bluuebunny/crossref_metadata_2025_split huggingface dataset:
Female sex hormone replacement therapy increases serum free 1,25‐dihydroxyvitamin D3: a 1‐year prospective study
Authors: Van Hoof  , Van Der Mooren  , Swinkels  , Sweep  , Merkus  , Benraad Th. J. 
Published: March 2003

OBJECTIVECurrently, hormone replacement therapy is applied successfully to reduce post‐menopausal bone resorption. However, the exact mechanism by which oestrogen exerts its effect has not yet been fully elucidated. In order to determine whether changes in the biologically active 1,25‐dihydroxyvitamin D3 may be of importance in this process, the concentrations of both total and free 1,25‐dihydroxyvitamin D3 in serum were assessed.DESIGNIn 36 post‐menopausal women the effect of hormone replacement therapy, with a combination of 17β‐oestradiol and norethisterone acetate, on the serum levels of total and free 1,25‐dihydroxyvitamin D3 was studied after 0, 3, 6 and 12 cycles.MEASUREMENTSThe total concentration of 1,25‐dihydroxyvitamin D3 in serum was assessed using a radioreceptor assay after diethylether extraction of the samples followed by paper chromatography. The free fraction of 1,25‐dihydroxyvitamin D3 was measured using symmetric dialysis. The free 1,25 dihydroxyvitamin D3 concentration was calculated by multiplying the total concentration by the free fraction.RESULTSDuring therapy, mean serum total 1,25‐dihydroxyvitamin D3 concentrations (± SD) were 106.4 pmol/l (± 27.5), 155.0 pmol/l (± 49.5), 176.7 pmol/l (± 70.0) and 161.1 pmol/l (± 55.3) at 0, 3, 6 and 12 cycles, respectively. Serum free 1,25‐dihydroxyvitamin D3 concentrations were 68 fmol/l (± 22), 107 fmol/l (± 35), 120 fmol/l (± 43) and 108 fmol/l (± 37), respectively. Baseline values of both total and free 1,25‐dihydroxyvitamin D3 were significantly lower than those during therapy at all time (P ≤ 0.001).CONCLUSIONBoth the serum total 1,25‐dihydroxyvitamin D3 and the serum free 1,25‐dihydroxyvitamin D3 concentrations are increased during combined 17β‐oestradiol and norethisterone acetate therapy for a year. Assuming that the free concentration 1,25‐dihydroxyvitamin D3 reflects the biologically active fraction, this rise may in part explain the preventive effect of hormone replacement therapy on osteoporosis.
Correlation between cortisol and insulin‐like growth factor‐binding proteins (IGFBPs) under physiological conditions in children
Authors: Martinelli Jr Carlos E. , Yateman Martin E. , Cotterill Andrew M. , Moreira Ayrton C. , Camacho‐Hübner Cecilia 
Published: March 2003

OBJECTIVEA positive correlation between 24‐h spontaneous growth hormone (GH) and cortisol secretion was previously reported in children. This observation prompted us to examine the relationship between physiological diurnal cortisol variation and the levels of insulin‐like growth factors (IGFs) and IGF‐binding proteins (IGFBPs) under physiological conditions.DESIGN AND PATIENTSStarting at 0800 h, blood was sampled every 20 minutes over 24 h for measurement of GH and cortisol concentration in nine non‐GH‐ deficient boys as part of a protocol for the investigation of short stature.MEASUREMENTSIGFBP‐1 and insulin were measured in samples drawn every 4 h over the 24‐h period while IGF‐I, IGF‐II, IGFBP‐2 and IGFBP‐3 were determined in samples collected at the end of the study.RESULTSNo correlation was observed between IGF‐I or IGF‐II and mean cortisol levels. IGFBP‐1 concentrations showed a marked circadian variation that was superimposed on the circadian rhythm for cortisol while a significant positive correlation was found for single point measurements between IGFBP‐1 concentrations and cortisol levels measured in the same sample (r = 0.53) or at the preceding 20 minutes (r = 0.43), 40 minutes (r = 0.47) and 2 h (r = 0.38), suggesting an interplay between cortisol and IGFBP‐1. A negative correlation (r = − 0.54) was found between IGFBP‐1 and insulin levels determined in the same sample. A negative correlation (r = − 0.93) was also found between IGFBP‐2 levels and mean cortisol concentrations during the preceding 12 h. No correlation was observed between plasma IGFBP‐3 measured by IRMA and mean cortisol levels.CONCLUSIONOur data indicate a clear correlation between cortisol and IGFBP‐1 and IGFBP‐2 levels. Thus, the interplay of spontaneous GH and cortisol secretion in children may involve changes in IGFBP‐1 and IGFBP‐2 levels.
Short‐term leptin infusion does not affect circulating levels of LH, testosterone or cortisol in food‐restricted pubertal male rhesus macaques
Authors: Lado‐Abeal Joaquin , Lukyanenko Yevgeniya O. , Swamy Sunita , Hermida Ramon C. , Hutson James C. , Norman Reid L. 
Published: March 2003

