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Links.cenegenics.comLow Serum Testosterone and Estradiol Predict
Mortality in Elderly Men
Åsa Tivesten, Liesbeth Vandenput, Fernand Labrie, Magnus K. Karlsson, O¨sten Ljunggren,Dan Mellstro¨m, and Claes Ohlsson The Wallenberg Laboratory for Cardiovascular Research (A.T.), Institute of Medicine, Sahlgrenska Academy, and Center forBone Research at the Sahlgrenska Academy (L.V., D.M., C.O.), Departments of Internal Medicine and Geriatrics,University of Gothenburg, S-413 45 Gothenburg, Sweden; Laboratory of Molecular Endocrinology and Oncology (F.L.),Laval University Hospital Research Center and Laval University, Que´bec, Canada G5Y 0H1; Clinical and MolecularOsteoporosis Research Unit (M.K.K.), Department of Clinical Sciences, Lund University, S-221 00 Lund, Sweden;Department of Orthopaedics (M.K.K.), Malmo¨ University Hospital, SE-205 02 Malmo¨, Sweden; and Department ofMedical Sciences (O.L.), University of Uppsala, SE-751 05 Uppsala, Sweden Context: Age-related reduction of serum testosterone may contribute to the signs and symptoms
of aging, but previous studies report conflicting evidence about testosterone levels and male
mortality. No large prospective cohort study has determined a possible association between serum
estradiol and mortality in men.
Objective: The main objective was to examine the association between serum testosterone and
estradiol and all-cause mortality in elderly men.
Design, Setting, and Participants: We used specific gas chromatography-mass spectrometry to
analyze serum sex steroids at baseline in older men who participated in the prospective population-
based MrOS Sweden cohort (n ϭ 3014; mean age, 75 yr; range, 69 – 80 yr).
Main Outcome Measure: All-cause mortality by serum testosterone and estradiol levels.
Results: During a mean follow-up period of 4.5 yr, 383 deaths occurred. In multivariate hazards
regression models, low levels (within quartile 1 vs. quartiles 2– 4) of both testosterone [hazard ratio
(HR), 1.65; 95% confidence interval (CI), 1.29 –2.12] and estradiol (HR, 1.54; 95% CI, 1.22–1.95)
associated with mortality. A model including both hormones showed that both low testosterone
(HR, 1.46; 95% CI, 1.11–1.92) and estradiol (HR, 1.33; 95% CI, 1.02–1.73) predicted mortality. Risk
of death nearly doubled (HR, 1.96; 95% CI, 1.46 –2.62) in subjects with low levels of both testos-
terone and estradiol compared with subjects within quartiles 2– 4 of both hormones.
Conclusions: Elderly men with low serum testosterone and estradiol have increased risk of mor-
tality, and subjects with low values of both testosterone and estradiol have the highest risk of
mortality. (J Clin Endocrinol Metab 94: 2482–2488, 2009)
Testosteronegraduallydeclinesasmenage(1).Astestoster- tosterone associates with increased fat mass, an adverse meta-
one has important physiological effects on, for example, bolic risk profile, and atherosclerosis (1, 5).
muscle, bone, fat mass, and brain in men, decreased testosterone Recently, much interest has focused on testosterone supple- levels may contribute to the symptoms and signs of aging, e.g. mentation in elderly men (1), as evidenced by a 20-fold increase decreased muscle mass and strength, impaired physical perfor- in testosterone sales in the United States during the 1990s (6).
mance and cognitive function, and lack of energy (1). Men with However, few large controlled studies demonstrate the efficacy low serum testosterone are at increased risk of falls, low bone and long-term safety of testosterone therapy (1, 7). Furthermore, mineral density, and fractures (2– 4). Moreover, low serum tes- testosterone supplementation has increased, despite relatively Abbreviations: BMI, Body mass index; CI, confidence interval; CV, coefficient of variation; CVD, cardiovascular disease; GC-MS, gas chromatography-mass spectrometry; HR, hazard Copyright 2009 by The Endocrine Society doi: 10.1210/jc.2008-2650 Received December 4, 2008. Accepted April 21, 2009.
