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The effect of the selective beta 1-adrenergic blocking agent atenolol (50 or 100 mg, orally) on spontaneous and GH-releasing hormone (GHRH)-stimulated GH release was evaluated in six GH-deficient children during long term therapy with GHRH. Nocturnal GH concentrations were determined every 20 min for 12 h under the following four conditions: 1) control, 2) atenolol administration only, 3) sc GHRH administration only, and 4) combined GHRH and atenolol administration. The mean 12-h nocturnal GH concentrations after administration of atenolol alone [2.4 +/- 0.6 microgram/L (mean +/- SEM)] or GHRH alone (2.7 +/- 1.0 micrograms/L) were indistinguishable from baseline values (2.0 +/- 0.5 microgram/L; P greater than 0.05). In contrast, the addition of atenolol to ongoing GHRH therapy caused a clear augmentation of 12-h overnight GH release compared to that during all other study periods (5.0 +/- 1.3 micrograms/L; P less than 0.05). In a subset of three subjects for whom GH pulse characteristics were determined, the primary mode of the enhanced GH release was through an increase in the amplitude of serum GH pulses. These results are consistent with the hypothesis that beta-adrenergic blocking compounds enhance the responsivity of the pituitary gland to agents that permit GH release by inhibiting hypothalamic somatostatin secretion or action. They suggest that atenolol may have potential as an adjunctive therapy in some children with abnormalities of GH secretion when GHRH is the primary therapeutic agent.

In vitro and in vivo studies of somatotroph responsivity to GHRH stimulation indicate that partial loss of GH responsiveness occurs during constant GHRH stimulation. To determine if these observations reflect either a short term effect of GHRH or if the absence of somatostatin effects somatotroph desensitization (as occurred in in vitro studies), we administered GHRH-40 (10 ng/kg.min) by continuous iv infusion for 14 days to five normal men and one GH-deficient boy. Serum insulin-like growth factor I (IGF-I) concentrations were measured at frequent intervals to assess the biological effect of GHRH on GH secretion. The GH secretory profiles were assessed by measuring serum GH levels every 20 min for 24 h before (day 0), on the 14th GHRH infusion day, and 14 days after discontinuation of the GHRH infusion in the normal men. The GH-deficient boy was studied before and during the 14th GHRH infusion day. A supramaximal iv GHRH dose was administered at the end of the 24-h sampling period, and the GH responses were compared. Serum IGF-I concentrations increased on the 14th day of GHRH infusion in the normal men [day 0 mean, 0.84 +/- 0.14 (+/- SE) X 10(3); day 14, 1.74 +/- 0.20 X 10(3) U/L; P less than 0.05] and from 0.20 X 10(3) on day 0 to a maximum of 0.67 X 10(3) U/L on day 3 in the GH-deficient boy; they declined to pretreatment levels after discontinuation of GDRH. The mean integrated serum GH concentrations in the normal men were 1.44 +/- 0.10 micrograms/L.h on day 0 and 3.11 +/- 0.95 on day 14 of GHRH infusion. The integrated GH concentration in the GH-deficient boy was 1.53 micrograms/L.h on day 0 and 4.23 on day 14 of GHRH infusion. Pulsatile GH secretion, assessed by cluster analysis, was preserved in the normal men and occurred de novo in the GH-deficient boy on the 14th GHRH infusion day. The GH response to bolus GHRH administration was also preserved; no attenuation of the response occurred in the normal men or the GH-deficient boy after 14 days of GHRH infusion. The increase in IGF-I concentrations during 14 days of continuous GHRH administration, the persistence of pulsatile GH release in normal men, the de novo appearance of GH pulses in the GH-deficient boy, and the preservation of the response to a supramaximal GHRH dose indicates that the somatotrophs remain responsive to prolonged constant stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

