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P Touraine

Publications and source records attributed to P Touraine.

At least 19 recordsLinked to original sources
PubMed2006

Serum anti-Müllerian hormone expression in women with premature ovarian failure.

BACKGROUND: Premature ovarian failure (POF) is generally irreversible. However, developing follicles up to the antral stage are reported in POF and anti-Müllerian hormone (AMH) might be a good indicator of follicular presence. This study analysed serum AMH, ovarian histology and AMH immunoexpression in POF patients. METHODS: A cross-sectional study of 48 POF patients in an Endocrinology Department setting. Patients had an ovarian biopsy simultaneously with serum AMH sampling and/or ovarian AMH immunostaining. RESULTS: Mean serum AMH was 1.04 +/- 1.66 ng/ml. Serum AMH was significantly higher in women with 15 or more follicles at ovarian histology (P = 0.001). Comparison of ovarian AMH immunostaining from POF patients and 10 normal controls revealed a normal AMH expression in POF pre-antral follicles, but a decreased expression at the early antral stages. Serum AMH was undetectable in 77% of the patients with 0-5 AMH immunopositive follicles and detectable in 100% of the patients with more than 15 AMH immunopositive follicles. CONCLUSIONS: AMH levels in POF patients could identify women with persistent follicles. The decrease of AMH immunoexpression in POF antral follicles could suggest a defect of antral development.

Adolescent↗
PubMed2006

Idiopathic premature ovarian failure in 63 young women.

BACKGROUND: Premature ovarian failure (POF) in adolescents is defined as primary or secondary amenorrhea associated with high follicle-stimulating hormone (FSH) levels. In normal 46,XX patients, its etiology is most often unknown. We have evaluated the clinical, hormonal and ovarian phenotypes in patients with a normal karyotype who were diagnosed with POF before the age of 18. METHODS: Sixty-three patients were included in this retrospective study. RESULTS: The mean patient age was 20.4 years. The patients presented with three clinical patterns: lack of pubertal development (n = 23), primary amenorrhea with interrupted puberty (n = 18), and secondary amenorrhea with normal puberty (n = 22). Ten patients had a familial history of POF and 6 presented with hypothyroidism. The FSH, estradiol and inhibin B levels were not statistically different in the three clinical groups. Fifty percent of the patients presented small ovaries (length <2 cm) at ultrasonography. The presence of follicles was found at histology in only 7 of the 27 patients who underwent an ovarian biopsy. CONCLUSION: 46,XX patients presenting with early POF rarely presented a specific, identifiable disorder. We discuss the clinical management and different diagnosis strategies to improve our current knowledge of this syndrome.

Adolescent↗
PubMed2006

[Traumatic brain injury and pituitary insufficiency].

Until recently, hypopituitarism was not considered as a potential consequence of traumatic brain injury (TBI) since only few case reports were described. However, since 2000, preliminary studies have underlined such an association. Hypopituitarism may occur during the acute phase of TBI, months after or even many years later. Among the multiple deficiencies, GH deficiency appears to be the most frequently observed. However multiple bias are described in such studies, especially the small number of patients analyzed and the diagnosis relying on baseline values. Most recently, some studies analyzed 50 to 100 patients confirming that up to 50% of patients may be affected by such an association and underlined the necessity to propose a prospective evaluation since the evolution of hypopituitarism is highly variable during follow-up. It also appears necessary to describe this association to allow when necessary to secondarily propose hormonal substitutive treatment which might be discussed in such a context.

Adult↗
PubMed2006

[KIMS observational study of GH therapy in GH-deficient adults: 12-month follow-up analysis of the French cohort].

KIMS study is an international, observational study initiated in 1994 in which France has been involved since 2003. Its aim is to collect on a widespread basis long-term data from GH-deficient adults treated or not treated with growth hormone in daily practice. Among 330 patients already enrolled by 128 centers in France at the data lock point for this first interim analysis, 122 patients were followed up for at least 12 months and their results are presented herein. After one year of treatment, IGF-1 level adjusted for age and sex was normalized for 77% of patients naive of GH-treatment, 71% of semi-naive patients and 85% of non naive patients. Lean mass increase was 5.1% and fat mass decrease 5.7%. Quality of life assessed through QoL-AGHDA questionnaire was improved with a median score decrease from 10 to 6. These are the first results available from French patients and suggest that growth hormone is an appropriate indication for adults with severe GH deficiency.

