Biomedical subjects

A Vottero

Publications and source records attributed to A Vottero.

28 records · Page 2Linked to original sources

PubMed1998

The aromatase excess syndrome is associated with feminization of both sexes and autosomal dominant transmission of aberrant P450 aromatase gene transcription.

Increased extraglandular aromatization has been reported as the cause of familial gynecomastia. We studied a kindred with aromatase excess inherited in an autosomal dominant manner, in which affected males had heterosexual precocity and/or gynecomastia, and affected females had isosexual precocity and/or macromastia. The propositus was a 9-yr-old boy with gynecomastia. His 7.5-yr-old sister had precocious puberty, and their father and paternal grandmother had peripubertal gynecomastia and macromastia, respectively. Serum concentrations of gonadal and adrenal steroid hormones were determined before and after the administration of corticotropin and/or hCG. Aromatase activity was determined by [3H]delta4-androstenedione to [3H]estrone conversion by cultured skin fibroblasts and/or Epstein-Barr virus-transformed lymphocytes and was detected by immunohistochemistry and/or Western analysis. Linkage was examined with a polymorphism of the aromatase (P450arom) gene. The P450arom messenger ribonucleic acid was analyzed by rapid amplification of complementary DNA (cDNA) ends, ribonuclease protection assay, and RT-PCR. hCG testing demonstrated a high rate of conversion of delta4-androstenedione to estrone and of testosterone to estradiol in the propositus and his father. Treatment of the propositus and his sister was initiated with an aromatase inhibitor (testolactone) and a GnRH analog, which successfully delayed skeletal and pubertal development in both children. Markedly increased aromatase activity was found in the patients' fibroblasts and Epstein-Barr virus-transformed lymphocytes. The P450arom polymorphism segregated with the disease in the family. A new 5'-splice variant was present in the patients' P450arom messenger ribonucleic acid, thus identifying yet another first exon of this gene, which appears to be aberrantly expressed in this family. In conclusion, a family with the aromatase excess syndrome is described, in which the condition was inherited in an autosomal dominant manner, led to feminizing manifestations in both sexes, and was associated with the aberrant utilization of a novel transcript of the P450arom gene.

Adult↗

PubMed1997

Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor beta.

In many chronic inflammatory disorders, glucocorticoid (GC) insensitivity is a challenging clinical problem associated with life-threatening disease progression. The molecular basis of GC insensitivity, however, is unknown. Alternative splicing of the GC receptor (R) pre-messenger RNA generates a second GCR, termed GCR-beta, which does not bind GCs but antagonizes the transactivating activity of the classic GCR, termed GCR-alpha. In the current study, we demonstrate that GC-insensitive asthma is associated with a significantly higher number of GCR-beta-immunoreactive cells in peripheral blood than GC-sensitive asthmatics or normal controls. Furthermore, we show that patients with GC-insensitive asthma have cytokine-induced abnormalities in the DNA binding capability of the GCR. These abnormalities can be reproduced by transfection of cell lines with the GCR-beta gene resulting in significant reduction of their GCR-alpha DNA binding capacity. We conclude that increased expression of GCR-beta is cytokine inducible and may account for GC insensitivity in this common inflammatory condition.

Asthma↗

PubMed1997

Corticotropin-releasing hormone (CRH) inhibits steroid biosynthesis by cultured human granulosa-lutein cells in a CRH and interleukin-1 receptor-mediated fashion.

