Context: Premature ovarian insufficiency (POI) may be secondary to chemotherapy, radiotherapy, or environmental factors. Genetic causes are identified in 20-25% of cases, but most POI cases remain idiopathic.Objective: This study aimed to identify new genes involved in POI and to characterize the implication of CPEB1 gene in POI.Design and Setting: This was a case report and cohort study replicate conducted in academic medical centers. Patients and Methods: A deletion including CPEB1 gene was first identified in a patient with primary amenorrhea. Secondly, 191 sporadic POI cases and 68 familial POI cases were included. For each patient, karyotype was normal and FMR1 premutation was excluded. Search for CPEB1 deletions was performed by quantitative multiplex PCR of short fluorescent fragments or DNA microarray analysis. Gene sequencing of CPEB1 was performed for 95 patients.Results: We identified three patients carrying a microdeletion in band 15q25.2. The proximal breakpoint, for the three patients, falls within a low-copy repeat region disrupting the CPEB1 gene, which represents a strong candidate gene for POI as it is known to be implicated in oocyte meiosis. No mutation was identified by sequencing CPEB1 gene. Therefore, heterozygous deletion of CPEB1 gene leading to haploinsufficiency could be responsible for POI in humans.Conclusion: Microdeletions of CPEB1 were identified in 1.3% of patients with POI, whereas no mutation was identified. This microdeletion is rare but recurrent as it is mediated by nonallelic homologous recombination due to the existence of low-copy repeats in the region. This result demonstrates the importance of DNA microarray analysis in etiological evaluation and counseling of patients with POI.

Les leucémies à grands lymphocytes granuleux (LGL) désignent des hémopathies caractérisées par la prolifération monoclonale de grands lymphocytes riches en granulations azurophiles, de phénotype T CD3+CD57+ ou Natural Killer (NK) CD3–CD56+. La classification de l’Organisation mondiale de la santé (OMS) distingue ainsi trois entités : les leucémies LGL T, les expansions chroniques à cellules NK et les leucémies agressives à cellules NK. Les leucémies LGL T et les expansions chroniques à cellules NK ont une évolution indolente, principalement marquée par l’existence d’une cytopénie ou d’une pathologie auto-immune associée. Leur pronostic est conditionné par l’existence de complications infectieuses secondaires à la neutropénie. Le traitement repose en première intention sur les immunosuppresseurs (méthotrexate, ciclosporine, cyclophosphamide). Les leucémies agressives à cellules NK se présentent sous la forme d’un syndrome tumoral qui fait rapidement suspecter l’hémopathie sous-jacente. Il s’agit d’hémopathies peu chimiosensibles dont le pronostic est réservé. Les progrès récents dans la connaissance de la physiopathologie de ces hémopathies ont permis de préciser les mécanismes à l’origine de la pérennisation du clone LGL et d’identifier de nouvelles cibles thérapeutiques.Large granular lymphocyte leukemia (LGL) is a hematologic disorder characterized by a monoclonal expansion of large lymphocytes containing azurophilic granules with a T CD3+CD57+ or Natural Killer (NK) CD3–CD56+ phenotype. The World Health Organization (WHO) classification identifies three entities: the T LGL, the chronic lymphoproliferative disorder of NK-cells, and the aggressive NK-cell leukemia. T LGL and chronic lymphoproliferative disorder of NK-cells are indolent diseases frequently associated with cytopenias and a wide spectrum of auto-immune manifestations. Neutropenia can lead to recurrent bacterial infections, which represent an indication of initiating a treatment in most of the cases. Immunosuppressive therapies are usually used in this context. In contrast, aggressive NK-cell leukemia follows a fulminant course with a poor prognosis because patients are refractory to most of the treatments. There is now a considerable interest in the pathophysiology of the disease with the perspective of new therapeutic options.