First Published Online April 28, 2009 J Clin Endocrinol Metab, July 2009, 94(7):2482–2488 J Clin Endocrinol Metab, July 2009, 94(7):2482–2488 few studies linking androgen deficiency in the elderly to health- ical diagnosis (diabetes, cancer, stroke, myocardial infarction, or angina related outcomes, including mortality.
pectoris) by a doctor. This study defined prevalent cardiovascular disease Circulating estradiol levels in men are low but measurable, (CVD) as a history of stroke, myocardial infarction, and/or angina pec- exceeding the levels found in postmenopausal women. Because toris. Physical activity was the subject’s estimation of average total dailywalking distance, including walking both as a means of exercise and leisure approximately 80% of circulating estradiol in men derives from and as a means of outdoor transportation in activities of daily life. We used androgens (1), serum levels of estradiol and testosterone are sig- standard equipment to measure height and weight (2), and calculated body nificantly associated (2). Studies investigating aromatase or es- mass index (BMI) as weight (in kilograms)/ height (meters)2.
trogen receptor deficiency in males demonstrated that estradiolhas important physiological effects on bone maturation and peak Serum analyses
bone mass in younger men (8, 9). The role of estradiol in elderlymen remains more unclear, and few studies have explored the We used a validated GC-MS system (21, 22) to analyze testosterone [detection limit, 0.05 ng/ml; intraassay coefficient of variation (CV), relationship between estradiol levels in elderly men and health- 2.9%; interassay CV, 3.4%] and estradiol (detection limit, 2.00 pg/ml; related outcomes. However, our earlier study in the Swedish intraassay CV, 1.5%; interassay CV, 2.7%) in baseline serum samples Osteoporotic Fractures in Men (MrOS) cohort showed that low (2). The blood specimens from the Go¨teborg cohort and the major part serum estradiol associates with an increased risk of fractures (2).
of the Uppsala and Malmo¨ cohorts were obtained between 0800 and Among the investigations that assessed the relationship be- 0830 h, but some of the specimens from the Uppsala and Malmo¨ cohorts tween serum testosterone and mortality in men (6, 10 –15), only were obtained between 1230 and 1330 h (approximately 31% of the three were large prospective population-based cohort studies (6, total number of serum samples included in the present analysis wereobtained between 1230 and 1330 h). An HP5973 quadrupole mass spec- 12, 13). One study showed an association between low serum trometer equipped with a chemical ionization source detected analytes testosterone and mortality in older men (6), whereas two studies and internal standards. Twenty-six subjects had serum estradiol levels in middle-aged men reported no similar association (12, 13).
that were below the lower limit of detection. We used immunoradio- Currently, no large prospective study has determined a possible metric assay (Orion Diagnostics, Espoo, Finland; detection limit, 1.3 association between serum estradiol and mortality in men.
nmol/liter; intraassay CV, 3%; interassay CV, 7%) to measure serum Immunoassay-based techniques provide questionable speci- SHBG. We calculated free testosterone and free estradiol according to the ficity for measuring sex steroids, especially at low hormone con- method described by Vermeulen et al. (23) and van den Beld et al. (24),taking concentrations of total testosterone, total estradiol, and SHBG centrations (16, 17). Indeed, the use of such techniques may into account and assuming a fixed albumin concentration (43 g/liter). All contribute to the disparate results of previous studies and also to samples were analyzed in one laboratory.
the paucity of studies on estradiol and clinical outcomes in men.
No previous mortality study has used the reference method massspectrometry to assess sex steroids (18).
Assessment of mortality
This prospective study investigated a possible link between We collected mortality data from the population statistics at Statistics serum testosterone and estradiol levels, assessed by gas chroma- Sweden and recorded follow-up time as the period between baseline visit(in 2004) and date of death or mortality data collection (March 1, 2008).
tography-mass spectrometry (GC-MS), and all-cause mortality Cause of death data were collected from the Swedish Cause of Death in the MrOS Study in Sweden, a large population-based cohort Register, held by the National Board of Health and Welfare in Sweden, in which all deaths in Sweden are registered with International Classi-fication of Diseases (ICD) codes, based on the information from deathcertificates. The data were collected from this register from the study startuntil the last update of the register on December 31, 2005 and from eval- Subjects and Methods
uation of copies of death certificates for deaths occurring after this date.
Based on the information from the register/death certificate, the underlying Study population
death cause was determined for each subject. The death causes were then The multicenter MrOS Study includes older men in Sweden, Hong classified as CVD (ICD-10 codes I00 to I99) or other (non-CVD).
Kong, and the United States. In Sweden, MrOS (n ϭ 3014) comprisesthree subcohorts in three different cities: Malmo¨ (n ϭ 1,005), Go¨teborg(n ϭ 1,010), and Uppsala (n ϭ 999). Study subjects (men aged 69 – 80 yr) Statistical analysis
were selected randomly from national population registers (19). Eligi-bility for study participation required the ability to walk unassisted, We used Cox proportional hazards regression to analyze the associ- provide self-reported data, and understand and sign an informed con- ations between serum sex steroids and mortality outcomes. Sex steroid sent; 45% of those contacted participated in the study. The MrOS Study levels were examined as quartiles based on the entire population or as in Sweden was approved by the ethics committees at Go¨teborg, Lund, dichotomous variables comparing quartile 1 to quartiles 2– 4. We also show the effect estimate for a 1 SD increase (z score) of log-transformed We investigated here the associations between serum sex steroids and sex steroid levels. We adjusted all estimates for age and MrOS site and mortality in the Swedish MrOS cohort. Levels of SHBG were available made further adjustments for BMI (log-transformed), current smoking for 97% of the entire cohort, and serum samples for sex steroid levels (yes/no), and physical activity (kilometers walked per day, entered as assessed by GC-MS (1 ml required) were available from 99% of the quartiles because of a nonnormal distribution).
