Sex- and Menopause-Specific Hormone-Related ECG Signatures and Incident Cardiovascular Risk in UK Biobank
- 1IIS, Aragon Institute of Engineering Research, University of Zaragoza, Zaragoza, Spain
Abstract
AimsSex differences in cardiac electrophysiology and cardiovascular (CV) risk are well established, but the extent to which circulating hormonal markers contribute to electrocardiogram (ECG) morphology remains unclear. We investigated whether hormone-related ECG components are associated with incident CV events and whether these associations differ by sex and menopausal status.
MethodsIn a prospective cohort (N=8,056 UK Biobank participants; median follow-up: 12.8 years), we first evaluated direct associations between sex hormones and incident CV disease. Based on initial risk signals, two-stage analyses focused on premenopausal females and males. Linear regressions evaluated associations between standardized hormonal markers and residualized lead-I ECG parameters after confounders adjustment. Cox proportional hazards models then tested whether the hormone-predicted ECG components were associated with incident CVD events.
ResultsIn premenopausal females (N=980), higher free androgen index (FAI) was positively associated with QRS amplitude ({beta}=19.17{micro}V, p-value=0.038) and the FAI-predicted QRS amplitude component was associated with incident CVD (Hazard Ratio [HR]=1.41, p-value=0.02). In males (N=3,997), FAI was inversely associated with QTc duration ({beta}=-0.95ms, p-value=0.005), and its predicted component with increased CVD risk (HR=1.32, p-value<0.001). Conversely, higher sex hormone-binding globulin (SHBG) prolonged QTc, with its predicted component also conferring risk (HR=1.15, p-value=0.004). Additionally, FAI directly associated with ST segment deviation ({beta}=19.17{micro}V), whose predicted component was protective (HR=0.76, p-value<0.001).
ConclusionThis study shows that SHBG and FAI subtly modulate specific depolarization and repolarization ECG parameters. Relative androgen excess in premenopausal females and lower androgenic status in males appear to be associated with subclinical electrophysiological variations linked to long-term CV risk.
Graphical Abstract.
O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/26362818v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): [email protected]@1318309org.highwire.dtl.DTLVardef@1920208org.highwire.dtl.DTLVardef@c36c6f_HPS_FORMAT_FIGEXP M_FIG C_FIG Lay summaryThis study shows that sex hormone levels are linked to subtle variations in the hearts electrical activity on an electrocardiogram (ECG) in a middle-aged population without prevalent cardiovascular disease, which may help identify long-term cardiovascular risk in both men and premenopausal women. O_LIIn premenopausal females: Higher levels of androgens, specifically those related to free testosterone, were linked to subtle changes in the hearts electrical signals, specifically higher electrical voltage during heart contraction, and a higher long-term risk of developing cardiovascular disease. C_LIO_LIIn males: Hormonal balance showed a dual effect; lower active androgen levels were linked to delays in how the heart resets between beats and a higher cardiovascular risk, whereas higher androgen levels appeared protective by supporting a healthier electrical recovery pattern (ST-segment profile) and preventing excessive heart muscle enlargement signals. C_LI
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BibTeX
@misc{hernandez2026menopausespecific,
title = {{Sex- and Menopause-Specific Hormone-Related ECG Signatures and Incident Cardiovascular Risk in UK Biobank}},
author = {A. Hernandez and J. Madrid and C. Sanchez and A. Sanz and W. J. Young and P. B. Munroe and A. Minchole and J. Ramirez},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.11.26362818},
url = {https://www.medrxiv.org/content/10.64898/2026.09.11.26362818v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Sex- and Menopause-Specific Hormone-Related ECG Signatures and Incident Cardiovascular Risk in UK Biobank
AU - A. Hernandez
AU - J. Madrid
AU - C. Sanchez
AU - A. Sanz
AU - W. J. Young
AU - P. B. Munroe
AU - A. Minchole
AU - J. Ramirez
PY - 2026
DA - 2026/09/11
PB - medRxiv
DO - 10.64898/2026.09.11.26362818
UR - https://www.medrxiv.org/content/10.64898/2026.09.11.26362818v1
AB - AimsSex differences in cardiac electrophysiology and cardiovascular (CV) risk are well established, but the extent to which circulating hormonal markers contribute to electrocardiogram (ECG) morphology remains unclear. We investigated whether hormone-related ECG components are associated with incident CV events and whether these associations differ by sex and menopausal status. MethodsIn a prospective cohort (N=8,056 UK Biobank participants; median follow-up: 12.8 years), we first evaluated direct associations between sex hormones and incident CV disease. Based on initial risk signals, two-stage analyses focused on premenopausal females and males. Linear regressions evaluated associations between standardized hormonal markers and residualized lead-I ECG parameters after confounders adjustment. Cox proportional hazards models then tested whether the hormone-predicted ECG components were associated with incident CVD events. ResultsIn premenopausal females (N=980), higher free androgen index (FAI) was positively associated with QRS amplitude ({beta}=19.17{micro}V, p-value=0.038) and the FAI-predicted QRS amplitude component was associated with incident CVD (Hazard Ratio [HR]=1.41, p-value=0.02). In males (N=3,997), FAI was inversely associated with QTc duration ({beta}=-0.95ms, p-value=0.005), and its predicted component with increased CVD risk (HR=1.32, p-value<0.001). Conversely, higher sex hormone-binding globulin (SHBG) prolonged QTc, with its predicted component also conferring risk (HR=1.15, p-value=0.004). Additionally, FAI directly associated with ST segment deviation ({beta}=19.17{micro}V), whose predicted component was protective (HR=0.76, p-value<0.001). ConclusionThis study shows that SHBG and FAI subtly modulate specific depolarization and repolarization ECG parameters. Relative androgen excess in premenopausal females and lower androgenic status in males appear to be associated with subclinical electrophysiological variations linked to long-term CV risk. Graphical Abstract. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/26362818v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): [email protected]@1318309org.highwire.dtl.DTLVardef@1920208org.highwire.dtl.DTLVardef@c36c6f_HPS_FORMAT_FIGEXP M_FIG C_FIG Lay summaryThis study shows that sex hormone levels are linked to subtle variations in the hearts electrical activity on an electrocardiogram (ECG) in a middle-aged population without prevalent cardiovascular disease, which may help identify long-term cardiovascular risk in both men and premenopausal women. O_LIIn premenopausal females: Higher levels of androgens, specifically those related to free testosterone, were linked to subtle changes in the hearts electrical signals, specifically higher electrical voltage during heart contraction, and a higher long-term risk of developing cardiovascular disease. C_LIO_LIIn males: Hormonal balance showed a dual effect; lower active androgen levels were linked to delays in how the heart resets between beats and a higher cardiovascular risk, whereas higher androgen levels appeared protective by supporting a healthier electrical recovery pattern (ST-segment profile) and preventing excessive heart muscle enlargement signals. C_LI
ER -