GH Excretion Research Articles

Endogenous and stimulated GH secretion, urinary GH excretion, and plasma IGF‐I and IGF‐II levels in prepubertal children with short stature after intrauterine growth retardation*

The pathophysiological mechanisms underlying the failure of catch up-growth in children with short stature after intrauterine growth retardation (IUGR) remain obscure. Since GH secretion disturbances might play a role in the growth retardation of these children we have investigated various aspects of the GH/IGF axis. Cross-sectional study in one group of patients. Forty prepubertal children (15 girls/25 boys; mean age (range) 7.5 years (3.4-10.8)) with short stature (height below the third centile) after IUGR, defined as a birth length below the third centile for gestational age, were studied. GH secretion was determined by a 24-hour plasma GH profile (sampling every 20 minutes) and, on a separate occasion, by a standard arginine provocation test (ATT). Plasma IGF-I and IGF-II levels were measured at the start of the GH profile. Urine was collected to measure urinary GH levels. Plasma and urinary GH were determined by double antibody RIA. IGF-I and IGF-II were determined by specific RIA after acid chromatography. The 24-hour GH profiles were analysed using Pulsar. Endogenous GH secretion was similar for boys and girls. Boys had significantly lower mean GH levels compared to healthy controls. Forty per cent of the children met our criteria for a normal 24-hour GH profile (group A; n = 16) and 60% (n = 24) did not. We subdivided these 24 children into two groups: group B (n = 14) (children with either mean GH levels less than controls but with at least one spontaneous GH peak above 20 mU/l and children with normal mean GH levels but with no GH peak above 20 mU/l (subnormal 24-hour GH profile)) and group C (n = 10) (children with mean GH levels less than controls and no GH peak above 20 mU/l (low 24-hour GH profile)). The GH secretory abnormalities were due to a decrease in pulse amplitude, not in pulse frequency. Mean (SD) maximal GH response during ATT was 22.3 (12.1) mU/l. Nineteen children (47.5%) had a maximal GH value < 20 mU/l. Moderate, but significant, correlations were found between several 24-hour GH profile characteristics and the maximal GH response during ATT (r = 0.31-0.35; P < 0.05). Mean (SD) overnight urinary GH excretion was 3.8 (2.1) and 4.4 (3.5) microU/night for boys and girls, respectively. Compared to healthy schoolchildren, overnight urinary GH was lower in boys, but not in girls. Mean (SD) IGF-I and IGF-II SDS levels for chronological age were -0.88 (1.40) and -0.64 (1.48), respectively. Plasma IGF-I and IGF-II levels were significantly reduced compared to controls. Height SDSCA or height velocity SDSCA did not correlate with either spontaneous or stimulated GH secretion, urinary GH excretion or plasma IGF-I or IGF-II levels. Our study indicates that 50-60% of children with short stature after intrauterine growth retardation have 24-hour GH profile abnormalities and/or subnormal responses to arginine provocation, while mean plasma IGF-I and IGF-II levels are significantly reduced, indicating GH insufficiency. Urinary GH excretion is lower in boys, but not in girls. The precise mechanism of the failure to catch up growth needs further elucidation. It seems justified to start clinical trials in order to investigate whether treatment with exogenous GH might be beneficial for these children.

The impact of gender and puberty on reference values for urinary growth hormone excretion: a study of 3 morning urine samples in 517 healthy children and adults.

