Biomedical subjects

S L Drop

Publications and source records attributed to S L Drop.

At least 37 records · Page 2Linked to original sources

PubMed2000

Human insulin-like growth factor (IGF) binding protein-1 inhibits IGF-I-stimulated body growth but stimulates growth of the kidney in snell dwarf mice.

The actions of insulin-like growth factor-I (IGF-I) are modulated by IGF binding proteins (IGFBPs). The effects of IGFBP-1 in vivo are insufficiently known, with respect to inhibitory or stimulatory actions on IGF-induced growth of specific organs. Therefore, we studied the effects of IGFBP-1 on IGF-I-induced somatic and organ growth in pituitary-deficient Snell dwarf mice. Human GH, IGF-I, IGFBP-1, and a preequilibrated combination of equimolar amounts of IGF-I and IGFBP-1 were administered sc during 4 weeks. Treatment with IGF-I alone induced a significant increase in body length (108% of control) and weight (112%) as well as an increase in weight of the submandibular salivary glands (135%), kidneys (124%), femoral muscles (111%), testes (129%), and spleen (126%) compared with saline-treated controls. IGFBP-1 alone induced a significant increase in weight of the kidneys (152% of control). Coadministration of IGF-I with IGFBP-1 neutralized the stimulating effects of IGF-I on body length and weight as well as on the femoral muscles and testes. In contrast, the weights of the submandibular salivary glands (143%) were not significantly different from those of IGF-I-treated animals, whereas the weights of the kidneys (171%) and spleen (156%) were significantly increased compared with IGF-I-treated mice. The effect of IGFBP-1 plus IGF-I on kidney weight was not significantly greater than the effect of IGFBP-1 alone. Western ligand blotting showed induction of the IGFBP-3 doublet as well as IGFBPs with molecular masses of 24 kDa, most probably IGFBP-4, by human GH, IGF-I alone, and IGF-I in combination with IGFBP-1. Our data show that coadministration of IGFBP-1 inhibits IGF-I-induced body growth of GH-deficient mice but significantly stimulates the growth promoting effects of IGF-I on the kidneys and the spleen. These data warrant further investigation because differences in concentrations of IGFBP-1 occurring in vivo may influence IGF-I-induced anabolic processes.

Animals↗

PubMed2000

Carbohydrate metabolism during long-term growth hormone (GH) treatment and after discontinuation of GH treatment in girls with Turner syndrome participating in a randomized dose-response study. Dutch Advisory Group on Growth Hormone.

To assess possible side-effects of GH treatment with supraphysiological doses on carbohydrate (CH) metabolism in girls with Turner syndrome (TS) during long term GH treatment and after discontinuation of GH treatment, the results of oral glucose tolerance tests and hemoglobin A1c measurements were analyzed in 68 girls with TS participating in a randomized dose-response trial. These previously untreated girls, aged 2-11 yr, were randomly assigned to 1 of 3 GH dosage groups: group A, 4 IU/m2 x day (-0.045 mg/kg x day); group B, first year ,4 IU/m2 day; thereafter, 6 IU/m2 x day (approximately 0.0675 mg/kg x day); group C, first year, 4 IU/m2 x day; second year, 6 IU/m2 x day; thereafter, 8 IU/m2 x day (approximately 0.090 mg/kg x day). After the first 4 yr, girls 12 yr of age or older started with 5 microg/kg BW-day 17beta-estradiol for induction of puberty. To assess the effects of long term high dose GH treatment on CH metabolism, the 7-yr data from the oral glucose tolerance tests in 9 girls of group C were evaluated (group C1). To determine whether the changes in CH metabolism during GH treatment would persist after discontinuation of GH treatment, the data for 28 girls who had reached adult height (group A, n = 9; group B, n = 10; group C, n = 9) were evaluated at baseline, after 4 yr of GH treatment, and 6 months after discontinuation of GH. Seven-year data for group C1 showed that glucose levels did not significantly change during GH treatment, whereas fasting insulin levels as well as glucose-induced insulin levels increased significantly. The data for the 28 girls who were treated with GH for a mean (SD) period of 85.3 (13.3) months demonstrated that the GH-induced higher insulin levels decreased to values close to or equal to pretreatment values after discontinuation of GH treatment. Changes in CH variables were not significantly related to the GH dose. Hemoglobin A1c levels never showed an abnormal value. The prevalence of impaired glucose tolerance was low, and none of the girls developed diabetes mellitus. In conclusion, long term GH treatment with dosages up to 8 IU/m2 x day in girls with TS has no adverse effects on glucose levels, but induced higher levels of insulin, indicating relative insulin resistance. The increased insulin levels during long term GH treatment decreased after discontinuation of GH treatment to values close to or equal to pretreatment values. Although the reversibility of the effects of long term GH is reassuring, the consequence of long term hyperinsulinism is still unknown.

