The authors report the clinical history of a seventeen years old boy with renal failure treated with chronic haemodialysis since eleven and a half years of age. Growth velocity was 1.5 cm/year. The stature was below 5 SD as compared to the mean for the age. Hormonal measurements showed a complete growth hormone (hGH) deficiency and hyperparathyroidism. Thyroid, adrenal and gonadic secretions were normal, but the responses of TSH and prolactin to TRH were abnormal, showing an hypothalamic disturbance. hGH treatment, with thyroxin substitution, enhanced growth velocity up to 4 cm/year. Respective influences of hGH treatment, puberty and hyperparathyroidism on the incomplete correction of growth velocity are discussed.

Somatomedin C/IGF I, dehydroepiandrosterone sulfate (DHAS), testosterone (T) or estradiol (E2) have been measured in 154 patients of a previous study in which growth hormone (GH) responses to classical pharmacologic stimuli and spontaneous growth hormone secretion during sleep were compared in short children before and at the beginning of puberty. Five groups were identified: Group I, normal growth hormone secreting children; group II, completely growth hormone deficient; group III, partially growth hormone deficient; group IV, with normal sleep secretion and low responses to stimuli; group V, with the reverse situation. The somatomedin C/IGF I levels were widely dispersed. In group I, the mean +/- SEM levels of somatomedin C/IGF I were 0.77 +/- 0.047 U/ml before puberty and 1.36 +/- 0.142 U/ml in early pubertal patients, with a relation to age (r = 0.52, p less than 0.001). The difference between prepubertal and pubertal patients was significant. In groups II to V, there was no pubertal rise of somatomedin C/IGF I. In group II, the mean IGF I level was 0.48 +/- 0.05 U/ml, significantly lower than in prepubertal patients of group I. In groups III, IV and V, it was 0.7 +/- 0.069 U/ml, 0.8 +/- 0.059 U/ml, and 0.73 +/- 0.059 U/ml respectively, not different from prepubertal patients of group I, but significantly lower than in early pubertal patients of the same group. In prepubertal patients, somatomedin C/IGFI was slightly but highly significantly correlated to the growth hormone sleep secretion (r = 0.27, p less than 0.001) and to dehydroepiandrosterone sulfate (r = 0.36, p less than 0.001), but growth hormone and dehydroepiandrosterone sulfate were not correlated together.(ABSTRACT TRUNCATED AT 250 WORDS)

In isolated GH deficiency, a too insufficient height at onset of a puberty leads to reduced adult height. In order to prevent this we have tried the efficiency of LHRH analogue in association with GH in such cases. Long-acting Trp 6 LHRH analogue (LHRHa) was used in 4 male patients aged 12 to 16 years, treated with hGH 20 IU/kg/yr from 1 to 6 years for isolated GH deficiency. LHRHa was injected IM monthly (3.7 mg in 2 patients, 1.8 in 2) from the onset of pubertal stage P2. The mean ± SD data before and after 12 months of LHRHa therapy were as follows : growth velocity (SDS) decreased from -1.79 ± 0.34 to -1.93 ± 0.46 for chronological age and increased from -0.80 ± 0.90 to -0.55 ± 1.11 for bone age; plasma testosterone (ng/ml) decreased from 1.95 ± 0.77 to 0.10 ± 0.05; ratio of bone age to height age (BA/HA) decreased from 1.12 ± 0.12 to 1.05 ± 0.10. Though preliminary, these results seem encouraging. Treatment with LHRHa allowed maintenance of plasma testosterone at pre-pubertal levels. Since control studies in pubertal patients with isolated GH deficiency treated with hGH alone showed an insufficient growth spurt, it is likely that the association of LHRHa with hGH may allow the improvement of final height.

