Estradiol, but not testosterone, heightens cortisol-mediated negative feedback on pulsatile ACTH secretion and ACTH approximate entropy in unstressed older men and women.

How sex steroids modulate glucocorticoid feedback on the hypothalamic-pituitary-corticotrope (HPC) unit is controversial in humans. We postulated that testosterone (T) in men and estradiol (E2) in women govern unstressed cortisol-mediated negative feedback on ACTH secretion. To test this hypothesis, 24 men and 24 women age 58 ± 2.4 yr were pretreated with leuprolide and either sex steroid (E2 in women, T in men) or placebo addback. Placebo or ketoconazole (KTCZ) was administered overnight to inhibit adrenal steroidogenesis during overnight 14-h intravenous infusions of saline or cortisol in a continuous versus pulsatile manner to test for feedback differences. ACTH was measured every 10 min during the last 8 h of the infusions. The main outcome measures were mean ACTH concentrations, pulsatile ACTH secretion, and ACTH approximate entropy (ApEn). ACTH concentrations were lower in women than men (P < 0.01), and in women in the E2+ compared with E2- group under both continuous (P = 0.01) and pulsatile (P = 0.006) cortisol feedback, despite higher cortisol binding globulin and lower free cortisol levels in women than men (P < 0.01). In the combined groups, under both modes of cortisol addback, ACTH concentrations, pulsatile ACTH secretion, and ACTH secretory-burst mass correlated negatively and univariately with E2 levels (each P < 0.005). E2 also suppressed ACTH ApEn (process randomness) during continuous cortisol feedback (P = 0.004). T had no univariate effect but was a positive correlate of ACTH when assessed jointly with E2 (negative) under cortisol pulses. In conclusion, sex steroids modulate selective gender-related hypothalamic-pituitary adrenal-axis adaptations to cortisol feedback in unstressed humans.

Corticotropic axis drive of overnight cortisol secretion is suppressed in adolescents and young adults with type 1 diabetes mellitus.

CONTEXT: Type 1 diabetes mellitus (T1DM) is a pro-inflammatory stress state, which, with its attendant hyperglycemia, likely disrupts hypothalamo-pituitary-adrenal (HPA) control, further dysregulating glucose homeostasis. OBJECTIVE: To test the hypothesis that endogenous adrenocorticotropic hormone (ACTH)-cortisol dose-responsive drive, estimated analytically, is significantly accentuated in adolescents and young adults with T1DM compared with healthy individuals. DESIGN, SETTING, PATIENTS, AND INTERVENTIONS: This was a pilot study of 11 volunteers with T1DM and 10 controls, ages 16-30 yr, at a medical center. Subjects underwent overnight frequent blood sampling (every 10 min for ACTH and cortisol and every 60 min for blood glucose) from 10 pm to 8 am. T1DM volunteers maintained their home insulin regimen. MAIN OUTCOMES: Deconvolution analysis and dose-response estimates were the key outcomes. RESULTS: Mean free cortisol, but not ACTH, concentrations were lower in the T1DM group compared with controls (p = 0.012). Non-invasive ACTH-cortisol dose-response estimates revealed that T1DM patients had reduced ACTH efficacy (maximal cortisol secretion, p = 0.009), reduced ACTH potency as quantified by greater EC50 (ACTH concentration driving half-maximal cortisol secretion, p = 0.04), and increased ACTH sensitivity (more positive ACTH-cortisol slope, p = 0.03). Post-hoc gender comparisons indicated that these differences were limited to females. Linear regression in women showed a strong correlation of both ACTH efficacy and EC50 with C-peptide levels (both p < 0.01). CONCLUSION: Compared with healthy individuals, T1DM patients manifest decreased overnight adrenal responsiveness to endogenous ACTH leading to lower free cortisol concentrations. These findings suggest impaired stress-related adaptations of the HPA axis in T1DM.