Carbohydrate Metabolism↗

PubMed2000

Final height after gonadotrophin releasing hormone agonist treatment for central precocious puberty: the Dutch experience.

Final height (FH) data of 96 children (87 girls) treated with GnRH agonist for central precocious puberty were studied. In girls mean FH exceeded initial height prediction by 7.4 (5.7) cm (p < 0.001); FH was significantly lower than target height, but still in the genetic target range. When treatment started < 6 years of age, height gain was significantly higher than when started > 8 years of age. Bone age (BA) and chronological age (CA) at start of treatment, as well as BA advance at cessation of treatment, were the most important variables influencing height gain in multiple regression analysis. BA advance at start of treatment was most important in simple correlation. In girls, GnRHa treatment seems to restore FH into the target range. A younger age and advanced bone age at start of treatment are associated with more height gain from GnRHa treatment.

Body Height↗

PubMed2000

The effect of epidermal growth factor and IGF-I infusion on hepatic and renal expression of the IGF-system in adult female rats.

Systemic administration of epidermal growth factor (EGF) in neonatal rats results in reduced body weight gain and decreased circulating levels of IGF-I, suggesting its involvement in EGF-induced growth retardation. We investigated the effect of EGF and/or IGF-I administration for 7 days on circulating IGF-I and IGFBP levels and hepatic and renal IGF-system mRNA expression profiles in adult female rats. EGF administration (30 microg/rat/day) did not influence body weight, liver or kidney weight. In contrast, IGF-I (400 microg/rat/day) and EGF/IGF-I administration increased both body weight and kidney weight. Also, serum IGF-I and the 30 kDa IGFBPs (IGFBP-1 and -2) were significantly increased in these groups. Serum IGFBP-3 levels increased in the IGF-I group along with increased hepatic IGFBP-1 and -3 mRNA levels. In contrast, in the EGF administration group serum IGFBP-3 levels were significantly decreased; however, the mRNA levels remained unchanged. In the EGF/IGF-I administration group, serum IGF-I and IGFBP-3 levels were significantly lowered when compared with the IGF-I administration group. This was in contrast to the effect on kidney weight increase that was identical for the IGF-I and EGF/IGF-I groups. The decrease in serum IGFBP-3 was not reflected at the hepatic IGFBP-3 mRNA level. IGFBP-3 expression might be regulated at a post-transcriptional level although EGF induced IGFBP-3 proteolysis could not be demonstrated in vitro. We conclude that EGF administration reduced serum IGFBP-3 whereas IGF-I administration increased the level of IGFBP-3 and IGF-I and resulted in an increased body and kidney weight in adult female rats.

Animals↗

PubMed2000

Dose-response effects of a new growth hormone receptor antagonist (B2036-PEG) on circulating, hepatic and renal expression of the growth hormone/insulin-like growth factor system in adult mice.