OBJECTIVESAlthough the adipocyte protein leptin has been implicated in the control of reproductive function in rodents, its role in primate reproductive physiology is poorly understood. Because primates in puberty show nighttime LH secretion and there is considerable evidence that the fertile state requires adequate nutrition, we reasoned that animals on the verge of reproductive competence would respond to leptin infusions by secreting LH. Food restriction reduces circulating leptin levels and slows or stops the GnRH pulse generator. Therefore, we examined the endocrine effects of leptin infusions in food‐restricted male pubertal primates during the night when they normally secrete LH. In addition, we investigated the effect of leptin on in vitro testosterone production by Leydig cells.SUBJECTSFour pubertal male rhesus macaques (Macaca mulatta), 4–5.5 kg in weight (2.5–4‐year‐old) were examined in this study. Leydig cells from adult male rats were to investigate in vitro effects of leptin.DESIGNTo document that animals had entered puberty, blood samples were collected from each of the four animals at 15‐minute intervals for 15 h both during the day and at night. Since at this age animals secrete LH mainly at night, blood samples were collected at 15‐minute intervals from each of the four animals on two separate occasions for 15 h between 1500 and 0600h. During the experiment, animals were feeding from 0800 to 0830h, cages were completely cleaned of food at 0900h and the afternoon meal was not given to individual animals on the day they were studied. One of the studies served as the control (food restricted group) and during the other, 2 mg (n = 4) or 0.3 mg (n = 3) of recombinant human leptin was administered intravenously during 2000–0100h (food restricted plus leptin group). Blood samples (1 ml) were collected through the indwelling catheter and immediately transferred from the plastic syringe into chilled glass tubes containing 10 μl 14% EDTA. The samples were centrifuged at 5‐h intervals and the plasma withdrawn and stored frozen at − 20°C in polypropylene vials until assays were performed.MEASUREMENTSBioactive LH was determined and testosterone, cortisol and leptin were measured by radioimmunoassay.RESULTSDuring daytime experiments in these animals, LH pulses were sometimes observed late in the day and generally continued for 12–15 h. Food‐restricted pubertal males showed delayed or absent LH pulses. Short‐term leptin administration to food‐restricted male rhesus macaques had no effect on LH, testosterone, or cortisol levels either during or after the infusion. Leptin also had no direct effect on basal or LH‐stimulated testosterone production in Leydig cells.CONCLUSIONSOur data support the notion that leptin is not the missing signal for the acute suppression of reproductive hormones secretion in food‐restricted primates.
Differences in the levels of TSH‐binding inhibitor immunoglobulins in goitrous and agoitrous autoimmune thyroiditis after twelve months of l‐thyroxine therapy
Authors: Khoo  , Eng  , Ho  , Fok  
Published: March 2003

