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S Lumbroso

Publications and source records attributed to S Lumbroso.

At least 19 recordsLinked to original sources
PubMed2006

The role of androgens or growth factors in the bone resorption process in recent spinal cord injured patients: a cross-sectional study.

STUDY DESIGN: This cross-sectional study compared the androgen and growth factor profiles and the bone turnover of patients with spinal cord injury (SCI) versus able-bodied controls (AB). OBJECTIVE: Determine whether androgens, GH, or either IGF-I or IGFBP-3, are implicated in bone turnover alteration in patients with recent SCI. SETTING: Propara Center, Montpellier, France. METHODS: In all, 16 men (31.3 years) with complete SCI, seven paraplegics and nine tetraplegics, who had sustained injury an average of 3 months earlier, and 12 AB who served as controls (27.5 years) participated. Androgens, growth hormone and its mediators were investigated. The bone resorption process was evaluated by urinary and plasma type I collagen C-telopeptide (CTXu, CTXp), while bone formation was evaluated by osteocalcin (OC) and bone alkaline phosphatase. RESULTS: Total testosterone (TT) and the free androgen index (FAI) were significantly lower in the SCI patients, whereas FSH was significantly higher (P<0.05). These hormonal variations were not related to the level of neurological lesion. There was no significant difference in GH, IGF-I, or IGFBP-3 levels. CTXu and CTXp indicated high bone resorption activity in the SCI patients (P<0.05). Regarding bone formation markers, only OC was affected by neurological lesion (P<0.05). Basal hormone levels did not correlate with markers of bone turnover. CONCLUSION: The high bone resorption process observed in SCI patients did not seem directly related to testicular endocrine abnormalities or an altered growth factor profile. Nevertheless, the reduced TT and FAI levels could be aggravating factors in the development of acute bone loss.

Adult↗
PubMed2006

Searching for somatic mutations in McCune-Albright syndrome: a comparative study of the peptidic nucleic acid versus the nested PCR method based on 148 DNA samples.

BACKGROUND: Activating mutations of the Gsalpha gene (GNAS), which encodes for the alpha-subunit of the stimulatory G protein, have been identified in patients with McCune-Albright syndrome (MAS). Accuracy and sensitivity in the molecular diagnosis of MAS is mandatory for optimal therapeutic strategy and adapted follow-up, especially for incomplete clinical forms of MAS. To date, the highly sensitive nested PCR method with intermediary digestion by a restriction enzyme at the mutation site is one of the most widely used techniques. This study evaluated a new diagnostic method using a peptidic nucleic acid (PNA) and compared it with the nested PCR method. MATERIAL AND METHODS: One hundred and forty-eight DNA samples from eighty-eight patients presenting clinical symptoms compatible with MAS were included. The DNA samples were mainly obtained from peripheral blood, ovarian tissue or cyst liquid, and bone lesions. The nested PCR method required 4 days. PNA clamping required 1.5 days and utilized the higher thermal stability and specificity of PNA-DNA coupling to inhibit PCR product formation. Direct sequencing was subsequently performed in all cases. RESULTS: The sensitivity of mutation detection was 54% (n = 80) for nested PCR and 46.6% (n = 69) for PNA (P > 0.05). The 11 cases where PNA failed to detect the mutation were mainly incomplete and atypical clinical forms of MAS (n = 10/11). The cost per sample was 50 Euros for PNA clamping versus 136 Euros for nested PCR. CONCLUSION: PNA clamping is a rapid, reliable, and economical method to diagnose MAS. It should be the first-line diagnostic method, although negative results, especially for incomplete clinical forms of MAS, should be confirmed by nested PCR.

Child↗
PubMed2005

[Clinical expression of precocious pubertal development in girls].

The paediatric endocrinologist is frequently asked whether pubertal development in a girl is normal, early or too early (precocious). This review will cover all clinical expression of premature development of puberty: central precocious puberty (neurogenic, secondary, and idiopathic) where treatment with GnRHa is considered, early puberty, partial puberty or pubertal variants and peripheral or pseudo precocious puberty related to an antonomous hypersecretion of estrogens by the ovaries. A special attention should be paid also to the role of environmental disruptors in the development of peripheral precocious puberty. GnRHa treatment should be considered only when evidence of central activation of the gonadotropic axis is proved by the LHRH-test.

Child↗
PubMed2004

Mutation of the androgen receptor (R840S) in an Egyptian patient with partial androgen insensitivity syndrome: review of the literature on the clinical expression of different R840 substitutions.