The effects of growth hormone (GH) in regulating the expression of the hepatic and renal GH and insulin-like growth factor (IGF) system were studied by administering a novel GH receptor antagonist (GHRA) (B2036-PEG) at different doses (0, 1.25, 2.5, 5 and 10 mg/kg/day) to mice for 7 days. No differences were observed in the groups with respect to body weight, food consumption or blood glucose. However, a dose-dependent decrease was observed in circulating IGF-I levels and in hepatic and renal IGF-I levels at the highest doses. In contrast, in the 5 and 10 mg/kg/day GHRA groups, circulating and hepatic transcriptional IGF binding protein-3 (IGFBP-3) levels were not modified, likely resulting in a significantly decreased IGF-I/IGFBP-3 ratio. Hepatic GH receptor (GHR) and GH binding protein (GHBP) mRNA levels increased significantly in all GHRA dosage groups. Endogenous circulatory GH levels increased significantly in the 2.5 and 5 mg/kg/day GHRA groups. Remarkably, increased circulating IGFBP-4 and hepatic IGFBP-4 mRNA levels were observed in all GHRA administration groups. Renal GHR and GHBP mRNA levels were not modified by GHRA administration at the highest doses. Also, renal IGFBP-3 mRNA levels remained unchanged in most GHRA administration groups, whereas IGFBP-1, -4 and -5 mRNA levels were significantly increased in the 5 and 10 mg/kg/day GHRA administration groups. In conclusion, the effects of a specific GHR blockade on circulating, hepatic and renal GH/IGF axis reported here, may prove useful in the future clinical use of GHRAs.

Animals↗

PubMed1999

The effects of long-term growth hormone treatment on cardiac left ventricular dimensions and blood pressure in girls with Turner's syndrome. Dutch Working Group on Growth Hormone.

OBJECTIVE: To assess the effects of long-term growth hormone (GH) treatment for short stature on left ventricular (LV) dimensions and systemic blood pressure (BP) in girls with Turner's syndrome without clinically relevant cardiac abnormalities. STUDY DESIGN: LV dimensions measured by echocardiography and systemic BP were assessed before and during 7 years of GH treatment in 68 girls with Turner's syndrome participating in a randomized dose-response study. These previously untreated girls, age 2 to 11 years, were randomly assigned to 1 of 3 GH dosage groups: group A, 4 IU/m(2)/d; group B, first year 4 IU/m(2)/d, thereafter 6 IU/m(2)/d; group C, first year 4 IU/m(2)/d, second year 6 IU/m(2)/d, thereafter 8 IU/m(2)/d. After the first 4 years, girls >/=12 years of age began receiving 17beta-estradiol, 5 microg/kg body weight per day, for induction of puberty. RESULTS: At baseline the LV dimensions of almost every girl were within the normal range, and the mean SD scores were close to zero. During 7 years of GH treatment, the growth of the left ventricle was comparable to that of healthy girls. No signs of LV hypertrophy were found. Before the start of GH treatment, mean BP was within the normal range but significantly higher than in healthy control subjects. Diastolic BP and systolic BP were above the 90th percentile in 23% and 28% of the girls, respectively. After 7 years of treatment, these percentages were 14% and 36%, respectively (not significantly different from baseline). The SD score of the diastolic BP showed a small decrease after 7 years of treatment. The growth of the left ventricle and the development of BP were not different between the GH dosage groups. CONCLUSIONS: Long-term GH treatment, even at dosages up to 8 IU/m(2)/d, does not result in LV hypertrophy or hypertension in girls with Turner's syndrome. Continued observation into adulthood is recommended to monitor the further development of the relatively high BP and to ensure that GH treatment has no long-term negative effect on the heart.

Blood Pressure↗

PubMed1999

Carbohydrate and lipid metabolism during various growth hormone dosing regimens in girls with Turner syndrome. Dutch Working Group on Growth Hormone.

