€> 1990 S. Karger AG. Basel 0301-0163/90/3310-0097S2.75/0
Horm Res 1990;33(suppl 4):97—101
Growth Hormone Treatment in Patients with Neurosecretory Dysfunction P. Rochiccioli, E. Dechaux, M.T. Tauber, C. Pienkowski, M. Tiberge Services de Pédiatrie (Unité d’EndocrinoIogie) et d’Exploration Neurologique, CHU Rangueil, Toulouse, France
Key Words. hGH therapy • Neurosecretory dysfunction • GH deficiency Abstract. Twenty-four children (14 boys and 10 girls) with neurosecretory dysfunction, defined by a response > 10 ng/ml to two pharmacological tests, and 24-hour GH secretion < 3 ng/ml/min, were treated with biosynthetic hGH. Mean age was 10 years 8 months ± 3 years 6 months. Growth retardation was -2.8 ± 0.8 SD. Eighteen children were prepubertal and six pubertal (P2). Mean peaks in two pharmacological stimulation tests were 25.8 ± 14.8 and 20.8 ± 11.5 ng/ml. Somatomedin C/insulin-like growth factor I level was 0.8 ± 0.6 IU/ml in the prepu bertal children. Twenty-four-hour integrated concentration of GH was low, at 2.2 ± 0.5 ng/ml/min. Analysis of secretory profiles showed 3 types: (1) hyperpulsatile profile with numerous peaks of low amplitude, (2) flat profile, (3) profile with an isolated peak > 10 ng/ml. Treatment with hGH (0.42 IU/kg/week) resulted in an increase in growth velocity from 4.9 ± 1.2 to 6.8 ± 2.2 cm/year. These results are comparable to those of a group with total GH deficiency receiving the same dose. Analysis of the results showed a group of good responders (n = 14, growth velocity: 8.1 cm/year) and a group of poor responders (n = 10, growth velocity: 4.9 cm/year). Thus, treatment of neurosecretory dysfunction with hGH gives results comparable to those obtained in classic GH secretory dysfunc tion.
children with neurosecretory dysfunction and compared the results with those of a group of children with total GH deficiency. Patients and Methods Twenty-four children with neurosecretory dysfunction (NSD), defined by a GH response > 10 ng/ml to two pharmacological stim ulation tests, and 24-hour endogenous GH secretion < 3 ng/ml/min, were selected for this study. There were 14 boys and 10 girls whose mean chronological age was 10 years 8 months (range 4-16 years). Bone age was 8 years 11 months ± 3 years 8 months (range 2-13 years). Growth retardation w as-2 .8 ± 0.8 SD. Eighteen children were prepubertal, with a mean growth velocity of 4.6 ± 0.8 cm/year, and 6 were Tanner stage P2, wiih a mean growth velocity of 5.9 ± 1.2 cm/year. All children underwent two pharmacological stimulation tests. The following tests were used:
Downloaded by: King's College London 137.73.144.138 - 12/3/2017 11:00:40 PM
For a long time, treatment with extractive GH was reserved only for total GH deficiencies, defined by a very low response to pharmacological tests. A few years ago, the development of biosynthetic GH made it possible to widen the indications. New investigations, such as the study of the endogenous secretion of GH, have of course confirmed the existence of total and partial deficiencies, but have also revealed situations where there is a dis crepancy between these two types of disorders. Among such situations, neurosecretory dysfunctions, which were isolated in 1984 [1], represent a particular type of GH deficiency, characterized by low endogenous secretion with a normal response to pharmacological tests. They have not yet been clearly identified, but they probably reflect an anomaly of GH secretion which can benefit from treatment with GH. In this study, we treated 24
Rochiccioli/Dcchaux/Taubcr/Pienkowski/Tiberge
98
3025-
I 20CD
c. 15-|
5JZ 10 5,__ 0
1
A
-I— I— I— I— I— I— I— I— I— I— I— I— I— I— I— I— I— I— I— I— I— I— I— I
2
11.00
8
10
12
14
16
18
20
22
24
Hours
Fig. 1. Analysis of 24-hour GH secretory profiles in NSD. a Hyperpulsatile profile with peaks of low amplitude, b Almost flat profile, c Presence of an iso lated peak > 10 ng/ml.
