Stimulated growth hormone (GH) secretion in children with delays in pubertal development before and after the onset of puberty: relationship with peripheral plasma GH-releasing hormone and somatostatin levels.

A reduced GH secretion has often been shown in prepubertal children with delays in pubertal development. In order to study the mechanism underlying this finding, we evaluated peripheral circulating levels of GH, GHRH, and somatostatin (SRIH) before and after the onset of sexual development in a group of eight late maturing children (six boys, two girls), comparing the results with those obtained in two groups of five prepubertal and four pubertal short children with familial short stature. GH was measured by a two-site immunoradiometric assay. Both GHRH and SRIH were assayed by specific RIAs after an acetone-petrolether extraction from plasma. Our data showed a significant increase (P less than 0.001) in GH, GHRH, and SRIH levels (peak vs. basal values) in response to L-dopa administration in all groups. In pubertal children with delays in pubertal development GH and GHRH peak values (15.8 +/- 2.2 micrograms/L and 120 +/- 18 pg/mL, respectively) were significantly greater (P less than 0.001) than in the same subjects before puberty (8.2 +/- 0.9 micrograms/L and 79 +/- 9 pg/mL, respectively), whereas SRIH peak values did not significantly change (41 +/- 6 vs. 41 +/- 5 pg/mL; P = NS). Furthermore, prepubertal subjects with delays in pubertal development showed GH and GHRH peak values lower (P less than 0.001) than those of prepubertal subjects with FSS (13.3 +/- 1.8 micrograms/L and 120 +/- 13 pg/mL, respectively), whereas no statistical difference was present between the two groups of subjects after pubertal development (18.2 +/- 2.9 micrograms/L and 128 +/- 11 pg/mL, respectively). In conclusion, these findings support the assumption that in late maturing subjects during prepubertal period the decreased GH secretion may be ascribed to a reduced GHRH secretion, reversible with the onset of puberty, without change in circulating SRIH levels.

[Thyroid and thyrotropin functions in subjects with pituitary nanism treated with growth hormone]. / Funzione tiroidea e tireotropinica nei soggetti con nanismo ipofisario in trattamento con ormone della crescita.

We have evaluated thyroid and thyrotropin functions before the beginning and during Growth Hormone (GH) treatment for a 2-6-year period in a group composed of 21 children (age: 6.6 +/- 1.1 years, m +/- SD) suffering from classic GH deficiency. Circulating levels of thyroxine, and basal thyroid-stimulating hormone (TSH) always resulted in the normal range. TSH response to thyreotropin-releasing hormone administration showed in some subjects (one out of 21 before the start of treatment, 2 out of 16 after 2 years, 3 out of 12 after 4 years and 2 out of 10 after 6 years) a delayed (after 90-120 minutes) and higher peak in comparison to that of normal subjects. All these high and delayed values have been showed in only one occasion by different children, with the exception of a child who has presented the higher values in two occasions. Growth response to GH treatment has not been modified by the change in thyrotropin response, as subjects with high TSH peak have had a height velocity similar to that of the other children in the corresponding periods of study.

[The effects of l-dopa administration on the prolactin levels in short-stature subjects]. / Effetti della somministrazione di l-dopa sui livelli di prolattina in soggetti di bassa statura.

In this study, on the basis of the inhibiting action of l-dopa administration on prolactin (PRL) secretion, we evaluated in a number of short children the levels of PRL during the provocative stimuli test with l-dopa in order to identify an index able to give reliability to the test and to investigate whether some differences may exist among the subjects showing a different response in growth hormone (GH) secretion to l-dopa. We examined 76 subjects (44 boys and 32 girls) with chronological age from 4.5-15.17 years. The subjects, on the basis of the GH peaks during two provocative stimuli tests [l-dopa and insulin-induced hypoglycemia (IIH)], were subdivided into 3 groups: group 1 (n = 24) with both deficient responses (peak less than 10 ng/ml); group 2 (n = 28) with discordant responses and further subdivided into group 2a (n = 14) with normal responses to IIH and 2b (n = 14) with a normal response to l-dopa; group 3 (n = 24) with both normal responses. PRL levels peaked between times -20' (58 cases) and +20' (2 cases) whereas nadir occurred between +80' (4 cases) and +120 (48 cases) without any significant difference (p = ns) among the groups. PRL levels significantly decreased in all groups, also in those with a deficient response to l-dopa (1 and 2a); furthermore no significant correlation between PRL and GH levels was demonstrated. In conclusion, this study showed the importance of PRL evaluation during l-dopa test in order to give reliability to the test and did not demonstrate any difference in PRL levels among the examined groups of short children.

