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CHR Research Update. David H Barad, MD 1,2 Norbert Gleicher, MD 1,3

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chr research update

CHR Research Update

David H Barad, MD1,2

Norbert Gleicher, MD1,3

1Center for Human Reproduction and Foundation for Reproductive Medicine; 2 Department of Obstetrics, Gynecology and Women’s Health, Albert Einstein College of Medicine; 3 Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine

slide2

The speaker declares the potential conflicts of interest.

Dr. Gleicher and Dr. Barad are listed as co-inventors on an already awarded and other pending patent applications which claim therapeutic benefits of DHEA in women with diminished ovarian reserve. Dr.s Gleicher and Barad are also listed as co-inventor son a pending patent application, which claims diagnostic benefits from evaluating the FMR1 gene in regards to ovarian reserve. Both doctors have received research support, speakers fees and travel funds from various pharmaceutical companies, none in any way related to the topic of this presentation.

slide3

The speakers declare that no brand-name medications and/or off-label, non-FDA-approved uses are discussed in the lecture.

slide5

How to measure aging?

How to treat aging?

how to measure aging
How to measure aging
  • FSH
  • AMH
  • AFC
  • CCT
  • FMR1

Appears to regulate ovarian reserve

box and whisker plot defining normal range of cgg repeats
Box and Whisker Plot, defining normal range of CGG repeats

This box and whisker plot for the whole study population of 339 women reconfirmed the previously defined normal range of 26-32 CGG repeats (median 30). The graph in the right lower corner represents the frequency distribution of individual alleles, confirming the median CGG count at 30.

Gleicher et al., RBN Online ; in press.

triple cgg counts by box and whisker plots for individual racial ethnic groups
Triple CGG counts by box and whisker plots for individual racial/ethnic groups

Gleicher et al RBM Online 2010;20:485-91.

fmr1 genotypes
FMR1 Genotypes
  • Normal: both alleles in 26 – 34 range
  • Heterozygous: one allele in 26 – 34 range one allele <26 or >34
    • Het-norm/low
    • Het-norm/high
  • Homozygous: both alleles outside of 26 – 34

range

linear regression of association between amh levels and age based on fmr1 status
Linear regression of association between AMH levels and age based on FMR1 status

The figure represents egg donors and infertility patients at all ages. Normal females at young ages have the highest, and women with homozygous CGG count abnormalities the lowest AMH levels. AMH levels, however, decline in normal women more rapidly than in heterozygous and homozygous patients. At approximately 35 years of age AMH levels in heterozygous women start to exceed those of normal women. AMH levels in homozygous women track those of normal women almost till age 50, when they start exceeding the latter.

Gleicher et al. Reprod Biomed Online; In Press.

amh levels in binned age groups based on fmr1 status
AMH levels in binned age groups based on FMR1 status

The figure represents egg donors and infertility patients of all ages. Under age 30years AMH levels significantly differ amongst all three patient groups (p=0.009). Specifically, AMH in normal women is significantly higher between normal women and homozygous females (p<0.001) and between heterozygous and homozygous patients (p=0.002). By age 34.99, these statistical differences no longer are present.

Gleicher et al. Reprod Biomed Online; In Press.

conclusions
Conclusions

Abnormal CGG counts on FMR1 denote risk for POA

Women identified at risk can be monitored with AMH

Continued POA→ Fertility preservation

→ Change in reproductive

planning

thyroid adrenal
Thyroid/Adrenal
  • Function
  • Autoimmunity
      • Suppressing
      • Stimulating
slide19

We previously postulated the presence of autoimmune-induced ovarian hyperactivity (PCO, stimulating antibodies) and hypoactivity (POA, suppressiveautoantibodies)

Gleicher et al, Autoimmune Rev, 2007;7:42-45.

slide20

Evidence of autoimmune activation in women with different FMR1-genotypes

Gleicher et al, ASRM, 2010.

materials methods
Materials & Methods
  • 339 consecutive patients
    • 183 (50.0%) norm
    • 62 (18.3%) het – norm/high
    • 94 (27.7%) het – norm/low
  • 206 (60.8%) no autoimmunity
  • 133 (39.2%) autoimmune +
  • 75 PCO (≥12 oocytes / AMH >4.0ng/mL)
slide22

