Sex differences in ACTH pulsatility following metyrapone blockade in patients with major depression

Abstract

SummaryNumerous studies suggest that increased central drive to the hypothalamic-pituitary adrenal axis occurs in patients with major depression. To determine if increased central drive occurs throughout the 24H, we evaluated ACTH secretion under metyrapone blockade of cortisol production. We collected blood every 10 minutes for measurement of ACTH and data were analyzed for ACTH pulsatility using the pulse detection algorithm deconvolution. We studied 28 patients with major depression and 28 age and sex matched control subjects, of which 9 pairs were men and 19 pairs were women. We found a significant group by sex interaction with number of ACTH pulses (p=.04); depressed men showed more ACTH pulses over 24H than matched control men (p=0.02). There was also a significant sex difference in AUC pulses with men showing a smaller AUC ACTH than women. Previous analyses of these data with RM-ANOVA showed a smaller ACTH response in depressed men compared to control men. These data suggest that pulsatility and mean ACTH levels are examining different aspects of HPA axis function, and that the types of HPA axis dysregulation in depression may differ between men and women.

17β-Estradiol Differentially Regulates Stress Circuitry Activity in Healthy and Depressed Women

“…Although deficits in HPA axis function are a hallmark of MDD (Gibbons and McHugh, 1962;Carroll et al, 1976a, b;Nemeroff et al, 1984;Arborelius et al, 1999;Webster et al, 2002;Parker et al, 2003;Holsen et al, 2013), gonadal hormone deficits are also evident Schmidt, 1996, 2006;Young et al, 2000Young et al, , 2007Himelein and Thatcher, 2006;Young and Korszun, 2002;Graziottin and Serafini, 2009; for a review, see Goldstein et al, 2014). For example, women with persistent MDD have twice the risk of early perimenopausal transition.…”

“…Throughout the lifecourse, changes in women's reproductive status have been associated with increased risk for mood disturbance and MDD (Rabin et al, 1990;Baischer et al, 1995;Schmidt, 1996, 2006;Harlow et al, 2003;Payne, 2003;Roca et al, 2003;Spinelli, 2005;Payne et al, 2009;Freeman et al, 2014). MDD incidence increases with pubertal onset in females (Angold and Costello, 2006), chronic use of oral contraceptives (Young et al, 2007), the postpartum period (Bloch et al, 2000;Brummelte and Galea, 2010), and perimenopause (Schmidt and Rubinow, 2009). A recent longitudinal population-based study of women found that the risk of depressive symptoms dropped significantly following menopause.…”

Organizational and Activational Effects of Testosterone on Masculinization of Female Physiological and Behavioral Stress Responses

“…Interestingly, one study using stressors that are etiologically related to affective disorders showed that women responded to social rejection with greater salivary-free cortisol than men (25). Furthermore, depressed women exhibit greater ACTH secretion in the evening compared with depressed men (26,27). Thus, women may have a distinct type of HPA axis sensitivity that is related to the vulnerability to affective disorders.…”

Impact of Gene-Gender Effects of Adrenergic Polymorphisms on Hypothalamic-Pituitary-Adrenal Axis Activity in Depressed Patients

“…It was further demonstrated that male subjects had a greater HPA axis response to a psychological stressor than female subjects, whereas women had a greater hormonal reactivity to pharmacologic stimulation [26] . Sex differences in ACTH pulsatility following metapyrone blockade were observed in another study, with men showing smaller ACTH AUCs than women [27] . The fact that highly anxious females exhibited lower cortisol release than highly anxious males further suggested that high trait anxiety females may be associated with an inability to respond with sufficient activation of the HPA axis under acute psychological stress [28] .…”