Cette revue a pour but d’etablir une mise au point des differents mecanismes physiopathologiques responsables de la dysovulation dans le syndrome des ovaires polykystiques (SOPK). Le trouble de la folliculogenese s’explique tout d’abord par une augmentation du nombre de follicules de classes 1 a 5 ainsi qu’une modification de la cinetique de croissance folliculaire. L’hyperandrogenie semble etre une des principales explications de ce phenomene. Cette synthese excessive d’androgenes pourrait etre liee a des facteurs extra-ovariens tels la LH et l’insuline autant qu’a des facteurs intra-ovariens avec dysregulation intrinseque des cellules thecales. Le second phenomene susceptible d’expliquer la dysovulation dans le SOPK est le defaut de selection du follicule dominant ou follicular arrest. Parmi les mecanismes impliques dans ce defaut de selection, sont evoques l’acquisition prematuree de recepteurs de la LH par les cellules de la granulosa, l’absence d’elevation intercyclique de FSH, l’exces local d’hormone antimullerienne (AMH) et eventuellement d’IGFBP-4. Secretee en exces dans les cellules de la granulosa des follicules en maturation finale, l’AMH est un candidat valable pour expliquer l’effet « auto-inhibiteur » de la cohorte folliculaire excessive conduisant a l’absence de selection d’un follicule dominant, probablement par le biais d’une inhibition de l’activite catalytique de l’aromatase. Il semblerait egalement que les cellules de la granulosa des follicules en croissance puissent presenter une dysregulation intrinseque responsable d’un defaut de maturation des follicules. L’insulinoresistance semble intervenir egalement dans le follicular arrest comme facteur aggravant plutot que causal. Enfin, l’ovocyte pourrait jouer un role dans le trouble de la folliculogenese en intervenant dans la regulation des cellules par la secretion de growth differentiation factor-9 (GDF-9) mais les donnees actuelles restent pauvres et controversees.

Introduction: Some authors reported a significant and positive correlation between serum anti-Mu ¨llerian hormone (AMH) and luteinizing hormone (LH) levels in normogonadotropic anovulatory infertile women (1).However, little experimental data is available so far to explain such a phenomenon, nor it is known whether it is involved in the follicular arrest of polycystic ovary syndrome (PCOS).Design: we prospectively followed the AMH and LH serum variations during a low-dose step-up protocol in 30 anovulatory women with PCOS who were resistant to clomiphene citrate (no response at 150 mg/ day or 6 cycles with ovulation but no pregnancy).PCOS was defined according to the Rotterdam Criteria.Materials and Methods: All women were investigated during only one cycle and received recFSH using the low-dose step-up protocol (starting dose: 50 UI/ day).Serum levels of estradiol, inhibin B, AMH, LH, FSH and ultrasound (U/ S) parameters (follicle count with distinction between diameters of 2-5, 6-9, 10-15 and.15 mm, ovarian area and volume, endometrial thickness) were assessed twice a week from the first day of stimulation until the day of hCG injection.Results: The day of dominance (day 0) was defined by the appearance of at least one follicle.10mm growing of 2 mm/ day.This was achieved after 18, 14, 11, 7 and 4 days of low-dose FSH administration (50 to 75 UI/day) in 10, 4, 4, 8 and 4 cycles, respectively.From day -18 before dominance (10 cycles) to day 24 (30 cycles), the AMH plasma level declined from 107+69 to 83+49 pMol/L (mean+SD, p¼ 0.72 by ANOVA).Relative values (100% being the value at day 0) declined significantly (p¼0.03)from 135+42% to 108+20%.Absolute LH values decreased significantly from 9.5+6.8 to 4.5+2.5 UI/L (p¼0.0004).At the same time, the mean FSH plasma level increased (p¼0.005 by ANOVA) from 90+12% to 106+20% (relatively to the day 0 value).In the pool of the 98 samples obtained from day 218 to day 24, absolute values of AMH were positively and negatively associated to those of LH and FSH, respectively, in an independent manner (r¼0.26,p¼0.009 and r¼20.26,p¼0.009, respectively).There was a trend toward a negative association between LH and FSH (r¼20.19,p¼0.06).The mean number of 2-5 mm follicles at U/S also declined between days 218 and 24, although not significantly (from 26.3+20 to 18.8+14.1,p¼0.71), but in tight relationship with the AMH values (r¼0.71,p,0.0001). Conclusion:In anovulatory women with PCOS, the serum AMH level declines significantly before a follicle becomes dominant, presumably under the effect of low-dose FSH administration.Whether the close parallelism between AMH and LH variations at the same time reflects an altered positive LH effect on AMH secretion or an altered positive AMH effect on LH pituitary production is an open issue that requires more experimental data.Indeed, some human data indicates that the AMH produced by cultured granulosa cells (GC) from primary to preovulatory follicles is positively regulated by LH, especially in GC from polycystic ovaries (2).Conversely, the AMH type II receptor is present in rodent pituitary cells where AMH has been shown to stimulate the activation of the LHß gene expression (3).

