Neurosecretory Dysfunction Research Articles

A visual motor psychological test as a predictor to treatment in nocturnal enuresis

Background and Aims: The neurological control of bladder function and the ability to be dry at night involves not only the acquisition of normal daytime control, but also the establishment...

Behavioral evaluation of GH treatment in short statured children and adolescents: findings from a pilot study.

A cohort of 93 short-statured children and adolescents undergoing GH treatment were evaluated with respect to behavior, emotions, and attitudes. The sample consisted of patients suffering from either idiopathic GH deficiency or neurosecretory dysfunction (no.=47), Turner syndrome (no.=20), organic GH deficiency due to brain tumors (no.=10), or other etiologies (no.=16). The Child Behavior Checklist (CBCL) together with a brief Evaluation of Treatment Questionnaire (ETQ) were filled out by the patient's parents. These evaluations were performed at onset and after 12 and 24 months of GH treatment, respectively. There was a highly significant but clinically small decline of behavioral abnormalities over time and parents saw major benefits of GH treatment in the total group of patients. The behavioral changes over time were independent of diagnostic category, gender, height velocity, puberty and age.

Late hormonal complications after brain tumor treatment in childhood and adolescence: literature review and a model of integrated hormone aftercare

The variety of endocrine late-effects after brain tumour therapy in childhood is well known. Growth is usually impaired first due to a hypothalamo-pituitary growth hormone (GH) deficiency or a radiation-induced neurosecretory dysfunction of GH secretion. Generally, all hypothalamo-pituitary axes can be affected. Disturbances of puberty, gonadal function, thyroid function and adrenal function can manifest after a long posttherapeutic interval. A retrospective analysis of the auxological and endocrinological data assessed within the German brain tumour study HIT 91 showed that endocrinological follow-up of these patients was not satisfactory. Therefore we have developed a concept for the new brain tumour study: auxological and laboratory parameters will be assessed before oncological therapy and in regular intervals (4, 12, 18, 24 months after the end of tumour therapy). 24 months after the end of tumour therapy all hypothalamo-pituitary axes are to be evaluated with pharmacological stimulation tests.

Reduction of the pituitary GH releasable pool in short children with GH neurosecretory dysfunction

The classical 'GH neurosecretory dysfunction' (GHNSD) refers to slowly growing children with normal GH responses to classical provocative tests but impaired spontaneous GH secretion over 24 h frequently leading to low IGF-I levels. Thus it has been assumed that these subjects have insufficiency of spontaneous GH secretion due to neuroendocrine abnormalities in spite of a normal releasable pool of GH. However, classical provocative tests do not reliably assess the maximal somatotroph capacity; thus it is still unclear if the GH pool is really preserved or not. GHRH + arginine test is more potent than the classical tests and evaluates the maximal secretory capacity of somatotroph cells. The GH response to this stimulus is reproducible and also independent of age and puberty. We studied the GH response to GHRH (1 microgram/kg iv) + arginine (ARG, 0.5 g/kg iv) in 19 short children with GHNSD (14 boys and 5 girls, age: 12.1 +/- 0.7 years, pubertal stages I-III, HV-SDS between -1.6 and -4.9; GH peak > 10 micrograms/l after classical stimuli but mean GH concentration (mGHc) < 3 micrograms/l). The results in GHNSD were compared with those in 38 short children with idiopathic or organic severe GHD (GHD, 29 boys and 9 girls, age: 11.2 +/- 0.6 years, pubertal stages I-III, HV-SDS between -1.8 and -4.4; GH peak < 10 micrograms/l after 2 classical provocative tests) and in 83 children with normal or familial short stature (NC, 59 boys and 24 girls, age: 11.5 +/- 0.3 years., pubertal stages I-III; HV-SDS > 25th centile, normal IGF-I levels). Mean IGF-I levels in GHNSD (121.9 +/- 20.3 micrograms/l) were lower (P < 0.001) than those in NC (270.3 +/- 13.8 micrograms/l) but higher (P < 0.001) than those in GHD (72.0 +/- 4.0 micrograms/l). The mean GH concentration (mGHc) in GHNSD (2.1 +/- 0.1 micrograms/l) was lower (P < 0.01) than that in NC (4.9 +/- 0.5 micrograms/l) but higher (P < 0.01) than that in GHD (1.5 +/- 0.2 micrograms/l). On the other hand, the mean peak GH response to GHRH + ARG in GHNSD (43.7 +/- 3.7 micrograms/l) was markedly higher (P < 0.001) than that in GHD (8.2 +/- 0.9 micrograms/l) but significantly lower (P < 0.01) than that in NC (60. 4 +/- 2.7 micrograms/l). All GHD patients had peak GH responses to GHRH + ARG below the 3rd centile limit of normality (20 micrograms/l), while all GHNSD patients had peak GH responses within the normal range. No significant correlation was found between GH peak after GHRH + ARG, mGHc and IGF-I levels in each group. Our study demonstrates that short children with 'GH neurosecretory dysfunction' show reduction in the GH releasable pool evaluated by the provocative and potent GHRH + arginine test. However, the peak GH response to a single GHRH + arginine test in GH neurosecretory dysfunction is always within the normal range indicating that this test as well as classical stimuli does not distinguish normal subjects from GH neurosecretory dysfunction.