Growth hormone (GH) was measured in 215 short children (147 males and 68 females, 123 prepubertal, 92 at early pubertal stages), comparing GH responses to classical pharmacologic stimulation tests and spontaneous GH secretion during sleep. GH secretion during sleep, but not GH responses to stimuli, was higher in early pubertal than in prepubertal subjects. The patients were classified into five groups, according to the agreement between GH responses to stimuli and GH secretion during sleep: group I, normal GH-secreting children; group II, completely GH-deficient; group III, partially GH-deficient; group IV, with normal secretion during sleep and low responses to stimuli; group V, with the reverse situation. 30% of the patients were in groups IV and V, both at prepubertal and early pubertal stages. 46 patients of groups II-V were treated with extracted human GH(hGH). The growth rate was enhanced in groups IV and V, to the same extent as in groups II and III. Four points can be concluded: (1) the rise of GH secretion during sleep is an early event at the onset of puberty; (2) the discrepancy between the GH responses to classical stimuli and GH secretion during sleep are of pathological significance; (3) disturbances of GH secretion might be diagnosed by measuring GH secretion during sleep rather than by using conventional stimulation tests; (4) a trial course of hGH treatment could be proposed in patients with both kinds of discrepancies between GH responses to stimuli and GH secretion during sleep.

GH sleep secretion (SS) and GH response to pharmacologic stimuli (PS) were compared in 215 short children (-3.2 ± 0.9 SD), aged from 2 to 18 years (147 boys, 68 girls), 123 at pubertal stage P1 and 92 P2. Somatomedin C (SmC), DHA sulfate (DHAS), testosterone (T) or estradiol (E2) were measured. SS and PS were slightly correlated at both stages P1 (r = 0.4; p<0.01) and P2 (r = 0.31; p<0.01), SS being higher at P2 than at PI. SS is related to growth velocity at P1. At P2, SS is positively correlated to T in boys and negatively to E2 in girls. SmC is correlated to SS and PS at P1 and P2, and is higher at P2. It is not significantly correlated to sex steroids. SS and PS are discrepant in 67 cases : either normal SS and low PS in 37 or the contrary in 30, and moreover SmC level did not rise at P2 in these patients. Some of the patients with such discrepancies enhanced their growth velocity under hGH treatment. It is concluded : 1/ Early pubertal increase of SS preceeds that of PS. It is controlled by sex steroids. 2/ SmC is related to SS and puberty, but there may be other regulation factors than sex steroids. 3/ SS/PS discrepancy was observed in 30 % of cases in this study. 4/ In these cases, SmC does not rise at P2 and hGH treatment may improve the growth velocity.

In cryptorchid infants, significantly decreased mean levels of plasma testosterone and luteinizing hormone (LH) were found between the ages of 30 and 120 days. The levels of testosterone and LH were significantly correlated. No significant difference was found between infants with bilateral or unilateral cryptorchidism. After 120 days there was no longer any significant difference between cryptorchid infants and controls. No significant change in plasma follicle-stimulating hormone (FSH) was found. These data suggest that subnormal secretion of LH could be the primary abnormality in a proportion of boys with so-called common cryptorchidism. Our studies using LH-releasing hormone and human chorionic gonadotropin stimulation tests in older infants and children agree with the data obtained by measurement of basal plasma hormone levels during the first months of life. Anti-gonadotroph antibodies were found in the sera of approximately 50% of the cryptorchid children and infants studied, using an immunofluorescence technique. A study of 17 mothers and their infants gave concordant results in 16 pairs, 9 with and 7 without antibodies. This lead us to speculate on the possible role of maternal autoantibodies as a cause of partial gonadotrophin deficiency in the perinatal period and thus of testicular maldescent. As cryptorchidism is a syndrome, these findings do not mean that a similar mechanism is operative in all cases. However, these data do suggest that alternatives to the classical anatomical view of the descent and nondescent of the testes should be considered.

