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The advent of the production of large quantities of recombinant growth hormone (GH) has made it possible to have sufficient material to assess its efficacy in adult growth hormone deficiency (GHD). Although some studies have shown that patients who are severely deficient benefit from GH therapy, the spectrum of GHD is broad, and the degree of deficiency at times is very difficult to define. In some cases, benefit is not easily quantified, and some studies have claimed benefits that, although statistically significant, are either not clinically important or are so marginal as to be questionable in terms of cost, difficulty of administration and potential risks. The purpose here is to identify the current problems in the diagnosis of GHD, to discuss the rationale for GH therapy and to assess the potential effects of GHD as well as the benefits of GH therapy in GHD adults. We will include a commentary as to which effects appear more robust than others and which are likely to result in the greatest patient benefit. Finally, some attention will be paid to long-term safety issues that should be monitored to ensure that this medication is safe even for the patients with the greatest need.

That growth hormone (GH) regulates its own secretion by negative feedback both directly and indirectly via somatomedins has been well-documented in the rat and assumed, on the basis of limited studies, to be true for man as well. Prior to proceeding with studies designed to investigate the nature of this feedback in various endocrine states, we sought first to confirm the existence of direct, short-latency GH feedback in normal individuals. Primed, continuous rate infusions of human GH in normal volunteers achieved a range of steady state GH levels. After 1 h of GH infusion, arginine HCl (500 mg/kg) was infused over 30 min and the GH response assessed. Seven of 8 subjects achieved steady state GH levels in the 8-21 ng/ml range with an infusion rate of 0.0045 U/min following a 0.277 U bolus. After arginine, there was a significant increment of GH levels (range 11.6-69.5 ng/ml) in all 7 subjects. With a higher infusion rate of 0.009 U/min following a 0.54 U bolus, 1 of 2 subjects reached a steady state of 31.0 ng/ml and no response to arginine was demonstrable. Two subjects reached steady state levels of 45.0 and 58 ng/ml during a 0.018 U/min infusion after a 1.08 U bolus and had increments of 26.2 and 25.9 ng/ml following arginine. In 3 subjects achieving levels of 64.5, 107.0 and 132.0 ng/ml, there were increments of 55.0, 61.7 and 13.0 ng/ml during infusions of 0.036 U/min following boluses of 2.16 U. However, only in the first of these 3 was a true steady state achieved.(ABSTRACT TRUNCATED AT 250 WORDS)

Twenty-nine patients with acromegaly (8 untreated and 21 previously treated in various ways) and 16 normal men were given iv bolus doses of human pancreatic tumor GH-releasing factor (hpGRF-40). Twenty-five of the 29 patients responded to hpGRF-40 with elevations of plasma GH. The magnitude of the responses varied widely. Responses of untreated patients were generally similar to those of the normal subjects. Previously treated patients had a significantly lower response than normal individuals [change in GH, 7.5 +/- 1.8 vs. 42.0 +/- 11.0 ng/ml (mean +/- SEM); P less than 0.01], and 4 patients who had received radiation therapy failed to respond to hpGRF-40. There was no significant correlation between the magnitude of the response and patients' age, sex, baseline GH levels, GH responsiveness of TRH, or GH suppression after oral glucose administration. Patients studied both pre- and postoperatively were responsive to hpGRF-40 at all times tested, but the magnitude of the response decreased after successful surgical removal of the adenoma. Thus, most patients with treated or untreated acromegaly respond to hpGRF-40, but their responses do not clearly distinguish them from normal subjects. GH-releasing hormone testing is unlikely to replace other endocrine tests available for the diagnosis and evaluation of acromegaly.

To investigate the feedback control of GH secretion, we examined the effects of human GH (hGH) and somatomedin C (SmC) on spontaneous GH secretory surges in unanesthetized, freely moving rats. Under pentobarbital anesthesia a right atrial catheter and an intracerebroventricular cannula were placed 7-10 days before the experimentation. For iv studies, hGH (0.3 U/ml.h) was infused for 6 h after an iv loading dose (0.3 U) at the beginning of the experiments. For intraventricular injections, hGH (0.1 U/10 microliter) or SmC (500 ng/10 microliter) were injected into the lateral ventricle 2 h before the experiments. The equivalent dose of crystalline BSA diluted in the same vehicle solutions was administered to the same rat as a control on a separate day. Venous blood samples were collected every 20 min for 6 h. Intravenous and intraventricular administration of crystalline BSA did not affect the typical rat GH (rGH) surges which appeared about every 3 h and reached peak values of more than 300 ng/ml. The iv infusion of hGH significantly inhibited the amplitude of rGH surges compared to controls (planimetric areas under the secretory profile 752 +/- 172 vs. 1921 +/- 183, P less than 0.01, n = 6). rGH secretion was similarly inhibited by intraventricular hGH (701 +/- 127 vs. 2208 + 225, P less than 0.01, n = 6) and by intraventricular SmC (537 +/- 70 vs. 1503 +/- 114, P less than 0.01, n = 6). These findings suggest that both GH and SmC are active in the feedback regulation of rGH secretion.

