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Biomedical subjects

C G Brook

Publications and source records attributed to C G Brook.

At least 55 records · Page 3Linked to original sources
PubMed1998

The relationship between the growth hormone and insulin-like growth factor axis in long-term survivors of childhood brain tumours.

OBJECTIVE: We compared IGF-1 and IGFBP3 concentrations in a group of adults treated for brain tumours in childhood with those of matched controls, and investigated the relationship between the GH secretory pattern and IGF-1/IGFBP3 concentrations in the entire group. DESIGN: We performed 24 h serum GH profiles using 20 minute sampling and measured corresponding fasting concentrations of IGF-1 and IGFBP3. PATIENTS: Fourteen adult male long-term survivors of childhood brain tumours were studied. All had received high dose cranial irradiation (> or = 30Gy; median 12.8 (range 5.8-14.5) years previously). Nine healthy male volunteers acted as controls. MEASUREMENTS: IGF-1 and IGFBP3 concentrations were measured at 06.00 hours. Peak and trough GH activity within the GH profile was analysed by a distribution method which determined the concentration at or below which the serum GH concentration in the profile spent 95% (peak) and 5% (trough) of the total time. RESULTS: Serum IGF-1 levels were significantly lower in the irradiated group (Irradiated: 200 micrograms/l vs CONTROL: 265 micrograms/l; P = 0.001) but the difference in serum IGFBP3 (Irradiated: 2.3 mg/l vs CONTROLs: 2.77 mg/l; P = 0.03) was less marked. Peak GH activity was lower in the Irradiated subjects (2.59 mU/l vs 9.04 mU/l; P = 0.0004) and correlated strongly with IGF-1 (r = 0.62; P = 0.002) but less so with IGFBP3 (r = 0.35; P = 0.09). This was strenghtened when the range of activity within the profle (peak-trough) was considered. Trough GH activity had a nonsignificant negative correlation with IGF-1 and IGFBP3 levels. CONCLUSION: The difference in serum IGF-1 concentrations between irradiated subjects and controls was greater than the difference in serum IGFBP3. Peak GH activity and the range of activity within the profile correlated strongly with IGF-1 concentrations but less so with IGFBP3.

Adolescent↗
PubMed1998

Growth in children with craniopharyngioma following surgery.

OBJECTIVE: Hypopituitarism, including severe GH deficiency, is an almost inevitable outcome of craniopharyngioma. However, some GH deficient children with this tumour may grow normally or even have accelerated growth postoperatively. To study this phenomenon we have investigated the endocrine status, including IGF-1 and its binding proteins IGFBP-1 and IGFBP3, in children referred for follow-up at various time intervals after surgery. PATIENTS: Twenty-five patients (14 boys and 11 girls, aged 3.8-18.9 years), were studied on 34 occasions between 0.5 to 10.8 years after surgery. The tumour was intrasellar in 11 cases and suprasellar in 14. METHODS: Height and height velocity were recorded as SDS values. Body mass index (BMI) was calculated as weight/height2. GH secretory status was evaluated by stimulation both with oral clonidine and with GH releasing hormone. Serum insulin (INS) levels were studied following an oral glucose load. IGF-1, IGFBP-3, IGFBP-1 and prolactin serum concentrations were evaluated in fasting samples. All hormones were measured by radioimmunoassay. RESULTS: All patients had growth hormone (GH) deficiency. Height (HtSDSCA) and height velocity SDS for chronological age (HVSDSCA) decreased progressively after surgery (r = -0.47, P = 0.005, and r = -0.4, P = 0.032, respectively) but four patients had normal HtSDSCA 6.1 to 10.8 years following their first surgery. There was a significant correlation between BMI and HtSDSCA (r = 0.37, P = 0.03). BMI in children with suprasellar craniopharyngioma was significantly greater than that in patients with intrasellar tumour (23.3 +/- 7.0 vs. 17.3 +/- 1.4 kg/m2; P = 0.001). In 13 of 33 cases oral glucose load was accompanied by hyperinsulinaemia with serum INS levels greater than 50 mU/l. The mean area under the curve (AUC) of INS after glucose load (INSAUC) in the suprasellar group was greater than in the patients with intrasellar lesion (6945.5 +/- 4411.8 vs. 2495.5 +/- 1768.8 mU/l. min P = 0-001). The log INSAUC correlated significantly with HtSDSCA (0.37, P = 0.03). Fasting serum IGF-1 and IGFBP3 levels were normal in 8 and 12 of the 31 measurements, respectively. Both IGF-1SDS and IGFBP-3SDS correlated significantly with HtSDSCA (r = 0.77, P = 0.0002 and r = 0.65, P = 0.0001, respectively) and the log INSAUC (r = 0.39, P = 0.035, r = 0.56, P = 0.002, respectively). As determined by forward stepwise regression analysis, IGF-1SDS was the single most important predictor of HtSDSCA (R2 = 0.33, P = 0.001) in the subset mode. CONCLUSION: A few children with craniopharyngioma grew normally after surgery, in spite of being GH-deficient. This growth phenomenon, which is usually accompanied by obesity, was more common in patients with suprasellar tumour and is likely to be associated with the effect of IGF-1 bioavailability, which, in turn, may be modulated largely by insulin.

