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Biomedical subjects

J C Job

Publications and source records attributed to J C Job.

At least 19 recordsLinked to original sources
PubMed1998

Growth hormone therapy with three dosage regimens in children with idiopathic short stature. European Study Group Participating Investigators.

OBJECTIVE: In children with idiopathic short stature (ISS) we studied the growth-promoting effect at 4 years of recombinant human growth hormone (rhGH) therapy in three dose regimens and evaluated whether increasing the dosage after the first year could prevent a decline in height velocity (HV). DESIGN: Included were 223 patients who were treated with subcutaneous administrations of rhGH 6 days per week. They were randomized to three groups: 3 IU/m2 body surface/day, 4.5 IU/m2/day, and 3 IU/m2/day during the first year and 4.5 IU/m2/day thereafter, corresponding with dosages of 0.2 and 0.3 mg/kg body weight/week, respectively. Growth was compared with a standard of 229 untreated children with ISS [ISS standard]. RESULTS: During the first year of treatment HV almost doubled and was higher with 4.5 IU/m2 than with 3 IU/m2. In the second year HV no longer differed among the groups, but increasing the dosage slowed the rate of the fall of HV. During 4 years of therapy the height SD score for age increased by a mean (SD) of 2.5 (1.0) [ISS standards], or 1.2 (0.7) (British standards), bone age increased by 4.8 (1.3) years, and predicted adult height SD score increased by 1.5 (0.7). After 4 years the results of the group with 4.5 IU/m2 were slightly better than those of the other groups. When dropouts were included in the analysis (assuming a stable height SD score after discontinuation of rhGH therapy), height gain was still significant. CONCLUSIONS: During 4 years of rhGH therapy, growth and final height prognosis improved, slightly more with 4.5 IU/m2 than with 3 IU/m2 or 3 to 4.5 IU/m2. However, bone age advanced on average 4.8 years during this period; therefore, any effect on final height will probably be modest.

Body Height↗
PubMed1997

Long-term results of growth hormone treatment in France in children of short stature: population, register based study.

OBJECTIVES: To describe the growth of children treated with growth hormone and to evaluate the prognostic factors for height at the end of treatment. DESIGN: Register based cohort study. SETTING: French national register of all children treated with growth hormone. SUBJECTS: 3233 short stature children (3165 of whom were deficient in growth hormone) who were treated with growth hormone (excluding children with Turner's syndrome) and whose treatment started between 1973 and 1989, last data being recorded in December 1993. MAIN OUTCOME MEASURES: Annual changes in height, and height at the end of treatment. RESULTS: Mean height SD score at the end of treatment, after a mean of 4.3 years, was -2, corresponding to gain in mean height SD score of 1 and to a height SD score of 1.1 below target height. In all, 923 children prematurely stopped taking growth hormone treatment, mainly because of insufficient response (insufficient growth) or tiredness. Variables that predicted height at the end of treatment were age, target height, aetiology of short stature, use of puberty inhibitors, and type of growth hormone. CONCLUSIONS: The outcome of children of short stature with growth hormone deficiency who were treated with growth hormone has been less favourable than initially assumed. Growth hormone treatment has not restored normal growth to these children. The highly demanding nature and high costs of this treatment require an optimised prescription, and this remains to be determined.

Adolescent↗
PubMed1997

Growth hormone testing for the diagnosis of growth hormone deficiency in childhood: a population register-based study.

Evaluation of GH secretion using pharmacological GH stimulation tests (GHST) remains a current practice, although the reliability of GHST has been questioned, and many pitfalls have been pointed out. We have analyzed all of the 6373 GH stimulation tests that led to the initiation of GH therapy in 3233 children treated in France from 1973-1989. Tests and GH measurements were performed by individual centers and collected by the Association France-Hypophyse. GH deficiency (GHD) was due to craniospinal irradiation (11%), was due to organic causes or associated with multiple deficiencies (22%), or was considered idiopathic (65%); 2% of the patients were considered non-GHD. Eleven different pharmacological tests were used, and 62 of the 66 theoretical pairs of tests were used at least once. The most frequent combination of tests (ornithine in one instance and insulin in another) was used in 12.7% of patients. The reliability of the GH peak measured by comparing the results of 2 tests in the same patient was poor, as measured by intraclass correlation coefficients below 0.8. Multivariate analysis identified several parameters positively or negatively associated with peak plasma GH: calendar year of initiation of treatment, etiology of GHD, height SD score, bone age SD score, puberty, weight SD score, genetic target height SD score, and the nature of the pharmacological agent used. We believe that several of these factors (weight SD score, genetic target height SD score, and nature of the agent) identify biases in the diagnosis of GHD. We conclude that GHST should be performed with a very limited number of agents, interpreted after the establishment of reference values in age-matched normal children, and associated with other clinical and biochemical parameters for establishing the diagnosis of GHD.