To analyze the effects of supraphysiological dosages of growth hormone (GH) on carbohydrate (CH) and lipid metabolism, we investigated 87 girls with Turner syndrome (TS) in two studies: (1) a 4-year GH dose-response (DR) study comparing three groups with stepwise GH dosage increases up to 8 IU/m2/d in girls aged 2 to 11 years, and (2) a 2-year GH administration frequency-response (FR) study in girls aged 11 to 17 years, comparing once-daily (OD) and twice-daily (BID) injections of a total GH dose of 6 IU/m2/d in combination with low-dose ethinyl estradiol (50 ng/kg/d orally). At baseline, impaired glucose tolerance (IGT) was present in 6% of the girls, and at the end of the studies, in 5%. In the DR study, the area under the curve for time-concentration (AUCab) for glucose after an oral glucose tolerance test (OGTT) showed no change over time and no significant difference between any of the study groups. However, in all three DR groups, the AUCab for insulin, fasting glucose, the insulinogenic index, hemoglobin A1c (HbA1c), and urinary C-peptide (uCp) were all significantly higher after 4 years compared with pretreatment (P<.05). In the FR study, group differences were not observed. Compared with healthy Dutch control subjects, the median baseline levels in relatively young girls in the DR study were similar for total cholesterol (TC) and lower for high-density lipoprotein (HDL) cholesterol. In contrast, the median TC levels of relatively older girls in the FR study were higher and HDL levels were similar. With increasing GH dosage in the DR study, median TC and low-density lipoprotein (LDL) levels decreased, whereas median HDL levels increased. The changes after 4 years were significant, including a decrease in the atherogenic index. GH treatment at the supraphysiological dosages used in this study did not increase the frequency of IGT or clinical diabetes. However, we observed an increased insulinogenic index indicative of insulin resistance. Therefore, long-term follow-up study is warranted in these otherwise healthy subjects. OD injection regimens changed the lipid profile toward a more cardioprotective direction with a significant reduction of the TC/HDL cholesterol ratio.

Carbohydrate Metabolism↗

PubMed1999

mRNA and protein localization of the IGF system during mouse embryonic development in areas with apoptosis.

We analysed mRNA and protein localization of the IGF system components in regions with apoptosis during mouse development between 9.5 and 13.5 days post coitum. A spatio-temporal relationship between these expression patterns and the onset of apoptosis in specific areas was sought. The IGFBP mRNA and protein expression patterns were tissue-specific. In most tissues, mRNA expression patterns colocalized with protein localization. Discrepancies between mRNA and protein detection were found in, for example, lens, neural layer of the retina, whiskers and somites. Localization of the IGFs, the type I IGF receptor and IGFBP-2 correlated well with cell death regions. When these genes were expressed no apoptosis occurred and vice versa. Correlation of IGFBP-3, -4 and -5 with apoptosis regions was noticed only at 13.5 days post coitum. In eye muscles, whiskers and somites, the expression of IGF system components preceded the occurrence of apoptotic cells. When IGF-I expression ceased, apoptosis occurred in these areas. In conclusion, our results suggest that IGF-I, the type I IGF receptor and IGFBP-2 inhibit apoptosis. In contrast, IGFBP-3, -4 and -5 may stimulate apoptosis by trapping the IGFs. Tissue-specific modulation of IGF protective action against apoptosis by the different IGFBPs during mouse embryonal development may contribute to organ specific morphology.

Animals↗

PubMed1999

Final height in girls with Turner's syndrome treated with once or twice daily growth hormone injections. Dutch Advisory Group on Growth Hormone.