subjects in the Go¨teborg cohort, 96% in the Malmo¨ cohort, and 68% in Unadjusted Kaplan-Meier survival curves illustrated the association between testosterone and estradiol status (quartile 1 vs. quartiles 2– 4)and all-cause mortality, and the log-rank test assessed statistical signif- Assessment of covariates
icance. Spearman rank correlation assessed the univariate association We used a standardized questionnaire (20) to gather information between serum testosterone and estradiol. We performed statistical anal- about smoking habits and physical activity as well as self-reported med- yses with SPSS for Windows, version 13.0 (SPSS, Chicago, IL).
Testosterone, Estradiol, and Male Mortality J Clin Endocrinol Metab, July 2009, 94(7):2482–2488 spectively (Table 2, model 1, adjusted for age). Further adjust- TABLE 1. Characteristics of study subjects
ment for age and BMI (model 2) as well as age, BMI, physical Variable
activity, and smoking (model 3) showed no major influence on mortality risk at low sex steroid levels (Table 2). Cumulative survival curves (Fig. 1) illustrate that subjects in the lowest quar- tile of testosterone (Fig. 1A) and estradiol (Fig. 1B) levels had higher all-cause mortality compared with subjects in quartiles Serum levels of total estradiol and testosterone were associated with each other (Spearman rank correlation coefficient 0.54; P Ͻ 0.001), as were the corresponding free hormone levels (0.62; P Ͻ 0.001). To study whether low testosterone and estradiol levels in- dependently predict total mortality, we entered both low estradiol (quartile 1 vs. quartiles 2– 4) and low testosterone (quartile 1 vs. quartiles 2– 4) in the same hazards regression analyses (Table 2,models 1–3). Low levels of both testosterone and estradiol inde- Values are given as mean (SD) unless otherwise indicated.
pendently predicted all-cause mortality in these models (Table 2).
To illustrate further the impact of low estradiol and/or testos- terone levels, we divided subjects into four groups according to both Table 1 shows the baseline characteristics of the MrOS Sweden estradiol and testosterone status: group 1 (referent), with medium/ cohort (n ϭ 3014). SHBG data (assessed by RIA) and serum sex high (ϭ within quartiles 2– 4) testosterone and estradiol levels steroids (assessed by GC-MS) were available for 2925 and 2639 (n ϭ 1667); group 2, with low (ϭ within quartile 1) testosterone subjects, respectively. The mean follow-up period was 4.5 yr, but medium/high estradiol levels (n ϭ 312); group 3, with low and the study included 13,527 person-years of follow-up. Dur- estradiol but medium/high testosterone levels (n ϭ 307); and ing the follow-up period, 383 persons (12.7%) died, yielding a group 4, with low levels of both testosterone and estradiol (n ϭ mortality rate of 28.3 per 1000 person-years at risk. Because 353). Risk of death approximately doubled [HR, 1.96 (95% CI, cause of death certificates were missing for 20 of the men who 1.46 –2.62); model 3, adjusted for age, BMI, physical activity, died during the follow-up, death cause was determined for 363 and smoking] in subjects with low levels of both testosterone and men; 144 (39.7%) of these deaths were due to CVD.
estradiol (group 4) compared with subjects within group 1. In Low physical activity [hazard ratio (HR), 0.88; 95% confi- contrast, neither low testosterone [HR, 1.27 (95% CI, 0.87– dence interval (CI), 0.80 – 0.96, per quartile increase] and smok- 1.86)] nor low estradiol [HR, 1.23 (95% CI, 0.87–1.74)], with ing (HR, 1.39; 95% CI, 1.00 –1.91; yes vs. no) at baseline pre- medium/high levels of the other sex hormone, associated with a dicted mortality. There was a nonlinear inverse relation between statistically significant increase in mortality risk. These results BMI and mortality [quartile 1 ϭ referent; quartile 2, HR, 0.72 were similar in models 1 and 2 (age or age plus BMI adjustment (95% CI, 0.55– 0.96); quartile 3, HR, 0.79 (95% CI, 0.60 –1.03); only). Figure 1C shows the survival plots of groups 1– 4 (log-rank and quartile 4, HR, 0.79 (95% CI, 0.60 –1.05); quartile 1 vs. test P Ͻ 0.001 for group 4 and nonsignificant for groups 2–3 pooled quartiles 2– 4, HR, 0.76 (95% CI, 0.61– 0.94)].
