H. Frisch

A Pharmacological Dose of Melatonin Increases PRL Levels in Males without Altering Those of GH, LH, FSH, TSH, Testosterone or Cortisol

Since reports on the influence of melatonin (aMT) on the human endocrine system are scant and inconsistent, the effect of an acute, pharmacological dose of aMT on various hormone levels in healthy males was examined in 3 different experiments. Experiment I: 80 or 240 mg of crystalline aMT were administered per os to 8 volunteers. Before, during and after this treatment, serum levels of aMT, PRL, LH, FSH and testosterone were examined. Although aMT increased at least 1,500-fold over basal levels, only PRL was significantly and consistently elevated after aMT treatment, whereas serum levels of the other hormones were not altered. Experiment II: in 2 subjects, the pulsatile secretion pattern of LH was monitored for 6 h before and 6 h after aMT administration (240 mg p.o.). Neither the amplitude nor the frequency of LH pulses was influenced by the pineal hormone. Experiment III: in 14 volunteers, serum PRL, GH, TSH and cortisol concentrations were examined, once after oral administration of 240 mg aMT and once after placebo. Serum PRL levels were significantly higher after aMT than after placebo; GH showed a slight but not significant trend towards elevation after aMT, whereas other hormones were not altered. An acute pharmacological dose of aMT causes isolated elevation of serum PRL levels and may slightly increase GH. Hormones of the pituitary gonadal axis as well as TSH and cortisol are not altered by aMT.

Pulsatile secretion of gonadotropins in early infancy

In adults, luteinizing hormone (LH) and follicle stimulating hormone (FSH) are secreted in a pulsaltile manner. Prior to puberty gonadotropin (GN) levels are low and show only small fluctuations. The following investigation was performed to elucidate the type of GN secretion in infants:LH and FSH were determined every 30 min over a period of 8 h in three different groups: Group 1:2 male and 2 female adults; Group 2:2 male and 2 female prepubertal children; Group 3:3 male and 3 female infants, aged 6–12 weeks.Group 1 showed a clear pulsatile secretion of LH (4.5–23.5 mIU/ml [range]) and FSH (6.9–16.0 mIU/ml). Group 2 demonstrated a rather constant secretion of LH (<1.5–2.3 mIU/ml) and FSH (1.6–4.9 mIU/ml). Group 3: In male infants pulsatile secretion of LH (3.6–34.7 mIU/ml)—and to a lesser degree of FSH (1.8–4.6 mIU/ml)—were found. In female infants the pulsatile secretion of FSH (6.5–22.7 mIU/ml) was more pronounced than that of LH (<1.5–4.7 mIU/ml). The secretory pattern in early infancy is of a pulsatile type.

Growth Patterns and Final Height in Congenital Adrenal Hyperplasia due to Classical 21-Hydroxylase Deficiency

Background: Longitudinal growth and bone age (BA) development are the most important clinical parameters for monitoring adequate glucocorticoid replacement in children with congenital adrenal hyperplasia (CAH). Aim of the Study: To analyze the growth pattern of patients treated for CAH of the salt wasting (SW) and simple virilizing (SV) clinical forms; to evaluate final height as compared to reference data and individual target height; to evaluate the course of BA development. Patients and Methods: A large database of 598 patients with CAH was created in 5 Central European countries and growth data of 341 treated patients with 21-hydroxylase deficiency were analyzed retrospectively. The patients were of Caucasian origin. Centiles were constructed in a cross-sectional manner and an additional longitudinal analysis was performed in order to evaluate the pubertal growth spurt by applying particular statistical methods (Preece-Baines model). Results: The growth of SW CAH patients was impaired in infancy and early childhood (0–3 years of age), but followed normal patterns in childhood until puberty. In contrast, children with SV CAH had normal patterns of growth in infancy and early childhood and were considerably taller than healthy references during childhood. In the longitudinal study, peak height velocity in both boys and girls was normal, but it occurred at an earlier age than in the standard population. The final height of patients with CAH was reduced in comparison to both the reference and the individual target height. No correlations were found between final height and age at the start of the therapy in SV patients or between final height and year of birth. BA was advanced in both types of CAH, but more accelerated in SV patients. Conclusion: Characteristic growth patterns for treated SV and SW CAH children were identified, with a normal pubertal growth spurt and reduced final height being observed.

