Sophie Christin-Maitre

Genome-wide association study in premature ovarian failure patients suggests ADAMTS19 as a possible candidate gene

BACKGROUNDnSpontaneous premature ovarian failure (POF) occurs in 1% of women and has major implications for their fertility and health. Besides X chromosomal aberrations and fragile X premutations, no common genetic risk factor has so far been discovered in POF. Using high-density single nucleotide polymorphism (SNP) arrays, we set out to identify new genetic variants involved in this condition.nnnMETHODSnA genome-wide association study involving 309 158 SNPs was performed in 99 unrelated idiopathic Caucasian POF patients and 235 unrelated Caucasian female controls. A replication study on the most significant finding was performed. We specifically focused on chromosomal areas and candidate genes previously implicated in POF.nnnRESULTSnSuggestive genome-wide significant association was observed for rs246246 (allele frequency P = 6.0 x 10(-7)) which mapped to an intron of ADAMTS19, a gene known to be up-regulated in the female mouse gonads during sexual differentiation. However, replication in an independent Dutch cohort (60 POF patients and 90 controls) could not confirm a clear association (P = 4.1 x 10(-5) in a joint analysis). We did not observe strong evidence for any of 74 selected POF candidate genes or linkage regions being associated with idiopathic POF in Caucasian females, although suggestive association (P < 0.005) was observed for SNPs that mapped in BDNF, CXCL12, LHR, USP9X and TAF4B.nnnCONCLUSIONnWe observed a possible association between POF and a SNP in a biologically plausible candidate gene. Although limited by sample size, this proof-of-principle studys findings reveal ADAMTS19 as a possible candidate gene for POF and thus a larger follow-up study is warranted.

Comparison of a 24-day and a 21-day pill regimen for the novel combined oral contraceptive, nomegestrol acetate and 17β-estradiol (NOMAC/E2): a double-blind, randomized study

BACKGROUND Nomegestrol acetate/17β-estradiol (NOMAC/E(2)) is a new monophasic oral contraceptive combining NOMAC (2.5 mg), a highly selective progesterone-derived progestogen, with E(2) (1.5 mg), which is structurally identical to endogenous estrogen. The objective of this study was to compare the effects on ovarian activity of two different NOMAC/E(2) regimens. METHODS This was a double-blind, randomized study. Healthy, premenopausal women (aged 18-38 years, previous menstrual cycle length 28 ± 7 days) were randomized by computer-generated code to once-daily NOMAC/E(2) for three consecutive 28-day cycles: either 24 days with a 4-day placebo interval (n = 40) or 21 days with a 7-day placebo interval (n = 37) per cycle. Follicular growth (primary outcome measure), plasma hormone profiles and bleeding patterns were assessed. RESULTS There was no evidence of ovulation during treatment with either NOMAC/E(2) regimen. The largest follicle diameter was significantly smaller in the 24-day group than in the 21-day group [mean (SD) mm in cycle 2: 9.0 (3.0) versus 11.3 (5.3) (P = 0.02); in cycle 3: 9.2 (3.0) versus 11.5 (6.0) (P = 0.04)]. Mean FSH plasma levels were significantly lower in the 24-day versus the 21-day group on Day 24 of cycles 1 and 2. Withdrawal bleeding duration was significantly shorter in the 24-day than in the 21-day group [mean (SD) days after cycle 1: 3.5 (1.3) versus 5.0 (2.6) (P = 0.002); after cycle 2: 3.9 (1.6) versus 4.8 (1.7) (P = 0.03)]. CONCLUSIONS The 24-day NOMAC/E(2) regimen was associated with greater inhibition of follicular growth and shorter duration of withdrawal bleeding than the 21-day regimen, suggesting the shorter pill-free interval results in a greater margin of contraceptive efficacy and tolerability, and fewer withdrawal symptoms.

