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Biomedical subjects

S Christin-Maitre

Publications and source records attributed to S Christin-Maitre.

At least 19 recordsLinked to original sources
PubMed2003

A comparative randomized multicentric study comparing the step-up versus step-down protocol in polycystic ovary syndrome.

BACKGROUND: The aim of the study was to evaluate follicular development and ovulation comparing the low-dose step-up and the step-down protocols, in women with clomiphene citrate (CC)-resistant polycystic ovaries. METHODS: Eighty-three women were randomized, and treated with recombinant (r) FSH (Puregon) using either the step-up (n=44) or step-down (n=39) protocol. They were followed up for three cycles unless pregnancy occurred. RESULTS: Monofollicular development occurred in 68.2% of the 85 cycles in the step-up group, as compared with 32% of the 72 cycles in the step-down group (P<0.0001). Hyperstimulation was statistically less frequent using the step-up procedure (4.7 versus 36%, P<0.0001). Both protocols used the same number of FSH units per cycle (951+/-586 versus 967+/-458 in step-up and step-down respectively, P=not significant). However, the duration of ovarian stimulation was statistically different (15.2+/-7.0 days in step-up versus 9.7+/-3.1 in step-down, P<0.001). Ovulation was observed in 70.3% of the cycles using the step-up procedure as compared with 51.3% using the step-down procedure (P<0.01). The cumulative rate of clinical gestations during the study did not differ between the two groups (38.6% in the step-up versus 30.8% in the step-down procedure). CONCLUSIONS: The step-up protocol using rFSH (Puregon), is more efficient in obtaining a monofollicular development and ovulation than the step-down protocol, in women with CC-resistant polycystic ovaries. Although the duration of stimulation is longer, the rate of ovarian hyperstimulation is much lower using the step-up protocol.

Adult↗
PubMed2003

A new clinical condition linked to a novel mutation in lamins A and C with generalized lipoatrophy, insulin-resistant diabetes, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy.

A-Type lamins, arising from the LMNA gene, are intermediate filaments proteins that belong to the lamina, a ubiquitous nuclear network. Naturally occurring mutations in these proteins have been shown to be responsible for several distinct diseases that display skeletal and/or cardiac muscle or peripheral nerve involvement. These include familial partial lipodystrophy of the Dunnigan type and the mandibuloacral dysplasia syndrome. The pathophysiology of this group of diseases, often referred to as laminopathies, remains elusive. We report a new condition in a 30-yr-old man exhibiting a previously undescribed heterozygous R133L LMNA mutation. His phenotype associated generalized acquired lipoatrophy with insulin-resistant diabetes, hypertriglyceridemia, hepatic steatosis, hypertrophic cardiomyopathy with valvular involvement, and disseminated whitish papules. Immunofluorescence microscopic analysis of the patient's cultured skin fibroblasts revealed nuclear disorganization and abnormal distribution of A-type lamins, similar to that observed in patients harboring other LMNA mutations. This observation broadens the clinical spectrum of laminopathies, pointing out the clinical variability of lipodystrophy and the unreported possibility of hypertrophic cardiomyopathy and skin involvement. It emphasizes the fact that the diagnosis of genetic alterations in A-type lamins requires careful and complete clinical and morphological investigations in patients regardless of the presenting signs.

Adult↗
PubMed2002

Mixed ductal-pancreatic polypeptide-cell carcinoma of the pancreas.

AIMS: Mixed ductal-endocrine carcinomas of the pancreas are rare tumours with 10 cases reported in the English literature. We report the first case with a polypeptide-cell component. METHODS AND RESULTS: : The tumour was fortuitously discovered in a 72-year-old woman during the exploration of an endometrial adenocarcinoma. It measured 100 mm and was located in the tail of the pancreas. On microscopic examination two intermingled endocrine and exocrine components were present. The endocrine component consisted of trabeculae and solid nests composed of cells immunoreactive for chromogranin A, synaptophysin and pancreatic polypeptide, but negative for p53 and Bcl-2 proteins. The exocrine component was composed of tubules lined by atypical cylindrical cells immunoreactive for CK19, CEA, p53 and Bcl-2. The stroma of the endocrine component contained amyloid deposits. CONCLUSION: Mixed ductal-endocrine carcinomas of the pancreas are often described in middle-aged patients. The tumours are usually large and located in the head of the pancreas. An endocrine syndrome is rare and the prognosis is often unfavourable. We report the first case of mixed endocrine-exocrine carcinoma of the pancreas with a pancreatic polypeptide-cell component. The histogenesis of mixed carcinoma of the pancreas is still uncertain but the over-expression of p53 and Bcl-2 could play a major role in the neoplastic progression of the ductal component.

