22 research outputs found
Hyperprolactinemia-induced ovarian acyclicity is reversed by kisspeptin administration
Hyperprolactinemia is the most common cause of hypogonadotropic anovulation and is one of the leading causes of infertility in women aged 25-34. Hyperprolactinemia has been proposed to block ovulation through inhibition of GnRH release. Kisspeptin neurons, which express prolactin receptors, were recently identified as major regulators of GnRH neurons. To mimic the human pathology of anovulation, we continuously infused female mice with prolactin. Our studies demonstrated that hyperprolactinemia in mice induced anovulation, reduced GnRH and gonadotropin secretion, and diminished kisspeptin expression. Kisspeptin administration restored gonadotropin secretion and ovarian cyclicity, suggesting that kisspeptin neurons play a major role in hyperprolactinemic anovulation. Our studies indicate that administration of kisspeptin may serve as an alternative therapeutic approach to restore the fertility of hyperprolactinemic women who are resistant or intolerant to dopamine agonists
The tyrosine kinase inhibitor sunitinib affects ovulation but not ovarian reserve in mouse: A preclinical study
The aim of the study was to evaluate ovarian toxicity of tyrosine kinase inhibitor (TKI) sunitinib, since only scarce data are available on gonadal function after this treatment. Six-weekold female mice received orally, once daily, vehicle or sunitinib (50 mg/kg/d) during 5 weeks. Fertility parameters were analyzed from ovulation to litter assessment. Sunitinib exposure significantly reduced (i) corpora lutea number per ovary (1.1 ± 0.38 in sunitinib group versus 4 ± 0.79 in control group, p<0.01) and (ii) serum Anti MĂŒllerian hormone (AMH) levels in sunitinib treated mice (12.01 ± 1.16) compared to control mice (14.33 ± 0.87 ng/ml, p< 0.05). However, primordial and growing follicles numbers per ovary were not different in both groups. After treatment withdrawal, female mice in both groups were able to obtain litters. These data could be helpful to counsel clinicians and patients, when fertility preservation methods are discussed, before TKI treatment in girls and young women
Hyperprolactinemia-induced ovarian acyclicity is reversed by kisspeptin administration
Hyperprolactinemia is the most common cause of hypogonadotropic anovulation and is one of the leading
causes of infertility in women aged 25â34. Hyperprolactinemia has been proposed to block ovulation through
inhibition of GnRH release. Kisspeptin neurons, which express prolactin receptors, were recently identified as
major regulators of GnRH neurons. To mimic the human pathology of anovulation, we continuously infused
female mice with prolactin. Our studies demonstrated that hyperprolactinemia in mice induced anovulation,
reduced GnRH and gonadotropin secretion, and diminished kisspeptin expression. Kisspeptin administration
restored gonadotropin secretion and ovarian cyclicity, suggesting that kisspeptin neurons play a major
role in hyperprolactinemic anovulation. Our studies indicate that administration of kisspeptin may serve as
an alternative therapeutic approach to restore the fertility of hyperprolactinemic women who are resistant or
intolerant to dopamine agonists.R. Millar is recipient of a
grant from the Medical Research Council (South Africa) and the
University of Pretoria.http://www.jci.or
KLB , encoding ÎČâKlotho, is mutated in patients with congenital hypogonadotropic hypogonadism
Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropinâreleasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 (FGFR1) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with ÎČâKlotho (KLB), the obligate coâreceptor for FGF21. We thus hypothesized that the metabolic FGF21/KLB/FGFR1 pathway is involved in CHH. Genetic screening of 334 CHH patients identified seven heterozygous lossâofâfunction KLB mutations in 13 patients (4%). Most patients with KLB mutations (9/13) exhibited metabolic defects. In mice, lack of Klb led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21. Peripheral FGF21 administration could indeed reach GnRH neurons through circumventricular organs in the hypothalamus. We conclude that FGF21/KLB/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction
Study of Few Factors in Ovarian Pathophysiology
Les donnĂ©es bibliographiques dĂ©crivent un nombre croissant de modĂšles murins caractĂ©risĂ©s sur le plan de la fertilitĂ© permettant une meilleure comprĂ©hension du phĂ©nomĂšne de la croissance folliculaire. Certains de ces modĂšles animaux, invalidĂ©s pour des facteurs de transcription reproduisent un phĂ©notype dâinfertilitĂ©, telle que lâinsuffisance ovarienne primaire (IOP). La comprĂ©hension des mĂ©canismes molĂ©culaires des facteurs de transcription essentiels Ă la fonction ovarienne nâest pas clairement Ă©tablie. Les protĂ©ines contenant des domaines liant lâADN, tels que les homĂ©odomaines ou les domaines forkhead jouent un rĂŽle-ClĂ© dans le dĂ©veloppement ovarien. NOBOX (Newborn Ovary Homeobox) est un facteur de transcription essentiel Ă la mise en place du stock folliculaire, et dont les mutations sont responsables dâIOP. La fonction exacte de NOBOX nâest pas connue, sâil est prĂ©sent dans lâovocyte, nous montrons pour la premiĂšre fois une forte expression de cette protĂ©ine dans les cellules de la granulosa des follicules primordiaux jusquâau stade secondaire. De plus, par diffĂ©rentes techniques molĂ©culaires, nous mettons en Ă©vidence une interaction entre NOBOX et un autre acteur important de la folliculogenĂšse FOXL2 (Forkhead box l2), contribuant Ă la rĂ©gulation de leurs gĂšnes cibles respectifs. Cette Ă©tude permet de mettre en lumiĂšre le rĂŽle de NOBOX dans les cellules de granulosa. LâIOP est une pathologie touchant 1 % des femmes ĂągĂ©es de moins de 40 ans. Sur le plan ovarien, il y a une dĂ©plĂ©tion du stock des follicules ou un blocage de la maturation folliculaire. De ce fait, la stĂ©rilitĂ© est le plus souvent dĂ©finitive. Une origine gĂ©nĂ©tique de cette maladie est parfois retrouvĂ©e avec des mutations des autosomes et/ou du chromosome X, mais dans plus de 80% des cas lâIOP est idiopathique. Lâenjeu est donc dâidentifier de nouveaux gĂšnes candidats pour cette pathologie. Dans cette Ă©tude nous validons la prĂ©valence des mutations du gĂšne NOBOX faisant de ce facteur un des gĂšnes clĂ©s de lâIOP. Puis, Ă lâaide dâune nouvelle technologie : le sĂ©quençage multiplex par puces PGMTM ION TORRENT, nous mettons en Ă©vidence dans 26% de la cohorte Ă©tudiĂ©e (100 femmes atteintes dâIOP sporadique primaire ou secondaire) un dĂ©faut gĂ©nĂ©tique de 10 gĂšnes, dont 4 nouveaux candidats Ă lâIOP. De façon intĂ©ressante, la prĂ©sence dâau moins deux gĂšnes mutĂ©s chez 9 patientes induit un phĂ©notype plus prĂ©coce. Cette Ă©tude contribue Ă une meilleure comprĂ©hension de lâorigine gĂ©nĂ©tique de lâIOP et met pour la premiĂšre fois en Ă©vidence le phĂ©nomĂšne dâoligogĂ©nisme chez des patientes en IOP.Single germline mutations found in women with primary ovarian insufficiency (POI), besides mouse models have provided substantial understanding into the factors involved in differentiation and ovarian development. POI is characterized by amenorrhea with elevated gonadotropin levels, and affects 1% of women before the age of 40 years.Several transcription factors involved in ovary development and folliculogenesis are mutated in reproductive disorders. We have shown a high prevalence of POI cases harboring mutations in the Newborn oogenesis homeobox (NOBOX) gene, which encodes a homeodomain-Containing transcription factor expressed preferentially in oocyte. NOBOX plays a critical role in early folliculogenesis and its absence leads to sterility. In addition to its oocyte localization, we show here that NOBOX is also expressed in granulosa cells (GCs), those surrounding the germ cell. Since NOBOX and FOXL2, a master regulator of GC development (belonging to forkhead family), are co-Expressed in GCs. Here, using several molecular approaches, we have demonstrated that NOBOX and FOXL2 indeed physically interact leading to a down-Regulation of their transactivation capacity. Altogether, these observations highlight a novel role for NOBOX in interaction with FOXL2, and suggest that they may be antagonistic transcription regulators. POI encompasses a heterogeneous spectrum of conditions, through two major mechanisms, follicle dysfunction and follicle