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.     

Nocturnal urinary growth hormone excretion in children with short stature

Nocturnal urinary growth hormone levels in children with short and normal stature were measured by a sensitive enzyme immunoassay. Urinary GH excretion during sleep correlated positively with peak plasma GH values during pharmacological (r = 0.74, P less than 0.001) and sleep (r = 0.85, P less than 0.001) tests. The amounts of urinary GH excretion during sleep differed significantly from each other in the following groups: complete GH deficiency (mean +/- SEM: 0.1 +/- 0.1 ng/m2 of body surface area; range: less than 0.1-0.4), partial GH deficiency (1.6 +/- 0.3 ng/m2; 0.2-3.1), and short stature without GH deficiency (3.7 +/- 0.6 ng/m2; 0.7-11.5). No significant difference was found between short stature without GH deficiency and normal stature (5.0 +/- 0.5 ng/m2; 2.1-10.5). Measurement of nocturnal urinary GH excretion is a simple method for screening of GH excretion and may be helpful in the differentiation of the various etiologies of short stature in children.     

Treatment of Turner's syndrome with methionyl human growth hormone for six months

Twenty patients with Turner's syndrome were treated with methionyl human growth hormone (met-hGH) produced by recombinant DNA technology. Plasma non-esterified fatty acid (NEFA) (mean +/- SEM) increased significantly from 0.52 +/- 0.06 to 1.30 +/- 0.09 mEq/l at 4 h after the first administration of 4 IU of met-hGH (P less than 0.001). Basal plasma somatomedin C (SM) levels were within the normal range; however, they increased significantly at 24 h after the first three daily injections of 4 IU of met-hGH (basal, 0.92 +/- 0.14; 24 h, 1.39 +/- 0.16; 48 h, 1.68 +/- 0.19; 72 h, 1.91 +/- 0.22 U/ml; P less than 0.001). For long-term treatment, the patients were given 16 IU of met-hGH per week for 6 months. The height increase during treatment was greater in 16 patients, but smaller in 4 than before treatment. The heights increased between 1.4 and 3.7 cm during 6 months of treatment, which corresponds to between 2.8 and 7.4 cm/year. The mean increase of 5.7 +/- 0.4 cm/year was greater than the pretreatment value of 3.7 +/- 0.2 cm/year (P less than 0.001). There was a positive correlation between growth rate and maximum increase in SM (r = 0.51, P less than 0.05). Antibody against hGH appeared in 3 patients after 2 months; 10 of the 20 patients had antibody after 6 months of treatment. However, the antibody did not suppress the growth effect of met-hGH. Otherwise there were no significant changes in physical, blood, or urine examinations. These results indicate that hGH treatment is useful for the acceleration of growth velocity in patients with Turner's syndrome.     

Urinary growth hormone (GH) measurements are useful for evaluating endogenous GH secretion

Daily (24-h) urinary GH excretion was measured using a highly sensitive sandwich enzyme immunoassay in 10 normal adults, 6 patients with hypopituitarism, 25 normal but short children who had normal plasma GH responses (peak plasma GH level, greater than 10 micrograms/L) to provocative tests, and 8 patients with acromegaly. The mean urinary GH values in the normal adults, patients with acromegaly, and patients with hypopituitarism were 13.8 +/- 4.0 (+/- SE) and 431.1 +/- 149.1 ng/g creatinine (Cr) (1.56 +/- 0.45 and 48.77 +/- 16.87 ng/mmol Cr) and undetectable, respectively; these mean values were significantly different from each other. In the normal but short children the urinary values ranged from undetectable to 55.8 ng/g Cr (6.31 ng/mmol Cr). All of the normal but short children and 4 patients with hypopituitarism participated in a 24-h endogenous GH secretion study. The urinary GH values correlated significantly with the mean 24-h plasma GH concentrations as an index of endogenous GH secretion (r = 0.81; P less than 0.001) and plasma somatomedin-C levels (r = 0.67; P less than 0.001), respectively. In 6 patients with acromegaly whose plasma GH levels were constant throughout a 4-h period, the urinary GH values also significantly correlated with the mean plasma GH levels (r = 0.95; P less than 0.01). These data indicate that urinary GH measurements reflect endogenous GH secretion and that measurement of urinary GH excretion is a useful, simple, and practical method for evaluating endogenous GH secretion.     

