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Biomedical subjects

Philippe Touraine

Publications and source records attributed to Philippe Touraine.

18 recordsLinked to original sources
PubMed2006

Long-term outcome of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

AIMS: Conflicting results exist regarding bone mineral density (BMD), metabolism and reproductive function of adult patients with congenital adrenal hyperplasia (CAH). We evaluated the long-term outcome and the impact of chronic glucocorticoid replacement in these patients. METHODS: Physical characteristics, serum hormone concentrations, BMD and metabolism were studied in 45 consecutive CAH adult patients. RESULTS: Among the 36 women, only 14 (39%) had regular menses. Among the 27 women with classical CAH, the mean number of surgical reconstructions of virilized genitalia was 2.1 +/- 0.2. Twenty of them (74%) were sexually active. Three men presented with testicular adrenal rest tumors. Twenty-five patients (55%) had decreased BMD at the femoral neck and/or at the lumbar spine. BMI was correlated with the BMD T-score at the femoral neck (p < 0.001) and at the lumbar spine (p < 0.01). Hydrocortisone dose was negatively correlated with the BMD T-score at the femoral neck (p = 0.04). Subjects with osteopenia had a significantly lower BMI and received higher hydrocortisone dose than those with normal BMD. Overweight was found in 21 patients (47%). There was a significantly positive correlation between HOMA and BMI (p < 0.001), and between HOMA and 17-OHP levels (p = 0.016). CONCLUSIONS: Adult patients with CAH treated with long-term glucocorticoids are at risk for decreased BMD, increased BMI, and disturbed reproductive function.

Adrenal Hyperplasia, Congenital↗
PubMed2006

A new mechanism for prolactin processing into 16K PRL by secreted cathepsin D.

Cathepsins are lysosomal enzymes that were shown to release the antiangiogenic fragments 16K prolactin (PRL), endostatin, and angiostatin by processing precursors at acidic pH in vitro. However, the physiological relevance of these findings is questionable because the neutral pH of physiological fluids is not compatible with the acidic conditions required for the proteolytic activity of these enzymes. Here we show that cathepsin D secreted from various tissues is able to process PRL into 16K PRL outside the cell. To specifically target extracellular proteolysis, we used tissues from PRL receptor-deficient mice, which are unable to internalize PRL. As assessed by the use of specific inhibitors of proton extruders, we show that the proteolytic activity of cathepsin D requires local acid secretion driven by Na(+)/H(+) exchangers and H(+)/ATPase. Although it is usually assumed that cathepsin-mediated generation of antiangiogenic peptides occurs in the moderately acidic pericellular milieu found in malignant tumors, we propose a new mechanism explaining the extracellular activity of this acidic protease under physiological pH. Our data support the concept that secreted lysosomal enzymes could be involved in the maintenance of angiogenesis dormancy via the generation of active antiangiogenic peptides in nonpathological contexts.

Animals↗
PubMed2006

[Vascular Ehlers-Danlos syndrome].

The vascular type of Ehlers-Danlos syndrome (EDS) is a rare genetic disease transmitted as an autosomal dominant trait. It is distinguished from other forms of EDS by its unstable acrogeric morphotype and by vascular, gastrointestinal, and obstetrical complications. Diagnosis is based on various clinical signs, noninvasive imaging, and on the identification of a mutation of the COL3A1 gene, which provides diagnostic certainty but has a sensitivity of only 61%. When two major diagnostic criteria are present, a genetic test should be proposed, performed and its result presented in a multidisciplinary group. The precautionary principle requires that preventive measures be implemented when the diagnosis is suspected. All artery puncture, surgery, and gastrointestinal and uterine endoscopy are contraindicated, permissible only in life-threatening emergencies. Straining against a closed glottis and all other situations or drugs likely to raise blood pressure must be avoided. Contraception must be discussed to avoid pregnancy during the diagnostic period. Arterial lesions suggestive of the disease include dissecting aneurysms of the internal carotid and iliac arteries and of the anterior visceral branches of the abdominal aorta, fusiform aneurysms of the splenic artery, and early onset nontraumatic direct carotid-cavernous fistulae. Early-onset varicose veins, spontaneous peritonitis or unusually important perineal lesions after giving birth should also attract the physician's attention. Psychological treatment and support of patients and their families is essential, to help them both to live with their disease and to deal with the information and screening issues. The prognosis of Ehlers-Danlos syndrome, vascular type, is grim but there is wide interindividual variability and life expectancy is best among patients receiving regular follow-up. Management by an experienced multidisciplinary team, implementation of drastic prevention measures and, depending on the results of the BBEST study, the possible prescription of beta-blockers should help to reduce the risk of complications and justify hope for a real improvement in prognosis in the near future.