Adolescent↗
PubMed1996

Follow-up of three years of treatment with growth hormone and of one post-treatment year, in children with severe growth retardation of intrauterine onset.

Seventy-eight prepubertal, non-GH-deficient children aged 8.1 +/- 0.2 y, with very short stature (mean, -3.2 SD) of intrauterine onset, were treated for 3 y with GH [0.4 (dose D1) or 1.2 (dose D2) IU/kg/wk] and 66 were followed during a 4th y without GH therapy. A 2-y intermediary report had demonstrated a GH dose-dependent acceleration of growth. During the 3rd y on GH, patients D2 (1.2 IU/kg/wk) continued with the same dose, whereas patients D1 (0.4 IU/kg/wk) were randomized to either continue on D1 (group D1) or be increased to D2 (group D1D2). After 3 y on GH, patients' mean height (SD) reached -2.37 (D1), -2.17 (D1D2), and -1.58 (D2) with a total mean height gain of 0.77 (D1), 0.93 (D1D2) (difference NS), and 1.61 SD (D2 significantly higher than D1 and D1D2, p < or = 0.0001). During the off-treatment year, mean growth rate (cm/y) decreased to 3.4 in patients D1, 3.7 in D1D2, and 4.1 in D2 (NS). During the 4 y, bone age advanced of 4.6, 4.6, and 5.3 y in D1, D1D2, and D2, respectively, and puberty started in 34 patients (10 during the off-treatment year). Age at onset of puberty, apparently within normal range, did not relate either to the dose or the duration of treatment. Clinical and biologic tolerance of treatment was good. In conclusion this study demonstrates a GH dose-dependent effect on growth acceleration in persistent postnatal severe growth retardation of intrauterine onset. This effect was sustained for 3 y at 1.2 IU/kg/wk followed by a peculiar growth deceleration at treatment discontinuation. Additional studies are necessary to optimize long-term GH treatment regimen and to document its effects on final height.

Body Height↗
PubMed1994

Growth and puberty in a fostered kindred.

A kindred of four children of different ages was at the same time adopted and transferred from a very poor to a fairly good environment. A rapid catch-up growth was observed in all four during the first 2 years after adoption. Beyond the 2nd year, physical development varied according to age, sex, and the rhythm of sexual maturation. Puberty was not advanced. Final height depended mainly on the height at the onset of puberty. The homogeneity of this familial story can contribute to a better understanding of the age-related interactions between the nutritional and environmental conditions and the genetic factors in human development. The growth and puberty of children coming from poor areas of the world to be fostered in families living in industrialized countries may shed some light on the role of nutritional and environmental factors in human development.

Adoption↗
PubMed1994

Present and potential uses of growth hormone in therapeutics.

In the first weeks of 1993, the accepted indications of growth hormone remain limited to the treatment of severe growth failure resulting directly from pituitary somatrotropic deficiency and to the improvement of height in Turner syndrome. Various other indications of GH may be considered as "potential". Each one has still to prove its real usefulness at more or less long term. Moreover, for all of them there will have to largely take into account the ethical side, mainly the ratio between the expected beneficial effects and the costs and burden, even if no serious inconveniences are presently known. The possible increase in the use of growth hormone is an extremely serious scientific question. It is important to keep it out from the changes in subjective opinions, the medical faschions, and the influences of public opinion or media.

Fetal Growth Retardation↗
PubMed1994

Molecular prenatal diagnosis of partial androgen insensitivity syndrome based on the Hind III polymorphism of the androgen receptor gene.