Some recent studies have indicated that measurement of urinary GH (U-GH) excretion may be a useful tool for the evaluation of GH insufficiency in children with growth disorders, although some investigators are skeptical about the diagnostic value of U-GH. Most current assays are only available for specific laboratories or require time-intensive pretreatments of the specimens. This limits the possibility for many centers to compare their patients' data with others or to establish their own reference ranges for U-GH excretion. Therefore, we investigated the performance of a commercially available kit, which allows direct measurement of U-GH in untreated urine specimens. We established a reference range for the geometric mean of 3 morning urine samples in 446 healthy children and 71 adults. U-GH could be determined in all but 9 of 1526 samples (99.4%). U-GH excretion was significantly dependent on pubertal maturation (P < 0.001) and sex (P < 0.001), whereas age had no significant influence in the prepubertal group (P > 0.3). Peak values occurred in Tanner stages 3 and 4 (369 and 391 pg/h in females; 503 and 882 pg/h in males), corresponding to an age interval of 11-18 yr in boys and 9-15 yr in girls. Short collection periods (< 6 h) were related to low values for U-GH excretion (nanograms per night; P < 0.02). This time effect disappeared if U-GH excretion was expressed as picograms per h. If U-GH was related to creatinine output, there was a decrease in U-GH excretion during prepuberty, a blunting of the pubertal peak, and lower values in adults than in prepubertal children (P < 0.0002). The intraindividual variation in U-GH excretion (picograms per h) ranged from 40-61%, constituting approximately two thirds of the interindividual variation. This variation was not lowered by relating U-GH to creatinine. We conclude that the assay was suitable for measurement of U-GH excretion in virtually all healthy volunteers. Sex and pubertal stage as well as urinary volume and clock times for collection periods should be registered when establishing a reference range for U-GH excretion and applying it for clinical purposes. Our reference values may be useful for further studies of patients with GH disorders.

Metabolic clearance of recombinant human growth hormone in health and chronic renal failure.

Despite the increasing therapeutic use of recombinant human growth hormone (rhGH), its metabolic clearance has not been investigated in detail. To evaluate the kinetics of rhGH as a possible function of GH plasma concentration and glomerular filtration rate (GFR), we investigated the steady state metabolic clearance rate (MCR), disappearance half-life, and apparent volume of distribution of rhGH at low and high physiological as well as supraphysiological plasma GH levels during pharmacological suppression of endogenous GH secretion in human subjects with normal and reduced renal function. GH in plasma and urine was determined by an immunoradiometric assay, and GFR by inulin clearance. In all subjects MCR decreased and plasma half-life increased with increasing plasma GH concentrations (P < 0.001). MCR of rhGH was approximately half in patients with chronic renal failure at each GH level and plasma half-life was increased by 25-50%. Allowing for the linear dependence of MCR on GFR and assuming single-compartment distribution, the estimated renal fraction of total MCR was 25-53 and 4-15% in controls and patients, respectively. Saturation of extrarenal disposal of GH was suggested by an inverse hyperbolic relationship between extrarenal MCR and plasma GH concentrations in all subjects. Fractional GH excretion was up to 1,000-fold higher in patients than in controls. We conclude that MCR of hGH is a function of plasma GH concentrations and GFR. Extrarenal elimination is saturable in the upper physiological range of GH concentrations, whereas renal MCR is independent of plasma GH levels. The kidney handles GH like a microprotein involving glomerular filtration, tubular reabsorption, and urinary excretion.

Urinary growth hormone excretion in the assessment off children with disorders of growth

We wished to evaluate the use of urinary GH measurements when compared to conventional GH provocation tests in the assessment of short children. Children presenting for the first time to a regional growth clinic were assessed clinically by one observer. Investigations comprising standard GH provocation tests and measurement of urinary GH were undertaken to exclude GH deficiency. Fifty-eight children aged 5.8-16 years were enrolled. Ten were diagnosed on clinical assessment as GH deficient, 43 had delayed growth and/or familial short stature, and five had idiopathic short stature; the 48 children in the last two groups were defined as short normal. GH secretion was evaluated by two standard provocation tests and by the measurement of GH in five overnight urine collections. A normal peak GH concentration was defined as > 16 mU/l. The values for urinary GH excretion were compared to normal ranges (+/- 2 standard deviations from the mean), established in healthy schoolchildren of normal stature. All children considered GH deficient on clinical grounds had low peak GH concentrations on provocation tests, while 8/10 had low values of urinary GH excretion. All short normal children with normal peak GH concentrations (n = 36) on provocation tests and 11/12 children with low peak GH concentrations had urinary GH excretion within the normal range. There was therefore a significant difference in the classification of 'normal' GH secretion in the two tests. If the clinical diagnosis was used as the standard by which GH tests were judged, the predictive value of a positive urinary GH test in the diagnosis of GH deficiency was 89% compared with 45% for GH provocation tests.