OBJECTIVEThe aims were to study the prevalence of TSH binding inhibitor immunoglobulins (TBII) in newly diagnosed patients with autoimmune hypo‐thyroidism, to determine if clinical and biochemical parameters in these patients differed, and to study the course of these antibodies after 12 months of l‐thyroxine (LT4) therapy.SUBJECTS AND DESIGNIn a prospective study, 111 consecutive patients with newly diagnosed auto‐immune hypothyroidism were enrolled. Patients were divided into groups according to the presence or absence of a goitre and TBII levels. Clinical and biochemical differences in these patients were analysed. Patients were then treated with l‐thyroxine (LT4) for 12 months and changes in their TBII monitored.MEASUREMENTSFree T4 and TSH levels were measured at baseline and then 6‐weekly during the titration of LT4 doses. Once TSH levels had normalized, these measurements were performed 3 monthly. TBII levels were measured in patients at baseline and 12 months. Thyroid stimulating blocking antibody (TSBAb) levels were measured 12–18 months after initiation of LT4 therapy.RESULTSTwenty patients were TBII‐positive, 10 goitrous and 10 agoitrous. Agoitrous TBII‐positive patients were found to have similar characteristics: these included TBII levels > 100 U/l, potent thyroid stimulating blocking antibody (TSBAb) activity and a tendency for TBII levels to remain unchanged or to rise after LT4 therapy. The degree of hypothyroidism seen in these cases was significantly greater than in all other groups. In contrast, goitrous TBII‐positive patients were heterogenous, most did not have significant TSBAb activity and TBII disappeared in 5 out of 10 cases after a year of LT4 treatment. While TBII disappeared in 6 of the 20 patients after a year, remission of hypothyroidism occurred in only 3 cases.CONCLUSIONSThe degree of hypothyroidism in agoitrous TSH‐binding inhibitor immunoglobulins‐positive patients appears to be more severe than that seen in other forms of AIT. The differences in thyroid stimulating blocking antiboby activity and response to LT4 therapy in agoitrous and goitrous autoimmune thyroiditis suggest that the TSH‐binding inhibitor immunoglobulins in these patients are fundamentally different. The disappearance of TSH‐binding inhibitor immunoglobulins in hypothyroid patients was not accompanied by the reversal of hypothyroidism in 50% of patients.
Reduced human growth hormone (hGH) bioactivity without a defect of the GH‐1 gene in three patients with rhGH responsive growth failure
Authors: Binder  , Benz  , Elmlinger  , Pflaum  , Strasburger  , Ranke  
Published: March 2003

BACKGROUNDA GH deficiency‐like phenotype with normal or high hGH secretion, pathologically low IGF‐I serum levels, and catch‐up growth under treatment with recombinant hGH is suggestive of the presence of biologically inactive hGH syndrome, whose presumably heterogenous molecular basis is substantially unknown.DESIGNSerum samples from patients who fulfilled the above criteria and from controls with idiopathic short stature were measured by polyclonal hGH‐RIA, Nb2 rat lymphoma proliferation assay, and hGH immunofunctional assay (IFA). If assays were suggestive of the presence of bioinactive GH, mutational analysis of the hGH‐1 gene was performed.PATIENTSThree patients were selected because of clinical and biochemical evidence. At the time of diagnosis mean age was 3.4 (2.2, 3.5, 4.5) years, mean height −3.5 (−2.8, −3.6, −4.2) SD score (SDS) and mean growth rate −1.5 (−1.4, −1.5, −1.6) SDS. Mean IGF‐I serum levels were −1.9 (−0.7, −2.4, −2.5) SDS and mean IGFBP‐3 serum levels −1.2 (−1.1, −1.2, −1.2) SDS. Stimulated and spontaneous GH peaks measured by a polyclonal radioimmunoassay were all above 14 μg/l. GHBP serum levels were normal, and antihGH antibodies were not detected. Therapy with rhGH was effective in causing catch‐up growth of the three children with an initial mean growth rate of + 2.9 (+ 1.7, + 2.1, + 5.0) SDS, and normalization of IGF‐I (mean: −0.66 SDS: −1.8, − 1.2, + 1.1 SDS) and IGFBP‐3 serum levels (mean: + 0.81 SDS: −0.2, + 0.8, + 1.8 SDS).RESULTSIn comparison to controls, the patients' serum hGH levels were much lower when measured by Nb2 rat lymphoma cell proliferation bioassay (mean: −2.3 SDS, range: −1.7– −4.1) and by the immunofunctional assay (IFA) (−1.5 SDS, range: −0.2– −3.1) than by RIA. Retesting of two of the three patients including an one year break of therapy confirmed the rhGH dependence of growth in spite of normal endogenous GH secretion. Radioactive direct sequencing of both strands of PCR‐amplified genomic DNA and cDNA excluded a GH‐1 gene mutation in all three children.CONCLUSIONMutations of the GH‐1 gene are probably not the main genetic defect in children with biologically inactive hGH syndrome. Posttranslational processing of hGH might reduce the biological activity of the normal translation product.
Association of the large multifunctional proteasome (LMP2) gene with Graves' disease is a result of linkage disequilibrium with the HLA haplotype DRB1*0304‐DQB1*02‐DQA1*0501
Authors: Heward  , Allahabadia  , Sheppard  , Barnett  , Franklyn  , Gough  
Published: March 2003