OBJECTIVE: Partial androgen insensitivity syndromes are the cause of genital ambiguity that is at times quite severe; there is, therefore, a high demand for prenatal diagnosis in families already afflicted with this syndrome. When the mutation has not been identified, the diagnosis can be made by the study of the polymorphisms of the androgen receptor gene. To perform molecular prenatal diagnosis in a family with partial androgen insensitivity syndrome, we studied the Hind III polymorphism of the androgen receptor gene on the trophoblastic DNA. The use of this restriction fragment length polymorphism tracked maternal X chromosome segregation and established prenatal diagnosis although the mutation had not yet been identified in this family. FAMILY: The mother had been previously described as heterozygous for the Hind III polymorphism and chromosomal segregation analysis showed that the affected allele was associated with the 6.7-kb Hind III fragment. MEASUREMENTS: Hind III RFLP with an androgen receptor gene cDNA probe was realized on the trophoblastic DNA, along with measurement of androgen binding activity on the trophoblastic cells. RESULTS: We detected the presence of the 6.7-kb fragment in the DNA of the trophoblastic cells suggesting the fetus was affected. Partial androgen insensitivity syndrome was confirmed by a considerable decrease in androgen binding activity on the trophoblastic cells and by sonography of the fetus. After a therapeutic abortion requested by the parents, the diagnosis was confirmed by clinical examination of the fetus, biochemical analyses of the fetal androgen receptor, and molecular studies of the fetal DNA. CONCLUSIONS: When the mutation of the androgen receptor gene has not been identified, Hind III polymorphism of the trophoblastic DNA is useful in the prenatal diagnosis of androgen insensitivity syndrome in high-risk families.

Androgens↗
PubMed1994

Growth of short normal children in puberty treated for 3 years with growth hormone alone or in association with gonadotropin-releasing hormone agonist.

GH, 0.1 IU/kg/day 6 days/week, was given to 30 early pubertal short patients for 3 years. There were 16 males, aged 14.4 +/- 0.8 years, and 14 females, aged 12.2 +/- 1.2 years, at pubertal stage 2 or 3 with slow growth (4.2 +/- 1.2 cm/year) and no detected GH insufficiency or other cause for short stature. They were randomized in 2 groups: group A with GH alone, and group B with GH and a gonadotropin-releasing hormone agonist during the first 2 years. 28 of the 30 patients completed 3 years of treatment. The annual growth rate increased during the 1st year in both groups and sexes, the increase being significant (p < 0.01) in group A only. Patients of group A kept an improved growth velocity in the 2nd year, then returned to pretreatment growth rate in the 3rd year, while completing their sexual development and bone maturation. Their height, expressed as standard deviation score (SDS) for bone age, improved in the first 2 years, but decreased thereafter. Group B patients returned to pretreatment growth velocity in the 2nd year, and had no significant improvement in growth rate in the 3rd year with GH alone. Their bone maturation, slow when on the GnRH agonist, accelerated when sexual development resumed. At the end of the 3 years, height, expressed as SDS for age, improved in group A from -2.5 +/- 0.6 to -1.5 +/- 0.4 in males (p < 0.05) and from -2.8 +/- 0.5 to -2.1 +/- 0.9 in females (NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Dose-dependent catch-up growth after 2 years of growth hormone treatment in intrauterine growth-retarded children. Belgian and French Pediatric Clinics and Sanofi-Choay (France).

This study reports the results of a 2-yr clinical trial with GH in 95 short prepubertal children with non-GH-deficient intrauterine growth retardation. This randomized, double blind, controlled study compared the effects of placebo (restricted to the first 6 months) and two doses of GH (0.4 and 1.2 IU/kg.week) given sc 6 days/week for 2 yr. A significant GH dose-dependent growth acceleration was observed. Mean height gain (SDS/CA) was 0.66 +/- 0.07 in group I (low dose, 0.4 IU/kg.week) compared to 1.25 +/- 0.07 in group II (high dose, 1.2 IU/kg.week). Mean bone maturation progression (expressed in months) was 26.2 +/- 1.7 and 30.2 +/- 1.5 over 24 months in groups I and II, respectively. Onset of puberty was observed in some patients of both groups. Whether chronic use of a high GH dose will advance the onset of puberty remains to be established. A great variability of growth acceleration was seen among GH dose groups, suggesting that factors in addition to GH dose might modulate individual responses to treatment. In conclusion, it is suggested that in these patients, dose-dependent catch-up growth could be induced by GH treatment.

