Aging and infertility in women The Practice Committee of the American Society for Reproductive Medicine
American Society for Reproductive Medicine, Birmingham, Alabama
addition to ovaries with average to low follicle numbers and
Female fertility begins to decline many years prior to the
onset of menopause despite continued regular ovulatory cy-cles. Although there is no strict definition of advanced re-
PHYSIOLOGY OF REPRODUCTIVE AGING
productive age in women, infertility becomes more pro-
The age at which menopause occurs reflects near complete
nounced after the age of 35. A classic report on the effect of
depletion of the ovarian follicular pool Subtle changes in
female age on fertility found that the percentage of women
early follicular phase serum concentrations of FSH (in-
not using contraception who remained childless rose steadily
crease) and inhibin B (decrease) precede changes in men-
according to their age at marriage: 6% at age 20 to 24, 9% at
strual regularity and ovarian steroid secretion. Risk factors
age 25 to 29, 15% at age 30 to 34, 30% at age 35 to 39, and
for early loss of ovarian reserve include smoking, family
64% at age 40 to 44 Similarly, a sharp decline in
history of premature ovarian failure, significant ovarian pa-
pregnancy rate with advancing female age is noted with
thology, and previous ovarian surgery.
donor insemination studies (which control for fertility of themale partner and coital frequency) and with assisted
The age-associated decline in female fecundity and in-
reproductive technologies (ART) including in vitro fertiliza-
creased risk of spontaneous abortion are largely attributable
tion (IVF). The risk of spontaneous abortion increases with
to abnormalities in the oocyte. The meiotic spindle in the
female age According to the 1999 Assisted Reproductive
oocytes of older women frequently exhibits abnormalities in
Technology Success Rates, the percentage of clinical preg-
chromosome alignment and microtubular matrix composi-
nancies (gestational sac as imaged with sonography) that
tion Higher rates of single chromatid abnormalities in
failed to result in a live birth rose according to the woman’s
oocytes as well as aneuploidy in preimplantation em-
age: 14% for patients under age 35, 19% at age 35 to 37,
bryos and ongoing pregnancies, are observed in older
25% at age 38 to 40, and 40% after age 40
women. The higher rate of aneuploidy is a major cause ofincreased spontaneous abortion and decreased live birth rates
A recent review of studies on the effects of male age on
in women of advanced reproductive age.
semen quality and fertility concluded that increasing age isassociated with a decline in semen volume, sperm motility,
The prevalence of uterine pathology, such as fibroids and
and sperm morphology, but not sperm concentration
endometrial polyps, increases with age yet there is little
There is some decline in male fertility with age, particularly
evidence that uterine factors have a significant impact on
over the age of 50, but the results of many of these studies
age-related infertility. Age does not appear to have a signif-
are confounded by female partner age. There is no absolute
icant effect on morphological or histological responses of the
age at which men cannot father a child. Fertility is thus more
uterus to steroid stimulation A recent study has not
related to the age of the female than the male partner.
found an age-related decline in ART cycle delivery rateswhen oocyte donation is performed
The average age of childbearing has increased over the
past three decades as more women have pursued higher
education and careers and postponed marriage. Concur-
Tests to evaluate infertility provide information about cur-
rently, a large cohort of women born during the “Baby
rent fertility but do not predict when the onset of age-related
Boom” (1946 –1964) have reached their late reproductive
infertility will occur. Although infertility is commonly de-
years, resulting in more women in this age group seeking
fined as the inability to conceive after one year of unpro-
assistance for infertility. Not all women of advanced repro-
tected intercourse, normal older women may take longer
ductive age who wish to conceive experience infertility.
than one year to conceive. Therefore, earlier evaluation of
Those older women who do present to physicians for infer-
infertility is warranted in women over the age of 35. The
tility may have other fertility problems (e.g., male factor) in
consequences of undiagnosed infertility factors can be moredetrimental to women who have limited time to achieve asuccessful pregnancy. In addition to infertility testing, the
Committee Opinion Under revision June 2006.
preconception medical evaluation should also include
screening for significant medical disorders such as hyperten-
sion and diabetes, which are more frequent in older women.
Correspondence to: Practice Committee, American Society for Repro-
In women 40 and older, it is advisable to perform mammog-
ductive Medicine, 1209 Montgomery Highway, Birmingham, Alabama35216.
raphy prior to attempting pregnancy. S248 Fertility and Sterilityா Vol. 86, Suppl 4, November 2006
Copyright 2006 American Society for Reproductive Medicine, Published by Elsevier Inc.