Age-adjusted (model 1) proportional hazards regression anal- To examine the possible influence of prevalent diseases at yses revealed an association between total and free testosterone baseline on the relationship between sex steroids and mortality, levels, total and free estradiol levels, and mortality when sex we calculated HRs for mortality after excluding subjects with steroids were entered as quartiles (P for trend Ͻ0.05) or as con- prevalent cancer, CVD, or diabetes (Table 3). Excluding preva- tinuous variables (Table 2). Further analyses using quartile 1 as lent diseases showed no major impact on the association between reference to allow direct comparison against quartiles 2, 3, and low total or free testosterone levels and all-cause mortality, and 4 showed that risk of death increased in men within quartile 1 of there was little impact on the association between low estradiol total and free testosterone levels and total and free estradiol levels levels and mortality after exclusion for prevalent CVD or dia- compared with quartiles 2, 3, and 4 of each respective hormone, betes. Excluding subjects with prevalent cancer attenuated the thus revealing a nonlinear association. Results were similar for association between total estradiol and mortality but had less total and free sex steroid levels. The associations remained after impact on the association between free estradiol and mortality.
further adjustment for age and BMI (model 2) as well as age, BMI, To study how follow-up time impacts the association between physical activity, and smoking (model 3). We observed no associ- sex steroids and mortality, we performed analyses that excluded ation between SHBG levels and all-cause mortality (Table 2).
subjects with a follow-up time of 3 yr or less (i.e. death within the Because subjects within the lowest quartile of estradiol and first 3 yr of follow-up; n ϭ 195 among 383 deaths). However, testosterone levels showed increased risk of mortality, we inves- this exclusion had no major influence on the results [HR (95% tigated increased mortality risk in the lowest quartile vs. the CI) for quartile 1 of total testosterone vs. quartiles 2– 4, 1.72 pooled quartiles 2– 4 (Table 2). Compared with subjects within (1.21–2.43), adjusted for age, BMI, physical activity, and smok- quartiles 2– 4, testosterone and estradiol levels within quartile 1 ing; corresponding analysis for total estradiol, HR, 1.47 (95% associated with an increased mortality risk of 50 and 60%, re- J Clin Endocrinol Metab, July 2009, 94(7):2482–2488 TABLE 2. HRs of sex steroids in quartiles for mortality
Risk for 1 SD increase in total testosterone Risk for 1 SD increase in free testosterone Risk for 1 SD increase in total estradiol Total testosterone (Q1 vs. Q2– 4) Model including both testosterone and estradiol Total testosterone (Q1 vs. Q2– 4) Data are expressed as HR (95% CI). Model 1, adjusted for age, MrOS site; model 2, adjusted for age, MrOS site, and BMI; model 3, adjusted for age, MrOS site, BMI,physical activity, and current smoking. Q, Quartile.
To analyze further the impact of BMI on the relation between low hormone levels. In contrast, although there was a tendency, sex hormones and mortality, we calculated the age-adjusted HR of the risk of death from cardiovascular causes was not significantly low testosterone or low estradiol (quartile 1 vs. pooled quartiles increased [age-adjusted HR (95% CI) for quartile 1 of total tes- 2– 4) for mortality within each quartile of BMI. Within BMI quartile tosterone vs. quartiles 2– 4 was 1.21 (0.81–1.79); corresponding 1, the HR (95% CI) was 1.79 (1.12–2.87) for low testosterone and analysis for total estradiol, 1.22 (0.82–1.81)].
1.62(1.09–2.41)forlowestradiol;thecorrespondingHRswithinBMIquartile 2 were 1.89 (1.14–3.11) and 1.61 (1.00 –2.60); withinBMI quartile 3, 1.34 (0.82–2.20) and 1.40 (0.83–2.35); and within Discussion
BMI quartile 4, 1.52 (0.97–2.39) and 1.68 (1.04 –2.71).
To study whether there was an increased incidence of car- This prospective study investigated a possible link between se- diovascular deaths, we analyzed the risk of CVD and non-CVD rum testosterone and estradiol levels, assessed by GC-MS, and death at low hormone levels. The risk of death from noncardio- mortality in a large population-based cohort of elderly men. Our vascular causes [age-adjusted HR (95% CI) for quartile 1 of total results show that risk of death increased for elderly men in the testosterone vs. quartiles 2– 4, 1.75 (1.30 –2.37); corresponding lowest quartile of both testosterone and estradiol levels. Testos- analysis for total estradiol, 2.00 (1.49 –2.69)] was increased at terone and estradiol predicted death independently of each other, Testosterone, Estradiol, and Male Mortality J Clin Endocrinol Metab, July 2009, 94(7):2482–2488 TABLE 3. HRs of low levels of sex steroids (quartile 1 vs.
quartiles 2– 4) for mortality, excluding subjects with prevalent
HR of low total testosterone for mortality HR of low free testosterone for mortality Data are expressed as HR (95% CI). Model 3, Adjusted for age, MrOS site, BMI,physical activity, and current smoking. Q, Quartile. Italics indicate reference data fromTable 2. and risk of death nearly doubled (96% increase) in subjects withboth low testosterone and low estradiol compared with subjectswithin quartiles 2– 4 of both hormones.
