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Biomedical subjects

J Argente

Publications and source records attributed to J Argente.

At least 73 records · Page 4Linked to original sources
PubMed1994

Molecular basis of familial growth hormone deficiency.

A significant proportion of cases of GH deficiency (5-30%) may be due to genetic causes. At least four Mendelian types of isolated GH deficiency (IGHD) have been delineated based on the mode of inheritance and the degree of GH deficiency: IGHD type IA, autosomal recessive with absent endogenous GH; type IB, autosomal recessive with diminished GH; type II, autosomal dominant with diminished GH; and type III, X-linked with diminished GH. Most patients with IGHD type IA have heterogeneous deletions, ranging in size from 6.7 kb to 45 kb, that encompass the entire gene encoding for pituitary GH, GH-1. Nonsense, frameshift and splice GH-1 mutations that predict a complete lack of bioactive GH synthesis in homozygotes have also been reported in association with IGHD IA. Additionally, some cases of IGHD type II have dominant negative mutations in one allele of the GH-1 gene. Panhypopituitary Dwarfism (PD), a condition characterized by deficiency of at least other pituitary trophic hormone in addition to GH deficiency, can have autosomal and X-linked modes of inheritance. Interestingly, both recessive and dominant mutations at the gene encoding for the pituitary transcription factor Pit-1 have been found in a specific subtype of PD that combines GH, prolactin and TSH deficiencies. In contrast, the loci and mutations responsible for the other Mendelian forms of IGHD and PD remain unknown. Linkage studies using genetic markers have excluded the GH locus on chromosome 20 in all the studied families (types IB and II) in whom the mutation cannot be traced to defects in these genes.(ABSTRACT TRUNCATED AT 250 WORDS)

Dwarfism, Pituitary↗
PubMed1993

Control of the transcription of the growth hormone-releasing hormone and somatostatin genes by sex steroids.

The growth hormone (GH)-secretory pattern is markedly sexually dimorphic in the adult rat. These secretory patterns change significantly throughout development, becoming different between the sexes only after pubertal onset. This observation suggests that pubertal sex steroids play an important role in the manifestation of this phenomenon. The neonatal steroid environment has also been shown to be intricately involved in the generation of the final adult GH-secretory pattern, but the mechanisms underlying this effect remain less known. We have addressed the question as to whether the developmental changes in the GH-secretory pattern are correlated with changes in the hypothalamic neuropeptides that regulate GHs release from the anterior pituitary, i.e. somatostatin (SS) and growth hormone-releasing hormone (GHRH). In addition, the effects of neonatal testosterone and adult testosterone treatments on these two neuropeptide systems have been studied. We have found that the synthetic capacity, as reflected in relative levels of messenger RNA (mRNA), of both SS and GHRH neurons changes throughout development in both sexes and that they are sexually dimorphic at specific times during maturation. Furthermore, these mRNA levels can be modulated by changes in postpubertal testosterone levels. Preliminary studies indicate that the neonatal sex steroid environment also influences both GHRH and SS neurons. These studies suggest that both the neonatal and adult sex steroid environments influence the adult GH-secretory pattern, at least in part, by modulating GHRH and SS neurons.

Aging↗
PubMed1993

Differential effects of the neonatal and adult sex steroid environments on the organization and activation of hypothalamic growth hormone-releasing hormone and somatostatin neurons.

