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T Gautier

Publications and source records attributed to T Gautier.

36 records · Page 2Linked to original sources
PubMed1990

DNA linkage analysis and studies of the androgen receptor gene in a large kindred with complete androgen insensitivity.

DNA linkage analysis of the X chromosome and studies with cDNA probes specific for the androgen receptor gene were performed on the largest known kindred with the syndrome of complete androgen insensitivity. The affected subjects (XY) have absent binding of dihydrotestosterone to the androgen receptor (the receptor negative form of androgen insensitivity). In this kindred there was maternal transmission of the gene, with all affected males expressing complete genital feminization. Linkage analysis studies were conducted with two DNA probes, DXS1 and PGK1, localized to the Xq11-Xq13 region of the long arm of the X chromosome near the centromere. The results demonstrate linkage to the markers in the order of DXS1-(AR; PGK1), thus localizing the AR gene to an area between Xq11 and Xq13. Three cDNA probes that span various parts of the androgen receptor gene, including the DNA and steroid binding domain, were used to evaluate the androgen receptor gene in normal individuals, carrier mothers, and affected subjects. Identical restriction fragment patterns were found in all three groups studied. Thus the androgen receptor gene was present in affected subjects without detectable DNA polymorphism at the androgen binding domain. Therefore, despite complete absence of binding to the androgen receptor, the defect in the androgen receptor gene in this kindred is not the result of a gene deletion. The results point to a mutation or a small insertion/deletion as the probable cause of the syndrome.

Cell Line↗
PubMed1986

The prevalence of 5 alpha-reductase deficiency in children with ambiguous genitalia in the Dominican Republic.

During a 10-year period 65 children and adolescents with ambiguous genitalia from the Dominican Republic, not known through kindred studies of 5 alpha-reductase deficiency, were evaluated. Plasma androgen determinations were performed before and/or after Leydig cell stimulation of the testes with human chorionic gonadotropin. Of the children there were 24 female pseudohermaphrodites, 21 of whom had 21-hydroxylase deficiency, 1 true hermaphrodite and 40 (62 per cent) male pseudohermaphrodites. One child had a human chorionic gonadotropin response suggestive of 17-20 desmolase deficiency, and on further evaluation he also had partial deficiencies of the enzymes 21-hydroxylase and 17 alpha-hydroxylase. Five subjects had a female phenotype and subnormal androgen responses to human chorionic gonadotropin. In 5 of 33 male pseudohermaphrodites with a normal testosterone response to human chorionic gonadotropin 5 alpha-reductase deficiency was suspected by elevated plasma testosterone/dihydrotestosterone ratios before and/or after human chorionic gonadotropin stimulation. The diagnosis of 5 alpha-reductase deficiency was confirmed by elevated 5 beta/5 alpha urinary C19 and C21 steroid metabolite ratios. One subject with 5 alpha-reductase deficiency was traced to the original Dominican kindred of 38 affected subjects. Pedigree analysis of another proband revealed 3 additional affected relatives. Four subjects with a normal testosterone response to human chorionic gonadotropin had XO/XY gonadal dysgenesis. There were 25 male pseudohermaphrodites with normal plasma testosterone and dihydrotestosterone responses to human chorionic gonadotropin, who were not diagnosed by this methodology. This study reveals that 5 alpha-reductase deficiency occurs with a frequency of 13 per cent as a cause of male pseudohermaphroditism in the Dominican Republic with approximately the same frequency as XO/XY gonadal dysgenesis. Unlike female pseudohermaphrodites, the majority of male subjects with pseudohermaphroditism remain unclassified by these techniques.

Adolescent↗
PubMed1986

The diagnosis of 5 alpha-reductase deficiency in infancy.

