Keenan, Daniel M.

Luteinizing hormone (LH) administered in pharmacological amounts downregulates Leydig cell steroidogenesis. Whether reversible downregulation of physiological gonadotropin drive operates in vivo is unknown. Most of the analytical models of dose-response functions that have been constructed are biased by the assumption that no downregulation exists. The present study employs a new analytical platform to quantify potential (but not required) pulsatile cycles of LH-testosterone (T) dose-response stimulation, desensitization, and recovery (pulse-by-pulse hysteresis) in 26 healthy men sampled every 10 min for 24 h. A sensitivity-downregulation hysteresis construct predicted marked hysteresis with a median time delay to LH dose-response inflection within individual T pulses of 23 min and with median T pulse onset and recovery LH sensitivities of 1.1 and 0.10 slope unit, respectively ( P < 0.001). A potency-downregulation model yielded median estimates of one-half maximally stimulatory LH concentrations (EC50 values) of 0.66 and 7.5 IU/l for onset and recovery, respectively ( P < 0.001). An efficacy-downregulation formulation of hysteresis forecasts median LH efficacies of 20 and 8.3 ng·dl−1·min−1 for onset and offset of T secretory burst, respectively ( P = 0.002). Segmentation of the LH-T data by age suggested greater sensitivity, higher EC50 (increased LH potency), and markedly (2.7-fold) attenuated LH efficacy in older individuals. Each of the three hysteresis models yielded a marked ( P < 0.005) reduction in estimated model residual error compared with no hysteresis. In summary, model-based analyses allowing for (but not requiring) reversible pituitary-gonadal effector-response downregulation are consistent with a hypothesis of recurrent, brief cycles of LH-dependent stimulation, desensitization, and recovery of pulsatile T secretion in vivo and an age-associated reduction of LH efficacy. Prospective studies would be required to prove this aging effect.

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.

Pituitary ACTH drives adrenal glucocorticoid (cortisol) pulses via a time-delayed asymptotic dose-response process. To test the postulate that ACTH stimulates cortisol secretion dynamically (unequally during the initiation and termination of a cortisol secretory burst), a mathematical formalism was developed in which dose-response hysteretic shifts were allowed, but not required, within the time evolution of ACTH-cortisol pulse pairs. A dual-waveform deconvolution model was used to quantify cortisol secretion rates and reconstruct ACTH concentration profiles in 28 healthy adults previously sampled every 10 min for 24 h in the unstressed state (8,120 measurements). ACTH concentration-cortisol secretion dose-response functions were then estimated in each subject 1) without hysteresis (base model) and with allowances for possible hysteresis in 2) ACTH potency, 3) adrenal sensitivity, and 4) ACTH efficacy. Model residual error was 40% lower in the potency and sensitivity models and 20% lower in the efficacy model than in the base model ( P < 0.001). Mean time shifts for inferable hysteretic inflection were model-independent, i.e., grand mean (95% confidence interval) 22 (12–39) min after the onset of a cortisol secretory burst. Half-maximally effective ACTH concentrations (EC50) differed before and after hysteretic inflection within individual pulses: 1) 9.4 and 54 ng/l in the potency model ( P < 0.001) and 2) 8.9 and 123 ng/l in the sensitivity model ( P < 0.001) compared with 16 ng/l in the no-hysteresis model ( P < 0.001). In the efficacy-shift model, estimated maximal ACTH drive varied by 17-fold within cortisol secretory bursts (from 22 to 1.3 nmol·l−1·min cortisol secretion−1, P < 0.001). The collective results introduce the basis for modeling the dynamics of rapid, reversible physiological downregulation within the span of single interpulse intervals in vivo. This construct should have utility in parsing mechanisms of physiological regulation in other integrative systems.

The mechanisms by which aging progressively depletes testosterone (Te) availability in the male are unknown. Accordingly, the objective was to estimate brain gonadotropin-releasing hormone (GnRH) outflow (release and action), which cannot be observed directly, on the basis of downstream effects on pituitary luteinizing hormone (LH) secretion. LH, in turn, feeds forward on (stimulates) gonadal Te secretion, which then feeds back on (inhibits) GnRH-driven LH secretion. LH and Te concentrations were measured repetitively (every 10 min) over 18 h during graded pharmacological blockade of endogenous GnRH outflow in 24 healthy 20- to 72-yr-old men. Data were analyzed using a new age-dependent regression model of GnRH-LH-Te interactions to estimate pulsatile LH secretion and elimination, GnRH outflow, LH feedforward, and Te feedback. By incorporating regression on age within the dose-response model, we show that aging erodes all three primary forward and reverse pathways linking the brain, pituitary gland, and testes. Aging is associated with concomitant deficits in GnRH → LH feedforward, LH → Te feedforward, and Te → GnRH/LH feedback. The analytical formalism should be generalizable to other ensemble regulatory systems, such as those that control growth, reproduction, stress adaptations, and glucose metabolism.

Abstract Background: Sex steroids influence GH secretion in complex ways. Hypothesis: Analyses in a low sex-steroid milieu will help unveil the effects of age and other nonsteroidal regulators on GH secretion. Context: The study was conducted in a tertiary medical center. Subjects: The study group included 13 healthy young men and 12 healthy older men. Methods: We used GnRH agonist-induced down-regulation of testosterone and estradiol secretion, followed by consecutive infusion of l-arginine and GHRH or GHRP-2, to test secretagogue efficacies. Outcomes: We measured basal and pulsatile GH secretion. Results: During experimental testosterone/estradiol deprivation, older (57 ± 1.7 yr) men maintained: 1) 6.8-fold less pulsatile GH secretion (P &lt; 0.001); and 2) 2-fold lower maximal GH responses to GHRH (P = 0.0065) and GHRP-2 (P = 0.022) than young (23 ± 1.1 yr old) individuals. Stepwise forward-selection regression analyses identified: 1) abdominal visceral fat as a dominant negative predictor of both GHRH (R2 = 0.49; P = 0.001) and GHRP-2 (R2 = 0.38; P = 0.005) efficacies; and 2) fasting IGF-I concentration as a major positive correlate of GHRH (R2 = 0.52; P &lt; 0.001) and GHRP-2 (R2 = 0.31; P = 0.018) efficacies. Unstimulated pulsatile GH secretion was jointly correlated with IGF-I and IGFBP-3 (P = 0.039). Conclusion: Measures of body composition (abdominal visceral fat) and pulsatile GH action (IGF-I) explain up to one half of interindividual variability in the efficacies of GHRH and GHRP-2 in sex steroid-depleted men. Accordingly, normative ranges for maximal single peptide-stimulated GH secretion in short-term hypogonadal states should incorporate the influence of these determinants as well as age.