Age and Fertility

By Steven T. Dodge, M.D.
California North Bay Fertility Medical Associates
Santa Rosa, CA, USA

Fertility declines as we age, that much is generally well known and accepted. But with all the reports in the lay press of celebrities becoming parents after age 40, the full impact of age on fertility is not understood by most people. It seems, from all these media stories of reproductive miracles, as if technology has no limits. Alas, reality is different and for most couples we see the age of the female partner is the single most important fertility-reducing factor they must deal with.

A woman's fertility declines steadily after reaching peak levels between ages 18 and 25. From then to age 35 the average woman's fertility drops by about one half and thereafter declines more rapidly. By age 40 the average fertility rate is 15% of that found at age 25. The down slope continues until it reaches very low levels (1% or less per month chance of pregnancy) at age 44 and beyond.

Studies looking at normal human fertility are of two basic types: epidemiological reviews of population data and direct observational analyses. The most common of the latter type are studies of groups of women who have stopped contraception in hopes of becoming pregnant or those women undergoing artificial insemination with donor sperm. The results of all these studies cluster around a 35% per month chance of pregnancy as the maximum of human fertility, seen in women between 18 and 25 years of age. By age 40 the chance of fertility declines to about 5% per month.

Most of the observational type studies were limited to women less than age 42 so the rate of decline of fertility beyond that point was not looked at. For that information we must turn to epidemiological studies and the in vitro fertilization data.

The most famous contribution to the study of human fertility by epidemiology is that of Tietze who published his analysis of the Hutterites in 1957. This homogeneous religious sect of the Dakotas and Montana was studied in detail by Eaton in the 1950s. The Hutterites' avoidance of all birth control methods and communal living made them the most fertile group ever studied. Tietze's analysis of Eaton's data showed that only 5 of 209 women (2.4%) were childless. A further 11% were infertile after age 34 and only 13% had pregnancies at or beyond age 45. This can be taken as a glimpse of human fertility at its absolute maximum.

In vitro fertilization (IVF) therapy provides another opportunity to look at the female age effect. Since IVF involves the harvesting of eggs from the ovaries, direct observation of the fertilization rate and then placement of the fertilized eggs (embryos) into the uterus, many confounding variables are controlled for. It doesn't matter in IVF, for example, if the fallopian tubes are blocked or normal or if any endometriosis is present in the woman's pelvis. Subtle fertilization problems, if present, can also be detected. By looking at the IVF success rates for couples in which fertilization is normal, the woman's uterus is also normal and the number of embryos transferred is the same, the main remaining variable is that of the woman's age.

Successful IVF programs, like ours, have found that their success rates in such couples remain quite high, 40-45% per attempt, through the thirties until age 35. Then the rates begin to drop fairly precipitously. Success rates at age 41 are generally half that of the below age 35 group and by age 45 they are essentially nil. Thus it appears that the IVF process, by harvesting multiple eggs and then transferring multiple embryos, can overcome the normal fertility decline observed in the thirties, up to a point. That point, which has been verified over and over again by IVF programs worldwide, is age 35. Something clearly happens at that time that even IVF, our most powerful infertility treatment, can not completely compensate for.

Egg Factor

For years there was considerable debate among infertility specialists as to why the fertility of women declines so rapidly as they approach 40. Is it due to solely to a gradual loss of eggs or to uterine factors or possibly to both? Several ovum donation studies done in the last 10 years have demonstrated no apparent decline in the chances of conceiving a successful pregnancy from ages 40 to 50 when eggs from a young donor were used. This clearly highlighted changes in the egg supply as the most likely cause of age related fertility loss.

Why this would be so is not clear at first glance. After all, the most rapid decline in female fertility begins at about age 30-31 which is, on average, 20 years before menopause, the time when the ovarian egg supply is exhausted. Basic science studies, completely separate from the fertility studies we discussed earlier, have now shed some light on this issue.

At about 20-24 weeks of fetal life the ovaries stop producing new eggs. The egg supply at that point is about 6-8 million. As with any biological "factory" there is considerable variation in quality: some of the eggs are outstanding, most are average and some are not so great. From this halfway point of pregnancy onward eggs are lost every day. Estimates are that by birth the ovaries are down to 1 or 2 million eggs and by puberty the inventory has declined to 400,000. This loss of eggs is, as far as anyone has been able to determine, completely independent of hormonal control. Thus it happens even if a woman is pregnant, breast feeding, on birth control pills, having regular periods or not having any periods at all. To date the only factors known to influence the rate of loss of eggs are those that increase it: cigarette smoking, cancer chemotherapy drugs and radiation therapy. Thus, along with all its other evils, cigarette smoking is now known to kill eggs. It is not clear at present if this also applies to second hand smoking.

These same basic science studies have demonstrated two probable reasons why IVF can not overcome the age-related loss of fertility past age 35. The first is that the rate of daily egg loss increases significantly in most women at or near age 35. The specific cause of this phenomenon is not yet understood but it is associated with clinical changes in the menstrual periods of most (but not all) women: the interval between periods shortens and the amount of bleeding diminishes. The second factor behind the fertility changes at this time has to do with egg quality. Studies looking at the chromosomal makeup of eggs have found a sharp increase in the percentage of abnormal eggs with time. This quality decline is not only part of the reason fertility declines with age, it also undoubtedly underlies the sharp increase in miscarriage rate that is observed in older women.

