PubMed Health⌕ Search

Biomedical subjects

B B Bercu

Publications and source records attributed to B B Bercu.

At least 19 recordsLinked to original sources
PubMed2001

Endocrine sequelae of cancer therapy in childhood.

New treatments for neoplastic diseases of childhood have significantly increased patients' long-term survival and the importance of recognizing and correcting late complications of medical therapy. In this review, we examine both central nervous system (CNS) and non-CNS-related endocrine morbidities associated with chemotherapy and radiation therapy of childhood cancer. These include effects on growth, puberty, fertility, thyroid and adrenal function which may present many years after the successful treatment of underlying disease.

Antineoplastic Agents↗
PubMed2001

Long-term therapy with recombinant human growth hormone (Saizen) in children with idiopathic and organic growth hormone deficiency.

In an open-label study, 69 children with organic or idiopathic growth hormone deficiency (GHD) were treated with recombinant human growth hormone (Saizen) for an average of 64.4 mo, with treatment periods as long as 140.9 mo. Auxologic measurements, including height velocity, height standard deviation score, and bone age, were made on a regular basis. The data suggest that long-term treatment with Saizen in children with GHD results in a positive catch-up growth response and proportionate changes in bone age vs height age during treatment. In addition, long-term Saizen therapy was well tolerated, with the majority of adverse events related to common childhood disorders or existing baseline medical conditions and not to study treatment. There were no significant changes in laboratory safety data or vital signs, and no positive antibody tests for Saizen.

Adolescent↗
PubMed2001

Outcome of growth hormone therapy in children with growth hormone deficiency showing an inadequate response to growth hormone-releasing hormone.

Saizen (recombinant growth hormone [GH]), 0.2 mg/(kg x wk), was given in an open-label fashion for an average of 51 mo to 27 children with presumed idiopathic GH deficiency who had withdrawn from a trial of Geref (recombinant GH-releasing hormone [GHRH] 1-29) because of inadequate height velocity (HV) (25 children), the onset of puberty (1 child), or injection site reactions (1 child). Measurements were made every 3-12 mo of a number of auxologic variables, including HV, height standard deviation score, and bone age. The children in the study showed excellent responses to Saizen. Moreover, first-year growth during Saizen therapy was inversely correlated with the GH response to provocative GHRH testing carried out 6 and 12 mo after the initiation of Geref treatment. These findings indicate that GH is effective in accelerating growth in GH-deficient children who do not show or maintain a satisfactory response to treatment with GHRH. In addition, they suggest that the initial response to GH therapy used in this way can be predicted by means of provoc-ative testing.

Adolescent↗
PubMed1998

The role of serial sampling in the diagnosis of growth hormone deficiency.

We analyzed 12-hour serial sampling of growth hormone (GH) levels in two cohorts of short children: 96 children referred to a university endocrine clinic or studied on a research protocol and 825 children in the National Cooperative Growth Study of children treated with exogenous GH. The mean 12-hour GH levels correlated with growth velocity in 60 children with normal height and growth velocity in the university study, and this correlation was stronger in the boys. The testosterone levels also correlated with growth velocity and mean 12-hour GH levels in the boys. The mean 12-hour GH levels were lower in a group of 36 children with idiopathic short stature than in the control subjects, as were the peak GH levels within 1 hour after the onset of sleep and the insulin-like growth factor I levels. In the National Cooperative Growth Study cohort, pooled 12-hour GH levels were lower in the group with idiopathic GH deficiency (n = 300) than in the group with idiopathic short stature (n = 525), but the difference was not significant. The duration of GH treatment was the most significant predictor of change in the height SD score in both groups. Indices of spontaneous secretion of GH were not predictive of the response to GH treatment, nor were the results of provocative GH testing, the responses to GH treatment being similar in both groups over time. We conclude that the results of GH testing must be interpreted for each patient and that several testing modalities may be helpful in finding GH insufficiency that originates at various levels of the somatotropic axis.

