Efficient short-term control of hypercortisolaemia by low-dose etomidate in severe paediatric Cushing's disease.

BACKGROUND: Paediatric Cushing's disease (CD) is rare, but is associated with considerable morbidity and requires effective treatment. Control of hypercortisolaemia is recommended prior to definitive therapy by transsphenoidal pituitary surgery with selective adenomectomy. We describe a 6.2-year-old male with severe hypercortisolaemia and life-threatening complications of Cushing's disease. Control of cortisol with metyrapone and ketoconazole was ineffective, and due to his deteriorating condition, the decision was taken to proceed to bilateral adrenalectomy. METHODS: Low-dose IV infusion of etomidate, with dose titration according to serum cortisol levels, was administered. RESULTS: Etomidate infusion (3.0 mg/h i.v.) decreased serum cortisol from 1,250 to 250 nmol/l within 24 h. Combined etomidate and hydrocortisone therapy was maintained to provide stable serum cortisol levels within the desired range for 12 days prior to successful bilateral adrenalectomy. CONCLUSION: In our experience, etomidate was effective and safe for short-term control of severe hypercortisolaemia in a severely ill child.

Cushing's syndrome caused by nodular adrenal hyperplasia in children with McCune-Albright syndrome.

McCune-Albright syndrome consists of fibrous dysplasia of bone, café-au-lait skin pigmentation, and endocrine dysfunction (usually precocious puberty). Other endocrine abnormalities occur in a minority of patients, and of these, Cushing's syndrome is the least often recognized. We present 5 children (4 girls) with features of McCune-Albright syndrome who had Cushing's syndrome in the infantile period (<6 months). In 2 children spontaneous resolution occurred, but the remaining 3 required bilateral adrenalectomy. In addition, all 4 girls have experienced precocious puberty, and 3 children demonstrated radiologic evidence of nephrocalcinosis. Understanding of the underlying defect causing McCune-Albright syndrome emphasizes the importance of searching for other endocrine dysfunction in these children.

Metabolic status of children with growth hormone insensitivity syndrome and responses to treatment with IGF-I.

Studies to date on the treatment with insulin-like growth factor I (IGF-I) of children with growth hormone (GH) insensitivity syndrome (GHIS) have concentrated principally on the effects of IGF-I therapy on the GH-IGF-I axis and on growth velocity. Little is known, however, about the metabolic status of children with GHIS and the consequences of IGF-I treatment on circulating intermediary metabolites involved in glucose homeostasis. We have studied 5 children with GHIS, aged 4.5-9 years, 3 male and 2 female, before and after 3 months of treatment with recombinant IGF-I, 80 microg/kg s.c. twice a day. The children were short (height SDS -3.8 to -7.3) and growing slowly (height velocity 1.8-3.4 cm/year). All were neurodevelopmentally normal at the time of the study with no history of severe symptomatic hypoglycaemia, in particular during the neonatal period. Before treatment, 4 of the 5 children demonstrated spontaneous hypoglycaemia (blood glucose <2.6 mmol/l), particularly at night, accompanied by substantial hyperketonaemia (range 1.43-4. 63 mmol/l) and hyperfattyacidaemia (range 1.11-3.08 mmol/l). After 3 months of IGF-I treatment, the blood glucose concentrations in the diurnal profile were increased, with improvement in spontaneous hypoglycaemia and with increased fasting tolerance. The postprandial insulin-to-glucose ratio was reduced. GHIS is thus associated with asymptomatic nocturnal hypoglycaemia without apparent neurological deficit. Despite functional GH deficiency, brisk counter-regulation to hypoglycaemia occurred as evidenced by hyperfattyacidaemia and hyperketonaemia. Treatment with IGF-I twice a day improved fasting glucose tolerance, diurnal blood glucose concentrations, and postprandial insulin-to-glucose ratios. There was no exacerbation of hypoglycaemia on treatment. We suggest that in severe GH resistance, a protective mechanism exists for the brain from the effects of hypoglycaemia, at least partially mediated by excessive production of counter-regulatory metabolic fuels.

Girls with virilisation in childhood: a diagnostic protocol for investigation.