Inhibition of ovulation by NOMAC/E2, a novel monophasic oral contraceptive combining nomegestrol acetate and 17β-oestradiol: A double-blind, randomised, dose-finding pilot study

Objectiveu2003To explore the optimal dose of the progestogen, nomegestrol acetate (NOMAC), required in a monophasic oral contraceptive, in combination with 1.5u2009mg 17β-oestradiol (E2), to inhibit ovulation. Methodsu2003A double-blind, randomised study assessing 41 normally cycling women (aged 18–35 years) over two screening cycles, one control cycle and one consecutive treatment cycle; 38 women completed the treatment period. Subjects received 0.625u2009mg NOMAC/1.5u2009mg E2 (nu200a=u200a9), 1.25u2009mg NOMAC/1.5u2009mg E2 (nu200a=u200a10), 2.5u2009mg NOMAC/1.5u2009mg E2 (nu200a=u200a10) or 2.5u2009mg NOMAC alone (nu200a=u200a9) for 21 days. Resultsu2003During the treatment cycle, ovulation was suppressed in all treatment groups. The lowest plasma E2 levels were observed with 2.5u2009mg NOMAC given alone. Addition of 1.5u2009mg E2 to 2.5u2009mg NOMAC resulted in statistically significant increases in E2 levels and decreases in mean follicle-stimulating hormone and luteinising hormone levels. In the three NOMAC/E2 combination groups, a statistically significant inverse correlation was found between E2 plasma levels and NOMAC dose. Conclusionu2003The dose of 2.5 mg NOMAC was confirmed to be optimal to inhibit both ovulation and follicular maturation. The antigonadotropic effect of 2.5u2009mg NOMAC was reinforced when combined with 1.5u2009mg E2.

L'insuffisance ovarienne prématurée

Premature ovarian failure (POF) is defined by at least four months of amenorrhea with elevated gonadotropins (usually above 40 UI/L) detected on two occasions a few weeks apart, in a woman before the age of 40. It occurs in 1 out of 10,000 in women below the age of 20, 1/1,000 below 30 and 1% in women before the age of 40. In 80% of POF cases, the etiology is unknown, except for Turner syndrome. The different etiologies identified are 1) iatrogenic following chemotherapy and/or radiotherapy, 2) autoimmune, 3) viral, 4) genetic (RFSH, FOXL2, FRAXA, BMP15, GDF9, GALT, 17 hydroxylase...). Management of these patients includes hormone replacement therapy in order to avoid an increase in cardiovascular risk and osteoporosis related to hypoestrogenism. Infertility is common, as only 3 to 10% of the patients will have natural conception. When fertility is desired, women with POF should be oriented towards oocyte donation centers. Research is currently performed in order to identify new genes involved in POF.

Genome-wide association study and premature ovarian failure

Premature ovarian failure (POF) is defined as an amenorrhea for more than 4months, associated with elevated gonadotropins, usually higher than 20mIU/ml, occurring in a woman before the age of 40. Some candidate genes have been identified in the past 15years, such as FOXL2, FSHR, BMP15, GDF9, Xfra premutation. However, POF etiology remains unknown in more than 90% of cases. The first strategy to identify candidate gene, apart from studying genes involved in ovarian failure in animal models, relies on the study of X chromosome deletions and X;autosome translocations in patients. The second strategy is based on linkage analysis, the third one on Comparative Genomic Hybridization (CGH) array. The latest strategy relies on Genome-Wide Association Studies (GWAS). This technique consists in screening single nucleotide polymorphisms (SNPs) in patients and controls. So far, three studies have been performed and have identified different loci potentially linked to POF, such as PTHB1 and ADAMTS19. However, replications in independent cohorts need to be performed. GWAS studies on large cohorts of women with POF should find new candidate genes in the near future.