Adolescent↗
PubMed1998

Direct effects of corticotrophin-releasing hormone on stimulated growth hormone secretion.

OBJECTIVE: This study evaluated the effect of corticotrophin-releasing hormone (CRH) on growth hormone releasing hormone (GHRH)-stimulated growth hormone (GH) release in man. DESIGN: Six healthy adult volunteers (age 20-35 years) were studied. On different occasions they each received an intravenous bolus of saline, CRH(1-41) (100 micrograms), adrenocorticotrophic hormone (ACTH) [Synacthen (500 ng/m2)] or hydrocortisone (50 mg), followed 30 minutes later by an intravenous bolus of either GHRH-(1-29)-NH2 (1.0 microgram/kg) or saline. MEASUREMENT: Serum GH concentrations were measured using an immunoradiometric assay, and cortisol concentrations were measured by commercial radioimmunoassay. TSH concentrations were measured using a solid phase immunoradiometric assay kit. RESULTS: Pretreatment with CRH(1-41) attenuated the GH response to GHRH [saline/GHRH-(1-29)-NH2 20.2 +/- 6.2 mU/l; CRH(1-41)/GHRH-(1-29)-NH2 10.9 +/- 2.8 mU/l (P = 0.01)]. This effect was not due to the rise in ACTH or cortisol induced by CRH(1-41), since pretreatment with either ACTH or hydrocortisone significantly augmented the GH response to GHRH-(1-29)-NH2 in the same subjects [ACTH/GHRH-(1-29)-NH2 30.3 +/- 8.8 mU/l (P = 0.01); hydrocortisone/GHRH-(1-29)-NH2 36.4 +/- 11.2 mU/l (P = 0.02)]. CONCLUSION: Our data suggest that the inhibitory effect of CRH(1-41) on GHRH-(1-29)-NH2-induced GH release is not a result of ACTH or cortisol release but reflects a direct action of CRH on GH secretion, possibly via stimulation of somatostatin release. The acute rise in GH following glucocorticoid administration could be explained in part by a rapid suppression of endogenous CRH.

Adrenocorticotropic Hormone↗
PubMed1998

Obesity in 21-hydroxylase deficient patients.