AIM: To analyse critically a protocol for the investigation of girls presenting with virilisation in childhood. METHODS: Twenty five girls aged 1.6-8.7 years with features of virilisation were evaluated. Twenty four had presented with pubic hair, eight with auxilliary hair, seven with facial acne, four with clitoromegaly, and 10 with tall stature. They underwent clinical assessment (height, weight, height velocity, staging of puberty, physical examination for acne, body odour, and clitoromegaly) and laboratory assessment comprising basal concentrations of cortisol, 17 OH-progesterone (17 OHP), androstenedione, dehydroepiandrosteronesulphate (DHEAS), testosterone, and oestradiol. The above steroids were also measured during the short synacthen test (0.25 mg intramuscularly) in 16 subjects and low dose dexamethasone suppression tests (0.5 mg at six hourly intervals over 48 hours). Pelvic ultrasound, computed tomography and magnetic resonance imaging of adrenals were carried out when the biochemical findings suggested that there might be an autonomous source of androgen secretion. RESULTS: Clinical and laboratory assessments differentiated the patients into three diagnostic categories: adrenarche (18 cases), congenital adrenal hyperplasia (five cases), and adrenocortical tumour (two cases). The last had elevated concentrations of DHEAS, 1.5 and 19.1 mumol/l (normal value < 0.5 mumol/l), androstenedione, 24.6 and 21.8 nmol/l (normal < 1 nmol/l), and testosterone, 4.5 and 2.4 nmol/l (normal < 0.8 nmol/l), with none suppressing on dexamethasone suppression. Congenital adrenal hyperplasia subjects had elevated basal serum concentrations of 17 OHP (n = 4): 250, 140, 14, and 14.1 nmol/l (normal < 10 nmol/l) and elevated peak values of 17 OHP after synacthen (n = 3): 76, 179.5, and 175 nmol/l. Adrenarche patients had elevated basal concentrations of DHEAS (median: 2.3 mumol/l; n = 17) and androstenedione (median 2.6 nmol/l; n = 17). Nine patients also had elevated basal serum testosterone concentrations (median 0.9 nmol/l). Peak values of 17 OHP after synacthen were significantly different from baseline (n = 12) and were < 50% of the lowest value in congenital adrenal hyperplasia. Serum DHEAS, androstenedione, and testosterone suppressed following dexamethasone suppression (n = 16), thereby distinguishing adrenarche patients from adrenal tumour patients. Clinical details did not distinguish patients, except for clitoromegaly which was present only in the tumour and congenital adrenal hyperplasia patients. CONCLUSIONS: This protocol proved useful and practical in cases of virilisation presenting particular diagnostic difficulty.

Growth and puberty in chronic inflammatory bowel disease.

The consequences of IBD during childhood and adolescence may be devastating in terms of loss of growth potential, particularly if there has been a clinical course of frequent relapses resulting in inadequate nutrition and associated with repeated courses of steroid treatment. There is to date, however, a paucity of data recording final adult heights in such patients. The anticipation of relapse should become easier with increasing awareness of the importance of parameters of growth and pubertal development. Early and intensive nutritional support, and the use of steroid-sparing agents should help reduce the frequency and severity of any height deficit. The performance and timing of surgery must take into account the child's status in terms of height velocity and pubertal development. The importance of inducing the remission before the onset of puberty is stressed and this remission should be sustained at all costs during the pubertal years so that valuable height is not lost as a consequence of a missed pubertal growth spurt. Thus, increasing awareness of the issues of growth and development in these patients should improve the accuracy of initial diagnosis and early recognition of relapse, such that these children are ensured the best possible provision for achieving their full height potential.

Impaired generation of cyclic adenosine 3',5'-monophosphate in a somatomammotroph cell line derived from dwarf (dw) rat anterior pituitaries.

