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How Old is Too Old? Age, Genetics and Reproduction Marcelle I. Cedars, M.D. Director, Division of Reproductive Endocrinology UCSF Slide 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 Slide 3 Slide 4 What is Reproductive Aging? Quality: decreased implantation potential Increase in meiotic non-disjunction Production-line theory Accumulated damage Deficiencies of the granulosa cells Slide 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 Slide 6 Slide 7 Normal Biological Decline Gougeon, Maturitas, 30:137-142, 1998 Slide 8 1976 1980 19851990 1995 35-39 30-34 40+ 15-19 25-29 20-24 Percent Increase in Birthrates CDC Vital and Health Statistics 2000 Slide 9 Slide 10 Concurrent Loss in Quantity AND Quality Slide 11 Oocyte Quality Chromosomes and DNA Mitochondria and ooplasm Slide 12 Abnormalities in oocytes increase with age Slide 13 Slide 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 Slide 15 Slide 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 Slide 17 Reproductive Aging Lifestyle Factors Weight: BMI 25 Female Alterations in hormonal profile and anovulation Increased time to conception Male Increased time to conception Slide 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 Slide 19 Reproductive Aging Lifestyle Factors Environmental Factors Organic solvents Pesticides Phthalates Slide 20 Loss of Ooctye Quality Abnormal fertilization, arrest of early development Failure to implant Post-implantation problems recognized loss developmentally delayed child (down syndrome) Slide 21 Assessing Reproductive Age What are you measuring? And Why? Reproductive performance Response to stimulation Live-born Slide 22 Assessing Reproductive Age Direct measures AFC/ovarian volume Anti-mullerian Hormone (AMH) Inhibin B Indirect measures FSH Slide 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) Slide 24 Antral follicle count Cycle day Follicle size < 3 diminished reserve Evaluation of the Ovary Testing of Ovarian Reserve Slide 25 Antral follicle count AFC = 18 AFC= 4 Slide 26 How to identify age-related problems? Body as bioassay Shortened menstrual cycles Pre-cycle spotting Slide 27 Slide 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 Slide 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 Slide 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). Slide 31 FSH Predicts Quantity, but not Quality P=0.3 P=0.05 P=0.06 P=0.01 Slide 32 AFC Predicts Quantity and Quality p=0.014 p=0.048 p