OBJECTIVES: To study final height in girls with Turner's syndrome treated with once or twice daily injections of growth hormone (GH) in combination with low dose ethinyl oestradiol. DESIGN: Until final height was reached, the effect of fractionated subcutaneous injections given twice daily was compared with once daily injections of a total GH dose of 6 IU/m2/day. Twice daily injections were given as one third in the morning and two thirds at bedtime. All girls concurrently received low dose oestradiol (0.05 microgram ethinyl oestradiol/kg/day, increased to 0.10 microgram/kg/day after 2.25 years). PATIENTS: Nineteen girls with Turner's syndrome aged > or = 11 years (mean (SD) 13.6 (1.7) years). MEASUREMENTS: To determine final height gain, we assessed the difference between the attained final height and the final height predictions at the start of treatment. These final height predictions were calculated using the Bayley-Pinneau (BP) prediction method, the modified projected adult height (mPAH), the modified index of potential height (mIPHRUS), and the Turner's specific prediction method (PTSRUS). RESULTS: The gain in final height (mean (SD)) was not significantly different between the once daily and the twice daily regimens (7.6 (2.3) v 5.1 (3.2) cm). All girls exceeded their adult height prediction (range, 1.6-12.3 cm). Thirteen of the 19 girls had a final height gain > 5.0 cm. Mean (SD) attained final height was 155.5 (5.4) cm. A "younger bone age" at baseline and a higher increase in height standard deviation score for chronological age (Dutch-Swedish-Danish references) in the first year of GH treatment predicted a higher final height gain after GH treatment. CONCLUSIONS: Division of the total daily GH dose (6 IU/m2/day) into two thirds in the evening and one third in the morning is not advantageous over the once daily GH regimen with respect to final height gain. Treatment with a GH dose of 6 IU/m2/day in combination with low dose oestrogens can result in a significant increase in adult height in girls with Turner's syndrome, even if they start GH treatment at a relatively late age.

Adolescent↗

PubMed1999

Auxological and biochemical evaluation of pubertal suppression with the GnRH agonist leuprolide acetate in early and precocious puberty.

We studied the auxological effects of treatment with the GnRH agonist leuprolide acetate (Lucrin((R))) at 3.75 mg/ 28 days in 38 children with early or precocious puberty. We present our newly developed scoring system, the Puberty Suppression Score (PSS), in which clinical and biochemical parameters determine whether suppression was effective. Leuprolide acetate suppressed pubertal development in the majority of cases. During treatment there was a significant correlation between the number of times that PSS was >0 and gain in predicted adult height (PAH) compared to initial prediction at the start of treatment. After 6 months of treatment, ineffective suppression measured by PSS was associated with the magnitude of gain in PAH. We conclude that a leuprolide acetate dosage of 3.75 mg every 28 days effectively suppresses puberty. PSS is helpful in monitoring the suppressive capacity of a GnRH agonist. We recommend to start with leuprolide acetate at 3.75 mg/28 days and to increase the injection frequency or dose in case PSS is >0 after 6 months of treatment.

Age Determination by Skeleton↗

PubMed1999

Generation of antisera to mouse insulin-like growth factor binding proteins (IGFBP)-1 to -6: comparison of IGFBP protein and messenger ribonucleic acid localization in the mouse embryo.

The insulin-like growth factor (IGF) system is an important regulator of fetal growth and differentiation. IGF bioavailability is modulated by IGF binding proteins (IGFBPs). We have generated six different antisera, directed to synthetic peptide fragments of mouse IGFBP-1 through -6. The specificity of the produced antisera was demonstrated by enzyme-linked immunosorbent assay, Western blotting, and by immunohistochemistry on sections of mouse embryos of 13.5 days post coitum. Specificity for the IGFBP-2 through -6 antisera also was confirmed immunohistochemically in liver and lung of corresponding gene deletion (knock-out) mutant mice and wild-type litter mates. Immunohistochemistry and messenger RNA (mRNA) in situ hybridization on sections of mouse embryos of 13.5 days post coitum revealed tissue-specific expression patterns for the six IGFBPs. The only site of IGFBP-1 protein and mRNA production was the liver. IGFBP-2, -4, and -5 protein and mRNA were detected in various organs and tissues. IGFBP-3 and -6 protein and mRNA levels were low. In several tissues, such as lung, liver, kidney, and tongue, more than one IGFBP (protein and mRNA) could be detected. Differences between mRNA and protein localization were extensive for IGFBP-3, -5, and -6, suggesting that these IGFBPs are secreted and transported. These results confirm the different spatial localization of the IGFBPs, on the mRNA and protein level. The overlapping mRNA and protein localization for IGFBP-2 and -4, on the other hand, may indicate that these IGFBPs also function in an auto- or paracrine manner.

