PYRIDOSTIGMINE TREATMENT SELECTIVELY AMPLIFIES THE MASS OF GH SECRETED PER BURST WITHOUT ALTERING GH BURST FREQUENCY, HALF-LIFE, BASAL GH SECRETION OR THE ORDERLINESS OF GH RELEASE

Growth hormone (GH) release from the anterior pituitary gland is predo minantly regulated by the two antagonistic hypothalamic peptides, grow th hormone-releasing hormone (GHRH) and somatostatin. Appraising endog enous GHRH action is thus made difficult by the confounding effects of (variable) hypothalamic somatostatin inhibitory tone. Accordingly, to evaluate endogenous GHRH actions, we used a clinical model of presump tively acute endogenous somatostatin withdrawal with concomitant GHRH release. To this end, we administered in randomized order placebo or t he indirect cholinergic agonist, pyridostigmine, for 48 h to 13 health y men of varying ages (29-77 years) and body mass indices (21-47 kg/m( 2)). We sampled blood at 10-min intervals for 48 h during both placebo and pyridostigmine (60 mg orally every 6 h) administration, and used an ultrasensitive GH chemiluminescence assay (sensitivity 0.002-0.005 mu g/l) to capture GH pulse profiles. Multiparameter deconvolution ana lysis was applied to quantitate the number, amplitude, mass, and durat ion of significant underlying GH secretory bursts, and simultaneously estimate the GH half-life and concurrent basal GH secretion. Approxima te entropy was utilized as a novel regularity statistic to quantify th e relative orderliness of the hormone release process. All measures of GH secretion/half-life and orderliness were statistically invariant a cross the two consecutive 24-h placebo sessions. In contrast, pyridost igmine treatment significantly increased the mean serum GH concentrati on from 0.23 +/- 0.054 mu g/l during placebo to 0.45 +/- 0.072 mu g/l during the first day of treatment (P<0.01). There was also a significa nt rise in the calculated 24-h pulsatile GH production rate from 8.9 /- 1.7 mu g/l/day on placebo to 27 +/- 5.6 mu g/l/day during active dr ug treatment (P<0.01). Pyridostigmine significantly and selectively am plified GH secretory burst mass to 1.5 +/- 0.35 mu g/l compared with 0 .74 +/- 0.19 mu g/l on placebo (P<0.01). This was attributable to stim ulation of GH secretory burst amplitude (maximal rate of GH secretion attained within the release episode) with no prolongation of estimated burst duration. Basal GH secretion and approximate entropy were not a ltered by pyridostigmine. However, age was strongly related to more di sorderly GH release during both days of pyridostigmine treatment (r=+0 .79, P=0.0013). During the second 24-h of continued pyridostigmine tre atment, most GH secretory parameters decreased by 15-50%, but in sever al instances remained significantly elevated above placebo. Body mass index, but not age, was a significantly negative correlate of the pyri dostigmine-stimulated increase in GH secretion (r=-0.65, P=0.017). In summary, assuming that somatostatin is withdrawn and (rebound) GHRH re lease is stimulated via pyridostigmine administration, we infer that r elatively unopposed GHRH action principally controls GH secretory burs t mass and amplitude, rather than apparent GH secretory pulse duration , the basal GH secretion rate, or the serial regularity/orderliness of the GH release process in the human. Moreover, we infer that increasi ng age is accompanied by greater disorderliness of somatostatin-withdr awn GHRH, and hence rebound GH, release. The strongly negative correla tion between pyridostigmine-stimulated GH secretion and body mass inde x (but not age) further indicates that increased relative adiposity ma y result in decreased effective (somatostatin-withdrawn) endogenous GH RH stimulus strength.