The infertility evaluation in women of advanced repro-
to gonadotropins In the future, transvaginal ultra-
ductive age should include an assessment of ovarian reserve.
sound may be an effective way of estimating ovarian reserve.
The term ovarian reserve describes a woman’s reproductive
Currently it seems reasonable to test ovarian reserve by
potential with respect to ovarian follicle number and oocyte
using day 3 FSH and estradiol or the CCCT in all infertile
quality. The measurement of serum basal FSH and estradiol
women age 35 and older who desire pregnancy. Ovarian
on day 3 of the menstrual cycle is often used to test for
reserve testing may be considered in patients under age 35 with
ovarian reserve. FSH and estradiol should be measured in the
a solitary ovary, history of ovarian surgery, poor response to
early follicular phase because accelerated follicular develop-
exogenous gonadotropins, exposure to chemotherapeutic agents
ment may be associated with reproductive aging. Elevated
or ionizing radiation, and unexplained infertility.
FSH and estradiol levels are independent predictors of poorprognosis in older women Common criteria fornormal ovarian reserve are an early follicular phase FSH
level of Ͻ10 mIU/mL and an estradiol level of Ͻ80 pg/mL.
Preconception counseling should include a discussion of the
Higher cutoff values for FSH have been reported (as high as
increased risks of aneuploidy, spontaneous abortion, and
20 to 25 mIU/mL for FSH) because of the use of different
obstetric complications such as delivery by cesarean section,
FSH assay reference standards The normal range for
hypertension, and gestational diabetes associated with
FSH ideally should be determined in a normal fertile popu-
increasing maternal age. The rate of all clinically significant
lation by each laboratory. In the event that such data are not
cytogenetic abnormalities in live births increases from about
available, the laboratory’s stated upper limit for the follicular
1/500 for women under 30 to 1/270 at age 30, 1/80 at age 35,
phase can be used as an arbitrary and imperfect cutoff to
Counseling after ovarian reserve testing should include a
The clomiphene citrate challenge test (CCCT), which is
discussion of the results. While they may predict a lower
another test of ovarian reserve, is performed by measuring a
pregnancy rate, abnormal ovarian reserve test results do not
day 3 FSH, administering clomiphene citrate 100 mg orally
preclude the possibility of pregnancy and should not be pre-
on cycle days 5 to 9, and then measuring FSH on cycle day
sented to patients as absolute. Likewise, ovarian reserve testing
10 The test is considered to be abnormal if either
alone may yield falsely reassuring results, as advanced maternal
the day 3 or the day 10 FSH is above the threshold value for
age and ovarian reserve test results are independent predictors
of infertility. Both should be used when counseling couplesregarding their chances for conception
Women with abnormal basal FSH, estradiol, or CCCT
have lower live birth rates with ovulation induction and
intrauterine insemination Women with dimin-ished ovarian reserve also experience decreased responses to
Treatment options for age-related infertility include con-
ovulation induction, require higher doses of gonadotropin,
trolled ovarian hyperstimulation with intrauterine insemina-
have higher IVF cycle cancellation rates, and experience
tion (COH/IUI), IVF, and oocyte donation. Except for oo-
lower pregnancy rates through IVF In a general
cyte donation, these treatments are intended to accelerate the
infertility population, an abnormal CCCT predicts that a
time to conception rather than directly affect oocyte or
successful pregnancy will be achieved about 5% of the time
embryo quality. Expectant management, which should be
A single elevated day 3 FSH value connotes a poor
reserved for couples who do not desire medical intervention,
prognosis, even when values in subsequent cycles are normal
is also considered a treatment option but is less likely to
result in pregnancy in women of advanced reproductive ageCOH/IUI consists of gonadotropins administered to
Other tests of ovarian reserve under study include circu-
initiate growth and ovulation of multiple follicles in con-
lating inhibin B levels, the gonadotropin-releasing hormone
junction with the placement of washed sperm in the uterine
agonist test, and small antral follicle count by ultrasound.