Plasma lipotropin increase in man after growth hormone administration. Comparison between extractive and biosynthetic hormones

The action of human growth hormone (hGH) on plasma lipotropins (beta-and gamma-LPH) in 15 GH deficient patients was studied by comparing the effects induced by the acute administration of the extracted and biosynthetic molecules. The purified extracted preparation (6 mg/m2 im) induced a dramatic rise in plasma LPH: basal (49 +/- 12 pg/ml (mean +/- SEM); peak 1,658 +/- 262 pg/ml. The same dose of biosynthetic methionyl-hGH (met-hGH) induced no significant change in plasma LPH. Both preparations caused identical plasma GH increases. Six different commercially available extracted hGH preparations (Choay, France; Serono, Italy; France Hypophyse, France; Kabi, Sweden; Nordisk, Denmark; International Standard, Great Britain) all showed definite cross-reactivity in the LPH radioimmunoasay, varying from 0.1 to 1.0%, on a weight basis. No cross reactivity was found with met-hGH (less than 0.0001%). On gel exclusion chromatography, the LPH immunoreactivity of the purified preparations was dissociated from the GH immunoreactivity and eluted at the position of beta-and gamma-LPH. These data show that extracted hGH preparations are all contaminated with LPH and raise the question of the possible consequences of chronically elevated plasma LPH in treated patients. The use of biosynthetic met-hGH should prevent this occurence.     

15N tracer techniques for the differential diagnosis of dwarfism and prediction of growth hormone action in children

[15N]Glycine in a single oral dose was used to study nitrogen turnover in 18 short children, aged 3-14 yr. On the basis of their serum GH responses to insulin-induced hypoglycemia, the patients were divided into 3 groups: complete GH deficiency (GHD; n = 5); partial GH deficiency (pGHD; n = 6), and children with constitutional growth delay and familial short stature (CGD/FSS; n = 7). The mean 48-h renal excretion of 15N by patients with GHD was 66.09 +/- 14.12% (+/- SD) of the tracer dose. This decreased to 27.64 +/- 5.33% after two injections of 10 IU/m2 GH (P less than 0.001). 15N excretion by patients with pGHD was 47.19 +/- 13.42%, and it decreased after GH injection to 22.69 +/- 4.58% (P less than 0.005). Patients with CGD/FSS had 15N excretion of 37.27 +/- 5.68%, and it did not change in response to GH. The mean protein synthesis rate in GHD patients was extremely low, and it increased after GH injection from 0.99 +/- 0.46 to 3.53 +/- 0.43 g/kg X day. In pGHD patients the protein synthesis rate increased from 2.62 +/- 0.84 to 4.50 +/- 1.09 g/kg X day. The CGD/FSS patients had no change in protein synthesis rate after GH. Our results suggest that studies of the metabolism of [15N]glycine might be of value in predicting responsiveness to GH therapy.     

Subcutaneous degradation of biosynthetic human growth hormone in growth hormone deficient patients

The aim of the present study was to look further into the question of local degradation of sc injected human GH in GH deficient patients. A comparison was made of serum GH levels after constant iv and sc infusion of the same amount of GH (33 ng.kg-1.min-1) in the same 9 GH deficient patients. A 3-h lag period was interposed between the iv and the sc infusion. Iv infusion was continued for 3 h. All 9 subjects subsequently received sc infusion for 19 h and five of them continued for additionally 24 h. The mean steady state serum GH level in the nine patients was 23.1 +/- 5.1 micrograms/l after iv and 6.8 +/- micrograms/l after sc administration (P less than 0.01). Extension of the sc infusion period in 4 of the subjects did not significantly alter the serum GH level (P less than 0.15), implying that a steady state was reached. The GH in the infusion system was stable throughout a 24-h period. We therefore conclude that sc injected GH is degraded locally to a substantial extent.     