To our knowledge, ours is the first study that shows estradiol as a predictor of mortality in elderly men. Furthermore, the presentstudy is the first large study to report on the association betweenestradiol and testosterone, assessed by the reference methodGC-MS (16, 17), and mortality (18). The absence of previous stud-ies demonstrating an association between low estradiol levels andmortality may result partly from the use of immunoassay-basedtechniques, which may provide questionable specificity at low es-tradiol levels (17). Moreover, such technical restraints may explainthe paucity of studies on serum estradiol levels and other health-related outcomes in men. However, our recent study on this co-hort reported that older men with low serum estradiol, assessedby GC-MS, have increased risk of fractures (2). Therefore, it isreasonable to believe that more sensitive and reliable techniques,such as GC-MS, will help unravel important physiological effectsof estradiol in men.
Three previous prospective population-based cohort studies investigated the relationship between serum testosterone and to-tal mortality (6, 12, 13). Although two studies observed no as- FIG. 1. Unadjusted Kaplan-Meier survival curves according to serum sex steroid
levels. A, Cumulative survival of subjects within the lowest Q of serum total
sociation between testosterone and survival (12, 13), Laughlin et testosterone compared with Q2– 4. B, Cumulative survival of subjects within the al. (6) showed that low testosterone associated with increased lowest Q of serum total estradiol compared with Q2– 4. C, Cumulative survival of mortality in men in the Rancho Bernado Study. The two negative subjects within the lowest quartile of both serum total testosterone and estradiol.
Group 1, Medium/high testosterone and medium/high estradiol; group 2, low studies investigated middle-aged men (mean age, 52 and 55 yr, testosterone and medium/high estradiol; group 3, low estradiol and medium/ respectively), whereas Laughlin et al. (6) studied elderly men high testosterone; group 4, low testosterone and low estradiol. Low estradiol, with a mean age comparable to that of the present study, possibly Subjects within the lowest Q of estradiol (Յ16 pg/ml); medium/high estradiol,subjects within Q2– 4 of estradiol (Ͼ16 pg/ml); low testosterone, subjects within accounting for the different results. In the study by Laughlin et al. the lowest Q of testosterone (Յ3.36 ng/ml); medium/high testosterone, subjects (6), 68% of the cohort (mean age, 71 yr; range, 50 –91) died during within Q2– 4 of testosterone (Ͼ3.36 ng/ml). Q, Quartile.
an average 11.8 yr of follow-up, yielding a mortality rate of 57.5 per J Clin Endocrinol Metab, July 2009, 94(7):2482–2488 1000 person-years at risk. In the present study, 13% of subjects Because androgen deprivation therapy (chemical or surgical) (mean age, 75 yr; range, 69 – 80 yr) died during an average 4.5 yr of during treatment of prostate cancer lowers serum testosterone follow-up, yielding a mortality rate of 28.5 per 1000 person-years levels, such treatment may affect the association between low at risk. Thus, our studied subjects are a few years older at baseline testosterone levels and mortality. However, our result that ex- and have a smaller age span, a shorter follow-up time, and a lower cluding subjects with self-reported cancer at baseline did not mortality rate compared with the Laughlin study. Furthermore, significantly influence the association between low testosterone whereas Laughlin et al. (6) used an immunoassay-based method to and mortality does not support androgen deprivation therapy as assess testosterone, we used GC-MS (16, 17). Despite these differ- a pivotal factor for the results of this study.
ences, both studies found that testosterone levels within the lowest Although there was a tendency, we did not find a statistically quartile associated with increased risk of all-cause death (38% for significant association between low testosterone (HR, 1.21) or es- Laughlin et al. vs. 65% in the present study). Nested case-control, tradiol levels (HR, 1.22) and CVD mortality risk in this cohort of retrospective, and smaller studies also support a link between low older men. Several previous prospective studies show no significant testosterone and all-cause mortality in elderly men (10, 11, 14, 15).
association between testosterone levels and CVD mortality in men We observed no relationship between SHBG levels and all-cause (12, 13, 28 –30), whereas an association between testosterone levels mortality, supporting an earlier prospective study (25).
