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

Thank you

Thank you

Thank you

Thank you