The presence of immunoreactive CRH was recently demonstrated in human ovaries. CRH immunoreactivity was localized by immunohistochemistry in the cytoplasm of thecal cells surrounding the ovarian follicles, in luteinized cells of the stroma, and in large granulosa-derived luteinized cells of developing corpora lutea. Also, CRH and its receptors were identified in Leydig cells of the testis where CRH was shown to inhibit testosterone biosynthesis. To examine the role of CRH in the ovary, we studied its effect on estradiol (E2) and progesterone (P4) release by human granulosa cells obtained from women undergoing in vitro fertilization for male factor infertility or uni- or bilateral tubal impatency. In all subjects, superovulation was induced by treatment with gonadotropins. The effects of graded doses of ovine CRH (10[-11]-10[-6] mol/liter) were evaluated in the conditioned medium obtained after 24 h incubation of the cells. All CRH concentrations employed except for the lowest one (10[-11] mol/liter) caused a significant decrease of media E2 and P4 levels. Maximal inhibition for both E2 and P4 production was obtained by 10[-6] mol/liter CRH concentration, which decreased hormone production by 39% and 34%, respectively. The alpha-helical CRH9-41 antagonist at 10(-6) and 10(-7) mol/liter blocked the suppressive effect of 10(-9) mol/liter CRH on both E2 and P4 secretion, while it had no effect when added to the culture media without CRH. Since interleukin (IL-1)-1 mediates certain actions of CRH on leukocytes, we examined whether the CRH effect on ovarian steroidogenesis was IL-1-mediated. Interleukin-1 receptor antagonist at 10(-7) and 10(-6) mol/liter blocked the inhibitory effects of CRH on E2 and P4 secretion, while it had no effect in the absence of CRH. In conclusion, CRH exerts a CRH- and IL-1 receptor-mediated inhibitory effect on ovarian steroidogenesis and might be actively involved in the still enigmatic processes of follicular atresia and luteolysis.

Adult↗

PubMed1997

Spontaneous thyrotropin and cortisol secretion interactions in patients with nonclassical 21-hydroxylase deficiency and control children.

Both exogenous and endogenous hypercortisolism result in reduced TSH secretion and mild hypothyroidism. However, little is known about the relation between endogenous TSH and cortisol secretion under physiological or slightly disturbed conditions. To examine this, we evaluated the pulsatility and circadian rhythmicity and time-cross-correlated the 24-h secretory patterns of cortisol and TSH in eight prepubertal children with nonclassical congenital adrenal hyperplasia (NCCAH) and eight age-matched short normal children. In both groups, TSH and cortisol were secreted in a pulsatile and circadian fashion, with a clear nocturnal TSH surge. Although no difference in mean 24-h TSH levels was observed between the two groups, daytime TSH levels were lower in the NCCAH group than in control children (P < 0.05). The cross-correlation analysis of the 24-h raw data showed that TSH and cortisol were negatively correlated, with a 2.5-h lag time for both groups, with cortisol leading TSH. This correlation might reflect a negative glucocorticoid effect exerted on the hypothalamic-pituitary-thyroid axis under physiological conditions. A significant positive correlation with TSH leading cortisol was observed at 8.5 and 5.5 h lag times for the control and NCCAH groups, respectively. The substantially shorter lag time of this positive correlation in NCCAH children than in controls suggests that in the latter, the nocturnal TSH peak occurs temporally closer to their compromised morning cortisol peak. These data indicate that the hypothalamic-pituitary-adrenal axis has a primarily negative influence on endogenous TSH secretion and that even mild disturbances in cortisol biosynthesis are associated with slight alterations in TSH secretion.

Adrenal Hyperplasia, Congenital↗

PubMed1996

Dideoxyfingerprinting (ddF) analysis of the type X collagen gene (COL10A1) and identification of a novel mutation (S671P) in a kindred with Schmid metaphyseal chondrodysplasia.

Schmid metaphyseal chondrodysplasia (SMCD; MIM 156500) is an autosomal dominant disorder of the skeleton that is manifested in early childhood by short stature, coxa vara, and a waddling gait. Patients with SMCD have mutations in the gene that codes for the alpha-1 chain of collagen X (COL10A1); however, mutation analysis of this gene is hampered by its size. We studied a family with SMCD: the mother, a 36-year-old woman with a height of 149 cm, had mild bilateral coxa vara. Her two sons presented with short stature, bowed legs, and coxa vara in early childhood. DNA was extracted from peripheral lymphocytes from the three patients and subjected to PCR amplification by COL10A1 gene-specific primers. In addition to single-strand conformational polymorphism (SSCP) analysis of the COL10A1 gene, we used a novel method, dideoxy fingerprinting (ddF). The genetic defect in this family was found to be a previously unreported missense mutation (T-to-C transition) at nucleotide 2011. This change resulted in a Ser-to-Pro substitution at position 671 of the carboxy-terminus of the COL10A1 protein. In addition, the two boys, but not the mother, were found to carry a trinucleotide (CCC) deletion at position 2048 of the 3' untranslated region, a polymorphism of the COL10A1 gene. We conclude that ddF can be used in the analysis of the COL10A1 gene along with SSCP. The S671P substitution is novel, but located in the same region with the other reported COL10A1 mutations, confirming type X collagen as the locus for this disease.

