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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

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how old is too old age genetics and reproduction

How Old is Too Old?Age, Genetics and Reproduction

Marcelle I. Cedars, M.D.

Director, Division of Reproductive Endocrinology


what is reproductive aging
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 aging4
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
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
Normal Biological Decline

Gougeon, Maturitas, 30:137-142, 1998

percent increase in birthrates












Percent Increase in Birthrates

CDC Vital and Health Statistics 2000

oocyte quality
Oocyte Quality
  • Chromosomes and DNA
  • Mitochondria and ooplasm
impact of genetics on ovarian aging
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
Reproductive AgingLifestyle 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 factors17
Reproductive AgingLifestyle 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 factors18
Reproductive AgingLifestyle 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 factors19
Reproductive AgingLifestyle Factors
  • Environmental Factors
    • Organic solvents
    • Pesticides
    • Phthalates
loss of ooctye quality
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
Assessing Reproductive Age
  • What are you measuring?
  • And Why?
  • Reproductive performance
    • Response to stimulation
    • Live-born
assessing reproductive age22
Assessing Reproductive Age
  • Direct measures
    • AFC/ovarian volume
    • Anti-mullerian Hormone (AMH)
    • Inhibin B
  • Indirect measures
    • FSH
reproductive aging is it quantity or quality
Reproductive AgingIs 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
Evaluation of the OvaryTesting 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
How to identify age-related problems?
  • Body as “bioassay”
    • Shortened menstrual cycles
    • Pre-cycle spotting
ovarian reserve testing
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
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 quality30
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).

age is the best predictor of quality
Age is the Best Predictor of Quality

PR = 46.7

IR = 28.4

PR = 28.7

IR = 15.9



quantity and quality

IR Poor Responders

P = 0.001



Quantity and Quality





decreased afc
Decreased AFC




# Follicles

10 20 30 40


reproductive aging treatment
Reproductive AgingTreatment
  • Counsel couple
    • Likelihood for success
  • Prepare treatment schedule
    • Stimulation based on ovarian (not chronological ) age
stimulations for advanced reproductive aging
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
Estradiol Priming
  • Goal: syncrhonize recruitment by preventing the premenstrual rise of FSH
minimal stimulation
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 stimulation43
Minimal Stimulation


Mild: closed

Conventional: open

androgen pretreatment
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 pretreatment45
Androgen Pretreatment

Balasch et al., 2006

Transdermal testosterone

2.5mg over 5 days

what to do
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

decide what is important
Decide What Is Important
  • Having a child to raise
  • Being pregnant
  • Sharing genetic make-up with partner
oocyte donation
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
The Bottom Line
  • Evaluate early
  • Give a fair estimate of outcome
  • Develop a time-limited treatment plan