P=0.003

P<0.0001

conclusions23
Conclusions

Het – norm/low defines an autoimmune-associated, quickly OR-depleting PCO phenotype, while het – norm/high defines low autoimmune risk

Confirms involvement of FMR1 in recruitment and functional OR

Establishes an association between het – norm/low genotype and female autoimmunity

slide24

Pregnancy chances based on FMR1 genotype

Gleicher et al, ASRM, 2010.

materials methods25
Materials & Methods

455 consecutive IVF cycles

Autoimmune profile: Y/N

FMR1 genotype

Multiple regression analyses adjusted for age, race, medication dosage, number of oocytes

results cont
Results cont.

Adjusted for age, het-norm/low maintained lowest rates (p=0.001), but significance was lost with adjustment for race, medication and oocyte numbers.

Controlling for all covariates, autoimmunity almost reached significance (p=0.06).

conclusions28
Conclusions

FMR1 genotype is predictive of pregnancy chances

Loss of significance with adjustment for ovarian factors suggests/confirms a direct effect of FMR1 on the ovary

In contrast, actual significance of autoimmunity independently may suggest an autoimmune effect not mediated by ovaries.

literature search
Literature Search
  • PubMed, Medline
  • Keywords/phrases
        • Autoimmunity
        • X chromosome
        • FMR1 gene
        • Xq27 region
results31
Results
  • Autoimmunity & POI/POF closely associated with X chromosome defects
      • Turner syndrome (XO)
turner syndrome xo
Turner Syndrome (XO)

Xq terminal deletions common

Often large & characterized by 1o/2o amenorrhea

Xq21 → 2o amenorrhea (FMR1 at Xq27)

Fertile Turners → proximal Xq deletions

POI: 4Mb locus exactly at Xq27-q28

turner syndrome xo cont
Turner Syndrome (XO) cont.
  • Small Xq27-q28 deletions → variable phenotypes, some early menopause but able to reproduce
  • Increased autoimmunity
      • Diseases
      • Autoantibodies
balanced translocations
Balanced Translocations

Only Xq23-q27 deletions associated with POI/POF

autoimmunit y in general associated with more non disjunctional events
Autoimmunity in general associated with more non-disjunctional events:

Down Syndrome

Klinefelter Syndrome

Turner Syndrome

slide36

Autoimmunity high in practically all X-linked disorders

  • May, therefore, be caused by genes/mutations on the X chromosome
summary
Summary

The long arm of the X chromosome is of paramount importance for autoimmunity as well as POI/POF

FMR1 maps to Xq27

slide41

Non-disjunctional events

  • Chromosomal abnormalities
  • Miscarriages
slide44
DHEA
  • Reduces (?) aneuploidy

Gleicher et al, ASRM 2007

  • Significantly reduces miscarriages

Gleicher et al, ReprodBiol & Endocrinol 2009;7:108

slide45
Comparison of miscarriage rates between DHEA supplemented infertility patients and 2004 national US IVF outcome data.

Gleicher et al. ReprodBiolEndocrinol 2009:108.

results46
RESULTS

When miscarriage rates were compared, equalized for number of patients, dhea supplementation reduced miscarriage rates even more significantly (p<0.0001), suggestive of a reduction of ~80%

slide47

Indirect proof

But direct evidence still lacking

materials methods48
Materials & Methods

22 DOR patients on DHEA

Each matched with 2 controls (no DHEA) based on age, years of cycle (mostly normal OR)

Univariate general linear model to assess DHEA effects on % aneuploidy after adjustments for age, indications for PGS, stimulation, gonadotropin dosage

results cont50
Results cont.

DHEA effects remained significant after adjustments (Exception: PGS for gender had lower aneuploidy; p<0.007)

Greatest reduction in aneuploidy with short-term treatment (4-12 weeks) (21.6% 95%CI – 2.871 – 46.031)

conclusion
Conclusion

First direct evidence that DHEA positively affects non-disjunctional events (aneuploidy)

slide52
DHEA

Positively affects autoimmunity

Autoimmunity increases non-disjunctional events

Does DHEA affect ovaries by reducing autoimmune effects?

slide53

?

?

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