The psychosocial consequences of GH deficiency and of its treatment with growth hormone (hGH) have been evaluated from 44 answers to a questionnaire mailed to 50 patients aged 18 to 36 years (m 21.7 ± 3.4 yrs), treated with hGH for at least 3 years (m 5.6 t 2.8 yrs), 22 idiopathic and 22 with detectable cause, 15 with isolated GH deficiency and 29 with multiple deficiencies. Final height was -2.9 ± 0.9 SD below the average. The results (%) were the following : From these results the final score among 43 patients may be considered as excellent in 9, good in 10, medium in 15, insufficient in 8, very bad in 6, in spite of appropriate medical and psychosocial support. Earlier care and perhaps some increase of doses of hGH could improve these results in the future.

In order to investigate the regulation of GH secretion in patients with idiopathic delayed puberty (IDP) either prepubertal (stage PI) or early pubertal (P2) GHRH levels in plasma were measured after stimulation with L-Dopa in a group of 16 patients with IDP. The results were compared to those obtained in 12 patients with constitutional short stature (CSS) at the same stage of puberty who underwent L-Dopa test for insufficient height. Plasma GHRH levels were measured after extraction by RIA. After L-Dopa intake the peak of GH was mean ± SEM 8.6 ± 1.4 ng/ml in IDP and 12.0 ± 0.8 ng/ml in CSS (NS). The peak of GHRH after L-Dopa was 41 ± 10 pg/ml in IDP and 96 ± 25 pg/ml in CSS (p<0.02). Basal plasma GHRH levels were measured in five patients with IDP before and after 3 × 1500 IU of hCG. Testosterone levels rose to 4.8 ± 0.9 ng/ml, no changes in plasma GHRH levels were observed (25 ± 13 pg/ml). Oxandrolone was given in 6 patients with IDP. Six months after when puberty was clearly started with an increase in growth velocity (6.3 ± 0.7 cm/6 months) peak GHRH levels during L-Dopa stimulation test increased significantly (p<0.02) from 48 ± 12 pg/ml to 142 ± 33 pg/ml, GH peaks being respectively 8.4 ± 3.2 pg/ml before, 11.4 ± 1.9 after. These results suggest an hypothalamic dysfunction in patient with IDP, reversible with the start of puberty. They indicate a relationship between the wellknown partial and transitory GH deficiency found in some adolescents having a pubertal delay and their secretion of GHRH.

A questionnaire having been mailed to 50 hypopituitary patients aged 18 to 36 years (m 21.7 +/- 3.4) previously treated with human growth hormone for at least 3 years, 44 answers have been received. The final height is 2.1 +/- 0.9 standard deviations below the average. However 57% of the patients consider it is sufficient. The smallness is felt as a handicap by 20% only of these adults, though 88% had suffered for it during their adolescence. The treatment is retrospectively considered as useful and acceptable by 68%, heavy but useful by 25%, heavy and useless by 7%, without correlation with the results. Only 41% are satisfied with their school achievements. However, more than two thirds of patients had severe school difficulties at the time of onset of the treatment. Actually 75% of the patients are professionally qualified, among whom 36% have achieved high school, and most have an educational level similar to that of their parents or even higher. But 41% only have an employment, 27% are still students and 32% are unemployed. The way of life of the young hypopituitary adults is severely affected: 6 only are married or living with a mate, 11 only write they have occasional sexual experiences, 16 remain completely alone. In contrast, leisure activities are good in more than 90%. A score taking all these data into consideration to evaluate their way of life shows, among the 43 complete answers to the questionnaire, 16% with excellent results, 49% with a rather good social status and 35% with poor final result.(ABSTRACT TRUNCATED AT 250 WORDS)

