Obesity is widespread in the United States and other industrialized nations (1
), leading to significant health problems that impact nearly every organ system. Multiple endocrine disturbances, such as type 2 diabetes and polycystic ovary syndrome, often coexist with obesity. In addition, changes in the functioning of the hypothalamic-pituitary-adrenal (HPA) axis have been implicated as both a cause and a consequence of obesity (3
). Furthermore, obesity constitutes a chronic stressor with central and peripheral consequences. It has been proposed that a prolonged period of HPA axis stimulation secondary to the chronic stress of obesity is followed by a breakdown in the regulatory mechanisms of the HPA axis (5
). For example, individuals with increased abdominal obesity have greater endogenous glucocorticoid responses to a meal (6
) or adrenocorticotropic hormone (ACTH) challenge (7
). It is also known that exogenous glucocorticoids increase food intake (8
) and promote deposition of abdominal fat that is predictive of cardiovascular disease, particularly in women (5
). These observations support the notion that changes in the HPA axis in the setting of obesity may confer greater risk to develop obesity-related comorbidities including anxiety and depression, hypertension, hyperlipidemia, and diabetes.
Determining causality and directionality of the interactions between the HPA axis activity and obesity is hampered by difficulty, in characterizing a dynamic axis with a pronounced diurnal pattern. Not only is the cortisol rhythm diurnal, cortisol levels rise following meals or in response to illness, psychosocial challenge, and exercise. In the circulation, the greatest amount of cortisol is bound to plasma proteins (>90%), particularly corticosteroid binding globulin (CBG) and sex hormone binding globulin (SHBG), whereas tissues “see” only the free (unbound) fraction. Because the secretion of cortisol is diurnal and pulsatile, a single time point for cortisol is inherently unreliable in estimating the total cortisol secretion. Thus, it is not surprising that there are conflicting results concerning the association between cortisol and obesity using single cortisol measures (9
). More consistent findings were reported in studies using serial measures of the HPA axis (11
). Strain and colleagues revealed an increased metabolic clearance rate of cortisol among obese compared with non-obese women (13
) and a positive association between absolute cortisol production and relative body weight in men and women (14
). Stimulated measures of the HPA axis reflect the reactivity (i.e., hypoactivity vs. hyperactivity) of the stress system. Only one study examined the association between cortisol reactivity and obesity in children (15
), demonstrating a positive association between cortisol reactivity to a stressful situation and body mass index.
An individual’s reaction to acute and chronic stress has been hypothesized to be related to the development of obesity. Bjorntorp (16
) postulated that a heightened vulnerability to psychosocial stress increases exposure to stress-induced cortisol, which in turn promotes central fat deposition. Other studies supported this theory, particularly among women with central body fat distribution (increased waist-to-hip ratio) (12
). Additionally, research has evaluated whether increased stress contributed to the obesity epidemic in children (19
). In Swedish infants (N=7443) followed through age 5 years, children in families reporting stress in at least two of the four domains assessed had significantly higher odds (OR, 2.6) of being obese (19
The pediatric literature contains few studies involving the HPA axis and obesity. Chelew and colleagues evaluated serial serum cortisol concentrations over 20-24 hours in 16 obese males and females aged 5-16 years (20
). Compared with lean children, the obese children had significantly lower mean cortisol concentrations. Another study reported no significant associations between the HPA axis and percent body fat in prepubertal obese children (21
). However, when central adiposity was examined, a significant inverse association with salivary cortisol response to a meal was found among females but not males and a positive association between urinary glucocorticoid metabolites and central adiposity was also found among females (21
). Although studies have begun to explore associations between the HPA axis and obesity in childhood, much remains unknown; thus, investigations in younger, non-adult cohorts may provide insight into the roots of metabolic disease that are expressed in adulthood.
In examining the association between measures of the HPA axis and degree of adiposity in adolescent girls, we hypothesized that measures of adiposity would be correlated with increased HPA axis activity and reactivity. As a secondary aim, we evaluated whether measures of the HPA axis are independently associated with central adiposity when controlling for percent body fat. This study is unique in capturing multiple measures of both the HPA axis and adiposity in a large cohort of adolescent girls.