Growth during and after a trial of growth hormone releasing hormone 1-29 in children with idiopathic short stature or growth hormone neurosecretory dysfunction.

The growth promoting effects of once nightly subcutaneous injections of growth hormone releasing hormone (GHRH) 1-29 (30 microg/kg) for 6 months were studied in 16 slowly growing prepubertal children with idiopathic short stature (ISS; Group 1) and 8 similar children with growth hormone neurosecretory dysfunction (GHND; Group 2). Each child underwent endogenous growth hormone evaluation using both pharmacological and physiological testing; each had stimulated values > 10 microg/l and were subsequently placed into one of two groups based on pooled 12-hour overnight GH of < or > or = 3 microg/l. Each patient was followed every three months for one year. There were no significant differences in the two groups throughout the study with the exception of the endogenous GH levels. Both groups responded to GHRH therapy with similar significant increases in their rates of growth. Although a subset of patients (6 of 21) continued to grow at a rate significantly greater than the pre-therapy rate of growth, overall rates of growth were not significantly different from the pre-therapy growth rates 6 months following the discontinuation of GHRH treatment. We conclude that GHRH 1-29, given in the doses provided, leads to similar changes in growth rates in short, slowly growing children who are GH sufficient and those with GHND. Despite prior reports to the contrary, GHND patients do not experience a sustained increased in growth rate upon discontinuation of GHRH.

Somatostatin infusion withdrawal: studies in normal children and in children with growth hormone deficiency.

Withdrawal of a somatostatin infusion (SSIW) is followed by a rebound rise of GH in both animals and normal adult men, a phenomenon likely mediated by endogenous GHRH function. In the present study, we have evaluated the GH response to SSIW in a group of 28 prepubertal children (18 boys and 10 girls; aged 3.7-11.1 yr). Six children had GH deficiency [GHD; GH responses to pyridostigmine (PD)+GHRH and to clonidine <20 and <7 microg/L, respectively], 4 children had GH neurosecretory dysfunction (GHND; GH responses to PD+GHRH and to clonidine > or =20 and >7 microg/L, respectively; mean integrated nighttime GH concentrations <3 microg/L), and 18 children were short normal children [normal controls (NC)]. All children received a constant infusion of SS at the dose of 3 microg/Kg x h for 90 min. SSIW elicited a clear-cut GH rise in NC children (13.7+/-1.0 microg/L), but not in GH-deficient children, regardless of the underlying etiology (GHD, 1.6+/-0.4 microg/L; GHND, 2.4+/-0.3 microg/L). The GH response to SSIW was similar between GHD and GHND children. There was no overlapping of the maximum SSIW-stimulated GH peaks between NC and GHD or GHND children. In conclusion, we have demonstrated that SSIW elicits a significant GH rise in NC children, but not in GH-deficient children, regardless of the underlying etiology (GHD or GHND). This resulted in complete discrimination of NC from GHD or GHND children. Were these present findings confirmed on a larger number of children, SSIW, because of its testing efficaciousness and safety, procedural simplicity, and economy holds promise of being a useful diagnostic tool for GH-dependent growth disorders.