The distribution of a substance with human GH (hCG)-like immunoreactivity was studied in the rat brain after rapid fixation with acrolein. Using this method of tissue preparation, the hGH-like material (hGH-LM) was found in several hypothalamic and extrahypothalamic regions of the brain and extended into the spinal cord and posterior pituitary. On serial sections, the distribution of the hGH-LM was observed to be identical to that of TRH throughout the neuraxis. Sequential immunostaining of the hGH-LM and TRH in the same tissue section revealed the coexistence of these two peptides in the same neuronal cell bodies in the hypothalamus and brain stem and in beaded processes in all regions of the central nervous system studied. These findings demonstrate the intimate association between the hGH-LM and TRH in the central nervous system and raise the possibility that the hGH-LM forms part of a precursor hormone from which TRH is derived.

Using the peroxidase-antiperoxidase pre-embedding technique for immunoelectron microscopy, human growth hormone (hGH)-like material was demonstrated in large, dense core vesicles in axon terminals in the hypothalamic median eminence of the rat. The close association of immunoreactive terminals with fenestrated capillaries of the portal plexus, suggests that the hGH-like material is contained within the tuberoinfundibular neuronal system and may be a hypophysiotropic hormone.

To determine whether GRH stimulates PRL secretion we studied the effects of iv bolus injections and prolonged infusions of GRH 1-40-OH on PRL and GH serum levels in normal volunteers. Eight patients with acromegaly, two of whom had elevated basal levels of PRL, were also tested with single bolus injections. Six normal subjects given 3.3 micrograms/kg bolus injections of GRH showed a mean increment of GH of 22.0 +/- 1.7 ng/ml (mean +/- SE). A small rise in PRL was noted in 5 of the 6 subjects (mean peak level of 6.4 +/- 1.9 ng/ml vs basal level of 3.3 +/- 0.4 ng/ml, p less than 0.05). During the continuous intusion of GRH (10 ng/kg/min), GH levels rose gradually from a mean baseline of 1.1 +/- 0.1 ng/ml to a mean peak of 30.0 +/- 7.2 ng/ml at about 2 h and then slowly declined to a nadir of 4.2 +/- 0.4 ng/ml at 330 min. PRL levels did not rise significantly during the infusion. To determine whether the decline in GH levels in the face of continued infusion was due to loss of GH responsiveness, a 3.3 micrograms/kg bolus of GRH was given during the nadir at 330 min; this GH increment was significantly less than that obtained by the GRH bolus injection without the infusion (12.9 +/- 3.5 ng/ml vs 22.0 +/- 1.7 ng/ml, p less than 0.05). The PRL response to the GRH bolus was the same during the infusion of GRH as before. In each of 8 acromegalic patients (including two who had initially elevated basal PRL levels) GRH led to an increase in both GH and PRL levels. PRL and GH levels spontaneously fluctuated in parallel in 4 acromegalic cases studied with repeated samples over 6 h during placebo administration. These experiments show that GRH has significant, though weak, PRF effect in normals and that it is more potent PRF in acromegalic patients. Furthermore, the effects on GH and PRL of a sustained infusion of GRH for 5 1/2 h are both qualitatively and quantitatively different. These results suggest that the GRH effect is exerted either on different pituitary receptors for GH and PRL regulation, or that the releasable pools of the two hormones have different sizes and/or turnover times.

Through use of an antiserum directed against hGH, an immunoreactive hGH-like material has been identified in the rat brain by peroxidase immunohistochemistry. Peroxidase-positive material was found in beaded, neuronal fibers in the external zone of the median eminence, lateral septum, and organum vasculosum of the lamina terminalis and was unaffected by prior hypophysectomy. After pretreatment with intraventricular colchicine, numerous immunoreactive neuronal cell bodies were visualized within the parvocellular medial division of the paraventricular nucleus, periventricular nucleus, dorsomedial nucleus, lateral hypothalamus, and preoptic area. Immunohistochemical staining was completely abolished by preincubation of the antiserum with 10(-6) M hGH, the 20,000 mol wt variant of hGH. hGH dimer, core peptide 20-64/135-167, proteolytically derived hGH fragments 1-134 and 147-91, and human placental lactogen. There was no diminution in staining after preincubation with hGH N-terminal fragment 1-43, hGH C-terminal fragment 171-191, rat GH, rat or human PRL, and numerous other neuropeptides and anterior pituitary hormones. Bilateral electrolytic ablation of the paraventricular nucleus area caused a loss of immunostaining in the median eminence. These results indicate the presence of a hitherto undescribed intrinsic neuronal system in rat brain that contains a substance bearing immunological similarity to the midportion of the hGH molecule and to human placental lactogen. It is proposed that this substance is part of a tuberoinfundibular neuronal system deriving from the parvocellular medial division of the paraventricular nucleus-immunoreactive perikarya and may, therefore, be involved in hypophysial regulation. It may also act as a neuromodulator of limbic lobe structures and other hypothalamic regions.