Amino Acid Sequence↗

PubMed1999

17Beta-hydroxysteroid dehydrogenase-3 deficiency: diagnosis, phenotypic variability, population genetics, and worldwide distribution of ancient and de novo mutations.

17Beta-hydroxysteroid dehydrogenase-3 (17betaHSD3) deficiency is an autosomal recessive form of male pseudohermaphroditism caused by mutations in the HSD17B3 gene. In a nationwide study on male pseudohermaphroditism among all pediatric endocrinologists and clinical geneticists in The Netherlands, 18 17betaHSD3-deficient index cases were identified, 12 of whom initially had received the tentative diagnosis androgen insensitivity syndrome (AIS). The phenotypes and genotypes of these patients were studied. Endocrine diagnostic methods were evaluated in comparison to mutation analysis of the HSD17B3 gene. RT-PCR studies were performed on testicular ribonucleic acid of patients homozygous for two different splice site mutations. The minimal incidence of 17betaHSD3 deficiency in The Netherlands and the corresponding carrier frequency were calculated. Haplotype analysis of the chromosomal region of the HSD17B3 gene in Europeans, North Americans, Latin Americans, Australians, and Arabs was used to establish whether recurrent identical mutations were ancient or had repeatedly occurred de novo. In genotypically identical cases, phenotypic variation for external sexual development was observed. Gonadotropin-stimulated serum testosterone/androstenedione ratios in 17betaHSD3-deficient patients were discriminative in all cases and did not overlap with ratios in normal controls or with ratios in AIS patients. In all investigated patients both HSD17B3 alleles were mutated. The intronic mutations 325 + 4;A-->T and 655-1;G-->A disrupted normal splicing, but a small amount of wild-type messenger ribonucleic acid was still made in patients homozygous for 655-1;G-->A. The minimal incidence of 17betaHSD3 deficiency in The Netherlands was shown to be 1: 147,000, with a heterozygote frequency of 1:135. At least 4 mutations, 325 + 4;A-->T, N74T, 655-1;G-->A, and R80Q, found worldwide, appeared to be ancient and originating from genetic founders. Their dispersion could be reconstructed through historical analysis. The HSD17B3 gene mutations 326-1;G-->C and P282L were de novo mutations. 17betaHSD3 deficiency can be reliably diagnosed by endocrine evaluation and mutation analysis. Phenotypic variation can occur between families with the same homozygous mutations. The incidence of 17betaHSD3 deficiency is 0.65 times the incidence of AIS, which is thought to be the most frequent known cause of male pseudohermaphroditism without dysgenic gonads. A global inventory of affected cases demonstrated the ancient origin of at least four mutations. The mutational history of this genetic locus offers views into human diversity and disease, provided by national and international collaboration.

17-Hydroxysteroid Dehydrogenases↗

PubMed1999

Body proportions during long-term growth hormone treatment in girls with Turner syndrome participating in a randomized dose-response trial.