Beta-thalassemia and normal growth: are they compatible?

The cause of growth retardation in the inherited blood disorder b-thalassemia major (b-thal) has long been a subject of debate. This has become an issue in the last few years since children with b-thal are undergoing hypertransfusion and iron chelation therapy, and now living well into their thirties and forties. Therefore, in addition to growth retardation, many of the endocrinopathies such as hypogonadism, hypothyroidism, hypoparathyroidism and diabetes mellitus, which were not apparent before, are now being diagnosed and treated. Despite the fact that much has been learned in the past few years about the etiology of growth retardation in children with b-thal, treatment is still difficult in many cases. Normal growth of b-thal children during the first 10 years of life depends upon the maintenance of hemoglobin levels above 8.5 g/dl. During this period of the child’s life hypoxia may be the main factor retarding growth, and the maintenance of hemoglobin levels above 10‐11 g/dl together with adequate iron chelation therapy makes the b-thal patients indistinguishable from their non-thalassemic peers (1). If deferoxamine, which is used for iron chelation therapy, is used before the age of 3 years it also produces marked stunted growth with a clinical and radiologic rickets-like syndrome (2). This is because, before there is iron overload from the blood transfusions, deferoxamine is thought to also chelate other essential minerals besides iron. After the age of 10 though, despite the fact that adequate levels of hemoglobin are maintained, many of the b-thal children start having decelerated growth. In the pubertal children there may be a reduced growth spurt with marked deceleration, for which iron overload may be responsible (3). In this age group truncal shortening, most likely due to hypogonadism secondary to iron deposition, may also be found. The hormonal cause of growth retardation in b-thal children is complex. Besides hypothyroidism and hypogonadism it has become apparent that growth hormone (GH) also plays a role in their abnormal growth. It still remains unclear, though, how the GH and insulin-like growth factor-I (IGF-I) axis may play a role. Several authors have reported reduced serum concentrations of IGF-I in the presence of a normal GH response to provocative studies (4, 5) and this led to the speculation that GH insensitivity is most likely the cause of the abnormal growth. Others have found, though, that classic GH deficiency and GH neurosecretory dysfunction (6) are the causes of the low IGF-I and short stature in many patients. The b-thal patients may have subnormal spontaneous GH secretion and an impaired GH response to GH-releasing hormone. Histologic examination at autopsy of the endocrine glands of b-thal patients has shown mild to moderate siderosis and a reduced number of cells in the pituitary gland together with fibrosis and siderosis of the thyroid gland and gonads (7). This is consistent with the view that many b-thal patients may have primary or secondary endocrine gland dysfunction. Undernutrition is also an important cause of low IGF-I and associated growth disturbances in this group. This may be compounded in certain cases of undernutrition by zinc deficiency. In the article by Soliman and coworkers (8), the authors studied the GH response to clonidine and glucagon, and the levels of IGF-I, insulin-like growth factor-binding protein-3 (IGFBP-3) and ferritin, and they also evaluated the levels of IGF-I after 1 day of GH administration. They also followed the growth velocity of three groups of children, b-thal patients, children with GH deficiency (GHD) and children with constitutional short stature (CSS), after 1 year of hGH therapy. They found that the b-thal children had a reduced IGF-I response after 1 day of GH administration, compared

Effect of long-term growth hormone treatment on carbohydrate metabolism in children with growth hormone deficiency.

