Sex Hormones and Ischemic Stroke: A Prospective Cohort Study and Meta-Analyses.
OBJECTIVE
Whether endogenous sex hormones are associated with ischemic stroke (IS) is unclear. We tested the hypothesis that extreme concentrations of endogenous sex hormones are associated with risk of IS in the general population.


METHODS
Adult men (n = 4615) and women (n = 4724) with measurements of endogenous sex hormones during the 1981-1983 examination of the Copenhagen City Heart Study, Denmark, were followed for up to 29 years for incident IS, with no loss to follow-up. Mediation analyses assessed whether risk of IS was mediated through potential mediators. Present and previous findings were summarized in meta-analyses.


METHODS
Plasma total testosterone and total estradiol were measured by competitive immunoassays. Diagnosis of IS was ascertained from the national Danish Patient Registry and the national Danish Causes of Death Registry and verified by experienced neurologists.


RESULTS
During follow-up, 524 men and 563 women developed IS. Men with testosterone concentrations ≤10th percentile compared to the 11th-90th percentiles had a hazard ratio for IS of 1.34 (95% confidence interval, 1.05-1.72); 21% of this risk was mediated by body mass index (P = .002) and 14% by hypertension (P = .02). In accordance with this, the corresponding hazard ratio was 1.46 (1.09-1.95) in overweight/obese and hypertensive men. The corresponding hazard ratio in the meta-analysis was 1.43 (1.21-1.70). Other extreme concentrations of testosterone or estradiol were not associated with risk of IS in men or women.


CONCLUSIONS
Extremely low endogenous testosterone concentrations were associated with high risk of IS in men, a risk mediated in part by body mass index and hypertension. Whether or not low testosterone is a causal factor for IS or merely a biomarker of poor metabolic health is still not known.
Department of Clinical Biochemistry (H.N.H., M.B.), Gentofte Hospital, 2900 Hellerup, Denmark; Department of Clinical Biochemistry (B.G.N.), Herlev Hospital, 2730 Herlev, Denmark; The Copenhagen City Heart Study (B.G.N., G.B.J., A.T.-H., M.B.), Frederiksberg Hospital, 2000 Frederiksberg, Denmark; Department of Clinical Biochemistry (A.T.-H.), Rigshospitalet, 2100 Copenhagen, Denmark; and Copenhagen University Hospitals (H.N.H., B.G.N., G.B.J., A.T.-H., M.B.), Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
Haya N
HN
Holmegard
Department of Clinical Biochemistry (H.N.H., M.B.), Gentofte Hospital, 2900 Hellerup, Denmark; Department of Clinical Biochemistry (B.G.N.), Herlev Hospital, 2730 Herlev, Denmark; The Copenhagen City Heart Study (B.G.N., G.B.J., A.T.-H., M.B.), Frederiksberg Hospital, 2000 Frederiksberg, Denmark; Department of Clinical Biochemistry (A.T.-H.), Rigshospitalet, 2100 Copenhagen, Denmark; and Copenhagen University Hospitals (H.N.H., B.G.N., G.B.J., A.T.-H., M.B.), Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
Børge G
BG
Nordestgaard
Department of Clinical Biochemistry (H.N.H., M.B.), Gentofte Hospital, 2900 Hellerup, Denmark; Department of Clinical Biochemistry (B.G.N.), Herlev Hospital, 2730 Herlev, Denmark; The Copenhagen City Heart Study (B.G.N., G.B.J., A.T.-H., M.B.), Frederiksberg Hospital, 2000 Frederiksberg, Denmark; Department of Clinical Biochemistry (A.T.-H.), Rigshospitalet, 2100 Copenhagen, Denmark; and Copenhagen University Hospitals (H.N.H., B.G.N., G.B.J., A.T.-H., M.B.), Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
Gorm B
GB
Jensen
Department of Clinical Biochemistry (H.N.H., M.B.), Gentofte Hospital, 2900 Hellerup, Denmark; Department of Clinical Biochemistry (B.G.N.), Herlev Hospital, 2730 Herlev, Denmark; The Copenhagen City Heart Study (B.G.N., G.B.J., A.T.-H., M.B.), Frederiksberg Hospital, 2000 Frederiksberg, Denmark; Department of Clinical Biochemistry (A.T.-H.), Rigshospitalet, 2100 Copenhagen, Denmark; and Copenhagen University Hospitals (H.N.H., B.G.N., G.B.J., A.T.-H., M.B.), Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
Anne
A
Tybjærg-Hansen
Department of Clinical Biochemistry (H.N.H., M.B.), Gentofte Hospital, 2900 Hellerup, Denmark; Department of Clinical Biochemistry (B.G.N.), Herlev Hospital, 2730 Herlev, Denmark; The Copenhagen City Heart Study (B.G.N., G.B.J., A.T.-H., M.B.), Frederiksberg Hospital, 2000 Frederiksberg, Denmark; Department of Clinical Biochemistry (A.T.-H.), Rigshospitalet, 2100 Copenhagen, Denmark; and Copenhagen University Hospitals (H.N.H., B.G.N., G.B.J., A.T.-H., M.B.), Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
Marianne
M
Benn
D000328:Adult; D000367:Age Factors; D000368:Aged; D015992:Body Mass Index; D002545:Brain Ischemia / Q000097:blood* / Q000453:epidemiology; D015331:Cohort Studies; D003718:Denmark / Q000453:epidemiology; D004958:Estradiol / Q000097:blood; D005260:Female; D005500:Follow-Up Studies; D012739:Gonadal Steroid Hormones / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D018570:Risk Assessment; D012737:Sex Factors; D020521:Stroke / Q000097:blood* / Q000453:epidemiology; D013739:Testosterone / Q000097:blood
D012739:Gonadal Steroid Hormones; D013739:Testosterone; D004958:Estradiol