The level of bioavailable growth hormone (GH) after the first GH injection predicts the first year's growth response in GH-deficient children

Serum GH levels were measured in 9 prepubertal children with growth hormone (GH) deficiency using an immunofluorometric assay (IFMA) and a Nb2 cell bioassay, prior to and 2, 4, 6 and 12 hours after the first hGH subcutaneous injection (sc) (0.1 IU/Kg). After this first acute phase, hGH treatment was continued regularly at a dose of 0.1 IU/kg per day at bedtime. The acute pharmacokinetic profile was similar in the patients irrespectively of the assay used: serum GH usually starts to rise after 2 hours, peaks by 4 or 6 hours and drops back to near baseline levels 12 hours after s.c. GH administration. A great variation in the amplitude of peak levels was observed among the patients. The assays significantly (p<0.0001) correlate with each other in all subjects. An increase in serum GH values as evaluated by the Nb2 bioassay was observed in most children after s.c. GH injection, suggesting that the administered hormone preserves its biological activity. The individual variations in GH bioactivity in our GH-deficient children could be due to different mechanisms of the drug's degradation at the site of injection or in circulation. Pre-treatment height velocity calculated as standard deviation scores (SDS) significantly increased (p<0.001) from -2.77+/-0.42 to 1.22+/-0.87 SDS after a 12-month period of GH treatment in 8 patients who had already completed the first year of therapy, although it varied considerably among subjects. A higher serum GH peak value evaluated by both assays corresponded to a higher growth response during the 1st year, but not in the 2nd year of GH therapy. In conclusion, the degree of GH bioactivity released into circulation after sc GH injection may vary considerably among GHD patients and correlates with the growth response observed during the 1st year of GH therapy.     

Short-term met-hGH infusion inhibits somatotroph response to growth hormone releasing hormone (1-44)

To determine whether the short-term administration of growth hormone inhibits pituitary responsiveness to h-GHRH we measured the somatotroph response to h-GHRH-44 (0.3 micrograms/kg) stimulation in ten normal subjects from the third to the fifth hour of an infusion of met-hGH (2 micrograms/kg/h) or saline. Insulin, insulin-like growth factors (IGF), somatomedins, free fatty acids (FFA), glycerol, and glucose levels also were assessed during the first 3 hours of infusion. Steady-state GH levels of 5 to 20 ng/mL were achieved during met-hGH infusion. No significant changes in IGF, insulin, or glucose levels measured at the beginning and again after three hours of infusion occurred within or between conditions. Infusion of met-hGH was associated with a significantly greater increase in FFA levels (69 +/- 50 mumol/L following saline v 433 +/- 57 mumol/L following three hours of met-hGH infusion (P less than .001)). The somatotroph response to h-GHRH-44 was significantly blunted during met-hGH infusion (incremental area under the GH/time curve decreasing from 1,196 +/- 183 (ng/mL) X min to 380 +/- 139 (ng/mL) X min (P less than .005)). These data demonstrate that this blunting can occur following short-term exogenous GH administration and at serum GH levels comparable to those achieved during naturally occurring bursts of GH secretion. They also suggest that acute mediation of GH release must occur, at least in part, at the pituitary somatotroph level and that IGFs and/or insulin may not be the primary inhibitors. This phenomenon may be directly or indirectly due to GH-dependent metabolic factors such as FFA or glycerol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Quantitation of urinary somatomedin-C and growth hormone in preterm and fullterm infants and normal children

Urinary GH and somatomedin-C/insulin-like growth factor I (Sm-C/IGF-I) excretion were measured in 12-h urine collections obtained from 43 infants (27 stable preterm infants and 16 healthy fullterm infants) and 31 normal children, aged 3-17 yr. Urinary Sm-C/IGF-I was excreted as the free hormone, since no binding of radiolabeled Sm-C/IGF-I to any urine protein with a mol wt similar to those described for plasma Sm-C/IGF-I-binding proteins was found. The preterm infants excreted significantly more urinary GH [13.5 +/- 2.1 (+/- SE) ng/kg.12 h] than either the fullterm infants (5.3 +/- 1.6 ng/kg.12h) or the children (0.27 +/- 0.02 ng/kg.12 h; P less than 0.01). The mean urinary Sm-C/IGF-I excretion in the preterm infants (98.9 +/- 7.5 mU/kg.12 h) was comparable to that in fullterm infants (87.6 +/- 9.7 mU/kg.12 h); both groups excreted significantly more urinary Sm-C/IGF-I than children (28.4 +/- 2.1 mU/kg.12 h; P less than 0.01). The group differences were similar when the results were expressed in terms of creatinine excretion. Urinary GH excretion correlated positively with urinary Sm-C/IGF-I excretion (r = 0.68). The higher output of these peptides in rapidly growing infants and their positive correlation in urine provide additional support for the Sm hypothesis.     