The dwarf (dw) mutation in rats results in 40-50% growth retardation associated with a selective reduction in pituitary somatotroph number, GH content, and GH mRNA levels and a decreased GH secretory response to GH-releasing factor (GRF). Recent studies in freshly dispersed pituitary cells have provided evidence for a defect in adenylate cyclase-linked GRF signal transduction in dw somatotrophs. To further examine this defect in a more specific cell population, we developed a somatomammotroph cell line (DP) derived from anterior pituitaries of male dw rats. A similar cell line from normal rats (Po) was used as control. We studied acute GH (4-h release) and cAMP (30-min intracellular accumulation) responses to GH secretagogues known to interact with the adenylate cyclase system. Basal GH release in both cell lines was 80-130% of the cell content, thus limiting the capacity for further GH responses. GRF (10(-8) M) produced a doubling of cAMP levels in Po and DP cells (P less than 0.01), but inconsistent effects on GH release. (Bu)2cAMP (5 x 10(-3) M) increased GH secretion by 50-100% in both groups (P less than 0.01). Cholera toxin (10(-9) M) increased GH release by 50% in both Po and DP (P less than 0.01), but the cAMP response in DP cells was only half that in Po cells (P less than 0.01). Forskolin (10(-5) M), a direct stimulator of adenylate cyclase, doubled GH release in both groups (P less than 0.01). However, cAMP generation was impaired in DP, with a maximal response to forskolin less than one third that in Po (P less than 0.01). In somatotrophs, cAMP mediates not only GRF-stimulated GH release, but also GH synthesis and mitogenesis. The impairment in maximal cAMP generation in DP cells, while not affecting acute GH release, may underlie the defect in somatotroph cell number and GH content in the dw pituitary gland.

The interaction of growth hormone releasing hormone and somatostatin in the generation of a GH pulse in man.

OBJECTIVE: To study the regulation of the growth hormone (GH) response to growth hormone releasing hormone (GHRH) in the presence or absence of somatostatin pretreatment. DESIGN: Seven healthy adult male volunteers of normal height and weight and aged between 19 and 29 years underwent four separate studies (each containing three cycles in one day) in random order. The studies were separated from each other by at least a week. On day 1, three consecutive cycles (between 0800 and 2000 hours) consisted each of a saline infusion for 3 hours which was stopped prior to a bolus injection of saline and followed by 60 minutes of more intensive blood sampling. On day 2, the bolus injections were of GHRH given after saline infusion. On days 3 and 4 somatostatin infusions were administered instead of saline over the 3-hour periods followed by bolus injections of saline or GHRH respectively. In all studies, samples were collected for the measurement of serum GH concentration at 15-minute intervals from time 0 to 180 minutes and then at 5-minute intervals for a further 60 minutes, this cycle being repeated three times. MEASUREMENTS: Serum GH concentrations were analysed by serial array averaging. RESULTS: Prompt release of GH was observed in response to GHRH given against a saline background (day 2, cycle 1) (mean at 60 minutes 49.2 +/- 14.7 mU/l) but the responses observed during the second and third cycles were attenuated (mean at 60 minutes 17.2 +/- 4.0 mU/l; P = 0.025). GH release between somatostatin infusions (somatostatin withdrawal; day 3) occurred twice as often as that observed during saline infusions (62% day 3: 29% day 1). The response, although qualitatively similar to that induced by GHRH, was reduced in amplitude and the time of onset variable (5-45 minutes). On day 4, the administration of GHRH as a bolus injection combined with somatostatin withdrawal led to consistent and repeatable GH responses (mean at 60 minutes, cycle 1, 39.7 +/- 10.8 mU/l; cycles 2 and 3, 37.4 +/- 9.4 mU/l) which were similar to those observed with GHRH alone (day 2, cycle 1) (mean 39.7 +/- 10.8 mU/l) (P = NS). CONCLUSIONS: These data suggest that endogenous somatostatin secretion is important in determining the ability of the somatotroph to respond to repeated growth hormone releasing hormone stimulation and that for regular GH pulse generation a close interplay between growth hormone releasing hormone and somatostatin is required.

The pituitary gland is capable of responding to two successive doses of growth hormone releasing hormone (GHRH)

We have studied the serum growth hormone (GH) response to two consecutive doses of growth hormone releasing hormone (GHRH) (50, 100, 200 micrograms) given 1, 2 or 3 h apart in seven adult males. The serum GH profile was analysed by deconvulution incorporating a variable half-life for GH. All three doses of GHRH stimulated maximal GH secretion: 50 micrograms, 146.0 mU/min (SEM 24.0); 100 micrograms, 128.1 mU/min (SEM 14.3); 200 micrograms, 134.1 mU/min (SEM 20.5) (one-way ANOVA, P = NS). The magnitude of the second secretory burst after the second dose of GHRH was less than that induced by the first injection of GHRH, particularly when doses of 200 micrograms were used. Factors influencing the response to the second dose were the GH secretory status at the point that the stimulus was applied and the time interval between administration of the first and second doses. These studies demonstrate that the pituitary gland is capable of responding to two consecutive doses of GHRH although the second response is always less than the first. The data demonstrate the importance of using methods of assessing GH secretion and not relying simply on measured serum GH concentration values.