OBJECTIVES: To evaluate the natural history and timing of adiposity rebound (nadir of body mass index (BMI)) in children with congenital adrenal hyperplasia 21-hydroxylase deficiency (CYP21). STUDY DESIGN: A retrospective mixed longitudinal study. METHODS: Height and changes in body composition (BMI; weight (kg)/height2 (m)), triceps and subscapular skinfolds) were analysed in 22 (14 girls, eight boys) prepubertal patients with CYP21 for whom continuous anthropometric data were available for at least seven years. BMI and height SD scores were compared at 1, 5, and 10 years of age. Skinfold SD scores were compared at 2.5 and 5.5 years. Thirteen children (nine girls, four boys) had records available from birth which allowed the estimation of the age at adiposity "peak" and "rebound". RESULTS: A significant increase in BMI SD score was found at 5 and 10 years compared with those at 1 year. No significant change in height SD score was observed at these ages. Triceps and skinfold SD score were increased significantly at 5.5 compared with 2.5 years. The "rebound" in BMI SD score took place at 1.74 years (range 0.71-4.57) compared with 5.5 years (range 3.5-7.0) in the normal UK populations. CONCLUSIONS: Normally growing patients with CYP21 increased their BMI throughout childhood. Adiposity rebound took place on average three years earlier than in the general population. These findings suggest that even when well controlled in terms of their disease process, patients with CYP21 are at risk of obesity, which may have important implications for the evolution of reproductive function (polycystic ovaries), diabetes, hypertension, and cardiovascular disease in these subjects.

Adolescent↗
PubMed1998

Skeletal dysplasias.

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Bone Diseases, Developmental↗
PubMed1998

Cortisol, androstenedione (A4), dehydroepiandrosterone sulphate (DHEAS) and 17 hydroxyprogesterone (17OHP) responses to low doses of (1-24)ACTH.

The dose of 250 microg used in the standard short synacthen test is supraphysiological and lower doses may provide a more sensitive test. We examined steroid responses to 125ng/m2, 250ng/m2 and 500 ng/m2 (1-24)ACTH in 6 normal males, looking at effects of dose and the within- and between-subject coefficients of variation (CV). Subjects were given each dose 3 times, blood samples were taken at 10 minute intervals. There was a dose response relationship between dose of (1-24)ACTH and peak values for cortisol and 17OHP (p<0.05). There was no difference between peaks of A4 at different doses and no clear peaks were reached for DHEAS. 86% of the peaks for 17OHP, 63% for A4 and 25% for cortisol were at 10 minutes and 14%, 29% and 65% respectively at 20 mins (p=0.001). Within-subject CV for cortisol was 12.6% and between subject 10.1%. Tests of adrenal function using low doses of (1-24)ACTH have acceptable between- and within-subject CV for peak values with a dose as low as 125 ng/m2 (1-24)ACTH. Protocols for low dose synacthen tests, with traditional sampling at zero, 30 and 60 minutes or even as shown here at 10 minute intervals, fail to fully define the changes in steroid levels following adrenal stimulation. More frequent blood sampling will be needed to accurately detect peak levels in particular of 17OHP and A4.

17-alpha-Hydroxyprogesterone↗
PubMed1998

Birth weight influences the initial response to growth hormone treatment in growth hormone-insufficient children.

OBJECTIVE: To determine the influence of birth weight on the first year response to growth hormone (GH) replacement in children with isolated GH insufficiency. STUDY DESIGN: A longitudinal study of response to daily GH treatment (15-26 IU/m2/week) was performed in 16 singleton Caucasian prepubertal children (11 boys, 5 girls) with isolated GH insufficiency (peak GH response to insulin tolerance test <13.5 mU/L) attending a pediatric endocrinology clinic. Change in height velocity standard deviation scores, during the 6 to 12 months before starting GH and the 12 months after, were used to reflect responsivity to GH treatment. Potential influencing variables considered by regression analysis were birth weight standard deviation score (BWSDS), peak GH response to insulin tolerance testing, midparental height standard deviation score, age at treatment, and dose of GH administered. RESULTS: Mean BWSDS was -0.51 (SD, 1.0). Change in height velocity standard deviation score was correlated positively with BWSDS (r = 0.64) and negatively with peak GH (r = -0.59). Stepwise linear regression analysis confirmed the influence of BWSDS on response to GH treatment. CONCLUSIONS: The continuum of birth weight influences initial responsivity to GH treatment in GH-insufficient children. This may reflect relative insensitivity in the growth hormone or insulin-like growth factor axis. The influence of birth weight on final height and benefit of using higher doses of GH in these children remains to be seen.