Endogenous growth hormone (GH) secretion in male rats is synchronized to pulsatile GH infusions given at 3-hour intervals

The feedback effects of GH on its own secretion were studied in conscious male rats receiving intermittent iv infusions of human GH. Male Sprague-Dawley rats (150-180 g) were implanted with double bore iv cannula. Infusions of human GH (hGH) or buffer were given for up to 32 h, while frequent microsamples (20 microliters) of blood were withdrawn simultaneously using an automatic blood-sampling system. The endogenous GH pulses became synchronized to pulsatile hGH infusions (2.1 U/kg.infusion) given at 3-h intervals. After two or more hGH infusions episodic GH release was present in most rats, and all endogenous pulses occurred concomitantly with the hGH infusions. After 24 h of hGH treatment the endogenous pulses were still synchronized to the every 3 h hGH infusions. In addition, the pulse amplitude was lower than that in vehicle-treated animals (74 +/- 12 vs. 215 +/- 35 ng/ml; P less than 0.01). At this time a complete (1.5-h) phase shift of the 3-hourly hGH infusions markedly suppressed endogenous GH pulses in all rats. In another experiment where the same daily dose of hGH was given in iv infusions every 1.5 h instead of every 3 h, the endogenous GH pulses were irregular, infrequent, and suppressed. Infusions at 3-h intervals of a lower dose of hGH (0.42 U/kg.infusion) did not affect the timing or amplitude of endogenous GH pulses compared to those in buffer-infused animals. The endogenous GH pulses were not synchronized between animals given 0.42 U/kg hGH or buffer at 3-h intervals. It is concluded that the endogenous GH pulses in male rats became synchronized to intermittent infusions of hGH at 3-h (but not 1.5-h) intervals. The fact that there were no endogenous pulses between the 3-hourly infusions suggests that the feedback effect of a GH pulse lasts for approximately 3 h. This mechanism may be involved in the control of the GH secretory pattern in male rats.     

Human growth hormone and somatomedin C suppress the spontaneous release of growth hormone in unanesthetized rats

To investigate the feedback control of GH secretion, we examined the effects of human GH (hGH) and somatomedin C (SmC) on spontaneous GH secretory surges in unanesthetized, freely moving rats. Under pentobarbital anesthesia a right atrial catheter and an intracerebroventricular cannula were placed 7-10 days before the experimentation. For iv studies, hGH (0.3 U/ml.h) was infused for 6 h after an iv loading dose (0.3 U) at the beginning of the experiments. For intraventricular injections, hGH (0.1 U/10 microliter) or SmC (500 ng/10 microliter) were injected into the lateral ventricle 2 h before the experiments. The equivalent dose of crystalline BSA diluted in the same vehicle solutions was administered to the same rat as a control on a separate day. Venous blood samples were collected every 20 min for 6 h. Intravenous and intraventricular administration of crystalline BSA did not affect the typical rat GH (rGH) surges which appeared about every 3 h and reached peak values of more than 300 ng/ml. The iv infusion of hGH significantly inhibited the amplitude of rGH surges compared to controls (planimetric areas under the secretory profile 752 +/- 172 vs. 1921 +/- 183, P less than 0.01, n = 6). rGH secretion was similarly inhibited by intraventricular hGH (701 +/- 127 vs. 2208 + 225, P less than 0.01, n = 6) and by intraventricular SmC (537 +/- 70 vs. 1503 +/- 114, P less than 0.01, n = 6). These findings suggest that both GH and SmC are active in the feedback regulation of rGH secretion.     