The X-linked androgen insensitivity syndrome (AIS) encompasses a heterogeneous group of defects in the androgen receptor (AR) that result in varying degrees of undermasculinization. In the current study, we characterize the R840S mutation on exon 7 of the AR ligand-binding domain. The Egyptian patient, who had been reared as female, presented ambiguous genitalia at 6.5 yr. Diagnosis of partial AIS (PAIS) was based on clinical phenotype and laboratory evidence of good testosterone response and normal testosterone/dihydrotestosterone (T/DHT) ratio. The therapeutic response to testosterone depot injections justified reassignment to male sex. To our knowledge, this mutation has been reported only once in two Brazilian brothers with PAIS. Three other mutations of this residue (R840C; R840G, nonconservative; and R840H, conservative) have been reported in patients with PAIS and, when expressed in vitro, they led to subnormal transactivation of a reporter gene. Each of these mutations was associated with a very diverse spectrum of phenotypes. These data highlight the role of the AR ligand-binding pocket (LBP) in the expression of transcriptional activity during prenatal sex differentiation.

Amino Acid Substitution↗
PubMed2004

A new mutation of the androgen receptor, P817A, causing partial androgen insensitivity syndrome: in vitro and structural analysis.

Androgen insensitivity syndrome (AIS) is an X-linked disease caused by mutations in the androgen receptor (AR) resulting in various degrees of defective masculinization in 46,XY individuals. In the present study, we describe a novel mutation in exon 7 of the AR gene in an Egyptian patient with partial AIS (PAIS). Sequencing analysis of the AR gene revealed a novel missense mutation, P817A, within the ligand-binding domain (LBD). This is the first report of a mutation within the short amino acid motif (codons 815-817) of the beta-strand lying between helices H8 and H9 of the AR LBD. The functional defects of the mutated protein were characterized by in vitro study and included significantly decreased ligand-binding affinity and impaired transactivation potential. Limited proteolysis assays performed with the wild-type and mutant AR receptors incubated with the synthetic agonist R1881 revealed that the P817A mutation resulted in a reduced stabilization of the AR active conformation. Structural analyses showed that this mutation is likely to perturb the beta-sheet interaction between residues 815-817 and 911-913. This structural alteration destabilizes the position of the C-terminal extension, which contains residues critical for androgen function.

Androgen-Insensitivity Syndrome↗
PubMed2003

A novel point mutation of the androgen receptor (F804L) in an Egyptian newborn with complete androgen insensitivity associated with congenital glaucoma and hypertrophic pyloric stenosis.

Androgen-insensitivity syndrome (AIS) is a major cause of male pseudohermaphroditism (MPH). Although AIS is usually reported as a monogenic disease resulting from androgen receptor (AR) mutations, on rare occasions it has been observed as part of a multiple congenital anomaly syndrome. We report here a patient who was the first newborn girl of an unrelated couple. Shortly after birth, the diagnoses of congenital glaucoma and pyloric stenosis were made. A detailed history of the father's family revealed that nine members presented glaucoma before 40 years of age. Clinical and ultrasound evaluation showed two inguinal testes, with female external genitalia and no Mullerian derivatives. The patient had a 46,XY karyotype, good testicular response to gonadotrophin stimulation and a remarkably high T : dihydrotestosterone ratio. Sequencing of the five exons of the 5alpha-reductase type 2 gene (SRD5A2) was normal. Conversely, a de novo point mutation was found in exon 6 of the AR gene, resulting in an F804L substitution, which has never been described previously. To our knowledge, the association of complete AIS, congenital glaucoma and pyloric stenosis has also never been reported previously.

Androgen-Insensitivity Syndrome↗
PubMed2003

Testosterone is significantly reduced in endurance athletes without impact on bone mineral density.

AIMS: To compare the basal plasma reproductive hormonal profile in three groups of athletes involved in different training programs, and to define the relationship between androgen level and bone mineral density (BMD) in male athletes. METHODS: Basal serum total testosterone (TT), free androgen index (FAI), sex hormone-binding globulin (SHBG), cortisol, cortisol to TT ratio, luteinizing hormone (LH), estrogen and BMD were evaluated in cyclists (CY; n = 11), triathletes (TR; n = 14) and swimmers (SW; n = 13) and compared with less active controls (n = 10). RESULTS: TT and FAI levels were lower (p < 0.05) in CY and TR, whereas the ratio of cortisol to TT was increased in CY only (p < 0.05). No alteration in serum LH, SHBG, estrogen or cortisol concentration was observed. BMD was higher in the proximal femur in TR (p < 0.05). No BMD or hormonal differences were found in SW. CONCLUSION: Only the endurance training of CY and TR induced androgen deficiency without apparent alteration of BMD.