Adenocarcinoma↗
PubMed2000

Bioassays of gonadotropins.

Bioassays constitute a unique approach to determine the functional aspects of gonadotropins. Indeed, these highly complex glycoprotein hormones, including pituitary lutropin (LH) and follitropin (FSH), are heterogeneous in terms of both peptidic and carbohydrate moieties, and, as a consequence, the bioactivity of the different molecular forms often does not match their immunoreactivity. In this article, we review the different types of LH and FSH bioassays. Conventional methods for measuring FSH bioactivity are first described and include the in vivo Steelman and Pohley bioassay, the radioligand receptor assays (RRAs), the in vitro Sertoli cell bioassay, the in vitro granulosa cell bioassay, and the inhibin immunoassay. Recent methods based on cell lines transfected with cloned receptors, particularly the human FSH receptor, are then described. Methods for developing these assays are presented, and the advantages and disadvantages of the different bioassays are discussed.

Animals↗
PubMed2000

A novel mutation in DAX1 causes delayed-onset adrenal insufficiency and incomplete hypogonadotropic hypogonadism.

Mutations in the DAX1 gene cause X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HHG). In affected boys, primary adrenal insufficiency occurs soon after birth or during early childhood; HHG is recognized at the expected time of puberty. In this report, we describe the novel phenotype of a man who presented with apparently isolated adrenal insufficiency at 28 years of age. Examination revealed partial pubertal development and undiagnosed incomplete HHG. Gonadotropin therapy did not improve his marked oligospermia, suggesting a concomitant primary testicular abnormality. Genomic analysis revealed a novel missense mutation, I439S, in DAX1. The mutant DAX-1 protein was studied for its ability to function as a transcriptional repressor of target genes. Consistent with the patient's mild clinical phenotype, the I439S mutation conferred intermediate levels of repressor activity of DAX-1 when compared with mutations associated with classic AHC. This unique case extends the clinical spectrum of AHC to include delayed-onset primary adrenal insufficiency in adulthood and milder forms of HHG. Furthermore, in accordance with findings in Ahch (Dax1) knockout mice, the clinical features in this patient suggest that DAX-1 function is required for spermatogenesis in humans, independent of its known effects on gonadotropin production.

Adrenal Glands↗
PubMed2000

Effect of gonadotrophin-releasing hormone (GnRH) antagonist during the LH surge in normal women and during controlled ovarian hyperstimulation.

OBJECTIVE: Several studies have suggested that GnRH is instrumental in triggering the LH surge. The present studies were performed to evaluate the effect of GnRH antagonist administration in women after the beginning of the LH surge. DESIGN: In study one, six normal cycling women were given a GnRH antagonist (20 mg Nal Glu s.c.) during an unstimulated cycle. Nal-Glu was administered when the LH level was higher than 10 U/l and associated with an oestradiol (E2) level higher than 730 pmol/l. In study two, a GnRH antagonist (3 mg Cetrorelix, ASTA-Medica, Frankfurt, Germany) was administered on day 8 of an IVF-ET cycle, in 157 women. Eighteen women among this cohort received the antagonist, when their LH level was higher than 10 U/l. RESULTS: In normal volunteers (study one), Nal-Glu was administered on day 13.7 +/- 1.4 (mean +/- SD) of the cycle when the LH level was 13.7 +/- 3.5 U/l with an E2 plasma level reaching 980 +/- 131 pmol/l. Twenty-four hours after administration of the antagonist, the LH surge had been interrupted in all subjects; it was postponed in three of the women, and abolished in the remaining three. LH levels fell by 68.5%, E2 by 42% and FSH by 53.2%. In study two, LH plasma levels 24 h after the antagonist administration fell by 94%. No premature ovulation occurred in any of the patients treated. Administering the antagonist before (n = 139) or during the LH surge (n = 18) made no statistically significant difference to the results of the IVF-ET attempt. CONCLUSIONS: Our results indicate that GnRH is required throughout the gonadotrophin surge in women, not only for the initiation but also for the maintenance of the LH surge. In addition, in our study, the suppression of the rise in LH, when the antagonist was given during the surge, had no detrimental impact on IVF-ET outcome. This suggests, if confirmed on a larger scale, that late follicular phase GnRH antagonist administration to prevent the LH surge in controlled ovarian hyperstimulation (COH) is a safe and useful treatment.

Adult↗
PubMed1999

[Premature ovarian insufficiency].

