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Newlife India has done research on Genetics of ovarian failure. Maire Peter has done the research on the same. By virtue of the extenssive reasearch we are able to give best results on IVF treatments.
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Genetics of Ovarian Failure
By: Maire Peters
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PRESENTS
Age at natural menopause
• Menopause is the cessation of reproductive function of the human ovaries.
• The median age at menopause– in Europe from 50.1 to 52.8 years,– in North America from 50.5 to 51.4 years, – in Latin America from 43.8 to 53 years, – in Asia from 42.1 to 49.5 years.
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Premature menopause
• Premature ovarian failure/primary ovarian insufficiency (POF/POI) is a cause of female infertility due to the loss of normal ovarian function in women before the age of 40 years.
• POI affects approximately 1 in 10,000 women by age 20; 1 in 1,000 women by age 30; 1 in 100 women by age 40.
• Early menopause (EM) is defined as menopause occurring at 40-45 years of age. EM occurs in 5-10% of women.
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Mechanisms leading to POI
Persani L et al. J Mol Endocrinol 2010;45:257-279
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Causes of POI
Figure adapted from Shelling 2010
POI
Familial genetic causes
Autoimmune conditions
IdiopathicX
chromosome abnormalities
Iatrogenic agents
≈ 10%
≈5%
≈ 20%
≈ 65%
FOXL2 FSHR
≈ 25%
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X chromosome defects
X chromosome defects Frequency of POI Frequency in POI
Turner’s syndrome 100% 4-5%
FMR1 premutation 13-26% 15% (familial)3% (sporadic)
Translocations, deletions 80-100% Unknown
BMP15 variants 0-10% 1.5%
7-54 CGG repeats
55-200 CGG repeats
more than 200 repeats
Normal
Premutation
Full mutation
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Autosomal defectsAutosomal defects Frequency in POIComplex diseases: galactosemia (GALT), BPES (FOXL2), mitochondrial (POLG), ovarian leukodystrophy (EIF2B)
Rare
FSH/LH resistance (FSHR and LHR) <1%INHA variants unknownGDF9 variants ≈1%NOBOX, FIGLA unknown
Each single gene is responsible for less than 1-6% of POI.
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Genes involved in POI pathogenesis
Persani L et al. J Mol Endocrinol 2010;45:257-279
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GWASs in POI
Ethnicity Sample size (cases/controls)
Replication Region SNP Reference
Korean 24/24 98/218 - - Pyun et al., 2012
Chinese 391/895 400/800 8q22.3 8 SNPs Qin et al., 2012
European 99/235 60/90 - - Knauff et al., 2009
GWAS – Genome-wide association study
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Genes associated with age at natural menopause
Function Genes Related genes
DNA repair EXO1, HELQ, UIMC1, TLK1, POLG, PRIM1
FAM175A, FANCI
Immune function NLRP11, BAT2 IL11
X-chromosome inactivation
ASH2L EIF4EBP1
Hormonal regulation - FSHB
Known binding partner for FMR1
TDRD3
Various functions RHBDL2, FNDC4, MCM8, SYCP2L, TMEM150B
EIF2B4
These 17 variants explain 2.5–4.1% of the population variation in menopausal age (Stolk et al., 2012). 10
Genetics of early menopause
• EM has a substantial genetic component. • A woman whose mother had an EM has a 6-fold
increased risk of having EM.• Large GWAS with sample size of 3,500 cases
(women with menopause before 45 years of age) and 13,500 controls (Perry et al., 2013).
• For all 17 variants associated with age at natural menopause, the allele that was associated with younger menopause age was also associated with increased risk of EM and POI (Perry et al., 2013).
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Genetics of early menopause
• Combining the effect of the 17 variants shows a larger effect on EM risk than smoking.
• It is hypothesized that EM and POI represent the tail of the menopause distribution, with individuals carrying more age at menopause-lowering variants having increased risk of EM and POI (Perry et al., 2013).
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Future perspectives
The discovery of additional genetic components involved in the determination of menopause age should make it possible to predict the onset of menopause, enabling women to make informed reproductive choices.
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Thank you for your attention
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