Adult↗

PubMed1996

Spontaneous cortisol and growth hormone secretion interactions in patients with nonclassic 21-hydroxylase deficiency (NCCAH) and control children.

Both exogenous and endogenous hypercortisolism result in reduced GH secretion and decreased somatic growth. However, little is known about the relation between endogenous cortisol and GH secretion under physiological or slightly disturbed conditions. To examine this, we measured and evaluated the pulsatility and circadian rhythmicity, and we cross-correlated the secretory patterns of cortisol and GH in six prepubertal patients with nonclassic 21-hydroxylase deficiency (NCCAH) and seven age-matched short-normal children. Cortisol and GH were secreted in a pulsatile fashion in both the NCCAH and control groups. The nocturnal peak cortisol increment and time-integrated area were lower in the NCCAH patients than in controls, whereas there was no difference in the total 24-h cortisol secretion between the two groups. The nocturnal increase of GH in NCCAH children, on the other hand, was associated with a significant augmentation of the pulse amplitude, whereas in control children there was an elevation of the baseline component. The cross-correlation analysis of the 24-h raw data showed that cortisol and GH were negatively correlated at brief lag times of 0-30 min, and positively correlated at long lag times of 12-12.5 h in both groups, with cortisol leading GH. The negative correlation might reflect either the negative effect of glucocorticoids on the adrenergic system, which stimulates GH secretion through GH-releasing hormone (GHRH) elevations and somatostatin (SRIH) decreases, or the absence of an inhibitory effect of CRH on SRIH. The positive correlation may reflect the positive effect of glucocorticoids on the GH gene. In conclusion, NCCAH children have a mild nocturnal cortisol deficiency compared with control children, as previously reported, and a distinct circadian pattern of pulsatile GH secretion. The hypothalamic-pituitary-adrenal (HPA) axis exerts both negative and positive influences on GH secretion, with mild disturbances in cortisol biosynthesis associated with slight alterations of GH secretion.

Adrenal Hyperplasia, Congenital↗

PubMed1996

Pituitary-ovarian responses to leuprolide acetate testing in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

To assess whether patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency exhibit a steroidogenic response to GnRH agonist consistent with functional ovarian hyperandrogenism (FOH) and elucidate the relationship between adrenal and ovarian hyperandrogenism, the LH, FSH, estradiol, 17-hydroxyprogesterone (17-OHP), androstenedione, total testosterone, dehydroepiandrosterone, and 17-hydroxypregnenolone responses to a sc dose of leuprolide acetate (500 micrograms) were evaluated in 10 patients with classic CAH (mean age, 18.4 +/- 0.95 yr), 7 of whom had oligomenorrhea, pretreated with dexamethasone (2 mg/day for 5 days, including the day of the test). The results were compared with those obtained in 11 patients with FOH (mean age, 18.7 +/- 0.46 yr) and 17 normal women (mean age, 19.68 +/- 0.59 yr) not pretreated with dexamethasone. Leuprolide acetate stimulation caused a significant augmentation of plasma E2, 17-OHP, androstenedione, testosterone, and 17-hydroxypregnenolone concentrations in all CAH patients. However, in only 6 (60%) of them, all with oligomenorrhea, was the 17-OHP response (posttest minus pretest value) similar to that of FOH patients and significantly higher than that in controls. In this subset of CAH patients, LH plasma levels after stimulation were significantly higher than those of CAH subjects with 17-OHP responses in the normal range, controls, and FOH patients, whereas FSH levels were similar to those of controls. In this latter group, plasma FSH concentrations after stimulation were significantly higher than those in FOH. In conclusion, the results of the present study indicate that LH-dependent functional ovarian hyperandrogenism is frequent in patients with classic CAH. As ovarian hyperandrogenism might be partially responsible for the menstrual irregularities that are common complications in such patients, all classic CAH patients with oligomenorrhea should undergo short term stimulation with GnRH agonists to ascertain the presence of ovarian hyperandrogenism and receive appropriate treatment.

