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Biomedical subjects

J M Wit

Publications and source records attributed to J M Wit.

At least 145 records · Page 8Linked to original sources
PubMed1993

Long-term effect of human growth hormone therapy on the prevalence of autoantibodies in Turner syndrome. The Dutch Growth Hormone Working Group.

Abnormalities of immune status, particularly a high prevalence (about 50%) of thyroid autoantibodies, have been reported before in Turner syndrome. Results are conflicting as regards other abnormalities of immune function. Growth hormone (GH) has immunomodulatory effects, but results of its effects on GH-deficient children are inconsistent. In this study, 42 girls with Turner syndrome, aged 7.3-19 years, are investigated before, during and after 4 years of human GH therapy. Girls over 12 years old also received ethinyl oestradiol. The prevalence of antithyroid antibodies was 16.7% initially, 35.3% after 24-45 months and 48% after 4 years of therapy though, as there was no control group, it was difficult to conclude that GH was enhancing their appearance. Hypothyroidism was extremely uncommon, and the growth response was no different in those who had the antibodies from those who had not. There were no dramatic increases in prevalence of any of the other antibodies investigated, though the prevalence of parietal cell antibodies was higher than expected.

Adolescent↗
PubMed1993

Slow baseline growth and a good response to growth hormone (GH) therapy are related to elevated spontaneous GH pulse frequency in girls with Turner's syndrome.

Spontaneous growth and growth responses to GH therapy vary considerably among girls with Turner's syndrome. In an attempt to clarify this variability, we assessed growth parameters, 24-h GH profiles, arginine-stimulated serum GH levels, and plasma insulin-like growth factor-I (IGF-I) concentrations in a group of 41 girls with Turner's syndrome with a mean (+/- SD) age of 13 +/- 3 yr (range, 6.7-18.9). We subsequently treated all girls with biosynthetic GH (24 IU/m2 x week) and documented the growth response after 1 yr of therapy. GH profiles were analyzed according to Pulsar and Cluster, and GH secretion rates were calculated by waveform-independent deconvolution (Pulse). Factor analysis selected the mean 24-h GH secretion rate and number of GH peaks according to Cluster and Pulse as the principal GH profile variables to be used for further analysis. The mean (+/- SD) daily pituitary GH secretion rate was 127 +/- 47 micrograms/L.24 h (range, 37-232). The GH secretion rate correlated inversely with body mass index (r = -0.45; P < 0.01; n = 41). There was no relationship between the GH secretion rate and the growth parameters before or after GH therapy. However, the number of GH peaks (Pulse) correlated negatively with baseline height velocity (r = -0.53; P = 0.03) and was a positive predictor for height velocity increment during the first year of GH therapy (r = 0.71, P = 0.001). The mean (+/- SD) IGF-I level was 217 +/- 91 ng/mL (range, 87-413). There was no relationship between GH secretion rate or growth parameters and IGF-I. However, the number of GH peaks correlated negatively with IGF-I (r = -0.49; P = 0.04; n = 17). We conclude that an elevated spontaneous GH pulse frequency pattern is associated with relatively low IGF-I levels and slow baseline growth in girls with Turner's syndrome and that girls with such a pulse pattern may benefit most from exogenous GH therapy.

Adolescent↗
PubMed1992

Mutation of the POU-specific domain of Pit-1 and hypopituitarism without pituitary hypoplasia.

A point mutation in the POU-specific portion of the human gene that encodes the tissue-specific POU-domain transcription factor, Pit-1, results in hypopituitarism, with deficiencies of growth hormone, prolactin, and thyroid-stimulating hormone. In two unrelated Dutch families, a mutation in Pit-1 that altered an alanine in the first putative alpha helix of the POU-specific domain to proline was observed. This mutation generated a protein capable of binding to DNA response elements but unable to effectively activate its known target genes, growth hormone and prolactin. The phenotype of the affected individuals suggests that the mutant Pit-1 protein is competent to initiate other programs of gene activation required for normal proliferation of somatotrope, lactotrope, and thyrotrope cell types. Thus, a mutation in the POU-specific domain of Pit-1 has a selective effect on a subset of Pit-1 target genes.

Animals↗
PubMed1992

Mutations in mitochondrial tRNA genes: non-linkage with syndromes of Wolfram and chronic progressive external ophthalmoplegia.

