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

Abstract

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.

Fig. 1.

Time profiles of LH (top) and testosterone (T; bottom) concentrations observed in 24 men by sampling blood every 10 min for 8 h after administration of placebo, flutamide, or bicalutamide for 4 days. Sampling began at 0800. Gonadotropin-releasing hormone (GnRH; 100 ng/kg) was injected by intravenous bolus after the 1st 6 h. Data are the arithmetic means ± SE.

Fig. 2.

Antiandrogens [flutamide (Fl) or bicalutamide (Bi)] augment baseline LH and T concentrations and peak GnRH-stimulated T concentrations compared with placebo (Pl). Data are the arithmetic means ± SE of 6-h values before and 2-h values after GnRH injection. *, ø, and †P values were determined by analysis of covariance and by post hoc Tukey's test. Differing (unshared) letters denote P < 0.05 contrast between the corresponding means.

Fig. 3.

Left and middle: basal (nonpulsatile) and pulsatile LH (top) and T (bottom) secretion in 24 men studied during administration of Pl, Fl, or Bi. Right: pulsatile LH and T secretion after GnRH injection. Data are box-and-whisker plots (median, interquartile range). Individual dots are outside the 80% confidence interval. Open bars, Pl; gray bars, Fl; black bars, Bi.

Fig. 4.

Primary LH and T pulse characteristics assessed by deconvolution analysis: secretory burst frequency (left) and secretory burst mass (right). Data are presented as in Fig. 3.

Fig. 5.

Top: impact of Pl and antiandrogens on approximate entropy (ApEn) of LH (left) and T (right) release over 6 h in 24 men. Bottom: feedforward (LH → T) and feedback (T → LH) paired synchrony within male gonadal axis as estimated by cross-ApEn. Data are depicted as described in Fig. 2. Higher ApEn or cross-ApEn denotes greater irregularity (less orderliness or less joint synchrony).

Fig. 6.

Linear regression of the mode of LH secretory bursts on age in 24 men sampled every 10 min for 8 h during exposure to placebo, flutamide, and bicalutamide. Unshared letters A and B denote P ≤ 0.025 difference in the indicated slopes and SD.