Variability in the urinary excretion of growth hormone in children: a comparison with other urinary proteins

As a basis for assessment of the clinical validity of urinary GH (uGH) measurements in children, the day-to-day variability in renal handling of GH has been compared with that of albumin, N-acetylglucosaminidase (NAG) and creatinine. Five overnight urine specimens were collected over a 2-week period from 78 healthy children (aged 5-16 years), 20 of normal stature and 58 with growth disorders; ten children were classified as GH-deficient (GHD) and 48 were designated short normal (SN). The variability of excretion of each substance was expressed as a coefficient of variation (C.V.) which was not influenced by expressing the urine results as total mass excreted, concentration, excretion rate or as a ratio to creatinine. There was considerable night-to-night variability in the excretion of all substances (mean C.V. values for all groups: 56% for albumin, 41% for GH, 33% for NAG and 27% for creatinine). No differences were found in the variability of GH excretion between males and females, nor between prepubertal and pubertal subjects. The mean C.V. for uGH excretion ranged from 37% in normal and 35% in SN children to 52% in those with GHD (P < 0.05). Assay variation rather than a change in renal protein handling accounted for the large variations in uGH concentrations of < 5 pg/ml, thus contributing to the high uGH C.V. of the GHD group.(ABSTRACT TRUNCATED AT 250 WORDS)

Maturational changes of urinary growth hormone excretion in the premature infant.

High plasma GH concentrations are observed in the newborn infant. To characterize the maturational change of GH secretion in premature infants, we serially measured 24-h urinary GH excretion in 30 premature infants. The gestational age ranged from 25-37 weeks and birth weight from 468-2415 g. Urinary GH excretion at 1 week of age was negatively correlated with gestational age, birth weight, and length of infants with adequate intrauterine growth. In the infants with 27 weeks of mean gestation (range, 25-28 weeks) mean urinary GH excretion was highest (6.1 micrograms/day) at the first week, decreased to 1.2 micrograms/day by the fourth week, and remained between 0.05 and 0.18 micrograms/day thereafter. When compared to the corresponding conceptional age, there was no postnatal difference in the pattern of GH excretion between infants with 27 and 31 (range, 29-32) weeks of mean gestational age. Persistent hyperexcretion of GH was observed in 4 of the 5 infants with intrauterine or postnatal growth retardation. Our results suggest that the postnatal change of 24-h urinary GH excretion is similar to ontogenic changes of plasma GH in fetus, and GH may have some effects on postnatal growth in premature infants.

VARIABILITY IN THE URINARY EXCRETION OF GROWTH HORMONE (GH) AND CREATININE IN CHILDHOOD

As a basis for assessment of the clinical validity of urinary GH measurements in children, the variability in renal handling of GH was compared to that of creatinine in 93 healthy children (aged 4-16 years), 20 of normal stature and 73 with growth disorders. 10 were classified as GH deficient (GHD), 48 as short normal (SN) and 15 had Turner syndrome (TS). 5 overnight urine samples were collected over 2 weeks, and the variability of excretion expressed as a coefficient of variation (CV) of the total overnight amount of GH or creatinine. There was considerable night to night variability in the excretion of both substances:* p<0.05 compared to Normal + SN, #p<0.05 compared to Normal.Assay variation rather than a change in renal protein handling accounted for the large variation in low uGH concentrations, thus contributing to the high uGH CV of the GHD group. Increasing the number of samples collected (upto 5) decreased the expected sample variation (error) for uGH but not significantly in all groups, and reduced the convenience and practicality of the test. These results indicate that variation in GH and creatinine excretion is considerable in both normal children and those with growth disorders. The use of multiple samples (upto 5) does not significantly reduce the variability inherent in uGH measurement.