We have recently identified a point mutation in the mitochondrially encoded tRNA(Leu(UUR)) gene which associates with a combination of type II diabetes mellitus and sensorineural hearing loss in a large pedigree. To extend this finding to other syndromes which exhibit a combination of diabetes mellitus and hearing loss we have sequenced all mitochondrial tRNA genes from two patients with the Wolfram syndrome, a rare congenital disease characterized by diabetes mellitus, deafness, diabetes insipidus and optic atrophy. In each patient, a single different mutation was identified. One is an A to G transition mutation at np 12,308 in tRNA(Leu(CUN)) gene in a region which is highly conserved between species during evolution. This mutation has been described by Lauber et al. (1) as associating with chronic progressive external ophthalmoplegia (CPEO). The other is a C to T transition mutation at np 15,904 in tRNA(Thr) gene. Both mutations are also present in the general population (frequency tRNA(Leu(CUN)) mutation 0.16, tRNA(Thr) mutation 0.015). These findings suggest that evolutionarily conserved regions in mitochondrial tRNA genes can exhibit a significant polymorphism in humans, and that the mutation at np 12,308 in the tRNA(Leu(CUN)) gene is unlikely to be associated with CPEO and Wolfram syndrome.

Base Sequence↗
PubMed1992

Growth hormone therapy in Turner's syndrome. Impact of injection frequency and initial bone age.

STUDY OBJECTIVE: To determine the influence of the injection frequency and the initial bone age on the efficacy of treatment with biosynthetic growth hormone in Turner's syndrome. DESIGN: Randomized study. SETTING: Referral-based pediatric endocrinology departments of seven university medical centers. PATIENTS: Fifty-two patients with Turner's syndrome confirmed with chromosomal analysis. TREATMENT: Somatotropin recombinant DNA (24 IU/m2 of body surface area) subcutaneously administered in three or six injections per week for 2 years. Patients who were older than 12 years at the beginning of the study received low doses of estrogen. RESULTS: The following statistically significant findings supported the use of six injections per week compared with three injections per week: the mean (+/- SD) increment in height during 2 years was 11.3 cm (3.8 cm) with six injections vs 8.6 cm (3.4 cm) with three injections; the increment in height standard deviation score was 0.9 cm (0.5 cm) vs 0.6 cm (0.3 cm); the growth velocity was 6.6 cm/y (2.0 cm/y) vs 5.2 cm/y (1.7 cm/y) in year 1 and 4.7 cm/y (2.0 cm/y) vs 3.4 cm/y (1.7 cm/y) in year 2; and the increment in height standard deviation score for bone age was 0.8 cm (0.5 cm) vs 0.4 cm (0.6 cm). For patients whose initial bone age was more than 13 years, growth velocity increased by 1 to 2 cm in year 1; in year 2 no increment was observed. We did not observe adverse effects. CONCLUSIONS: Biosynthetic growth hormone in a higher-frequency regimen in Turner's syndrome is more efficient in terms of increment in height, growth velocity, and height standard deviation score for bone age than treatment in a lower-frequency regimen. In patients with an initial bone age of more than 13 years, the response was poor. Longer follow-up is necessary to assess the effect on final height.

Adolescent↗
PubMed1992

Growth hormone treatment in Turner syndrome accelerates growth and skeletal maturation. Dutch Growth Hormone Working Group.

Sixteen girls with Turner syndrome (TS) were treated for 4 years with biosynthetic growth hormone (GH). The dosage was 4 IU/m2 body surface s.c. per day over the first 3 years. In the 4th year the dosage was increased to 6 IU/m2 per day in the 6 girls with a poor height increment and in 1 girl oxandrolone was added. Ethinyl oestradiol was added after the age of 13. Mean (SD) growth velocities were 3.4 (0.9), 7.2 (1.7), 5.3 (1.3), 4.3 (2.0) and 3.6 (1.5) cm/year before and in the 1st, 2nd, 3rd and 4th year of treatment. Skeletal maturation advanced faster than usual in Turner patients especially in the younger children. Although the mean height prediction increased by 5.6 cm and 11 of the 16 girls have now exceeded their predicted height, the height of the 4 girls who stopped GH treatment exceeded the predicted adult height by only 0 to 3.4 cm.

Adolescent↗
PubMed1992

Prepubertal height velocity references over a wide age range.

