Compliance with growth hormone treatment--are they getting it?
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Child↗
Biomedical subjects
C G Brook
Publications and source records attributed to C G Brook.
Strong bones don't break!
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Bone Density↗
The measurement of growth hormone bioactivity in patient serum using an eluted stain assay.
We have adapted the MTT-ESTA bioassay for human GH (hGH) to measure the lactogenic bioactivity of the hormone in human serum. This highly quantitative in vitro colorimetric bioassay is based upon the reduction of a tetrazolium salt, 3-[4,5-dimethyl-thiazol-2-yl]2,5-diphenyl tetrazolium bromide (MTT), to its formazan by lactogen-activated Nb2 cells. Relatively high concentrations of human serum (1-10%) modified responses to the hormone in a complex manner. As the serum effects varied between samples, it proved impossible to adapt the bioassay by the conventional approach of using a lactogen-depleted serum as a representative matrix. However, as the Nb2 cells were exceptionally sensitive to hGH, the serum effects could be diluted out. We adopted a dilution strategy by which all samples of human serum were included in the bioassay at a concentration of 0.625% or less. A valid assay was obtained, as judged by the criteria of parallelism between diluted samples and hGH standards, and recoveries of spiked samples that were close to 100%. Hormonal specificity was achieved with the use of a highly specific anti-PRL antiserum. A within-assay precision of between 2-5% over the dose range of 0.03-0.96 microgram hGH/L was attained. As only highly diluted samples could be used, the sensitivity of the clinical bioassay was 1.2-2.4 micrograms hGH/L. The between-assay precision was estimated to be 11% and 9% at initial hGH concentrations in serum of 4.8 and 19.2 micrograms hGH/L, respectively. By exploiting the high sample capacity of the eluted stain bioassay system, we followed the changes in bioactivity and immunoactivity of hGH in multiple timed samples after stimulation of hGH secretion in an adult by GHRH. Systematic and progressive changes were observed in the bioactive/immunoactive ratios. Analogous changes were observed after insulin-induced hypoglycemia in a child with short stature. We speculate that the changes in the bioactive/immunoactive ratios reflect alterations in the proportions of the isoforms of hGH in the circulation after acute stimulation.
Animals↗
Sexual precocity: sex incidence and aetiology.
The aetiology of 197 girls and 16 boys presenting with sexual precocity was reviewed. Ninety one girls and four boys had central precocious puberty (M:F 23:1); a cause was identified in all the boys but in only six girls. All boys with precocious puberty need detailed investigation; in girls investigation should be based on clinical findings, particularly the consonance of puberty.
Adrenal Hyperplasia, Congenital↗
Progress report: growth hormone in skeletal dysplasia.
Growth hormone is not a logical treatment for the short stature associated with skeletal dysplasia because growth hormone concentrations are normal in these individuals. Short-term trials of growth hormone have demonstrated an increase in growth velocity in most of the skeletal dysplasias. Only in the skeletal dysplasia associated with Turner syndrome do we have data confirming that growth hormone treatment results in an increase in final height. Studies in achondroplasia and hypochondroplasia have demonstrated an increase in growth velocity which has been sustained for up to 4 and 6 years, respectively. In the long term, increased knowledge of the defects involved in skeletal dysplasia may lead us to improvements in both diagnosis and treatment.
Achondroplasia↗
The effect of changing gonadotropin-releasing hormone pulse frequency on puberty.
