Sesh Kamal Sunkara Aberdeen Fertility Centre Aberdeen Maternity Hospital University of Aberdeen Aberdeen, UK Declared no potential conflict of interest
Genetic aetiology of poor and hyper responders Sesh Sunkara
Background Poor and hyper responders: two ends of the spectrum of response to ovarian stimulation Challenge to controlled ovarian stimulation (COS) Implications for IVF outcomes Long term consequences health implications
Poor ovarian response Depletion of ovarian follicle pool Insufficient initial follicle number Accelerated follicle loss Ovarian follicle dysfunction Signalling defect Enzyme deficiency Autoimmunity De Vos et al., LANCET. 2010
POR: aetiology Advanced age Genetic conditions Chromosomal anomalies Gene mutations Acquired conditions Endometriomas Chemo/ radiotherapy Ovarian surgery De Vos et al., LANCET. 2010
POR: genetic aetiology Chromosomal abnormalities Numerical: Turner syndrome Structural: macrodeletions (Xq; Xp) Genetic variations FMR1 FSH receptor mutation LH β polypeptide mutation De Vos et al., LANCET. 2010
Chromosomal abnormalities Higher incidence among subfertile women vs general population 1.5% - 3.3% vs 0.16% (Schreurs et al., Fertil Steril 2000; van der Ven et al., Hum Reprod 2000) Only small to moderate reproductive risk X chromosome loss - significant correlation with female age (Guttenbach et al., Am J Hum Genet 1995)
Sex chromosome aneuploidy Low level sex chromosome mosaicism Twice more common among subfertile women 9.6% vs 4.8% (Morel et al., Hum Reprod 2002) Impact of X chromosome mosaicism on IVF outcome? Congenital vs acquired age related mosaicism
Age (years) 33.3±0.95 33.6±0.80 Group I = 38 ICSI cycles in women with low level sex chromosome mosaicism Group II = 38 ICSI cycles in control group without chromosomal abnormality
Turner syndrome 4% 4% Incidence: 1/ 2500 newborn girls Ovarian dysgenesis 45% 45,X0 karyotype 9% 45,X0 46,Xi(Xq) 46% 45,X mosiacism 16% 45,X/46,XrX 45,X/Y+mosaicism 46,XdelX, and others 21% Danodille et al., Eur J Endocrinol 2012 Premature ovarian insufficiency with 45,X0 karyotype Variable phenotype with mosaics related to proportion/ location of affected cells Spectrum of POR to POI
J Pediatr Adolesc Gynecol 2014
X chromosome regions for ovarian function Portnoi et al., Hum Reprod 2006
X chromosome abnormalities and ovarian insufficiency X numerical abnormalities X-autosomal translocation X structural abnormalities XY cell line 5% 14% 52% 29% Jiao et al., Hum Reprod 2012
Genes linked to ovarian function De Vos et al., LANCET. 2010
FMR1 gene X chromosome FMR1 (fragile X mental retardation 1) gene located on the long (q) arm of the X chromosome at position 27.3 Codes for fragile X mental retardation protein (FMRP) FMRP essential for cognitive development and female reproductive function
FMR1 gene FMR1 gene contains a DNA segment CGG trinucleotide Four categories based on CGG repeat length Normal: FMR1 CGG repeat length < 45 Intermediate or gray zone : 45 54 repeats Premutation: 55 199 repeats Full mutation: 200 CGG repeats
FMR1 gene CGG repeats and ovarian reserve Gleicher et al., Fertil Steril 2009
FMR1 gene CGG repeats and ovarian function Karimov et al., Hum Reprod 2011 FMR1 premutation identified in 0.8 13% of women with PO1 (Conway et al., Hum Reprod 1998; Murray etal., J Med Genet 1998; Gersak et al., Hum Reprod 2003; Bussani et al., Eur J Obstet Gynecol Reprod Biol 2004)
FMR1 premutation and ovarian insufficiency Tosh et al., Arch Gynecol Obstet 2014
FSH receptor gene Chromosome 2p21 p16 Rousseau-Merck et al., Genomics 1992
FSH receptor genotype and ovarian response Perez Mayorga et al., JCEM 2000
Genetics of PCOS Complex polygenic trait Several genes in the multiple biochemical pathways implicated Genes involved in ovarian steroidogenic hormones Genes involved in steroid hormone effects Gonadotrophin release and action genes Insulin secretion and action genes Adipose tissue metabolism genes Pro-inflammatory cytokine/ cytokine receptor genes
Interaction of genetics and environment Deligeoroglou et al., Gynecol Endocrinol 2009
Genes involved in steroid biosynthesis HSD17B5 CYP19 Qin et al., JCEM 2006, Jin et al., BMC Med Genet 2012
Genes involved in steroid hormone effect Higher frequency of AR gene polymorphism in PCOS (Hickey et al., JCEM 2002) Correlation between increased serum testosterone and AR gene polymorphism Positive correlation between SHBG gene polymorphism and PCOS (Ferk et al., Hum Reprod 2007) Decreased SHBG concentrations contribute to increased androgen output to tissues
Genes related to insulin Genes related to insulin secretion and action Insulin gene on chromosome 11 Insulin receptor gene on chromosome 19 Insulin receptor substrate (IRS) -1 gene (Ruan et al., Endocr J 2012) IRS 2 gene Insulin growth factor (IGF) 1 gene IGF 2 gene (Millan et al., JCEM 2004)
Genetic basis of PCOS PCOS genes still await clearer unfolding Difficulties with genetic studies in PCOS Different diagnostic criteria Varied phenotypes Inadequate understanding of the pathophysiology Small sample size Failure to attempt replication of findings Lack of an animal model
Genetic basis of PCOS
Genome wide association studies Significant copy number variations (CNVs) among women with POI (Aboura et al., JCEM 2009) Strong association between PCOS and 3 loci: 2p16.3, 2p21 and 9q33.3 (Chen et al., Nat Genet 2011)
Conclusion Underlying genetics determining Ovarian reserve Ovarian response to stimulation POR and POI Hyper response and susceptibility to OHSS Further elucidation with advances in genetic evaluation Incorporation of pharmacogenomics into individualised fertility management
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