50 children with PP, 37 girls aged (mean ± SD) 6.6 ± 2.2 and 13 boys aged 7.6 ± 3.1 years, were treated for 30 months with monthly muscular injections (60 μg/kg) of DTrp 6, which normalized plasma gonadotropin and sex steroid levels. Before treatment mean height and bone ages were respectively 8.0 ± 2.6 and 9.1 ± 2.5 years in girls (HA/BA = 0.88 ± 0.1), 8.4 ± 3.1 and 8.9 ± 3.2 in boys (HA/BA = 0.93 ± 0.1). Height velocities (HV) were 10.8 ± 3.6 cm in girls, 11.0 ± 3.5 cm in boys. During the first 6 months HV and skeletal maturation remained accelerated and the HA/BA ratio decreased : 0.87 ± 0.1 in girls, 0.91 ± 0.09 in boys. After 6 months, HV decreased significantly to 5.5 ± 2.0 cm/year in girls (p<0.001) and 5.7 ± 1.6 in boys (p<0.005) while skeletal maturation decreased abruptly leading to a progressive and significant increase of HA/BA ratio reaching at 30 months 0.97 ± 0.08 in girls (p<0.001) and 1.04 ± 0.08 in boys (p<0.025). Mean growth hormone peak after ornithine was 13.6 ± 1.4 ng/ml before Trp 6, 12.3 ± 2.6 ng/ml after (NS) in both sexes and no correlation was found between plasma somatomedin C levels and HV. This data indicates that, in children of both sexes with PP, the perfect control of gonadotropin and gonadal secretions obtained by DTrp 6 leads, after a short delay, to a significant improvement of height prognosis.

Administration of high doses of magnesium is known to produce a decrease in parathyroid hormone (PTH) secretion in human patients but the effect of magnesium on the secretion of PTH in healthy man is not known. We have looked at the effect of a relatively moderate i.v. dose of magnesium (7.08 mmol) in seven healthy men. In addition and for comparison the effect of calcium (4.25 mmol) was studied. Two magnesium salts were considered, magnesium sulphate (MgSO4) and magnesium pyrrolidone carboxylate (MgPC). Four i.v. injections were given at 08.00 h (MgPC, NaCl (control), MgSO4 and Ca gluconate), with an interval of 1 week between each injection. Whatever the magnesium salt the variations in plasma concentrations of magnesium were the same whereas no change in erythrocyte magnesium was observed. Plasma concentration of C-terminal PTH did not show significant variations after MgPC or saline injection. Both MgSO4 and Ca gluconate produced a statistically significant 30% decrease in plasma PTH levels 45 min after the injection. The effect was more sustained with calcium (2 h) than with magnesium (45 min). The urinary excretion of magnesium was significantly higher after injection of MgSO4 than after MgPC. These results suggest that magnesium was, on a molar basis, less potent than calcium in regulating PTH secretion in vivo, that the nature of the magnesium salt used must be kept in mind for the interpretation of the effect of magnesium on PTH secretion in vivo and that the decrease in plasma PTH can partly explain the larger urinary excretion of magnesium after MgSO4 than after MgPC.