The secretory pattern of GH is markedly sexually dimorphic in the adult rat, a phenomenon that becomes manifest around the time of pubertal development. This event is due partially to the pubertal rise in gonadal steroids. However, the fetal and neonatal sex steroid environments also play an important role in generating this sexual dimorphism. Hypothalamic mRNA levels of GH-releasing hormone (GHRH) and somatostatin (SS), two neuropeptides implicated in the control of GH release, are sexually dimorphic in both neonatal and adult animals and, at least in the adult animal, are responsive to modulation by sex steroids. In this study, we examined the effects of neonatal testosterone on the number of GHRH and SS neurons in the adult hypothalamus as well as its effects on the responsivity of these neurons to later increases in sex steroids. To address these questions, male rats were either castrated or sham castrated on the day of birth (P0); these animals, along with intact females, received an injection of either testosterone or vehicle. At 60 days of age, half of each group received a Silastic capsule containing testosterone, and half received a sham implant. Growth rates were monitored throughout the study. At 75 days of age, animals were killed, and in situ hybridization to detect GHRH and SS mRNA containing neurons was performed. The number of GHRH neurons in the arcuate nucleus and ventromedial hypothalamus and the number of SS neurons in the periventricular nucleus and paraventricular nucleus were counted. Using a computerized image analysis system, GHRH and SS mRNA signal levels in individual neurons were also measured. Both neonatal and adult steroid treatments significantly increased growth rates. Those animals exposed to neonatal testosterone had significantly more detectable GHRH neurons than those that received only vehicle [P < 0.0001, by analysis of variance (ANOVA)]. Neonatal testosterone treatment had no effect on GHRH mRNA levels. Adult testosterone treatment, while having no effect on GHRH neuron numbers, stimulated GHRH mRNA levels in both males and females (P < 0.0001, ANOVA), but the magnitude of the increase depended upon whether the animal had been exposed to testosterone during the neonatal period. In contrast, the number of SS neurons was not affected by either steroid treatment. However, both treatments modulated SS mRNA levels (P < 0.0001, by ANOVA), with neonatal testosterone treatment alone resulting in significantly higher levels of SS mRNA in the adult animal. Adult testosterone treatment also significantly increased SS mRNA levels, and this was independent of previous exposure to sex steroids.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1993

Normative data for insulin-like growth factors (IGFs), IGF-binding proteins, and growth hormone-binding protein in a healthy Spanish pediatric population: age- and sex-related changes.

The normal values of insulin-like growth factors (IGFs) after extraction, their binding proteins, and the high affinity GH-binding protein are not well established in infancy or childhood. We report the relationship between serum IGF-I, IGF-II, their binding proteins IGFBP-1 and IGFBP-3, and GH-binding protein in 600 normal Spanish children who were divided into 5 groups according to Tanner stage: I, 150 males and 102 females; II, 40 males and 42 females; III, 45 males and 45 females; IV, 42 males and 55 females; and V, 23 males and 56 females. Serum IGF-I levels increase slowly during childhood in both sexes, exhibiting a dramatic increase during puberty and a significant decline [P < 0.001, by analysis of variance (ANOVA)] during adulthood. The pubertal peak occurs approximately 2 yr earlier in girls than in boys. In contrast, serum IGF-II levels remain stable throughout childhood, showing no pubertal peak. In boys, there is a significant decline in IGF-II levels during adulthood (P < 0.001). Serum IGFBP-3 levels show a pattern similar to that of IGF-I, with a significant increase during childhood and a significant decline during adulthood (P < 0.001, ANOVA) in both males and females. In contrast, serum IGFBP-1 levels decrease dramatically during childhood in both boys and girls (P < 0.001 and P < 0.005, respectively, by ANOVA). A significant decline in serum GH-binding protein levels is observed between prepubertal and pubertal children of both sexes (P < 0.001). There is a close linear correlation between the sum of serum IGF-I plus IGF-II levels vs. serum IGFBP-3 (r = 0.724; P < 0.0001). In contrast, there is a nonlinear correlation between serum IGF-I vs. serum IGFBP-3 (concave curve) as well as between serum IGF-II and serum IGFBP-3 (convex curve). A negative correlation was found between serum IGF-I vs. IGFBP-1 (r = -0.51; P < 0.0001) as well as between the sum of serum IGF-I plus IGF-II vs. IGFBP-1 (r = -0.47; P < 0.0001), but not between serum IGF-II and IGFBP-1. These data emphasize that when these tests are performed in the clinic, their interpretation should be based upon age- and sex-specific criteria.