Growth hormone (GH) has well known effects on carbohydrate metabolism. We have evaluated the effects of long-term growth hormone (GH) therapy on carbohydrate metabolism in children with classical GH deficiency (GHD) or GH neurosecretory dysfunction (GHND). Glucose, insulin and C-peptide concentrations at baseline and during oral glucose tolerance test (OGTT) were measured before and after 18 and 36 months of GH therapy (0.6-0.8 IU/Kg/week in 6 evening doses) in 13 GHD and 7 GHND children (15 boys and 5 girls, 15 prepubertal and 5 early pubertal; age at diagnosis 2.11-13.1 y). Mean fasting insulin and C-peptide concentrations after 18 months were similar to the pretreatment values, while after 36 months they were significantly higher than before treatment. Fasting glucose concentrations were similar to pretreatment both after 18 and 36 months. The mean areas under the curve (AUC) during OGTT for glucose, insulin, and C-peptide were significantly increased after 18 and 36 months. There were no differences between GHD and GHND patients. During the treatment period 10 of the 15 prepubertal patients entered puberty. A significant increase of insulin and C-peptide concentrations occurred after 36 months of GH treatment in the patients that remained prepubertal during treatment as well as in those who were pubertal when treatment was started. In three of our patients GH treatment caused glucose intolerance, which resolved after 6-12 months of a normal calorie low-simple carbohydrate diet without requiring discontinuation of treatment. Our data show that long-term GH treatment in GH deficient children causes hyperglycaemia and increased insulin secretion. These effects may in some patients induce glucose intolerance, which is reversible with appropriate dietary measures and does not require discontinuation of treatment.

Arm span, serum IGF-1 and IGFBP-3 levels as screening parameters for the diagnosis of growth hormone deficiency in patients with myelomeningocele--preliminary data.

Short stature is a common problem in patients with myelomeningocele (MMC) and hydrocephalus. We evaluated auxological and laboratory parameters to differentiate short stature due to neurological defect from short stature additionally caused by growth hormone deficiency (GHD). In a group of 38 prepubertal patients with MMC and hydrocephalus aged 3.8-11.0 years, auxological parameters, including arm span and bone age, and serum insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) levels were measured. Patients with normal supine length (n = 15) had normal arm span. Serum IGF-1 and IGFBP-3 levels were normal (> or = 10th percentile) in 14/15 patients. Twenty-three MMC patients had short stature (height SDS < -2), 11/23 patients had reduced arm span (SDS < -2), and 12/23 had normal arm span. Serum IGF-1 and IGFBP-3 levels were normal in 10/12 of short statured patients with normal arm span, but low (< 10th percentile) in those patients with reduced arm span (IGF-1: 8/11 patients, P < 0.05; IGFBP-3: 9/11 patients, P < 0.005). In 7/11 short statured MMC patients with reduced arm span and low serum IGF-1 and IGFBP-3 levels, growth hormone secretion was investigated. All had a disturbed growth hormone secretion (GHD: n = 4; neurosecretory dysfunction: n = 3). Arm span, serum IGF-1 and IGFBP-3 levels are estimated to be appropriate screening parameters for GHD in patients with MMC. Initiating growth hormone therapy should be considered not only according to endocrine findings but also with respect to neurological and orthopaedic anomalies.

Predictive Value of Serum Follicle-Stimulating Hormone Levels in the Differentiation between Hypogonadotropic Hypogonadism and Constitutional Delay of Puberty

Objective: Gonadotropin secretion was evaluated to predict hypogonadotropic hypogonadism (HH) in 36 children suspected of having HH. Methods: LH was measured for 24 h at 10-min intervals, and FSH and estradiol or testosterone at 1-hour intervals. Twenty boys (age 15.7, range 13.2–19.3 years) and 16 girls (age 16.1, range 13.0–20.6 years) were studied. Results: LH pulses were detected in 9 boys and 5 girls. HH was confirmed in all 11 LH apulsatile boys and in 8 of 11 LH apulsatile girls. Random FSH values of ≤1.11 and ≤2.86 IU/l in boys and girls, respectively, discriminated patients with LH pulses from patients without (sensitivity for lack of LH pulses 97 and 100%, respectively). In boys testicular volume was not discriminatory. In 1 girl LH pulses were observed without estradiol production, suggesting LH neurosecretory dysfunction. Conclusions: Low FSH levels in adolescence are strongly related to a lack of LH pulses. Lack of LH pulses is highly suspect for HH. FSH may be a tool in the differentiation between HH and delayed puberty.