Blood Specimen Collection↗
PubMed1997

Autoimmune hyperthyroidism in prepubertal children and adolescents: comparison of clinical and biochemical features at diagnosis and responses to medical therapy.

We explored our clinical impression that young children with autoimmune hyperthyroidism are more thyrotoxic at presentation and require a longer course of medical therapy than do adolescents to achieve remission. A retrospective chart review of clinical and biochemical data at presentation and response to therapy in 32 prepubertal (PREPUB) and 68 pubertal (PUB) children and adolescents with autoimmune hyperthyroidism was undertaken. Initial therapy included prophylthiouracil or methimazole in all but 11 patients who chose radioactive iodine (131I); 30 additional patients ultimately chose 131I or surgery after an initial period of medical therapy. In PREPUB children there were significantly longer duration of symptoms (7.8+/-7.7 months) and higher serum concentrations of triiodothyronine (T3) 708+/-330 ng/dL) at presentation than in the PUB group (4.7+/-3.4 months; p < .05) (537+/-197 ng/dL; p < .01). Duration of symptoms correlated negatively with chronologic age (r = -0.24; p < .02) but not with T3 or thyroxine (T4) levels (p = .1). PUB children had significantly higher titers of thyroid microsomal antibodies (positive dilution factor 1:6022+/-14572) than did PREPUB children (1:592+/-1226; p < .05). There was a higher familial incidence of thyroid disease in boys (80%) than in girls (64%) (p < .02). The duration of medical therapy was significantly longer (3.5+/-2.9 years) in PREPUB children compared to the PUB group (2.2+/-1.8 years) (p < .05). Only 17% of PREPUB treated 5.9+/-2.8 years compared with 30% of PUB treated 2.8+/-1.1 years achieved a 1-year remission after stopping antithyroid medication (percentage between groups, p < .01; years of treatment, p < .05). The median time to remission after medical therapy was 8 years in PREPUB and 4 years in PUB (p < .02). PREPUB children continued to remit after prolonged medical therapy (>6 years) whereas PUB patients did not. Total treatment length correlated negatively with chronological age (r = -0.26; p < .05) and positively with T4 and T3 concentrations at diagnosis (r = 0.31; p < .01). The diagnosis of hyperthyroidism is delayed in prepubertal children compared to adolescents. This delay may contribute to the higher T3 levels observed in this group at presentation. Prepubertal children also appear to require longer medical therapy to achieve a lower rate of remission, but do continue to remit after prolonged treatment. These differences in response to therapy should be considered when discussing therapeutic options with the family.

Adolescent↗
PubMed1997

Growth hormone secretagogues in children with altered growth.

A diagnostic test was devised to evaluate pituitary growth hormone (GH) secretory potential. GH secretory dynamics were assessed in children with and without GH deficiency. The GH response was measured to GH-releasing hormone (GHRH) and the GH-releasing peptide GHRP-2, administered sequentially. The mean (+/- SEM) peak GH response to GHRP-2 was 20.1 +/- 5.5, 63.6 +/- 24.9 and 42.2 +/- 4.3 micrograms/l for GH-deficient, slowly growing non-GH-deficient and control children, respectively (p < 0.02 and p < 0.05 for GH-deficient vs controls and slowly growing children, respectively). Corresponding values for area under the curve (AUC) were 995 +/- 371. 2460 +/- 953 and 1598 +/- 274 micrograms/l x minute. Peak GH (and AUC) responses to GHRH were 19.6 +/- 5.1 micrograms/l (924 +/- 232 micrograms/l x minute), 31.4 +/- 8.4 micrograms/l (1544 +/- 449 micrograms/l x minute) and 39.8 +/- 7.8 micrograms/l (2201 +/- 437 micrograms/l x minute) for the same three groups, respectively (p < 0.05 for peak GH in GH-deficient patients vs controls, and p < 0.02 and p < 0.01 for AUC in GH-deficient vs slowly growing children and controls, respectively). The ratio of the peak GH response to GHRP-2 and GHRH was similar in all three groups. As these secretagogues stimulate different aspects of hypothalamic function (i.e., they are functional complements), robust GH secretion in response to GHRH or GHRP could suggest adequate endogenous GHRP or GHRH, respectively. A poor response to either GH secretagogue administered individually could represent inadequacy of its endogenous complement. The integrity of functional pituitary elements could be differentiated from inadequate complements by administering both GH secretagogues simultaneously. Application of these principles should allow a better definition of the underlying disorder and provide the basis for therapeutic strategies for those patients with abnormal GH production and/or secretion.