Supplemental growth hormone increases the tumor cytotoxic activity of natural killer cells in healthy adults with normal growth hormone secretion

Using double-blind, placebo-controlled procedures, the effects of methionyl-human growth hormone (met-hGH) on the tumor cytotoxic activity of natural killer (NK) cells were studied in seven healthy adults using a repeated measures experiment. Subjects were assigned at random to either a placebo (bacteriostatic water) treatment condition or a met-hGH (16.0 mg/wk of Protropin) treatment condition, then crossed-over to the alternative treatment. Treatments were delivered on alternate days (3 d/wk) for 6 weeks. Without bias from the met-hGH treatment, there was no evidence for GH hyposecretion as measured by the peak circulating GH response to exercise stimulation (14.1 +/- 3.1 ng/mL) or insulin-like growth factor (IGF-I) levels (0.82 +/- 0.09 U/mL). When compared with placebo, met-hGH induced a significant overall increase in the percent specific lysis (%SL) of K562 tumor target cells (placebo 22.2 +/- 1.7 v met-hGH 28.5 +/- 2.1 %SL; P = .008). NK activity was increased within the first week of treatment and this level was maintained throughout the remaining period of supplementation. There was a trend (P = .057) for the met-hGH-induced percent change in NK activity (NK%) to be inversely related to placebo IGF-I levels (r = -.761), while there were significant positive correlations between NK% and the met-hGH-induced percent changes in IGF-I (r = .727; P = .035), the fat-free mass (FFM)/fat mass (FM) ratio derived by hydrodensitometry (r = .792; P = .012), and the endogenous GH response to exercise (r = .469; P = .034).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of acute and chronic growth hormone (GH) administration on GH secretion in patients with idiopathic GH deficiency

The effect of acute and chronic administration of GH on plasma GH responses to GHRH were studied in patients with idiopathic GH deficiency (GHD). Nine untreated GHD patients, 1 untreated patient with postoperative craniopharyngioma, and 7 normal short children were given synthetic human GHRH-44 (100 micrograms, iv) injection before and 2 days after being given a single dose of 4 IU biosynthetic methionyl human GH (mGH), im. Twelve GHD patients, who had been treated with 0.31-0.48 IU/kg.week pituitary-derived hGH (pdGH), im, for 8-79 months, were given GHRH 2 and 14 days after a final injection of 4 IU pdGH. Three other GHD patients were given GHRH before and after 2 yr of pdGH therapy (0.35-0.39 IU/kg.week). The GHRH-induced GH response (max delta GH) was significantly inhibited after mGH administration in the 9 untreated GHD patients [2.7 +/- 0.3 (+/- SE) vs. 4.7 +/- 0.6 micrograms/L; P less than 0.01]. The patient with secondary GH deficiency also had a marked reduction in her peak plasma GH value after mGH administration (from 32.0 to 11.7 micrograms/L). Similarly, the mean max delta GH response in the 7 normal short children was significantly inhibited by prior mGH injection (max delta GH, 12.7 +/- 2.0 vs. 28.8 +/- 4.8 micrograms/L; P less than 0.01). In the 12 treated GHD patients the GHRH-induced GH response on the 2nd day after discontinuation of pdGH therapy was significantly lower than that on the 14th day (max delta GH, 3.4 +/- 1.2 vs. 6.9 +/- 1.6 micrograms/L; P less than 0.02). In the 3 GHD patients who were studied before and after 2 yrs of pdGH therapy, the plasma GH responses were similar. In each group, plasma somatomedin-C levels on the second day after GH administration were slightly but not significantly higher than those before or 14 days after the administration. The GH responses to GHRH given on 2 occasions at 7- to 14-day intervals in individuals not receiving GH were similar in both 9 normal children and 10 GHD patients. These results indicate that acute GH administration inhibits somatotroph function in GHD patients, but chronic GH therapy does not cause irreversible damage to the somatotrophs. The acute inhibition of GHRH-induced GH release after GH administration is more likely due to direct and indirect pituitary inhibition by somatomedin-C and/or somatostatin than decreased GHRH secretion.     

