How Old is Too Old?
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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.  
  • 4. What is Reproductive Aging?
    • Quality: decreased implantation potential
      • Increase in meiotic non-disjunction
        • “ Production-line” theory
        • Accumulated damage
        • Deficiencies of the granulosa cells
  • 5. 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
  • 6.  
  • 7. Normal Biological Decline Gougeon, Maturitas, 30:137-142, 1998
  • 8. Percent Increase in Birthrates CDC Vital and Health Statistics 2000 1976 1980 1985 1990 1995 35-39 30-34 40+ 15-19 25-29 20-24
  • 9.  
  • 10. Concurrent Loss in Quantity AND Quality
  • 11. Oocyte Quality
    • Chromosomes and DNA
    • Mitochondria and ooplasm
  • 12. Abnormalities in oocytes increase with age
  • 13.  
  • 14. 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
  • 15.  
  • 16. Reproductive Aging Lifestyle 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
  • 17. Reproductive Aging Lifestyle Factors
    • Weight: BMI < 20 or > 25
      • Female
        • Alterations in hormonal profile and anovulation
        • Increased time to conception
      • Male
        • Increased time to conception
  • 18. Reproductive Aging Lifestyle 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
  • 19. Reproductive Aging Lifestyle Factors
    • Environmental Factors
      • Organic solvents
      • Pesticides
      • Phthalates
  • 20. Loss of Ooctye Quality
    • Abnormal fertilization, arrest of early development
    • Failure to implant
    • Post-implantation problems
      • recognized loss
      • developmentally delayed child (down syndrome)
  • 21. Assessing Reproductive Age
    • What are you measuring?
    • And Why?
    • Reproductive performance
      • Response to stimulation
      • Live-born
  • 22. Assessing Reproductive Age
    • Direct measures
      • AFC/ovarian volume
      • Anti-mullerian Hormone (AMH)
      • Inhibin B
    • Indirect measures
      • FSH
  • 23. Reproductive Aging Is 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)
  • 24.
    • Antral follicle count
      • Cycle day
      • Follicle size
      • < 3 – diminished reserve
    Evaluation of the Ovary Testing of Ovarian Reserve
  • 25. Antral follicle count AFC = 18 AFC= 4
  • 26. How to identify age-related problems?
    • Body as “bioassay”
      • Shortened menstrual cycles
      • Pre-cycle spotting
  • 27.  
  • 28. 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
  • 29. 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
  • 30. 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).
  • 31. FSH Predicts Quantity, but not Quality P=0.3 P=0.05 P=0.06 P=0.01
  • 32. AFC Predicts Quantity and Quality p=0.014 p=0.048 p<0.001 p<0.001
  • 33. Age is the Best Predictor of Quality IR = 28.4 IR = 15.9 p<0.001 PR = 28.7 PR = 46.7 p<0.001
  • 34. Quantity and Quality IR 21.6% 22.6% P=0.78 IR  Poor Responders 38.9% 14.5% P = 0.001
  • 35. Decreased AFC 10 20 30 40 AFC Age # Follicles Reproductive window
  • 36. Reproductive Aging Treatment
    • Counsel couple
      • Likelihood for success
    • Prepare treatment schedule
      • Stimulation based on ovarian (not chronological ) age
  • 37.  
  • 38. Stimulations for Advanced Reproductive Aging
    • High dose protocols
    • Flare protocols
    • Halt protocols
    • Antagonist protocols
    • What’s new?
      • Estradiol priming
      • Minimal stimulation
      • Androgen pretreatment
  • 39. Estradiol Priming
    • Goal: syncrhonize recruitment by preventing the premenstrual rise of FSH
  • 40. Estradiol Priming addition of luteal phase GnRH antagonist
  • 41. 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…
  • 42. Minimal Stimulation
  • 43. Minimal Stimulation Stimulation Mild: closed Conventional: open
  • 44. 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
  • 45. Androgen Pretreatment Balasch et al., 2006 Transdermal testosterone 2.5mg over 5 days
  • 46.  
  • 47.  
  • 48. 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
  • 49.  
  • 50.  
  • 51. IVF – Pregnancy and Livebirth CDC 2004
  • 52. Decide What Is Important
    • Having a child to raise
    • Being pregnant
    • Sharing genetic make-up with partner
  • 53. Oocyte Donation
    • Candidates
      • diminished ovarian reserve
      • premature ovarian failure
      • genetic problems
    • Success rate
      • 50-60%/cycle
      • 70-90% cumulative
    • Provides evidence that the age of the egg, NOT the uterus, is the critical factor
  • 54. The Bottom Line
    • Evaluate early
    • Give a fair estimate of outcome
    • Develop a time-limited treatment plan
  • 55. Thank you for your attention