Adult↗
PubMed2006

Drug Insight: prolactin-receptor antagonists, a novel approach to treatment of unresolved systemic and local hyperprolactinemia?

Prolactin is a polypeptide hormone whose major biological actions are related to normal lactation and reproduction. Abnormally high prolactin levels, referred to as hyperprolactinemia, can result in various reproductive disorders. Currently, therapeutic management of hyperprolactinemia relies on dopamine agonists, since dopamine is the primary physiological suppressor of pituitary prolactin production. Epidemiologic studies have shown that prolactin levels in the high-normal range, as well as medications that interfere with dopamine action (e.g. certain antipsychotic drugs), might correlate with increased breast cancer risk. In addition to circulating prolactin, it is now well established that prolactin is also produced locally within various tissues, including breast and prostate. Increasing evidence, mainly from animal studies at present, suggests that excess locally produced prolactin may promote the growth of breast and prostate tumors via an autocrine or paracrine mechanism. These findings have renewed the interest in finding alternative strategies to suppress prolactin actions when dopamine agonists are ineffective. Our studies of the relationship between prolactin structure and function have resulted in the development of pure prolactin-receptor antagonists. These molecules prevent endogenous prolactin from exerting its actions via a competitive mechanism for receptor binding. In this review, we discuss the possible future therapeutic utility of this novel class of compounds.

Animals↗
PubMed2006

Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure.

BACKGROUND AND OBJECTIVE: Mutations in bone morphogenic protein 15 (BMP15) and growth/differentiation factor 9 (GDF9) lead to altered fertility in animal models. In the human, a heterozygous point mutation of BMP15 has been associated with premature ovarian failure (POF). SUBJECT AND METHODS: We have directly sequenced both genes in a cohort of 203 POF patients presenting with primary or secondary amenorrhea and high FSH levels and in a control population including 54 women with regular menstrual cycles who had at least one child. RESULTS: We have identified several heterozygous variants. One alteration in GDF9 (S186Y) and one in BMP15 (L148P) may have pathogenic effects as both positions are conserved in vertebrate species, ranging from the chicken to mammals. These variants were absent in the control samples. We also found synonymous and neutral substitutions. CONCLUSIONS: We propose that although mutations in BMP15 and GDF9 are not a major cause of ovarian insufficiency, they may be involved in POF.

Adult↗
PubMed2006

Local over-expression of prolactin in differentiating mouse mammary gland induces functional defects and benign lesions, but no carcinoma.

Experimental, clinical, and epidemiological data support the growth-promoting role of endocrine prolactin (PRL) in mammary tumors. PRL is also produced by the breast, where it is now recognized to act as a growth/survival factor via autocrine/paracrine mechanisms. Recent transgenic (Tg) mouse models have revealed the pro-oncogenic effect of PRL over-expression in virgin mammary glands. To address the question whether PRL tumorigenicity was maintained on differentiated mammary glands, we generated mammary-specific Tg mice expressing human (h)PRL under the control of the milk whey acidic protein promoter, which directs autocrine hPRL over-expression in late gestation throughout lactation. Minimal levels of transgene expression were detected in the mammary glands of virgin animals, which at best induced partial ductal branching and lobulo-alveolar structures in older nulliparous females. As expected, expression of mammary hPRL dramatically increased at the end of first pregnancy, and from this point it never returned to baseline, although it peaked at each gestation/lactation cycle. Over-expression of hPRL that starts when the gland is already well into the differentiation process led to various morphological mammary alterations, including abnormally differentiated epithelium, atropy of the myoepithelial layer, dilated ducts, cysts, and lymphocytic infiltrates. These phenotypes tended to worsen with successive pregnancies, also reflecting cumulative damage of failure of involution. Although some older, multiparous females developed benign tumors (papillomas and metaplasias), none of the animals studied developed mammary carcinomas. In addition, we noticed that half of the Tg females exhibited lactation defects, leading to significantly increased pup mortality. This phenotype was due neither to failure of milk production nor to modification of its protein content, but rather it was correlated to lipid enrichment of the milk, which, in combination with profoundly altered morphology of the gland, led to impaired milk extrusion through the nipple. In summary, these data show that over-expression of autocrine hPRL in a differentiating mammary gland induces dramatic functional and morphological defects, but not carcinoma. This deserves further investigations on the emerging concept that autocrine PRL may have different effects on pathological development of the mammary gland depending on the differentiation state of the latter.

