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How Old is Too Old? Age, Genetics and Reproduction

How Old is Too Old? Age, Genetics and Reproduction. Marcelle I. Cedars, M.D. Director, Division of Reproductive Endocrinology UCSF. What is Reproductive Aging?. Quantity: Natural process of oocyte loss Fourth month of fetal development 6-7 million Birth 1-2 million Menarche 400,000

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How Old is Too Old? Age, Genetics and Reproduction

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  1. How Old is Too Old?Age, Genetics and Reproduction Marcelle I. Cedars, M.D. Director, Division of Reproductive Endocrinology UCSF

  2. What is Reproductive Aging? • Quantity: Natural process of oocyte loss • Fourth month of fetal development • 6-7 million • Birth • 1-2 million • Menarche • 400,000 • Loss acceleration (approx. age 37) • 25,000 • Menopause • 1000 • Process: Apoptosis

  3. What is Reproductive Aging? • Quality: decreased implantation potential • Increase in meiotic non-disjunction • “Production-line” theory • Accumulated damage • Deficiencies of the granulosa cells

  4. Reproductive Aging: Why do we care? • Changing Demographics • 20% of women wait until they are at least 35 years of age before having their first child • Establishment of a career • Awaiting a stable relationship • Desire for financial security • False sense of security provided by high-tech fertility procedures

  5. Normal Biological Decline Gougeon, Maturitas, 30:137-142, 1998

  6. 35-39 30-34 40+ 15-19 25-29 20-24 1976 1980 1985 1990 1995 Percent Increase in Birthrates CDC Vital and Health Statistics 2000

  7. Concurrent Loss in Quantity AND Quality

  8. Oocyte Quality • Chromosomes and DNA • Mitochondria and ooplasm

  9. Abnormalities in oocytes increase with age

  10. Impact of Genetics on Ovarian Aging • Complex Trait • Genetic • Familial association with age at menopause • 30-85% estimates of heritability • Environmental • Oxidative stress • Alterations in blood flow • Toxins in the environment

  11. Reproductive AgingLifestyle Factors • Cigarette smoking • Female • Affect the follicular microenvironment • Affect hormonal levels of the luteal phase • Accelerates oocyte loss (menopause 1-4 years earlier) • Male • Negative affect on sperm production, motility and morphology • Increased risk for DNA damage

  12. Reproductive AgingLifestyle Factors • Weight: BMI < 20 or > 25 • Female • Alterations in hormonal profile and anovulation • Increased time to conception • Male • Increased time to conception

  13. Reproductive AgingLifestyle Factors • Stress • Lack of clear evidence • Difficult to measure • Some reduction with ART outcome noted • Caffeine • Studies with problems of recall bias • Suggestion of association with reduced fertility • Alcohol • Studies with problems of recall bias • Biological plausibility

  14. Reproductive AgingLifestyle Factors • Environmental Factors • Organic solvents • Pesticides • Phthalates

  15. Loss of Ooctye Quality • Abnormal fertilization, arrest of early development • Failure to implant • Post-implantation problems • recognized loss • developmentally delayed child (down syndrome)

  16. Assessing Reproductive Age • What are you measuring? • And Why? • Reproductive performance • Response to stimulation • Live-born

  17. Assessing Reproductive Age • Direct measures • AFC/ovarian volume • Anti-mullerian Hormone (AMH) • Inhibin B • Indirect measures • FSH

  18. Reproductive AgingIs it Quantity or Quality • FSH • Indirect measure of follicular pool • Decrease in inhibin B leads to increase FSH • Not associated with increased risk of aneuploidy (vanMongfrans, 2004) • Decreased predictive ability in populations with a low prevalence (young women)

  19. Evaluation of the OvaryTesting of Ovarian Reserve • Antral follicle count • Cycle day • Follicle size • < 3 – diminished reserve

  20. Antral follicle count AFC = 18 AFC= 4

  21. How to identify age-related problems? • Body as “bioassay” • Shortened menstrual cycles • Pre-cycle spotting

  22. Ovarian Reserve Testing • Goal: To determine the functional capacity of the ovary. Specifically the quantity and quality of oocytes remaining. General Population Chance of conception Determine the time before ovarian aging begins Sub-fertile Population Chance of conception, with or without treatment Optimal dose or protocol for treatment Maheshwari, et al, 2006

  23. Does Quantity = Quality? • Quantity  number of oocytes retrieved • Allows for selection • Allows for freezing • Affect on pregnancy rate/retrieval • BUT does quantity = quality?? • Quality • Pregnancy rate • Surrogate marker: Implantation rate per embryo transferred

  24. Does Quantity = Quality? Markers of ovarian reserve, such as basal AMH or FSH levels and AFCs, can predict quantity of oocytes, but are not good predictors of oocyte quality (defined as pregnancy success).

  25. P=0.05 P=0.01 P=0.06 P=0.3 FSH Predicts Quantity, but not Quality

  26. p=0.048 p=0.014 p<0.001 p<0.001 AFC Predicts Quantity and Quality

  27. Age is the Best Predictor of Quality PR = 46.7 IR = 28.4 PR = 28.7 IR = 15.9 p<0.001 p<0.001

  28. IR Poor Responders P = 0.001 38.9% 14.5% Quantity and Quality IR P=0.78 21.6% 22.6%

  29. Decreased AFC AFC Reproductive window # Follicles 10 20 30 40 Age

  30. Reproductive AgingTreatment • Counsel couple • Likelihood for success • Prepare treatment schedule • Stimulation based on ovarian (not chronological ) age

  31. Stimulations for Advanced Reproductive Aging • High dose protocols • Flare protocols • Halt protocols • Antagonist protocols • What’s new? • Estradiol priming • Minimal stimulation • Androgen pretreatment

  32. Estradiol Priming • Goal: syncrhonize recruitment by preventing the premenstrual rise of FSH

  33. Estradiol Primingaddition of luteal phase GnRH antagonist

  34. Minimal Stimulation • Cancellation of a short treatment cycle is not a great burden.. • Few oocytes is not bad at all.. • Quality is more important than Quantity. • Less oocytes means less burden at aspiration… • Mild stimulation cycles have a higher repeat rate…

  35. Minimal Stimulation

  36. Minimal Stimulation Stimulation Mild: closed Conventional: open

  37. Androgen Pretreatment • Role of androgens in follicular development • Precursors for ovarian estrogen synthesis • Augmentation of granulosa cell FSH receptor expression • Stimulate IGF-I and IGF-I receptor in preantral and antral follicles • Aromatase inhibitors • Transdermal testosterone • DHEA

  38. Androgen Pretreatment Balasch et al., 2006 Transdermal testosterone 2.5mg over 5 days

  39. What to do? • Early complete infertility evaluation • including testing of ovarian reserve • Limit treatment recommendations to 3-4 months • Improve endocrine environment/increase egg number

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