and CVD death was found in the prospective cohort study of Laugh- Interestingly, low estradiol and low testosterone predicted death lin et al. (6) (HR, 1.36) as well as in a recent nested case-control independently of each other, and subjects with low levels of both study of Khaw et al. (15). To our knowledge, there are only two testosterone and estradiol showed the highest risk of mortality in the previous, smaller prospective studies on estradiol and CVD death in present study. These results suggest that both hormones contribute men, and these studies showed no significant association (28, 31).
additively to risk of death and that both low testosterone and low In this study, the HRs for mortality were similar for total and free estradiol may serve as markers of mortality risk in elderly men.
hormone levels. Because obesity is associated with low SHBG (30), We propose two major hypotheses regarding the association somewhat more diverging results for free and total hormone levels between low sex steroid levels and mortality: 1) low sex steroid could be expected. On the other hand, this population of men is only levels cause or worsen disease and thereby cause death; or 2) low sex mildly overweight (average BMI, 26.4 kg/m2). In accordance with steroid levels are a result of disease and therefore associate with the present data, the HRs of free and total testosterone/estradiol death. The second hypothesis, i.e. low testosterone/estradiol is an levels for incident fractures in this cohort were also similar (2).
epiphenomenon of preexisting diseases, is supported by evidence We found that subjects with low BMI (within quartile 1) had that both acute and chronic illnesses reduce testosterone production an increased risk of death compared with subjects within quar- (1, 26). In acute illness, testosterone is often profoundly depressed tiles 2– 4, in accordance with most studies reporting either no through mechanisms that act both directly at the testicular level and relation, an inverse or a U-shaped relation between BMI and indirectly through gonadotropin suppression (1, 26). Furthermore, all-cause mortality in the elderly (32). The relation between low hypogonadism due to primary testicular failure (e.g. cytokines act- testosterone and estradiol and mortality was rather consistent ing directly upon the testes) accompanies many chronic diseases across BMI quartiles, but with a slight tendency to be U-shaped with such as renal disease, alcoholic liver disease, and rheumatic diseases the lowest HR of both hormones for mortality within BMI quartile (1, 26). Therefore, low serum sex steroids might represent a general 3, indicating that the sex hormone status is somewhat more pre- marker of poor health and thereby associate with increased mor- dictive of survival in subjects with low or high BMI. Importantly, tality risk. In our study, the association between testosterone/estra- BMI does not distinguish fat mass from lean mass, and BMI in the diol and mortality remained significant even after we excluded lower range is a less valid indicator of body fatness in the elderly in deaths that occurred during the first 3 yr of follow-up, thus arguing which low BMI rather may indicate low lean mass (33).
against a substantial role of prevalent diseases for our observations.
Our study has limitations. The fact that only a total of 45% Furthermore, excluding subjects with prevalent diseases (cancer, of the subjects who were contacted participated in the study may CVD, or diabetes) had no major impact on the association between restrict the generalizability of our findings. The results are based low sex steroid levels and mortality, although excluding subjects on single measurements of sex steroids and may underestimate with prevalent cancer slightly attenuated the association between the true associations between the markers we studied and the risk total estradiol and mortality. The hypothesis that low sex steroid of death. Although most of the blood specimens in this study levels worsen disease and thereby may cause death is supported by were obtained between 0800 and 0830 h, some samples were the fact that testosterone has important physiological effects on, for obtained between 1230 and 1330 h, and given the well-docu- example, muscle, bone, fat mass, and brain in men (1). Thus, low mented diurnal variation in serum testosterone levels (34), this testosterone levels may contribute to frailty that affects the individ- may contribute to increased variability and underestimation of ual’s capability to recover after any disease event and thereby affects serum testosterone levels in the present study. However, a recent survival. Furthermore, men with low serum testosterone are at in- study showed that the diurnal variation of serum testosterone is less creased risk of falls, low bone mineral density, and fractures (2– 4).
in older men (70 yr), with 10% lower levels at 1600 h than at In addition, a pathogenic role of low testosterone in the develop- 0800 h, compared with a 20 –25% difference in men 30 – 40 yr old ment of the metabolic syndrome has been suggested (18, 27). Thus, (34). A population-based study such as ours could imply inclusion there are several putative mechanisms by which low testosterone of subjects treated with compounds that affect mortality risk and/or could contribute to increased mortality, but additional studies are sex steroid levels, thus affecting interpretation of our results. In addition, our results are limited to elderly Caucasian men. A large Testosterone, Estradiol, and Male Mortality J Clin Endocrinol Metab, July 2009, 94(7):2482–2488 number of analyses have been performed in the present study, and 12. Smith GD, Ben-Shlomo Y, Beswick A, Yarnell J, Lightman S, Elwood P 2005
problems associated with multiple testing may complicate the in- Cortisol, testosterone, and coronary heart disease: prospective evidence fromthe Caerphilly study. Circulation 112:332–340 terpretation of results. However, our main hypothesis, i.e. that low 13. Araujo AB, Kupelian V, Page ST, Handelsman DJ, Bremner WJ, McKinlay JB
serum testosterone and estradiol predict all-cause mortality, was 2007 Sex steroids and all-cause and cause-specific mortality in men. Arch directly assessed by only a small number of analyses, and the other 14. Shores MM, Moceri VM, Gruenewald DA, Brodkin KI, Matsumoto AM,
analyses should be considered as exploratory subanalyses.