La fisiopatología del hiperandrogenismo, que se manifiesta desde el punto de vista clínico sobre todo por la presencia de hirsutismo, acné y/o alteración menstrual, se debe esencialmente a la hiperproducción ovárica o suprarrenal de andrógenos. Su carácter patológico resulta difícil de establecer en el período peripuberal debido a la existencia de inmadurez fisiológica del eje hipotálamo-hipofisario. Su etiología más frecuente es el síndrome de ovarios polimicroquísticos (SOPMQ). Su diagnóstico en la mujer adulta se basa en criterios precisos que requieren su adaptación al caso particular de la adolescente. La evaluación clínica de la rapidez de instalación y de la intensidad de los signos de hiperandrogenismo así como el estudio bioquímico sistemático de inicio permiten descartar las demás causas, particularmente los tumores ováricos y suprarrenales, el déficit de 21-hidroxilasa, las endocrinopatías y las causas iatrogénicas. Dejando aparte el tratamiento etiológico, la actuación terapéutica consiste en la administración de antiandrógenos, principalmente acetato de ciproterona. En caso de SOPMQ, cuando se asocian alteraciones metabólicas, la educación sanitaria respecto a las normas higienicodietéticas resulta fundamental.

OBJECTIVE:To emphasize the difficulties to distinguish between uterine agenesis and extreme uterine hypotrophy in the context of primary amenorrhoea with delayed puberty.PATIENTS AND METHODS:Among adolescents who consulted with our center because of primary amenorrhoea, from 1997 to 2005, three patients were referred for a suspicion of Mayer-Rokitansky-Kuster-Hauser Syndrome, after ultrasonography had failed to visualize the uterus. The 3 patients underwent endocrine and genetic evaluations. Transabdominal ultrasonography and MRI performed pelvic examination. Patients were placed under estrogen treatment.RESULTS:Endocrine evaluation indicated primary ovarian failure for patient 1, and hypogonadotrophic hypogonadism for patients 2 and 3. Karyotype was 46,XX in all patients. Initial pelvic ultrasonography revealed the absence of uterus. MRI allowed visualizing prepubertal uterus for patient 1, a hypotrophic uterus for patient 3 and concluded to uterine agenesis for patient 2. In all cases estradiol substitutive therapy induced uterine growth and confirmed retrospectively the diagnosis of extreme uterine hypotrophy.DISCUSSION AND CONCLUSION:Pelvic ultrasonography can be misleading in the evaluation of primary amenorrhoea. No visualization of uterus on ultrasonography can occur in the context of delayed puberty and should not induce a premature diagnosis of Mayer-Rokitansky-Kuster-Hauser syndrome. Indeed, such a diagnosis has therapeutic, reproductive and psychological consequences.

We present the case of a male patient who presented progressive cerebellar ataxia since childhood who developed partial hypogonadotropic hypogonadism discovered when searching for a cause of low fecundity. The association of these two entities has been described in several rare syndromes: Homes ataxia, Boucher-Neuhauser syndrome and Richards-Rundle syndrome. The genetic background of these three syndromic associations defined solely on the basis of clinical manifestations remains to be elucidated, leading to uncertain diagnosis. The present case suggests the syndromic entity could be associated with autosomal recessive spinocerebellar ataxia with hypogonadotropic hypogonadism which includes several genotypic entities.

