In Obesity, HPA Axis Activity Does Not Increase with BMI, but Declines with Aging: A Meta-Analysis of Clinical Studies

Abstract

Background: Obesity is one of the major public health challenges worldwide. It involves numerous endocrine disorders as etiological factors or as complications. Previous studies strongly suggested the involvement of the hypothalamic-pituitary-adrenal (HPA) axis activity in obesity, however, to date, no consistent trend in obesity-associated alterations of the HPA axis has been identified. Aging has been demonstrated to aggravate obesity and to induce abnormalities of the HPA axis. Thus, the question arises whether obesity is correlated with peripheral indicators of HPA function in adult populations.

Objectives: We aimed to meta-analyze literature data on peripheral cortisol levels as indicators of HPA activity in obesity during aging, in order to identify possible explanations for previous contradictory findings and to suggest new approaches for future clinical studies.

Data sources: 3,596 records were identified through searching of PubMed, Embase and Cochrane Library Database. Altogether 26 articles were suitable for analyses.

Study eligibility criteria: Empirical research papers were eligible provided that they reported data of healthy adult individuals, included body mass index (BMI) and measured at least one relevant peripheral cortisol parameter (i.e., either morning blood cortisol or 24-h urinary free cortisol).

Statistical methods: We used random effect models in each of the meta-analyses calculating with the DerSimonian and Laird weighting methods. I-squared indicator and Q test were performed to assess heterogeneity. Meta-regression was applied to explore the effect of BMI and age on morning blood and urinary free cortisol levels. To assess publication bias Egger's test was used.

Results: Obesity did not show any correlation with the studied peripheral cortisol values. On the other hand, peripheral cortisol levels declined with aging within the obese, but not in the non-obese groups.

Conclusions: Our analysis demonstrated that obesity or healthy aging does not lead to enhanced HPA axis activity, peripheral cortisol levels rather decline with aging.

Fig 1. Flowchart of the study selection procedure.

Fig 2. Forest plot representing the differences in mean morning blood cortisol values of obese and non-obese groups.

Squares show the difference in mean values with the grey area reflecting the weight assigned to the study. Horizontal bars indicate 95% confidence intervals (95% CI). The diamond shows the overall effect size (ES) with its corresponding 95% CI.

Fig 3. Forest plot representing the differences in mean 24-h urinary free cortisol values of obese and non-obese groups.

Squares show the difference in mean values with the grey area reflecting the weight assigned to the study. Horizontal bars indicate 95% confidence intervals (95% CI). The diamond shows the overall effect size (ES) with its corresponding 95% CI.

Fig 4. Forest plot indicating the mean values of morning blood cortisol in non-obese (N), mildly (MO) or severely obese (SO) groups.

The grey areas reflect the weight assigned to the study. Horizontal bars indicate 95% confidence interval (95% CI). The diamond indicates the weighted mean of each subgroup with the corresponding 95% CI. ES: effect size.

Fig 5. Forest plot indicating the mean values of 24-h urinary free cortisol in non-obese (N), mildly (MO) or severely obese (SO) groups.

The grey areas reflect the weight assigned to the study. Horizontal bars indicate 95% confidence interval (95% CI). The diamond indicates the weighted mean of each subgroup with the corresponding 95% CI. ES: effect size.

Fig 6. Meta-regression of mean morning blood cortisol levels versus mean age of the 26 obese groups from our analyzed studies (Table 1).