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

Abstract

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.

Decreased maternal hypothalamic-pituitary-adrenal axis activity in very severely obese pregnancy: Associations with birthweight and gestation at delivery

“…Cortisol is not considered to be synthesized in the placenta, so it is unlikely that this contributes to the lower cortisol we found in very severely obese pregnancy. In contrast to our findings of lower cortisol and lower estrogen in very severely obese pregnant women, a small study in postmenopausal women suggested that higher estrogen levels may magnify the negative feedback of cortisol on the HPAA in postmenopausal women, leading to lower cortisol levels (35). To the best of our knowledge, there are no other data describing the effects of estrogen on cortisol in severely obese pregnant women.…”

Impact of age, sex and body mass index on cortisol secretion in 143 healthy adults

“…Because of a higher pulse frequency, no sex difference emerged for total cortisol secretion. Although the role of (premenopausal) estrogen is not so clear ( 18 ), in older adults short-term administration of estradiol, but not testosterone, heightens cortisol-mediated inhibition of pulsatile ACTH secretion ( 15 ). In principle, therefore, an estrogenic milieu could lower mean cortisol in premenopausal women.…”

Clarifying the heterogeneity in psychopathic samples: Towards a new continuum of primary and secondary psychopathy

“…However, when artificially hypogonadal males (i.e., due to Leuprolide administration) were subsequently administered T compared to placebo, they showed a significantly dampened C secretion but paradoxically also an increased CRH-stimulated ACTH secretion, indicating that the effect of T on the HPA-axis is likely to be exerted peripherally instead of centrally (Rubinow et al, 2005). In fact, since peripherally stimulated C secretion is known to provide feedback autoregulation on HPA-axis activity, this finding may actually suggest that T dampens HPA-axis feedback inhibition and thus prolongs its activation (e.g., Sharma et al, 2014). Accordingly, a number of studies have reported tight coupling between the HPA- Thus, in addition to a mutually inhibitory effect, there are likely also some mutually excitatory effects (see also Sharma, Aoun, Wigham, Weist, & Veldhuis 2014).…”