
Genuine novelty in the residual-regression stage
Candid limitations section
Weaknesses
Circular outcome analysis undermines the central claim
No multiple-comparison control
Unadjusted outcome models
Fragile premenopausal female results
Reproducibility and numeric hygiene
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Scope & Claims
This medRxiv preprint (posted 2026-09-17, not peer reviewed) asks whether circulating sex hormones (total testosterone, SHBG, derived FAI; oestradiol excluded for ~80% missingness) shape lead-I ECG morphology, and whether hormone-related ECG components predict incident cardiovascular disease (CVD), stratified by sex and menopausal status in 8,056 UK Biobank participants of European ancestry (4,059 women: 980 premenopausal, 2,814 postmenopausal; 3,997 men; median follow-up 12.8 years). Headline claims: (i) FAI associates with QRS amplitude in premenopausal women (β=19.17 μV/SD, p=0.038) and its predicted component with incident CVD (HR=1.41); (ii) in men, FAI inversely tracks QTc (β=−0.95 ms) and positively tracks ST deviation (β=1.12 μV), SHBG positively tracks QTc (β=0.83 ms), with corresponding components yielding HRs 0.76–1.32; (iii) menopause carries a QRS-amplitude/T-wave ECG signature beyond age; (iv) endocrine-aware ECG phenotyping could aid risk stratification.
The remaining sections cover Methodology Assessment, Statistical Evidence, Results & Reproducibility, Limitations & Risks, and Verdict & Recommendations.
- All 5 strengths & 5 weaknesses, analyzed in detail
- 6 risk flags with severity, section & reviewer questions
- Methods & statistical evidence assessment
- 5 questions a peer reviewer would ask
- Full six-dimension evaluation report & recommendations
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Frequently asked questions
Do sex hormones affect ECG readings?
This UK Biobank study of 8,056 adults found small, sex- and menopause-specific links between androgen-related markers (free androgen index, SHBG) and ECG features: higher FAI was associated with taller QRS complexes in premenopausal women (about 19 μV per standard deviation) and with shorter QTc and larger ST deviation in men, while higher SHBG was associated with slightly longer QTc in men. Effects are subtle and the design is observational.
Is low testosterone a heart disease risk factor for men?
In this preprint, men with higher free androgen index had lower cardiovascular risk (hazard ratio 0.77 per standard deviation) and shorter QTc, while higher SHBG — reflecting lower free testosterone — carried higher risk (HR 1.15). These are unadjusted observational associations from a non-peer-reviewed preprint, not evidence for testosterone testing or treatment.
Why didn't the study analyze estrogen in women?
Oestradiol was measured with an assay whose floor (175 pmol/L) left values missing or undetectable for roughly 80% of the women, and progesterone is not available in UK Biobank, so the female analyses rely on testosterone-derived FAI and SHBG. The authors flag this as a key limitation.
Has this paper been peer reviewed?
No. It is a medRxiv preprint posted September 17, 2026, explicitly marked as not certified by peer review, and its own disclaimer states it should not be used to guide clinical practice.
About this review
This is an AI-generated preliminary review by Evolve.Pub, produced from the openly available text of the paper. It is not peer review and does not represent the authors' views. The canonical record of the paper is at the publisher link above.
- Figures 1–4, the graphical abstract and all supplemental figures/tables are image-based and could not be analyzed from the extracted text.
- Supplemental Methods (incident/prevalent CVD definitions, UKB field IDs, assay details) were not included in the extraction.
- The extracted text contains OCR artifacts (interleaved running headers, line numbers); quoted numbers were cross-checked against Results and Table 1 where possible.
- The central circularity finding is derived arithmetically from the reported HRs/β values; the authors' analysis code was not available for inspection.
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