We have examined the effect of using different pulse frequencies of exogenous GnRH to induce puberty and the time relationship among LH, FSH, sex steroids, and GH in these individuals. Five girls and three boys with delayed puberty received exogenous GnRH at either 3-h frequency (slow) or every 45 min (fast). Treatment was initially given overnight and increased to 24 h when breast stage 3 in girls or testicular volume of 10 mL in boys was attained. Twenty-four-hour gonadotropin profiles were performed after 5 days, 1 month, 3 months, 6 months, and 1 yr of treatment. Temporal relationships among LH, FSH, and estradiol; LH and testosterone; GH and estradiol; and GH and testosterone were examined by cross-correlation. There was no difference in the rate of pubertal progress between the groups. Mean serum gonadotropin and sex steroid levels did not differ. LH was correlated with estradiol for both groups at 240 min (slow group, r = 0.54; fast group, r = 0.50). Estradiol correlated with LH at 300 min in the slow group (r = -0.41) and 200 min in the fast group (r = -0.37). FSH correlated with estradiol at 140 min in the slow group (r = 0.62) and 160 min in the fast group (r = 0.50). A rise in estradiol occurred 140-160 min after a rise in FSH and 240 min after a rise in LH. A rise in estradiol was followed 200-300 min later by a fall in LH. LH was correlated with testosterone at 60 min in the slow group (r = 0.73) and at 40 min in the fast group (r = 0.55). Testosterone correlated with LH at 420 min in the slow (r = -0.67) and 460 min in the fast group (r = -0.40). A rise in LH was followed 40-60 min later by a rise in testosterone. A rise in testosterone was followed by fall in LH 420-460 min later. GH correlated with estradiol at 320 min in the slow group (r = 0.37) and 380 min in the fast group (r = 0.38). A rise in GH was followed, after 320-380 min, by a rise in estradiol. There was a correlation between GH and testosterone in the slow group after 280 min (r = 0.44). A rise in GH was followed by a rise in testosterone after 280 min. The pituitary-gonadal axis is sufficiently robust to allow puberty to progress with different fixed pulse frequencies. There is a temporal relationship among LH, FSH, and estradiol secretion and between LH and testosterone secretion. We have demonstrated the feedback effect of sex steroids at the level of the pituitary and the time course of the effect of GH on gonadal function.
Adolescent↗
Therapeutic controversies: growth hormone (GH) treatment of non-GH deficient subjects.
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Child↗
Low-dose growth hormone-releasing hormone tests: a dose-response study.
We have evaluated parameters of the serum growth hormone (GH) concentration response to saline and 1-, 10- and 100-micrograms intravenous bolus doses of amide analogue of GH-releasing hormone (GHRH (1-29)NH2) given in random order to 10 adult male volunteers of median body weight 68 (60-90)kg. Compared with saline, both 10- and 100-micrograms GHRH(1-29)NH2 doses (but not 1 microgram) resulted in significant peak GH responses (means and 95% confidence intervals: 24.03 (11.22-51.29) vs 26.09 (16.40-41.50) mU/l, respectively). Although the average rate of serum GH rise was similar after both 10 micrograms (2.05 (1.13-2.97) mU.l-1.min-1) and 100 micrograms of GHRH(1-29)NH2 (1.52 (0.69-2.35) mU.l-1.min-1; ANOVA F = 0.93, p = 0.35), the average rate of serum GH decline after peak GH was slower after the higher dose (10 micrograms vs 100 micrograms: 0.65 (0.40-0.90) vs 0.37 (0.23-0.50) mU.l-1.min-1; ANOVA F = 5.14, p = 0.04), suggesting continued GH secretion. Increasing GHRH(1-29)NH2 doses delayed the time to peak GH (1 microgram: 7.00 (3.50-10.52) min; 10 micrograms: 15.80 (13.62-17.98) min; 100 micrograms: 24.80 (18.40-31.12) min) and serum GH levels were still elevated significantly 2 h after injection of 100 micrograms GHRH(1-29)NH2 compared with other doses (saline: 0.98 (0.48-2.04) mU/l; 1 microgram: 0.68 (0.48-0.93) mU/l; 10 micrograms: 1.07 (0.56-2.04) mU/l; 100 micrograms: 5.01 (2.34-10.86) mU/l; ANOVA F = 11.10, p < 0.001). In a second study we tested five adult male volunteers with lower doses (0.5-10 micrograms) of GHRH(1-29)NH2.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Inhibition of growth hormone bioactivity by recombinant human growth hormone-binding protein in the eluted stain assay system.
