Transcript 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
UCSF
What is Reproductive Aging?
 Quantity: Natural process of oocyte
– 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
loss
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
35
30
Preantral (0.15-0.2 mm)
25
Early Antral (0.2-0.4 mm)
20
Small Antral (0.4-0.9 mm)
15
Small Antral (1-2 mm)
10
Selectable (2-5 mm) - Only
follicles seen by ultrasound
5
0
19-30
31-35
36-40
41-45
>45
Gougeon, Maturitas, 30:137-142, 1998
Percent Increase in Birthrates
200
35-39
180
30-34
40+
160
140
120
15-19
25-29
20-24
100
80
60
40
20
0
1976
1980
1985
1990
1995
CDC Vital and Health Statistics
2000
Birthrate (births per 1000 women)
Birthrates by Maternal Age
140
120
25-29
20-24
100
30-34
80
60
15-19
40
35-39
20
0
40+
1976
1980
1985
Year
1990
1995
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
 Increased time to conception
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
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
Sub-fertile Population
Chance of conception
Determine the time before
ovarian aging begins
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
60
Younger,
Normal FSH
50
40
Younger,
High FSH
P=0.05
30
20
Older, Low
FSH
P=0.01
P=0.06
10
P=0.3
0
IR
Pregnancy Rates
Older, High
FSH
AFC Predicts Quantity
and Quality
50
45
40
35
30
25
20
15
10
5
0
Younger,
Normal AFC
p=0.048
Younger,
Low AFC
Older,
Normal AFC
p=0.014
p<0.001
p<0.001
IR
Pregnancy Rates
Older, Low
AFC
Age is the Best
Predictor of Quality
60
PR = 46.7
Younger,
Normal FSH
50
40
IR = 28.4
PR = 28.7
30
20
10
Younger,
High FSH
Older, Low
FSH
IR = 15.9
Older, High
FSH
p<0.001
p<0.001
IR
Pregnancy Rates
0
Quantity and Quality
40
IR
35
30
IR Poor Responders
P=0.78
40
25
35
20
15
21.6%
22.6%
30
25
10
38.9%
P = 0.001
20
5
15
0
Good Response
Poor Response
14.5%
10
5
0
Younger
Older
Reproductive
window
# Follicles
Decreased AFC
AFC
10
Age
20
30
40
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
 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