To investigate whether GH secretion in acromegaly is subject to regulatory control by the hypothalamic GH-releasing hormone (GHRH) we studied GH secretion in 22 patients with acromegaly. Parameters of pulsatile GH secretion were assessed using frequent blood sampling (every 20 or 10 min for 24 h). Acute GH responses to GHRH-44 (0.1, 0.33, and 1.0 micrograms/kg BW, iv) were measured, and GH secretion during therapy with the long-acting somatostatin analog SMS 201-995 (Sandoz) was assessed. The results were compared to those in normal volunteers. Spontaneous GH pulse frequency was greater in patients with acromegaly than in 6 control subjects (8.6 +/- 0.6 vs. 4.3 +/- 1.1 pulses/24 h), as estimated by the 20-min sampling frequency. The 10-min sampling frequency revealed 12.9 +/- 0.7 pulses/24 h in acromegalics. Spontaneous GH pulse amplitude and acute GH rises in response to GHRH did not differ between control and acromegalic subjects. A similar degree of nocturnal augmentation of GH secretion was observed in both groups, and it persisted during SMS 201-995 therapy in patients with acromegaly. These observations suggest that GH secretion in acromegaly remains under stimulatory control by GHRH, which may be released at an abnormally high rate.

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When GnRH is radioiodinated by the chloramine-T method, two immunoreactive labeled species are formed at pH 6.5 with a chloramine-T: GnRH molar ratio of 11:1, whereas four bands (I, IIa, IIb, and III) are separated by polyacrylamide gel electrophoresis when the hormone is iodinated at pH 7.5 in a system containing a 97:1 molar ratio of chloramine-T:GnRH. Because they were more stable and were more immunoreactive than the other products, band I and band IIa from the latter system were used separately as tracers with Niswender antiserum R-42 in radioimmunoassays for GnRH. The standard curves of each tracer are distinct: when analyzed after log-logit transformation, the band I curve had a mean slope of -3.31 +/- 0.2 (SE) and a 50% B/Bt level of 9 +/- 0.8 pg (n=8) of synthetic GnRH, whereas the band IIa standard curve had a slope of -2.30 +/- 0.6 and a 50% B/Bt value of 20 +/- 0.9 pg (n=11). The sensitivity of both assays is approximately 2.0 pg. Gn RH concentrations in plasma and serum samples assayed with band I were consistently greater than those assayed with band IIa. Normal adult male plasmas assayed with band I measured 21 +/- 0.9 pg/ml, whereas band IIa values were 8 +/- 0.4 pg/ml. No difference between plasma and serum was detected, nor was there any difference among adult men, adult women, prepubertal children, hypogonadal patients, or hypopituitary patients with either assay. Plasma GnRH concentrations were also similar in jugular and vena cava samples from intact and castrated male rats. Because many of the samples were at or below the sensitivity of the band IIa assay, they were concentrated after extraction with either methanol or acid-ethanol. However, endogenous immunoreactive GnRH could not be concentrated by these extraction procedures. As measured in the band IIa assay, hypothalamic extracts from control adult male rats contained 3.1 +/- 0.4 ng while hypothalami from castrated rats contained 1.4 +/- 0.1 ng. Similar but slightly lower values were obtained with band I. In contrast, the GnRH content of pineal glands from intact and castrated male rats was similar (approximately 150 pg) when determined in either assay. These studies emphasize that: 1) the characteristics of the radioiodinated hormone can influence the quantitation of GnRH; and 2) endogenous plasma concentrations of GnRH are much lower than previously reported.

To evaluate the diagnostic and prognostic usefulness of the GnRH test, gonadotropin responses to iv GnRH (Parke-Davis) were determined in 82 young patients (2,5 mo.-21 yr.) and 6 normal men. After extensive evaluation, 40 patients (31 boys and 9 girls) were considered "endocrinologically normal." Repeat tests were performed in 17 patients at 6-12 mo. intervals. Nine patients with presumed isolated hGH deficiency and 3 patients with multiple pituitary deficiencies were studied before and at the end of 12 mo. of hGH therapy. Serial blood samples were obtained before and after an iv bolus injection of GnRH (2.5 mug/kg, 74 tests, or 10 mug/m2, 36 tests). LH and FSH were determined by radioimmunoassay. Maximum concentration, maximum increment (deltamax), and response area were compared with degree of skeletal maturation to evaluate responses. Clinically, the most useful determination was the deltamax LH. All "normal" children with bone ages greater than 12 yr had LH responses in or slightly above the range of the values of the 6 normal men: deltamax LH, 39 +/- 8 (SE) mIU/ml; range 13-57. Severely blunted or absent responses were seen in 14/15 patients (bone ages 3 mo.-14 yr.) with multiple pituitary deficiencies. Boys with isolated hGH deficiency and bone ages of less than 10 yr had significantly lower responses than "short normal" boys with similar skeletal maturation: deltamax LH, 4.8 +/- 0.9 vs 8 +/- 1.3 mIU/ml, P is less than .05. Although the mean growth velocity of hGH-treated children increased from 3.2 to 8.9 cm/yr, LH and FSH responses were unchanged. These studies indicate that 1) children with idiopathic hypopituitarism (including those with presumed isolated hGH deficiency) have significantly decreased responsiveness to GnRH which does not respond to 6 to 12 months of hGH treatment; and 2) decreased responsiveness to GnRH in patients with bone ages of greater than 12 yr is presumptive evidence of gonadotropin deficiency.