Adult↗
PubMed2002

Mutant luteinizing hormone receptors in a compound heterozygous patient with complete Leydig cell hypoplasia: abnormal processing causes signaling deficiency.

Over the past 5 yr several inactivating mutations in the LH receptor gene have been demonstrated to cause Leydig cell hypoplasia, a rare autosomal recessive form of male pseudohermaphroditism. Here, we report the identification of two new LH receptor mutations in a compound heterozygous case of complete Leydig hypoplasia and determine the cause of the signaling deficiency at a molecular level. On the paternal allele of the patient we identified in codon 343 a T to A transversion that changes a conserved cysteine in the hinge region of the receptor to serine (C343S); on the maternal allele a T to C transition causes another conserved cysteine at codon 543 in trans-membrane segment 5 to be altered to arginine (C543R). Both of these mutant receptors are completely devoid of hormone-induced cAMP reporter gene activation. Using Western blotting of expressed LH receptor protein with a hemagglutinin tag, we further show that despite complete absence of total and cell surface hormone binding, protein levels of both mutant LH receptors are only moderately affected. The expression and study of enhanced green fluorescent protein-tagged receptors confirmed this view and further indicated that initial translocation to the endoplasmic reticulum of these mutant receptors is normal. After that, however, translocation is halted or misrouted, and as a result, neither mutant ever reaches the cell surface, and they cannot bind hormone. This lack of processing is also indicated by reduced presence of an 80-kDa protein, the only N-linked glycosylated protein in the LH receptor protein profile. Thus, complete lack of signaling by the identified mutant LH receptors is caused by insufficient processing from the endoplasmic reticulum to the cell surface and results in complete Leydig cell hypoplasia in this patient.

Amino Acid Sequence↗
PubMed2002

Mutations of the 5alpha-steroid reductase type 2 gene in six Turkish patients from unrelated families and a large pedigree of an isolated Turkish village.

We describe six Turkish patients with 5alpha-steroid reductase type 2 deficiency from unrelated Turkish families and a large pedigree of one of these patients who reside north-west of Anatolia. Patients NA, KS, BD and SY presented for evaluation of bilateral inguinal masses with female phenotypes. Patient ABE had penoscrotal hypospadias with male phenotype. Homozygous mutation of the 5alphaSR2 gene was identified in five of these patients by genomic DNA analysis. These mutations were Leu55Gln in exon 1 (in patients FG, BD and ABE), deltaMet157 in exon 3 (in patient NA), and splice junction abnormality in intron 1 (in patient SY). One individual (patient KS) was found to be a compound heterozygous carrier of two different mutations, Leu55Gln in exon 1 and Arg171Ser in exon 3. Patient FG had a large pedigree with the Leu55Gln mutation in exon 1. The pedigree of this family with marital consanguinity is remarkable, and possibly due to the isolation of this family because of economic and social problems. A further 85 individuals belonging to this family were analyzed for exon 1 Leu55Gln mutations in the 5alphaSR2 gene. Forty-two of these 85 individuals (49.41%) had this alteration; 11 were homozygous (8 genetic male, 3 genetic female) and 31 heterozygous (18 genetic male, genetic female) for this mutation. It was interesting to see asymptomatic homozygous female carriers. In conclusion, according to our results and those of other Turkish patients reported by different investigators, 5aSR2 gene mutation analysis, especially for Leu55Gln in exon 1 and deltaMet157 in exon 3, must be carried out in Turkish patients with male pseudohermaphroditism. Homozygous asymptomatic female carriers must be taken into consideration in this clinical entity, especially in a closed population, because of the risk of transmitting the disease to their offspring.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2002

[The androgen receptor: molecular pathology].

Androgens play a crucial role in the development, maintenance and regulation of male phenotype and reproductive physiology through the androgen receptor, a transcription factor. Testosterone or dihydrotestosterone binding induces a trans-conformation of the androgen receptor and allows its translocation into the nucleus, where it recognizes specific DNA sequences. Recent developments in molecular genetics, as well as structural analysis of the androgen receptor, allow a better understanding of the structure/function relationship of this nuclear receptor. Molecular analyses of androgen insensitivity syndrome, as well as hormone-resistant prostate cancer, Kennedy's disease and isolated male infertility, have been proved useful as privileged models for this purpose. In the absence of identified AR receptor mutations in androgen insensitivity syndromes, abnormalities of transcriptional cofactor should be considered. Finally, identification of androgen-dependent genes will be helpful for evaluating the degree of the molecular defect of androgen action within target cells.