ABSTRACT.Job, J.‐C., Chaussain, J.‐L., Garnier, P., Rolland, A. and Joah N. (Hôpital Saint‐Vincent‐de‐Paul, Paris, France). Dose‐response relationship in the treatment of hypopituitary children with human growth hormone: a retrospective survey. Acta Paediatr Scand [Suppl] 337:93, 1987.During the past 15 years, dose‐response studies of hGH have been limited to prepubertal patients with complete somatotrophic deficiency, who have usually been treated with hGH three times/week within a dose range of 10–40 IU/kg/year. In such studies a weak positive correlation has been found (r = 0.429, p < 0.001) with marked important individual variations. Very few or no data have been published regarding the dose‐response relationship after the first year of hGH treatment, or when the dose is increased because the growth rate is waning, or during puberty. The present paper reports some data on these issues. A group of 32 young hGH deficient children, whose hone age was 0–4 years, was followed up for at least 3 years with hGH given intramuscularly three times weekly at doses of 12–48 IU/kg/year (mean, 25 ± 9 IU/kg/year‐i.e. approximately 0.15 IU/kg/injection). A dose‐response relationship existed during the first year hut not during the following 2 years nor for the height gain obtained at the end of the third year of treatment.The results of an increase of the dose of hGH by 33–66% in 13 prepubertal hGH deficient children whose growth rate had decreased after 2–5 years of treatment were fair in 6, limited in 4 and absent in 3, and did not relate to the extent of dose increase. However, this series is too small to allow definite conclusions.The growth rate of 67 adolescents with complete hGH deficiency and normal spontaneous puberty was close to the normal mean in the 45 males hut much less in the 22 females. Although the least favourable results came from cases with post‐radiotherapy hypopituitaryism, the mean total pubertal growth spurt in patients with idiopathic hGH deficiency Was also below the average, mainly in the girls, and with a large range of individual variation. An important fact was that hone age increased more than height age or chronological age in these hypopituitary pubertal patients. No dose‐response relationship was found in this group, within a limited range of doses (40 patients receiving 16–20 IU/kg/year injected three times weekly, 19 receiving less than 16 IU/kg/year and 8 receiving more than 20 IU/kg/year).It may he concluded that in prepubertal hypopituitary children, hGH at a dose of approximately 20 IU/kg/year at the onset of treatment is probably appropriate. The lack of a dose‐response relationship after the first year of treatment suggests that higher initial doses should he avoided. The usefulness of increasing doses when the growth rate decreases after 2 years or more of treatment, and the optimal size of dose increase, are still uncertain. At puberty, higher doses could be tried, mainly in females, with the hope of improving the pubertal height gain. Probably an earlier start of treatment in hGH deficient children, and changing the usual frequency of administration from three to six injection/week, would be a better way of improving the final results than using high doses of hGH. Prospective studies must be organized to allow the long‐term evaluation of the dose‐response relationship and the cost‐effectiveness of dose increases.

ABSTRACT. In order to investigate the regulation of GH secretion in patients with idiopathic delayed puberty (IDP), either prepubertal (stage P1) or early pubertal (P2), GHRH levels in plasma were measured after stimulation with L‐Dopa in a group of 16 patients with IDP. The results were compared to those obtained in 12 patients with constitutional short stature (CSS) at the same stages of puberty, who underwent L‐Dopa test for insufficient height. Plasma GHRH levels were measured, after extraction and concentration on C18 Sep Pack columns, by radioimmunoassay using an antibody against 1–40 GHRH, which cross‐reacts 100% with 1–44 GHRH. The sensitivity of the assay is 6–8 pg/ml. After L‐Dopa intake, the peak of GH was mean ± SEM 8.6±1.4 ng/ml in IDP and 12.0±0.8 ng/ml in CSS (NS). The peak of GHRH after L‐Dopa was 41±10 pg/ml in IDP and 96±25 pg/ml in CSS (p<0.02). A significant (p<0.02) decrease of plasma GHRH peak values (mean ±SEM 17.3±4.4 pg/ml) was noted in the five patients with IDP whose growth velocity was below ‐2 SD for their bone age compared to the patients with normal growth velocity (mean ± SEM 75.0±14.5 pg/ml). These results suggest a hypothalamic dysfunction in patients with IDP, and a relationship between the well‐known partial and transitory somatotropic deficiency found in some adolescents having a pubertal delay and their secretion of the releasing hormone GHRH.

The growth hormone (GH) response to GH-releasing factor (GRF) was studied in 54 severely growth-retarded patients (-2.1 to -6.5 SD) aged from 5 to 20 years (32 males and 22 females), among whom 34 were prepubertal and 20 at early pubertal stages. The patients were also submitted to a standard evaluation of their GH secretion, consisting of at least two classical pharmacologic stimulation (CPS) tests, such as ornithine, arginine and/or insulin, and one study of the GH sleep secretion (SS). The results of the standard evaluation allowed to distinguish 5 groups: (I) endocrinologically normal (n = 26); (II) completely GH deficient (n = 5); (III) partially GH deficient (n = 8); (IV) dissociated GH secretions with normal SS (n = 9), and (V) dissociated GH secretions with low SS (n = 6). The GH responses to GRF were correlated with both responses to CPS and SS. There was a large overlap of the individual responses to GRF between the 5 groups, but the mean responses in groups II, IV and V were significantly lower than in group I. Furthermore, the mean responses of groups IV and V were in the lower range of the normal. It is concluded that the GRF test may be useful to ascertain the diagnosis of functional or partial GH deficiency when the responses to CPS and SS are dissociated.

