title: 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.
authors.affiliation: Endocrine Research Unit, Mayo School of Graduate Medical Education, Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota.
authors.forename: Animesh N
authors.initials: AN
authors.lastname: Sharma
authors.forename: Paul
authors.initials: P
authors.lastname: Aoun
authors.forename: Jean R
authors.initials: JR
authors.lastname: Wigham
authors.forename: Suanne M
authors.initials: SM
authors.lastname: Weist
authors.forename: Johannes D
authors.initials: JD
authors.lastname: Veldhuis
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000378:metabolism*; D000367:Age Factors; D000375:Aging / Q000502:physiology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D004958:Estradiol / Q000008:administration & dosage*; D025461:Feedback, Physiological; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage*; D007006:Hypogonadism / Q000139:chemically induced / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism; D007262:Infusions, Intravenous; D007654:Ketoconazole / Q000008:administration & dosage; D016729:Leuprolide / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000378:metabolism; D011446:Prospective Studies; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism; D000075462:Serum Albumin, Human; D012737:Sex Factors; D013739:Testosterone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D013997:Time Factors; D014156:Transcortin / Q000378:metabolism
chemical_list: C422455:ALB protein, human; D004791:Enzyme Inhibitors; C534935:SERPINA6 protein, human; D012709:Serum Albumin; D013739:Testosterone; D004958:Estradiol; C004648:testosterone enanthate; D000324:Adrenocorticotropic Hormone; D014156:Transcortin; D016729:Leuprolide; D007654:Ketoconazole; D006854:Hydrocortisone; D000075462:Serum Albumin, Human
keywords: adrenocorticotropin; glucocorticoids; pulsatile; regulation; sex steroids