Adult↗
PubMed2005

Breast inflammatory gigantomastia in a context of immune-mediated diseases.

CONTEXT: Localized breast lesions have been described in lupic or diabetic patients. However, the description of breast gigantomastia in women presenting with autoimmune diseases has not been reported. SETTING: The study took place within the Department of Endocrinology and Reproductive Medicine, Necker Hospital, Paris, France. PATIENTS: We describe eight patients with inflammatory gigantomastia, occurring in a context of immune-mediated diseases: myasthenia, chronic arthritis, or thyroiditis. MAIN OUTCOME MEASURES: Together with hormonal, immunological, and breast magnetic resonance imaging (MRI) evaluation, breast histology enabled us to perform immunocytochemical and indirect immunofluorescence studies. Control sera were obtained from patients with (n = 10) and without (n = 7) antinuclear antibodies. RESULTS: Six of the eight patients developed gigantomastia either at puberty or during pregnancy. Neither a hormonal oversecretion nor a specific immunological pattern was observed. All patients except one presented antinuclear antibodies. Histological study revealed a diffuse, stromal hyperplasia and a severe atrophy of the lobules. A rarefaction of adipocytes was also noted, as previously suggested on MRI. There was a perilobular lymphocytic infiltrate made of CD3+ lymphocytes. Study of sera from five of six cases of gigantomastia showed a nuclear immunofluorescence pattern in normal mammary ductal and lobular glandular epithelium, as well as in kidney and intestine epithelial cells. In control sera, a nuclear signal was observed only when antinuclear antibodies were present. CONCLUSIONS: We suggest that breast tissue may be a target tissue in autoimmune diseases, this process being favored by the hormonal milieu. However, the precise mechanism of such association is not individualized. The fact that stromal hyperplasia is the main histological feature justifies the search for the involvement of growth factors in such a process.

Adolescent↗
PubMed2005

Aspirin and non steroidal anti-inflammatory drugs hypersensitivity review (2002-2004).

According to physician, Aspirin and NSAIDS hypersensitivity are causing three major problems: how to make the diagnosis? Which treatment are to he given to these patients? What kind of anti-inflammatory drugs are to be prescribed? For these last three years, several articles regarding these matters were being published.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2003

Delayed puberty and primary amenorrhea associated with a novel mutation of the human follicle-stimulating hormone receptor: clinical, histological, and molecular studies.

Inactivating mutations of the FSH receptor have been described in rare cases of premature ovarian failure. Only one mutation was associated with a complete phenotype, including delayed puberty, primary amenorrhea, and small ovaries. We describe here a new patient presenting a similar complete phenotype of premature ovarian failure, with high plasma FSH levels associated with very low estrogen and inhibin B levels. No biological response to high doses of recombinant FSH was detected. A novel homozygous Pro(519)Thr mutation was found in this patient. This mutation is located in the second extracellular loop of the FSH receptor, within a motif highly conserved in gonadotropin and TSH receptors. The mutation totally impairs adenylate cyclase stimulation in vitro. FSH binding experiments and confocal microscopy showed that this mutation alters the cell surface targeting of the mutated receptor, which remains trapped intracellularly. Histological studies of the ovaries of the patient showed an increase in the density of small follicles compared with age-matched normal women. A complete block in follicular maturation after the primary stage was also observed. Immunocytochemical studies allowed detection of the expression of c-Kit and proliferation cellular nuclear antigen, whereas no apoptosis was shown by the 3'-end-labeling method. This observation supports the concept that in humans FSH seems mandatory for the initiation of follicular growth only after the primary stage. In our patient complete FSH resistance yields infertility, which is remarkably associated with the persistence of a high number of small follicles.

Adult↗
PubMed2001

Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype--phenotype correlation.

