THE FACTS > FROM THE EXPERTS
How Age Reduces Fertility and What You Can Do About ItDaniel A. Potter, MD, FACOG
Board Certified, Reproductive Endocrinologist
BackgroundInfertility as a consequence of delayed child bearing is affecting more couples than ever before. It is important, therefore, to educate and inform not only fertility patients, but all women of the role of increasing age on fertility. Recent statistics from the Centers of Disease Control indicate that nearly 25% of all mothers are over 35 years of age at the time of the birth of their first child. These levels are unprecedented and reflect several societal trends as women are participating in the work force, pursuing higher education and marrying later in life in numbers not seen in previous generations.
Because fertility declines with increasing female age, delayed child bearing has resulted in an increase in the number couples seeking treatment for infertility. This decline in fertility with female age was well demonstrated in a classic study of the Hutterite sect. It was found that in this group, the age of the female partner directly correlated with the incidence of infertility. The incidences were 7% at age 30, 11% at age 35, 33% at age 40 and 87% at age 45. The Hutterites were selected for study because of ideal circumstances promoting fertility. The incidence of infertility at a given age in the general population almost certainly exceeds the numbers listed above.
Age-related infertility in the male seems to be nominal and is primarily related to the diminished sexual function and the increased incidence of systemic diseases that occur with aging. Documented male fertility has occurred well beyond the age of 80. As such, we will concentrate on the effects of female age in this article. The cause, diagnosis, treatment and prevention of age related infertility will be explored.
MechanismThe decline in fertility that occurs with aging is primarily a function of the diminished egg and embryo quality that accompany it. Women are born with all of the eggs that they will ever have. During the fetal stage, the female has a peak of about 6,000,000 eggs. This number has already declined to 2,000,000 by birth and further drops to about 400,000 by the onset of puberty. The process of egg loss is termed atresia. Throughout the reproductive portion of a woman's life, she will ovulate fewer than 500 eggs.
The remainder is subject to atresia so that in menopause, the number of eggs remaining is effectively zero. This process of atresia is ongoing whether the patient is a little girl, on birth control pills, pregnant, breast feeding or otherwise not ovulating. They don't teach you that smoking can promote infertility, but it can. Atresia is known to be accelerated by smoking, certain autoimmune diseases, and certain types of chemotherapy as well as rare chromosomal and enzymatic deficiencies. In simplified terms, the best and most fit eggs ovulate first. As the egg supply (also known as ovarian reserve) dwindles, the quality and competency of the remaining eggs are diminished. This diminished quality is manifested not only in the in a decrease in fertility, but also in increases in miscarriages and chromosomal abnormalities such as Down syndrome.
Ovarian Reserve and PrognosisThe two most important prognostic factors in fertility treatment are the age of the female partner and the level of ovarian function (ovarian reserve). The age can be said to set a baseline prognosis that is then altered by level of ovarian reserve. While these two factors are usually related, this is not always the case.
For example, a young woman with premature ovarian failure would have a poorer prognosis than an older woman with normal ovarian reserve. Ovarian reserve is usually assessed by checking the levels of follicle stimulating hormone (FSH) and estradiol (E2) on the third day of menstrual bleeding (cycle day three). As ovarian reserve diminishes, FSH rises. In most laboratories, normal day three levels are less than 10 mIU/mL for FSH and less than 65 pg/mL for E2. When levels exceed these limits, a Clomid challenge test should be done to further clarify your results.
The Clomid challenge test is more sensitive than a cycle day three FSH/ E2 and should be employed whenever decreased ovarian reserve is suspected or likely. This is especially the case in women over 35, women with unexplained infertility and women with abnormal cycle day three lab values. The Clomid challenge test is performed by drawing FSH and E2 levels on cycle day three, then administering Clomid (100 mg per day) on cycle days five through nine. A repeat FSH level is then drawn on cycle day 10. The prognosis with fertility treatment is no better than the highest level of FSH on either day three or day 10.