In order to correct height velocities for the confounders age and sex, SD scores can be calculated using the mean and the SD of the height velocity in the normal population. However, current methods are inappropriate for prepubertal children in the age range in which puberty occurs, because reference groups then consist of a mixed prepubertal/pubertal population. The mathematical infancy-childhood-puberty (ICP) model opens up the possibility of dissecting the puberty component from the total growth curve. New references for height velocity for prepubertal children calculated over a 12 month interval up to the ages of 15.5 years (boys) and 13.5 years (girls) have been constructed on the basis of adaptations of the ICP model and the Swedish longitudinal growth study.

Age Factors↗
PubMed1992

Growth of infants with neonatal growth hormone deficiency.

In view of contradictory reports on the growth hormone dependency of early postnatal growth we studied the growth curves of 15 infants with neonatal growth hormone deficiency. In seven infants the growth curve was parallel to the standards of the infancy-childhood-puberty (ICP) model (group 1), but in the remaining infants there was an immediate deviation of the growth curve (group 2). In this group the mean (SD) at 4 and 9 months of age was -3.3 (1.1) and -4.9 (1.4), respectively, when compared with the ICP model. The mean birth length in both groups was decreased and five out of 15 had a birth length of less than -2 SD. Serial measurements of the growth hormone response to provocation tests in two patients in group 2 showed decreasing concentrations, while four patients with documented complete growth hormone deficiency belonged to group 2. We conclude that growth hormone is needed for early infant growth and that the normal growth pattern in some infants with neonatal pituitary dysfunction is due to incomplete insufficiency.

Adrenal Glands↗
PubMed1992

Comparison of four computerized models to estimate 24-hour growth hormone secretion in girls with Turner's syndrome.

Daily pituitary growth hormone (GH) secretion can be estimated from a 24-hour GH profile by various methods. We have used four methods to assess GH secretion in 36 girls with Turner's syndrome: the method described by Thompson et al., the Pulsar algorithm combined with the method of Hellman et al. and two deconvolution techniques. The number of detected peaks varied considerably among the methods. The mean (+/- SD) total daily secretion per square meter body surface was 0.53 (0.19) U/m2.day by deconvolution, in contrast to 0.31 (0.17) with the Hellman method and 1.06 (0.37) according to Thompson. The differences are explained by different assumptions about the metabolic clearance rate and various methodological aspects. Assuming a degradation rate of 50%, the growth hormone substitution dosage would be 1-2 IU/m2.day in GH-deficient children. The usual dosage in girls with Turner's syndrome is expected to lead to serum GH levels approximately 4 times higher than in the untreated state.

Adolescent↗
PubMed1992

Dose-response study of biosynthetic human growth hormone (GH) in GH-deficient children: effects on auxological and biochemical parameters. Dutch Growth Hormone Working Group.

A multicenter dose-response study evaluated the effect of two different doses of biosynthetic GH on auxological and biochemical parameters in 38 prepubertal children with GH deficiency (GHD). Twenty-one were newly diagnosed, while 17 transfer patients had been on GH treatment for at least 1 yr before the study. New and transfer patients alike were treated with either 2 or 4 IU GH/m2.day sc. At evaluation all new patients had completed 1 yr of treatment, while transfers had completed 2 yr of treatment under study. In the new patients both doses resulted in a significant increase in height velocity (HV) and height SD score (SDS), with comparable bone maturation. After correction for the severity of GHD, the increase in HV SDS was significantly greater with 4 IU than with 2 IU (P less than 0.01). In the transfer patients HV, height SDS, and predicted adult height only increased significantly with 4 IU (P less than 0.05). Bone maturation was comparable for the two doses. There was a significant correlation between first year growth response and GH dose. In the new patients, the plasma insulin-like growth factor-I (IGF-I) concentration increased significantly without a significant difference between dosage groups. There was a positive correlation between growth response and increment of plasma IGF-I SDS. In new and transfer patients alike, above normal plasma IGF-I levels were observed, particularly with 4 IU. Hemoglobin-A1 remained constant with both GH doses in both groups, while cholesterol and LDL levels tended to decrease. In the new patients, the mean apolipoprotein-A1 level was lower than the control value after 1 yr on 4 IU GH. Treatment with 4 IU GH/m2.day led to a greater growth response than a dose of 2 IU in newly diagnosed as well as previously treated GHD patients. Bone maturation was comparable for both doses. No adverse effects were observed with the higher GH dose, but the long term effects on IGF-I and lipid metabolism need further attention.