11 %, respectively. All measurements for the same child were carried out in the same assay. Polygraphic sleep recording (electroencephalogram, electromyo gram. electro-oculogram, respiration) was carried out after a prelim inary night of adaptation in 7 children, and the results were com pared with those of a control group and of a group with GH defi ciency [3]. The electroencephalographs were analyzed using the cri teria of Kales and Reichstaffen. Statistical analysis was done using Student’s t test for matched series and straight linear correlation according to Sperman’s law.
Treatment All children received biosynthetic hGH at an average dose of 0.42 IU/kg/week, with extremes ranging from 0.23 to 1.1 IU/week. The number of injections was 3-6/week. A clinical examination was carried out every 3 months, and a radiological check-up every 6 months. Twenty-four children were treated for 6 months, and 15 of these children for 1 year. A control group of children with total GH deficiency (maximum peak in two tests: m = 4.4 ng/ml) was also studied. This group was identical to the NSD group: the same number of patients (n = 24), chronological age (10 years 2 months, and dose of hGH (0.42 IU/kg/ week).
Downloaded by: King's College London 137.73.144.138 - 12/3/2017 11:00:40 PM
(1) Z.-dopa test: at 0 min, an oral dose of 125 mg for children weighing < 15 kg. 250 mg for children from 15 to 30 kg, and 500 mg for children > 30 kg was administered. Samples were taken for mea surement of GH at 0, 15, 30, 45, 60, 90 and 120 min. (2) Clonidine and betaxolol test: an oral dose of clonidine (0.025 mg/m: body surface area) and betaxolol (0.25 mg/kg) at 0 min was administered. Samples were taken for measurement of GH at 0, 30, 60, 90, 120, 150 and 180 min. Study of 24-hour GH secretion was performed by sampling of 1 ml of blood every 30 min during the day, and every 20 min during the night. The maximum peak, area under the curve, integrated concentration (1C) and number of peaks > 5 ng/ml were calculated for the day, the night and the 24-hour period. The GHRH test was carried out by intravenous injection of GHRH 1-44 (2 gg/kg) at 0 min, and blood samples were taken for measurement of GH every 15 min for 2 h. Somatomedin C (SM-C)/insulin-like growth factor 1 (IGF-I) was measured by double-antibody radioimmunoassay (R1A) in unex tracted plasma using standard serum and iodinated SM-C (Amersham) [2], Plasma GH was measured by double-antibody RIA using the CIS-ORIS kit (1 ng = 2 pU). The sensitivity of the method was 0.2 ng/ml. The intra- and interassay variation coefficients were 7.7 and
99
Neurosecretory Dysfunction
Hours
Results In the two pharmacological stimulation tests, the results were always > 10 ng/ml: 25.8 ± 14.8 ng/ml for the first test, 20.8 ± 1 1 .5 ng/ml for the second test. Twenty-four-hour GH secretion (IC) was low, always < 3 ng/ml/min, with a mean of 2.2 ± 0.5 ng/ml/min. IC during the day was 1.46 ± 0.44 ng/ml/min, and 2.9 ± 0.9 ng/ml/min during the night. The number of peaks > 5 ng/ml was 3.3 ± 1.9. Analysis of the 24-hour GH secretory profiles showed 3 types of profiles (fig. 1): the first characterized by numer ous peaks of low amplitude, the second practically flat, the third characterized by 1 isolated peak > 10 ng/ml. Response to the GHRH test was strong at 30.2 ± 10.5 ng/ml. Lastly, the SM-C/IGF-I level was 0.6 ± 0.2 U/ml
in the prepubertal group, and 1.01 ± 0.3 U/ml in the pubertal group. The polygraphic sleep recordings were compared with those of a group of normal children (n = 7) and of chil dren with partial GH deficiency (n = 12). The duration of stages I and II was identical in the 3 groups. However, the duration of stages III and IV was markedly lower in the NSD group, i.e. 22 instead of 36 and 31 %, respec tively. Moreover, the duration of REM sleep was mark edly higher in the NSD group, 21.9 instead of 10.5 and 9.4%, respectively (table 1). These results are clearly seen in the graphs in figure 2. Growth velocity in the NSD group increased from 4.9 ± 1.2 cm/year before treatment to 6.8 ± 2.2 cm/year after 6 months, and 6.2 ± 1.3 cm/year after 12 months of treatment. These results were very similar to those of
Downloaded by: King's College London 137.73.144.138 - 12/3/2017 11:00:40 PM
Fig. 2. EEG sleep recording in 2 chil dren of different ages (6 and 12 years) with NSD (a, b), and in I child with partial GH deficiency (c). Decreased duration of stages III and IV and increased duration of REM sleep.