L’objectif de cette étude rétrospective est d’évaluer les issues des cycles de fécondation in vitro au cours de cycles naturels modifiés en fonction des dosages de l’hormone anti-müllérienne (AMH) au troisième jour du cycle. Trois cent quarante-deux patientes faisant le premier cycle de FIV en cycle naturel modifié ont été incluses. Ces patientes ont divisées en trois groupes en fonction de leur dosage d’AMH : groupe 1 avec des AMH inférieurs à 0,97 ng/mL (25e percentile), groupe 2 avec des AMH entre 0,97 et 2,60 ng/mL et groupe 3 avec des AMH entre 2,61 et 6,99 ng/mL (75e percentile). Les critères principaux étaient les taux d’annulations, de transferts embryonnaires, de grossesses cliniques, de grossesses évolutives et d’implantations. Aucune différence n’a été observée sur ces différents taux dans les trois groupes de notre étude, avec en particulier des taux de grossesses cliniques dans les trois groupes respectivement de 12,8 ± 3,6 % versus 12,5 ± 2,5 % versus 13,4 ± 4,2 %. En conclusion, la fécondation en cycle naturel modifié peut être proposée aux patientes ayant une AMH inférieure à 1 ng/mL. L’AMH semble être un marqueur quantitatif mais non qualitatif de la réserve ovarienne. Aussi, l’AMH ne semble pas avoir de valeur pronostique en cycle naturel modifié.The objective is to compare the IVF procedures in modified natural cycle outcomes according to serum anti-Mullerian hormone (AMH) levels. We included in this retrospective study 342 patients undergoing their first IVF in modified natural cycle. Patients were regrouped in three groups according to their serum AMH level: group 1 was defined by patients with AMH level < 0.97 ng/mL (<25th percentile), group 2, patients with AMH level between 0.97 ng/mL and 2.60 ng/mL (25–75th percentile), and group 3, patients with AMH level between 2.61 ng/mL and 6.99 ng/mL (>75th percentile). The main outcomes were cancellation rate, embryo transfer rate and clinical pregnancy rate, ongoing pregnancy rate and implantation rate. No difference has been observed on cancellation rate, embryo transfer rate, clinical pregnancy rate and implantation rate. The ongoing pregnancy rate per IVF cycle was respectively: 12.8 ± 3.6% for AMH inferior to 0.97 ng/mL versus 12.5 ± 2.5% for AMH between 0.97 to 2.60 ng/mL and 13.4 ± 4.2% for AMH between 2.61 ng/mL and 6.99 ng/mL. In conclusion, IVF in modified natural cycles procedures should be considered as an option for patients with an altered ovarian reserve defined by a serum AMH inferior to 1 ng/mL. Serum AMH level seems a quantitative marker of the ovary but not a quality factor. Serum AMH level does not seem to be a prognostic factor for ongoing pregnancy rated in IVF modified cycles.

We present the case of a male patient who presented progressive cerebellar ataxia since childhood who developed partial hypogonadotropic hypogonadism discovered when searching for a cause of low fecundity. The association of these two entities has been described in several rare syndromes: Homes ataxia, Boucher-Neuhauser syndrome and Richards-Rundle syndrome. The genetic background of these three syndromic associations defined solely on the basis of clinical manifestations remains to be elucidated, leading to uncertain diagnosis. The present case suggests the syndromic entity could be associated with autosomal recessive spinocerebellar ataxia with hypogonadotropic hypogonadism which includes several genotypic entities.

It is now well demonstrated that the serum AMH level correlates tightly to the ovarian follicle content. Therefore, it presents itself as a good candidate for predicting the ovarian response to COH and for helping the decision in ART. To test this hypothesis, we used a new "second generation" enzyme immunoassay for AMH (Beckman-Coulter-Immunotech, Villepinte, France), specially designed to improve the lack of sensitivity of the previous one for the measurements of serum AMH in women. 350 women aged 21-40 yrs were selected from our IVF database for retrospective analysis. The AMH assay was performed in the serum previously collected in early follicular phase of a spontaneous cycle two to six months before a first IVF cycle. The analysis also included the results of the serum levels of FSH and inhibin B previously measured on the same serum sample as AMH, as well as the antral follicle count at ultrasonography, no follicle being larger than 9 mm. COH was performed using recFSH with cumulated doses varying from 850 to 6,075 units, under desensitization with short-acting triptorelin injections. Oocyte retrieval was performed in 323 (92%) patients, with oocyte number varying from 0 to 31 (group A, n= 65 : >15; group B, n= 223 : 5 to 14; group C, n= 35 : ≤ 4). The attempt was cancelled in 27 patients (8%) (group D) because of insufficient follicular development under COH. The mean serum AMH level was significantly different between the 4 groups (p<0.0001 by ANOVA) (group A: 43.7 ± 22.3; group B: 37.0 ± 27.3; group C: 26.6 ± 20.7 and group D: 25.3 ± 27.1 pMol/L). It correlated less tightly to the number of oocytes retrieved than the AFC (r=0.22, p<0.0005 and 0.29, p<0.0001, respectively), but stronger than FSH (-0.182, p<0.004) or inhibin B (p=0.11). FSH was the parameter the best correlated to the total number of embryos (r=-0.174, p<0.006) before the AFC (r=0.156, p<0.02) and AMH (0.125, p<0.05). The mean serum AMH level was not significantly different between cycles resulting (n=75) or not (n=275) in a clinical pregnancy (p=0.69). In order to test the predictive value of each parameter by ROC analysis, groups A and B were gathered in a single group "success" (n=288) and groups C and D in a group "failure" (n=62). The area under the ROC curve (AUC) for AMH yielded a weak value of 0.689 (95% CI: 0.608-0.77), indicating that no satisfying compromise between sensitivity and specificity could be drawn. In comparison, AUC for AFC, FSH and inhibin B was 0.624, 0.581, and 0.546, respectively Pre-treatment AMH serum level is well correlated to the main COH outcomes. However, although yielding higher AUC in ROC analysis than AFC, FSH or inhibin B, this parameter did not appear as a good predictor for poor ovarian response by itself in this retrospective series. For example, a threshold set at 20 pMol/L (2.8 ng/mL) yielded a sensitivity of 76% and a specificity of only 62%.