Active Transport, Cell Nucleus↗
PubMed2001

Environmental xenoestrogens, antiandrogens and disorders of male sexual differentiation.

Over the past 20 years, the documented increase in the disorders of male sexual differentiation, such as hypospadias, cryptorchidism, and micropenis, has led to the suspicion that environmental chemicals are detrimental to normal male genital development in utero. Male sexual differentiation is critically dependent on the normal action of androgens, and unbalanced androgen/estrogen ratios can disturb it. Environmental xenoestrogens (such as herbicides, pesticides, PCBs, plasticizers, and polystyrenes) that mimic estrogens or environmental antiandrogens (such as polyaromatic hydrocarbons, linuron, vinclozolin, and pp'DDE) that disturb endocrine balance, cause demasculinizing effects in the male foetus. These environmental chemicals are often referred to as endocrine disruptors: they are thought to mimic endogenous estrogens by entering the cell, binding to the receptor and activating transcription, they may also antagonize normal androgen action. We have established numerous cell lines to assess the estrogenicity and antiandrogenicity of compounds found in the environment and to identify new products present in wastewater effluents that are able to disrupt endocrine functions. Several cell lines responding to estrogens have been obtained in our group, including cells with different enzymatic equipment and cells expressing chimeric receptor or natural estrogen receptors alpha and beta. These cell lines have proved to be useful for assessing the biological activity of pesticides, fungicides, and chemicals found in plastic or discarded in the environment. In order to generate a powerful tool for the investigation of androgen action and the rapid screening of potential antagonists, we developed a new stable prostatic cell line. The PALM cell line is an original cellular model to characterize the response of hAR, and it provides an easy and rapid bioluminescent test to identify new antagonists. We also developed a model based on a fusion protein between the androgen receptor (AR) and the green fluorescent protein (GFP) to study the intracellular dynamics of AR. The GFP-AR model was applied to define the ability of several xenoestrogens and antiandrogens to inhibit the nuclear transfer of AR. The ubiquitous presence of endocrine disruptors in the environment and the increased incidence of neonatal genital malformation support the hypothesis that disturbed male sexual differentiation may in some cases be caused by increased exposure to environmental xenoestrogens and/or antiandrogens.

Androgen Antagonists↗
PubMed2001

Lack of influence of the androgen receptor gene CAG-repeat polymorphism on sex steroid status and bone metabolism in elderly men.

OBJECTIVE: Population means for serum testosterone (T) levels in healthy men decrease with ageing but there is considerable interindividual variability of serum T in elderly men. Ultimate androgen action is mediated through the androgen receptor. Subtle differences in androgen sensitivity might contribute to serum T variability through the T negative feedback regulation. The androgen receptor gene (AR) contains in exon 1 a polymorphic trinucleotide CAG-repeat, whose length modulates androgen receptor action. The aims of the study were to assess the potential contribution of the AR CAG-repeat polymorphism in the interindividual variability of serum T and in the determination of bone metabolism in ambulatory elderly men. DESIGN AND PATIENTS: We used cross-sectional baseline data of a longitudinal study investigating the process of ageing, in particular the changes in hormonal status and bone metabolism, in a cohort of 273 community-dwelling healthy men, between age 71 and 86 years. MEASUREMENTS: AR CAG-repeat length was determined by automated DNA sequencing of exon 1 of the AR gene. Serum T, sex hormone binding globulin, LH and oestradiol were measured by specific immunoassays. Bone mineral density (BMD) was determined by dual energy X-ray absorptiometry. Bone turnover was assessed by measurement of serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-terminal type I procollagen peptide, serum and urinary C-terminal telopeptides of type I collagen and urinary deoxypyridinoline levels, with use of immunoassays. RESULTS: No significant association was found between the AR CAG-repeat length and either total or free T, LH or the androgen sensitivity index (LHxT). BMD measurements at the hip and the forearm were not associated with AR CAG-repeat length and there was no association of this AR polymorphism with any of the biochemical markers of bone turnover. Results were not different after adjustments for age and body mass index. CONCLUSIONS: The findings of the present study do not support the view that in community-dwelling, healthy elderly men the androgen receptor gene CAG-repeat polymorphism has a substantial impact on interindividual variability of serum testosterone levels or on the determination of bone turnover and bone mineral density.