Rochiccioli/Dcchaux/Tauber/Pienkowski/Tiberge
100
Good responders (n = 14)
Poor responders (n = 10)
Fig. 3. Individual results of hGH treatment in NSD showing two groups, one of good responders (n = 14) and one of poor responders (n = 10).
NSD n=7 Stage I, % Stage II. % Stages III + IV, % REM. % Sleep time, min Sleep efficiency Chronological age, years
10.5 44.3 22.9 21.9 476.2 0.72 10% 2
Control group n=7 10.4 42.5 36.5 10.5 491 0.66 IO6/,,
Partial GH deficiency n ■= 12 19.4 40 31.4 9.4 455 0.62 l l 3/, 2
the control group with total deficiency whose growth velocity was 6.4 cm/year at 12 months. In the NSD group, no correlation was found between growth velocity at 12 months and chronological age, bone age, growth retardation, maximum peak during pharmacological tests, 24-hour 1C or SM-C level. How ever. there was a positive correlation between growth velocity and the hGH dose given. Analysis of the results also revealed the existence of a group of good responders (n = 14, height increase > 2 cm/year) and a group of poor responders (n = 10, height increase < 2 cm/year; fig. 3). Growth velocity was signif icantly higher at 6 and at 12 months in the group of good
responders (8.1 and 7.3 cm/year) than in that of poor responders (4.9 and 5.3 cm/year). There was no differ ence between these two groups regarding chronological age, bone age, growth retardation, growth velocity, GH response to pharmacological tests and to the GHRH test, or in 24-hour IC. Only SM-C/IGF-I was lower in the group of good responders (0.6 U/ml) than in that of poor responders (1.07 U/ml), and lastly, the dose of hGH was slightly higher in the group of good responders, though not significantly so. Finally, we studied growth velocity at 12 months according to the 24-hour GH secretory profiles. There were better results in the children with type 3 profiles (a single isolated peak: 8.3 cm/year) than in those with type 1 and type 2 profiles (hyperpulsatility of low amplitude: 6.1 cm/year and flat profile: 5.1 cm/year).
Discussion NSD is a particular form of growth hormone deficinency characterized by low endogenous GH secretion whereas response to pharmacological tests is normal. This form was described in 1984 by Spiliotis [1], and other authors later published works on the same subject [4, 5]. However, the reality of this distinction is still a matter of discussion and is not universally accepted. In fact, this form of GH deficiency emphasizes the exis tence of a discrepancy between the results of pharmaco
Downloaded by: King's College London 137.73.144.138 - 12/3/2017 11:00:40 PM
Table 1. Polygraphic sleep recording in 7 children with NSD and in two control groups, normal children and children with partial GH deficiency
101
Neurosecretory Dysfunction
In conclusion, GH treatment in NSD gives results which are comparable with those obtained in total GH deficiency treated with the same dose. The dose we used (0.42 U/kg/week) is probably insufficient and should be increased to 0.6 or 0.7 U/kg/week in order to improve the results. Identification of NSD or low endogenous secretion does, therefore, correspond to a real entity which justi fies this type of investigation so that certain children ful filling these criteria can benefit from treatment with GH.
References 1 Spiliotis BE, August CP, Hung W, Sonis W, Mendelson W. Bercu BB: Growth hormone neurosecretory dysfunction: A treatable cause of short stature. JAMA 1984;251:2223-2230. 2 Châtelain PG, Van Wyck J, Copeland K.C, Blethen SL, Under wood LE: Effect of in vitro action of scrum protease or exposure to acid on measurable immunoreactive somatomedin C in se rum. J Clin Endocrinol Metab 1983;56:376-383. 3 Rochiccioli P, Sanz NT, Calvet U, Arbus L, Châtelain P, Ber nard MT, Dutau G, Sablayrolles B. Enjaume C: Etude de la sécrétion somatotrope de sommeil dans 60 cas de retards statu raux de l’enfant. Arch Fr Pédiatr 1985:8:665-670. 4 Bercu BB, Shulman D, Root AW, Spiliotis BE: Growth hormone (GH) provocative testing frequently does not reflect endogenous GH secretion. J Clin Endocrinol Metab 1986:63:709—716. 5 Zadik Z, Chalew SA. Raiti S, Kowarski AA: Do short children secrete insufficient growth hormone? Pediatrics 1985:76:335— 360. 6 Rochiccioli P: Comparison of pharmacological tests and 24-hour growth hormone secretion in 130 children with delayed growth. Acta Paediatr Scand Suppl 1987;337:72. 7 Bierich JR: Scrum growth hormone levels in provocation tests and during nocturnal spontaneous secretion: A comparative study. Acta Paediatr Scand Suppl 1987;337:48-59.