Short stature and failure of pubertal development in thalassaemia major: evidence for hypothalamic neurosecretory dysfunction of growth hormone secretion and defective pituitary gonadotropin secretion.

In patients with beta-thalassaemia major, frequent blood transfusions combined with desferrioxamine chelation therapy lead to an improved rate of survival. Endocrine disorders related to secondary haemosiderosis such as short stature, delayed puberty and hypogonadism are major problems in both adolescent and adult patients. A total of 32 patients with beta-thalassaemia major undergoing treatment at the Children's Hospital, University of Göttingen were examined. Fourteen of these were short in stature. Growth hormone (GH) secretion was investigated in 13 patients exhibiting either a short stature or reduced growth rate. The stimulated GH secretion of 10 patients in this subgroup lay within the normal range. Studies of their spontaneous GH secretion during the night revealed that these patients had a markedly reduced mean GH and reduced amplitudes in their GH peaks. Low insulin-like growth factor (IGF)-I levels were seen in the growth-retarded thalassaemic patients. Eight were subjected to an IGF generation test and showed a strong increase in both IGF-I and insulin-like growth factor binding protein (IGFBP)-3 levels indicating intact IGF-I generation by the liver. Hypogonadotropic hypogonadism was found to be present in both the male and female patients with impaired sexual development. After priming with LH-releasing hormone (GnRH) per pump in 2 female and 5 male patients, no change in either their serum oestradiol or testosterone levels or in LH/FSH response to GnRH was observed suggesting that they were suffering from a severe pituitary gonadotropin insufficiency. Three male patients at the age of puberty but exhibiting short stature. low GH, low IGF-I and hypogonadism received low dose long-acting testosterone. After 3 12 months of therapy there was a marked growth spurt, higher nocturnal GH levels and an increase in both IGF-I and IGFBP-3. Reduced GH secretion and low IGF-I in thalassaemic patients are related to a neurosecretory dysfunction due to iron overload rather than to liver damage. Hypogonadotropic hypogonadism is caused by the selective loss of pituitary gonadotropin function. In patients with both GH deficiency and hypogonadism, low dose sexual steroid treatment should be considered either as an alternative or an additional treatment before starting GH therapy.

Magnetic resonance images of 91 children with different causes of short stature: pituitary size reflects growth hormone secretion.

In order to validate an association between pituitary size and severity of growth hormone deficiency (GHD) we evaluated the magnetic resonance images (MRI) of 107 children with different causes of short stature. Ninety-one MRIs were evaluable (64 male, 27 female; age: 9.1 +/- 3.9 years). The levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3), and tests of GH stimulation and spontaneous secretion, led to the following subgroups: severe isolated GHD (SIGHD) (GH < 7 ng/ml) (n = 21); partial, isolated GHD (GH 7-10 ng/ml) (n = 22); multiple pituitary hormone deficiency (MPHD) (n = 13); neurosecretory dysfunction (n = 10); non-classifiable diagnosis (NC) (n = 13); idiopathic short stature (n = 9); and intra-uterine growth retardation (n = 3). Pituitary height (PHT) was measured and hypoplasia was assumed when PHT was < -2 SDS. An ectopic posterior pituitary with missing stalk and a hypoplastic anterior pituitary was present in 12 (57%) SIGHD cases, 12 (92%) MPHD cases and 1 patient from the NC group. An isolated hypoplastic anterior pituitary was observed in 15%-33% of the other groups. PHT (mm; mean, SD) in MPHD (1.7 +/- 0.5) was lower than in SIGHD (2.7 +/- 1.0, P < 0.05), with PHT of both groups being lower than in all the other groups (3.8 +/- 0.9, P < 0.0001). PHT SDS correlates with IGF-I SDS (r = 0.48, P < 0.0001), IGFBP-3 SDS (r = 0.46, P < 0.0001) and the highest peaks in tests of GH stimulation and GH spontaneous secretion (r = 0.36, P < 0.0001). In contrast to all the other groups, no correlation with age was observed in MPHD and SIGHD. Breech delivery was recorded in up to 26% of patients in all seven groups. Surprisingly, only 1 out of 23 patients with an ectopic posterior pituitary was born by breech delivery, suggesting that ectopia of the posterior lobe is not necessarily related to breech delivery. PHT is significantly correlated with GH secretion in several types of short stature. Patients with ectopic posterior pituitary, missing stalk and hypoplastic anterior pituitary either suffer from SIGHD or MPHD, and this anatomical defect is not necessarily related to breech delivery.

