A. Gomez-Pan

INFLUENCE OF DOPAMINERGIC, ADRENERGIC AND CHOLINERGIC BLOCKADE AND TRH ADMINISTRATION ON GH RESPONSES TO GRF 1–29

In order to establish the influence of dopaminergic, á‐adrenergic and cholinergic pathways on GRF‐mediated GH release we have studied the GH responses to GRF 1–29 (100 or 50 μg as i.v. bolus) alone and in combination with metoclopramide (MCP, 10 mg, i.v.), thymoxamine (THYM, 210 μg/min, 150 min infusion), and atropine (1.2 mg, i.v.). We have also investigated any possible interaction between TRH and GRF in view of the reported inhibitory effects of TRH infusion on stimulated GH release. Dopaminergic and á‐adrenergic blockade with MCP and THYM respectively, did not have any effect on the GH responses to GRF. This lack of effect strongly suggests that any action which these neurotransmitters may exert on GH secretion is not at a pituitary level. TRH did not modify the GH response to GRF suggesting that the inhibitory effect on stimulted GH secretion is exerted at a hypothalamic level. In contrast, GH responses to GRF were significantly reduced by prior administration of atropine. These data support the view that cholinergic pathways play an important role in the regulation of GH secretion and such control may be exerted at both hypothalamic and pituitary levels.

Influence of Somatostatin and Growth Hormone-Releasing Factor on Behavior

Administration of hypothalamic peptides has been reported to induce behavioral changes and to modify neurological functions such as locomotor activity and learning. Somatostatin (SS) and growth hormone-releasing factor (GRF) exert opposite effects on anterior pituitary secretion. Similarly, at the central nervous system (CNS) level, SS and GRF display antagonistic actions on behavioral parameters. The authors were able to confirm these effects in male Wistar rats by means of a computerized electronic maze measuring locomotor activity and learning. SS concentration is reduced in specific areas of the CNS in patients with late onset of senile dementia of the Alzheimers type (SDAT). In early onset SDAT a GRF test elicits a growth hormone response much greater than that observed in normal controls of the same age or in patients with late onset SDAT. Thus, administration of GRF to patients with early onset SDAT has been followed by a significant improvement in locomotion, appetite, mental performance and social interaction. A possible therapeutic role of GRF in the management of patients with dementia remains to be explored.

Growth hormone responses to GRF 1-29 in patients with primary hypothyroidism before and during replacement therapy with thyroxine

It is well known that hypothyroidism is frequently associated with impaired GH responses to different stimuli. In the present study we have evaluated GH responses to GH‐releasing factor (GRF) in patients with primary hypothyroidism before and during T4 replacement therapy. Fourteen patients (age range 26–60 years) underwent two GRF tests (1 μg/kg) before and during replacement therapy (150 μg/d). Administration of T4 increased peak GH responses to GRF in 9 patients and in the group as a whole (mean ± SEM, 17·0 ± 2·8 vs 32·6 ± 5·7 mU/l, P > 0·02). When the data are analysed by means of area under the curve (AUC), the GH response to GRF was increased by T4 in 10 patients and in the group as a whole (mean ± SEM, 51·7 ± 14·3 vs 101·5 ± 28·1, P > 0·02). These data indicate that thyroid hormone replacement therapy enhances the responsiveness of the somatotroph to GRF 1–29 in patients with primary hypothyroidism.

Size Changes of a Growth Hormone- and Prolactin-Producing Adenoma during and after Sandostatin Treatment

A 46-year-old woman with acromegaly and marked hyperprolactinemia was treated chronically with sandostatin (50 micrograms b.i.d. up to 100 micrograms t.i.d.). Plasma growth hormone (GH) was reduced by 90% of basal values and prolactin (PRL) dropped from initially 204 to 74 ng/ml. Serial CAT scans detected a volume reduction of the pituitary adenoma of 46.7%, but discontinuation of therapy was followed by re-expansion of the tumor. Tissue collected at transsphenoidal adenomectomy was examined by immunohistology and found positive for both GH and PRL. This characteristic would explain the dual hormonal response to the specific GH inhibitor sandostatin.

