Sesh Kamal Sunkara - EXCEMED · 2015. 10. 26. · (Schreurs et al., Fertil Steril 2000; van der Ven...
Transcript of Sesh Kamal Sunkara - EXCEMED · 2015. 10. 26. · (Schreurs et al., Fertil Steril 2000; van der Ven...
Sesh Kamal Sunkara Aberdeen Fertility Centre
Aberdeen Maternity Hospital
University of Aberdeen
Aberdeen, UK
Declared no potential conflict of interest
Sesh Sunkara
Genetic aetiology of poor and hyper responders
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
Group I = 38 ICSI cycles in women with low level sex chromosome mosaicism Group II = 38 ICSI cycles in control group without chromosomal abnormality
Age (years) 33.3±0.95 33.6±0.80
Turner syndrome
Incidence: 1/ 2500 newborn girls
Ovarian dysgenesis
45% 45,X0 karyotype
Premature ovarian insufficiency with 45,X0 karyotype
Variable phenotype with mosaics related to proportion/ location of affected cells
Spectrum of POR to POI
46%
21%
16%
9%
4% 4%
45,X0
46,Xi(Xq)
45,X mosiacism
45,X/46,XrX
45,X/Y+mosaicism
46,XdelX, and others
Danodille et al., Eur J Endocrinol 2012
J Pediatr Adolesc Gynecol 2014
X chromosome regions for ovarian function
Portnoi et al., Hum Reprod 2006
X chromosome abnormalities and ovarian insufficiency
52%
29%
14%
5%
X numerical abnormalities X structural abnormalities
X-autosomal translocation XY cell line
Jiao et al., Hum Reprod 2012
Genes linked to ovarian function
De Vos et al., LANCET. 2010
FMR1 gene
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
X chromosome
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
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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