How Old is Too Old?


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How Old is Too Old?

  1. 1. How Old is Too Old? Age, Genetics and Reproduction Marcelle I. Cedars, M.D. Director, Division of Reproductive Endocrinology UCSF
  2. 2. What is Reproductive Aging? <ul><li>Quantity: Natural process of oocyte loss </li></ul><ul><ul><li>Fourth month of fetal development </li></ul></ul><ul><ul><ul><li>6-7 million </li></ul></ul></ul><ul><ul><li>Birth </li></ul></ul><ul><ul><ul><li>1-2 million </li></ul></ul></ul><ul><ul><li>Menarche </li></ul></ul><ul><ul><ul><li>400,000 </li></ul></ul></ul><ul><ul><li>Loss acceleration (approx. age 37) </li></ul></ul><ul><ul><ul><li>25,000 </li></ul></ul></ul><ul><ul><li>Menopause </li></ul></ul><ul><ul><ul><li>1000 </li></ul></ul></ul><ul><li>Process: Apoptosis </li></ul>
  3. 4. What is Reproductive Aging? <ul><li>Quality: decreased implantation potential </li></ul><ul><ul><li>Increase in meiotic non-disjunction </li></ul></ul><ul><ul><ul><li>“ Production-line” theory </li></ul></ul></ul><ul><ul><ul><li>Accumulated damage </li></ul></ul></ul><ul><ul><ul><li>Deficiencies of the granulosa cells </li></ul></ul></ul>
  4. 5. Reproductive Aging: Why do we care? <ul><li>Changing Demographics </li></ul><ul><li>20% of women wait until they are at least 35 years of age before having their first child </li></ul><ul><ul><li>Establishment of a career </li></ul></ul><ul><ul><li>Awaiting a stable relationship </li></ul></ul><ul><ul><li>Desire for financial security </li></ul></ul><ul><ul><li>False sense of security provided by high-tech fertility procedures </li></ul></ul>
  5. 7. Normal Biological Decline Gougeon, Maturitas, 30:137-142, 1998
  6. 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
  7. 10. Concurrent Loss in Quantity AND Quality
  8. 11. Oocyte Quality <ul><li>Chromosomes and DNA </li></ul><ul><li>Mitochondria and ooplasm </li></ul>
  9. 12. Abnormalities in oocytes increase with age
  10. 14. Impact of Genetics on Ovarian Aging <ul><li>Complex Trait </li></ul><ul><ul><li>Genetic </li></ul></ul><ul><ul><ul><li>Familial association with age at menopause </li></ul></ul></ul><ul><ul><ul><li>30-85% estimates of heritability </li></ul></ul></ul><ul><ul><li>Environmental </li></ul></ul><ul><ul><ul><li>Oxidative stress </li></ul></ul></ul><ul><ul><ul><li>Alterations in blood flow </li></ul></ul></ul><ul><ul><ul><li>Toxins in the environment </li></ul></ul></ul>
  11. 16. Reproductive Aging Lifestyle Factors <ul><li>Cigarette smoking </li></ul><ul><ul><li>Female </li></ul></ul><ul><ul><ul><li>Affect the follicular microenvironment </li></ul></ul></ul><ul><ul><ul><li>Affect hormonal levels of the luteal phase </li></ul></ul></ul><ul><ul><ul><li>Accelerates oocyte loss (menopause 1-4 years earlier) </li></ul></ul></ul><ul><ul><li>Male </li></ul></ul><ul><ul><ul><li>Negative affect on sperm production, motility and morphology </li></ul></ul></ul><ul><ul><ul><li>Increased risk for DNA damage </li></ul></ul></ul>
  12. 17. Reproductive Aging Lifestyle Factors <ul><li>Weight: BMI < 20 or > 25 </li></ul><ul><ul><li>Female </li></ul></ul><ul><ul><ul><li>Alterations in hormonal profile and anovulation </li></ul></ul></ul><ul><ul><ul><li>Increased time to conception </li></ul></ul></ul><ul><ul><li>Male </li></ul></ul><ul><ul><ul><li>Increased time to conception </li></ul></ul></ul>