Analysis of Variance↗
PubMed1993

Failure to improve height prediction in short-stature pubertal adolescents by inhibiting puberty with luteinizing hormone-releasing hormone analogue.

A group of 17 endocrinologically normal short stature adolescent (9 females aged 11.8 +/- 1.5 years and 8 males aged 13.2 +/- 1.1 years) referred at a pubertal stage II-III according to Tanner with a height prediction below -2.5 SD according to Bayley and Pinneau, were treated with long-acting D-Trp6-luteinizing hormone-releasing hormone (3.75 mg i.m. monthly for 24 months) and observed for a period of 13.4 +/- 5.8 months. Pubertal progression was suppressed during the 2 years of analogue therapy, then resumed shortly after the end of treatment. Annual growth rate remained in the prepubertal range during the treatment period and did not increase with the resumption of sexual development. A reduced rate of bone maturation was observed during the 2 years of analogue treatment without clear-cut improvement of the height to bone age relationship at the end of the treatment nor after the post-treatment observation period. Thus, after approximately 3 years of study, no significant improvement of predicted adult stature was obtained. There were no side-effects, but psychological problems mainly related to the failure to increase height. Though methods for predicting adult height are not accurate, these data suggest that use of luteinizing hormone-releasing hormone analogue in endocrinologically normal short subjects entering puberty at normal age with a poor height prognosis does not offer enough possible advantages on growth to offset the possible psychological drawbacks, and cannot be considered as routine treatment in this situation.

Adolescent↗
PubMed1992

Prenatal prediction of androgen insensitivity syndrome using exon 1 polymorphism of the androgen receptor gene.

Exon 1 polymorphism of the androgen receptor (AR) gene is characterized by a (CAG)n(CAA) repeat at position 172 following the translation start codon. The aim of this study was to determine whether AR gene exon 1 polymorphism could be used to perform prenatal diagnosis in high risk families with complete or partial androgen insensitivity syndrome. After enzymatic amplification of a 1 kilobase exon 1 fragment, each DNA was simultaneously digested by MspI and PstI restriction enzymes. After electrophoresis on a 15% electrophoresis on a 15% acrylamide gel or a 6% Nusieve gel, we measured the size of the obtained fragments and determined the number of CAG repeats since a 282 basepair fragment corresponds to 21 CAG. We previously showed that the number of CAG repeats within the AR gene exon 1 in 23 families with complete or partial androgen insensitivity syndrome was 19 +/- 4. By this method, we detected heterozygosity in 50% of the mothers. We present here 2 exclusion prenatal diagnoses using exon 1 polymorphism of the AR gene. Family A presented a boy with a severe form of partial androgen insensitivity syndrome. The mother had 2 uncles with ambiguous genitalia. In family B, the affected child had a complete androgen insensitivity syndrome. In both families, analysis of the AR gene exon 1 polymorphism of the trophoblastic DNA showed the presence of the normal maternal X chromosome. The parents decided to carry on the gestation. In family A, the newborn had normal male external genitalia. In family B, sonography confirmed the presence of normal male external genitalia. These data suggest that exon 1 polymorphism of the AR gene could be prenatally used to predict androgen insensitivity syndrome.

Androgens↗
PubMed1992

Molecular analysis of the androgen receptor gene in 52 patients with complete or partial androgen insensitivity syndrome: a collaborative study.