The diagnosis of 5 alpha-reductase deficiency in infancy is reported for the first time in three male pseudohermaphrodites from the Dominican Republic. Basal plasma testosterone to dihydrotestosterone ratios were significantly elevated in two of the three affected infants, and increased markedly in all three infants after administration of hCG. Since urinary etiocholanolone to androsterone ratios could not be determined accurately in this age group, the diagnosis of 5 alpha-reductase deficiency was confirmed by the finding of elevated urinary tetrahydrocortisol (THF) to 5 alpha-tetrahydrocortisol (5 alpha-THF) ratios, as determined by gas chromatography/mass spectrometry, in the affected male infants compared to those in age-matched normal infants. The THF/5 alpha-THF ratios, however, were lower in both the normal children and the affected infants, suggesting increased 5 alpha-reductase activity in infancy. The affected infants had THF/5 alpha-THF ratios comparable to ratios in adult carrier males and significantly lower than ratios in adult homozygotes. Two of the three affected infants are related to the large Dominican kindred we studied previously and initially were raised as females but, after parental counseling, were changed to a male sex of rearing.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1985

Male pseudohermaphroditism due to multiple defects in steroid-biosynthetic microsomal mixed-function oxidases. A new variant of congenital adrenal hyperplasia.

A six-month-old 46,XY infant with a female phenotype and ambiguous genitalia was evaluated for male pseudohermaphroditism. The principal findings were (1) low basal plasma levels of all measured C19 steroids and their sulfates, which were unchanged or only minimally increased after stimulation with human chorionic gonadotropin or ACTH, (2) no urinary metabolites of C19 11-deoxy steroids, and decreased amounts of C19 11-oxosteroids, (3) normal basal plasma cortisol levels and normal urinary excretion of cortisol metabolites, (4) high plasma corticosterone and deoxycorticosterone levels and elevated urinary excretion of their metabolites, (5) high plasma progesterone and pregnenolone levels and increased urinary excretion of pregnanediol and pregnenediol, (6) high plasma 17 alpha-hydroxyprogesterone and 21-deoxycortisol levels and increased urinary excretion of pregnanetriol, 17 alpha-hydroxypregnanolone, and pregnenetriolone, (7) high plasma and urinary levels of 5-pregnene-3 beta,20 alpha-diol sulfate, (8) low plasma levels of 21-hydroxy-pregnenolone and 5-pregnene-3 beta,17 alpha, 20 alpha-triol sulfate, (9) high plasma ACTH levels, and (10) suppression of the high plasma steroid levels by dexamethasone. The unusual pattern of plasma and urinary steroids indicated that this child had multiple abnormalities of steroid-biosynthetic microsomal mixed-function oxidases--21-hydroxylase, 17 alpha-hydroxylase, and 17,20 desmolase. The deficit in the activities of the first two enzymes resulted in decreased cortisol synthesis with subsequent increased ACTH secretion and adrenocortical hyperplasia. The male pseudohermaphroditism resulted from deficient testosterone synthesis due to deficiency of 17 alpha-hydroxylase and 17,20 desmolase. The mother and two sisters of the affected child had evidence of mild 17 alpha-hydroxylase deficiency.

17-Hydroxycorticosteroids↗
PubMed1985

Urinary steroid metabolites in subjects with male pseudohermaphroditism due to 5 alpha-reductase deficiency.

To investigate the enzymatic basis for abnormal steroid metabolism in subjects with male pseudohermaphroditism due to 5 alpha-reductase deficiency, the ring A reduced urinary 5 beta and 5 alpha metabolites of testosterone, androstenedione, 11 beta-hydroxyandrostenedione, cortisol and corticosterone were measured by gas chromatography. Assays of the four pairs of urinary 5 beta and 5 alpha steroid metabolites revealed decreased conversion of the parent steroids to 5 alpha-reduced urinary metabolites, with increased 5 beta to 5 alpha urinary steroid metabolite ratios. These studies establish that increased urinary 5 beta/5 alpha ratios are distinctive for this disorder, and represent the most reliable method for confirming the diagnosis of primary inherited 5 alpha-reductase deficiency. These data also suggest that the conversion on the many delta 4-3 ketosteroids to 5 alpha-reduced steroids may be due to a single enzyme with broad specificity, or multiple enzyme reductases with a common regulator.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1985

Decreased urinary C19 and C21 steroid 5 alpha-metabolites in parents of male pseudohermaphrodites with 5 alpha-reductase deficiency: detection of carriers.