Animals↗
PubMed2005

[When and how should hyperprolactinemia be treated?].

Hyperprolactinemia affects the gonadotropic axis. Its results in women include amenorrhea, menstrual disorders and galactorrhea; in men, the frequency of macroadenomas tends to lead to problems related to sexual performance or tumor volume. Radioimmunoassays make diagnosis easy. Secondary causes of hyperprolactinemia, drug reactions in particular, must be ruled out before MRI exploration to look for a pituitary tumor. First-line treatment of prolactin adenomas is based on the use of dopaminergic agonists, especially cabergoline, because of their excellent efficacy and the risk of relapse following surgery. For patients who wish to become pregnant, the dopaminergic agonist must be continued during pregnancy for those with macroadenoma and withdrawn for women with microadenoma. When hyperprolactinemia is induced by anti-psychotic agents, treatment requires an in-depth assessment.

Dopamine Agonists↗
PubMed2005

Development and potential clinical uses of human prolactin receptor antagonists.

There is a large body of literature showing that prolactin (PRL) exerts growth-promoting activities in breast cancer, and possibly in prostate cancer and prostate hyperplasia. In addition, increasing evidence argues for the involvement of locally produced (autocrine) PRL, perhaps even more than pituitary-secreted (endocrine) PRL, in tumor growth. Because dopamine analogs are unable to inhibit PRL production in extrapituitary sites, alternative strategies need investigation. To that end, several PRL receptor antagonists have been developed by introducing various mutations into its natural ligands. For all but one of these analogs, the mechanism of action involves a competition with endogenous PRL for receptor binding. Such compounds are thus candidates to counteract the undesired actions of PRL, not only in tumors, but also in dopamine-resistant prolactinomas. In this review, we describe the different versions of antagonists that have been developed, with emphasis on the controversies regarding their characterization, and the limits for their potential development as a drug. The most recently developed antagonist, Delta1-9-G129R-hPRL, is the only one that is totally devoid of residual agonistic activity, meaning it acts as pure antagonist. We discuss to what extent this new molecule could be considered as a lead compound for inhibiting the actions of human PRL in the above-mentioned diseases. We also speculate on the multiple questions that could be addressed with respect to the therapeutic use of PRL receptor antagonists in patients.

Animals↗
PubMed2005

Ovarian steroidogenesis and serum androgen levels in patients with premature ovarian failure.

Women with premature ovarian failure (POF) have been reported to have lower serum androgen levels compared with normal women. We reviewed the androgen profiles of 143 POF patients and found androgen levels above normal for postmenopausal women in 16% of these subjects. To determine the source of androgens in those women, we studied the available ovarian biopsy samples of 15 POF patients with increased androgen levels using immunohistochemistry, with a panel of antibodies directed against the main steroidogenic enzymes. Five of the ovarian biopsies exhibited abnormal follicles characterized by hypertrophied theca interna expressing steroidogenic enzymes involved in androgen synthesis. In five other biopsies, the steroidogenic activity was scarce and confined to a small number of ovarian stromal cells, sometimes situated in the proximity of follicular remnants. Finally, in five patients, we found no histological evidence of present or past follicular development beyond the quiescent follicular stage, and no steroidogenic cells were detected by immunohistochemistry. Our findings suggest that ovarian theca-derived cells are a source of androgens in some women with POF, whereas in others, as in most postmenopausal patients, the adrenals or the ovarian hilus cells may synthesize a significant quantity of androgens under LH stimulation.

Adolescent↗
PubMed2005

Benign breast diseases.

Benign breast diseases have always been neglected in comparison to cancer, despite the fact that there are many more patients with such diseases than patients presenting to a breast clinic for cancer. Like normal breast tissues, benign breast diseases are under a complex system of controls by both systemic hormonal and local factors. In this review, we attempt to present an overview of the latest knowledge concerning the epidemiology, classification, clinical presentation, management, and physiopathology of these disorders.

Adolescent↗
PubMed2004

Cathepsin D processes human prolactin into multiple 16K-like N-terminal fragments: study of their antiangiogenic properties and physiological relevance.

