Discussion
In two separate large COPD cohorts with baseline measurement of testosterone and longitudinal data pertaining to health outcomes, we demonstrated that circulating testosterone levels are not associated with COPD exacerbations, cardiovascular outcomes or all-cause mortality. However, in both ECLIPSE and ERICA, male participants with moderate airflow limitation (GOLD stage 2), an inverse association between testosterone levels and all-cause mortality was observed with and without adjustment for age, BMI, current smoking and FEV1% predicted.
The independent inverse association of testosterone levels with increased risk of all-cause mortality in males with COPD with moderate airflow limitation only, in both cohorts, suggests this finding is specific to this subgroup of participants. What specific cause(s) of death may have accounted for this relationship is uncertain, given that, in the ERICA cohort, no association of testosterone with cause specific respiratory-related mortality, or cardiovascular hospitalisation or mortality was observed in GOLD stage stratified analyses, possibly due to small numbers of individuals within subgroups. Besides modest negative correlations of testosterone with FFM and 6MWD (a known predictor of mortality), there were no significant associations of testosterone with other parameters assessed (ie, quadriceps strength, SPPB, vascular markers, H-AECOPD rates or cardiovascular outcomes) in this subgroup of GOLD stage 2 males. This implies these characteristics are unlikely to be important factors in testosterone’s association with all-cause mortality in this patient group. This relationship may be consistent with the association of lower testosterone levels associated with increased all-cause mortality observed in elderly male population studies.1 2 However, even in general population studies, what accounts for this association of lower testosterone levels with increased mortality, is unclear—it has, however, been postulated that testosterone levels may be a non-specific marker of general health.31 We speculate that the lack of statistically significant association between testosterone and all-cause mortality in the male participants in the overall cohorts, and in GOLD 3 or 4 males, is because the presence of severe COPD dominates mortality in these analyses. The fact we observed no statistically significant association between testosterone and rates of H-AECOPD, or with vascular markers or cardiovascular outcomes in ERICA implies that low testosterone is unlikely to be an important pathophysiology factor or of clinical prognostic significance in these outcomes or variables. It may be noted that a retrospective non-randomised study found that testosterone replacement therapy was associated with reduced risk of respiratory-related hospitalisations in men with COPD. However, there are a number of methodological factors of this study that makes it difficult to comparable with our cohorts.32 Two further small studies explored the relationships between testosterone and COPD outcomes. One of these did not find any difference in the number of exacerbations between patients with low testosterone compared with a control group with normal testosterone levels. Both studies found that lower FEV1, was associated with lower testosterone levels, which has been adjusted for in our analyses however, so should account for any confounding.33 34
The strongest cross-sectional correlation observed was an inverse association between BMI and testosterone in males in both cohorts and was due to weight rather than height. This may be explained by increased adipose tissue with increased weight (rather than skeletal muscle), which is associated with relatively higher oestrogen than testosterone in males, this correlation has been described in other (non-disease) cohorts.35 36 The inverse association between both FFM and quadriceps strength with testosterone in males prior to adjustment for BMI, was an unexpected finding. Nonetheless, there are contrasting data published on this relationship of FFM with testosterone.37 38 Possible reasons for this may be confounding from BMI and that FFM is inclusive not only of muscle mass but connective tissue, bone and organs, and skeletal muscle has a relatively lower contribution to FFM in our cohorts of elderly men with COPD. Moreover, our population has a relatively skewed and narrow distribution of age, FFM and testosterone over which to assess these associations. Further analyses in individuals who have frequent exacerbations who experience more rapid muscle loss could test this hypothesis. Further body composition measurements such as waist and trunk circumference were not measured in this study and may have provided further insights into understanding these associations with testosterone. As for QMVC, a positive relationship between quadriceps strength and testosterone has previously been evaluated in a small cohort of males with COPD.39 Our study is much larger however and differences in characteristics (lower 6MWD especially) may account for the difference in findings.
These analyses are the first comprehensive assessment of circulating testosterone levels in relation to health outcomes in substantially sized COPD cohorts of males and females. The strengths of these analyses are the range of clinically important outcomes assessed and association with parameters of functional and physical capacity, muscle strength, lung function and cardiovascular risk in COPD. We elected to use continuous analyses using multivariate logistic regression models rather than splitting the cohorts in quartiles of testosterone values as has been the approach in some other population studies assessing testosterone, providing statistical power for analyses. The cohorts also reflect different COPD populations, ECLIPSE was a multinational study including sites in North America and Europe. ERICA only included sites in the UK. There are recognised limitations to this study. The main limitation being that the ECLIPSE and ERICA studies were both observational in design, and therefore, we cannot infer causality for any of the associations that we have observed in these analyses. In addition, menopause status, which may be an important factor in interpreting circulating testosterone levels for women, was not recorded. However, both studies had inclusion criterion of >40 years of age, therefore, most women eligible would have been postmenopausal. It is also likely that the number of cases of prostate cancer may be higher than recorded; in ERICA, prostate cancer was recorded in only one participant’s record on the study database, although finasteride use, a drug to treat benign prostatic hyperplasia, was recorded in 12 participants. However, given the similar results in ECLIPSE and ERICA, it seems unlikely to impact results. Patient-level data were not available from ECLIPSE to enable further in-depth statistical analysis. Different reporting methods of H-AECOPD (patient reported at follow-up for ECLIPSE, HES data for ERICA) and mortality were used, although separate analysis for individual cohorts were undertaken. Also, analyses were restricted to hospitalised exacerbations. ERICA also had a longer duration of follow-up than ECLIPSE. However, evaluating the proportion of participants who ever had an H-AECOPD for both cohorts, showed they are reasonably similar (32% for ECLIPSE, 39% for ERICA males). A higher H-AECOPD proportion in females in ERICA (43%) is consistent with other studies data regarding sex difference in COPD exacerbations.40 The lower baseline 6MWD and higher mMRC score in the ERICA cohort may reflect a higher morbidity cohort than ECLIPSE, despite similar FEV1% predicted. The higher mortality in ERICA is likely due to a longer period of follow-up. Despite the differences in cohort characteristics, healthcare systems and methodologies of health outcome records between the two cohorts, the consistent results observed in separate analyses of ECLIPSE and ERICA are reassuring and indicate the statistically significant of association with all-cause mortality in GOLD stage 2 is valid, as are the lack of other statistically significant associations with other health outcomes. We also undertook analyses using serum free testosterone values as well as TT presented here, and observed no significant differences in the results.
In summary, this is the first evaluation of circulating testosterone levels in both men and women with COPD and with focus on its association with clinically important health outcomes. Although levels of circulating testosterone are a biomarker of interest, given its association with muscle strength and mass and physical performance in population studies and possible protective effect in asthma, we have found in patients with COPD, it is unlikely to be a biomarker that provides significant utility in clinical assessment for patients with COPD. However, the notable association with all-cause mortality in males with COPD GOLD stage 2 in both cohorts, suggests further research on the clinical importance of circulating testosterone levels and testosterone supplementation in this select group of patients with COPD, may be useful.