[Growth hormone secretion in response to the administration of thyrotropin releasing hormone (TRH) in children with insulin-dependent diabetes mellitus]. / Secrezione di ormone della crescita in risposta alla somministrazione di thyrotropin releasing hormone (TRH) in bambini con diabete mellito insulino-dipendente.

In this study the Authors examined the response in growth hormone (GH) to thyrotrophin releasing hormone (TRH) administration in a group composed of 29 children (17 males, 12 females) suffering from insulin-dependent diabetes mellitus (IDDM) (group 1). All subjects were prepubertal, had a chronological age of 8.82 +/- 1.76 years (m +/- SD), a bone age of 8.60 +/- 1.65 years; the time elapsed since the diagnosis was 2.45 +/- 1.51 years, glycosylated hemoglobin (HbA1c) was 7.33 +/- 1.80%. Some of the same subjects (all those with a response in GH to TRH higher than 4 ng/ml; no. 11; group 2) were examined again 12-18 months later; as controls, 13 short children were also examined (group 3). All the subjects of the three groups showed a TSH peak ranging from 10-25 microU/ml, whereas GH peak resulted higher than 4 ng/ml ("paradoxical" response) in 6 subject of the group 1 and in an only subjects of the group 2. All the responders of the 3 groups showed a value in HbA1c higher than 8%. A significant difference was not present between males and females in GH and TSH values. Cortisol levels and glycaemia remained almost constant during the performance of the tests. By considering all the groups, TSH and GH values during TRH-test were not correlated with glycaemia, chronological age, bone age, the time elapsed since the diagnosis, height, height velocity, HbA1c values. In conclusion, our data demonstrated that "paradoxical" response in GH to TRH administration was present only in some subjects and particularly in those with a poor metabolic control of the disease.

[Correlation between growth velocity and hematologic levels of somatomedin C during the treatment with growth hormones (GH) in subjects with "classic" and "non-classic" deficits of GH]. / Correlazione tra velocità di crescita e livelli ematici di somatomedina C durante il trattamento con ormone della crescita (GH) in soggetti con deficit "classico" e "non classico" di GH.

In this study the authors examined 14 subjects with "classic" growth hormone (GH) deficiency and 40 with "non classic" GH deficiency treated with GH for a period of 6-36 months. Height velocity (HV) and plasma Somatomedin C (SmC) levels have been evaluated every 6 months during GH therapy. Both HV and SmC significantly increased (p < 0.001) during GH therapy in comparison to pretreatment values, but without any difference between the two groups; furthermore no significant difference was present among each six-monthly value of SmC. During GH treatment the following correlations resulted between SmC and HV: at time 0, r = 0.494 (p = 0.0004); after 6 months, r = 0.779 (p < 0.0001); after 12 months, r = 0.660 (p = 0.0001); after 18 months, r = 0.657 (p = 0.0001); after 24 months, r = 0.593 (p = 0.0038); after 30 months, r = 0.550 (p = ns); after 36 months, r = 0.465 (p = ns). Furthermore, mean value of SmC (y) correlated with mean value of HV (x) during GH treatment: r = 0.697, p < 0.0001; regression equation: y = 242x + 576. Finally no correlation was present among six-monthly SmC values, including those pre-treatment, and HV values in each of following periods. In conclusion, during GH treatment in subjects with GH deficiency plasma SmC levels correlate with HV, but have not a predictive value of the growth response to GH treatment itself.

The evaluation of 24-hour spontaneous GH secretion in short children: relationship between mean concentration and pulsatile parameters.