Professor P. Rochiccioli Service de Pédiatrie (Unité d'Endocrinologie) Service d'Exploration Neurologique CHU Rangueil F-31054 Toulouse (France)
Downloaded by: King's College London 137.73.144.138 - 12/3/2017 11:00:40 PM
logical tests and the study of endogenous 24-hour secre tion [6, 7], The term ‘low endogenous secretors’ better defines the reality of this anomaly than NSD, which implies a physiopathological mechanism not yet clari fied. This distinction is useful because investigation of endogenous secretion makes it possible to identify a form of GH deficiency which is not recognized by phar macological tests and which can be treated with GH. It was thus of interest to assess therapeutic efficacy in this group. In our work, we did this by comparing the results with a group with total GH deficiency. During treat ment, growth velocity increased in the NSD group, and this increase was identical to that observed in the total GH deficiency group. The height increase may seem moderate, but this is probably due to the dose used, which may be considered low (0.42 U/kg/week, the dose generally recommended in France by the ‘Commission France-Hypophyse’). A higher dose would probably have given better results, as in our series there was a positive correlation between growth velocity at 12 months and the dose used. In addition, the results show a distinction between a group of good responders and a group of poor respond ers. However, we found no clinical or hormonal criteria predicting the result of treatment. Two points should be stressed in our work: firstly, the differences observed in the polygraphic sleep recording, with a marked decrease in the duration of stages III and IV and an increase in the duration of REM sleep. This observation is interesting in view of the relationship which is known to exist between endogenous GH secre tion and the stages of deep sleep. However, these are preliminary results which require confirmation by stud ies of larger series; secondly, the varying therapeutic response according to the 3 types of profile of endoge nous GH secretion. Response was better in the profiles characterized by a single isolated peak than in the flat profiles or in the hyperpulsatile profiles with numerous peaks of low amplitude.
Horm Res 1990;33(suppl 4):97—101
Growth Hormone Treatment in Patients with Neurosecretory Dysfunction P. Rochiccioli, E. Dechaux, M.T. Tauber, C. Pienkowski, M. Tiberge Services de Pédiatrie (Unité d’EndocrinoIogie) et d’Exploration Neurologique, CHU Rangueil, Toulouse, France
Key Words. hGH therapy • Neurosecretory dysfunction • GH deficiency Abstract. Twenty-four children (14 boys and 10 girls) with neurosecretory dysfunction, defined by a response > 10 ng/ml to two pharmacological tests, and 24-hour GH secretion < 3 ng/ml/min, were treated with biosynthetic hGH. Mean age was 10 years 8 months ± 3 years 6 months. Growth retardation was -2.8 ± 0.8 SD. Eighteen children were prepubertal and six pubertal (P2). Mean peaks in two pharmacological stimulation tests were 25.8 ± 14.8 and 20.8 ± 11.5 ng/ml. Somatomedin C/insulin-like growth factor I level was 0.8 ± 0.6 IU/ml in the prepu bertal children. Twenty-four-hour integrated concentration of GH was low, at 2.2 ± 0.5 ng/ml/min. Analysis of secretory profiles showed 3 types: (1) hyperpulsatile profile with numerous peaks of low amplitude, (2) flat profile, (3) profile with an isolated peak > 10 ng/ml. Treatment with hGH (0.42 IU/kg/week) resulted in an increase in growth velocity from 4.9 ± 1.2 to 6.8 ± 2.2 cm/year. These results are comparable to those of a group with total GH deficiency receiving the same dose. Analysis of the results showed a group of good responders (n = 14, growth velocity: 8.1 cm/year) and a group of poor responders (n = 10, growth velocity: 4.9 cm/year). Thus, treatment of neurosecretory dysfunction with hGH gives results comparable to those obtained in classic GH secretory dysfunc tion.
