Aging and infertility in women
The Practice Committee of the American Society for Reproductive Medicine American Society for Reproductive Medicine, Birmingham, Alabama BACKGROUND
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 EVALUATION
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 COUNSELING
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 TREATMENT
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 & STERILITY
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 1999 Embryo implantation rates as a function of
Assisted Reproductive Technology Success Rates, live birth female age
rates per cycle were 32.2% in women under 35, 26.2% in Implantation rate
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
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Acknowledgments: This report was developed under the direction of the 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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Aging and infertility in women



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