Birth Weight↗
PubMed1997

Interaction of the growth hormone releasing peptide hexarelin with somatostatin.

OBJECTIVE: Growth hormone releasing peptides (GHRPs) are potent growth hormone (GH) secretagogues. Their interaction with growth hormone releasing hormone (GHRH) has been studied extensively. Data on their interaction with somatostatin (SS) are limited. The aim of this study was to determine the effect of changing SS tone and the effects of SS withdrawal on the somatotroph response to hexarelin and GHRH, alone or in combination. In addition, we studied the effect of SS on the prolactin (PRL) and cortisol response to hexarelin. DESIGN: Boluses of saline, hexarelin (1 microgram/kg), GHRH-(1-29)-NH2 (1 microgram/kg) or hexarelin plus GHRH-(1-29)-NH2 were administered intravenously 1 hour after the start of a 3-hour constant intravenous infusion of saline, SS(1-14) (20 micrograms/m2/h) (SS20) or SS(1-14) (50 micrograms/m2/h) (SS50). In a second group of studies, the same boluses as above were administered intravenously at the time of withdrawal of a 3-hour constant intravenous infusion of saline or SS20. In a subset of the second group of studies, saline, hexarelin (0.5 microgram/kg) or GHRH-(1-29)-NH2 (0.5 microgram/kg) was administered intravenously two hours before the withdrawal of the SS(1-14) infusion, which was administered at a higher dose of 50 micrograms/m2/h. Studies were performed in a random order. SUBJECTS: Twelve healthy adult males (20.3-34.6 years) were studied. MEASUREMENTS: Serum GH and PRL concentrations were measured by immunoradiometric assays. Serum cortisol concentrations were measured by radioimmunoassay. RESULTS: Infusion of SS20 resulted in a significant reduction in the peak GH response to hexarelin, GHRH-(1-29)-NH2 or hexarelin plus GHRH-(1-29)-NH2 (P < 0.05). The peak serum GH concentrations following the intravenous administration of the two secretagogues, separately or in combination, were reduced further by the higher dose of SS50, but these were not significantly different from their respective peak serum GH concentrations obtained during the infusion of SS20. The peak serum GH concentration following the intravenous administration of hexarelin plus GHRH-(1-29)-NH2 remained large (52.6 +/- 7.2 mU/l; mean +/- SEM) despite the high dose of SS(1-14) (50 micrograms/m2/h). SS(1-14) did not affect the PRL and cortisol response to hexarelin. Withdrawal of SS20 infusion at the time of intravenous bolus administration of hexarelin, but not GHRH-(1-29)-NH2 or hexarelin plus GHRH-(1-29)-NH2, resulted in a significant increase in peak serum GH concentration (P = 0.03). The intravenous administration of hexarelin (0.5 microgram/kg) or GHRH-(1-29)-NH2 (0.5 microgram/kg) during an intravenous infusion of SS50 resulted in a small GH response (peak concentrations 6.8 +/- 3.6 mU/l and 2.4 +/- 0.5 mU/l, respectively) but the later withdrawal of the infusion was not followed by a rise in serum GH concentrations. CONCLUSIONS: This study shows that SS and hexarelin counteract their respective inhibitory and stimulatory action on GH secretion and provides further evidence for their interaction in vivo. The stimulatory effect of hexarelin on the lactotroph and the hypothalamo-pituitary-adrenal axis is unaltered by SS. Hexarelin plus GHRH are synergistic and have potent GH-releasing activity despite a high dose SS infusion. Withdrawal of SS enhances the GH response to hexarelin, which may reflect simultaneous endogenous GHRH release synergizing with hexarelin. A single cycle of pretreatment with hexarelin during SS infusion is insufficient to allow synthesis and storage of sufficient GH to influence its release following SS withdrawal. These findings add further to the data already gathered about GHRPs and their complex interaction with the main regulators of GH secretions.