children with neurosecretory dysfunction and compared the results with those of a group of children with total GH deficiency. Patients and Methods Twenty-four children with neurosecretory dysfunction (NSD), defined by a GH response > 10 ng/ml to two pharmacological stim ulation tests, and 24-hour endogenous GH secretion < 3 ng/ml/min, were selected for this study. There were 14 boys and 10 girls whose mean chronological age was 10 years 8 months (range 4-16 years). Bone age was 8 years 11 months ± 3 years 8 months (range 2-13 years). Growth retardation w as-2 .8 ± 0.8 SD. Eighteen children were prepubertal, with a mean growth velocity of 4.6 ± 0.8 cm/year, and 6 were Tanner stage P2, wiih a mean growth velocity of 5.9 ± 1.2 cm/year. All children underwent two pharmacological stimulation tests. The following tests were used:
Downloaded by: King's College London 137.73.144.138 - 12/3/2017 11:00:40 PM
For a long time, treatment with extractive GH was reserved only for total GH deficiencies, defined by a very low response to pharmacological tests. A few years ago, the development of biosynthetic GH made it possible to widen the indications. New investigations, such as the study of the endogenous secretion of GH, have of course confirmed the existence of total and partial deficiencies, but have also revealed situations where there is a dis crepancy between these two types of disorders. Among such situations, neurosecretory dysfunctions, which were isolated in 1984 [1], represent a particular type of GH deficiency, characterized by low endogenous secretion with a normal response to pharmacological tests. They have not yet been clearly identified, but they probably reflect an anomaly of GH secretion which can benefit from treatment with GH. In this study, we treated 24
Rochiccioli/Dcchaux/Taubcr/Pienkowski/Tiberge
98
3025-
I 20CD
c. 15-|
5JZ 10 5,__ 0
1
A
-I— I— I— I— I— I— I— I— I— I— I— I— I— I— I— I— I— I— I— I— I— I— I— I
2
11.00
8
10
12
14
16
18
20
22
24
Hours
Fig. 1. Analysis of 24-hour GH secretory profiles in NSD. a Hyperpulsatile profile with peaks of low amplitude, b Almost flat profile, c Presence of an iso lated peak > 10 ng/ml.
11 %, respectively. All measurements for the same child were carried out in the same assay. Polygraphic sleep recording (electroencephalogram, electromyo gram. electro-oculogram, respiration) was carried out after a prelim inary night of adaptation in 7 children, and the results were com pared with those of a control group and of a group with GH defi ciency [3]. The electroencephalographs were analyzed using the cri teria of Kales and Reichstaffen. Statistical analysis was done using Student’s t test for matched series and straight linear correlation according to Sperman’s law.
Treatment All children received biosynthetic hGH at an average dose of 0.42 IU/kg/week, with extremes ranging from 0.23 to 1.1 IU/week. The number of injections was 3-6/week. A clinical examination was carried out every 3 months, and a radiological check-up every 6 months. Twenty-four children were treated for 6 months, and 15 of these children for 1 year. A control group of children with total GH deficiency (maximum peak in two tests: m = 4.4 ng/ml) was also studied. This group was identical to the NSD group: the same number of patients (n = 24), chronological age (10 years 2 months, and dose of hGH (0.42 IU/kg/ week).
Downloaded by: King's College London 137.73.144.138 - 12/3/2017 11:00:40 PM
(1) Z.-dopa test: at 0 min, an oral dose of 125 mg for children weighing < 15 kg. 250 mg for children from 15 to 30 kg, and 500 mg for children > 30 kg was administered. Samples were taken for mea surement of GH at 0, 15, 30, 45, 60, 90 and 120 min. (2) Clonidine and betaxolol test: an oral dose of clonidine (0.025 mg/m: body surface area) and betaxolol (0.25 mg/kg) at 0 min was administered. Samples were taken for measurement of GH at 0, 30, 60, 90, 120, 150 and 180 min. Study of 24-hour GH secretion was performed by sampling of 1 ml of blood every 30 min during the day, and every 20 min during the night. The maximum peak, area under the curve, integrated concentration (1C) and number of peaks > 5 ng/ml were calculated for the day, the night and the 24-hour period. The GHRH test was carried out by intravenous injection of GHRH 1-44 (2 gg/kg) at 0 min, and blood samples were taken for measurement of GH every 15 min for 2 h. Somatomedin C (SM-C)/insulin-like growth factor 1 (IGF-I) was measured by double-antibody radioimmunoassay (R1A) in unex tracted plasma using standard serum and iodinated SM-C (Amersham) [2], Plasma GH was measured by double-antibody RIA using the CIS-ORIS kit (1 ng = 2 pU). The sensitivity of the method was 0.2 ng/ml. The intra- and interassay variation coefficients were 7.7 and