16K prolactin (PRL) is the name given to the 16-kDa N-terminal fragment obtained by proteolysis of rat PRL by tissue extracts or cell lysates, in which cathepsin D was identified as the candidate protease. Based on its antiangiogenic activity, 16K PRL is potentially a physiological inhibitor of tumor growth. Full-length human PRL (hPRL) was reported to be resistant to cathepsin D, suggesting that antiangiogenic 16K PRL may be physiologically irrelevant in humans. In this study, we show that hPRL can be cleaved by cathepsin D or mammary cell extracts under the same conditions as described earlier for rat PRL, although with lower efficiency. In contrast to the rat hormone, hPRL proteolysis generates three 16K-like fragments, which were identified by N-terminal sequencing and mass spectrometry as corresponding to amino acids 1-132 (15 kDa), 1-147 (16.5 kDa), and 1-150 (17 kDa). Biochemical and mutagenetic studies showed that the species-specific digestion pattern is due to subtle differences in primary and tertiary structures of rat and human hormones. The antiangiogenic activity of N-terminal hPRL fragments was assessed by the inhibition of growth factor-induced thymidine uptake and MAPK activation in bovine umbilical endothelial cells. Finally, an N-terminal hPRL fragment comigrating with the proteolytic 17-kDa fragment was identified in human pituitary adenomas, suggesting that the physiological relevance of antiangiogenic N-terminal hPRL fragments needs to be reevaluated in humans.

Amino Acid Sequence↗
PubMed2004

Hyperandrogenism in a postmenopausal woman presenting with a metastatic ileum endocrine tumor.

OBJECTIVE: To elucidate the mechanism of the hyperandrogenism found in a postmenopausal woman presenting an ileum endocrine tumor with ovarian metastases. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A postmenopausal woman was referred for hirsutism. Basal plasma testosterone was high, 6.6 nM/L (normal, <or=0.7 nM/L). Pelvic magnetic resonance imaging revealed a 6-cm left ovarian mass. INTERVENTION(S): Bilateral salpingo-oophorectomy was performed. Pathological examination found a bilateral metastatic endocrine ovarian tumor, associated with a functional stroma. A primary ileum endocrine tumor was discovered and resected. MAIN OUTCOME MEASURE(S): Immunohistochemical study of the expression of steroidogenic enzymes and beta and alpha subunits of hCG. RESULT(S): Immunohistochemical expression of steroidogenic enzymes was found in the ovarian stromal tissue surrounding the tumor but not in the metastatic tumoral cells. A substantial percentage of the metastatic tumoral cells was immunopositive for the beta and alpha subunit of hCG but not the ileal cells. CONCLUSION(S): These data suggest an hCG paracrine effect of the ovarian metastases tumor on the adjacent interstitial cells, resulting in the virilization of the patient.

Cholesterol Side-Chain Cleavage Enzyme↗
PubMed2004

Pegvisomant Pfizer/Sensus.

Pfizer (formerly Pharmacia), in collaboration with its wholly owned subsidiary Sensus, has developed and launched pegvisomant, a pegylated, genetically modified human growth hormone (hGH), for the treatment of acromegaly. Pegvisomant, in contrast to classical somatostatin analogs which lower hGH synthesis, exerts its anti-hGH action by preventing GH receptor activation. This drug is now available in the US and Europe for the treatment of acromegaly.

Acromegaly↗
PubMed2003

X chromosome-linked Kallmann syndrome: clinical heterogeneity in three siblings carrying an intragenic deletion of the KAL-1 gene.

Kallmann syndrome (KS) is characterized by the association of hypogonadotropic hypogonadism and anosmia. The gene underlying the X chromosome-linked form of the disease, KAL-1, consists of 14 coding exons. It encodes a glycoprotein, anosmin-1, which is involved in the embryonic migration of GnRH-synthesizing neurons and the differentiation of the olfactory bulbs. We describe herein the clinical heterogeneity in three affected brothers who carry a large deletion (exons 3-13) in KAL-1. All three had a history of hypogonadotropic hypogonadism with delayed puberty. Although brain magnetic resonance imaging showed hypoplastic olfactory bulbs in the three siblings, variable degrees of anosmia/hyposmia were shown by olfactometry. In addition, these brothers had different phenotypic anomalies, i.e. unilateral renal aplasia (siblings B and C), high-arched palate (sibling A), brachymetacarpia (sibling A), mirror movements (siblings A and B), and abnormal eye movements (sibling C). Last but not least, sibling A suffered from a severe congenital hearing impairment, a feature that had been reported in KS but had not yet been ascribed unambiguously to the X-linked form of the disease. The variable phenotype, both qualitatively and quantitatively, in this family further emphasizes the role of putative modifier genes, and/or epigenetic factors, in the expressivity of the X-linked KS.