In patients with androgen insensitivity syndrome (AIS), RFLP study of the androgen receptor gene made it possible to analyze whether deletions or mutations could be responsible for abnormalities in androgen responsiveness. We studied RFLPs of DNA from 25 46,XY patients with partial AIS (PAIS), defined as a concentration of androgen receptor in genital-skin fibroblasts less than 340 fmol/mg DNA, and DNA from 27 46,XY patients with complete AIS (CAIS) with no detectable androgen receptor site. DNA samples were digested with BamHI, EcoRI, HindIII and TaqI restriction enzymes and hybridized with three cDNA probes covering the three domains of the androgen receptor. When we had the maternal and an unaffected brother's DNA, we analyzed the two androgen receptor gene polymorphisms described, the HindIII and the exon 1 CAG repeat polymorphisms, in order to distinguish the two maternal X chromosomes, and to detect carriers of AIS. We did not find any large deletion among the 52 patients. We observed a heterozygous mother in 3 of 14 families studied with the HindIII polymorphism, and in 12 of 25 families using the exon 1 CAG repeat polymorphism. This study suggests that in AIS, abnormalities in androgen receptor response could be related to point mutations or microdeletions rather than to gross structural alterations of the androgen receptor gene. Furthermore, unless the point mutation has been described, exon 1 and HindIII polymorphism studies would enable the identification of carriers in 50% of families, and the prenatal diagnosis of AIS.

Androgens↗
PubMed1992

Growth response to recombinant human growth hormone of mammalian cell origin in prepubertal growth hormone-deficient children during the first two years of treatment.

In five clinical studies performed in Austria, France, the FRG, Italy, Switzerland, the UK and the USA, 304 growth hormone (GH)-deficient children were treated with recombinant human GH (rhGH) of mammalian cell origin. Two hundred and twenty-five patients were previously untreated (naive patients), and 79 were transferred from pituitary hGH after interruption of therapy for at least 6 months (transfer patients). Two treatment protocols, differing in both dose and frequency of injections, were used: (1) a dose of 0.6 IU/kg body weight per week was administered in 3 s.c. injections to 203 patients (178 naive, 25 transfer; group 1); and (2) a dose of 0.45 IU/kg body weight per week was administered in 7 s.c. injections to 101 patients (47 naive, 54 transfer; group 2). After 1 and 2 years of treatment, 143 and 109 naive, and 51 and 46 transfer patients, respectively, were still prepubertal, and their data were analyzed for efficacy. During the 1st year of treatment, both naive and transfer patients on daily injections (group 2) demonstrated better growth than those on 3 injections per week (group 1), with height velocities (HVs) of 10.6 +/- 2.7 cm/year (group 2) versus 8.6 +/- 2.0 cm/year (group 1) for naive patients (p < 0.001), and 9.9 +/- 1.9 cm/year (group 2) versus 7.2 +/- 2.7 cm/year (group 1) for transfer patients (p < 0.001). The corresponding changes in height standard deviation score (delta H SDS) for chronological age (CA) were +1.3 +/- 0.6 (group 2) versus +0.8 +/- 0.5 (group 1) for naive patients (p < 0.01), and +1.1 +/- 0.3 (group 2) versus +0.6 +/- 0.4 (group 1) for transfer patients (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Epidemiologic survey of patients treated with growth hormone in France in the period 1959-1990: preliminary results.

Because the delivery of growth hormone (GH) was centralized from 1977 in France, it has been possible to conduct, during the second half of 1990, a nationwide survey of the health status of patients treated with GH from the year 1959. A questionnaire regarding the 5,546 patients recorded for the period 1959-1990 was sent to the prescribers or the patients. 5,418 more or less completely documented reports were obtained. The mean age of the patients at the onset of GH treatment was 11.0 +/- 4.1 years. 1,937 of them had at this time some important disease associated with GH deficiency. The mean duration of treatment was 3.99 +/- 3.05 years. 3,446 patients were still under follow-up. Very recent information (1990-1991) was given for 82.7% of patients, less recent data (1985-1989) for 13.4%. For 3.9%, no data beyond 1985 were obtained. 77 patients had died, 38 from neoplastic disease (mainly recurrence of a primary malignancy), 10 from accident, 3 by suicide, 7 with neurological disease [only 1 case of Creutzfeldt-Jakob disease (CJD) was reported at the time of the survey], the others from various causes. No abnormal frequency of posttreatment leukemia, lymphoma, malignancies, hip diseases, glucose intolerance or other disease focusing attention, was found in the survey. From the time when this survey was completed (December 1990) to that of this report (May 1992), other cases of CJD have been reported in France: 3 ascertained, 7 clinically resembling but not yet certain. These 10 patients were treated for complete GH deficiency, 6 of congenital or neonatal cause and 4 after neurosurgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