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 1976 1980 1985 1990 1995 35-39 30-34 40+ 15-19 25-29 20-24 CDC Vital and Health Statistics 2000

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

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 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)

Evaluation of the Ovary Testing of Ovarian Reserve Antral follicle count Cycle day Follicle size < 3 – diminished 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

AFC Predicts Quantity and Quality

Age is the Best Predictor of Quality IR = 28.4 PR = 28.7 IR = 15.9 p<0.001 p<0.001

Quantity and Quality IR Poor Responders IR P=0.78 21.6% 22.6% 38.9% 14.5% P = 0.001 P=0.78 21.6% 22.6%

Decreased AFC AFC Reproductive window # Follicles 10 20 30 40 Age

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 Success rate 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