The effects of a recombinant human GH-binding protein (rhGHBP; amino acids 1-238) on GH stimulation of rat Nb2 lymphoma cells were examined with an eluted stain assay system (ESTA). This precise bioassay utilizes the colorimetric reduction by stimulated Nb2 cells of a yellow tetrazolium salt (3-[4,5-dimethyl-thiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) to a purple formazan as its end-point. The use of a lactogenic bioassay allowed the investigation of hGHBP specificity for human GH (hGH) as opposed to prolactin. rhGHBP inhibited pituitary hGH bioactivity in a dose-dependent manner. No significant inhibition of prolactin or ACTH bioactivity occurred. It was confirmed that recombinant 20 kDa hGH also stimulated the Nb2 cells and that its relative potency was approximately 10% of that of pituitary-derived hGH. Stimulation by 20 kDa hGH was also inhibited by rhGHBP. The highly quantitative ESTA system demonstrated that the binding protein inhibited in a competitive manner. hGH activation of the Nb2 cells did not appear to be governed by a Michaelian first-order reaction. As might then be anticipated, the concentration of rhGHBP required for 50% inhibition of GH bioactivity (IC50) changed with agonist concentrations for both 20 kDa and 22 kDa hGH. However, with equimolar concentrations of these two isohormones, the IC50 of the binding protein was virtually identical. Potentiation of hGH bioactivity in vivo by low concentrations of hGHBP has been reported but was not observed in our in vitro system when tested over a wide range of binding protein concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Changes in gonadotrophin secretion during childhood and puberty.
The changes in gonadotrophin secretion in childhood and puberty involve changes in the pulsatile pattern as well as mean concentration. We have examined pulsatile secretion using 24-h LH profiles in 78 children aged 4.2-15.6 years and six adult men. The profiles were analysed by a method which gives an estimate of peak and baseline levels and by spectral analysis. Prepubertal children were divided into groups by age and pubertal children by pubertal stage. Baseline LH levels in children aged 4.2-6.9 years were higher than in those aged 7.1-9.8 years. Pulse frequency in both groups was slow (periodicities 140-200 min). In the oldest prepubertal group there was an increase in peak levels with increased spectral power at periodicities of 100-120 min. Pulse frequency did not change in puberty (periodicity 120-160 min). Girls demonstrated an increase in both peak and baseline LH concentrations in early puberty. Boys had an increase in only peak levels in early puberty; there was no increase in baseline concentrations until a testicular volume of 10 ml was attained. In conclusion, these data show that LH levels do not reach a nadir until 8 years of age. We have detected a sex difference in the pattern of LH secretion seen in early puberty, and this mirrors clinical findings. The mature pattern attained by the end of puberty in both sexes is probably important for fertility.
Adolescent↗
Physiological levels of growth hormone fail to suppress growth hormone releasing hormone (1-29) NH2-stimulated growth hormone secretion in man.
We studied 11 normal adult males. Six subjects (Study A) received a bolus of saline or of 50 mU biosynthetic human growth hormone (r-hGH) or a one hour iv infusion of r-hGH (80 mU/h) in random order. On each occasion this was followed by an iv bolus of GHRH (1-29) NH2 (100 micrograms) 90 minutes after the first event. Five subjects (Study B) received a bolus iv injection of saline or of 500 mU r-hGH followed by iv GHRH (1-29) NH2 (100 micrograms) 90 minutes later. There was no significant difference in the serum GH concentrations achieved following the 50 mU bolus or iv infusion of r-hGH (range 5.6-67.0 mU/l). Higher concentrations of GH (mean +/- SE, 238.4 +/- 21.3 mU/l) were achieved with the 500 mU bolus of r-hGH. The peak GH responses to iv GH-RH (1-29) NH2 were similar in all instances. The most important factor determining the response to exogenous GHRH (1-29) NH2 was the serum GH concentration at the time that the GHRH (1-29) NH2 was administered and the mode of r-hGH administration (iv bolus or iv infusion). These data demonstrate that within the range of physiological serum GH concentrations the mode of presentation of GH (bolus or infusion) and GH secretory status are the most important factors in determining GH responsivity to GHRH. Under these circumstances GH would appear not to participate in a rapid-acting short-loop negative feedback mechanism in man as the response to exogenous GHRH was not attenuated.