GLOMERULAR FILTRATION RATE (GFR) DETERMINES METABOLIC CLEARANCE RATE (MCR) OF HGH

Supraphysiological doses of rhGH are used for treatment of renal growth failure. Because of reduced renal MCR of rhGH this may result in accumulation of rhGH. To determine the quanlity of renal and extrarenal MCR of rhGH in chronic renal failure (CRF) we performed stepwise steady-state infusion studies of rhGH in 12 patients (pts) with CRF (6 adults, 6 children; GFR range 8 to 44 ml/min × 1.73 m2) and 24 healthy adult controls (Co). Endogenous GH secretion was suppressed by i.v. infusion of octreoude (2 ug/1.73 m2 × h). HGH was infused at three different rates, resulting in mean plasma levels of 5 (I), 30 (II) and 57 (III) ug/l. GFR was measured by simultaneous inulin clearance. Plasma and urin hGH concentrations were measured by monoclonal IRMA. - MCR of rhGH was significantly reduced in pts compared to Co at each infusion rate (I: 139 ± 65 vs 207 ± 61, p < .01; II: 76 ±35 vs 124 ± 22, p< .001; III: 58± 15 vs 113 ± 17, p < .001 ml/min × m2). In both pts and Co MCR decreased significantly with increasing GH plasma concentrations (p < .01). MCR was correlated to GFR (r = 0.86, p< .001). Calculated extrarenal MCR did not differ between pts and Co at any given GH plasma concentration. T 1/2 was significantly prolonged in pts compared to Co (I: 22 ± 9 vs 13 ± 4, p < .01; II: 27 ± 6 vs 18 ± 5, p< .001; III: 30 ± 6 vs 21 ± 4, p < .001 min). In Co urinary GH excretion was dose dependent but minimal and urinary excretion fraction (0.1 × 10−4) remained constant.Conclusions: (I) In Co renal MCR and rhGH amounts 10 about 50 % of total MCR. (II) Renal and total MCR is correlated to GFR. (III) Extrarenal MCR does not increase if renal MCR is low. (IV) In Co and pts MCR is inversely correlated to GH plasma concentration, pointing to extrarenal saturation mechanisms. (V) Adjustment of rhGH doses to GFR should be considered in CRF.

Urinary excretion of GH in healthy individuals and patients with acromegaly, hypopituitarism and dwarfism

Urinary GH excretion reflects average plasma levels. Using a highly sensitive sandwich enzyme immunoassay we determined GH concentrations in the 24 h accumulated urine samples of 54 healthy persons (aged 1.5-90 years), 8 acromegalic patients, 4 acromegalic patients after enucleation of a GH-producing adenoma, 8 patients with partial hypopituitarism and in first morning urine and 12 h accumulated daytime urine of 4 healthy children and 3 children with growth failure. GH secretion is age-dependent, with high rates between ages 1 and 20 (ages 0-20 years: 10.4 ng/g creatinine +/- 6.3 vs age > 20-75 years: 3.1 ng/g creatinine +/- 1.6). An age-dependent increase in urinary GH is found in the pubertal age group (10 ng/24 h +/- 6.8 vs prepubertal group: 4.6 ng/24 h +/- 2.95). GH excretion of patients with acromegaly differs significantly from healthy subjects (72 ng/24 h +/- 49 vs 3.9 ng/24 h +/- 2.3). After a successful operation, acromegalic patients do not differ from the collective norm. Six of 8 patients with partial hypopituitarism show lower GH concentrations in urine than healthy subjects (1.2 ng/l +/- 0.2 vs 2.6 ng/l +/- 1.2), but daily GH output does not differ, since significantly more urine is then excreted. At night, healthy children secrete significantly more GH than during the day (night: 0.16 ng.kg-1 x (12 h)-1 +/- 0.02 vs day: 0.07 ng.kg-1 x (12 h)-1 +/- 0.03), while output is the same for GH-deficient children. Both groups have similar GH daytime output, but GH-deficient children have significantly less nocturnal output.(ABSTRACT TRUNCATED AT 250 WORDS)

Low urinary growth hormone values in patients with Turner's syndrome.