99
Neurosecretory Dysfunction
Hours
Results In the two pharmacological stimulation tests, the results were always > 10 ng/ml: 25.8 ± 14.8 ng/ml for the first test, 20.8 ± 1 1 .5 ng/ml for the second test. Twenty-four-hour GH secretion (IC) was low, always < 3 ng/ml/min, with a mean of 2.2 ± 0.5 ng/ml/min. IC during the day was 1.46 ± 0.44 ng/ml/min, and 2.9 ± 0.9 ng/ml/min during the night. The number of peaks > 5 ng/ml was 3.3 ± 1.9. Analysis of the 24-hour GH secretory profiles showed 3 types of profiles (fig. 1): the first characterized by numer ous peaks of low amplitude, the second practically flat, the third characterized by 1 isolated peak > 10 ng/ml. Response to the GHRH test was strong at 30.2 ± 10.5 ng/ml. Lastly, the SM-C/IGF-I level was 0.6 ± 0.2 U/ml
in the prepubertal group, and 1.01 ± 0.3 U/ml in the pubertal group. The polygraphic sleep recordings were compared with those of a group of normal children (n = 7) and of chil dren with partial GH deficiency (n = 12). The duration of stages I and II was identical in the 3 groups. However, the duration of stages III and IV was markedly lower in the NSD group, i.e. 22 instead of 36 and 31 %, respec tively. Moreover, the duration of REM sleep was mark edly higher in the NSD group, 21.9 instead of 10.5 and 9.4%, respectively (table 1). These results are clearly seen in the graphs in figure 2. Growth velocity in the NSD group increased from 4.9 ± 1.2 cm/year before treatment to 6.8 ± 2.2 cm/year after 6 months, and 6.2 ± 1.3 cm/year after 12 months of treatment. These results were very similar to those of
Downloaded by: King's College London 137.73.144.138 - 12/3/2017 11:00:40 PM
Fig. 2. EEG sleep recording in 2 chil dren of different ages (6 and 12 years) with NSD (a, b), and in I child with partial GH deficiency (c). Decreased duration of stages III and IV and increased duration of REM sleep.
Rochiccioli/Dcchaux/Tauber/Pienkowski/Tiberge
100
Good responders (n = 14)
Poor responders (n = 10)
Fig. 3. Individual results of hGH treatment in NSD showing two groups, one of good responders (n = 14) and one of poor responders (n = 10).
NSD n=7 Stage I, % Stage II. % Stages III + IV, % REM. % Sleep time, min Sleep efficiency Chronological age, years
10.5 44.3 22.9 21.9 476.2 0.72 10% 2
Control group n=7 10.4 42.5 36.5 10.5 491 0.66 IO6/,,
Partial GH deficiency n ■= 12 19.4 40 31.4 9.4 455 0.62 l l 3/, 2
the control group with total deficiency whose growth velocity was 6.4 cm/year at 12 months. In the NSD group, no correlation was found between growth velocity at 12 months and chronological age, bone age, growth retardation, maximum peak during pharmacological tests, 24-hour 1C or SM-C level. How ever. there was a positive correlation between growth velocity and the hGH dose given. Analysis of the results also revealed the existence of a group of good responders (n = 14, height increase > 2 cm/year) and a group of poor responders (n = 10, height increase < 2 cm/year; fig. 3). Growth velocity was signif icantly higher at 6 and at 12 months in the group of good
responders (8.1 and 7.3 cm/year) than in that of poor responders (4.9 and 5.3 cm/year). There was no differ ence between these two groups regarding chronological age, bone age, growth retardation, growth velocity, GH response to pharmacological tests and to the GHRH test, or in 24-hour IC. Only SM-C/IGF-I was lower in the group of good responders (0.6 U/ml) than in that of poor responders (1.07 U/ml), and lastly, the dose of hGH was slightly higher in the group of good responders, though not significantly so. Finally, we studied growth velocity at 12 months according to the 24-hour GH secretory profiles. There were better results in the children with type 3 profiles (a single isolated peak: 8.3 cm/year) than in those with type 1 and type 2 profiles (hyperpulsatility of low amplitude: 6.1 cm/year and flat profile: 5.1 cm/year).
