Norbert Gleicher MD David H Barad MD MS Genetically programmed premature ovarian aging the FMR1 gene Distribution of CGG Triple Repeat Expansions on the FMR1 in the Whole Study Population of Infertile Women in Comparison with a General Population ID: 1048171
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1. CHR Spring Research UpdateNorbert Gleicher, MDDavid H. Barad, MD, MS
2. Genetically programmed (premature) ovarian aging:the FMR1 gene.
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5. Distribution of CGG Triple Repeat Expansions on the FMR1 in the Whole Study Population of Infertile Women in Comparison with a General Population The figure demonstrates the distributions of CGG triple repeat counts on allele-1 (interrupted line) and allele-2 (solid line) against the shaded background distribution curve reported by Fu et al for a general population. Infertile women demonstrate a mild shift for allele-1and much clearer shift for allele-2 towards higher triple repeats.
6. Logistic Regressions in Groups A and CThe figure represents logistic regressions, demonstrating predicted relative risk (RR) of having AMH of less than 0.8 ng/ml over CGG repeat counts, stratified by age. Blue dots (and blue line) represent women ≥ 38 years of age; Red dots (and green line) represent age < 38 years. The black line reflects women of all ages. RR of diminished ovarian reserve, as reflected by AMH, progressively increases in the presence of CGG counts below and above 30 repeats. For every 5 repeat decrease in CGG count below 30, the relative risk of low AMH increases by 60%. For every 5 repeat increase in CGG repeat count above 30 the relative risk of low AMH is increased by 40%.
7. Triple CGG Counts by Box and Whisker Plotfor Entire Patient Population
8. Triple CGG Counts by Box and Whisker Plots for Individual Racial/Ethnic Groups
9. Heterozygous vs. Homozygous
10. Normal CGG range: 26-32Median CGG count: 30
11. Box and Whisker Plot,Defining Normal AMHLevels and OutliersThe figure reflects AMH levels in egg donors and infertility patients based on zygosity in women under age 38 years, when physiological diminution of ovarian reserve due to advancing age affects ovarian function only to a lesser degree. * Denotes one allele in normal count range (26-33) and one allele outside of normal range. ** Denotes both alleles outside of normal range. A reflects egg donors and B infertility patients. The bold horizontal line within each box reflects the median value.AMH values in egg donors did not vary statistically, though they seem to mildly trend upwards from normal to heterozygous and homozygous. Amongst infertility patients results differed significantly between the three patient groups (p=0.032). Specifically, homozygous women demonstrated significantly lower AMH levels than normal patients (p=0.009) and a strong trend towards lower levels in comparison to heterozygous women (p=0.063).
12. Linear Regression of Association between AMH Levels and Age Based on FMR1 StatusThe 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.
13. AMH Levels in Binned Age Groups Based on FMR1 StatusThe 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.
14. Barad et al. Obstet Gynecol 2007: 109; 1404-10.
15. Previously ReportedReproductive Benefits of DHEAImproves egg/embryo numbersImproves egg/embryo qualityImproves spontaneous pregnancy ratesImproves IVF pregnancy ratesImproves time to conceptionImproves cumulative pregnancy ratesCarson et al. Hum Reprod 2000 Barad and Gleicher, Hum Reprod 2006Barad and Gleicher, Fertil Steril 2005 Barad et al, J Assist Reprod Genet 2007
16. Survival Function for Cumulative Failure to Conceive Stratified by AgeCumulative Failure to ConceiveMonths Since Starting DHEA02 8641.21.0.8.2.4.6AGE >=42 38 ->42 <38
17. Cumulative pregnancy rate based on Cox regression of time from initial visit to clinical pregnancy or censor by DHEA use stratified by ovarian reserve and adjusted for ART treatment, race/ethnicity, age and baseline FSH (HR 3.8; 95% CI 1.2-11.8; p<0.05)Premature Ovarian AgingDiminished Ovarian ReserveDHEADHEAControlControlMonths from Initial VisitMonths from Initial VisitCumulative Pregnancy0.50.40.30.20.10.00.50.40.30.20.10.00 2 4 6 8 10 0 2 4 6 8 10 Barad et al. J Assist Reprod Genet 2007: 24; 629-634.
18. Comparison of Miscarriage Rates between DHEA Supplemented Infertility Patients and 2004 National US IVF Outcome Data.
19. AMH inhibits recruitment and growthLa Marca & Volpe: Clinical Endocrinology (2006) 64, 603–610
20. AMH is stable across the menstrual cycle
21. AMH / FSH and AGE Nomogram
22. Retrievals (by year and age)
23. AMH by Age Category
24. Percent Retrievals by Age and Year
25. Retrievals per Year %by Age