At our center, an age appropriate prognosis is expected when the FSH is less than 10 mIU/mL for each measurement. If the highest measurement is between 10 and 12.5 mIU/mL, the age appropriate prognosis is reduced by half. If the level is 12.5-15 mIU/mL, it is reduced by half again. Pregnancies with FSH levels greater than 15 mIU/mL do occur but are rare.
For example, at out center a 30 year old would be expected to have a 54% pregnancy rate with IVF. This would be the case with FSH levels less than 10 mIU/mL. If the highest FSH were 13.0 mIU/mL, we would expect a 13.5% pregnancy rate (54 x ½ x ½). It is very important for you, the fertility patient, to have accurate prognostic information before starting expensive fertility treatment. Another method for assessing ovarian reserve is checking inhibin B levels. Inhibin B is an excellent direct marker of ovarian reserve as it is made by the egg complexes (follicles) in the ovaries. Unfortunately, the inhibin B assay is not as well standardized as the FSH assay making the interpretation of results less clear in subtle cases.
Fertility Work-up and TreatmentThe evaluation and treatment of the older fertility patient should occur quickly and efficiently to maximize the 'window of opportunity' that exists. The effective evaluation of the older fertility patient begins with timely identification of the problem. Women age 38 and up should go directly to the fertility specialist if not pregnant after six months of well-timed intercourse. A thorough fertility evaluation, including ovarian reserve testing, should occur over the course of not more than two cycles. Accurate diagnostic information will prevent wasting precious time on ineffective treatments. The work-up is designed to discover the truth. The truth is incredibly valuable for patients as it allows them to make informed decisions. Informed decisions about whether or which fertility treatments to pursue are much less likely to be regretted later than decisions based on incomplete or inaccurate information. At the end of your work-up, you should have a clear idea of which treatment options are available to you and your prognosis with each.
Mildly Impaired Ovarian Reserve/Advanced AgeTreatment of women over 38 should be relatively aggressive. Women in this age group that are ovulatory rarely benefit from Clomid. Injections of fertility drugs with insemination can be tried if appropriate (open tubes, normal sperm) but should be abandoned if success had not been achieved after 2-3 cycles.
IVF is appropriate in most cases and should be pursued earlier rather than later. When diminished ovarian reserve is identified, consideration should be given to going directly to IVF if the peak FSH is less than 12.5 mIU/mL. Additionally, older patients with 'unexplained infertility' are usually best served going directly to IVF. In older patients with diminished ovarian reserve and intermediate FSH levels (10-12.5 mIU/mL), stimulation strategies aimed at poor responders may be tried initially.
These strategies include flare, micro-lupron flare, and antagonist (Antagon/Cetrotide) rather than lupron) protocols. The transfer of a larger number of embryos is also appropriate in older patients. The rate of high order multiple gestation is very low even when as many as 5-6 embryos are transferred under these conditions. There are also data that suggest that 'assisted hatching' may benefit women over 38 and those with diminished ovarian reserve. The benefit, or lack there of, of assisted hatching remains controversial but the downside seems to be minimal.
Egg donation will always yield a higher pregnancy rate than cycles using eggs from older patients, even when normal ovarian reserve is present. All patients with either advanced age or abnormal ovarian reserve should consider egg donation. Egg donation carries with it a success rate that approaches 70% in most instances. Although more costly, this high success rate makes it a more cost-effective strategy than other fertility treatments.
The decision about whether or not to use your own eggs, donor eggs, adopt or not pursue treatment at all is an intensely personal one. Make sure that you have gathered accurate information about each of these options before making a decision regarding which treatment to pursue.
Severely Impaired Ovarian Reserve/Advanced AgePatients over 40 with FSH levels between 12.5-15 mIU/mL should give strong consideration to egg donation. Pregnancy rates with regular IVF in this group are in the single digits. In this group, regular IVF pregnancy rates approach the rates seen with injections and inseminations. Because of the great difference in cost, patients in this group desiring to use their own eggs may be better served pursuing inseminations if the tubes are open and sperm is normal.