Area Under Curve↗
PubMed1996

Enhanced levels of wild-type versus mutant thyroid hormone receptor beta 1 messenger RNA in fibroblasts from heterozygotes of kindred S with thyroid hormone resistance.

Thyroid hormone resistance syndromes, which result from heterozygous mutations in the beta 1 thyroid hormone receptor gene, are sometimes associated with adult short stature, but more frequently with delayed bone age (BA). Primary fibroblasts from young children with both delayed BA and short stature from a kindred A have been reported to overexpress the mutant allele. However, in fibroblasts from affected members of two different kindreds with thyroid hormone resistance, S and Mf, there were equal levels of mutant and wild-type beta 1 mRNA. We investigated the ontogeny of differential allelic expression using competitive reverse transcription with PCR (RT-PCR) to measure relative mRNA levels for beta 1 and S receptor in very young affected children of kindred S. Total RNA was prepared from fibroblasts of two patients (ages 3-0.5/12 and 1-4/12 years) with delayed BA but normal growth curves. Using PCR amplimers that create an Mlu-1 site in wild-type but not mutant cDNA products from the competitive RT, we quantitated mRNA levels. Normal beta 1 mRNA was present at nearly twice the level of the mutant mRNA in cells from these patients. Relative expression of the c-erbA beta alleles thus appeared to be increased during this period of somatic growth. The relative overexpression of the normal allele potentially counteracted the potent dominant negative effect of the S receptor during early childhood ameliorating a deleterious effect on linear growth.

Age Determination by Skeleton↗
PubMed1996

Evaluation of pituitary function in children using growth hormone secretagogues.

We have devised a diagnostic test to directly evaluate pituitary secretory potential, and also to identify the most appropriate therapy for slow growing children. The test compares responses to GH releasing hormone (GHRH) and GH releasing peptides or their non-peptidyl mimics (GHRP) administered sequentially and in combination. Since they are functional complements, robust GH secretion in response to GHRH or GHRP could be interpreted as representing adequate endogenous GHRP or GHRH, respectively. Alternatively, assuming that all pituitary cellular and molecular elements for GHRH- and GHRP-mediated GH secretion are functional, a poor response to either GH secretagogue administered individually could represent inadequacy of its endogenous complement. The integrity of functional pituitary elements could be differentiated from inadequate endogenous complement by administering both GH secretagogues simultaneously. Based upon this hypothesis, the proposed pituitary function diagnostic scheme could be used to test for endogenous GH secretagogue adequacy, as well as pituitary secretory capacity. The data resulting from application of these principles would allow appropriate selection of therapeutic entities, ranging from GHRH or GHRP administered separately or in combination, or alternatively, recombinant GH for those patients lacking a pituitary mechanism for GH production and/or secretion.

Adolescent↗
PubMed1995

The effects of high altitude on hypothalamic-pituitary secretory dynamics in men.

