Association of genetic markers within the BMP15 gene with anovulation and infertility in women with polycystic ovary syndrome

González, Alejandro Rodríguez; Ramírez-Lorca, Reposo; Calatayud, Carmen Ródenas; Mendoza, Nicolás; Ruiz, Agustı́n; Sáez, María Eugenia; Morón, Francisco Jesús

doi:10.1016/j.fertnstert.2007.06.083

Cited by 21 publications

(19 citation statements)

References 16 publications

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“…In women with PCOS, patients carrying the heterozygous genotype for BMP15 gene present an advantage for fecundity, with a protective effect against anovulation and infertility [11]. In a recent published work, the same BMP15 markers associated with anovulation and infertility in PCOS women are associated with high follicle production in patients undergoing COH [37].…”

Section: Discussionmentioning

confidence: 94%

“…Transgenic deletions and other modifications in mice [8], sheep [9] and humans [10,11] have provided much of the new information on the mechanisms by which the oocyte affects follicular development [12,13]. The synergistic process of folliculogenesis is regulated mainly by GDF9 and BMP15 as well as their receptors (e.g., BMPR2, TR1, and BMPR1B) [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

“…The synergistic process of folliculogenesis is regulated mainly by GDF9 and BMP15 as well as their receptors (e.g., BMPR2, TR1, and BMPR1B) [14][15][16][17]. These two members of the TGF-β superfamily are coexpressed in human oocytes and play a fundamental role in granulosa cells steroidogenesis, ovulation, oocyte maturation, and embryo development in mammals [11,18,19].…”

Section: Introductionmentioning

confidence: 99%

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Single-cell expression analysis of BMP15 and GDF9 in mature oocytes and BMPR2 in cumulus cells of women with polycystic ovary syndrome undergoing controlled ovarian hyperstimulation

Resende

Vireque

Santana

et al. 2012

J Assist Reprod Genet

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Purpose To detect expression of bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9) in oocytes, and their receptor type 2 receptor for BMPs (BMPR2) in cumulus cells in women with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization (IVF), and determine if BMPR2, BMP15, and GDF9 expression correlate with hyperandrogenism in FF of PCOS patients. Methods Prospective case-control study. Eighteen MIIoocytes and their respective cumulus cells were obtained from 18 patients with PCOS, and 48 MII-oocytes and cumulus cells (CCs) from 35 controls, both subjected to controlled ovarian hyperstimulation (COH), and follicular fluid (FF) was collected from small (10-14 mm) and large (>18 mm) follicles. RNeasy Micro Kit (Qiagen ® ) was used for RNA extraction and gene expression was quantified in each oocyte individually and in microdissected cumulus cells from cumulus-oocyte complexes retrieved from preovulatory follicles using qRT-PCR. Chemiluminescence and RIA assays were used for hormone assays. Results BMP15 and GDF9 expression per oocyte was higher among women with PCOS than the control group. A positive correlation was found between BMPR2 transcripts and hyperandrogenism in FF of PCOS patients. Progesterone values in FF were lower in the PCOS group. Conclusion We inferred that BMP15 and GDF9 transcript levels increase in mature PCOS oocytes after COH, and might inhibit the progesterone secretion by follicular cells in PCOS follicles, preventing premature luteinization in cumulus cells. BMPR2 expression in PCOS cumulus cells might be regulated by androgens.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Single-cell expression analysis of BMP15 and GDF9 in mature oocytes and BMPR2 in cumulus cells of women with polycystic ovary syndrome undergoing controlled ovarian hyperstimulation