Plasma growth hormone (GH) responses to single and repetitive subcutaneous administration of GH releasing factor (hpGRF-44) in normal and GH deficient children

Synthetic human pancreatic GRF (hpGRF-44) was administered sc to 8 normal children with short stature and 11 patients with GH deficiency. After a dose of 100-200 micrograms hpGRF-44, mean plasma GH levels reached a peak at 15 min of 27.2 +/- 6.4 (+/- SE) ng/ml in normal children. However the responses were variable and peak plasma GH varied from 10.1 to 56.5 ng/ml. Eight of 11 patients with idiopathic GH deficiency did not respond to sc administration of 100-300 micrograms hpGRF-44. However, a plasma GH increase of more than 5 ng/ml occurred in 2 patients and to twice the basal level in 1 patient. Their GH values were 14.3, 5.2 and 3.4 ng/ml, respectively. After repetitive administration of hpGRF-44 (200 micrograms, twice a day) sc for 5 consecutive days, 2 of 8 patients restored their responsiveness, but the remaining patients did not show GH rise in response to both sc and iv bolus administration of hpGRF-44. Repetitive hpGRF-44 administrations for 5 days had no effect on somatomedin-C production.     

Dietary carbohydrate content determines responsiveness to growth hormone in energy-restricted humans

To determine if diet composition influences responses to GH, we fed 11 obese women diets containing 12 Cal/kg ideal BW (IBW) for 2 5-week study intervals. Nonprotein calories were supplied to 6 subjects as 72% carbohydrate (high carbohydrate diet), and 5 subjects received 80% of their nonprotein calories as lipid (high lipid diet). Protein intake was constant (1.0 g/kg IBW) in both groups. During 1 study interval we gave injections of GH (0.1 mg/kg IBW) every other day for 3 weeks (weeks 2-4), and in the other interval injections of vehicle were given. Subjects ingesting the high carbohydrate diet excreted significantly less urinary nitrogen [660.2 +/- 124.1 mmol/day (mean +/- SD)] than those who received high lipid (794.2 +/- 198.5 mmol/day; P less than 0.001), and GH injections reduced nitrogen excretion in the high carbohydrate subjects (532.8 +/- 123.8 mmol/day), but not in the high lipid subjects (743.7 +/- 126.6 mmol/day). The subjects receiving the high carbohydrate diet had a significant increase in serum insulin-like growth factor-I (IGF-I; from 36.2 +/- 9.7 to 55.9 +/- 6.6 nmol/L) and urinary C-peptide excretion (from 43.9 +/- 25.6 to 60.8 +/- 29.4 nmol/day) in response to GH. The IGF-I response attenuated slowly over the 3-week treatment interval. On the other hand, the high lipid group had lesser increases in IGF-I (from 31.0 +/- 6.5 to 41.7 +/- 8.8 nmol/L) and C-peptide excretion (from 24.3 +/- 28.9 to 29.8 +/- 32.8 nmol/day), and IGF-I concentrations declined to control values after only 5 days of GH injection. We believe that this initial IGF-I response was due to an antecedent 35-Cal balanced diet. The mean increment in serum FFA 4 h after GH injection was significantly less in subjects fed the high lipid diet (0.53 +/- 0.40 meq/L) than in those fed the high carbohydrate diet (0.83 +/- 0.43 meq/L). GH injections produced more body fat loss than injections of vehicle whether expressed as percent body fat lost (GH, 3.7 +/- 1.0%; vehicle, 2.8 +/- 0.7%, P less than 0.05) or as the fraction of weight lost as fat (fat loss/weight loss; GH, 0.81 +/- 0.13; vehicle, 0.64 +/- 0.08; P less than 0.005). There was an inverse correlation between the percentage of body fat lost and mean urinary C-peptide excretion during GH injections (r = -0.70; P less than 0.05), suggesting that stimulation of insulin secretion by GH might antagonize the tendency of GH to promote fat loss.(ABSTRACT TRUNCATED AT 400 WORDS)     