Craniocerebral imaging in children with short stature

To analyse the type and frequency of cranial CT and NMR imaging anomalies in children of short stature. We studied 57 children of short stature with a mean age (+/-SD) of 10.1 +/- 3.8 years, 34 boys and 23 girls, all of them with auxometric criteria of GH deficiency. After studying the pituitary function and determination of karyotype in the girls, the children were classified in to five groups:-Isolated GHD (IGHD) (n = 32), multiple pituitary hormone deficiency (MPHD) (n = 6), neurosecretory dysfunction (NSD) (n = 8), Turner syndrome (n = 7) and idiopathic short stature (ISS) (n = 4). The imaging methods used were cranial CT or NMR. Of the 57 children studied the CT/NMR was abnormal in 37(64.9%) children. We found anomalies in 65.6% of IGHD patients, 62.5% of NSD patients, 100% of MPHD patients and 57.1% and 25% in the Turner s. patients and ISS patients respectively. The most frequent anomaly was hypoplastic pituitary found in 50% of IGHD patients, 37.5% of NSD patients and 33.3% of MPHD patients. None of the cases of Turner s. or ISS had hypoplastic pituitary. An empty sella was the second most frequent anomaly found in 7 patients (IGHD-3, MPHD-3, DNS-1). Of the 25 children in which NMR was performed, 8 had hypoplastic pituitary and stalk and 2 had interruption of the pituitary stalk and ectopic neurohypophysis. These results strengthen the necessity for CT/NMR imaging in children of short stature which, besides allowing identification of tumors, also permits the diagnosis of idiopathic GHD because of its frequent association with cranial imaging anomalies, mainly hypoplastic pituitary.

Growth hormone (GH) response to GH-releasing hormone in short children: Lack of correlation with endogenous nocturnal GH secretion

The growth hormone (GH) response to iv administration of GH-releasing hormone (GHRH, 0.3 microgram/Kg) was evaluated in 21 short children (13 boys and 8 girls, age 6.7-13.8 yr). Fourteen had familial short stature and/or constitutional growth delay, one had coeliac disease, and 6 were ultimately diagnosed as non-classical GH deficiency or neurosecretory dysfunction on the basis of subnormal integrated spontaneous GH concentrations (ICGH). The response was compared with 12-h spontaneous GH secretion measured every 30 min from 20:00 to 08:00. Mean ICGH ranged from 2.0-17.7 micrograms/l, with a maximum nocturnal GH peak ranging from 5.4-74 micrograms/l. The maximum GH peak after GHRH ranged from 9.4-50 micrograms/l, and the area under the curve (AUC) from 406-3012 micrograms.min/l. No correlation was found between the maximum GH peak and the AUC after GHRH and the maximum overnight GH peak, the ICGH and the overnight AUC. This study confirms that the GH response to GHRH is highly variable among short children with a wide range of spontaneous GH secretion, and that this response is not correlated with the spontaneous ability to secrete GH.

Insulin-like growth factor-I and its binding protein-3 in serum: are they good screening properties for the diagnosis of growth hormone deficiency?