Adolescent↗
PubMed1993

Diverse growth hormone receptor gene mutations in Laron syndrome.

To better understand the molecular genetic basis and genetic epidemiology of Laron syndrome (growth-hormone insensitivity syndrome), we analyzed the growth-hormone receptor (GHR) genes of seven unrelated affected individuals from the United States, South America, Europe, and Africa. We amplified all nine GHR gene exons and splice junctions from these individuals by PCR and screened the products for mutations by using denaturing gradient gel electrophoresis (DGGE). We identified a single GHR gene fragment with abnormal DGGE results for each affected individual, sequenced this fragment, and, in each case, identified a mutation likely to cause Laron syndrome, including two nonsense mutations (R43X and R217X), two splice-junction mutations, (189-1 G to T and 71 + 1 G to A), and two frameshift mutations (46 del TT and 230 del TA or AT). Only one of these mutations, R43X, has been previously reported. Using haplotype analysis, we determined that this mutation, which involves a CpG dinucleotide hot spot, likely arose as a separate event in this case, relative to the two prior reports of R43X. Aside from R43X, the mutations we identified are unique to patients from particular geographic regions. Ten GHR gene mutations have now been described in this disorder. We conclude that Laron syndrome is caused by diverse GHR gene mutations, including deletions, RNA processing defects, translational stop codons, and missense codons. All the identified mutations involve the extracellular domain of the receptor, and most are unique to particular families or geographic areas.

Adolescent↗
PubMed1992

Growth in malnutrition related to gastrointestinal diseases: coeliac disease.

Coeliac disease in children is frequently associated with a slow growth rate. This observation may be linked to the malabsorption that occurs in these patients; however, the underlying mechanism remains unknown. To better understand this phenomenon, we have studied the growth patterns of 153 patients with coeliac disease for 2-9 years. Gastro-intestinal biopsies were performed before and after gluten exclusion. In a second group of 79 children, somatostatin levels and binding properties in the plasma and jejunal mucosa were measured. In a third group of 40 patients we measured insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGF-BP3) levels. We found that in children diagnosed before 2 years of age weight was the most affected growth parameter. In children diagnosed after this age, height was more affected. Suppression of gluten intake induced an acceleration of growth velocity. Although plasma levels of somatostatin were not significantly altered, somatostatin concentrations in the jejunal mucosa of patients in the active phase of the disease were significantly elevated (p < 0.05). Children with coeliac disease exhibited significantly lower levels of IGF-BP3 when compared to patients with normal stature and growth velocities. In contrast, these patients showed an increase in IGF-BP3 levels after gluten exclusion from the diet.

Body Height↗
PubMed1991

Association of a thyrotropin-secreting pituitary adenoma and a thyroid follicular carcinoma.

The different factors involved as etiological agents in thyroid cancer have in common long term thyroid follicle stimulation. On this base, a patient with a TSH-producing pituitary adenoma could be at high risk for developing thyroid cancer. A patient consulting for a single thyroid nodule was studied in our unit. He was diagnosed as having a TSH-producing pituitary adenoma and the Thyroid nodule was shown to be a follicular carcinoma following removed. We speculate that elevated TSH levels could have contributed to neoplastic transformation of the thyroid in this patient.

Adenocarcinoma↗
PubMed1991

Sexual dimorphism of growth hormone-releasing hormone and somatostatin gene expression in the hypothalamus of the rat during development.