  13. 18. Reproductive Aging Lifestyle Factors <ul><li>Stress </li></ul><ul><ul><li>Lack of clear evidence </li></ul></ul><ul><ul><li>Difficult to measure </li></ul></ul><ul><ul><li>Some reduction with ART outcome noted </li></ul></ul><ul><li>Caffeine </li></ul><ul><ul><li>Studies with problems of recall bias </li></ul></ul><ul><ul><li>Suggestion of association with reduced fertility </li></ul></ul><ul><li>Alcohol </li></ul><ul><ul><li>Studies with problems of recall bias </li></ul></ul><ul><ul><li>Biological plausibility </li></ul></ul>
  14. 19. Reproductive Aging Lifestyle Factors <ul><li>Environmental Factors </li></ul><ul><ul><li>Organic solvents </li></ul></ul><ul><ul><li>Pesticides </li></ul></ul><ul><ul><li>Phthalates </li></ul></ul>
  15. 20. Loss of Ooctye Quality <ul><li>Abnormal fertilization, arrest of early development </li></ul><ul><li>Failure to implant </li></ul><ul><li>Post-implantation problems </li></ul><ul><ul><li>recognized loss </li></ul></ul><ul><ul><li>developmentally delayed child (down syndrome) </li></ul></ul>
  16. 21. Assessing Reproductive Age <ul><li>What are you measuring? </li></ul><ul><li>And Why? </li></ul><ul><li>Reproductive performance </li></ul><ul><ul><li>Response to stimulation </li></ul></ul><ul><ul><li>Live-born </li></ul></ul>
  17. 22. Assessing Reproductive Age <ul><li>Direct measures </li></ul><ul><ul><li>AFC/ovarian volume </li></ul></ul><ul><ul><li>Anti-mullerian Hormone (AMH) </li></ul></ul><ul><ul><li>Inhibin B </li></ul></ul><ul><li>Indirect measures </li></ul><ul><ul><li>FSH </li></ul></ul>
  18. 23. Reproductive Aging Is it Quantity or Quality <ul><li>FSH </li></ul><ul><ul><li>Indirect measure of follicular pool </li></ul></ul><ul><ul><ul><li>Decrease in inhibin B leads to increase FSH </li></ul></ul></ul><ul><ul><li>Not associated with increased risk of aneuploidy (vanMongfrans, 2004) </li></ul></ul><ul><ul><li>Decreased predictive ability in populations with a low prevalence (young women) </li></ul></ul>
  19. 24. <ul><li>Antral follicle count </li></ul><ul><ul><li>Cycle day </li></ul></ul><ul><ul><li>Follicle size </li></ul></ul><ul><ul><li>< 3 – diminished reserve </li></ul></ul>Evaluation of the Ovary Testing of Ovarian Reserve
  20. 25. Antral follicle count AFC = 18 AFC= 4
  21. 26. How to identify age-related problems? <ul><li>Body as “bioassay” </li></ul><ul><ul><li>Shortened menstrual cycles </li></ul></ul><ul><ul><li>Pre-cycle spotting </li></ul></ul>
  22. 28. Ovarian Reserve Testing <ul><li>Goal: To determine the functional capacity of the ovary. Specifically the quantity and quality of oocytes remaining. </li></ul>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. 29. Does Quantity = Quality? <ul><li>Quantity  number of oocytes retrieved </li></ul><ul><ul><li>Allows for selection </li></ul></ul><ul><ul><li>Allows for freezing </li></ul></ul><ul><ul><li>Affect on pregnancy rate/retrieval </li></ul></ul><ul><ul><li>BUT does quantity = quality?? </li></ul></ul><ul><li>Quality </li></ul><ul><ul><li>Pregnancy rate </li></ul></ul><ul><ul><li>Surrogate marker: Implantation rate per embryo transferred </li></ul></ul>
  24. 30. Does Quantity = Quality? <ul><li>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). </li></ul>