Growth-promoting effect of growth hormone and low dose ethinyl estradiol in girls with Turner's syndrome

Forty patients with Turner's syndrome, aged 5.0-16.6 yr, were randomly allocated to receive daily sc injections of recombinant human GH (hGH) at a dose of 1 IU/kg.week alone (group I) or in combination with 25 ng/kg.day ethinyl estradiol (E2; group II). The mean pretreatment height velocity was 3.8 cm/yr for both groups. During the first year of treatment height velocity increased significantly (P less than 0.001) in both groups, to 7.5 +/- 1.3 and 8.1 +/- 1.6 cm/yr, respectively. The difference between the two groups was not significant. The mean (+/- SD) height velocity expressed as the SD score for chronological age (Turner references) was 0.0 +/- 1.2 for group I and 0.2 +/- 1.4 for group II and increased significantly (P less than 0.001) during the first year of treatment to +4.3 +/- 1.1 in group I and +5.4 +/- 1.2 in group II. The difference between both groups was statistically significant (P less than 0.01). Height SD score for chronological age (Turner references) increased from -0.2 +/- 0.9 to +0.6 +/- 1.0 in group I and from -0.2 +/- 1.0 to +0.7 +/- 1.1 in group II. Mean bone age progressed similarly in both treatment groups (1.1 +/- 0.6 yr during 1 yr of treatment). However, bone age maturation accelerated more rapidly in younger patients. Twelve girls (three in group I and nine in group II) had minor breast development. No major adverse effects were reported. We conclude that daily sc therapy with hGH stimulates height velocity in Turner's syndrome. The beneficial effect on height velocity increment of E2 addition was small. Furthermore, even very low doses of E2 may induce breast development at an early age and accelerate bone maturation. For these reasons, the addition of E2 to hGH is not warranted in young patients with Turner's syndrome.     

Intestinal permeability in adult patients with growth hormone deficiency

Pathological disruption of the intestinal mucosa increases the paracellular pathway, leading to an increase in the penetration of large molecules. Since growth hormone (GH) has a trophic intestinal effect, we used a double marker test to enable examination of intestinal permeability, which reflects the state of integrity of the intestinal mucosa. We recruited 22 adult patients, mean age 54+/-13.3 years, with GH deficiency due to partial or total hypopituitarism. None had received GH treatment at any time, although they were all in optimized replacement therapy. A control group was composed of 19 healthy age-matched relatives. The intestinal permeability test was performed with lactulose (5 g) and mannitol (1 g) after an oral load of 100 ml of aqueous solution. The urinary lactulose/mannitol ratio and the percentages of lactulose and mannitol excreted were determined on a 5-h urine collection. There were no significant differences between the patients and the control group in the lactulose/mannitol ratio (0.087+/-0.059 vs 0.077+/-0.064, respectively) or in the urinary excretion percentages of lactulose (0.067+/-0.048% vs 0.073+/-0.070%, respectively) or mannitol (5.127+/-3.269% vs 5.068+/-2.985%, respectively). In conclusion, no increase in intestinal permeability was detected in patients with GH deficiency, so that in spite of the known trophic effects of GH on the epithelial crypt cells, there was no intestinal hyperpermeability in these patients.     

Outpatient assessment of residual growth hormone secretion in treated acromegaly with overnight urinary growth hormone excretion, random serum growth hormone and insulin like growth factor-1