Short stature is one of the major symptoms in Turner's syndrome (TS). The cause of short stature is not clearly known at present. In this study we initially assessed GH secretory status in TS by determinations of urinary human (h) GH excretion for 2 consecutive days. Secondly, the therapeutic dose of hGH used for treatment of short stature in TS was evaluated by measurements of urinary hGH after recombinant hGH (r-hGH) injections. Twenty-four-hour urinary hGH excretion for the 2 days combined was significantly lower in patients with TS than in normal children [2.3 +/- 1.8 ng/day (n = 7) vs. 13.4 +/- 3.2 (n = 16); P less than 0.001], although four of seven patients with TS had normal GH responses to the provocative tests. The mean level of urinary hGH in TS after 2 days was comparable to that in complete GH deficiency (1.9 +/- 0.9 ng/day; n = 14) that we previously reported. Treatment with daily sc injections of 1.0 IU (0.37 mg)/kg.week r-hGH, given in seven divided doses, normalized urinary hGH excretion and induced remarkable catch-up growth in all patients with TS. These results indicate that the 24-h endogenous GH secretion in seven patients with TS is impaired. The measurement of 24-h urinary hGH excretion may prove to be useful as a marker to assess the abnormal GH secretion and the adequacy of treatment with hGH in patients with TS. The therapeutic dose of hGH in TS is approximately 0.37 mg/kg.week, given in seven divided doses. To convert international units of r-hGH to milligrams, divide by 2.7.

Urinary Growth Hormone Excretion During Puberty in Type 1 (Insulin‐dependent) Diabetes Mellitus

The excretion of urinary growth hormone was measured by a highly sensitive direct immunoradiometric assay in a cross-sectional study during puberty in 70 children with Type 1 (insulin-dependent) diabetes mellitus and 94 normal children. In normal children (n = 24) and diabetic children (n = 17) overnight urinary growth hormone excretion correlated significantly with the mean overnight plasma concentration (r = 0.70, p less than 0.001, and r = 0.70, p less than 0.001), indicating that urinary GH excretion reflects the circulating endogenous GH level. Overnight urinary growth hormone excretion increased during puberty. In normal and in diabetic children there was a peak in boys at genital stage 4 (both p less than 0.01), and in girls at breast stage 2 (both p less than 0.02). The diabetic children excreted more urinary growth hormone than the normal children at every pubertal stage. Excretion of albumin, retinol binding protein and N-acetyl-beta-D-glucosaminidase was measured in urine from 38 diabetic children. Urinary growth hormone correlated weakly with urinary albumin (r = 0.49, p less than 0.01), retinol binding protein (r = 0.42, p less than 0.01), and N-acetyl-beta-D-glucosaminidase (r = 0.43, p less than 0.01). Urinary GH excretion was not related to blood glucose control (HbA1) in boys (n = 31) or girls (n = 39). The measurement of urinary growth hormone provides an assessment of endogenous growth hormone during puberty in normal and diabetic children. However, caution must be exercised in interpreting urinary growth hormone data from diabetic patients with increased excretion of albumin and retinol binding protein.

A Case of Dwarfism with Severely Reduced Activity of Growth Hormone-Binding Protein

We presented a 16-year-old boy with severe growth retardation and markedly decreased levels of growth hormone-binding protein (GHBP) in plasma, which was shown to correspond to the extracellular composition of hepatic GH receptor and suggested to reflect tissue concentration of the receptor. His height was 92.5 cm (-13.5 SD), the weight 9.6kg (-5.8 SD) and Tanner stage was I. His bone age was 3.5 years old at 16 years of age. Karyotype was 46,XY and thyroid function was normal. SM-C levels, determined by Nichols RIA using unextracted plasma, were within the low normal range, 0.67/0.68U/ml. In contrast, using a method of acid-ethanol extraction, IGF-I and IGF-II levels were definitely low, 29ng/ml (normal 88-240) and 165ng/ml (374-804) respectively. GH responses in various provocation tests, including insulin, arginine and GRF, were within normal. Basal GH levels were 20 +/- 12ng/ml and urinary GH excretion rates 217 +/- 85pg/mg. Cr, which were elevated compared to age-matched control. Molecular size of his circulating GH was similar to control subjects. The biological activities of GH, evaluated by radioreceptor assay and Nb2 cell bioassay, were proportional to the immunoactivities of GH. SM bioactivities, which were determined by the stimulatory effects on DNA synthesis of rabbit costal chondrocytes and human fibroblasts, were apparently reduced. Electrophoretic patterns of IGF-binding protein was similar to those of GH deficient cases. Daily administration of hGH (4U/day) for 5 days resulted in a poor response of SM-C production (before 0.68, after 0.77U/ml). GHBP activities were definitely low by gel-filtration, immunoprecipitation and charcoal methods, as seen in Laron dwarfism which is defined as a syndrome of congenital GH receptor defects. These results indicate that the tissue content of GH receptor in this case was quantitatively reduced and as a result, he showed a resistance to endogenous and exogenous GH. It remains to be elucidated whether the GH receptor defect in our case is derived from a genetic origin or an acquired condition.