Adult↗
PubMed1997

Transsphenoidal surgery for pituitary tumours.

OBJECTIVES: Transsphenoidal surgery (TSS) is the preferred method for the excision of pituitary microadenomas in adults. This study was carried out to establish the long term efficacy and safety of TSS in children. STUDY DESIGN: A 14 year retrospective analysis was carried out on 23 children (16 boys and seven girls), all less than 18 years of age, who had undergone TSS at our centre. RESULTS: Twenty nine transsphenoidal surgical procedures were carried out. The most common diagnosis was an adrenocorticotrophic hormone (ACTH) secreting adenoma (14 (61%) patients). The median length of follow up was 8.0 years (range 0.3-14.0 years). Eighteen (78%) patients were cured after the first procedure. No death was related to the operation. The most common postoperative complication was diabetes insipidus, which was transient in most patients. Other complications were headaches in two patients and cerebrospinal fluid leaks in two patients. De novo endocrine deficiencies after TSS in children were as follows: three (14%) patients developed panhypopituitarism, eight (73%) developed growth hormone insufficiency, three (14%) developed secondary hypothyroidism, and four (21%) developed gonadotrophin deficiency. Permanent ACTH deficiency occurred in five (24%) patients, though all patients received postoperative glucocorticoid treatment until dynamic pituitary tests were performed three months after TSS. CONCLUSIONS: TSS in children is a safe and effective treatment for pituitary tumours, provided it is performed by surgeons with considerable experience and expertise. Surgical complications are minimal. Postoperative endocrine deficit is considerable, but is only permanent in a small proportion of patients.

Adenoma↗
PubMed1997

Factors involved in the rate of fall of thyroid stimulating hormone in treated hypothyroidism.

The rate of fall of serum thyroid stimulating hormone (TSH) concentrations in 32 hypothyroid infants (11 boys, 21 girls) was studied after starting treatment with thyroxine to determine whether it was influenced by initial TSH concentration or the cause of the hypothyroidism. Of 27 patients who had isotope scans before treatment was started, 11 (40%) were athyrotic, 10 (38%) had an ectopic gland, and six (22%) probably had dyshormonogenesis. Treatment was started with thyroxine at 100 micrograms/m2/24 hours at a mean age of 26 days (range 14-45). Serum TSH concentrations remained increased in 26 (81%) at 3 months, 20 (62.5%) at 6 months, and nine (28%) at 1 year and beyond. The mean age for serum TSH to reach the normal range was 0.79 years (range 0.15-2.1 years). Diagnosis (in 27 patients) and initial results (in 32) made no difference to the rate of fall.

Analysis of Variance↗
PubMed1997

Clinical indications for the use of urinary steroid profiles in neonates and children.

For a number of rare adrenal disorders, some of which are life threatening in childhood, laboratories need access to specialist endocrine investigations. Measurements of hormones in blood samples may be diagnostic in some cases but not all of the requisite steroid hormone assays are available. Multiple plasma steroid measurements may be required to prove the nature of a steroid biosynthetic disorder but in newborn children immunoassays, performed without prior solvent extraction, can be misleading. A urine steroid profile by gas chromatography coupled with mass spectrometry examines many steroid metabolites simultaneously and provides specific diagnostic information. A urine steroid profile can provide precise information of the secretory nature of tumours and causes of virilization, salt loss and hypertension often from a spot urine sample rather than a 24 h collection. However, a steroid profile is not helpful in making a diagnosis in neonatal genetic males with poorly developed genitalia.