The interaction between clonidine and growth hormone releasing hormone in the stimulation of growth hormone secretion in man.

Six normal adult males were given clonidine and GHRH either separately, or in combination, in random order. The peak serum GH concentrations elicited by clonidine or GHRH were variable but one factor influencing the GH response to GHRH was the GH secretory status in the hour prior to the administration of the GHRH. Peak serum GH concentrations attained were significantly greater when serum GH concentrations were rising (mean 52.9 mU/l, SD 17.2) than if they were falling (mean 27.5 mU/l, SD 13.3) or unchanged/undetectable (mean 20.6 mU/l, SD 9.8) (one-way ANOVA, F = 8.77; P = 0.004). The GH response to clonidine was not influenced by the secretory status in the hour prior to administration of clonidine. Pretreatment with clonidine did not augment the peak serum GH response to GHRH but the direction of response was more predictable than when GHRH was administered separately or repeatedly. Prior treatment with GHRH(1-29)-NH2 led to a marked attenuation of the peak serum GH response to clonidine. These results suggest that the alpha-2 adrenergic agonists probably stimulate GH secretion through pathways other than just GHRH.

Continuous subcutaneous GHRH(1-29)NH2 promotes growth over 1 year in short, slowly growing children.

We have treated eight pre-pubertal children with partial GH insufficiency with continuous subcutaneous infusions of GHRH(1-29)NH2 at a dose of 60 ng/kg/min for periods of up to 1 year. In five children treated for 1 year, mean growth velocity increased from 4.6 cm/year (range 4.4-5.2) to 7.0 cm/year (5.7-8.7) (P = 0.04). Three children treated for 3-6 months showed similar height velocity increases. A return to pretreatment growth rates was seen after cessation of treatment in all children. Twenty-four-hour GH profiles performed at intervals of 3 months showed sustained augmentation of pulsatile GH secretion without evidence of desensitization. The presence of pulsatile GH secretion during continuous GHRH administration provides strong evidence in man for the role of somatostatin in determining GH pulse frequency. The ability of the pituitary to respond to a supramaximal bolus of GHRH remained constant during the treatment. Continuous administration of GHRH(1-29)NH2 will become a practicable treatment when formulated into a sustained release or depot preparation. We have shown this to be an effective therapy for some short, slowly growing children. Further studies are required to establish the optimal dosage regimen.

The half-life of exogenous growth hormone after suppression of endogenous growth hormone secretion with somatostatin.

We have estimated the half-life of serum growth hormone (GH) in six subjects on 14 occasions following an intravenous bolus injection of either 50 or 500 mU of biosynthetic human growth hormone (B-hGH) while endogenous GH secretion was suppressed by a continuous infusion of somatostatin. The disappearance curve of serum GH was mono-exponential and the mean half-life was 8.9 min (SD 1.5). This is less than previously reported and has important implications for the performance of GH profiles, which should be performed with 10-15 min sampling intervals, and the calculation of pituitary GH secretion rates.

Tinnitus in childhood.

Ninety-three healthy children attending routine school and community medical examinations were questioned about tinnitus, 27 of them (29%) described tinnitus. Nine children (9.6%) were bothered by their symptom, the others were not. The incidence of tinnitus in this group was compared with that in a group of 109 children with ear disease. Forty-two children (38.5%) in this group reported tinnitus. This difference is not statistically significant. Details of children attending paediatric ENT clinics were recorded by two ENT surgeons. Four hundred and three children were seen during the study period and of these 13 (3%) reported tinnitus spontaneously. All these children had evidence of ear disease at the time of the consultation. The incidence of tinnitus in those members of this group with abnormal ears was significantly higher than in those children with no evidence of ear disease (P = less than 0.02). Tinnitus may be a manifestation of ear disease in children, but may also be described by children with normal ears.