Premature ovarian failure is defined as amenorrhea with hypo-oestrogenism and elevated gonadotrophins occurring before the age of 40 years. In theory, ovarian failure may occur because of a decreased pool of primordial follicles, because ovarian apoptosis is increased or accelerated or because the follicle maturation is interrupted before the preovulatory stage. The mechanisms inducing premature ovarian failure have been described in a few number of cases. Atm or c-kit gene mutations induce a very low pool of primordial follicles. In chromosome X abnormalities, chemotherapy, galactosemia and blepharophimosis syndrome apoptosis is increased. Follicle maturation is interrupted in FSH and LH receptor mutations or in autoimmunity. However, in most cases, the etiology remains idiopathic. A better knowledge in genes involved in ovarian apoptosis should enhance our understanding of premature ovarian failure. Meanwhile, the best treatment is to give hormonal replacement therapy and send the patient to oocyte donation program when they desire to be pregnant.

Adult↗
PubMed1999

Main inhibitor of follicle stimulating hormone in the luteal-follicular transition: inhibin A, oestradiol, or inhibin B?

The roles of oestradiol, inhibin A and inhibin B in the luteal-follicular transition were assessed by means of specific assays. Six premenopausal women were studied during a control and then a cycle treated with percutaneous oestradiol 0.1 mg/day from day 10 after the luteinizing hormone (LH) surge until day 4 of the following cycle. Inhibin A concentrations decreased similarly in control and treated cycles from day -5 to day 2, then increased in control cycle to 23.3 +/- 3.4 pg/ml on day 10 (mean +/- SEM). They remained low until day 5 in treated cycles and were lower than controls on day 10 (P < 0.01). Follicle stimulating hormone (FSH) concentrations increased on day 1 in controls and on day 5 in treated cycles when oestradiol concentration fell abruptly. Inhibin B concentrations remained low until day 1 in controls and day 4 in treated cycles. In both, inhibin B concentrations increased 1 day after FSH, peaking at 160 pg/ml. FSH concentrations began to plateau when inhibin B concentrations were >100 pg/ml and oestradiol concentrations below 200 pmol/l. These data suggest that inhibin A is not responsible for FSH suppression in the luteal phase and that the negative control of FSH shifts from oestradiol in the luteal phase to inhibin B in the mid-follicular phase.

Adult↗
PubMed1999

Resistance of hypogonadic patients with mutated GnRH receptor genes to pulsatile GnRH administration.

We have studied a kindred with three siblings with isolated hypogonadotropic hypogonadism caused by compound heterozygote mutations in the GnRH receptor gene. The disorder was transmitted as an autosomal recessive trait. The R262Q mutation in intracellular loop 3 of the receptor was associated with a mutation in the third transmembrane domain of the receptor, A129D, that has never been described before. This A129D mutation results in a complete loss of function, indicated by the lack of inositol triphosphate (TP3) 3 production by transfected Chinese hamster ovary (CHO) cells after GnRH stimulation. The two brothers had microphallus and bilateral cryptorchidism and were referred for lack of puberty, whereas their sister had primary amenorrhea and a complete lack of puberty. Their basal gonadotropin concentrations were below the reference range, and their endogenous LH secretory patterns were abnormal, with a low-normal frequency of small pulses or no apparent LH pulse. Pulsatile GnRH administration (10 microg/pulse every 90 min for 40 h) resulted in increased mean LH without any significant changes in testosterone levels in the two brothers, whereas the LH secretory profile of their sister remained apulsatile. Larger pulses of exogenous GnRH (20 microg every 90 min for 24 h) caused the sister to produce recognizable low amplitude LH pulses. The concentrations of free alpha-subunit significantly increased in all patients during the pulsatile GnRH administration. Thus, these hypogonadal patients are partially resistant to pulsatile GnRH administration, suggesting that they should be treated with gonadotropins to induce spermatogenesis or ovulation rather than with pulsatile GnRH.

Adolescent↗
PubMed1999

[Genes and ovarian insufficiency].

Premature ovarian failure is defined as hypoestrogenism with elevated gonadotropins, occurring before the age of 40. The prevalence of this syndrome is 3% of the women population. In most cases its etiology remains unknown. In theory, ovarian failure may occur by the following mechanisms: the pool of primordial follicule is too low; the atresia ou apoptosis is increased in the ovarian follicle; the follicle maturation is interrupted. In the past few years, several genes have been implicated in the pathogenesis of human or murine premature ovarian failure. Those genes can be classified according to the potential mechanisms previously described. Atm and c-kit gene code for proteins involved in maintaining the pool of primordial follicles. Genes located on the X chromosome, genes involved in blepharophimosis, in galactosemia code for proteins involved in follicular atresia. The gonadotropins, their receptors, GDF9 and connexin 37 are involved in follicle maturation. A better understanding of the family of genes involved in oocyte and follicular atresia should allow a better understanding of premature ovarian failure. Up to now, the better care for those patients is to give them hormonal replacement therapy and suggest oocyte donation when they desire to be pregnant.

Adult↗
PubMed1998

Genes and premature ovarian failure.