Which thyroid cancer patients need periodic stimulation tests

PurposeRecurrences are frequent in thyroid cancer patients and long-term follow-up is therefore necessary. We evaluated the yield of rhTSH stimulation in three groups of patients, classified according to the UICC/TNM risk stratification and the results of first follow-up testing.MethodsThe study population comprised 129 patients referred for rhTSH testing. All had undergone first follow-up testing after thyroid hormone withdrawal (off-T4) within 1xa0year of 131I ablation. Negative first follow-up testing was defined as Tg <2xa0ng/ml and no neck uptake on 131I diagnostic whole-body scan. Seventy-five patients had stage I thyroid cancer and negative first follow-up testing (group A), 19 had stage I disease and positive first follow-up testing (group B), and 35 had stage II–IV disease (group C). RhTSH stimulation was performed an average of 6xa0years after first follow-up testing.Results131I diagnostic scanning after rhTSH was negative in all 75 group A patients. Only one group A patient had detectable Tg after rhTSH injection (1.5xa0ng/ml), but Tg had also been detected at baseline in this patient (1.45xa0ng/ml). Given the absence of a response to stimulation, suggesting an interference, Tg was reassessed with a different technique and proved to be undetectable (<0.1xa0ng/ml). Stimulation with rhTSH in group B showed residual Tg in seven patients and residual 131I uptake in the thyroid bed in two patients, but none of these patients had signs of disease progression. Five group C patients (14%) had a positive rhTSH test result, and this was suggestive of disease progression in at least two cases.ConclusionThe first follow-up testing is essential for prognostic classification after 131I ablation of thyroid cancer. In stage I patients, undetectable Tg and negative 131I scan 1 year after ablation define a large population of subjects who have a very low risk of recurrence and who do not require further stimulation tests. In contrast, periodic rhTSH stimulation tests appear useful in higher-risk patients.

Fertility defects revealing germline biallelic nonsense NBN mutations.

Biallelic mutations in the NBN/NBS1 gene are the cause of Nijmegen breakage syndrome (NBS), a severe pediatric disease characterized by dysmorphy with a bird‐like face, microcephaly, growth retardation, immune deficiency, and proneness to cancer. We here report two adult siblings that are compound heterozygotes for two previously unreported NBN nonsense mutations. These patients presented with the unique clinical symptom of fertility defects. Contrasting with the absence of any developmental abnormality, biological analyses revealed defects similar to those observed in NBS patients, including chromosomal instability, cellular hyperradiosensitivity and checkpoint defects as measured by radioresistant DNA synthesis (RDS). NBN mutations should thus be considered a new cause of infertility, and should be searched for if associated with the biological abnormalities of NBS. Hum Mutat 0, 1–7, 2008.

First Birth Achieved After In Vitro Maturation of Oocytes From a Woman Endowed With Multiple Antral Follicles Unresponsive to Follicle-stimulating Hormone

CONTEXTnThe association of primary amenorrhea, gonadotropin levels at menopausal range, and normal antral follicle endowment is a rare clinical condition that suggests unresponsiveness of antral follicles to FSH. This affection is frequently misdiagnosed ovarian failure and patients are referred to egg donation to treat their infertility. Because these patients notably have an age-compatible number of antral follicles, we hypothesized that in vitro maturation (IVM) of oocytes might constitute a useful approach for treating their infertility.nnnOBJECTIVEnWe report the first pregnancy and live birth obtained after IVM of oocytes in a 29-year-old patient suffering from ovarian resistance to FSH.nnnDESIGNnThis is a case report.nnnSETTINGnThe work was conducted in a university hospital.nnnPATIENTnWhereas serum FSH (40.3 and 38.4 mIU/mL) and LH (35.7 and 31.7 mIU/mL) levels were repeatedly around the menopausal range, serum anti-Müllerian hormone (4.50 and 4.36 ng/mL) levels and total counting of antral follicles (23 and 18 follicles) remained normal.nnnINTERVENTIONnWe aspirated antral-stage follicles and subsequently matured the oocytes in vitro.nnnMAIN OUTCOME MEASUREnWe assessed the competence of oocytes retrieved in a patient suffering from ovarian resistance to FSH.nnnRESULTSnAspiration of antral-stage follicles allowed the retrieval of 15 immature oocytes. Following IVM, 12 of them reached metaphase II. Seven embryos were obtained and three of them were transferred into the uterus. This patient became pregnant and delivered a healthy baby at term.nnnCONCLUSIONSnWe report the first pregnancy and live birth achieved using IVM in a woman whose ovaries were resistant to FSH. This approach was based on the remarkable normalcy of AMH and antral follicle measurements in this patient. Therefore, IVM is a viable alternative to egg donation for women suffering from resistance to FSH. Importantly, this condition should be looked for as it may lurk undetected in women wrongly diagnosed with ovarian failure.