The urinary 5 beta/5 alpha ring A-reduced metabolites of C19 and C21 steroids from obligate carrier parents of male pseudohermaphrodites with 5 alpha-reductase deficiency were analyzed by gas chromatography. Etiocholanolone/androsterone, 11 beta-hydroxyetiocholanolone/11 beta-hydroxyandrosterone, tetrahydrocortisol/allotetrahydrocortisol, and tetrahydrocorticosterone/allotetrahydrocorticosterone were the paired 5 beta/5 alpha-metabolite ratios measured. Increased mean 5 beta/5 alpha ratios were found for all paired metabolites compared to mean ratios in normal subjects. In men, the highest index of discrimination of the carrier state was the tetrahydrocorticosterone/allotetrahydrocorticosterone ratio, while in women, the etiocholanolone/androsterone ratio was more diagnostic. In obligate carrier men, plasma testosterone, dihydrotestosterone, androstenedione, and 17 alpha-hydroxyprogesterone levels were normal, as were testosterone/dihydrotestosterone ratios. These studies demonstrate a generalized defect in 5 alpha-reductase activity involving C19 and C21 steroid metabolism in obligate carrier parents and provide further confirmation of an autosomal recessive mode of inheritance in this condition. The data from parents of sporadic cases of male pseudohermaphrodites with primary 5 alpha-reductase deficiency suggest that there is a carrier rate within the general population, although the exact frequency remains unknown.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1979

Androgens and the evolution of male-gender identity among male pseudohermaphrodites with 5alpha-reductase deficiency.

To determine the contribution of androgens to the formation of male-gender identity, we studied male pseudohermaphrodites who had decreased dihydrotestosterone production due to 5 alpha-reductase deficiency. These subjects were born with female-appearing external genitalia and were raised as girls. They have plasma testosterone levels in the high normal range, show an excellent response to testosterone and are unique models for evaluating the effect of testosterone, as compared with a female upbringing, in determining gender identity. Eighteen of 38 affected subjects were unambiguously raised as girls, yet during or after puberty, 17 of 18 changed to a male-gender identity and 16 of 18 to a male-gender role. Thus, exposure of the brain to normal levels of testosterone in utero, neonatally and at puberty appears to contribute substantially to the formation of male-gender identity. These subjects demonstrate that in the absence of sociocultural factors that could interrupt the natural sequence of events, the effect of testosterone predominates, over-riding the effect of rearing as girls.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1977

Male pseudohermaphroditism due to steroid 5-alpha-reductase deficiency.

A new inherited form of male pseudohermaphroditism has been investigated in a pedigree of 24 families with 38 affected males. At birth, the affected males (46 XY) have a clitoral-like phallus, bifid scrotum and urogenital sinus. The testes are in the inguinal canals or labial-scrotal folds. The Wolffian structures are normally differentiated; there are no Mullerian structures. At puberty a muscular male habitus develops with growth of the phallus and scrotum, voice change and no gynecomastia. The subjects have erections, ejaculations and a libido directed towards females. They have decreased body hair, a scant to absent beard, no temporal hair line recession and a small prostate. Testicular biopsy reveals a normal testis. The mean plasma T levels in affected adults are significantly higher, and the mean plasma DHT levels are significantly lower when compared to those in normal subjects. The plasma T:DHT ratios range from 35 to 84 compared to 8 to 16 in normal subjects. After the administration of hCG, the T:DHT ratios in affected male children range from 74 to 162 compared to 3 to 26 in the control subjects. In affected adults, mean plasma LH and FSH levels are significantly higher than in normal subjects. In the affected subjects, the metabolic clearance rates of T and DHT are normal, but the conversion ratio of T to DHT is less than 1 per cent. The endogenous mean urinary E:A and E-OH:A-OH ratios, and the urinary E:A and E-OH:A-OH ratios after the infusion of radioactive T are significantly higher than in normal males. Inheritance is autosomal recessive with some sibling sisters showing the same biochemical defect, and obligate carrier parents showing an intermediate defect. These data support our thesis that the defect in these male pseudohermaphrodites is secondary to decreased steroid delta 4-5 alpha-reductase activity. The affected subjects provide a clinical model for delineating the roles of T and DHT in sexual differentiation and development. This entity also demonstrates an inherited disorder of steroid metabolism in which the basic enzyme deficiency resides in the target tissues.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1974

Steroid 5alpha-reductase deficiency in man: an inherited form of male pseudohermaphroditism.