Serum insulin-like growth factor-I and insulin-like growth factor binding protein-3 are simply-determined screening analytes if growth hormone deficiency is suspected. The analysis of growth hormone secretion using standardised stimulation tests and secretion profiles is complicated and expensive in comparison. In retrospect, we have examined the value of insulin-like growth factor-I and its binding protein-3 for the diagnostic clarification of patients with short stature (n = 117). In 39/117 patients growth hormone secretion was investigated as ward patients. Growth hormone deficiency was diagnosed in 10 patients, for 16 patients the diagnosis was neurosecretory dysfunction. For all patients (n = 7) with lowered insulin-like growth factor binding protein-3 and insulin-like growth factor-I values (insulin-like growth factor binding protein-3 < 5th percentile, insulin-like growth factor-I < 10th percentile) a growth hormone disorder was proven. Conversely, however, only 3/10 patients with classical growth hormone deficiency (n = 3) showed a lowering of both analytes. 8/10 patients with classical growth hormone deficiency and 8/16 patients with neurosecretory dysfunction had at least one lowered value. Two patients showed normal values for insulin-like growth factor-I and insulin-like growth factor binding protein-3 despite biochemically proven growth hormone deficiency. The combined determination of insulin-like growth factor-I and insulin-like growth factor binding protein-3 can provide valuable help during preliminary diagnosis of patients of short stature, indicating a disturbance of the growth hormone secretion if the values are lowered. Normal values do not, however, exclude the possibility of a growth hormone deficiency. Inpatient endocrinological testing is indispensible if growth hormone deficiency is suspected.

Secretion of growth hormone in children with familial dwarfism

Thirty-two patients with familial dwarfism were examined. Stimulated and spontaneous secretion of growth hormone was studied in all of them. Stimulated secretion was assessed in two standard pharmacologic tests, spontaneous one was examined during the first 3 h of night sleep. Analysis of the results showed an irregular pattern of growth hormone secretion. Disorders of the hormone secretion of the neurosecretory dysfunction type with a partial deficit of growth hormone were revealed in the majority (20 out of 32) patients, which may be the cause of growth retardation. In twelve patients the levels of both stimulated and spontaneous secretion were normal.

Measurement of spontaneous, 12-hour sleep-associated GH secretion in prepubertal children with short stature: clinical relevance and practicability?

We have asked whether or not sleep-associated 12-hour GH profiles were a clinically relevant and practicable tool to identify short children with low spontaneous GH secretion. In 67 prepubertal patients (19 girls and 48 boys, mean age 9.34 years, range 1.99-14.5) sleep-associated 12-hour GH profiles were obtained by drawing peripheral venous blood every 30 min over a 12-hour night period. The diagnosis of GH deficiency (GHD, n = 26), constitutional delay of puberty and growth (CDPG, n = 19), familial short stature (FSS, n = 8), GH neurosecretory dysfunction (GHND, n = 5), and constitutional delay of puberty and growth plus familial short stature (CDPGFSS, n = 9) was made by clinical parameters (SDS height range:-0.69 to -5.59, SDS growth velocity:-4.6 to -2.4) and provocative testing of GH secretion. Integrated GH secretion (area above baseline = AOB, area above zero line = AOOL), peak frequency, area under the peaks, peak amplitude length, peak amplitude height, maximal peak values, and median peak values were calculated using the PULSAR program. Significant differences of GH secretion between patient groups in regard to mean values for area over baseline, area over zero line, amplitude height, maximal peak values, and median peak values of secretion were found. However, there was a large interindividual variation of integrated GH secretion within each patient group and, most importantly, a large overlap between the different patient groups. We conclude that the assessment of pulsatile GH secretion during sleep, even if it can contribute to distinguish between different groups of short children, is not helpful to distinguish between different causes of short stature in an individual child. We suggest that measurement of sleep-associated spontaneous GH secretion needs to be restricted to research facilities.