depletion. Genetic component such as X chromosome abnormalities, deletions, FMR1 premutations, BMP15 variants, were identified as the first genetic causes of the pathophysiology. Today, the genetic origin of POI is supported by the existence of monogenic forms in humans and animal models but the relevance of several loci for POI pathogenesis should not be ruled out. By means of a next-Generation sequencing , a multiplex (PGM-Ion Torrent technology) sequencing of 19 genes was undertaken in a cohort of 100 nonsyndromic women with POI. In 26 patients, we reported 10 gene defects, among them, missense mutations in 4 new candidates were detected. Our aggregate data suggest that point mutations in these candidate genes are causative of the disease by prediction analysis assays. Two to three gene defects can synergize to produce a more severe phenotype in POI patients than either alone. This study identifies for the first time in a large proportion of POI patients specific sets of germline mutations that, together, may account for this disease. Thus, oligogenicity also has implications for genetic counseling regarding POI
Novel NOBOX loss-of-function mutations account for 6.2% of cases in a large primary ovarian insufficiency cohort
International audienc
R-spondin2, a novel target of NOBOX: identification of variants in a cohort of women with primary ovarian insufficiency
Abstract Background R-spondin2 (Rspo2) is a secreted agonist of the canonical Wnt/ÎČ-catenin signaling pathway. Rspo2 plays a key role in development of limbs, lungs and hair follicles, and more recently during ovarian follicle development. Rspo2 heterozygous deficient female mice become infertile around 4Â months of age mimicking primary ovarian insufficiency (POI). The study aimed to investigate the regulation of RSPO2 and its potential involvement in pathophysiology of POI. Methods We cloned the RSPO2 promoter and performed transcriptional assays to determine if RSPO2 can be regulated by NOBOX, an ovarian transcription factor. Then, we evaluated 100 infertile women after obtaining a detailed history of the disease and follicle-stimulating hormone measurements, besides karyotype determination and fragile-X premutation syndrome investigation. All exons, intron-exon boundaries and untranslated regions of the RSPO2 gene were identified by sequencing, and the results were statistically analyzed. Results We found that RSPO2 can be regulated by NOBOX via the presence of NOBOX Binding Element in its promoter. Among 9 identified variants in POI women, 4 of them were equally homozygous, 4 have never been described (c.-359CÂ >Â G, c.-190GÂ >Â A, c.-170Â +Â 13CÂ >Â T and c.-169-8Â TÂ >Â A), only one c.557Â TÂ >Â C was predicted to alter a single amino acid in the RSPO2 protein (p.Leu186Pro). Conclusions RSPO2 is a novel target gene of the NOBOX key transcription factor, confirming its important role during the follicular growth in ovary. However, RSPO2 mutations are rare or uncommon in women with POI
Germline Prolactin Receptor Mutation Is Not a Major Cause of Sporadic Prolactinoma in Humans
International audienc
The tyrosine kinase inhibitor sunitinib affects ovulation but not ovarian reserve in mouse: A preclinical study
textabstractThe aim of the study was to evaluate ovarian toxicity of tyrosine kinase inhibitor (TKI) sunitinib, since only scarce data are available on gonadal function after this treatment. Six-weekold female mice received orally, once daily, vehicle or sunitinib (50 mg/kg/d) during 5 weeks. Fertility parameters were analyzed from ovulation to litter assessment. Sunitinib exposure significantly reduced (i) corpora lutea number per ovary (1.1 ± 0.38 in sunitinib group versus 4 ± 0.79 in control group, p<0.01) and (ii) serum Anti MĂŒllerian hormone (AMH) levels in sunitinib treated mice (12.01 ± 1.16) compared to control mice (14.33 ± 0.87 ng/ml, p< 0.05). However, primordial and growing follicles numbers per ovary were not different in both groups. After treatment withdrawal, female mice in both groups were able to obtain litters. These data could be helpful to counsel clinicians and patients, when fertility preservation methods are discussed, before TKI treatment in girls and young women