Discussion NSD is a particular form of growth hormone deficinency characterized by low endogenous GH secretion whereas response to pharmacological tests is normal. This form was described in 1984 by Spiliotis [1], and other authors later published works on the same subject [4, 5]. However, the reality of this distinction is still a matter of discussion and is not universally accepted. In fact, this form of GH deficiency emphasizes the exis tence of a discrepancy between the results of pharmaco
Downloaded by: King's College London 137.73.144.138 - 12/3/2017 11:00:40 PM
Table 1. Polygraphic sleep recording in 7 children with NSD and in two control groups, normal children and children with partial GH deficiency
101
Neurosecretory Dysfunction
In conclusion, GH treatment in NSD gives results which are comparable with those obtained in total GH deficiency treated with the same dose. The dose we used (0.42 U/kg/week) is probably insufficient and should be increased to 0.6 or 0.7 U/kg/week in order to improve the results. Identification of NSD or low endogenous secretion does, therefore, correspond to a real entity which justi fies this type of investigation so that certain children ful filling these criteria can benefit from treatment with GH.
References 1 Spiliotis BE, August CP, Hung W, Sonis W, Mendelson W. Bercu BB: Growth hormone neurosecretory dysfunction: A treatable cause of short stature. JAMA 1984;251:2223-2230. 2 Châtelain PG, Van Wyck J, Copeland K.C, Blethen SL, Under wood LE: Effect of in vitro action of scrum protease or exposure to acid on measurable immunoreactive somatomedin C in se rum. J Clin Endocrinol Metab 1983;56:376-383. 3 Rochiccioli P, Sanz NT, Calvet U, Arbus L, Châtelain P, Ber nard MT, Dutau G, Sablayrolles B. Enjaume C: Etude de la sécrétion somatotrope de sommeil dans 60 cas de retards statu raux de l’enfant. Arch Fr Pédiatr 1985:8:665-670. 4 Bercu BB, Shulman D, Root AW, Spiliotis BE: Growth hormone (GH) provocative testing frequently does not reflect endogenous GH secretion. J Clin Endocrinol Metab 1986:63:709—716. 5 Zadik Z, Chalew SA. Raiti S, Kowarski AA: Do short children secrete insufficient growth hormone? Pediatrics 1985:76:335— 360. 6 Rochiccioli P: Comparison of pharmacological tests and 24-hour growth hormone secretion in 130 children with delayed growth. Acta Paediatr Scand Suppl 1987;337:72. 7 Bierich JR: Scrum growth hormone levels in provocation tests and during nocturnal spontaneous secretion: A comparative study. Acta Paediatr Scand Suppl 1987;337:48-59.
Professor P. Rochiccioli Service de Pédiatrie (Unité d'Endocrinologie) Service d'Exploration Neurologique CHU Rangueil F-31054 Toulouse (France)
Downloaded by: King's College London 137.73.144.138 - 12/3/2017 11:00:40 PM
logical tests and the study of endogenous 24-hour secre tion [6, 7], The term ‘low endogenous secretors’ better defines the reality of this anomaly than NSD, which implies a physiopathological mechanism not yet clari fied. This distinction is useful because investigation of endogenous secretion makes it possible to identify a form of GH deficiency which is not recognized by phar macological tests and which can be treated with GH. It was thus of interest to assess therapeutic efficacy in this group. In our work, we did this by comparing the results with a group with total GH deficiency. During treat ment, growth velocity increased in the NSD group, and this increase was identical to that observed in the total GH deficiency group. The height increase may seem moderate, but this is probably due to the dose used, which may be considered low (0.42 U/kg/week, the dose generally recommended in France by the ‘Commission France-Hypophyse’). A higher dose would probably have given better results, as in our series there was a positive correlation between growth velocity at 12 months and the dose used. In addition, the results show a distinction between a group of good responders and a group of poor respond ers. However, we found no clinical or hormonal criteria predicting the result of treatment. Two points should be stressed in our work: firstly, the differences observed in the polygraphic sleep recording, with a marked decrease in the duration of stages III and IV and an increase in the duration of REM sleep. This observation is interesting in view of the relationship which is known to exist between endogenous GH secre tion and the stages of deep sleep. However, these are preliminary results which require confirmation by stud ies of larger series; secondly, the varying therapeutic response according to the 3 types of profile of endoge nous GH secretion. Response was better in the profiles characterized by a single isolated peak than in the flat profiles or in the hyperpulsatile profiles with numerous peaks of low amplitude.