In 116 short children (height < -1.6 SDs), the authors examined GH secretion over 24 hours, by taking blood samples every 20 min and performing an electroencephalographic sleep control. The following GH parameters were evaluated: 24-h mean GH concentration (MGHC); maximum GH peak during the initial cycle of sleep (iMGHP), the nocturnal 12 h (nMGHP) or diurnal 12 h (dMGHP), the number of GH pulses over 24 h (NP), or nocturnal 12 h (nNP) or diurnal 12 h (dNP), the mean pulse amplitude over 24 h (MPA), or nocturnal 12 h (nMPA) or diurnal 12 h (dMPA). The subjects were divided into 3 groups: group 1, 12 subjects with low responses to provocative tests and MGHC < 3 ng/ml; group 2, 36 subjects with normal responses to provocative tests and MGHC < 3 ng/ml; group 3, 68 subjects with MGHC > 3 ng/ml. MGHC was highly correlated (p < 0.001) with iMGHP (r = 0.80), nMGHP (r = 0.82), dMGHP (r = 0.59), MPA (r = 0.85), nMPA (r = 0.86), dMPA (r = 0.56), NP (r = 0.70), nNP (r = 0.68), dNP (r = 0.46). By the analysis of the regression equations, the values corresponding to 3 ng/ml for MGHC were 11.08 ng/ml for iMGHP, 11.66 ng/ml for nMGHP, 5.21 ng/ml for dMGHP, 7.29 ng/ml for MPA, 8.40 ng/ml for nMPA, 4.25 ng/ml for dMPA, 3.2 for NP, 2.41 for nNP and 0.78 for dNP. By using these values as cut-off points, the diagnostic accuracy yielded 83.6% for iMGHP, 84.5% for nMGHP, 69.8% for dMGHP, 92.2% for MPA, 90.5% for nMPA, 81.9% for dMPA, 80.2% for NP, 77.6% for nNP, 71.5% for dNP. In conclusion, we found a strong correlation between mean GH secretion over 24 h and the number or amplitude of pulses: particularly, nocturnal pulsatile GH parameters show a higher correlation in comparison with diurnal pulsatile GH parameters, so that the examination of GH values during nocturnal hours may be considered a reliable index of GH secretory status.

Evaluation of 24-hour growth hormone spontaneous secretion: comparison with a nocturnal and diurnal 12-hour study.

Spontaneous growth hormone (GH) secretion in 116 short children was studied by sampling blood for GH measurement every 20 min over 24 h. We calculated 24-h mean GH concentration (MGHC), diurnal 12-h MGHC (dMGHC) and nocturnal 12-h MGHC (nMGHC). The children were subdivided into four groups: prepubertal children with 'classical' GH deficiency (group 1, n = 12, low responses to two provocative stimuli tests and MGHC less than 3 ng/ml), prepubertal children with 'nonclassical' GH deficiency (group 2, n = 36, normal GH responses to two provocative tests and MGHC less than 3 ng/ml), short normal children (normal GH responses to two provocative tests and MGHC greater than 3 ng/ml) at stage P1 of puberty (group 3, n = 41) and at stage P2 of puberty (group 4, n = 27). The values of MGHC, dMGHC and nMGHC were significantly higher in groups 3 and 4 than in groups 1 and 2, and in group 4 than in group 3. The values of MGHC and nMGHC were significantly higher in group 2 than in group 1. MGHC correlated highly with nMGHC and dMGHC (r = 0.97 and 0.94, respectively; p less than 0.001). On the basis of regression equations between MGHC and nMGHC or dMGHC, the study of the diagnostic accuracy showed values higher for nMGHC than for dMGHC: 94.1 vs. 89.6% for sensitivity, and 93.7 vs. 89.7% for specificity, respectively.

GHRH-test in short children with "non classic" GH deficiency. A comparison with "classic" GH deficiency and short normal stature.

In this study GHRH-test has been performed (2 micrograms/Kg of an iv bolus of GHRH 1-44) sampling for GH measurement every 15 min over 2 hours in three groups of short children. Group 1 consisted of 10 subjects with classic GH deficiency (CGHD): GH response less than 10 ng/ml to two conventional tests and 24-h mean GH concentration (MGHC) less than 3 ng/ml; group 2 consisted of 16 subjects with non-classic GH deficiency (NCGHD): response greater than 10 ng/ml to at least one conventional test and MGHC less than 3 ng/ml; group 3 consisted of 18 subjects with short normal stature: GH response greater than 10 ng/ml to at least one conventional test and MGHC greater than 3 ng/ml. GH peak and area under the curve (AUC) values were significantly lower in group 1 than groups 2 and 3 and in group 2 than group 3. GH peak and AUC values statistically correlated with height, height velocity, bone age/chronological age ratio and MGHC. Six children in group 1, 14 children in group 2 and all 18 children in group 3 showed after GHRH a GH peak greater than 10 ng/ml and were considered as 'responders'. Considering only the responders, GH peak and AUC values were significantly lower in group 1 than groups 2 and 3 and in group 2 than group 3. In conclusion, our data have shown that 87% of children with NCGHD responded to a single bolus of GHRH with an increase in GH levels greater than 10 ng/ml and that their responses were intermediate compared to those of CGHD and short normal subjects.