Secretory Dynamics of Growth Hormone in an Acromegalic Patient Associated with Graves' Disease*

The dynamics of GH secretion were investigated in an acromegalic patient with Graves' disease during treatment with antithyroid drugs and radioactive iodine. The mean (+/- SE) basal plasma GH levels were 16.5 +/- 0.9 and 7.8 +/- 0.7 micrograms/L during the hyperthyroid and euthyroid states, respectively. There was a positive correlation (r = 0.902) between basal GH and free T4 levels. Twenty-four-hour plasma GH and urinary GH excretion both increased during the thyrotoxic state. Intravenous administration of TRH induced a marked increase in plasma GH levels during euthyroidism and a modest increase when the patient was hyperthyroid, whereas GH release induced by GH-releasing hormone was not altered by thyroid status. These findings suggest that hyperthyroidism stimulated spontaneous GH secretion from the pituitary adenoma, but inhibited the stimulating effect of TRH.

Correlation of Urinary Albumin andβ-2-Microglobulin and Growth Hormone Excretion in Patients with Diabetes Mellitus and Short Stature*

We examined the correlation between urinary GH, urinary albumin, and beta-2-microglobulin excretion to determine how the excretion of GH relates to markers of renal glomerular and tubular function. Urinary albumin and GH excretion was determined in timed daytime and nighttime urine collections obtained from both subjects with diabetes mellitus and subjects with short stature. For subjects with diabetes, urinary GH excretion rate correlated highly with urinary albumin concentration and excretion rate in both the range of 0 to 1.6 g/L (r = 0.75), P less than 0.001) and in the microalbuminuria range, 0 to 0.4 g/L (r = 0.53, P less than 0.001). Changes in GH and albumin excretion occurred in parallel in 71% of the subjects with diabetes and elevated albumin excretion. The mean GH excretion rate was higher in the group with elevated albumin excretion rate (AER) during both day and night compared to the group with microalbuminuria during the day and normal AER at night. For subjects with short stature, the mean albumin excretion rate was 0.7 +/- 1.3 micrograms/min (range 0.05-8.3 micrograms/min) using a sensitive enzyme-linked immunosorbent assay to measure albumin concentration. The correlation of GH and albumin excretion rates for the subjects with short stature was not statistically significant (r = 0.14, P less than 0.5). About half of the subjects with diabetes and elevated AER (greater than 10 micrograms/min) had a GH excretion rate within the range observed in subjects with short stature. The GH and albumin excretion rate were not correlated in this group. There was a positive correlation of both albumin and GH excretion rate with age in the subjects with diabetes. Urinary GH and beta-2-microglobulin excretion rates were determined in a larger group of subjects with diabetes and a separate group with short stature. Urinary GH and beta-2-microglobulin excretion were correlated both in subjects with diabetes (r = 0.46, P less than 0.001) and with short stature (r = 0.64, P less than 0.001). The association was present in urine collected either during the day or night. The mean GH excretion rate of the group with diabetes was greater than the group with short stature. In conclusion, there was an association of urinary GH and albumin excretion rate in subjects with abnormal glomerular function as indicated by elevated albumin excretion rate. An association of urinary GH and beta-2-microglobulin excretion was observed in subjects with normal tubular function.(ABSTRACT TRUNCATED AT 400 WORDS)

Twenty-Four-Hour Plasma Growth Hormone (GH) Profiles, Urinary GH Excretion, and Plasma Insulin-Like Growth Factor-I and -II Levels in Prepubertal Children with Chronic Renal Insufficiency and Severe Growth Retardation*