Mutations in FOXL2, a forkhead transcription factor gene, have recently been shown to cause blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) types I and II, a rare genetic disorder. In BPES type I a complex eyelid malformation is associated with premature ovarian failure (POF), whereas in BPES type II the eyelid defect occurs as an isolated entity. In this study, we describe the identification of novel mutations in the FOXL2 gene in BPES types I and II families, in sporadic BPES patients, and in BPES families where the type could not be established. In 67% of the patients studied, we identified a mutation in the FOXL2 gene. In total, 21 mutations (17 of which are novel) and one microdeletion were identified. Thirteen of these FOXL2 mutations are unique. In this study, we demonstrate that there is a genotype--phenotype correlation for either types of BPES by the finding that mutations predicted to result in a truncated protein either lacking or containing the forkhead domain lead to BPES type I. In contrast, duplications within or downstream of the forkhead domain, and a frameshift downstream of them, all predicted to result in an extended protein, cause BPES type II. In addition, in 30 unrelated patients with isolated POF no causal mutations were identified in FOXL2. Our study provides further evidence that FOXL2 haploinsufficiency may cause BPES types I and II by the effect of a null allele and a hypomorphic allele, respectively. Furthermore, we propose that in a fraction of the BPES patients the genetic defect does not reside within the coding region of the FOXL2 gene and may be caused by a position effect.

Alleles↗
PubMed2001

Resumption of luteinizing hormone pulsatility and hypogonadotropic hypogonadism after endoscopic ventriculocisternostomy in a hydrocephalic patient.

OBJECTIVE: To study gonadotropin pulsatility before and after surgical cure of hydrocephalus. DESIGN: Case report. SETTING: Department of Endocrinology and Centre d'Investigations Cliniques, Necker Hospital, Paris, France. PATIENT(S): A 29-year-old woman who presented with secondary amenorrhea. INTERVENTION(S): The patient underwent an endoscopic ventriculocisternostomy that led to restoration of normal menses and resolution of hypogonadism. MAIN OUTCOME MEASURE(S): A gonadotropin pulse study was performed before and 2 and 5 months after surgery. RESULT(S): No LH pulse was observed before surgery. Emergence of pulsatility was observed 2 months after surgery, and pulses became clearly individualized after 5 months. CONCLUSION(S): This observation strongly suggests that amenorrhea, in case of chronic hydrocephalus, is indeed due to a hypothalamic dysfunction of the GnRH pulse generator.

Adult↗
PubMed2001

Long-term follow-up of 246 hyperprolactinemic patients.

BACKGROUND: We wanted to evaluate the very long-term effects of bromocriptine on prolactin (PRL) levels and pituitary tumor size in a large cohort of hyperprolactinemic patients. METHODS: We conducted a retrospective cohort study in the Department of Endocrinology from Necker Hospital in Paris, France. Two hundred and forty-six patients consulted primarily for menstrual disorders, with diagnosis of hyperprolactinemia. Patients were followed-up for 99.9+/-3.6 months. One hundred and ninety-one were treated with bromocriptine, 32 underwent surgery, and 23 received no treatment. RESULTS: The mean initial plasma PRL level was 135.0+/-20.2 ng/ml. Presence of an adenoma was detected in 60% of our patients and comprised a microadenoma in 64% of cases. Compared to oligomenorrheic women, amenorrheic patients had significantly higher levels of PRL and larger pituitary tumor size. In the bromocriptine group, PRL levels decreased from 99.6+/-7.9 to 20.0+/-1.5 ng/ml (p=0.00001). The medical treatment was associated with disappearance of the adenoma in 45% of the women and with stabilization of pituitary tumor size in 40% of patients. Surgery led to disappearance of the adenoma in almost all cases, but failed to definitively cure hyperprolactinemia. CONCLUSION: In this large-scale retrospective study, the medical treatment of mild hyperprolactinemia was shown to be effective and sufficient after 9 years of follow-up.

Adenoma↗
PubMed2000

Human prolactin (hPRL) antagonists inhibit hPRL-activated signaling pathways involved in breast cancer cell proliferation.

The involvement of human prolactin (hPRL) in breast cancer has been recently reconsidered based on its autocrine/paracrine proliferative effect described in human mammary tumor epithelial cells. Therefore, there is growing interest in the development of potent hPRL antagonists that may inhibit this effect. We previously designed hPRL analogs displaying antagonistic properties in a human transcriptional bioassay. We now report that the most potent of those analogs, G129R-hPRL, antagonizes all hPRL-induced effects analysed in various breast cancer cell lines, including cell proliferation. The analog per se lacks intrinsic agonistic activity on PRL receptor-activated signaling cascades, cell proliferation and apoptosis, indicating that its mode of action only occurs through competitive inhibition of hPRL. We provide some molecular basis of this antagonistic effect by demonstrating that G129R-hPRL competitively inhibits hPRL-activation of the JAK-STAT and MAPK pathways, two signaling cascades involved in the mitogenic effect of hPRL in mammary epithelial cells. This competitive inhibition persists for at least 48 h, as evidenced by long term analysis of STAT5b activation or of progression through cell cycle. These results are the first demonstration at the molecular level that hPRL antagonists interfering with receptor dimerization disrupt signaling events in breast cancer cells, which prevents hPRL-induced cell proliferation.