To assess body proportions in girls with Turner syndrome (TS) during long term GH treatment, height, sitting height (SH), hand (Hand) and foot (Foot) lengths, and biacromial (Biac) and biiliacal (Biil) diameters were measured in 68 girls with TS participating in a GH dose-response trial. These previously untreated girls with TS, aged 2-11 yr, were randomly assigned to 1 of 3 GH dosage groups: group A, 4 IU/m2 x day; group B, first year 4 and thereafter 6 IU/m2 x day; group C, first year 4, second year 6, and thereafter 8 IU/m2 x day. Seven-year data were evaluated to assess the effect of GH treatment on body proportions during childhood. In addition, data from all girls who had reached adult height were evaluated to determine the effect on the adult body proportions. All results were adjusted for age and sex and expressed as SD scores using reference values of healthy Dutch girls. To describe the proportions of SH, Hand, Foot, Biac, and Biil to height, these values were adjusted for the SD score of height and were expressed as shape values, using the formula, e.g. for SH: shape SH = (SH SD score - height SD score)/square root(2 - 2 x correlation coefficient between SH and height in the reference population). Furthermore, SD scores using references of untreated girls with TS were calculated for height and SH. Values less than -2 or more than +2 were considered outside the normal range. At baseline, the shape values of all measurements were significantly higher than zero, but most mean shape values were still within the normal range. Seven-year data of 64 girls and adult height data of 32 girls showed that an increase in height was accompanied by an even higher increase in Foot, resulting in mean SD scores above zero and shape values of +2 and higher. The increase in the shape value of Foot was significantly higher in groups B and C compared to that in group A after 7 yr of GH treatment, but there were no significant differences between the GH dosage groups in the girls who had reached adult height. The shape values of SH had decreased to values closer to zero after reaching adult height, especially in group A. A similar pattern in the relationship of SH to height was seen using references of girls with TS. No significant changes in the other proportions were found after reaching adult height. In conclusion, on the average, untreated girls with TS have relatively large trunk, hands, and feet, and broad shoulders and pelvis compared to height. The increase in height after long term GH treatment is accompanied by an even higher increase in Foot and a moderate improvement of the disproportion between height and SH. Recently published reference data from untreated adults with TS and the results of a different patient group receiving a comparable GH dosage suggest that the disproportionate growth of feet has to be considered a part of the natural development in TS, but might be influenced by higher GH dosages. The development of large feet can play a role in the decision of the girl to discontinue GH treatment in the last phase of growth.

Body Constitution↗

PubMed1999

Normalization of height in girls with Turner syndrome after long-term growth hormone treatment: results of a randomized dose-response trial.

Short stature and ovarian failure are the main features in Turner syndrome (TS). To optimize GH and estrogen treatment, we studied 68 previously untreated girls with TS, age 2-11 yr, who were randomly assigned to one of three GH dosage groups: group A, 4 IU/m2 day (approximately 0.045 mg/kg x day); group B, first yr 4, thereafter 6 IU/m2 x day (approximately 0.0675 mg/kg/day); group C, first yr 4, second yr 6, thereafter 8 IU/m2 x day (approximately 0.090 mg/kg x day). In the first 4 yr of GH treatment, no estrogens for pubertal induction were given to the girls. Thereafter, girls started with 17beta-estradiol (5 microg/kg bw x day, orally) when they had reached the age of 12 yr. Subjects were followed up until attainment of adult height or until cessation of treatment because of satisfaction with the height achieved. Seven-year data of all girls were evaluated to compare the growth-promoting effects of three GH dosages during childhood. After 7 yr, 85% of the girls had reached a height within the normal range for healthy Dutch girls. The 7-yr increment in height SD-score was significantly higher in groups B and C than in group A. In addition, we evaluated the data of 32 of the 68 girls who had completed the trial after a mean duration of treatment of 7.3 yr (range, 5.0 - 8.75). Mean (SD) height was 158.8 cm (7.1), 161.0 cm (6.8), and 162.3 cm (6.1) in groups A, B, and C, respectively. The mean (SD) difference between predicted adult height before treatment and achieved height was 12.5 cm (2.1), 14.5 cm (4.0), and 16.0 cm (4.1) for groups A, B, and C, respectively, being significantly different between group A and group C. GH treatment was well tolerated in all three GH dosage groups. In conclusion, GH treatment starting in relatively young girls with TS results in normalization of height during childhood, as well as of adult height, in most of the individuals. With this GH and estrogen treatment regimen, most girls with TS can grow and develop much more in conformity with their healthy peers.

Adolescent↗

PubMed1999

A limited repertoire of mutations of the luteinizing hormone (LH) receptor gene in familial and sporadic patients with male LH-independent precocious puberty.