We studied 24-h plasma GH profiles, maximal GH responses to arginine provocation and insulin-like growth factor-I (IGF-I) and IGF-II levels in plasma in 22 euthyroid prepubertal children (mean age, 9.5 yr) with chronic renal insufficiency (glomerular filtration rate, less than 20 mL/min.1.73 m2) and severe growth retardation [mean (+/- SD) height SD score (SDS), -2.8 (1.1)]. The 24-h GH profiles were analyzed using the Pulsar program. Girls had significantly higher 24-h GH secretion than boys (P less than 0.004). Children with end-stage nephrotic syndrome had higher baseline GH levels and total area under the curve (AUCo) than patients with dysplastic kidneys (P less than 0.05), while the area under the curve above baseline (AUCb) was similar in all types of renal diseases. The type of treatment (conservative, peritoneal, hemodialysis) did not significantly influence the 24-h GH secretion. No correlation was found between 24-h GH profiles and age, height SDS for chronological age, height velocity SDS for bone age, and weight for height. Fourteen children showed a normal 24-h GH profile, defined as a GH profile with well defined, regular GH peaks returning to baseline GH levels and a distinct day and night pattern (AUCb, 90-300 micrograms/L.24 h). Four children had low profiles, with GH peaks below 10 micrograms/L, returning to baseline GH levels and occurring almost exclusively during the night (AUCb, less than 90 micrograms/L.24 h). The remaining four children had elevated 24-h GH profiles, with GH peaks on top of elevated baseline GH levels of more than 3 micrograms/L (AUCb, 35-205 micrograms/L.24 h; AUCo greater than 300 micrograms/L.24 h). In all patients 24-h urinary GH and beta 2-globulin excretion was 100-1000 times higher than that in controls. The urinary GH excretion correlated significantly with all characteristics of the 24-h GH profiles (r = 0.57-0.59; P less than 0.05). The maximal GH response during the arginine tolerance test was normal in 66% of the children. The mean (+/- SD) SDS for bone age for the IGF-I plasma levels was +1.1 (1.9), and that for IGF-II was +3.6 (3.4). IGF-I levels correlated significantly with the AUCb, maximum GH, and GH peak characteristics of the 24-h GH profiles (r = 0.05-0.73; P less than 0.02-0.001). IGF-II levels did not show any correlation with the characteristics of the endogenous GH secretion.(ABSTRACT TRUNCATED AT 400 WORDS)

OVERNIGHT URINARY GROWTH HORMONE MEASUREMENT IN THE DIAGNOSIS OF ACROMEGALY

Several studies report higher urinary GH excretion in acromegalic patients compared to control subjects. We investigated the diagnostic potential of overnight urinary GH excretion in acromegaly, using a recently developed enzyme-linked immunosorbent assay. Overnight urine samples were obtained from 117 control subjects and nine patients with untreated acromegaly. GH excretion was higher in acromegalic patients compared to control subjects, with geometric mean total overnight values of 46.35 and 5.73 microU respectively. The range for total overnight urinary GH in control subjects was 0.75-21.75 microU and two of the nine patients with untreated acromegaly had GH measurements within this range. Urinary GH measurements were corrected using predictive clinical variables but this resulted in minimal improvement in discrimination between control subjects and acromegalic patients. Lack of complete discrimination between control subjects and acromegalic patients limits the usefulness of a single overnight urinary GH measurement as a screening test for acromegaly.

Urinary excretion of human growth hormone: daily variation and relationship with albumin and α1-microglobulin in urine

Urinary excretion of growth hormone during night-time was measured by a highly sensitive enzyme immunoassay in 6 normal men for 18-24 days. Urinary GH excretion distributed widely from 0.12 to 4.7 pg/mumol creatinine and the coefficient of variation in each subject ranged from 37 to 57% (mean 49%). Urinary excretion of albumin and alpha 1-microglobulin also showed moderate day-to-day variations (mean coefficients of variation: 37 and 42%, respectively). No correlation was found among urinary excretion of GH, albumin and alpha 1-microglobulin. Plasma and urinary GH levels were determined every 5 min and 2 h, respectively, from 09.00 h to 17.00 h in 4 normal men. Urinary GH excretion every 2 h during daytime closely reflected the change of plasma GH levels in each subject, suggesting that physiological GH secretory dynamics are reflected on the urinary GH excretion. Repeated measurements of urinary GH excretion are required to evaluate GH secretory capacity.

