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    Presentation Marcelle Presentation Marcelle Presentation Transcript

    • 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
        • Loss acceleration (approx. age 37)
          • 25,000
        • Menopause
          • 1000
      • Process: Apoptosis
    •  
    • What is Reproductive Aging?
      • Quality: decreased implantation potential
        • Increase in meiotic non-disjunction
          • “ Production-line” theory
          • Accumulated damage
          • Deficiencies of the granulosa cells
    • 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
    •  
    • Normal Biological Decline Gougeon, Maturitas, 30:137-142, 1998
    • 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
    •  
    • Concurrent Loss in Quantity AND Quality
    • Oocyte Quality
      • Chromosomes and DNA
      • Mitochondria and ooplasm
    • Abnormalities in oocytes increase with age
    •  
    • 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
    •  
    • 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
    • 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
    • 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
    • Reproductive Aging Lifestyle Factors
      • Environmental Factors
        • Organic solvents
        • Pesticides
        • Phthalates
    • Loss of Ooctye Quality
      • Abnormal fertilization, arrest of early development
      • Failure to implant
      • Post-implantation problems
        • recognized loss
        • developmentally delayed child (down syndrome)
    • Assessing Reproductive Age
      • What are you measuring?
      • And Why?
      • Reproductive performance
        • Response to stimulation
        • Live-born
    • Assessing Reproductive Age
      • Direct measures
        • AFC/ovarian volume
        • Anti-mullerian Hormone (AMH)
        • Inhibin B
      • Indirect measures
        • FSH
    • 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)
      • Antral follicle count
        • Cycle day
        • Follicle size
        • < 3 – diminished reserve
      Evaluation of the Ovary Testing of Ovarian Reserve
    • Antral follicle count AFC = 18 AFC= 4
    • How to identify age-related problems?
      • Body as “bioassay”
        • Shortened menstrual cycles
        • Pre-cycle spotting
    •  
    • 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
    • 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
    • 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).
    • FSH Predicts Quantity, but not Quality P=0.3 P=0.05 P=0.06 P=0.01
    • AFC Predicts Quantity and Quality p=0.014 p=0.048 p<0.001 p<0.001
    • 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
    • Quantity and Quality IR 21.6% 22.6% P=0.78 IR  Poor Responders 38.9% 14.5% P = 0.001
    • Decreased AFC 10 20 30 40 AFC Age # Follicles Reproductive window
    • Reproductive Aging Treatment
      • Counsel couple
        • Likelihood for success
      • Prepare treatment schedule
        • Stimulation based on ovarian (not chronological ) age
    •  
    • Stimulations for Advanced Reproductive Aging
      • High dose protocols
      • Flare protocols
      • Halt protocols
      • Antagonist protocols
      • What’s new?
        • Estradiol priming
        • Minimal stimulation
        • Androgen pretreatment
    • Estradiol Priming
      • Goal: syncrhonize recruitment by preventing the premenstrual rise of FSH
    • Estradiol Priming addition of luteal phase GnRH antagonist
    • 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…
    • Minimal Stimulation
    • Minimal Stimulation Stimulation Mild: closed Conventional: open
    • 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
    • Androgen Pretreatment Balasch et al., 2006 Transdermal testosterone 2.5mg over 5 days
    •  
    •  
    • 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
    •  
    •  
    • IVF – Pregnancy and Livebirth CDC 2004
    • Decide What Is Important
      • Having a child to raise
      • Being pregnant
      • Sharing genetic make-up with partner
    • 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
    • The Bottom Line
      • Evaluate early
      • Give a fair estimate of outcome
      • Develop a time-limited treatment plan
    • Thank you for your attention