Women with decreased ovarian responsiveness to gonado-
COH/IUI has limited efficacy for women over 40 with
tropin may have decreased serum inhibin B levels even when
otherwise unexplained infertility, yielding a per cycle deliv-
FSH levels are normal This finding suggests that in-
ery rate of 5% or less (range 1.4% to 5.2%) This
hibin B may be a more sensitive marker of ovarian reserve
compares with a live birth rate per cycle of 17% to 22% for
than FSH. However, routine testing for serum inhibin B
women under 35 and 8% to 10% for women aged 35 to 40
levels is not recommended at this time due to limited avail-
There have been no studies comparing COH/
ability of reliable assays and conflicting data regarding its
IUI with IVF. Unfortunately, most reports have been retro-
prognostic value The gonadotropin-releasing hormone
spective case series or cohort studies that would be expected
agonist challenge test is not recommended for routine clin-
to overestimate treatment effectiveness.
ical use because of limited data on its prognostic value. Thenumber of small antral follicles visible on transvaginal ul-
The presence of male factor, tubal disease, endometriosis,
trasound appears to correlate directly with ovarian response
or pelvic adhesions would argue for proceeding directly to
FERTILITY & STERILITYா
IVF in women of advanced reproductive age. Pregnancy
rates from IVF are generally higher than from COH/IUI butalso decline significantly with age. According to the 1999Embryo implantation rates as a function of Assisted Reproductive Technology Success Rates, live birth
rates per cycle were 32.2% in women under 35, 26.2% in
women aged 35 to 37, 18.5% in women aged 38 to 40, 9.7%in women aged 41 to 42, and approximately 5% in women
In a recent multicenter review of 431 initiated IVF cycles
in women Ն41 years, there were no clinical pregnancies in
women Ն45 years and no deliveries in women Ն44 years of
Reprinted with permission (Fertil Steril 1996;65:783–
age . This age-related decline in IVF success is related to
decreased ovarian responsiveness to gonadotropins and, more
Source: Centers for Disease Control and Prevention,
importantly, to a marked decline in embryo implantation rates
American Society for Reproductive Medicine, Society
Embryonic aneuploidy is likely the major reason for
for Assisted Reproductive Technology, RESOLVE. 1999 Assisted Reproductive Technology Success
Rates. Atlanta, GA. Centers for Disease Control and
The following alternative approaches have been described
for IVF treatment in women with decreased ovarian reserve:
ASRM Practice Committee. Aging and infertility in women. Fertil Steril2006.
1. Microdose GnRH agonist flare protocol or other flare
2. Use of a GnRH antagonist with gonadotropins. 3. Low-dose GnRH agonist suppression before gonadotro-
Unfortunately, there are no randomized trials to compare
the relative efficacy of these approaches. Exclusion of ane-
uploid embryos with preimplantation genetic diagnosis
5. Use of estrogen or oral contraceptives in the cycle prior to
(PGD) may lower the spontaneous abortion rate in IVF
cycles However, the technique is expensive and is notyet widely available. Its role in the treatment of age-relatedinfertility has yet to be defined.
Nuclear (germinal vesicle) transfer is an experimental
Pregnancy and live birth rates for ART cycles
technique in which the nucleus from the oocyte of an older
using fresh, nondonor eggs or embryos, by female
woman is transferred to the enucleated oocyte of a younger
age, 1999. Data from reference 4. Gray line ϭ live
woman. The safety and efficacy of this technique is currently
birth rate; solid line ϭ pregnancy rate. ASRM.
Aging and infertility in women. Fertil Steril 2002. Source: Centers for Disease Control and
No treatment other than oocyte donation has been shown
Prevention, American Society for Reproductive
to be effective for women over 40 and for those with com-
Medicine, Society for Assisted Reproductive
promised ovarian reserve. Although the resulting child will
not be biologically related to the birth mother, oocyte dona-
reproductive technology success rates. Atlanta,
tion yields the highest live birth rate of any ART treatment.
GA: Centers for Disease Control and Prevention,
It is the treatment of choice for age-related infertility not
successfully addressed by other methods. Pregnancy rateswith oocyte donation are dependent on the age of the donorrather than the recipient.
● A relatively large group of women is experiencing age-
related infertility due to social trends that lead to deferredchildbearing and to the current age of the “Baby Boom”generation.
● Age-related infertility is due to oocyte abnormalities and
● Clinical tests to estimate ovarian reserve include FSH and
estradiol levels in the early follicular phase (e.g., day 3) or
ASRM Practice Committee. Aging and infertility in women. Fertil Steril 2006.
a clomiphene citrate challenge test. Aging and infertility in women
● Evaluation and treatment of infertility should not be de-
outcome in patients undergoing in vitro fertilization. Fertil Steril
17. Navot D, Rosenwaks Z, Margalioth EJ. Prognostic assessment of fe-
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Practice Committee of the American Society for Reproductive Medicine
19. Scott RT, Leonardi MR, Hofmann GE, Illions EH, Neal GS, Navot D.
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A prospective evaluation of clomiphene citrate challenge test screening
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