Regulation of basal, pulsatile, and entropic (patterned) modes of GH secretion in a putatively low-somatostatin milieu in women

Abstract

Somatostatin (SS) released by hypothalamic neurons inhibits GH exocytosis noncompetitively. Therefore, we postulated that attenuation of GH feedback-induced SS outflow would help to unmask covariates of endogenous secretagogue drive. To this end, 42 healthy pre- and postmenopausal women were randomly assigned to receive leuprolide plus estradiol (E(2)) or leuprolide plus placebo. A putatively low-SS milieu was imposed by L-arginine infusion. Deconvolution and regularity analyses were applied to 6-h GH concentration-time profiles. By two-way ANOVA, age negatively (P < 0.001) and E(2) positively (P = 0.001) determined pulsatile GH secretion in the presumptively SS-deficient milieu (P < 0.001). Comparable effects were exerted on the mass of GH secreted per burst per unit distribution volume (age P = 0.001, E(2) P < 0.001, overall P < 0.001). E(2) alone predicted basal (nonpulsatile) GH secretion (P = 0.004). Stepwise forward-selection multivariate regression demonstrated that age (P = 0.0017) and E(2) (P = 0.0002) together explained 46% of intersubject variability in pulsatile GH secretion (P < 0.001) and fully replaced the negative univariate effect of abdominal visceral fat (r(2) = 0.32, P < 0.001). Moreover, age and E(2) (but not AVF) interacted to supervise GH regularity (P = 0.007). We conclude that age and E(2) availability individually and together constitute primary predictors of basal, pulsatile, and patterned GH secretion in an inferentially feedback-silenced context in healthy women. Therefore, both factors must be considered in framing hypotheses of endogenous GH drive.

Fig. 1.

Age and estradiol (E₂) determine pulsatile growth hormone (GH) secretion in a putatively low-somatostatin milieu. Two-way analysis of variance in 42 women given leuprolide with placebo or E₂ addback transdermally and then intravenous infusion of l-arginine. Volunteers were sampled every 10 min for 6 h, which included a 2-h baseline. Tukey's honestly significantly different (HSD) test was applied to compare means post hoc. P values are as indicated. The number of subjects in each of the 4 groups is stated within each bar. Data are means ± SE. PRE, premenopausal; POST, postmenopausal.

Fig. 2.

E₂ augments the mass of GH secreted per burst in PRE and POST women, with ∼3-fold greater responses in PRE than in POST individuals. Data are otherwise presented as described in Fig. 1.

Fig. 3.

Impact of E₂ and PRE vs. POST status on basal (unstimulated nonpulsatile) GH secretion in 42 women studied under a leuprolide clamp. The format is that of Fig. 1.

Fig. 4.

Univariate linear regression of pulsatile GH secretion unleashed by l-arginine infusion on abdominal visceral fat (top) or body mass index (bottom). Data were obtained from 42 women. P values reflect Pearson's correlation coefficient with corresponding r².

Fig. 5.

Combined contributions of age and E₂ concentrations to pulsatile GH secretion (top) and the mass of GH secreted per burst (bottom) in 42 women assigned to E₂ or placebo addback after leuprolide suppression of the gonadal axis. Partial P values are indicated below the overall P value for the forward-selection stepwise multivariate analysis.

Fig. 6.

Interactive effects of PRE and POST status and E₂ repletion/depletion on the regularity of GH secretion. Approximate entropy (ApEn) was used to quantify orderliness (regularity) of GH secretory patterns during l-arginine infusion. Increased ApEn denotes greater irregularity, which signifies less feedback control and/or less coordinated feedforward drive.