17-alpha-Hydroxypregnenolone↗

PubMed1996

Dose-dependent inhibition of growth hormone (GH)-releasing hormone-induced GH release by corticotropin-releasing hormone in prepubertal children.

Previous studies have shown that CRH is capable of inhibiting GH release in response to GHRH in adult subjects, and this effect appeared to be sex dependent and more pronounced in women than in men. To assess whether CRH has an inhibitory action on GH release in children also, the effects of graded doses of CRH on the GHRH-induced GH secretion were studied in three groups of prepubertal children. All subjects underwent a GHRH test (1 microgram/kg), followed, on separate occasions, by the combined administration of GHRH (1 microgram/kg) and CRH (1 microgram/kg, group A, n = 6; 1.5 microgram/kg, group B, n = 6; 2 microgram/kg, group C, n = 7). GH concentrations in response to the single GHRH injection were comparable in the three groups. The combined administration of GHRH and CRH resulted in serum GH concentrations similar to those obtained in the same subjects in response to GHRH alone when 1 and 1.5 microgram/kg CRH were given. In contrast, the administration of 2 microgram/kg CRH together with GHRH led to an increase in GH concentrations significantly lower than those after the GHRH injection alone (GH area under the curve, 1022.18 +/- 106.26 vs. 3109.16 +/- 794.29 microgram/Lx24 h; P < 0.05). No differences in the GH response to GHRH alone or to GHRH plus CRH were detected between male and female subjects. The results of the present study indicate that CRH is capable of inhibiting GHRH-induced GH release in children. Moreover, the inhibitory effect by CRH appears to be dose dependent and not sex related.

Adolescent↗

PubMed1994

Dynamics of 24-hour pulsatile cortisol, 17-hydroxyprogesterone, and androstenedione release in prepubertal patients with nonclassic 21-hydroxylase deficiency and normal prepubertal children.

To assess whether the quantitative and qualitative aspects of cortisol, 17-hydroxyprogesterone (17-OHP), and androstenedione (D4A) secretion in patients with nonclassic congenital adrenal hyperplasia (NCCAH) differ from those in normal children, 24-hour serum concentrations of these steroids were measured in five prepubertal patients with NCCAH and five normal prepubertal children. Adrenal steroid profiles obtained by 30-minute sampling were analyzed by the Pulsar program. In comparison to normal children, the 24-hour quantitative parameters of 17-OHP and D4A secretion were significantly greater in NCCAH patients, but serum cortisol concentrations were similar in the two groups. When daytime and nighttime hormone releases were separately analyzed, a significant nocturnal elevation of the cortisol area under the curve above zero level (AUCo) and 12-hour mean and 17-OHP AUCo, AUC above baseline, mean peak height, amplitude, area, and 12-hour mean was detected in normal subjects only. Conversely, NCCAH patients exhibited an increased frequency and number of 17-OHP secretory peaks at night together with a reduction of the interpeak interval. No significant day/night differences in D4A concentrations were detected either in normals or in the patients. In conclusion, the results of the present study indicate that patients with NCCAH have a distinct pattern of adrenal steroid secretion characterized by a high-frequency 17-OHP release accompanied by a relative nocturnal cortisol deficiency.

17-alpha-Hydroxyprogesterone↗

PubMed1994

Isolated growth hormone deficiency type IA associated with a 45-kilobase gene deletion within the human growth hormone gene cluster in an Italian family.

An Italian family with three children presenting with isolated growth hormone (GH) deficiency type IA is described. Restriction endonuclease analysis revealed that the cause of hGH deficiency was a 45-kb gene deletion within the hGH-chorionic somatomammotropin (CS) gene cluster, encompassing the GH-1, CS-L, CS-A, and GH-2 genes. DNA sequence analysis and polymerase chain reaction amplification between two sequences located on each side of the deletion breakpoint accurately identified the deletion breakpoints and indicated that the regulatory sequences located upstream from the TATA box of the mutant CS-B belong to the GH-2 gene. Two of the affected children developed high-titer anti-hGH antibodies after recombinant hGH treatment with secondary growth arrest, whereas the third one maintained normal growth in the presence of very low-titer antibodies. This is the first report of a large deletional mutation within the hGH-CS gene cluster accompanied by phenotypic heterogeneity in terms of growth response and antibody formation in the different patients.

Base Sequence↗