OBJECTIVE: Individuals adapted to high altitude (HA) have abnormalities in endocrine function and specifically in the pituitary-thyroid axis and aldosterone regulation. In this study we assessed hypothalamic-pituitary function in men adapted to high altitude living using exogenous administration of synthetic hypothalamic hormones. DESIGN: Growth hormone releasing hormone (Geref 1-29) 1 microgram/kg, TRH 500 micrograms, GHRH 100 micrograms and ovine corticotrophin releasing hormone (oCRH) 1 microgram/kg were simultaneously administered intravenously to two groups of men: 12 born and raised in the city of Pasto, Colombia, South America, located at an altitude of 2600 m in the southern Colombian Andes (HA group) and 10 men living at sea level (SL) in Tampa, Florida. MEASUREMENTS: The following hormones were measured: GH, IGF-I, TSH, T4, free T4, free T3, PRL, ACTH, beta-endorphin and cortisol. IGF binding protein-3 (IGFBP-3) and cortisol binding globulin (CBG) were also measured. RESULTS: GH response to GHRH in HA men was exaggerated compared to SL men, and IGF-I concentration was also significantly increased in the presence of normal levels of IGFBP-3. No differences in TSH or PRL responses were found following TRH. HA men had lower basal total T4 levels, but higher free T4 and free T3 concentrations. The basal ACTH concentrations in the HA men were significantly lower than SL, although the response to oCRH was still present. beta-Endorphin basal levels were similar at HA and SL but the response to oCRH at HA was blunted. At HA, basal cortisol levels as well as CBG were elevated compared to SL and, in contrast to SL, did not increase significantly after endogenous ACTH secretion. CONCLUSIONS: This study is the first description of exaggerated GH response to the administration of GHRH in HA men and also of a significant increase in IGF-I concentration in the same subjects in the presence of normal levels of IGFBP-3. An altered hypothalamic-pituitary response was found in HA men after administration of oCRH characterized by a significantly lower basal ACTH concentration at HA, although the response to oCRH was present but the beta-endorphin response to oCRH was blunted. At HA, basal cortisol levels, as well as CBG, were elevated and the cortisol levels did not significantly increase after endogenous ACTH secretion. We have characterized the differences in hypothalamic-pituitary dynamics after the administration of TRH, GnRH and oCRH in HA men comparing their response to age/sex matched SL men.

Adaptation, Physiological↗
PubMed1995

Effect of haemoglobin and endogenous erythropoietin on hypothalamic-pituitary thyroidal and gonadal secretion: an analysis of anaemic (high EPO) and polycythaemic (low EPO) patients.

OBJECTIVE: Correction of anaemia with recombinant human erythropoietin (rHu-EPO) improves the responsiveness of thyroidal and gonadal axes to exogenous TRH and GnRH in chronic haemodialysis patients, but the mechanisms remain to be fully elucidated. In order to assess the influences of endogenous erythropoietin on the hypothalamo-hypophyseal thyroidal and gonadal axes, we studied the response of polycythaemic and anaemic patients, in comparison to normal controls, after the administration of exogenous TRH and GnRH. DESIGN: Exogenous hypothalamic factors, 500 micrograms TRH and 100 micrograms GnRH, were administered as a bolus and blood samples were obtained over a 3-hour period at 30, 60, 90, 120 and 180 minutes. PATIENTS: Five male polycythaemic patients (low EPO), three male anaemic patients (high EPO) and six normal age and sex matched controls were studied. MEASUREMENTS: Blood samples were centrifuged immediately and the serum was stored at -20 degrees C until assayed for total T4, free T4, free T3, TSH, prolactin, growth hormone (TRH test), and FSH, LH, testosterone (GnRH test). Haematological parameters and biochemical profiles were also measured. RESULTS: After TRH administration, both patient groups showed a normal TSH response; however, their free T4 and free T3 secretion was blunted compared to controls. Normal basal PRL levels increased in an exaggerated fashion, whereas, when compared to chronic renal failure patients on chronic haemodialysis, we did not see a paradoxical GH response or a basal GH increase in these 5 patients. GnRH administration in the study groups elicited a normalization in the LH response without an increase in testosterone levels; however, an exaggerated FSH response was found in the polycythaemic patients (low EPO). CONCLUSIONS: Thus by investigating the role of low endogenous EPO levels in non-anaemic and anaemic patients with high EPO levels, our study suggests that the underlying chronic disease state may be the major contributing factor in the regulation of the hypothalamo-hypophyseal thyroid and gonadal axes, rather than the EPO levels.

