Treatment of radiation-induced growth hormone deficiency with growth hormone-releasing hormone.

UNLABELLED: In children with hypothalamic causes for GH deficiency there are theoretical reasons why a GHRH analogue might be better than conventional GH therapy in promoting growth. OBJECTIVE: We have aimed to determine the efficacy and safety of growth hormone-releasing hormone (GHRH) (1-29)-NH2 given as a twice daily subcutaneous injection in the treatment of growth failure in children with radiation-induced GH deficiency. DESIGN: A multicentre study comparing growth before and after 1 year of treatment with GHRH (1-29)-NH2, 15 micrograms/kg twice daily, by subcutaneous injection in children with radiation-induced GH deficiency. On completion of the study year all children were treated with GH (0.5 U/kg/week) and growth parameters were documented over the next year. PATIENTS: Nine children (six boys) with radiation-induced GH deficiency following cranial (n = 4) or craniospinal (n = 5) irradiation for a brain tumour distant from the hypothalamic-pituitary axis (n = 8) or prophylaxis against central nervous system leukaemia (n = 1) were studied. All were prepubertal when the study commenced, which was at least 2 years from radiotherapy. MEASUREMENTS: Anthropometry and pubertal staging were carried out at 3-monthly intervals and bone age estimations at 6-monthly intervals (TW2 method). Pretreatment standing height velocities were compared with values during the year of GHRH treatment and then after the first year of GH therapy. In those that had received craniospinal irradiation, a change in leg-length Standard deviation score (SDS) was noted before and after GHRH therapy. Changes in skin-fold thickness and bone age during the GHRH study year were documented. Adverse events and 3-monthly measurements of clinical chemistry, haematology, lipid profile and thyroid function were recorded. RESULTS: There was a significant increase in height velocity from 3.3 (SD 1.1) cm/year before treatment, to 6.0 (SDS 1.5) cm/year after 1 year of GHRH treatment (P = 0.004). GHRH maintained or improved the leg length SDS in children who had received craniospinal irradiation. Bone age increased by a mean of 1.1 years/chronological year during treatment with GHRH. Subsequent height velocity during 1 year of GH therapy was 7.5 (SD 1.5)cm/year. No adverse changes in biochemical or hormonal analyses were noted or adverse events that could be attributed to GHRH therapy. One child went into puberty during the GHRH study year and three were pubertal during the first year of GH therapy. CONCLUSION: In cranially irradiated children, GHRH was effective in increasing growth velocity but this was less than that seen in response to GH therapy, although it matched that in children with isolated idiopathic GH deficiency treated with the same dose and schedule of GHRH administration.

Pyridostigmine partially reverses dexamethasone-induced inhibition of the growth hormone response to growth hormone-releasing hormone.

The GH response to insulin-induced hypoglycaemia and growth hormone-releasing hormone (GHRH) has been shown to be impaired in subjects with Cushing's syndrome and in healthy volunteers given oral glucocorticoids. Pyridostigmine is an anticholinesterase that stimulates GH secretion, probably by inhibition of hypothalamic somatostatin secretion. This work was designed to study the site of action of glucocorticoids in inhibiting the secretion of GH. Eight healthy male volunteers were studied on three occasions in random order. They took 2 mg oral dexamethasone or placebo at precisely 6-hourly intervals for 48 h before receiving 120 mg oral pyridostigmine or placebo, followed 60 min later by GHRH (100 micrograms) i.v. Samples for measuring GH were obtained at 15 min intervals for 2 h. The 'area under the curve' (AUC) for each of the treatments was significantly different: dexamethasone-pyridostigmine-GHRH (mean +/- S.E.M., 1938 +/- 631 mU/min per l), dexamethasone-placebo-GHRH (634 +/- 211) and placebo-placebo-GHRH (4267 +/- 1183) (P < 0.02, Wilcoxon test). In conclusion, dexamethasone given for 48 h significantly inhibited the AUC for GH following treatment with GHRH. However, pretreatment with pyridostigmine significantly reversed the inhibition although this was still partial. Our data suggested that this short-term suppressive effect of dexamethasone was independent of GHRH, and most probably relates to stimulation of the release of somatostatin.

A new syndrome: hearing loss and familial salivary gland insensitivity to aldosterone in two brothers.

Two male siblings presented in infancy with hyponatremia. The levels of plasma renin activity and aldosterone were elevated. Sodium supplement was necessary to maintain normal sodium balance. The salivary sodium concentrations were markedly elevated, with sweat sodium levels being in the upper normal range. Urinary sodium concentration and renal epithelial exchange between sodium and potassium were normal. This was felt to be due to an autosomal recessive disorder. Both siblings were later diagnosed as having a bilateral moderate to severe sensorineural hearing loss with intermittent conductive overlay due to middle ear fluid. The sensorineural loss was also felt to be autosomal recessive in origin, but the possibility of a disturbance of sodium balance in the inner ear has been questioned.

Familial salivary gland insensitivity to aldosterone: a variant of pseudohypoaldosteronism.

Two male siblings presented in infancy with hyponatraemia. Levels of plasma renin activity and aldosterone were elevated. Sodium supplementation was necessary to maintain normal sodium balance. Urinary sodium concentration and renal epithelial exchange between sodium and potassium were normal; however, salivary sodium concentrations were markedly elevated with sweat sodium levels being in the upper normal range. Excess salivary sodium loss accounted for sodium depletion in these cases who present a new variant of pseudohypoaldosteronism associated with normal renal sodium transport.

Stilboestrol pretreatment of children with short stature does not affect the growth hormone response to growth hormone-releasing hormone.