Magnetic resonance tomography studies of the hypophysis in children with growth hormone deficiency, born with umbilical cord entanglement

Eight children with either panhypopituarism, severe growth hormone deficiency or neurosecretory dysfunction for growth hormone with a common history of umbilical cord encirclement around the neck underwent magnetic resonance imaging of the pituitary gland and the hypothalamus. Panhypopituitarism was associated with small to absent adenohypophysis, narrow or absent stalk and ectopic neurohypophysis whereas patients with partial GHD showed normal anatomical structures. Etiology of the endocrinopathy could be a primary malformation of the pituitary gland, an apoplexy of the gland or disturbation within the hypothalamus. We believe that the latter cause is predominant in umbilical cord encirclement.

The Relationship between Adiposity and Height Responses during the First Two Years of Growth Hormone Therapy in Prepubertal Children with Idiopathic Growth Hormone Deficiency

Data for a total of 287 prepubertal patients with growth hormone deficiency (GHD) from the International Cooperative Growth Study (ICGS) treated with recombinant growth hormone (GH) for more than two years were analyzed for the relationship between adiposity and growth response. The percent overweight index was used for assessing the degree of adiposity. One hundred eightyeight patients with GH neurosecretory dysfunction on GH treatment from the same database served as controls. Results: There was a statistically significant decline in % overweight only during the first year. There was no change in adiposity between the first and second year. In a comparison between thin patients with GHD and obese patients, obese patients had better first year growth response (height velocity, its SD score, increase in height SD score) despite older age, and lower GH dosage/kg. Among obese children with GHD, there was a tendency toward better height response in more obese individuals. Simple correlation analysis revealed variables that negatively correlated with % overweight were GH peak levels, GH dosage and height velocity before treatment and variables that positively correlated were the number of injections/week and the first year growth response. Multiple regression analysis in patients with GHD and GH neurosecretory dysfunction revealed that adiposity is an independent factor promoting height response during the first year of GH treatment in prepubertal GHD patients.

Is IGF binding protein‐3 assessment helpful for the diagnosis of GH deficiency?

The measurement of serum immunoreactive IGFBP-3 levels has been proposed as a screening test to identify children with growth hormone deficiency (GHD). We tested the sensitivity and specificity of the IGFBP-3 assessment in comparison with the measurement of IGF-I. We assessed the IGFBP-3 and IGF-I circulating levels in normal subjects and patients with GHD or idiopathic short stature (ISS). Eighty-two normal subjects, 16 GHD, and 10 children with ISS were studied. Controls were divided into three age groups: group A, 1-4 years (n = 16); group B, 5-9 years (n = 35), and group C, 10-14 years (n = 31). All subjects underwent standard anthropometry. In short patients, GH secretory status was assessed by clonidine and arginine stimulation tests. IGFBP-3 and IGF-I circulating levels were measured by radioimmunoassay. IGFBP-3 and IGF-I levels were closely related (r = 0.51, P < 0.0001) and IGFBP-3 was less age dependent than IGF-I (r = 0.57, P < 0.02 vs r = 0.64, P = 0.0001). Sensitivity (true positive ratio) and specificity (true negative ratio) of IGFBP-3 measurement were 50 and 92% respectively, whereas sensitivity and specificity of IGF-I assessment were 75 and 90% respectively. Below the age of 5 years, sensitivity was 20% for IGFBP-3 and 40% for IGF-I; specificity was 94% for IGFBP-3 and 88% for IGF-I. IGFBP-3 measurement had poor sensitivity in detecting growth hormone deficient patients, offering no diagnostic advantage over IGF-I, even in the first years of life, although, due to the high specificity, the finding of subnormal levels of IGFBP-3 was strongly suggestive of growth hormone deficiency. The presence of low IGFBP-3 and IGF-I levels in a short child with normal GH response to provocative tests should prompt further investigations, such as the determination of spontaneous GH secretion or assessment of the GH binding proteins together with an IGF-I and/or IGFBP-3 generation test, in order to identify neurosecretory dysfunction or GH receptor deficiency. Finally, we believe that there is no definitive test for diagnosing or excluding growth hormone deficiency and detailed analysis of the results of endocrine tests, clinical findings and other laboratory and radiological information is necessary to maximize diagnostic accuracy.