LACK OF EFFECT OF MUSCARINIC CHOLINERGIC BLOCKADE ON THE GH RESPONSES TO GRF 1–29 AND TRH IN ACROMEGALIC SUBJECTS

It is well known that muscarinic cholinergic blockade either reduces or abolishes stimulated GH release in normal subjects. In this study we have investigated whether cholinergic muscarinic blockade could reduce the GH responses to GRF 1–29 and TRH in acromegalic subjects. Eight acromegalic subjects underwent two GRF tests (GRF 1–29, 1 μg/kg i.v.) with and without pirenzepine (0.6 mg/kg, i.v.). A further four of these patients received TRH (200 μg/kg, i.v.) on separate occasions with and without pirenzepine (0.6 mg/kg, i.v.). Cholinergic muscarinic blockade did not alter the GH responses to GRF and TRH in patients with acromegaly. These findings are in contrast with previous data reported on the effects of cholinergic blockade on stimulated GH levels in normal subjects and in patients with type I diabetes mellitus and are compatible with the view that somatotroph adenomas are functionally disconnected from hypothalamic control mechanisms.

REDUCED DOPAMINERGIC INHIBITION OF THYROTROPHIN RELEASE IN STATES OF PHYSIOLOGICAL HYPERPROLACTINAEMIA

We have tested the hypothesis that physiological puerperal hyperprolactinaemia may be secondary to reduced hypothalamic dopaminergic inhibition of prolactin (PRL) release. Nine post‐partum females with physiological hyperprolactinaemia (aged 19–40 years; mean basal PRL±SE, 2099±257 mU/l, range 1002–3762 mU/l) were studied and results compared with fourteen normoprolactinaemic females (basal PRL<400 mU/l; aged 18–36 years). Puerperal hyperprolactinaemic females showed a reduced TSH response to dopamine (DA) receptor blockade with metoclopramide (10 mg i.v.) compared with normal females over a 60‐min period following drug administration (total incremental TSH change, mean ±SE, mU/l; 0.5±0.3 v. 3.1±1.0, P<0.005). This finding of reduced dopaminergic inhibition of TSH release in females with physiological puerperal hyperprolactinaemia supports the view that an overall reduction in hypothalamic dopaminergic tone may contribute towards hyperprolactinaemia in post‐partum women.

Growth progression and 24-hour hormone profile in an infant treated chronically with a long-acting somatostatin derivative.

The diagnosis of nesidioblastosis was established in a 9-month-old male child with a history of recurrent convulsive seizures and hypoglycemia. After unsuccessful subtotal pancreatectomy, treatment was started with the long-acting somatostatin derivative Sandostatin (Octreotide, Sandoz) at a dosage of 25 micrograms t.i.d. spaced between carbohydrate-enriched meals. With this regime, blood glucose was maintained at the low normal range and seizures ceased. During a 30-month observation period, growth velocity and weight progression were well within the predicted limits. A 24-hour hormone profile recorded at the end of the observation period revealed the following: (1) failure to improve blood glucose with carbohydrate-enriched food due to reactive hyperinsulinemia; (2) hyperglycemic reaction after administration of Sandostatin caused by a reduction of plasma insulin; this effect was particularly marked during sleep; (3) low mean GH, decreased spiking frequency and reduced area covered by the nocturnal peaks by recognized standards, and (4) normal somatomedin C levels for age. Interpretation of growth hormone (GH) data is hindered by the lack of pertinent information from the patients age group. Recording of normal growth progression in the case illustrated here can only be explained by the capability of a reduced GH secretory rate to maintain full biological activity as shown by the normal plasma level of somatomedin C. Indeed, recent evidence has been provided elsewhere for normal growth progression in the presence of low GH secretion, although other factors unrelated to this hormone may also be operative at this early age. Further reports concerning the treatment of non-GH-dependent conditions with somatostatin derivatives will certainly contribute to the better understanding of the mechanisms governing growth in the postnatal period.

Effect of a Long-Acting Somatostatin Analog (Sms 201–995) on Glucose Homeostasis in Type I Diabetes and in Acromegaly

Recently, Bauer et al. (1) have reported the synthesis of an octapeptide SMS 201–995 (DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol), found in animal experiments to be about 45 times more potent than native somatostatin (SRIF).