Aged↗
PubMed1994

Effects of stimulated growth hormone secretion on age-related changes in plasma cholesterol and hepatic low density lipoprotein messenger RNA concentrations.

Growth hormone (GH) secretion declines during aging. Since GH alters plasma cholesterol (PC) concentrations, it was of interest to determine how GH secretagogues affect age-related hypercholesterolemia. Fischer 344 rats (3 and 14 months old) were co-administered (s.c.) GH releasing hormone (3 micrograms/kg; GHRH) and GH releasing hexapeptide (100 micrograms/kg; GHRP) for 120 consecutive days. Aging was associated with a progressive increase in PC, which was reduced in rats administered GHRH and GHRP compared to those administered vehicle, i.e. changes in PC during the study were 26.5 +/- 1.2 mg/dl vs. 40.1 +/- 0.9 mg/dl (P < 0.05) in the younger rats and 17.6 +/- 2.3 mg/dl vs. 31.6 +/- 5.3 mg/dl (P < 0.05) in the older rats, respectively. The lower concentrations of PC in GH secretagogue-treated older rats were associated with higher mean concentrations of hepatic LDL receptor mRNA (1.27 +/- 0.4 vs. 0.4 +/- 0.1; P < 0.05) but not cholesterol 7-alpha hydroxylase mRNA. Although GH secretagogue treatment was also associated with lower plasma cholesterol in the younger rats, it was not accompanied by quantitative changes in mean group concentrations of hepatic LDL receptor mRNA. Instead, daily administration of GHRH and GHRP in the younger rats correlated with a significant reciprocal relationship (P < 0.05) between PC and hepatic LDL receptor mRNA for individual group members. The results of this study suggest that reduced GH secretion during aging contributes, at least in part, to a progressive increase in plasma cholesterol that can be partially prevented with GH secretagogues. Furthermore, the effects on PC may result from GH-mediated, qualitative and quantitative changes in hepatic LDL receptor mRNA that increase receptor-mediated cholesterol clearance.

Aging↗
PubMed1994

The effects of corticotropin and growth hormone releasing hormones on their respective secretory axes in chronic hemodialysis patients before and after correction of anemia with recombinant human erythropoietin.

Endocrine abnormalities in chronic hemodialysis patients are in part corrected by control of anemia with recombinant human erythropoietin (rHu-EPO). We further examined the role of rHu-EPO in select hormonal abnormalities thought to be anemia related as well as the GH-insulin-like growth factor 1 (GH-IGF-1) axis that is abnormal in hemodialysis patients. We studied responses to the administration of two hypothalamic hormones, GHRH and ovine corticotropin-releasing hormone (CRH), in five anemic male patients on chronic hemodialysis before and after correction of the anemia with rHu-EPO. For comparison, five age-matched normal male volunteers were tested once. Anemic patients on chronic hemodialysis had high basal GH concentrations, an exaggerated GH response to exogenous GHRH, increased levels of IGF-1, and elevated levels of IGF-1 binding protein-3 in comparison to controls. ACTH response to CRH was comparable in dialysis patients and normal controls, but the cortisol response to endogenous ACTH release was prolonged. The cortisol binding globulin was similar to the controls. After correction of anemia, the basal elevation of GH was no longer present, but the exaggerated response of GH to exogenous GHRH persisted. IGF-1 and IGF-1 binding protein-3 levels remained elevated. The ACTH response to CRH, which was normal before correction of the anemia, became exaggerated in terms of elevated levels. Nevertheless, the prolonged cortisol response persisted. It appears that correction of the anemia in hemodialysis patients with rHu-EPO can partly correct perturbations in the GH secretory axis but may lead to new abnormalities in the CRH-ACTH axis.

Adult↗
PubMed1993

Spectrum of serum thyroglobulin elevation in congenital thyroid disorders.