OBJECTIVE: To assess the outpatient investigations, overnight urinary growth hormone (uGH) excretion, random serum GH and insulin like growth factor 1 (IGF-1), and GH indices from the oral glucose tolerance test (OGTT) (fasting, nadir and mean GH), as measures of mean GH secretion in treated acromegaly, in comparison with a GH day series, which served as a gold standard. DESIGN: Prospective cross-sectional study, with patients admitted to a metabolic ward for the following investigations: random GH, IGF-1, 6 point GH day series (day 1), 9 h timed overnight uGH excretion, OGTT with GH response (day 2). Agreements between the mean GH during the day series and the other outcome measures, and the diagnostic performance of the latter, for the presence or absence of active acromegaly (mean GH during day series > or = 5 or < 5 mU/l, respectively) were determined. PATIENTS: 26 patients with treated acromegaly (11 with inactive acromegaly off drug therapy). MEASUREMENTS: Serum GH and uGH were measured by immunoradiometric assays and IGF-1 by radioimmunoassay. RESULTS: Agreements with the mean GH during the day series were perfect for the nadir GH during the OGTT with a 2 mU/l cutoff (Cohen's kappa (kappa) = 1, P < 0.00001), almost perfect for the fasting and mean GH throughout the OGTT (both kappa = 0.92, P < 0.0001) and random GH (kappa = 0.85, P < 0.0001), and substantial for the nadir GH with a 5 mU/l cutoff (kappa = 0.77, P < 0.0001), IGF-1 (kappa = 0.62, P < 0.001) and overnight uGH excretion (kappa = 0.61, P = 0.002). Nadir GH with a 2 mU/l cutoff was completely accurate for diagnosing the presence or absence of active acromegaly (positive and negative predictive values (% +/- standard error percentage) 100 +/- 8% and 100 +/- 10%). None of the outpatient tests used alone was an adequate diagnostic test (positive and negative predictive values: overnight uGH excretion -86 +/- 10% and 75 +/- 13%; random GH -100 +/- 11% and 85 +/- 11%; IGF-1 -92 +/- 10% and 71 +/- 13%) and so combinations of tests were assessed. The best was overnight uGH excretion plus random GH (positive and negative predictive values 88 +/- 9% and 100 +/- 12%). Using all three outpatient investigations, the positive predictive value of three raised results was 100 +/- 13%. CONCLUSIONS: In treated acromegaly, residual GH secretion can be reliably assessed with the OGTT, using standard diagnostic criteria. It can also be assessed on an outpatient basis with overnight uGH excretion and random GH, as direct measures, and IGF-1. If these are all normal, active acromegaly is excluded. Three raised results denote active acromegaly, and one or two raised results would need further investigation with a GH day series.     

Growth hormone (GH) provocative testing frequently does not reflect endogenous GH secretion

GH secretion was studied in 73 children with classical GH deficiency or GH neurosecretory dysfunction (GHND), intrinsic short stature, or normal stature. The GH-deficient group was defined by a peak GH secretory response below 10 ng/ml to all provocative tests (arginine, L-dopa, insulin hypoglycemia, and clonidine). GHND was defined by a mean serum 24-h GH concentration below 3 ng/ml, with a normal response (greater than or equal to 10 ng/ml) to provocative testing. Twenty-one GH-deficient children, 21 children with GHND, and 18 short control children underwent provocative GH testing and a 24-h study with GH sampling every 20 min. A group of 13 normal stature control children also underwent 24-h GH sampling. The mean stimulated peak serum GH level [4.7 +/- 0.6 (+/- SEM) ng/ml] in the GH-deficient group was significantly below that in the GHND (19.5 +/- 1.7 ng/ml) and short control groups (24.0 +/- 3.5 ng/ml; P less than 0.01). The mean 24-h serum GH concentration was reduced in GH-deficient (1.5 +/- 0.2 ng/ml) and GHND (2.0 +/- 0.1 ng/ml) children compared to those in short (5.6 +/- 0.5 ng/ml) and normal stature (5.8 +/- 0.8 ng/ml) control children (P less than 0.01). Peak GH concentrations after provocative testing correlated poorly with 24-h mean concentrations in GH-deficient, GHND, and short control children (r = 0.38, 0.23, and 0.41, respectively; P = NS for all groups). Mean serum GH concentrations from blood sampling intervals of 12 h (day/night; 0800-2000/2000-0800 h, respectively) or even 6 h (day; 0900-1500 h) were statistically different in GHND or GH-deficient groups compared to those in control children; however, there was significantly more overlap for individual children using the 6- and 12-h daytime intervals than for the 24-h data. Plasma somatomedin-C/insulin-like growth factor I correlated with mean 24-h GH concentration endogenous secretion (r = 0.7; P less than 0.001). These data suggest that provocative GH testing frequently does not correlate with endogenous GH secretion.