Every biologic process demonstrates considerable variation from one individual to the next. This gives us the "standard (or bell-shaped) distribution curve" which means that a few individuals have a lot of whatever you are measuring, most have an average amount and a few have very little. The same principle applies to the egg supply. Therefore the size of the initial egg cohort varies and, most importantly of all, there are differences in the rate of loss of eggs from one woman to the next. Thus we have seen 33 and 34 year old women who seemed to be at the very end of their egg supply and yet have also seen a few women 10 years older who seemed to have a great number of eggs left.

Uterine Effect

The ovum donation studies we mentioned earlier initially seemed to indicate that all of the age caused female fertility decline was due to the changes in egg number and quality. More recent data has shown that to not be completely correct. There actually is some loss of "uterine fertility" over time, caused most likely by a combination of reduced pelvic blood flow and a gradual loss of hormone receptors in the endometrium.

Uterine diseases can also contribute to a decline in fertility. Multiple large leiomyomas (fibroid tumors), intrauterine scarring and a disease called adenomyosis can all reduce fertility. Fortunately such problems are relatively uncommon and a woman's uterus usually remains healthy until well into her fifties. The natural decline in uterine receptivity, which is due to a gradual loss of hormone receptors inside the cells lining the uterine cavity, is relatively gradual until the mid fifties. Therefore, up to age 55 the observed decline in female fertility with age is 90-95% due to "egg effect" and 5-10% "uterine effect."

Sperm Effect

The decline of fertility with age is not all one sided. Male fertility also diminishes with time. Because sperm are continually produced throughout a man's life, the age effect is less severe than in women, where the egg supply is fixed before birth. It is important to realize that we are severely hampered on the male side by the lack of good studies with which to accurately gauge the rate of fertility loss. The ideal study, where young women are randomized into receiving donor sperm from men of varying ages, is just not possible to do.

Nonetheless it is clear that male fertility does decline. The total number of motile sperm in each ejaculate gradually drops with increasing age. Age 50 seems to be the point at which this decline first reaches clinical significance. In a fashion similar to what happens in women, quality is also effected. Beginning at age 50 sperm chromosomal abnormalities become more common. This refers to both the new appearance of autosomal gene mutations and an extra chromosome (trisomy). Although not yet specifically demonstrated in the laboratory, we believe there are other manifestations of this decline in sperm quality: lowered sperm velocity, ability to attach to an egg and fertilizing capacity.

The time observed decline in male fertility is due in large measure to the normal aging process but lifestyle effects can also be very important. Cigarette smoking, heavy use of alcohol and other drugs and other toxic exposures can accelerate the fertility decline significantly.

Measuring the Age Effect

Given the normal biologic variation between individuals, it would be very helpful to have something besides a person's number of birthdays to determine the age effect on fertility. Unfortunately there is no simple test that will tell us precisely where someone is on the fertility-age continuum. We have a few tests that can give us certain clues as to fertility status but that is the limit of current technology.

In women what we have is the FSH Test, a blood test to measure Follicle Stimulating Hormone. FSH is produced by the pituitary gland at the base of the brain and when the ovaries are working well, only a small amount of FSH is needed to stimulate them. Thus under normal circumstances the FSH levels in blood are low, say 10 mIU/ml or less. This number, by the way, does vary a bit from one lab to the next, depending on which assay system is used. Also, the FSH Test has value only when the blood sample is obtained on menstrual cycle day 2 or 3 (day 1 is the day true menstrual bleeding begins).

When the ovaries run low on good quality eggs the circulating blood level of FSH rises. So when a particular woman's FSH level is high we know she has a big problem with her ovarian egg supply. Fertility rates are extremely low, even with IVF treatment, when a single FSH level is 20 or more. Values between 10 and 20 represent a situation of considerably reduced fertility. This part of the FSH Test, the bad news side, is very reliable. Where it is not so useful is at the other end, the supposed good news side. A low, or normal, FSH level on day 2 or 3 unfortunately does not guarantee that everything is fine with the egg supply.

There are also "dynamic tests" of ovarian reserve, which are useful in certain situations. The most common of these is the Clomiphene Citrate Challenge Test in which two tablets of clomiphene citrate ("Clomid") are given for 5 days. Blood tests to measure FSH are drawn before and immediately after the clomiphene. If either FSH level is found to be over 10 then a compromised egg supply is suspected.

On the male side we have only the semen analysis to guide us. Fertilization tests, such as those that use specially prepared hamster eggs, are not currently reliable enough for clinical use. If the semen analysis is normal then we must assume fertility potential exists and accept, if the man is over age 50, the fact that the per month chances of success will be somewhat reduced. In many such situations it may ultimately be necessary to use IVF to maximize fertilization potential.

Final Thoughts

All this information reinforces the notion that time waits for no one. It is important to proceed expeditiously when confronting infertility. For women aged 40-44 a very aggressive approach is needed. For those 35-39 we can afford to try lesser therapies, but only on a limited basis, before proceeding to high tech treatments such as IVF. Although a more casual strategy is possible for women under age 35 we still recommend getting the problem solved in quick order. Otherwise infertility testing and therapy can drag on forever, tainting years or even a decade of what should be the best part of life.