Age and Ageing Advance Access originally published online on March 12, 2008
Age and Ageing 2008 37(4):461-464; doi:10.1093/ageing/afn048
Serum testosterone but not leptin predicts mortality in elderly men
SIR—In men ageing is associated with a gradual progressive decline of total serum testosterone concentration [1–5]. A substantial proportion of older men, ranging from 20% in 60 years old to 50% in 80 years old, have testosterone concentrations below the normal range of younger men [4]. Low testosterone associates with occurrence of various cardiovascular risk factors [6, 7], and most epidemiological studies suggest that association of testosterone with coronary artery disease is either favourable or neutral [8]. Some studies have suggested that leptin is also an independent predictor of cardiovascular morbidity and mortality [9–11], but this association has not been seen in all studies [12]. After adjustment for age, concentration of testosterone in serum is inversely correlated with intima-media thickness of the carotid artery, whereas no such association is seen between serum leptin and carotid artery thickness [12]. Thus, endogenous testosterone may have a protective role in the development of atherosclerosis in ageing men, but information on associations between testosterone and mortality or coronary heart disease is lacking.We performed a longitudinal 10-year study to clarify the association of endogenous testosterone and leptin with all-cause mortality in ageing men. The results suggest an association between low endogenous testosterone concentration and mortality in elderly men.
During the years 1991–92, a survey investigating the health of elderly men in the city of Turku, Southwest Finland, was performed. All home-dwelling male residents at the specified age and living in the defined geographical area were offered the possibility to participate; 370 men (73%) responded. Testosterone measurements were available for 310 men. We then excluded subjects with diabetes mellitus (n = 23), subjects being unable to walk at least 500 m (n = 49) and those experiencing themselves either sick or very sick at the time of the investigation (n = 51). The age of the remaining 187 men was between 71 and 72 years at the time of inclusion in the study.
The subjects visited a local health centre for medical examination, had an oral glucose tolerance test done and after an overnight fast donated serum for further studies. A list of questions such as the use of alcohol (nil/less often than once a week/at least once a week), smoking habits (yes/has finished/no) and the drug use were also asked, and the Zung self-rating depression scale questionnaire [13] was completed. The diagnosis of cardiac insufficiency and coronary heart disease, if any, was based on clinical examination and medical records. The study was approved by the local Institutional Ethics Committee. For descriptive demographic and biochemical data of the participants, please see Appendix 1 in the supplementary data on the journal's website (http://www.ageing.oupjournals.org).
The cohort was followed up for 10 years. Time and cause of death of deceased men were ascertained from the national Death Register kept by Statistics Finland, and the causes were categorised as cardiovascular and other. The register covers information on all death certificates of Finnish residents, and assures complete coverage. A unique national personal identification number assigned to every permanent resident of the country was used in the computerised record linkage.
The statistical calculations were performed with SAS version 8.2 (SAS Institute Inc., Cary, NC, USA). The power analysis was performed with NCSS 2004 (Kaysville, UT, USA) software. A P-value <0.05 was considered as statistically significant. For details on laboratory and statistical methods, please see Appendix 2 in the supplementary data on the journal's website (http://www.ageing.oupjournals.org).
During the 10-year follow-up, 68 out of 187 men had died. The cause of death was cardiovascular in 27 cases.
The mean baseline serum testosterone concentration was 
14% higher (P < 0.024) in men who were alive at the end of the follow-up period compared to the deceased men, whereas serum leptin did not differ between the groups (Table 1). There was no difference in serum testosterone and leptin concentrations between subjects with cardiovascular and other causes of death.
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The logistic regression analysis including information on cardiovascular diseases and potential confounding factors (Table 2) was performed among men with complete data (n = 152). Testosterone concentration at baseline was inversely associated with mortality (P = 0.021). A direct association existed between smoking and mortality (P = 0.0005), but not between leptin (P = 0.59) or any other factors with mortality. Similar findings were seen in the Cox regression analysis. In addition, the use of alcohol (P = 0.025) and self-rated depression value (P = 0.022) were inversely associated with the risk to die.