Kivlahan DR 2004 Low testosterone is associated with decreased function and
In conclusion, low serum testosterone and estradiol, assessed by increased mortality risk: a preliminary study of men in a geriatric rehabilitation specific GC-MS, associate with risk of death in older Swedish men, and subjects with low values of both testosterone and estradiol have 15. Khaw KT, Dowsett M, Folkerd E, Bingham S, Wareham N, Luben R, Welch A,
Day N 2007 Endogenous testosterone and mortality due to all causes, cardiovas-
the highest risk of mortality. Thus, both low testosterone and low cular disease, and cancer in men: European prospective investigation into cancer in estradiol may serve as markers of mortality risk in elderly men.
Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation 116:2694–2701 16. Wang C, Catlin DH, Demers LM, Starcevic B, Swerdloff RS 2004 Measure-
ment of total serum testosterone in adult men: comparison of current labora-tory methods versus liquid chromatography-tandem mass spectrometry. J Clin Acknowledgments
17. Lee JS, Ettinger B, Stanczyk FZ, Vittinghoff E, Hanes V, Cauley JA, Chandler
We thank Maud Peterson and the MrOS study personnel for excellent W, Settlage J, Beattie MS, Folkerd E, Dowsett M, Grady D, Cummings SR
2006 Comparison of methods to measure low serum estradiol levels in post-
menopausal women. J Clin Endocrinol Metab 91:3791–3797 18. Snyder PJ 2008 Might testosterone actually reduce mortality? J Clin Endocri-
Address all correspondence and requests for reprints to: Åsa Tivesten, Wallenberg Laboratory for Cardiovascular Research, Bruna Stråket 16, 19. Mellstro¨m D, Johnell O, Ljunggren O, Eriksson AL, Lorentzon M, Mallmin H,
Sahlgrenska University Hospital, S-413 45 Go¨teborg, Sweden. E-mail: Holmberg A, Redlund-Johnell I, Orwoll E, Ohlsson C 2006 Free testosterone
is an independent predictor of BMD and prevalent fractures in elderly men: This work was supported by the Swedish Research Council, the MrOS Sweden. J Bone Miner Res 21:529 –535 Swedish Foundation for Strategic Research, the ALF/LUA research grant 20. Orwoll E, Blank JB, Barrett-Connor E, Cauley J, Cummings S, Ensrud K,
in Gothenburg, the Swedish Heart-Lung Foundation, the Marianne and Lewis C, Cawthon PM, Marcus R, Marshall LM, McGowan J, Phipps K,
Sherman S, Stefanick ML, Stone K 2005 Design and baseline characteristics of
Marcus Wallenberg Foundation, the Lundberg Foundation, the Torsten the osteoporotic fractures in men (MrOS) study–a large observational study of and Ragnar So¨derberg’s Foundation, Petrus and Augusta Hedlunds the determinants of fracture in older men. Contemp Clin Trials 26:569 –585 Foundation, Endorecherche, and the Novo Nordisk Foundation.
21. Labrie F, Be´langer A, Be´langer P, Be´rube´ R, Martel C, Cusan L, Gomez J,
Disclosure Summary: Å.T., L.V., M.K.K., O Candas B, Castiel I, Chaussade V, Deloche C, Leclaire J 2006 Androgen glu-
nothing to declare. F.L. has received research grants from Endorecherche.
curonides, instead of testosterone, as the new markers of androgenic activityin women. J Steroid Biochem Mol Biol 99:182–188 22. Vandenput L, Labrie F, Mellstro¨m D, Swanson C, Knutsson T, Peeker R,
Ljunggren O, Orwoll E, Eriksson AL, Damber JE, Ohlsson C 2007 Serum
levels of specific glucuronidated androgen metabolites predict BMD and pros-tate volume in elderly men. J Bone Miner Res 22:220 –227 1. Kaufman JM, Vermeulen A 2005 The decline of androgen levels in elderly men
23. Vermeulen A, Verdonck L, Kaufman JM 1999 A critical evaluation of simple
and its clinical and therapeutic implications. Endocr Rev 26:833– 876 methods for the estimation of free testosterone in serum. J Clin Endocrinol 2. Mellstro¨m D, Vandenput L, Mallmin H, Holmberg AH, Lorentzon M, Ode´n
A, Johansson H, Orwoll ES, Labrie F, Karlsson MK, Ljunggren O, Ohlsson C
24. van den Beld AW, de Jong FH, Grobbee DE, Pols HA, Lamberts SW 2000
2008 Older men with low serum estradiol and high serum SHBG have an Measures of bioavailable serum testosterone and estradiol and their relation- increased risk of fractures. J Bone Miner Res 23:1552–1560 ships with muscle strength, bone density, and body composition in elderly men.