Perspectives of longitudinal growth in cystic fibrosis from birth to adult age

The longitudinal growth in 139 patients with cystic fibrosis (CF) was investigated from birth until the age of 19 years. Already at birth weight and length were reduced (weight: −0.83±0.13 SDS in girls, −0.44±0.13 SDS in boys; length: −0.55±0.13 SDS in girls, −0.39 ±0.14 SDS in boys; mean ± SEM). Both variables showed a further decline until diagnosis was established (weight: −1.57±0.21 SDS in girls, −1.46±0.25 SDS in boys; length: −1.15±0.32 SDS in girls, −1.03 ±0.52 SDS in boys; mean ± SEM). Six to 12 months after diagnosis length improved and reached the 25th percentile in both sexes. Height and weight followed the 25th percentile throughout childhood. Growth velocity was fairly normal during this period. There was a loss in percentiles of both height and weight after the age of 8 years and the pubertal growth spurt was delayed and reduced. However, the 25th percentile was reached again in the adolescent period. At the age of 19 years median height was 161,5 cm in girls and 173 cm in boys, both representing the 25th percentile. Using a sensitive statistical method for analysis of growth data we present CF specific growth curves for height, weight and growth velocity. There was no significant effect of pulmonary colonization withPseudomonas aeroginosa on growth velocity.

Final Height and Pubertal Development in Children with Growth Hormone Deficiency after Long-Term Treatment

Auxological data and final height were analysed in 42 patients with growth hormone deficiency (GHD), 10 had isolated GHD (group 1), 23 had multiple pituitary hormone deficiencies (group 2) and 9 had organic GHD (group 3). Patients received growth hormone (GH) for a mean of 6.5 +/- 2.6 (group 1), 8.0 +/- 2.9 (group 2) and 2.9 +/- 1.5 years (group 3). Most patients were treated with pituitary GH (pGH), 11 IU/m2/week (mean) in 3 divided doses, which was not changed during puberty. Six patients, treated with daily injections of recombinant GH, showed a significantly better height velocity than those treated with pGH (2.1 vs. -0.3 SDS), though the mean dose was identical (p = 0.03). Final heights for boys and girls were -2.8 and -3.3 SDS (group 1), -1.9 and -1.6 SDS (group 2), and -2.9 and -3.2 SDS (group 3). Only 20% of group 1, 70% of group 2 and 22% of group 3 reached final heights within target limits. Final height was positively correlated with height at onset of puberty, but there was no association with the timing or magnitude of pubertal growth.

Procedure for Neonatal Screening for Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

The value of screening of neonates for congenital adrenal hyperplasia is not universally accepted. Procedures for screening are recommended here in order to provide a structure to the testing and ultimately bring together data that will allow the effect of screening to be judged for benefit or dismissed as no better than clinical recognition of the disease state.

Auxological, Ophthalmological, Neurological and MRI Findings in 25 Austrian Patients with Septo-Optic Dysplasia (SOD)

Septo-optic dysplasia (SOD) comprises ophthalmological, endocrinological and neurological disorders resulting from varying degrees of midline malformation of the forebrain like visual impairment by optic nerve hypoplasia, endocrine deficits due to hypothalamic and/or pituitary anomalies, and psychomental retardation by associated cortical malformation. MRI shows aplasia/hypoplasia of the septum pellucidum and corpus callosum as a radiological hallmark. For etiology, genetic defects (Hesx1/HESX1 gene) as well as vascular disruption during embryonic brain development are discussed. Aim: To perform detailed analysis of morphological findings and clinical symptoms and to improve care of SOD patients by interdisciplinary management. Patients: We investigated 25 patients with a mean age of 5.1 years at diagnosis. Results: Pituitary insufficiency was present in 11/25 patients, multiple deficits in 6 of them. Bilateral optic nerve hypoplasia was found in 70% of patients, unilateral in 20%. Mild or moderate neurological disorders were observed in the majority of patients (14/20), EEG was usually normal (12/19). Analysis of MRI films revealed very heterogeneous morphological anomalies, ranging from isolated agenesis of the septum pellucidum to multiple malformations, involving the cortex. Malrotation of the hippocampal structures was a common finding. Conclusion: We conclude that only interdisciplinary management of SOD patients can ameliorate the exact diagnosis and outcome, depending on early visual or developmental support as well as early diagnosis and substitution of potentially life-threatening endocrine deficits.