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The adjusted odds ratio (OR) and hazard ratio (HR) (95% confidence interval) for testosterone to explain mortality and hazard to die were 0.93 (0.87–0.99) and 0.95 (0.91–1.00), respectively, indicating a favourable effect of endogenous testosterone on survival in elderly men. The corresponding OR and HR for leptin were 0.97 (0.87–1.08) and 0.97 (0.89–1.06), respectively, indicating that the effect of leptin was not statistically significant.
We demonstrate for the first time that serum total testosterone concentration in elderly men is inversely associated with mortality. This association is independent of several confounding factors. The magnitude of the associations is modest but statistically significant.
To reduce confounding by other factors potentially reducing survival, we excluded patients with frank diabetes, being frail or experiencing themselves as sick or being in institutionalised care. Our results therefore apply to home-dwelling men in rather good physical and mental condition.
Our results corroborate earlier findings from cross-sectional studies in a cohort followed for 10 years and agree with a recent study showing an inverse association between serum testosterone and severe aortic atherosclerosis and its progression in men [14].
The reasons of the favourable effects of testosterone may be mediated through reduced vascular risk. For example, testosterone influences lipoprotein patterns in a favourable way [15]. Other mechanisms may be important as well. Low testosterone concentration is associated with an increased risk for bone resorption and falls [16, 17], and with low-trauma hip fractures [18, 19]. In older men, low testosterone levels are found in subjects with depressed mood and reduced cognitive function [20, 21].
The adverse effects of smoking are well known [22], and therefore the association of smoking with risk to die was not surprising. Also, in the Cox regression model, the use of alcohol was associated with a beneficial outcome. This is in accordance with the J-shaped association of the use of alcohol and mortality reported earlier [23]. Apart from small number of subjects with high value in Zung depression scale, indicative for depressive mood, we could not find any obvious explanation for the inverse association of the scale with hazard to die.
Hyperleptinaemia has also been claimed to be an independent predictor of cardiovascular morbidity and mortality in several pathologic conditions [9–11], but results have been inconsistent [12]. Our results do not support the concept that leptin would be an independent predictor of mortality in elderly men.
In summary, we have demonstrated an independent inverse association between endogenous testosterone concentration in serum and mortality in 70-year-old non-diabetic men followed for 10 years. The results do not allow conclusions on causality. The association may be coincidental and reflect some underlying disease process. Use of exogenous testosterone in elderly men to reduce mortality cannot be recommended so far.
- An inverse association between serum testosterone at baseline and mortality was evident when elderly men were followed for 10 years.
- The association existed even after adjusting for confounding variables, including leptin.
None
Supplementary data for this article are available online at http://ageing.oxfordjournals.org.
1 Department of Geriatrics, Turku City Hospital, and University of Turku, 20 701 Turku, Finland
2 Department of Pharmacology, Drug Development and Therapeutics, University of Turku, and Department of Clinical Pharmacology, TYKSLAB, Health Care District of Southwest Finland, Itäinen Pitkäkatu 4B, 20 014 Turun yliopisto, Finland
3 Department of Public Health, University of Helsinki, 00 014 Helsingin yliopisto, Finland, and South Ostrobothnia Central Hospital, Seinäjoki, Finland
4 Statcom Ltd, Salo, Finland
5 Department of Physiology, University of Turku, Kiinamyllynkatu 10, 20 014 Turun yliopisto, Finland
6 Department of Geriatrics, University of Helsinki, 00014 Helsingin yliopisto, Finland
* To whom correspondence should be addressed E-mail: risto.huupponen{at}utu.fi
References
- Vermeulen A, Rubens R, Verdonck L. Testosterone secretion and metabolism in male senescence. J Clin Endocrinol Metab (1972) 34:730–5.
[Abstract/Free Full Text] - Gray A, Berlin JA, McKinlay JB, et al. An examination of research design effects on the association of testosterone and male aging: results of a meta-analysis. J Clin Epidemiol (1991) 44:671–4.[CrossRef][Web of Science][Medline]
- Morley JE, Kaiser FE, Perry HM, et al. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism (1997) 46:410–3.[CrossRef][Web of Science][Medline]
- Harman SM, Metter EJ, Tobin JD, et al, Baltimore Longitudinal Study of Aging. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab (2001) 86:724–31.