OBJECTIVEThe large multifunctional proteasome (LMP) molecules are over expressed in thyrocytes, the target cells of Graves' disease, and the LMP genes are found within the MHC class II region. The LMP genes may therefore play a role in susceptibility to Graves' disease. The aim of this this study was to determine whether polymorphisms of the LMP genes, LMP 2 and LMP 7 are in linkage disequilibrium with Graves' disease.DESIGNTarget DNA was amplified using the polymerase chain reaction. The distribution of an Arg‐His polymorphism in the LMP2 gene and a G/T polymorphism in the LMP 7 gene, both of which lead to the presence of an HhaI restriction site, were investigated in a population based case control and family based study in patients with Graves' disease.PATIENTSWe obtained DNA from 306 patients with Graves' disease and 364 control subjects for the population based case‐control study. In an independent family based study, DNA was obtained from 129 families including both parents, an affected sibling with Graves' disease and an unaffected sibling. All families, patients and control subjects were white caucasians.MEASUREMENTSFrequencies of the alleles and genotypes of the LMP 2 and LMP 7 genes were compared between patients and control subjects using the χ2 test. Transmission of alleles from heterozygous parents to affected and unaffected offspring was assessed using the transmission disequilibrium test (TDT).RESULTSIn the case control study, no difference in allele or genotype frequency was seen between patients and control subjects at the LMP7 locus. At the LMP2 locus the R allele and the RH genotype were increased in subjects with Graves' disease when compared with control subjects (R allele: 36.3% vs. 29.5%, pc = 0.0164; RH genotype: 56.5% vs. 45%, pc = 0.0102). However, the R allele was in linkage disequilibrium with the associated HLA DRB1*0304‐DQB1*02‐DQA1*0501 haplotype, δ = 0.102. Within the family based study, no preferential allelic transmission was seen from heterozygote parents to offspring at either loci.CONCLUSIONThese results show that association of the LMP 2 locus with Graves' disease is due to linkage disequilibrium with the associated HLA haplotype DRB1*0304‐DQB1*02‐DQA1*0501.
Fetal pituitary negative feedback at early gestational age
Authors: Rakover Yardena , Weiner Ehud , Mosh Netanel , Shalev Eliezer 
Published: March 2003

We describe an early prenatal diagnosis and the successful treatment of fetal Graves' disease from transplacental transfer of maternal thyroid stimulating autoantibodies (TSAb). The diagnosis of fetal thyrotoxicosis was made by umbilical cord sampling (UBS) at 20 weeks gestation, based on suppressed TSH with elevated FT4 levels. Therapy with propylthiouracil (PTU) improved fetal thyroid function tests as well as the clinical signs of fetal Graves' disease. Three more UBS were conducted before delivery indicating persisting mild fetal hyperthyroidism.Undetectable concentrations of thyrotrophin in fetal serum in the presence of markedly elevated FT4, suggests pituitary negative feedback at as early as 20 weeks gestation.Amniotic fluid thyrotrophin levels were measured at 20,24 and 26 weeks and were shown to correlate better with (elevated) maternal rather than (suppressed) fetal TSH values; therefore, we believe that amniotic fluid thyrotrophin measurement is unreliable for prediction of fetal thyroid status.Our observation is the first documentation of an intact feedback mechanism so early in fetal development and it suggests that pituitary maturation occurs earlier than previously believed.
Increased prevalence of type 2 diabetes mellitus and impaired glucose tolerance in first‐degree relatives of girls with a history of precocious pubarche
Authors: Ibáñez Lourdes , Castell Conxa , Tresserras Ricard , Potau Neus 
Published: March 2003

OBJECTIVETo assess whether abnormal responses to an oral glucose load, dyslipidaemia and hyperandrogenaemia, which are commonly found in girls with a history of precocious pubarche, can also be detected in first‐degree relatives of these patients.PATIENTS AND DESIGNSixty first‐degree relatives (age, 41.4 ± 4.4 years; BMI, 26.9 ± 3.3 kg/m2) of girls diagnosed with precocious pubarche were studied. The prevalence of gestational diabetes mellitus and the hirsutism score were assessed in the females. The study was performed during the early follicular phase of the menstrual cycle in females and at random in males.MEASUREMENTSAll subjects underwent a standard 75 g 2‐h oral glucose tolerance test (OGTT). Serum lipids and lipoproteins were measured in baseline blood samples in all subjects, while serum testosterone, sex hormone‐binding globulin (SHBG) levels and the free androgen indices were determined only in females. Impaired glucose tolerance (IGT) and type 2 diabetes mellitus were diagnosed according to the criteria of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.RESULTSSeven subjects (11.6%) had type 2 diabetes while a further 14 (23.3%) had IGT; prevalences significantly higher than those reported for the present population of the same age (type 2 diabetes, 2.5% and IGT, 7.5%; P < 0.001 and P < 0.001, respectively). BMIs were similar in patients with either normal or abnormal glucose tolerance. Abnormal levels of at least two lipid parameters were found in 40% of subjects. Four out of 10 hirsute women and six non‐hirsute women reported gestational diabetes. Mean serum SHBG levels were lower in female relatives compared with population controls (P < 0.0005).CONCLUSIONSFirst‐degree relatives of girls with precocious pubarche are at a higher risk of impaired glucose tolerance and type 2 diabetes which, in most cases, is accompanied by an unfavourable lipid profile. Hyperandrogenism and an increased prevalence of gestational diabetes mellitus are frequent among females. These data may prove useful in identifying a specific subset of the population at increased risk of developing metabolic disturbances known to predispose to cardiovascular disease.
RAD51 as a candidate parathyroid tumour suppressor gene on chromosome 15q: absence of somatic mutations
Authors: Carling Tobias , Imanishi Yasuo , Gaz Randall D. , Arnold Andrew 
Published: March 2003