Autocrine Communication↗
PubMed2000

Involvement of prolactin in breast cancer: redefining the molecular targets.

The mammary gland is the major target tissue of prolactin (PRL) in mammals. Although this pituitary hormone has been long suspected to be involved in the progression of human breast cancer, the failure of clinical improvement by treatment with dopamine agonists (which lower circulating levels of PRL) rapidly reduced the interest of oncologists concerning a potential role of PRL in the development of breast cancer. Within the last few years, however, several studies reported first, that PRL is also synthesized by mammary epithelial cells, and second that it may exert a proliferative action in an autocrine/paracrine manner. In agreement with a recent epidemiological study, these observations have led to a reconsideration of the role of PRL as an active participant in breast cancer, and are an impetus to redefine the molecular targets of anti-prolactin strategies since dopamine analogs are assumed to be inefficient on extrapituitary PRL synthesis. In this review, we briefly summarize the current knowledge of PRL effects on both normal and tumor mammary cells, and we discuss the most relevant articles supporting the autocrine-paracrine action of PRL in the breast. With the aim of defining putative new molecular targets, we propose an overview of the main PRL receptor signaling cascades known to be triggered by PRL in mammary epithelial cells or, when not available, in other cell types. Finally, because proteolytic fragments of rat PRL have been shown to inhibit the angiogenic process, which may be relevant for preventing the progression of solid tumors such as breast tumors, we discuss the hypothesis that the enzymatic cleavage of human PRL could also represent a new molecular target in the search for alternative strategies in the treatment of breast cancer.

Animals↗
PubMed2000

Lamin A/C gene: sex-determined expression of mutations in Dunnigan-type familial partial lipodystrophy and absence of coding mutations in congenital and acquired generalized lipoatrophy.

Missense mutations of the lamin A/C gene, LMNA, have been recently identified in Dunnigan-type familial partial lipodystrophy (FPLD), which belongs to a heterogeneous group of rare disorders affecting adipose tissue distribution and metabolism. In this study, we sequenced the LMNA coding region from patients presenting with FPLD or other forms of lipodystrophy. We identified two heterozygous mutations in exon 8, R482W and R482Q, in FPLD patients (six families and one individual) with various clinical presentations. In addition, we found a novel heterozygous mutation (R584H) in exon 11, encoding specifically the lamin A isoform, in a patient with typical FPLD. Clinical and biochemical investigations in FPLD patients revealed that the expression and the severity of the phenotype were markedly dependent on sex, with female patients being more markedly affected. In subjects with generalized lipoatrophy, either congenital (13 case subjects) or acquired (14 case subjects), or Barraquer-Simon syndrome (2 case subjects), the entire LMNA coding sequence was normal. Although FPLD mutations are predominantly localized in exon 8 of LMNA, the finding of a novel mutation at codon 584, together with the R582H heterozygous substitution recently described, confirms that the C-terminal region specific to the lamin A isoform is a second susceptibility region for mutations in FPLD.

Adipose Tissue↗
PubMed1999

Should prolactin be reconsidered as a therapeutic target in human breast cancer?