[Abstract/Free Full Text] - Gruenewald DA, Matsumoto AM. Testosterone supplementation therapy tor older men: potential benefits and risks. J Am Geriatr Soc (2003) 51:101–15.[CrossRef][Web of Science][Medline]
- Phillips GB, Pinkernell BH, Jing TY. The association of hypotestosteronemia with coronary artery disease in men. Arterioscler Thromb (1994) 14:701–6.
[Abstract/Free Full Text] - Simon D, Charles M-A, Nahoul K, et al, The Telecom Study. Association between plasma total testosterone and cardiovascular risk factors in healthy adult men. J Clin Endocrinol Metab (1997) 82:682–5.
[Abstract/Free Full Text] - Alexandersen P, Haarbo J, Christiansen C. The relationship of natural androgens to coronary heart disease in males: a review. Atherosclerosis (1996) 125:1–13.[CrossRef][Web of Science][Medline]
- Leyva F, Godsland IF, Ghatei M, et al. Hyperleptinemia as a component of a metabolic syndrome of cardiovascular risk. Arterioscler Thromb Vasc Biol (1998) 18:928–33.
[Abstract/Free Full Text] - Söderberg S, Ahrén B, Jansson J-H, et al. Leptin is associated with increased risk of myocardial infarction. J Intern Med (1999) 246:409–18.[CrossRef][Web of Science][Medline]
- Wallace AM, McMahon AD, Packard CJ, et al. Plasma leptin and the risk of cardiovascular disease in the west of Scotland coronary prevention study (WOSCOPS). Circulation (2001) 104:3052–6.
[Abstract/Free Full Text] - van den Beld AW, Bots ML, Janssen JA, et al. Endogenous hormones and carotid atherosclerosis in elderly men. Am J Epidemiol (2003) 157:25–31.
[Abstract/Free Full Text] - Zung A. A self-rating depression scale. Arch Gen Psychiatry (1965) 12:63–70.
[Abstract/Free Full Text] - Hak AE, Witteman JCM, De Jong FH, et al. Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: The Rotterdam Study. J Clin Endocrinol Metab (2002) 87:3632–9.
[Abstract/Free Full Text] - Haffner SM, Mykkänen L, Valdez RA, et al. Relationship of sex hormones to lipids and lipoproteins in nondiabetic men. J Clin Endocrinol Metab (1993) 77:1610–5.[Abstract]
- Szulc P, Claustrat B, Marchand F, et al. Increased risk of falls and increased bone resorption in elderly men with partial androgen deficiency: the MINOS study. J Clin Endocrinol Metab (2003) 88:5240–7.
[Abstract/Free Full Text] - Orwoll E, Lambert LC, Marshall LM, et al. Endogenous testosterone levels, physical performance and fall risk in older men. Arch Intern Med (2006) 166:2124–31.
[Abstract/Free Full Text] - Stanley HL, Schmitt BP, Poses RM, et al. Does hypogonadism contribute to the occurrence of a minimal trauma hip fracture in elderly men? J Am Geriatr Soc (1991) 39:766–71.[Web of Science][Medline]
- Jackson JA, Riggs MW, Spiekerman AM. Testosterone deficiency as a risk factor for hip fractures in men: a case-control study. Am J Med Sci (1992) 304:4–8.[Web of Science][Medline]
- Barrett-Connor E, Von Mühlen DG, Kritz-Silverstein D. Bioavailable testosterone and depressed mood in older men: The Rancho Bernardo Study. J Clin Endocrinol Metab (1999) 84:573–7.
[Abstract/Free Full Text] - Barrett-Connor E, Goodman-Gruen D, Patay B. Endogenous sex hormones and cognitive function in older men. J Clin Endocrinol Metab (1999) 84:3681–5.
[Abstract/Free Full Text] - Rehm J, Taylor B, Room R. Global burden of disease from alcohol, illicit drugs and tobacco. Drug Alcohol Rev (2006) 25:503–13.[CrossRef][Web of Science][Medline]
- Di Castelnuovo A, Constanzo S, Bagnardi V, et al. Alcohol dosing and total mortality in men and women: an updated meta-analysis of 34 prospective studies. Arch Intern Med (2006) 166:2437–45.
[Abstract/Free Full Text]
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