Urinary growth hormone during puberty in normal and diabetic children.

The measurement of GH in urine may have many clinical applications, particularly in childhood. We have used a highly sensitive direct immunoradiometric assay to examine urinary GH excretion in children during puberty. Fifty-five healthy schoolchildren collected timed overnight urine samples. A further 36 children (15 normal, six of short stature and 15 diabetic) collected urine samples during a total of 50 overnight plasma GH secretory profiles (15-min sampling). Overnight urinary GH excretion increased during puberty, with a peak at breast stage 2 in girls, and genital stage 4 in boys, before declining at stage 5. There was a positive correlation (r = 0.57, p = 0.003) with height velocity in girls, but not in boys. At each puberty stage except 2, the diabetics excreted more urinary GH than the normal children. There was a highly significant correlation (r = 0.79, p less than 0.001) between mean overnight plasma GH concentrations and urinary GH excretion, suggesting that the latter accurately reflects physiological GH secretion.

91 URINARY GROWTH HORMONE (GH) – CLINICAL APPLICATION

A radiometric assay for GH was applied to unprocessed urine (technical details previously described). A significant correlation between plasma profiles and urinary GH excretion has been found (i.e. 24 h plasma integrated concentrations (IC) to urine pg/24 h, r = 0.45. Plasma IC 24 h to night urine GH/creatinine 0.69, night plasma IC to night urine 0.58, for all correlations N = 40). In 155 24 h-urines of “normal” children (partly referred for suspected growth problems), a mean GH-excretion of 6.2 ± 6.5 ng/24 h (median 4.1, P. 10 1.3, P. 90 13.6) has been found. No clear relation was found to chronological age, bone age or puberty ratings. 10 patients with “precocious puberty” (5 idiopathic, 5 treated CAH) had a mean excretion of 9.7 ± 5.4 (median 8.4, P. 10 4.6, P. 90 19). In active acromegaly, the values varied from 73 to 500 ng/24 h. Patients with “complete” (N = 9) and “partial” (N = 7) GH-deficiency had a mean (median) excretion of 0.79 (0.75) and 3.3 (1.8) ng/24 h off therapy. The values increased to 6.2 (3.8) and 11.3 (10.5) ng/24 h during therapy (2 IU daily s.c). Before more conclusions can be drawn, the important intraindividual variation of GH-excretion has to be considered. Nevertheless, urinary GH mirrors an actual GH-production over a set time and can be applied to clinical states with suspected “abnormal” GH-production or for therapy survey.

90 DOSE URINARY GROWTH HROMONE (GH) REFLECT PLASMA GROWTH GORMONE LEVELS?

In 40 children, a 24 h-plasma GH profile has been compared to urinary GH excretion. Plasma was assayed with a conventional radioimmnunoassay (kit CEA). For urine, a radiometric assay has been developed with a solid-phase goat antibody for immunextraction and a I125 monoclonal antibody for quantification. The assay is insensitive to pH 5-8, NaCl/urea 0.1-0.5 mol and to sample volumes up to 10 ml. The sensitivity of 2 pg in the standard results in a detection limit of 1 pg/ml, if 2.5 ml of urine are used. Coefficients of variation are 10-14% for inter-, and 2.5-3.5% for intra-assay. Plasma GH was expressed as integrated concentration (IC, ng/ml/h) per 24 h or night/day periods, urinary GH as pg per 24 h or night/day and was related to creatinine. 1) Correlations for plasma were: IC 24 h to a) IC night 0.93, b) IC day 0.77. 2) Correlations for urine (± creatinine): 24 h to a) day 0.73, b) night 0.8, 24 h/cr. to a) day/cr. 0.53, b) night/cr. 0.83. 3) Correlations for plasma to urine: Plasma IC 24 h to a) urine 24 h 0.45, b) urine 24 h/cr. 0.60, c) urine night/cr. 0.69. It can thus be concluded that urinary GH reflects plasma levels and a daily GH-production. GH-assays in urine are an additional help for the diagnosis of states of deficiency or excess and for the control of suppressive or stimulating therapies.