The pattern and degree of variation in pituitary responsivity to GHRH was examined in four GH-deficient children (two boys and two girls, aged 4 3/12 to 10 4/12 yr). All children were studied before and on multiple (three to six per child) occasions during long term GHRH therapy (1 or 2 micrograms/kg, sc, every 3 h) in an identical fashion. Each study comprised withdrawal of blood for serum GH measurements every 20 min between 2000 and 0800 h. All subjects received GHRH at 2000, 2300, 0200, and 0500 h as well as at 0800, 1100, 1400, and 1700 h throughout the long term treatment period (6-18 months). Although all children had low level (less than 7.0 micrograms/L) pulsatile GH secretion during baseline studies, the maximal peak values occurred at times other than 0500 h. Before GHRH treatment, serum GH levels rose significantly in response to 91% (62 of 68) of the GHRH doses administered. GH pulse amplitudes varied throughout the studies in all children, and this variability persisted despite 1300-3600 consecutive doses in each child. In all 17 study periods the highest serum GH concentration occurred shortly after the 0500 h GHRH dose. The mean peak GH concentration after the 0500 h GHRH dose [18.4 +/- 3.5 (+/- SE) micrograms/L] was significantly higher than those after the 2000 h (5.3 +/- 1.0 micrograms/L; P = 0.0001), 2300 h (7.4 +/- 2.1 micrograms/L; P = 0.0003), and 0200 h (10.9 +/- 2.5 micrograms/L; P = 0.011) doses. These results demonstrate that the responsivity of the pituitary to GHRH varies throughout the night in some GH-deficient children. There appears to be a direct relationship between the time of night and the degree of pituitary responsivity to GHRH. We suggest that this variable responsivity may be due to intermittent hypothalamic somatostatin secretion.

We tested the hypothesis that selective beta 1-adrenergic blockade will enhance growth hormone (GH) secretion in boys with constitutional delay of growth in response to both exogenously administered growth hormone-releasing hormone as well as to endogenous GH-releasing hormone pulsations. The study group comprised eight healthy, short, prepubertal boys ranging from 7 2/12 to 15 0/12 yr old with bone ages delayed 15 to 42 months. All had demonstrated GH levels of greater than 10 ng/ml following a pharmacologic or physiologic stimulus. During two consecutive nights, blood samples were withdrawn every 20 min for GH determination between 2000 and 0800 h. Immediately after each 0800 h blood withdrawal, 1 microgram/kg of GH-releasing hormone (1-40)-OH was administered intravenously to each subject and blood was withdrawn every 15 min for an additional 2 h. During the day before the second overnight sampling period each subject received atenolol, 25 mg orally, at 1030 and 1600 h to induce beta-adrenergic blockage. The six subjects in whom beta-adrenergic blockade could be documented had enhanced GH release after GH-releasing hormone administration on the atenolol treatment day both in terms of higher peak GH levels achieved (p less than 0.05) as well as greater total GH secretion (3916 +/- 701 versus 5624 +/- 986 ng/ml.min, p less than 0.01). In contrast, there were no differences in endogenous, unstimulated nocturnal GH pulse characteristics between study and control days.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine whether a normal complement of androgen receptors is required to permit full expression of sex-related differences in pituitary GH secretion, we compared the GHRH-stimulated GH secretory responses of continuously perifused anterior pituitary cells from normal male, normal female, and androgen-resistant testicular feminized (Tfm) rats. In each experimental replicate, acutely dispersed pituitary cells were exposed to GHRH (0.03-100 nM) administered as 2.5-min pulses in random order at 30-min intervals. The eluate was collected in 5-min fractions for GH determination by RIA. Basal unstimulated secretion of GH by cells from male rats was greater than that by cells from female (P = 0.007) and Tfm (P = 0.03) rats; basal secretion by the other two groups was similar (P = 0.55). Linear concentration-response relationships between GHRH and GH release were defined for cells from male (P = 0.0002), female (P = 0.0001), and Tfm (P = 0.0002) rats. Overall GHRH-stimulated GH secretion by cells from male rats was greater (P less than 0.0001) than that by cells from female rats. Overall secretion by cells from Tfm rats was less (P less than 0.001) than that by cells from male rats but greater (P less than 0.001) than that by cells from female rats. For all experimental groups, body weight was strongly correlated with both basal (r2 = 0.42; P = 0.001) and GHRH-stimulated (r2 = 0.53; P = 0.0001) GH secretion by the dispersed pituitary cells. These data suggest that a deficiency of androgen receptors results in a diminution of the in vitro GH secretory capability of anterior pituitary cells to a level below that by cells from normal males, but not to the level in normal females. The intermediate position of cells from the Tfm rat may represent a partial masculinization or defeminization within this generally female phenotype.