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.

Short-term estradiol supplementation potentiates low-dose ghrelin action in the presence of GHRH or somatostatin in older women.

CONTEXT: Ghrelin is a potent gastric-derived GH-releasing peptide. How ghrelin interacts with sex steroids, GHRH, and somatostatin (SS) is not known. OBJECTIVE: Our objective was to test the hypotheses that ghrelin's interactions with GHRH (synergistic) and SS (disinhibitory) are ghrelin dose-dependent and amplified by estrogen. SUBJECTS, SETTING, AND DESIGN: Healthy postmenopausal women were treated with placebo (n=12) or 17ß-estradiol (E2) (n=12) at the Center for Translational Science Activities in a randomized double-blind prospective study. METHODS: Ghrelin dose-dependence was assessed by nonlinear curve fitting of the relationship between deconvolved GH secretory-burst mass and 5 randomly ordered ghrelin doses (0, 0.03, 0.135, 0.6, and 2.7 µg/kg bolus iv) during saline, GHRH, and SS infusion. RESULTS: Under placebo, neither GHRH nor SS altered the ED50 of ghrelin (range 0.64-0.67 µg/kg). Under E2 (median E2 88 pg/mL), the ED50 of ghrelin declined in the presence of GHRH to 0.52 µg/kg. In contrast, the efficacy of ghrelin rose markedly during GHRH vs saline exposure with and without E2: placebo and saline 52±1.0 vs GHRH 173±3.8 µg/L; and E2 and saline 56±0.90 vs GHRH 174±3.7 µg/L. Sensitivity to ghrelin was similar under all conditions. SUMMARY: Short-term E2 supplementation in postmenopausal women reduces the ED50 (increases the potency) of ghrelin when GHRH is present, without altering ghrelin efficacy (maximal effect) or hypothalamo-pituitary sensitivity (slope of dose response) to ghrelin. The data suggest possible physiological interactions among sex steroids (endogenous), ghrelin, and GHRH during E2 replacement in postmenopausal women.

Analysis of the impact of intravenous LH pulses versus continuous LH infusion on testosterone secretion during GnRH-receptor blockade.

Gonadotrophin-releasing hormone (GnRH) pulsatility is required for optimal luteinizing hormone (LH) secretion, but whether LH pulsatility is required for physiological testosterone (T) secretion is not known. To test the postulate that pulses of recombinant human (rh) LH stimulate greater T secretion than continuous infusion of the same dose, a potent selective GnRH antagonist was administered overnight to 19 healthy men ages 18-49 yr. Subjects then received saline or rhLH intravenously continuously or as 6-min pulses intravenously every 1 or 2 h at the same total dose. Blood was sampled every 10 min for 10 h to quantify T responses. For the four interventions, the descending rank order of mean LH and mean T concentrations was 1-h = 2-h rhLH pulses > continuous rhLH > saline (P < 10(-3)). Plateau LH and T concentrations correlated positively (R(2) = 0.943, P = 0.029) as did LH concentrations and LH half-lives (R(2) = 0.962, P = 0.019). Percentage pulsatile T secretion assessed by deconvolution analysis (Keenan DM, Takahashi PY, Liu PY, Roebuck PD, Nehra AX, Iranmanesh A, Veldhuis JD. Endocrinology 147: 2817-2828, 2006) was the highest (P = 0.019), and half-time to attain peak T concentrations was the shortest (P < 10(-6)), for 1-h rhLH pulses. Approximate entropy (a pattern-regularity measure) revealed more orderly T secretion for 1- than 2-h rhLH pulses (P = 0.0076). Accordingly, a pulsatile LH signal, while not obligatory to maintain mean T concentrations, controls the mean plasma LH concentration and determines quantifiable patterns of T secretion. These data introduce the question whether blood T patterns in turn supervise distinctive target-tissue responses.

Age disrupts androgen receptor-modulated negative feedback in the gonadal axis in healthy men.

Testosterone (T) exerts negative feedback on the hypothalamo-pituitary (GnRH-LH) unit, but the relative roles of the CNS and pituitary are not established. We postulated that relatively greater LH responses to flutamide (brain-permeant antiandrogen) than bicalutamide (brain-impermeant antiandrogen) should reflect greater feedback via CNS than pituitary/peripheral androgen receptor-dependent pathways. To this end, 24 healthy men ages 20-73 yr, BMI 21-32 kg/m2, participated in a prospective, placebo-controlled, randomized, double-blind crossover study of the effects of antiandrogen control of pulsatile, basal, and entropic (pattern regularity) measurements of LH secretion. Analysis of covariance revealed that flutamide but not bicalutamide 1) increased pulsatile LH secretion (P = 0.003), 2) potentiated the age-related abbreviation of LH secretory bursts (P = 0.025), 3) suppressed incremental GnRH-induced LH release (P = 0.015), and 4) decreased the regularity of GnRH-stimulated LH release (P = 0.012). Furthermore, the effect of flutamide exceeded that of bicalutamide in 1) raising mean LH (P = 0.002) and T (P = 0.017) concentrations, 2) accelerating LH pulse frequency (P = 0.013), 3) amplifying total (basal plus pulsatile) LH (P = 0.002) and T (P < 0.001) secretion, 4) shortening LH secretory bursts (P = 0.032), and 5) reducing LH secretory regularity (P < 0.001). Both flutamide and bicalutamide elevated basal (nonpulsatile) LH secretion (P < 0.001). These data suggest the hypothesis that topographically selective androgen receptor pathways mediate brain-predominant and pituitary-dependent feedback mechanisms in healthy men.