  25. 31. FSH Predicts Quantity, but not Quality P=0.3 P=0.05 P=0.06 P=0.01
  26. 32. AFC Predicts Quantity and Quality p=0.014 p=0.048 p<0.001 p<0.001
  27. 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
  28. 34. Quantity and Quality IR 21.6% 22.6% P=0.78 IR  Poor Responders 38.9% 14.5% P = 0.001
  29. 35. Decreased AFC 10 20 30 40 AFC Age # Follicles Reproductive window
  30. 36. Reproductive Aging Treatment <ul><li>Counsel couple </li></ul><ul><ul><li>Likelihood for success </li></ul></ul><ul><li>Prepare treatment schedule </li></ul><ul><ul><li>Stimulation based on ovarian (not chronological ) age </li></ul></ul>
  31. 38. Stimulations for Advanced Reproductive Aging <ul><li>High dose protocols </li></ul><ul><li>Flare protocols </li></ul><ul><li>Halt protocols </li></ul><ul><li>Antagonist protocols </li></ul><ul><li>What’s new? </li></ul><ul><ul><li>Estradiol priming </li></ul></ul><ul><ul><li>Minimal stimulation </li></ul></ul><ul><ul><li>Androgen pretreatment </li></ul></ul>
  32. 39. Estradiol Priming <ul><li>Goal: syncrhonize recruitment by preventing the premenstrual rise of FSH </li></ul>
  33. 40. Estradiol Priming addition of luteal phase GnRH antagonist
  34. 41. Minimal Stimulation <ul><li>Cancellation of a short treatment cycle is not a great burden.. </li></ul><ul><li>Few oocytes is not bad at all.. </li></ul><ul><li>Quality is more important than Quantity . </li></ul><ul><li>Less oocytes means less burden at aspiration… </li></ul><ul><li>Mild stimulation cycles have a higher repeat rate… </li></ul>
  35. 42. Minimal Stimulation
  36. 43. Minimal Stimulation Stimulation Mild: closed Conventional: open
  37. 44. Androgen Pretreatment <ul><li>Role of androgens in follicular development </li></ul><ul><ul><li>Precursors for ovarian estrogen synthesis </li></ul></ul><ul><ul><li>Augmentation of granulosa cell FSH receptor expression </li></ul></ul><ul><ul><li>Stimulate IGF-I and IGF-I receptor in preantral and antral follicles </li></ul></ul><ul><li>Aromatase inhibitors </li></ul><ul><li>Transdermal testosterone </li></ul><ul><li>DHEA </li></ul>
  38. 45. Androgen Pretreatment Balasch et al., 2006 Transdermal testosterone 2.5mg over 5 days
  39. 48. What to do? <ul><li>Early complete infertility evaluation </li></ul><ul><ul><li>including testing of ovarian reserve </li></ul></ul><ul><li>Limit treatment recommendations to 3-4 months </li></ul><ul><li>Improve endocrine environment/increase </li></ul><ul><li>egg number </li></ul>
  40. 51. IVF – Pregnancy and Livebirth CDC 2004
  41. 52. Decide What Is Important <ul><li>Having a child to raise </li></ul><ul><li>Being pregnant </li></ul><ul><li>Sharing genetic make-up with partner </li></ul>
  42. 53. Oocyte Donation <ul><li>Candidates </li></ul><ul><ul><li>diminished ovarian reserve </li></ul></ul><ul><ul><li>premature ovarian failure </li></ul></ul><ul><ul><li>genetic problems </li></ul></ul><ul><li>Success rate </li></ul><ul><ul><li>50-60%/cycle </li></ul></ul><ul><ul><li>70-90% cumulative </li></ul></ul><ul><li>Provides evidence that the age of the egg, NOT the uterus, is the critical factor </li></ul>
  43. 54. The Bottom Line <ul><li>Evaluate early </li></ul><ul><li>Give a fair estimate of outcome </li></ul><ul><li>Develop a time-limited treatment plan </li></ul>
  44. 55. Thank you for your attention