Oestrogens are known to enhance both basal and stimulated GH secretion. To examine whether this effect is mediated through the hypothalamus or the pituitary we performed insulin tolerance and GH-releasing hormone (GHRH) tests with and without oestrogen priming in a group of 14 short children. Pretreatment with stilboestrol increased basal levels of GH and both peak and incremental levels during insulin hypoglycaemia. In contrast, there was no effect of stilboestrol priming on the GH response to either an i.v. bolus of 100 micrograms or 0.1 microgram/kg (range 2-6 microgram) of GHRH. The children had significantly higher GH responses to an unprimed GHRH than unprimed insulin tolerance test. We conclude stilboestrol priming acts through the hypothalamus presumably by increasing endogenous GHRH release, and that short children with a subnormal GH response to insulin hypoglycaemia show a greater response to GHRH; this suggests the presence of a hypothalamic cause for their decreased GH secretion.

Growth hormone pretreatment in man blocks the response to growth hormone-releasing hormone; evidence for a direct effect of growth hormone.

The effect of pretreatment with biosynthetic methionyl human GH (hGH) on the GH response to GHRH has been studied in normal subjects. Eight volunteers were given either 4 IU hGH or placebo s.c. 12-hourly for 72 h before a GHRH test, or a single s.c. dose of 4 IU hGH 12 h before a GHRH test. Somatomedin-C (Sm-C) levels at the time of the GHRH tests were significantly elevated after treatment with hGH compared to placebo, and the GH response to GHRH was significantly attenuated. A further six subjects were given 2 IU hGH or placebo i.v., and i.v. GHRH 3 h later; there was no rise in Sm-C for the 5 h of the study after either treatment; nevertheless, the response to GHRH was completely abolished by pretreatment with hGH. These results demonstrate that GH can regulate its own secretion independently of changes in Sm-C levels, through a mechanism other than the inhibition of GHRH release. The attenuated response to GHRH in the presence of elevated Sm-C levels may be related to Sm-C, or be a more direct effect of the recently elevated GH levels.

Normal circulating immunoreactive growth hormone releasing factor (hGRF) concentrations in patients with functional hypothalamic hGRF deficiency.

Using a highly specific radioimmunoassay we have measured the concentrations of human growth hormone releasing factor (ir-hGRF) in the peripheral circulation of six individuals with acquired hypothalamic hGRF deficiency. Despite their hypothalamic dysfunction venous plasma ir-hGRF increased normally in every patient after the stimulus of a mixed breakfast, from an average concentration basally of 13.6 +/- 6.0 pg/ml to a maximum of 29.0 +/- 8.4 pg/ml (mean +/- SEM) at 120 min. The findings indicate that circulating hGRF is at least in large part extrahypothalamic in origin, which in turn implies a physiological role for hGRF in the periphery.

Cranial irradiation for cerebral and nasopharyngeal tumours in children: evidence for the production of a hypothalamic defect in growth hormone release.

A synthetic 29-amino acid analogue of human pancreatic GH-releasing hormone (GHRH(1-29)NH2) has recently been shown to stimulate the release of GH in normal subjects. We have studied the GH response to GHRH(1-29)NH2 in nine children irradiated for brain and nasopharyngeal tumours, who were not growing and were deficient in GH as assessed by insulin-induced hypoglycaemia. Serum GH rose in response to GHRH(1-29)NH2 in all the children, and in five the peak serum GH response was greater than 20 mu./l. The data suggest that when hypothalamo-pituitary irradiation results in GH deficiency, this is due to a failure of the synthesis or delivery of endogenous GHRH from the hypothalamus to the pituitary cells. It also suggests that it may be possible to treat such children using synthetic GHRH in place of exogenous GH.

Growth hormone-releasing hormone in the diagnosis and treatment of growth hormone deficient children.

A growth hormone-releasing hormone (GHRH) has recently been extracted and synthesised, and appears to be identical to human hypothalamic GHRH. Immunoreactive GHRH is found in the venous blood of normal subjects and GH-deficient children, but is probably not hypothalamic in origin and therefore not important in GH regulation. GHRH is a potent specific stimulator of GH secretion in man, and provides a valuable diagnostic test in differentiating hypothalamic from pituitary causes of GH deficiency. Preliminary data suggests that GHRH may promote linear growth in some GH deficient children. GHRH may well prove an important alternative therapy for GH deficient children especially if depot preparations or intranasal administration prove effective.

Growth hormone releasing factor: comparison of two analogues and demonstration of hypothalamic defect in growth hormone release after radiotherapy.

Human pancreatic growth hormone releasing factor (hpGHRF(1-40] stimulates the release of growth hormone in normal subjects and some patients with growth hormone deficiency. A study comparing the shorter chain amidated analogue hpGHRF(1-29) with an equivalent dose of hpGHRF(1-40) in seven normal subjects showed no significant difference in growth hormone response between the two preparations. Six patients with prolactinomas were also tested; these patients had received megavoltage radiotherapy previously but had developed growth hormone deficiency as shown by insulin induced hypoglycaemia. In all six patients 200 micrograms hpGHRF(1-40) or hpGHRF(1-29)NH2 produced an increase in the serum growth hormone concentration. These data suggest that hpGHRF(1-29)NH2 may be useful for testing the readily releasable pool of growth hormone in the pituitary and that cases of hypothalamo-pituitary irradiation resulting in growth hormone deficiency may be due to failure of synthesis or delivery of endogenous GHRF from the hypothalamus to pituitary cells.

Growth-hormone-releasing factor in growth hormone deficiency: demonstration of a hypothalamic defect in growth hormone release.

Four patients with hypothalamic tumours or idiopathic growth hormone (GH) deficiency, who were GH deficient by conventional criteria, responded to 200 micrograms synthetic hpGRF-40 with a clear rise in circulating GH.