Adolescent↗
PubMed1992

Growth hormone secretion in patients with Turner's syndrome as determined by time series analysis.

Twenty-four-hour growth hormone (GH) profiles in 26 girls with Turner's syndrome were compared with those of 26 normally growing short children and 24 slowly growing short children. All children were prepubertal and below 12 years of age. A subgroup of 13 girls was treated with ethinyl estradiol and a 24-h GH profile was reassessed. In an additional group of 45 girls with Turner's syndrome (aged 6.7-18.9 years) the effect of age, spontaneous breast development and ethinyl estradiol treatment was studied. The profiles were assessed by Fourier analysis. The oscillatory activity and the mean 24-h GH concentration were similar in children with Turner's syndrome and the normally growing short children, in contrast to lower levels in the slowly growing short children. The periodicity of GH secretion was similar in all groups. In the longitudinal study, ethinyl estradiol treatment resulted in a significant increase in pulse amplitude, but not in periodicity. In the cross-sectional study there was no significant difference between the subgroups of girls with either presence or absence of breast development or ethinyl estradiol treatment. GH secretion was not significantly related to age, height in standard deviation score or height velocity. These data imply that there is no abnormality in GH secretion in girls with Turner's syndrome.

Aging↗
PubMed1992

[Historical perspective on growth hormone treatment in children].

The history of growth hormone treatment can be divided into two episodes. Between 1958 and 1985 growth hormone was extracted from human pituitaries. Because of the scarcity little scientific research was carried out and efficacy was not optimal. In 1985 biosynthetic growth hormone became available, which facilitated research on the use of growth hormone for various indications. In the future further research is needed on the pathophysiology of growth disturbances, on methods to improve efficacy, and on possible side-effects of pharmacological dosages.

Child↗
PubMed1992

[Turner syndrome: a virtually certain indication for growth hormone treatment].

Short stature is a feature in almost all cases with Turner syndrome. The etiology is unknown, but GH secretion appears to be normal. The treatment with anabolic steroids does not seem to increase final height. Oestrogens are needed for secondary sex characteristics, but should be given in a low dosage and at approximately 12-13 years of age, in order not to compromise final height. Growth hormone increases growth velocity and leads to an average gain of 5 cm in terms of final height. The addition of oxandrolone leads to an even higher growth rate, but final height is probably similar to that reached by growth hormone alone. The dosage, injection frequency, age and bone age at the start of therapy have influence on the efficacy. GH in the dosages given appears safe.

Age Determination by Skeleton↗
PubMed1992

[Growth hormone treatment in short stature of unknown origin].

Most children with idiopathic short stature can be classified under the diagnoses familial short stature and constitutional delay of growth and adolescence. Administration of growth hormone leads to faster growth, but also faster bone maturation. Daily injections are more efficacious than three injections per week. There is a dose-response relationship. In a Dutch prospective study, the acceleration of growth was only slightly more than bone age advance, so that the average predicted adult height increased only by 3 cm over a period of 4-5 year. In an untreated control group final height was 1 cm lower than predicted. There were great inter-individual differences in terms of growth and bone maturation, which could not be predicted on the basis of clinical and biochemical variables.

Body Height↗
PubMed1992

[Growth hormone therapy in dysmorphic syndromes and chronic disease].

Many clinical syndromes are associated with short stature, which can be proportionate or disproportionate. In the first group of syndromes, such as Turner syndrome and its variants, Down syndrome, Prader-Willi-Labhart syndrome, Noonan syndrome, and Silver-Russell syndrome growth hormone therapy can lead to increased growth velocity, but so far only short-term results have been reported. Growth hormone is contraindicated in syndromes with an increased risk of chromosomal breakage, e.g. Bloom syndrome. In disproportionate syndromes, such as hypochondroplasia, pseudopseudohypoparathyroidism, spina bifida, and hypophosphataemic rickets, the results of growth hormone therapy are not encouraging. Growth hormone therapy in children with rheumatoid arthritis and thalassaemia appears little effective. Long-term clinical trials of reasonable size are needed before reliable conclusions can be drawn about the value of growth hormone therapy in these conditions.

Abnormalities, Multiple↗