Adrenal Hyperplasia, Congenital↗
PubMed1997

Peak and trough growth hormone concentrations have different associations with the insulin-like growth factor axis, body composition, and metabolic parameters.

GH is secreted in a pulsatile fashion, promoting growth and anabolism. The components of the pulsatile signal involved in these diverse effects are unclear. We constructed (20-min sampling interval) and analyzed 24-h serum GH profiles in 45 adult male volunteers, 59.4-69.9 yr old, body mass index (BMI) 21.9-36.5 Kg/m2, using Fourier transformation and a concentration distribution analysis that determines the concentration at or below which the serum GH concentrations in the 24-h profile spend a percentage of the total time. The observed concentrations (OC) below which 95% and 5% of the values in the time series lie [lsb]OC95 (peaks) and OC5 (troughs)] and mean 24-h serum GH concentrations were related to measures of the insulin-like growth factor (IGF) family, parameters of body composition, fasting insulin and cholesterol measures, and GH-binding protein concentrations. Mean 24-h serum GH concentrations ranged between 0.19 and 2.15 mU/L (1 microgram/L = 2.6 mU/L). Pulse periodicity was between 180 and 200 min. There was a positive relationship between peak GH levels and serum IGF-1 and IGFBP-3 levels (r = 0.39; P = 0.009 and r = 0.32; P = 0.03, respectively). GH trough levels were unrelated to these measures of the IGF family. In contrast, GH troughs were related inversely to BMI (r = -0.31; P = 0.04) and waist-hip ratio (r = -0.4; P = 0.006). Peak GH levels were not related to these measures. Factors known to influence these measures, fasting insulin concentration, or cortisol secretion did not alter the trough GH relationship in multiple regression analysis. All GH parameters were related inversely to fasting insulin concentration. Although GH parameters were related inversely to cholesterol and low-density lipoprotein-cholesterol, this effect disappeared when age and fasting insulin levels were introduced into the regression. GH-binding protein levels related most strongly to BMI (r = 0.60; P < 0.001), with no effect of any GH parameter observed in multiple regression analysis. These results suggest that the peak values of a GH concentration profile may influence the IGF axis, whereas trough values may influence body composition and metabolic parameters of GH action.

Aged↗
PubMed1996

Final height of short normal children treated with growth hormone.

BACKGROUND: Short-term studies have demonstrated acceleration of growth rate following administration of biosynthetic human growth hormone (r-hGH) to short normal children. We describe the effect of such treatment on final height. METHODS: This was an open study of consecutive referrals to a growth disorder clinic from which 16 short children (height standard deviation score [SDS] -2.17 [range -1.8 to -3.3]; height velocity SDS -0.44 [0.33]; peak serum GH response to stimulation 27.9 mU/L [9.2] were treated with r-hGH, and 7 short children who declined treatment (height SDS -2.34 [0.61]; height velocity SDS -0.36 [0.28]; peak serum GH response 28.2 mU/L [6.8]) acted as an observation group. Subcutaneous r-hGH dose ranged between 12.2 and 21.0 U/m2 per week (0.02-0.04 mg/kg per day) for the first 2 years of treatment and 20 U/m2 per week thereafter, 3 untreated children were lost to long-term follow-up. FINDINGS: r-hGH significantly increased the difference in final height compared with pretreatment predicted height (+0.42 SDS [0.79], p = 0.03) but this change was not significantly greater than that of the observation group (+0.16 SDS [0.20]). Treatment had no effect on the timing of puberty. Boys progressed slightly faster through puberty, associated with an acceleration in bone-age maturation. No untoward effects on glucose metabolism were observed. Long-term therapy did not alter body-fat distribution or blood pressure. INTERPRETATION: Long-term therapy in this group of children appears safe but the small increment in final height, approximately 2.8 cm in boys and 2.5 cm in girls, does not justify the widespread use of r-hGH for short normal children.

Blood Pressure↗