Adolescent↗
The relationship between endogenous testosterone and gonadotrophin secretion.
OBJECTIVE: The secretion of luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone in the adult male was studied by means of 48-hour profiles. The aim of the study was to examine the effects of the endogenous circadian variation in serum testosterone concentration on LH pulsatility, and to determine the temporal relationships between FSH and LH, and between LH and testosterone by cross-correlation, and the pulse frequency of these hormones by spectral analysis, as revealed by extended sampling periods. DESIGN: Hormone profiles were obtained by 20-minute sampling over 48 hours. SUBJECTS: Six healthy adult males, aged between 21 and 23 years. MEASUREMENTS: LH and FSH were measured using an immunoradiometric assay and testosterone with a solid-phase radioimmunoassay. RESULTS: The profiles showed pulsatile secretion of all three hormones, and a circadian rhythm with levels highest between 0200 and 0600 h. Cross-correlation analysis: There was a significant relationship between LH and FSH (r = 0.5; P = 0.001) at 0 minutes (i.e. no time lag). A pulse of testosterone followed on average 60 minutes after a pulse of LH (r = 0.26; P = 0.001). Fourier transformation: Spectral analysis showed the dominant period for LH and FSH pulsatility to be 200 minutes. The dominant period for testosterone pulsatility was 400 minutes. The effect of endogenous variations in serum testosterone concentrations: The LH profiles were divided into periods when the serum testosterone concentration was high or low, and Fourier transformation carried out on these shorter periods. These transforms showed that the dominant period during high serum testosterone concentration was 180 minutes, and during low serum testosterone was 120 minutes (P < or = 0.025). CONCLUSIONS: FSH and LH are co-secreted, and a pulse of testosterone follows a pulse of LH by 60 minutes. The physiological changes in serum testosterone concentration that occur during the day result in changes in the pulse frequency of LH. Testosterone concentrations thus have rapidly acting feedback activity at hypothalamic level.
Adult↗
The effects of oxandrolone on the growth hormone and gonadal axes in boys with constitutional delay of growth and puberty.
OBJECTIVE: We studied the effects of oxandrolone on serum concentrations of LH, FSH, testosterone, GH, SHBG, DHEAS, IGF-I and insulin in boys with constitutional delay of growth and puberty. DESIGN: Ten boys with constitutional delay of growth and puberty, mean age 13.8 years (range 12.4-15.5) were studied. Twenty-four-hour serum concentration profiles of GH, LH and FSH were constructed by drawing blood samples at 20-minute intervals. Three study occasions over a period of 6 months were chosen to assess hormone concentrations before, during and 6 weeks after a 3-month course of oxandrolone (2.5 mg once daily) therapy. RESULTS: Growth velocity increased during oxandrolone treatment and stayed higher after therapy (pre 3.9 +/- 0.5; on 6.3 +/- 0.8; post 6.4 +/- 0.9 cm/year (mean +/- SEM) two way ANOVA, F = 5.3, P = 0.02). Oxandrolone had androgenic effects, suppressing mean serum LH concentrations from 1.7 +/- 0.3 to 1.1 +/- 0.2 U/I and serum testosterone concentrations from 1.9 +/- 0.6 to 0.8 +/- 0.1 nmol/l. SHBG concentrations were also reduced from 130.9 +/- 14.6 to 30.7 +/- 7.3 nmol/l. Serum GH concentration fell slightly from 5.9 +/- 0.6 to 4.8 +/- 0.5 mU/l. After cessation of treatment, there was a significant 'rebound' in mean 24-hour serum LH (2.6 U/l +/- 0.4) and testosterone concentrations (3.2 +/- 0.9 nmol/l) but no change in serum GH concentrations. SHBG values also rose but not to the same extent as those observed before therapy (82.0 +/- 8.4 nmol/l). There were no statistically significant differences in serum concentrations of FSH, DHEAS, IGF-I and insulin over the study period. In a stepwise multiple regression analysis of factors that might influence the growth rate observed, the 24-hour mean serum testosterone concentration and the treatment (on or off) with oxandrolone were the main influences. The relationship was described by the equation Height velocity = 0.69 (24-hour mean serum testosterone concentration)+1.70 (treatment regimen)+3.37 (adjusted R2 = 0.35, F = 8.39, P = 0.001). CONCLUSIONS: Oxandrolone has an androgenic action as shown by changes in serum LH, testosterone and SHBG concentrations and by the lack of effect on FSH. No effect of oxandrolone on the GH axis was documented. We suggest that the growth promoting effects of oxandrolone are related in part to the mild androgenic effects of the steroid and the growth acceleration following oxandrolone withdrawal may reflect increasing total serum testosterone concentrations and decreasing levels of SHBG and progress in puberty.