Aged↗
PubMed2001

Macroorchidism due to autonomous hyperfunction of Sertoli cells and G(s)alpha gene mutation: an unusual expression of McCune-Albright syndrome in a prepubertal boy.

We report an unusual observation of a 3.8-yr-old boy with McCune-Albright syndrome (MAS) associated with abnormal prepubertal testis enlargement and no sexual precocity. Physical examination showed café-au-lait skin lesions, enlarged testes, prepubertal sized penis, and no pubic or axillary hair. Skeletal radiography disclosed fibrous dysplasia. The serum testosterone level was 0.58 nmol/L and remained below 1.4 nmol/L during the 4-yr follow-up. By contrast, serum inhibin B and anti-Mullerian hormone concentrations were abnormally increased up to 255 pg/mL (childhood range, 35--180) and 792 pmol/L (childhood range, 309--566), respectively. The LH response to a GnRH test was in the prepubertal range, whereas the FSH response was blunted. This abnormal hormone concentration profile indicates autonomous hyperfunction of Sertoli cells, with no evidence of Leydig cell activation. Testicular histology showed tubules with marked Sertoli cell hyperplasia and very rare germinal cells, and interstitial tissue containing mesenchymal cells but no mature Leydig cells. DNA sequence analysis from bone and testis tissues detected the known activating mutation in MAS that results in replacement of Arg by His at codon 201 of the G(s)alpha protein. Other endocrine tests showed excessive GH secretion and moderate adrenal androgen hypersecretion. These findings are consistent with the occurrence of an activating mutation of the G(s)alpha gene mainly expressed in Sertoli cells and weakly expressed or absent in Leydig cells. Abnormal prepubertal testicular enlargement extends the clinical spectrum of MAS, suggesting that determination of serum inhibin B and anti-Mullerian hormone should be considered in boys with this syndrome. This observation demonstrates the usefulness of detailed molecular and biological investigations in atypical cases of MAS.

Base Sequence↗
PubMed2000

Specific recognition of androgens by their nuclear receptor. A structure-function study.

Androgens, like progestins, are 3-ketosteroids with structural differences restricted to the 17beta substituent in the steroid D-ring. To better understand the specific recognition of ligands by the human androgen receptor (hAR), a homology model of the ligand-binding domain (LBD) was constructed based on the progesterone receptor LBD crystal structure. Several mutants of residues potentially involved in the specific recognition of ligands in the hAR were constructed and tested for their ability to bind agonists. Their transactivation capacity in response to agonist (R1881) and antagonists (cyproterone acetate, hydroxyflutamide, and ICI 176344) was also measured. Substitution of His(874) by alanine, only marginally impairs the ligand-binding and transactivation capacity of the hAR receptor. In contrast, mutations of Thr(877) and, to a greater extent, Asn(705) perturb ligand recognition, alter transactivation efficiency, and broaden receptor specificity. Interestingly, the N705A mutant acquires progesterone receptor (PR) properties for agonist ligands but, unlike wild type AR and PR, loses the capacity to repress transactivation with nonsteroidal antagonists. Models of the hAR.LBD complexes with several ligands are presented, which suggests new directions for drug design.

Amino Acid Sequence↗
PubMed2000

Demonstration of McCune-Albright mutations in the liver of children with high gammaGT progressive cholestasis.

Two patients presented with neonatal cholestasis and acholic stools as first manifestations of McCune-Albright syndrome. Both went through an extensive evaluation including an exploratory laparotomy with peroperative cholangiography which ruled out biliary atresia. One patient presented from the fourth month of life with the classical café-au-lait spots following Blaschko's lines, while less classical café-au-lait spots were seen in the second patient at the age of 4 years. Bone lesions were seen in one patient at the age of 2.5 years and in the other at the age of 4 years. Despite the severity of presentation, both patients cleared their jaundice within 6 months, but still had mild abnormalities of liver function tests. Both patients showed an activating mutation of codon 201 in the gene encoding the alpha-subunit of the G-protein that stimulates adenylcyclase in liver tissue, suggesting that this metabolic defect could be responsible for the cholestatic syndrome. Similar mutations have been found in other affected tissues in patients with the McCune-Albright syndrome. We propose that McCune-Albright syndrome be included in the list for differential diagnosis of neonatal cholestasis and chronic cholestasis of infancy, as a rare cause.

Arginine↗