Patients with FSH levels above 15 mIU/mL that are also of advanced age should be offered egg donation as other modes of treatment do not provide significant benefit beyond trying on their own. Patients in this category that do not want to use egg donation have been treated by monitoring ovulation and cycle day three lab levels to try to identify 'fertile cycles'. Inseminations are then performed without medication timed by ultrasound or ovulation predictor kits. Anecdotal reports of success using this approach have been reported.
Another group of patients, those with premature ovarian failure have been reported to have successful pregnancies after FSH level that have repeatedly exceeded 100 mIU/mL. Such patients have generally been on cyclic hormone replacement at the time of conception. The exact mechanism is not known. I have a patient in my practice that had FSH levels ranging from 68 to 111 mIU/mL in her late 20s.
She was referred to the NIH as a possible candidate for a research project involving premature ovarian failure and fertility but was rejected when her FSH at the NIH was recorded at 100 mIU/mL. She was placed on cyclic hormone replacement therapy and set out to find an egg donor only to become pregnant on her own and deliver a healthy girl. The literature has a number of reports of similar cases. While lightening does strike, it tends to do so in very young patients with poor ovarian function.
PGDSeveral procedures have been investigated to attempt to improve pregnancy rates in older patients. Pre-implantation genetic diagnosis (PGD) involves a biopsy of the embryos created with IVF at the 8 cell stage to eliminate genetically abnormal embryos. Rates of aneuploidy (abnormal chromosome number) are as high as 80% in women over 40. It has been proposed that the elimination of these genetically abnormal embryos may somehow improve pregnancy rates. To date, this has not proven to be the case.
The 80% rate of aneuploidy seen at the embryo stage compares to aneuploidy rates of 1-3% in the same population at the time of amniocentesis. This indicates that the body itself has an excellent system in place for 'filtering out' abnormal pregnancies. PGD is of value in cases where there are more good quality embryos than the couple/doctor want to transfer.
Unfortunately, this is rarely a problem in patients over 40. PGD is also helpful in couples that would not terminate an aneuploid (e.g. Down syndrome) pregnancy. PGD may reduce miscarriage rates by eliminating chromosomally abnormal pregnancies destined to miscarry, but is unlikely to increase overall delivery rates in most cases.
Prevention of InfertilityThe best treatment for any condition is always effective prevention. Prevention involves educating women regarding the age-related decline in pregnancy so that a conscious decision can be made regarding this issue, with full understanding of the consequences. Women over 35 desiring a family should consider having their ovarian reserve tested if they feel that this will help with decision-making. Long acting forms of contraception, such as Depo-Provera, should be avoided.
When attempts at pregnancy begin, careful documentation of cycles and timing of intercourse using both basal body temperatures and urine ovulation predictor kits should start immediately. If there are any factors that put either the man or woman at risk for infertility, consideration should be given to evaluation if pregnancy has not occurred after 3-6 months. These factors include a history of pelvic infection, sexually transmitted disease or endometriosis in the female and a history of testicular trauma and undescended testicles/hernia repair in infancy for the male. All women over 38 without conception after 6 or more months of well-timed intercourse should see a reproductive endocrinologist and infertility subspecialist as soon as they are able.
Other methods of prevention include the experimental procedures of banking eggs or ovarian tissue by young women for use later in life. There have been a limited number of pregnancies from this procedure in the United States and this remains an active area of research. Attempts to freeze eggs or ovarian tissue for the purpose of preserving fertility are highly experimental and should be limited to programs involved in active (and externally reviewed) research programs.
Closing RemarksAging is the most daunting foe in all of reproductive medicine. While it is not possible to turn back the clock, it is possible to take charge of your fertility care, optimize your reproductive potential and rapidly learn the truth about the options available to you. It is the hope of all reproductive endocrinologists that our patients achieve their dreams of parenting whether by using their own eggs, donated eggs or adoption. It is also our hope that we can assist those patients not electing to pursue parenthood in making this an informed choice rather than the consequence of inaction.