Spontaneous growth in turner syndrome: Evidence for a minor pubertal growth spurt

Spontaneous growth of 141 untreated girls with Turner syndrome was analysed. Of the patients 25% were born prematurely; their weight and height were normal when compared to prematurely born healthy infants. However, birth weight and height was significantly retarded in Turner patients born at term. A curve for height and growth velocity for the age range 0–16 years was constructed with a sensitive statistical method. By use of a mathematical model equations were created for calculating z-scores and the related percentiles for the height of individual patients at given age. median height of 18 untreated patients at 18 years was 143.8 cm. Analysis of growth velocity revealed a minor but significant growth spurt at the age of 12.5 years. This growth spurt was also detectable in patients without signs of spontaneous puberty and occurred later in patients with 45,X0 karyotype. Bone age progression was linear up to the age of 7.5 years and decelerated thereafter.

Long-term treatment in children with hypopituitarism: pubertal development and final height.

Auxological data, pubertal development and final height were analyzed in 25 patients with growth hormone (GH) deficiency who were treated only with pituitary GH in 3 doses/week. 15 patients had a spontaneous onset of puberty and in 10 puberty was induced. The duration of therapy was 7.5 years, the dosage was about 11 U/m2/week and was not changed during puberty. 80% of the patients with induced puberty, but only 33% of the children with spontaneous puberty reached final heights within the 2 SD range. Final height was correlated with height at the start of treatment only in patients with spontaneous puberty, which shows the necessity of early treatment initiation in this group. The lack of this correlation in patients with induced puberty might be attributed to gonadotropin deficiency. Height at the onset of puberty was related to final height only in the group with gonadotropin deficiency. A prediction model for calculation of the first year height velocity which was derived from present treatment procedures showed a too favorable prediction for our patients. The reasons for the insufficient final results may be due to impure GH preparations, suboptimal dosage, low frequency of injections and late onset of therapy.

Congenital Adrenal Hyperplasia: Lessons from a Multinational Study

A study group of paediatric endocrinologists was established in Austria, Czech Republic, Hungary, Slovenia and Slovakia in order to investigate various aspects in children with congenital adrenal hyperplasia (CAH). Five hundred and ninety-eight patients with CAH who were diagnosed between 1969 and 1998 were included in order to analyze the following questions. Epidemiological data: There were significantly fewer males (43%) than females (57%), and the percentage of males did not increase during the observation period. Salt wasters (SW) totalled 64.7%, whereas 35.3% had simple virilizing (SV) CAH. Diagnosis was established significantly later in boys than in girls (median of 26 vs. 13 days for SW, p < 0.0001; 1,817 vs. 1,010 days for SV, p < 0.03). Mortality in the general population was significantly lower than in CAH siblings (1.8% vs. 7.0%, p < 0.0001) or in SW children (2.2% vs. 11.3%, p < 0.0001). According to our calculation with the present clinical diagnostic criteria in Central Europe, from 40 expected CAH patients/year, 2–2.5 SW, and one female and four male SV patients will not be diagnosed. Auxological data: Growth data from 341 patients were analyzed retrospectively. Percentiles were constructed in a longitudinal/cross-sectional study and pubertal growth was described in a longitudinal analysis. Growth of SW patients was impaired in early childhood (0–3 years), but followed a normal course until puberty. In contrast, SV children had a normal growth pattern during early childhood, but were above the standard thereafter. The pubertal growth spurt was of normal magnitude in boys and girls, but started too early. Final height was reduced compared with both standard and target heights. There was no correlation between final height and age of starting treatment or the year of birth. Bone age was accelerated in both CAH types, but more so in SV patients. Molecular genetics: Three hundred and fifty-six patients were investigated for 11–14 of the most frequent mutations by direct allele-specific polymerase chain reaction (PCR) and/or PCR followed by sequence-specific oligonucleotide, single strand chain polymorphism and restriction fragment length polymorphism. In the group as a whole, we most frequently found the Intron 2 splice mutation (30.8%) or a deletion/conversion (28.5%). The Intron 2 mutation was most frequent in the Hungarian population, whereas deletions/conversions were found more frequently in Slovenians. The other mutations had a similar distribution to those seen in other populations. Genotype-phenotype correlation confirms previous reports.