Premature ovarian failure (POF) is an heterogeneous syndrome. Among genetic causes, X monosomy as in Turner syndrome or X deletions and translocations are known to be responsible for POF. The genes involved in ovarian function, located on the X chromosome are still unknown. On the other hand, autosomal abnormalities have been identified in POF patients such as mutations of the FSH gene, the LH and FSH receptor genes, chromosome 3q containing the blepharophimosis gene, the ATM gene (Ataxia-telangiectasia gene). Mutations in the AIRE gene (responsible for APECED syndrome) can involve ovarian insufficiency. It is likely that studies on the function of the protein AIRE might improve our knowledge on follicular development. Furthermore, different mouse models of ovarian failure such as mouse lacking connexins or mice lacking GDF9 (growth derived factor 9), might increase our knowledge of ovarian failure. In the future, a better knowledge of the cellular and biochemical components involved in folliculogenesis and apoptosis should elucidate the mechanisms of POF.

Animals↗
PubMed1998

The GnRH receptor gene is preferentially expressed in functioning gonadotroph adenomas and displays a Mae III polymorphism site.

OBJECTIVE: Given the central role of the GnRH receptor (GnRHR) in the regulation of the gonadotrophin secretion, it might be implicated directly or indirectly in the pathogenesis of gonadotroph tumours. DESIGN: We determined if GnRHR mRNA was expressed in gonadotroph tumours using RT-PCR and analysed the GnRHR gene for the presence of mutations in its coding region, using direct sequencing of PCR products. Results were analysed according to the pattern of expression of alpha, beta-FSH and beta-LH subunit (SU) genes. SUBJECTS: RNA was extracted from 20 gonadotroph tumours identified by immunohistochemistry (> 10% of stained cells): 9 adenomas were functioning (high serum gonadotrophin levels), 3 were associated with high alpha-SU levels and 8 were nonfunctioning. Genomic DNA was extracted from 64 normal subjects. RESULTS: We found GnRHR mRNA in 12 tumours (60%): 8/9 functioning (88%), 1/3 alpha-secreting (33%) and 3/8 nonfunctioning (37.5%) gonadotroph adenomas. There was a significant association between GnRHR expression and immunostaining for beta-FSH (P = 0.014). The nucleotide sequence of the amplified products was identical to that of human pituitary except for the presence, in 3 functioning adenomas, of a silent C to T transition at nucleotide 453 encoding for the serine residue situated in the second intracellular loop at position 151. Heterozygosity provided evidence that both alleles were transcribed in these tumours. This substitution creates a Mae III restriction site. Genomic DNA from normal subjects were then tested for the presence of this new polymorphism. The frequency of the heterozygosity (18.7%) was not significantly different from that found in gonadotroph tumours (25%) and this new Mae III polymorphism site cannot be used as a tumoural marker. CONCLUSION: The GnRHR gene is preferentially expressed in functioning rather than in nonfunctioning gonadotroph adenomas, but no mutations altering the coding region of the gene were found to further substantiate its role in the pathogenesis of gonadotroph tumours.

Adenoma↗
PubMed1998

A spontaneous and severe hyperstimulation of the ovaries revealing a gonadotroph adenoma.

We report an unusual case of a gonadotroph adenoma in a 34-yr-old woman, revealed by a dramatic rise in the plasma estradiol (E2) concentration (26,800 pmol/L; normal, <370), with nonsuppressed FSH and LH levels (4.9 and 2.4 mIU/mL, respectively). The PRL level was 503 ng/mL. The testosterone and progesterone levels were 7 and 17 nmol/L, respectively. The levels of inhibin alpha, inhibin A, and inhibin B were increased compared to normal values in both the follicular (fp) and luteal (lp) phases of the menstrual cycle [inhibin alpha, 1986 IU/L (fp normal, <700; lp normal, <1650); inhibin A, 254 pg/mL (fp normal, <20; lp normal, <120); inhibin B, 246 pg/mL (fp normal, <150; lp normal, <30 lp)]. Pituitary magnetic resonance imaging revealed a huge pituitary adenoma. After transphenoidal surgery, the patient presented with pituitary insufficiency and diabetes insipidus. RT-PCR of the tumor tissue was positive for LHbeta, FSHbeta, alpha-subunit, and PRL. This case is of particular interest because 1) although the E2 level was extremely high, the patient did not present with ascitis, suggesting that chronic elevated E2 does not play a crucial role in the hyperstimulation symptoms; 2) the extreme rise in E2 was related to the cosecretion of FSH and LH, confirming the two-cell two-gonadotropin theory; and 3) the rise in inhibin B is associated with FSH secretion, whereas the rise in inhibin A is probably due to luteinization.

Adenoma↗