Fourty-five minutes after an intravenous injection of Mg SO4 (170 mg of element Mg), in 7 young and healthy men, a significant decrease in circulating 53-84 PTH has been observed. An injection of magnesium pyrrolidone carboxylate (170 mg of Mg) failed to induce changes in plasma levels of PTH. The urinary excretion of Mg was 2-fold higher after the injection of Mg SO4 than after the injection of magnesium pyrrolidone carboxylate. For both magnesium salts used, the time patterns of plasma magnesium concentrations were the same and red blood cells magnesium was not increased. These results suggest that, in our experimental conditions, the retention of magnesium was higher after magnesium pyrrolidone carboxylate than after Mg SO4 and that the drop in plasma PTH could partly explain the larger urinary excretion of magnesium after Mg SO4.

Maximal response (peak) of growth hormone (GH) after conventional pharmacologic stimuli have been compared to maximal level reached during sleep in 215 children (123 prepubertal, 92 early pubertal) (group A). A weak correlation (r = 0.37, p less than 0.001) was observed. Five sub-groups of patients could be distinguished according to their GH pharmacologic or sleep peaks: 115 with normal secretion in both cases (I), 10 with complete deficiency (II), 27 with partial deficiency (III), 34 with normal GH sleep secretion and low responses to stimuli (IV) and 29 with the inverse situation (V). A second group (B) of 30 very short children (17 prepubertal and 13 early pubertal) had borderline or variable responses after several pharmacologic stimuli. hGH therapy was done to every patients of sub-group A II, 12 of sub-group A III, 9 of subgroup A IV, 5 of sub-group A V and every one of group B. A sharp rise of growth rate has been obtained with hGH in every patients of sub-groups A II and A III, in 10 out of 14 patients of sub-groups A IV and A V and in almost all patients of group B. A sharp rise of growth rate has been obtained with hGH in every patients of sub-groups A II and A III, in 10 out of 14 patients of sub-groups A IV and A V and in almost all patients of group B. hGH effect in the three last kinds of patients, with atypical GH secretion, was better in those who were in early puberty.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum carboxyterminal parathyroid hormone (PTH) concentration (homologous measurement of the 53-84 fragment and heterologous bovine measurement) has been measured and correlated with both clinical and radiological findings of secondary hyperparathyroidism (HPT), studied quantitatively according to a score published in literature, in 95 patients with chronic renal failure on maintenance hemodialysis. Mean serum PTH concentration (53.84) is statistically higher in patients with severe clinical and radiological evaluation of HPT than in patients with moderate or slight manifestations of HPT (M +/- DS: 515.8 +/- 243.7 pg/ml VS 271.3 +/- 166.1 pg/ml p less than 0.001). However, even with high serum concentration, serum PTH level does not allow to predict HPT severity, suggesting a retention of PTH fragments in serum without biologic activity probably.

Dispersed cells obtained from 10 GH-secreting adenomas were studied in perifusion columns, eluted with Krebs Ringer buffer. Fractions were collected each 5 min for 5 hours and assayed by RIA for GH and SRIF contents. Basal GH secretion was variable (10 to 94 ng/ml/ 106 cells). Within the first 15 minutes of the perifusion SRIF was detected in 5 cases (5 to 41 pg/ml/106 cells). However in 5 cases a great release of SRIF was only observed after 90 minutes or more (7 to 25 pg/ml/ 1O6 cells). In 2 cases, during the perifusion, the variations of GH and SRIF levels were significantly negatively correlated (p<0.001). Conclusions: 1) SRIF is released in vitro from human pituitary GH-secreting cells, 2) origin of SRIF release: internalization or synthesis ? 3) the inverse correlation between SRIF and GH levels suggests a role of the intracellular SRIF in the regulation of GH secretion.