OBJECTIVELoss of heterozygosity (LOH) at chromosome 15q is frequent in parathyroid adenomas, but no tumour suppressor gene of importance to parathyroid tumour development has been isolated from this region. The RAD51 gene has been localized to chromosome 15q and possesses regulatory functions involving DNA stability and cell proliferation, suggesting its possible role in tumorigenesis. Additionally, mutations in the RAD51 gene cause reduced resistance to ionizing radiation, which is a major risk factor for primary hyperparathyroidism. RAD51 was therefore analysed as a candidate tumour suppressor gene in a group of parathyroid adenomas for which mutations in a 15q tumour suppressor should be most readily detectable.PATIENTS AND DESIGNFrom a total of 55 parathyroid adenomas, nine were selected based on their LOH pattern showing DNA loss at chromosome 15q in the vicinity of the RAD51 gene. RAD51 mRNA expression was investigated by reverse transcription–polymerase chain reaction (RT‐PCR), and sequence analysis of the entire coding region of the RAD51 cDNA was performed in all nine adenomas.RESULTS RAD51 mRNA expression was substantiated in all parathyroid adenomas. Compared with the normal RAD51 cDNA sequence, no point mutations or microdeletions could be found in the parathyroid tumor cDNA.CONCLUSIONThese observations suggest that somatic inactivating mutations of the RAD51 gene are uncommonly, if ever, associated with parathyroid tumourigenesis.
Mutations in intron 3 of GH‐1 gene associated with isolated GH deficiency type II in three Japanese families
Authors: Kamijo Takashi , Hayashi Yoshitaka , Shimatsu Akira , Kinoshita Eiichi , Yoshimoto Masaaki , Ogawa Masamichi , Seo Hisao 
Published: March 2003

OBJECTIVEIsolated GH deficiency (IGHD) type II is a disorder inherited in an autosomal dominant manner. Three mutations at the donor splice site of intron 3 of the GH‐I gene have been identified in five families. In this report, we describe a novel mutation also at the donor splice site of intron 3 in patients with IGHD type II.PATIENTSFive individuals diagnosed as IGHD: two sporadic cases and one family with three affected individuals (two siblings and their father).MEASUREMENTGenomic DNA was extracted from peripheral mononuclear cells. All the exons and introns of the GH‐I gene were amplified by polymerase chain reaction (PCR) and subjected to sequence analysis.RESULTSA guanine to adenine transition at the fifth base of intron 3 (mutE), which has not been reported, was identified in the familial case but not in unaffected members of the family including the paternal grandparents. In the other two families with sporadic cases, a guanine to adenine transition at the first base of intron 3 (mutA) was identified in the affected subjects but not in other members of the families.CONCLUSIONMutE has not been previously reported and is the fourth mutation associated with IGHD type II. The guanine residue mutated in mutA was the second nucleotide of a CpG dinucleotide, which is regarded as a hot spot for mutations by a methylation‐deamination mechanism. Since mutA has previously been identified in three type II IGHD kindreds belonging to different ethnic backgrounds, this appears to be the most frequent GH‐I gene mutation in IGHD with a dominant inheritance. Because de novo mutations appeared to have occurred in all three families analyzed in the present study and the presence or absence of these mutations can easily be tested by PCR and restriction enzyme digestion, not only the familial cases but also sporadic cases with IGHD should be examined for a possible mutation at the donor splice site of intron 3 in the GH‐1 gene.