Fertility over 40 - Age-Related Infertility
by Samuel C. Pang, MD., Associate Medical Director
Reproductive Science Center, Lexington, MA
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Many People are aware that the fertility potential of a woman declines with
increasing age. Most, however, are not aware of how soon fertility begins
to decline. The fertility potential of the average woman begins to decline
appreciably at the age of 35 years, and begins to decline dramatically
beyond the age of 40 years. This article will discuss the main factors that
contribute to the decline in fertility potential of women with increasing
age, as well as some of the assessment tests and treatment options. There
are two main reasons that explain the decline in fertility potential of
women beyond the age of 40 years. The first is the phenomenon of
chromosomal aneuploidy and the second is the concept of decreasing ovarian
reserve.
This term refers to the abnormal number of chromosomes in the egg or the
embryo. As a woman ages, an ever-increasing proportion of the eggs she
releases contain an abnormal number of chromosomes. Eggs are produced in
the ovary by cell division, and the older a woman gets the more likely
there are to be mistakes in the process of cell division such that the egg
ends up with an abnormal number of chromosomes. A theory that has been
proposed to explain this phenomenon suggests that this occurs because the
eggs being released by an older woman have gone through multiple
generations of cell division, and with each generation of cell division,
the likelihood of error in distribution of chromosomes increases.
Chromosomal aneuploidy accounts for three consequences in the reproductive
efforts of women who are 35 years of age or older. The first is the well-
known phenomenon of higher risks of having a baby with Down Syndrome with
increasing age beyond 35 years. However, this is simply the tip of the
iceberg. Chromosomal aneuploidy also causes the higher risk of spontaneous
miscarriages in women with increasing age beyond 35 years. Down Syndrome is
the result of Trisomy 21, which causes relatively mild abnormalities in the
fetus. Aneuploidies involving most of the other chromosomes typically
result in more severe abnormalitites of the fetus, which will result in
spontaneous miscarriage. There are also chromosomal aneuploidies that
result in such severe abnormalities of the embryo such that the embryo does
not even implant to result in pregnancy. This explains why it becomes
progressively more difficult for women to conceive with increasing age
beyond 35 years. In summary, the phenomenon of chromosomal aneuploidy
explains the increasing difficulty to conceive, the increasing risk of
spontaneous miscarriage, as well as the increasing risk of having a baby
with Down Syndrome of other chromosomal anomalies.
All women are born with a genetically pre-determined lifespan to their
ovarian function. The average woman's ovaries stop functioning at the age
of 50 or 51 years. This event is referred to as the menopause. However,
there are some normal women whose ovaries stop functioning as early as 40
years, and others whose ovaries may continue to funtion into their late
50's. Environmental factors or disease conditions may shorten the lifespan
of a woman's ovaries. Smoking cigarettes is one of the most common and
important factors that has been found to decrease ovarian reserve. Other
examples of environmental factors that may decrease ovarian reserve include
exposure to chemotherapy agents or radiation therapy used in the treatment
of cancer. Disease conditions of the ovaries, such as ovarian endometriomas
(ovarian cysts caused by endometriosis), may require surgery to remove the
endometriomas, which can destroy ovarian tissue, and may result in
decreasing ovarian reserve.
The ovarian reserve of each woman generally begins to decline about 15
years prior to menopause. This reflects a diminishing supply of eggs in the
ovaries, and is manifested by an increase in Follicle Stimulating Hormone
(FSH) and Estradiol (E2) levels in the blood during the time of
menstruation. A test commonly used to evaluate a woman's ovarian reserve is
the Clomiphene Citrate Challenge Test (CCCT). The FSH & E2 levels in the
blood are measured on cycle day (CD) #3 of the menstrual cycle, following
which the woman takes clomiphene citrate 100 mg daily form CD#5 to CD#9.
The FSH & E2 levels are repeated on CD#10. The CCCT is considered normal if
the FSH levels on CD#3 and CD#10 are 12 mIU/mL or less. The CCCT is
generally considered abnormal if the E2 level is higher than 75 pg/mL on
CD#3 or if the FSH level on either CD#3 or CD#10 is higher than 12 mIU/mL.
(These thresholds may differ depending on the laboratory in which the tests
are done. Each fertility center has usually established their own threshold
levels based on their own laboratory and clinical outcome data, so it may
not be appropriate to interpret results of these tests done in the
laboratory of one fertility center using the threshold levels established
by another fertility center.)
Another blood hormone test that has been proposed for assessing ovarian
reserve is Inhibin B. In theory, a low level of inhibin B on CD#3 suggests
decreased ovarian reserve. However, the threshold level which divides
"normal" and "abnormal" is not well defined, and some studies have
suggested that inhibin B may not be a very useful test for measuring
ovarian reserve.
Another blood hormone test that is currently being evaluated for its
potential usefulness in measuring ovarian reserve is the Anti-Mullerian
Hormone (AMH), which have also been referred to as the Mullerian-Inhibiting
Substance (MIS) or Factor (MIF). Although this test holds some promise, it
is still being tested experimentally, has not been validated for assessment
of ovarian reserve, and is not yet commercially available for use.
Another method of evaluating ovarian reserve, which does not involve
testing blood hormone levels, involves ultrasound evaluation of the size of
the woman's ovaries and the number of measurable small (antral) follicles
during the early follicular phase of the cycle (which is typically during
mentration). This test has been used by some physicians to predict ovarian
response to gonadotropin stimulation.
Unfortunately, decreased ovarian reserve is a condition that cannot be
reversed with medical treatment. Despite major advances in medical
technology, no magic pill has been invented which reverses the aging
process of the ovaries. Therefore, the first-line option for dealing with
decreased ovarian reserve is using very high doses of gonadotropins to
stimulate the ovaries, together with various novel protocol strategies
which may (or may not) improve ovarian response in some women. Some of
these protocol strategies may involve using pre-treatment with oral
contraceptive pills, using a specially diluted dosage of Lupron (often
referred to as the Lupron Microdose protocol), using an antagonist
protocol, Cetrotide or Antagon, using a combination of clomiphene and
gonadotropins, etc. If none of these strategies is successful, then the
remaining option for achieving a successful pregnancy is the use of donor
eggs.
The above article is reprinted with permission from RESOLVE: The National
Infertility Association.
See a fertility specialist now
Don't wait, see a specialist (reproductive endocrinologist) for a
consultation. We're a national network of over 100 fertility specialists.
Samuel Pang, M.D.,
is an infertility specialist with the Reproductive
Science Center, a state-of-the-art fertility clinic serving Boston and New
England.