Adolescent↗
Blood pressure and the renin-angiotensin-aldosterone system in children receiving recombinant human growth hormone.
OBJECTIVE: We investigated the effect of growth hormone (GH) treatment on salt and water metabolism and the renin-angiotensin-aldosterone system in children with short stature. DESIGN: Randomized, controlled study. PATIENTS: Twenty-nine short, pre-pubertal children referred to two specialist growth clinics for further assessment. MEASUREMENTS: Serial measurements of blood pressure, body weight, plasma renin activity (PRA), aldosterone, electrolytes, insulin and insulin-like growth factor I (IGF-I) have been made following the initiation of GH treatment. RESULTS: A small and transient increase in systolic blood pressure was observed during the first week of GH treatment. The increase in blood pressure over baseline was -1.1 mmHg in controls compared to +11.5 and +3.0 mmHg in children receiving standard (20 units/m2/week) and high dose (40 units/m2/week) GH respectively (P = 0.004). Over the same time interval body weight also tended to increase with GH compared with controls. These changes were greater in those children receiving the lower dose of GH and were not significantly related to age or prior GH status. PRA did not change with GH treatment. Although plasma aldosterone concentration tended to increase with GH, maximal values did not differ from controls and all remained within our normal range. Plasma IgF-I levels were increased by a similar amount in both treatment groups (1.5 and 1.12 U/ml compared to 0.44 U/ml in controls at 4 months). No difference in plasma insulin concentration was noted after 7 days of GH. CONCLUSIONS: In contrast to adult subjects, treatment with high dose GH in childhood is not associated with activation of the renin-angiotensin-aldosterone system. Clinical signs consistent with transient salt and water retention are observed with GH therapy, however, suggesting either a direct effect of GH or of IGF-I on renal tubular function. Blood pressure, plasma renin activity and plasma aldosterone levels were not increased after more prolonged GH therapy. These data suggest that high dose GH therapy in childhood is unlikely to be associated with the increased risk of hypertension seen in adults with GH hypersecretion.
Aldosterone↗
Deoxycorticosterone, 11 beta-hydroxylase and the adrenal cortex.
We report a child in whom DOC excess secondary to congenital adrenal hyperplasia (CAH, 11 beta-hydroxylase deficiency) caused malignant hypertension. Clinical and metabolic control could be achieved only by replacement of both glucocorticoid and mineralocorticoid, thus confirming in clinical practice the hypothesis that DOC is produced from both the zonae fasciculata and glomerulosa of the adrenal cortex under the independent control of the ACTH and renin-angiotensin systems respectively.
Adrenal Cortex↗
Optimum method for growth hormone treatment.
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Calibration↗
Compliance with growth hormone treatment--are they getting it?
A study was undertaken to investigate compliance in patients receiving growth hormone treatment. Two hundred patients completed a questionnaire designed to establish understanding about and compliance with treatment; 50% of our patients failed to comply with all aspects of their treatment. Failure to respond to treatment seems to be associated with poor compliance.
Growth Hormone↗