The secretory pattern of GH secretion is markedly sexually dimorphic in the adult rat. The patterning of GH secretion is determined by the coordinated activity of somatostatin (SS)- and GH-releasing hormone (GHRH)-containing neurosecretory cells located in the hypothalamus. In this study we examined whether there is sexual dimorphism in the expression of the SS and GHRH genes and, if so, at what developmental stage this becomes evident. To address these questions, we measured SS messenger RNA (mRNA) levels in neurons of the periventricular nucleus and GHRH mRNA levels in the arcuate nucleus and ventromedial nucleus of the hypothalamus in male and female rats at 10, 25, 35, and 75 days of age. Using in situ hybridization and a computerized image analysis system, we measured SS mRNA and GHRH mRNA signal levels in individual neurons and compared these levels among the different age groups. We found that male animals had significantly higher levels of SS mRNA than females at every age. Similarly, males had higher GHRH mRNA levels than females; however, this difference was statistically significant only at 10 and 75 days of age. Developmental changes in GHRH mRNA levels were similar for both sexes, with GHRH message levels increasing gradually over the course of maturation. SS mRNA signal levels also changed over the course of development in both male and female animals. In the male rat, SS mRNA levels increased significantly between 10 and 25 days of age and declined significantly between 35 and 75 days of age. In the female rat, SS mRNA levels increased gradually between 10 and 35 days of age, then, as in the male, declined significantly between days 35 and 75. We conclude that sex differences and age-dependent changes in the expression of the SS and GHRH genes may subserve the sexual dimorphism and developmental alterations in the pattern of GH secretion in the rat.

Aging↗
PubMed1990

Regulation of somatostatin and growth hormone-releasing hormone gene expression in the rat brain.

We have studied the regulation of somatostatin (SS) and growth hormone-releasing hormone (GHRH) gene expression in the brain of the laboratory rat. We report that hypophysectomy in the adult male reduces SS mRNA in cells of the periventricular nucleus (PeN), while GH reverses this effect. We demonstrate that cellular levels of SS mRNA in the PeN are higher in male compared to female animals. We report that castration reduces cellular levels of GHRH mRNA and SS mRNA in the arcuate nucleus and PeN, respectively, and that testosterone reverses this effect through an androgen receptor-dependent mechanism. Finally, we present a theoretical model to explain the generation of the ultradian rhythm in GH secretion, which implicates the reciprocal interaction between GH feedback and the transcriptional regulation of the SS and GHRH genes and the kinetics of these relationships.

Animals↗
PubMed1990

Somatostatin messenger RNA in hypothalamic neurons is increased by testosterone through activation of androgen receptors and not by aromatization to estradiol.

Growth hormone (GH) secretory patterns are influenced by sex steroids, at least in part, through modulation of the secretion of hypothalamic somatostatin (SS) and GH-releasing hormone. Neurons in the periventricular nucleus (PeN) expressing the messenger RNA (mRNA) for SS are modulated by physiological levels of testosterone. However, it is uncertain whether testosterone's action is mediated directly by androgen receptor activation or indirectly through aromatization to estradiol and subsequent binding to the estrogen receptor. We examined this question by evaluating the effectiveness of 17 beta-estradiol and the nonaromatizable androgen, dihydrotestosterone (DHT), to mimic the effects of testosterone. Adult male rats were castrated and implanted subcutaneously with a Silastic capsule that contained either testosterone, 17 beta-estradiol or DHT, or a sham capsule. Intact animals were sham-operated. We used in situ hybridization to assess the effect of these treatments on SS mRNA signal levels in individual neurons of the hypothalamus. Following castration, SS mRNA content was reduced in cells of the PeN (intact, 195 +/- 12 grains/cell, vs. castrated, 139 +/- 4 grains/cell). Replacement with physiological levels of testosterone prevented the decline in SS mRNA signal levels (castrated testosterone-replaced, 214 +/- 15 grains/cell) as did replacement with the nonaromatizable androgen DHT (castrated DHT-replaced, 213 +/- 16 grains/cell). Treatment with 17 beta-estradiol failed to prevent the postcastration decline in SS mRNA content (castrated estrogen-replaced, 145 +/- 4 grains/cell). Castrated 17 beta-estradiol-treated animals were not significantly different from the castrated sham-treated animals (castrated, 139 +/- 4 grains/cell, vs. castrated estrogen-replaced, 145 +/- 4 grains/cell).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