In male pseudohermaphrodites born with ambiguity of the external genitalia but with marked virilization at puberty, biochemical evaluation reveals a marked decrease in plasma dihydrotestosterone secondary to a decrease in steroid 5alpha-reductase activity. In utero the decrease in dihydrotestosterone results in incomplete masculinization of the external genitalia. Inheritance is autosomal recessive.

Androsterone↗
PubMedDate not supplied

Fluorescence-based assessment of LRP activity: a comparative study.

BACKGROUND: Broad resistance to anticancer drugs is a major cause of failure in cancer treatment. The Lung Resistance-related Protein (LRP) is a protein associated with drug resistance, which is involved in nucleo-cytoplasmic transport and is known to predict a poor response to chemotherapy in acute myeloid leukaemia. The only method allowing the detection of LRP activity is based on radio-labelled daunorubicin incorporation. Our goal was to develop a fluorescence-based assay to analyse LRP function. MATERIALS AND METHODS: We used human colon carcinoma cell lines treated with sodium butyrate (NaB) in order to induce LRP expression. Daunorubicin efflux in isolated nuclei was measured by flow cytometry, the localization and quantification of Daunorubicin analysed by confocal laser scanning microscopy (CLSM) and the diffusion coefficient of this drug estimated by Fluorescence Correlation Spectrometry (FCS). RESULTS: According to the method using [14C] Doxorubicin cells incubated with NaB displayed an efflux of Daunorubicin out of isolated nuclei demonstrated by flow cytometry or CLSM. The FCS method was able to evaluate kinetics of Daunorubicin molecules in nucleus and cytoplasm and showed a higher dispersion of Daunorubicin kinetics with cells previously NaB-treated. This argument is in favour of an increase of nucleo-cytoplasmic exchange. CONCLUSION: Using CLSM we showed that LRP was able to modify anticancer drug repartition in the cells. LRP activity assessment needs either isolated nuclei if flow cytometry is employed, or FCS, and only a few cells may be analysed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Epoprostenol (PGI2) prevents postischemic ventricular fibrillation and improves outcome in a canine model of sudden death.

In a left circumflex coronary artery occlusion-reperfusion canine model of sudden death the hemodynamic, antiplatelet, antiischemic and antifibrillatory activities of 100 ng.kg-1.min-1 infusion of epoprostenol (Prostacyclin, Flolan, Wellcome Foundation, London, UK) were investigated at random in 40 animals. Significant changes were observed on epoprostenol infusion for mean arterial blood pressure (80 +/- 4 vs 93 +/- 7 mmHg, p less than 0.01), systemic vascular resistance (2379 +/- 769 vs 3290 +/- 768 dynes.s.cm-5, p less than 0.01) and rate-pressure product (10800 +/- 1200 vs 13450 +/- 2500 mmHg.beat.min-1, p less than 0.01) while heart rate did not change. In addition platelet aggregation intensity to ADP decreased by 50% (p less than 0.001). On occlusion treated animals presented with lower systemic vascular resistance (3132 +/- 895 vs 4931 +/- 1079 dynes.s.cm-5, p less than 0.05), rate-pressure product (9950 +/- 850 vs 12168 +/- 1980 mmHg.beat.min-1, p less than 0.01) and mean heart rate (145 +/- 10 vs 169 +/- 10 beats.min-1, p less than 0.01) while the anti-platelet activity persisted. A lower D2-3 mean ST segment elevation occurred at 3 min postocclusion in epoprostenol treated dogs (7.7 +/- 5 vs 14 +/- 8.7 mm, p less than 0.02). The incidence of postischemic ventricular fibrillation was significantly reduced (5/20 i.e. 25% vs 12/20 i.e. 60%, p less than 0.05) in the epoprostenol treated dogs. At the end of the occlusion-reperfusion period treated animals showed an improvement of outcome (10/20 i.e. 50% vs 2/20 i.e. 10%, p less than 0.01). It is suggested that the hemodynamic effect of the drug may provide guidelines for the clinical management of patients with acute myocardial ischemia, when a concomitant antiarrhythmic effect is looked for.

Animals↗