Adolescent↗
PubMed2003

[SERMs and uterus].

The uterus is one of the target organs of sexual steroids synthesized in the ovary. Estrogen is known to stimulate cell proliferation in the endometrium while progesterone has an anti-estrogenic secretory effect on this tissue. Renewed interest in the action of new anti-estrogenic agents on the uterus has arisen over the last decade, but not simply in order to achieve new therapeutic strategies for the prevention or cure of uterine tumors. New compounds were developed for their action on other tissues such as the breast, but it rapidly became clear that they were a source of uterine disease. A clear example is tamoxifen which has a powerful anti-estrogenic effect on breast tissue. It was hoped however that this compound, which behaves either like an antagonist or an agonist, depending on the target tissue, could have an anti-estrogenic effect on the uterus and on the contrary an agonistic estrogenic protective effect on bony and vascular tissue. This approach progressively led to the development of SERMs (Selective Estrogen Receptor Modulators), non-steroidal compounds modulating the action of estrogens. The first member of this new pharmaceutical class was raloxifen, marketed in France under the brand name Evista, which has an estrogenic effect on vertebral bone, warranting its authorization for use in patients with vertebral osteoporosis with or without fracture. Raloxifen thus has a beneficial estrogenic effect, at least on trabecular bone, and an anti-estrogenic effect on the uterus and breast. The goal today is to continue the development of new compounds in the SERM family with well targeted, and well understood, agonistic and/or antagonistic actions on different body tissues.

Estrogen Antagonists↗
PubMed2002

Prolactin: the new biology of an old hormone.

Prolactin (PRL) is a paradoxical hormone. Historically known as the pituitary hormone of lactation, it has had attributed to it more than 300 separate actions, which can be correlated to the quasi-ubiquitous distribution of its receptor. Meanwhile, PRL-related knockout models have mainly highlighted its irreplaceable role in functions of lactation and reproduction, which suggests that most of its other reported target tissues are presumably modulated by, rather than strictly dependent on, PRL. The multiplicity of PRL actions in animals is in direct opposition to the paucity of arguments that suggest its involvement in human pathophysiology other than effects on reproduction. Although many experimental data argue for a role of PRL in the progression of some tumors, such as breast and prostate cancers, drugs lowering circulating PRL levels are ineffective. This observation opens new avenues for research into the understanding of whether local production of PRL is involved in tumor growth and, if so, how extrapituitary PRL synthesis is regulated. Finally, the physiological relevance of PRL variants, such as the antiangiogenic 16K-like PRL fragments, needs to be elucidated. This review is aimed at critically discussing how these recent findings have renewed the manner in which PRL should be considered as a multifunctional hormone.

Animals↗
PubMed2002

Pegvisomant. Pharmacia.

Pegvisomant, a polyethylene glycol (PEG) derivative of human growth hormone (GH) that acts as a highly selective GH receptor antagonist, is under development by Pharmacia (formerly Sensus) as a potential treatment for acromegaly. By February 2001, Sensus had submitted an NDA for the treatment of acromegaly, and an approvable letter indicating outstanding issues had been received by July 2001. Pegvisomant was granted Orphan Drug status by the FDA and was designated for Priority Review. Pegvisomant also received Orphan Drug designation in the EU and Japan. In March 2001, additional regulatory filings were being planned for later in 2001. In October 2001, Pharmacia was preparing an NDA in Japan for the treatment of acromegaly. By September 1998, phase 1 trials of the treatment were underway for diabetic retinopathy, and were planned for diabetic nephropathy in 1999. By September 1997, a phase II trial to test the effects of pegvisonant an insulin sensitivity and secretion in type II diabetes patients was underway. However, no development has been reported for these indications since the dates given. By 1994, Sensus had licensed technology for development of GH receptor antagonists from Genentech and Ohio University. Sensus was to pay Genentech, and Genentech was to receive equity in Sensus and royalties from the commercialization of any product resulting from the agreement. In April 2000, the company entered into a licensing agreement with Shearwater Polymers for the PEGylation of pegvisomant using Shearwater's proprietary technology, which is now used to produce the 20-kDa PEG-derivative of pegvisomant. In June 1999, Pharmacia Corp (formerly Pharmacia & Upjohn) signed an agreement to purchase 19.9% of Sensus and to potentially acquire the remainder of the company at a later date. In March 2001, Pharmacia completed its purchase of Sensus. Analysts at Merrill Lynch predicted in February 2002 that the product would be launched in 2003, with US revenues of $20 million, rising to $115 million in 2006.

Animals↗