Herein, we report mutation analysis of the LH receptor gene in 17 males with LH-independent precocious puberty, of which 8 were familial and 9 had a negative family history. A total of 7 different mutations (all previously reported) were detected in 12 patients. Among 10 European familial male-limited precocious puberty (FMPP) patients who had a LH receptor gene mutation, none had the Asp578Gly mutation, which is responsible for the vast majority of cases in the U.S. The restricted number of activating mutations of the LH receptor observed in this and other studies of FMPP strongly suggests that an activating phenotype is associated with very specific sites in the receptor protein. Clinical follow-up of the 5 patients who did not have LH receptor mutations shows that such cases most likely do not have true FMPP. LH receptor mutation analysis provides a sensitive tool for distinguishing true FMPP from other causes of early-onset LH-independent puberty in males.

Amino Acid Sequence↗

PubMed1998

The IGF system during fetal-placental development of the mouse.

Insulin-like growth factors (IGF-I and -II) promote cellular mitosis and differentiation and have been implicated in fetal and placental growth. Together with the IGF receptors and IGF binding proteins (IGFBPs) they form a complex network, with tissue specific activity. This review will discuss the data generated to elucidate the functions of the IGF system during mouse development.

Animals↗

PubMed1998

[Hormonal therapy of constitutionally tall children].

Children of constitutionally tall stature may experience serious problems related to their height. Treatment with high dose sex steroids may be considered in order to limit final adult height. Prediction of adult height plays a central part in the management of children of tall stature. Various aspects of height prediction in children of tall stature are discussed. The height reducing effect varies between studies from 2 to 10 cm. Recently, in a large Dutch study the mean effects of therapy were 0.7 and 2.4 cm for boys and girls respectively. The effect depended on the bone age at start of treatment. Beyond a critical bone age of about 14 years treatment had no effect. Minimal age for intervention is 9.5-10 year for boys and 9.0-9.5 year for girls. Recommended treatment for boys is 250 mg testosterone esters i.m. per week and for girls ethinyloestradiol orally 200 micrograms per day in combination with medroxyprogesterone or dydrogesterone (both 5-10 mg per day) during the first 12-14 days of the cycle. Treatment has to be continued until complete closure of the epiphyses. While side effects during hormonal therapy are frequent, they are mostly temporary and mild and seldom lead to cessation of therapy. So far there have been no indications of adverse effects on, for instance, gonadal function.

Administration, Oral↗

PubMed1998

mRNA expression patterns of the IGF system during mouse limb bud development, determined by whole mount in situ hybridization.

During limb development the primary limb bud requires various signals to differentiate. Insulin-like growth factor (IGF)-I and IGF-II serve as ubiquitous cellular growth promoters and are modulated by their binding proteins (IGFBPs), which inhibit or augment IGF bioavailability. This is the first study to give a complete overview of the mRNA expression patterns of Igf-1, Igf-2, type 1 Igf receptor (Igf1r) and six Igf binding proteins (IGFBP-1-6) in embryonic mouse limbs, at various stages of development, by whole mount in situ hybridization (ISH). Our results show that all the members of the Igf system, except Igfbp-1 and -6, have specific spatio-temporal mRNA expression patterns. IGFBP-2 and -5 are found in the apical ectodermal ridge (AER), and IGF-I and IGFBP-4 in the region of the zone of polarizing activity (ZPA). IGF-II and IGF1R are found in regions of pre-cartilage formation. At 13.5 days post coitus (dpc) the IGF system colocalizes with apoptosis areas; IGFBP-2, -4 and -5 are found in the interdigital zone, while IGFBP-3 and IGF-I border this region. Furthermore, IGFBP-3, -4 and -5 are found in the phalangeal joint areas, at an early stage of joint formation. This supports the hypothesis that the IGF system may be involved in chondrogenic differentiation of mesenchyme and the regulation of apoptosis in the developing limb.

Animals↗