Infertility in an adult cohort with primary ciliary dyskinesia: phenotype–gene association

Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder (prevalence 1:10u200a000 to 1:40u200a000 births) characterised by impaired mucociliary clearance because of abnormal motile ciliary function [1, 2]. Five main ultrastructural PCD phenotypes have been described. Most result from a lack of dynein arms (DAs): no outer and inner DAs (2DAs), outer DAs alone (ODA) or inner DAs with microtubular disorganisation (IDA/MTD); or defects yielding an abnormal central complex (CC). Some patients with genetically confirmed PCD have apparently normal ciliary structure on electron microscopy (nEM). More than 30 genes encoding proteins involved in the structure or assembly of the axoneme, the ciliary internal cytoskeleton, are implicated in PCD [3]; their analysis enables identification of bi-allelic disease-causing mutations in 50–75% of patients. Approximately half of PCD cases are associated with situs inversus, thereby defining Kartageners syndrome. Moreover, because motile cilia and sperm flagella share common axonemal structures, most PCD-affected males are thought to be infertile [4]. According to the literature, male infertility is caused by severe or total asthenozoospermia and is currently treated by recourse to in vitro fertilisation or intracytoplasmic sperm injection [5, 6]. However, spontaneous fatherhood of PCD patients has been reported. Infertility, observed in 75% of male and 61% of female PCD patients, is dependent on ultrastructural and gene defects http://ow.ly/P4K030fPnPp

Obésité et fertilité de la femme

Weight, fat mass and obesity have been shown to play a major role in female reproduction. Obese women have a greater risk than nonobese women of infertility and they fail to become pregnant in both natural and assisted conception cycles. This cannot be explained only by their lack of ovulation. There are several potential mechanisms. On one hand, the endometrium seems to be partially responsible for this low fecundity in obese women. On the other hand, the oocyte seems to be implied. In a model of obese mouse, maternal obesity prior to conception is associated with altered mitochondria in mouse oocytes and an increased generation of reactive oxygen species (ROS). Furthermore, compared with controls, obese mice have significantly more decreased embryonic IGF-IR staining, smaller fetuses and smaller pups. In this model, all weaned pups have been fed with a regular diet. At 13 weeks, pups delivered from obese mice were significantly larger, and these pups demonstrated early development of a metabolic-type syndrome. These findings suggest that maternal obesity has adverse effects as early as the oocyte and preimplantation embryo stages and that these effects may contribute to lasting morbidity in offspring, underscoring the importance of optimal maternal weight and nutrition before conception.Weight, fat mass and obesity have been shown to play a major role in female reproduction. Obese women have a greater risk than nonobese women of infertility and they fail to become pregnant in both natural and assisted conception cycles. This cannot be explained only by their lack of ovulation. There are several potential mechanisms. On one hand, the endometrium seems to be partially responsible for this low fecundity in obese women. On the other hand, the oocyte seems to be implied. In a model of obese mouse, maternal obesity prior to conception is associated with altered mitochondria in mouse oocytes and an increased generation of reactive oxygen species (ROS). Furthermore, compared with controls, obese mice have significantly more decreased embryonic IGF-IR staining, smaller fetuses and smaller pups. In this model, all weaned pups have been fed with a regular diet. At 13 weeks, pups delivered from obese mice were significantly larger, and these pups demonstrated early development of a metabolic-type syndrome. These findings suggest that maternal obesity has adverse effects as early as the oocyte and preimplantation embryo stages and that these effects may contribute to lasting morbidity in offspring, underscoring the importance of optimal maternal weight and nutrition before conception.