3. Orwoll E, Lambert LC, Marshall LM, Blank J, Barrett-Connor E, Cauley J,
Ensrud K, Cummings SR 2006 Endogenous testosterone levels, physical per-
25. Kalme T, Seppa¨la¨ M, Qiao Q, Koistinen R, Nissinen A, Harrela M, Loukovaara
formance, and fall risk in older men. Arch Intern Med 166:2124 –2131 M, Leinonen P, Tuomilehto J 2005 Sex hormone-binding globulin and insulin-like
4. Meier C, Nguyen TV, Handelsman DJ, Schindler C, Kushnir MM, Rockwood
growth factor-binding protein-1 as indicators of metabolic syndrome, cardiovas- AL, Meikle AW, Center JR, Eisman JA, Seibel MJ 2008 Endogenous sex hor-
cular risk, and mortality in elderly men. J Clin Endocrinol Metab 90:1550 –1556 mones and incident fracture risk in older men: the Dubbo Osteoporosis Epi- 26. Karagiannis A, Harsoulis F 2005 Gonadal dysfunction in systemic diseases.
demiology Study. Arch Intern Med 168:47–54 5. Vandenput L, Mellstro¨m D, Lorentzon M, Swanson C, Karlsson MK, Brandberg
27. Basaria S, Dobs AS 2007 Testosterone making an entry into the cardiometa-
J, Lo¨nn L, Orwoll E, Smith U, Labrie F, Ljunggren O, Tivesten A, Ohlsson C 2007
bolic world. Circulation 116:2658 –2661 Androgens and glucuronidated androgen metabolites are associated with meta- 28. Barrett-Connor E, Khaw KT 1988 Endogenous sex hormones and cardiovascular
bolic risk factors in men. J Clin Endocrinol Metab 92:4130 – 4137 disease in men. A prospective population-based study. Circulation 78:539 –545 6. Laughlin GA, Barrett-Connor E, Bergstrom J 2008 Low serum testosterone
29. Liu PY, Death AK, Handelsman DJ 2003 Androgens and cardiovascular dis-
and mortality in older men. J Clin Endocrinol Metab 93:68 –75 7. Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, Aleman A, Lock TM,
Bosch JL, Grobbee DE, van der Schouw YT 2008 Effect of testosterone sup-
30. Wu FC, von Eckardstein A 2003 Androgens and coronary artery disease.
plementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA 299:39 –52 31. Haffner SM, Moss SE, Klein BE, Klein R 1996 Sex hormones and DHEA-SO4 in
8. Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams
relation to ischemic heart disease mortality in diabetic subjects. The Wisconsin TC, Lubahn DB, Korach KS 1994 Estrogen resistance caused by a mutation in
Epidemiologic Study of Diabetic Retinopathy. Diabetes Care 19:1045–1050 the estrogen-receptor gene in a man. N Engl J Med 331:1056 –1061 32. Heiat A, Vaccarino V, Krumholz HM 2001 An evidence-based assessment of
9. Gennari L, Nuti R, Bilezikian JP 2004 Aromatase activity and bone homeosta-
federal guidelines for overweight and obesity as they apply to elderly persons.
sis in men. J Clin Endocrinol Metab 89:5898 –5907 10. Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR 2006 Low serum tes-
33. Willett WC, Dietz WH, Colditz GA 1999 Guidelines for healthy weight.
tosterone and mortality in male veterans. Arch Intern Med 166:1660 –1665 11. Lehtonen A, Huupponen R, Tuomilehto J, Lavonius S, Arve S, Isoaho H,
34. Brambilla DJ, Matsumoto AM, Araujo AB, McKinlay JB 2009 The effect of
Huhtaniemi I, Tilvis R 2008 Serum testosterone but not leptin predicts mor-
diurnal variation on clinical measurement of serum testosterone and other sex tality in elderly men. Age Ageing 37:461– 464 hormone levels in men. J Clin Endocrinol Metab 94:907–913
Innovator duty of care in the pharmaceutical industryDoes the inventor or “innovator” of a brand-name drug have a duty of care to the consumers of that drug’s generic equivalent manufactured by a competitor? The Ontario Superior Court of Justice considered this question in the recent case of Goodridge v Pfizer Canada1 and determined that, for now, no such duty exists. In that decision, th