The Association of Reproductive Hormone Levels and All-Cause, Cancer, and Cardiovascular Disease Mortality in Men.
BACKGROUND
Testosterone (T) levels have been associated with mortality, but controversy exists.


OBJECTIVE
Our objective was to investigate associations between serum levels of total T, SHBG, free T, estradiol, LH and FSH, and subsequent mortality with up to 30 years of follow-up.


METHODS
This was a prospective cohort study consisting of men participating in four independent population-based surveys (MONICA I-III and Inter99) from 1982 to 2001 and followed until December 2012 with complete registry follow-up.


METHODS
A total of 5350 randomly selected men from the general population aged 30, 40, 50, 60, or 70 years at baseline participated.


METHODS
All-cause mortality, cardiovascular disease (CVD) mortality, and cancer mortality were the main outcomes.


RESULTS
A total of 1533 men died during the follow-up period; 428 from CVD and 480 from cancer. Cox proportional hazard models revealed that men in highest LH quartile had an increased all-cause mortality compared to lowest quartile (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.14-1.53). Likewise, increased quartiles of LH/T and estradiol increased the risk of all-cause mortality (HR, 1.23; 95% CI, 1.06-1.43; HR, 1.23; 95% CI 1.06-1.43). No association to T levels was found. Higher LH levels were associated with increased cancer mortality (HR, 1.42; 95% CI, 1.10-1.84) independently of smoking status. Lower CVD mortality was seen for men with T in the highest quartile compared to lowest (HR, 0.72; 95% CI, 0.53-0.98). Furthermore, negative trends were seen for SHBG and free T in relation to CVD mortality, however insignificant.


CONCLUSIONS
The observed positive association of LH and LH/T, but not T, with all-cause mortality suggests that a compensated impaired Leydig cell function may be a risk factor for death by all causes in men. Our findings underpin the clinical importance of including LH measurement in the diagnostic work-up of male patients seeking help for possible androgen insufficiency.
University Department of Growth and Reproduction (S.A.H., T.K.J., N.E.S., A.J., A.-M.A.), Rigshospitalet, 2100 Copenhagen, Denmark; Department of Biostatistics (E.V., T.S.), University of Copenhagen, Denmark; Research Centre for Prevention and Health (A.L., L.L.N.H.), The Capital Region, Denmark; Department of Clinical Experimental Research (A.L.), Rigshospitalet, Glostrup, Denmark; and Department of Clinical Medicine (A.L.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Stine A
SA
Holmboe
University Department of Growth and Reproduction (S.A.H., T.K.J., N.E.S., A.J., A.-M.A.), Rigshospitalet, 2100 Copenhagen, Denmark; Department of Biostatistics (E.V., T.S.), University of Copenhagen, Denmark; Research Centre for Prevention and Health (A.L., L.L.N.H.), The Capital Region, Denmark; Department of Clinical Experimental Research (A.L.), Rigshospitalet, Glostrup, Denmark; and Department of Clinical Medicine (A.L.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Eleni
E
Vradi
University Department of Growth and Reproduction (S.A.H., T.K.J., N.E.S., A.J., A.-M.A.), Rigshospitalet, 2100 Copenhagen, Denmark; Department of Biostatistics (E.V., T.S.), University of Copenhagen, Denmark; Research Centre for Prevention and Health (A.L., L.L.N.H.), The Capital Region, Denmark; Department of Clinical Experimental Research (A.L.), Rigshospitalet, Glostrup, Denmark; and Department of Clinical Medicine (A.L.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Tina Kold
TK
Jensen
University Department of Growth and Reproduction (S.A.H., T.K.J., N.E.S., A.J., A.-M.A.), Rigshospitalet, 2100 Copenhagen, Denmark; Department of Biostatistics (E.V., T.S.), University of Copenhagen, Denmark; Research Centre for Prevention and Health (A.L., L.L.N.H.), The Capital Region, Denmark; Department of Clinical Experimental Research (A.L.), Rigshospitalet, Glostrup, Denmark; and Department of Clinical Medicine (A.L.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Allan
A
Linneberg
University Department of Growth and Reproduction (S.A.H., T.K.J., N.E.S., A.J., A.-M.A.), Rigshospitalet, 2100 Copenhagen, Denmark; Department of Biostatistics (E.V., T.S.), University of Copenhagen, Denmark; Research Centre for Prevention and Health (A.L., L.L.N.H.), The Capital Region, Denmark; Department of Clinical Experimental Research (A.L.), Rigshospitalet, Glostrup, Denmark; and Department of Clinical Medicine (A.L.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Lise Lotte N
LL
Husemoen
University Department of Growth and Reproduction (S.A.H., T.K.J., N.E.S., A.J., A.-M.A.), Rigshospitalet, 2100 Copenhagen, Denmark; Department of Biostatistics (E.V., T.S.), University of Copenhagen, Denmark; Research Centre for Prevention and Health (A.L., L.L.N.H.), The Capital Region, Denmark; Department of Clinical Experimental Research (A.L.), Rigshospitalet, Glostrup, Denmark; and Department of Clinical Medicine (A.L.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Thomas
T
Scheike
University Department of Growth and Reproduction (S.A.H., T.K.J., N.E.S., A.J., A.-M.A.), Rigshospitalet, 2100 Copenhagen, Denmark; Department of Biostatistics (E.V., T.S.), University of Copenhagen, Denmark; Research Centre for Prevention and Health (A.L., L.L.N.H.), The Capital Region, Denmark; Department of Clinical Experimental Research (A.L.), Rigshospitalet, Glostrup, Denmark; and Department of Clinical Medicine (A.L.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Niels E
NE
Skakkebæk
University Department of Growth and Reproduction (S.A.H., T.K.J., N.E.S., A.J., A.-M.A.), Rigshospitalet, 2100 Copenhagen, Denmark; Department of Biostatistics (E.V., T.S.), University of Copenhagen, Denmark; Research Centre for Prevention and Health (A.L., L.L.N.H.), The Capital Region, Denmark; Department of Clinical Experimental Research (A.L.), Rigshospitalet, Glostrup, Denmark; and Department of Clinical Medicine (A.L.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Anders
A
Juul
University Department of Growth and Reproduction (S.A.H., T.K.J., N.E.S., A.J., A.-M.A.), Rigshospitalet, 2100 Copenhagen, Denmark; Department of Biostatistics (E.V., T.S.), University of Copenhagen, Denmark; Research Centre for Prevention and Health (A.L., L.L.N.H.), The Capital Region, Denmark; Department of Clinical Experimental Research (A.L.), Rigshospitalet, Glostrup, Denmark; and Department of Clinical Medicine (A.L.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Anna-Maria
AM
Andersson
D000328:Adult; D000367:Age Factors; D000368:Aged; D002318:Cardiovascular Diseases / Q000401:mortality*; D015331:Cohort Studies; D004522:Educational Status; D004958:Estradiol / Q000097:blood; D043373:Follicle Stimulating Hormone, Human / Q000097:blood; D005500:Follow-Up Studies; D012739:Gonadal Steroid Hormones / Q000097:blood*; D006306:Health Surveys; D006801:Humans; D008017:Life Expectancy; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000401:mortality*; D011446:Prospective Studies; D012907:Smoking / Q000401:mortality; D013739:Testosterone / Q000097:blood
D043373:Follicle Stimulating Hormone, Human; D012739:Gonadal Steroid Hormones; D013739:Testosterone; D004958:Estradiol; D007986:Luteinizing Hormone