Resende

Vireque

Santana

et al. 2012

J Assist Reprod Genet

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show abstract

“…Indeed, a mutational screening of the BMP15 open reading frame (which included a short 5′exon 1-UTR region and intron-exon boundaries) in a panel of 202 Indian women with POF revealed that the c.-9G allele was part of a haplotype associated with the phenotype (Dixit et al, 2006). A study of 398 polycystic ovary syndrome (PCOS) women showed that, although the c.-9C>G variant was not related to disease pathogenesis, it might have been associated with specific clinical features, such as infertility (Gónzalez et al, 2008). Additionally, the c.-9C/G alleles have been related to differential ovarian response to recombinant FSH (rFSH) during assisted reproduction techniques, as the G allele has been linked to high responders Hanevik et al, 2011;Morón et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, although the gene's complete promoter region has not been sequenced in large panels of patients, previous reports have suggested a functional association between the c.-9C>G sequence variant and ovarian phenotypes, including POF (Dixit et al, 2006;Gónzalez et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

BMP15 c.-9C>G promoter sequence variant may contribute to the cause of non-syndromic premature ovarian failure

Fonseca

Ortega‐Recalde

Esteban-Pérez

et al. 2014

Reproductive BioMedicine Online

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BMP15 has drawn particular attention in the pathophysiology of reproduction, as its mutations in mammalian species have been related to different reproductive phenotypes. In humans, BMP15 coding regions have been sequenced in large panels of women with premature ovarian failure (POF), but only some mutations have been definitely validated as causing the phenotype. A functional association between the BMP15 c.-9C>G promoter polymorphism and cause of POF have been reported. The aim of this study was to determine the potential functional effect of this sequence variant on specific BMP15 promoter transactivation disturbances. Bioinformatics was used to identify transcription factor binding sites located on the promoter region of BMP15. Reverse transcription polymerase chain reaction was used to study specific gene expression in ovarian tissue. Luciferase reporter assays were used to establish transactivation disturbances caused by the BMP15 c.-9C>G variant. The c.-9C>G variant was found to modify the PITX1 transcription factor binding site. PITX1 and BMP15 co-expressed in human and mouse ovarian tissue, and PITX1 transactivated both BMP15 promoter versions (-9C and -9G). It was found that the BMP15 c.-9G allele was related to BMP15 increased transcription, supporting c.-9C>G as a causal agent of POF.

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Effect of the interaction of metformin and bone morphogenetic proteins on ovarian steroidogenesis by human granulosa cells

Iwata

Hasegawa²,

Fujita³

et al. 2018

Biochemical and Biophysical Research Communications

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In the present study, we studied the effects of metformin and its interactions with the actions of bone morphogenetic proteins (BMPs) on ovarian steroidogenesis. It was revealed that metformin treatment enhanced progesterone production by human granulosa KGN cells and rat primary granulosa cells induced by forskolin and FSH, respectively. In human granulosa cells, it was found that metformin treatment suppressed phosphorylation of Smad1/5/9 activated by BMP-15 compared with that induced by other BMP ligands. Moreover, metformin treatment increased the expression of inhibitory Smad6, but not of that Smad7, in human granulosa cells, while metformin had no significant impact on the expression levels of BMP type-I and -II receptors. Thus, the mechanism by which metformin suppresses BMP-15-induced Smad1/5/9 phosphorylation is likely, at least in part, to be upregulation of inhibitory Smad6 expression in granulosa cells. The results suggest the existence of functional interaction between metformin and BMP signaling, in which metformin enhances progesterone production by downregulating endogenous BMP-15 activity in granulosa cells.

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Association of genetic markers within the BMP15 gene with anovulation and infertility in women with polycystic ovary syndrome

Cited by 21 publications

References 16 publications

Single-cell expression analysis of BMP15 and GDF9 in mature oocytes and BMPR2 in cumulus cells of women with polycystic ovary syndrome undergoing controlled ovarian hyperstimulation

Single-cell expression analysis of BMP15 and GDF9 in mature oocytes and BMPR2 in cumulus cells of women with polycystic ovary syndrome undergoing controlled ovarian hyperstimulation

BMP15 c.-9C>G promoter sequence variant may contribute to the cause of non-syndromic premature ovarian failure

Effect of the interaction of metformin and bone morphogenetic proteins on ovarian steroidogenesis by human granulosa cells

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