Serum thyroglobulin (Tg) data are presented for 47 infants with congenital thyroid disorders. Abnormal elevation of serum Tg (> 250 micrograms/L) occurred in 17% of the population studied, whereas values in excess of 1,000 micrograms/L were demonstrated in 11% of infants. The latter group includes the first report of supraphysiologic Tg elevation in an infant with thyroid gland ectopia, and the highest reported thyroglobulin level in the syndrome of generalized thyroid hormone resistance in an infant homozygous for a novel deletion in the c-erbA beta receptor. Mechanisms involved in the pathogenesis of Tg elevation are discussed. We conclude that Tg elevation in congenital thyroid disorders is more common than previously recognized, and values > 1,000 micrograms/L identify infants with a spectrum of anatomic and biochemical abnormalities.

Congenital Hypothyroidism↗
PubMed1993

Competitive polymerase chain reaction quantitation of c-erbA beta 1, c-erbA alpha 1, and c-erbA alpha 2 messenger ribonucleic acid levels in normal, heterozygous, and homozygous fibroblasts of kindred S with thyroid hormone resistance.

Mutations in the T3-binding domain of the thyroid hormone receptor gene c-erbA beta result in dominant negative proteins and thyroid hormone resistance syndromes. Variable clinical manifestations of resistance to thyroid hormones have been reported, including short stature and neuropsychological abnormalities. The molecular bases for heterogeneity of phenotype among and within kindreds have not been fully elucidated. Recent investigations have considered differential expression of mutant and wild-type beta 1-receptor alleles and the regulation thereof as a mechanism to explain differential sensitivity to thyroid hormones. We used reverse transcription-competitive polymerase chain reaction (PCR) to measure c-erbA beta 1, c-erbA alpha 1, and c-erbA alpha 2 mRNAs in skin fibroblasts cultured from normal subjects, heterozygotes, and a severely affected homozygous mutant of kindred S. The homozygous mutant of kindred S had severe growth and mental retardation. After reverse transcription with primers specific for each of the c-erbA mRNAs, first strand cDNAs were amplified by PCR using subtype-specific amplimers. Primer design allowed simultaneous detection of wild-type and mutant messages in heterozygous fibroblasts and showed an approximately 1:1 ratio of these mRNAs in three patients. Inclusion of competitive standard cDNAs of known concentration in the PCR reactions allowed quantitation of the absolute levels of the beta 1-, alpha 1-, and alpha 2 mRNAs by comparison of products on ethidium bromide-stained agarose gels. These studies showed no effect of the presence of the mutant beta 1-allele, as fibroblast RNA from normal subjects, heterozygotes, and the homozygote gave values of 56-184, 2.8-12, and 23-40 attomol/5 micrograms total RNA for beta 1-, alpha 1-, and alpha 2 mRNAs, respectively. We conclude that these sensitive methods allow the detection of molecular species present at levels as low as 10 molecules/cell, and that this potent dominant negative receptor does not disrupt c-erbA expression at the level of mRNA. The neuropsychological sequelae of the kindred S mutation are not due to relative overexpression of the mutant allele.

Alleles↗
PubMed1992

Effect of somatotropin of mammalian cell origin in growth hormone deficiency.

Sixty-nine growth hormone-deficient patients were treated for 1 year with somatotropin (recombinant DNA-derived human growth hormone) produced in mouse cells. The growth velocity of the 50 patients (72%) in whom the effectiveness of this growth hormone could be evaluated increased from a mean (+/- SD) of 3.5 +/- 1.1 to 8.7 +/- 1.6. cm/y. An enhanced rate of weight gain was also observed. Bone age was not unduly accelerated. One of 66 patients developed antibodies to recombinant growth hormone, which did not affect the response to therapy. No patient developed antibodies to host cell proteins. An increased insulin response to a standard glucose load, without any change in glucose tolerance, was observed after 1 year of treatment. This authentic sequence human growth hormone preparation produced in mammalian cells is both effective and safe in the treatment of children with growth hormone deficiency.

Adolescent↗