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 DeclineGougeon, 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 Geneticson 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