Some experimental data indicates that the AMH produced by the granulosa cells (GC) from primary to preovulatory follicles is negatively regulated by FSH. We previously hypothesized that the excess of AMH in PCOS could reflect the lack of action of FSH at the CG level and could be therefore involved in the follicular arrest. However, previous clinical studies are controversial since they showed that AMH plasma levels does not change during the follicular phase of the spontaneous menstrual cycle while it decreases during FSH-treated cycles for IVF in normal women. We investigated therefore whether a drop in the serum AMH level was concomitant to the appearance of a dominant follicle induced by administration of mild amounts of exogenous FSH in women with PCOS. This prospective study included 14 women with PCOS willing a pregnancy who were resistant to clomiphene citrate (no response at 150mg/day or 6 cycles with ovulation but no pregnancy). PCOS was defined according to the Rotterdam Criteria. All women were investigated during only one cycle and received FSH using the low-dose step-up protocol (starting dose: 50 UI/day). Serum levels of estradiol, inhibin B, AMH, LH, FSH and ultrasound parameters (follicle count with distinction between diameters of 2-5, 6-9, 10-15 and > 15 mm, ovarian area and volume, endometrial thickness) were assessed twice a week from the first day of stimulation until the day of hCG injection. Data were normalized to the day of dominance (day 0) defined by a follicle > 10 mm growing of 2 mm/ day and/or serum E2 level > 100 pg/mL. From day -14 to day -4 before dominance (day 0), the AMH plasma levels slightly declined from 127 ± 34 % to 106 ± 28% of the day 0 value, but this was not significant by ANOVA. However, at days -7 and -4, the AMH values were negatively and significantly correlated to the serum levels of FSH (r=-0.584, p<0.05 and r=-0.637, p<0.02, respectively), while no such relationship was observed at days -14 and -11. The number of 2-5 mm and 6-9 mm follicles did not change during the ovarian stimulation, even at the time when a follicle became dominant. Our results with mild FSH stimulation in PCOS might indicate a very subtle decline in the serum AMH level before dominance, but it is necessary to study more patients before such a conclusion can be drawn. However, the present data discloses a temporal negative relationship between serum AMH and FSH, appearing in the few days preceding the dominance. This could suggest that rising serum FSH level exerts at that time a physiological suppressive effect on AMH production, which presumably would be lacking in non-stimulated anovulatory women with PCOS. Whether such a phenomenon is responsive for the follicular arrest of PCOS needs further investigations.

CONTEXT:Despite its frequency, the polycystic ovary syndrome (PCOS) is still a difficult diagnosis in endocrinology, gynecology, and reproductive medicine. To help solve this issue, the Rotterdam consensus conference proposed to include the ultrasonographic follicle count as a new diagnostic criterion, in addition to hyperandrogenism and oligo-anovulation. Unfortunately, its assessment does not offer sufficient reliability worldwide. OBJECTIVE:The aim of our study was to check whether anti-Müllerian hormone (AMH) measurement in the serum could be a surrogate for antral follicle count in the diagnostic criteria of PCOS. DESIGN, SETTING, AND PATIENTS:Serum AMH was measured with a second-generation immunoassay in a cohort of 73 PCOS patients and 96 controls, and its diagnostic power was evaluated by receiver operating characteristic curves. PCOS was diagnosed according to the Rotterdam definition. RESULTS:Serum AMH levels were 3-fold higher in PCOS patients than in controls (81.6 vs. 33.5 pmol/liter; P < 0.001) and were significantly related to the follicle number in the two groups. The area under the receiver operating characteristic curve for the AMH assay was 0.851, indicating a good diagnostic potency. Setting the threshold at 60 pmol/liter offered the best compromise between specificity (92%) and sensitivity (67%). CONCLUSIONS:The serum AMH level is an accurate marker of the ovarian early antral follicle number and offers a good diagnostic potency. In situations where accurate ultrasonographic data are not available, AMH could thus be used instead of the follicle count as a diagnostic criterion and incorporated as such in the Rotterdam definition of PCOS.