Although prolactin (PRL) has been long suspected to be involved in the progression of human breast cancer, the failure of clinical improvement by treatment with dopamine agonists, which lower circulating levels of PRL, rapidly reduced the interest of oncologists concerning a potential role of this pituitary hormone in the development of breast cancer. Within the last few years, however, several studies reported first, that PRL is also synthesized in the mammary gland, and second that it exerts its proliferative action in an autocrine/paracrine manner. These observations have led to a reconsideration of the role of PRL as an active participant in breast cancer and are an impetus to search for alternative strategies aimed at inhibiting the proliferative effects of PRL on tumor mammary cells. In this report, we discuss the three possible levels that can be targeted for this purpose: the mammary synthesis of PRL, the interaction of the hormone with its receptor at the surface of mammary cells, and the intracellular signaling cascades triggered by the activated receptor. For each of these steps, we discuss the molecular event(s) that can be targeted, our understanding of the mechanisms involving these putative targets as well as the tools currently available for their inhibition. Besides its proliferative effect, PRL is also involved in the control of angiogenesis through one of its cleaved fragments, named PRL 16K, which has been shown to inhibit the angiogenic process. In view of this biological activity, we discuss first the cleavage of PRL with respect to the human mammary gland and, second, the hypothesis speculating that a balance between the proliferative effect of intact PRL and the anti-angiogenic activity of its 16K-like fragments might be physiologically relevant in the evolution of mammary tumors. If true, our hypothesis would suggest that the enzymatic cleavage of PRL could represent a new molecular target in the search for alternative strategies in the treatment of breast cancer.

Breast Neoplasms↗
PubMed1999

From the molecular biology of prolactin and its receptor to the lessons learned from knockout mice models.

Prolactin (PRL), a polypeptide hormone secreted mainly by the pituitary and, to a lesser extent, by peripheral tissues, affects more physiological processes than all other pituitary hormones combined since it is involved in > 300 separate functions in vertebrates. Its main actions are related to lactation and reproduction. The initial step of PRL action is the binding to a specific membrane receptor, the PRLR, which belongs to the class 1 cytokine receptor superfamily. PRL-binding sites have been identified in a number of tissues and cell types in adult animals. Signal transduction by this receptor is mediated, at least in part, by two families of signaling molecules: Janus tyrosine kinases and signal transducers and activators of transcription (STATs). Disruption of the PRLR gene has provided a new mouse model with which to identify actions directly associated with PRL or any other PRLR ligands, such as placental lactogens. To date, several different phenotypes have been analyzed and are briefly described in this review. Coupled with the SAGE technique, this PRLR knockout model is being used to qualitatively and quantitatively evaluate the expression pattern of hepatic genes in two physiological situations: transcriptomes corresponding to livers from both wild type and PRLR KO mice are being compared, and following statistical analyses, candidate genes presenting a differential profile will be further characterized. Such a new approach will undoubtedly open future avenues of research for PRL targets. To date, no pathology linked to any mutation in the genes encoding PRL or its receptor have been identified. The development of genetic models provides new opportunities to understand how PRL can participate to the development of pathologies throughout life, as for example the initiation and progression of breast cancer.

Adult↗
PubMed1999

New natural inactivating mutations of the follicle-stimulating hormone receptor: correlations between receptor function and phenotype.

Premature ovarian failure occurs in almost 1% of women under age 40. Molecular alterations of the FSH receptor (FSHR) have recently been described. A first homozygous mutation of the FSHR was identified in Finland. More recently, we described two new mutations of the FSHR in a woman presenting a partial FSH-resistance syndrome (patient 1). We now report new molecular alterations of the FSHR in another woman (patient 2) who presented at the age of 19 with primary amenorrhea contrasting with normal pubertal development. She had high plasma FSH, and numerous ovarian follicles up to 3 mm in size were evidenced by ultrasonography. Histological and immunohistochemical examination of ovarian biopsies revealed the presence of a normal follicular development up to the antral stage and disruption at further stages. DNA sequencing showed two heterozygous mutations: Asp224Val in the extracellular domain and Leu601Val in the third extracellular loop of FSHR. Cells transfected with expression vectors encoding the wild type or the mutated Leu601Val receptors bound hormone with similar affinity, whereas binding was barely detectable with the Asp224Val mutant. Confocal microscopy showed the latter to have an impaired targeting to the cell membrane. This was confirmed by its accumulation as a mannose-rich precursor. Adenylate cyclase stimulation by FSH of the Leu601Val mutant receptor showed a 12+/-3% residual activity, whereas in patient 1 a 24+/-4% residual activity was detected for the Arg573Cys mutant receptor. These results are in keeping with the fact that estradiol and inhibin B levels were higher in patient 1 and that stimulation with recombinant FSH did not increase follicular size, estradiol, or inhibin B levels in patient 2 in contrast to what was observed for patient 1. Thus, differences in the residual activity of mutated FSHR led to differences in the clinical, biological, and histological phenotypes of the patient.

Adenylyl Cyclases↗