Ten
to 15 % of all reproductive
age couples suffer from infertility. As
a board certified reproductive
endocrinologist I spend most of my time treating both
men and women, who contribute equally to this insidious
disease that afflicts millions. Infertility is defined
as one year of unprotected sexual relations without
conception. The probability of achieving a pregnancy
within one menstrual cycle, ideally each month, is on
the average only 25% for normal, young, and healthy
couples; thus, these couples have approximately an 85%
chance of conceiving with in one year and 93% in two
years. Unfortunately, this probability decreases dramatically
by one third to one half as women approach their mid
30's and early 40's.
Every
time we watch a TV news magazine or open a print magazine
we are entertained and enlightened by exposure to the
latest advances in reproductive medicine, famous people
revealing their difficulties, pursuits, failures and
successes in having a baby, and the exceedingly rare,
and thus always news-worthy occurrence of, high order
multiple gestations, the "X-tuplets". Due
to our present day frequent exposure and since years
ago we rarely spoke or heard about people who were suffering
in silence from this devastating disease, we tend to
think that the rate of infertility is increasing exponentially.
This is not necessarily true.
There
have been a number of significant developments that
have changed the practice of reproductive medicine and
the public's awareness over the past quarter century.
One of the most significant events was the introduction
of the assisted reproductive technologies based on in
vitro fertilization where eggs are removed from a woman,
fertilized with sperm from a man in glassware, in vitro,
and then the resultant fertilized egg (embryo) is transferred
to a hormonally prepared uterus. The process is sometimes
called making "test tube babies". With the
birth of Louise Brown on July 25, 1978 and with assistance
from the mass media, the medical community and the entire
world became aware of novel and promising treatments
for those suffering from the once considered shameful
disease of infertility.
This
publicity generated new hope for many where there was
once only despair and emptiness. It also resulted in
a domino effect increasing the number of researchers
investigating novel diagnostic and treatment regimens,
making reproductive services more widely available,
successful, and affordable, and making infertility a
more socially acceptable disease. This culminated in
generating an immense increase in patient consults seeking
fertility related care.
Another
significant change that the fertility specialists have
witnessed over the last 10 years was the dramatic increase
in the number of women over age 35 requesting medical
intervention for infertility. Approximately 20% of women
in United States are having a first child after age
35. This is most likely due to a combination of older
age at the time of first marriage and more significantly
due to the delay of childbearing in marriage. Other
attributable causes resulting in older women seeking
fertility care and shortening the time interval in which
they desire to reproduce genetically related children
are a reflection of the current socio-economic times
and morays.
Two
income households are more the rule than the exception,
even with dual incomes there is still financial instability
and uncertainty, liberalization of abortion, effects
of sexually transmitted diseases, increased worry and
panic about being infertile, and increased use of various
contraception options. It has become clear that what
modern society is experiencing and fertility specialists
are seeing is a dramatic increase in age related infertility
in the baby boomer generation since they were the first
group of women who could easily exercise control over
their fertility.
Countless
clinical trials have revealed that a woman's fertility
declines significantly with increasing age,
yet aging only minimally effects male fertility. Another
gender difference is that a man continuously produces
sperm throughout his adult life, in contrast to a woman
who is born with her unique life time supply of eggs.
This number continually decreases until she stops ovulating
at menopause. In addition, research supports that this
decline in female fertility is more likely related to
the aging egg and less likely due to an aging uterus.
The healthiest, most fertile eggs are ovulated when
a woman is in her teens through her late 20's, a woman's
time of peak fertility. When a woman reaches her mid
to late 30's, the remaining eggs have substantially
less potential for fertilizing and establishing a healthy
pregnancy. This is mostly due to chromosomal injuries
that normally occur as eggs age within the ovaries.
Advanced egg age probably accounts
for the increased risk of both miscarriage and infertility
in women over the age of 35 and especially by the age
of 40. Because this is primarily a problem related to
the chromosomes and cellular machinery of the eggs,
there is little that can be done to correct or reverse
this biological trend. This knowledge and clinical trials
lead to the very successful treatment that employs egg
donors where the entire egg cells are obtained from
women usually in their 20's and fertilized with the
infertile woman's husband's sperm. Nuclear transfer,
where the nucleus of an infertile woman's adult cell
is replaced for the nucleus in a younger woman's donor
egg cell, and cytoplasmic transfer, where the cytoplasm
of a fertile woman's egg is injected into the infertile
woman's egg cell, have both been experimented with and
pending FDA approval. The goal of both techniques is
to maintain the older woman's genetics housed in the
nucleus, but utilize the healthy cell replicating machinery
located in the cytoplasm of the younger donor egg cell.
Unfortunately, some genetic material is also found in
the cytoplasm, so new questions have been raised and
must be answered before these techniques become standard
of care.
In
women less than 35
years of age, the vast majority of eggs ovulated
have a normal chromosomal composition. As the woman
progresses beyond 35 years of age, an increasing number
of her eggs are likely to be genetically abnormal, aneuploid.
This is a natural process of aging. Egg quantity and
quality declines at an exponential rate.
Chromosomally
abnormal eggs may fertilize, but will infrequently establish
a healthy pregnancy. When defective genetic embryos
inadvertently implant into the uterine lining, the resultant
pregnancies often result in spontaneous first trimester
miscarriages. This has been evidenced by an overall
miscarriage rate as high as 75% in women 40 years and
older. If this were not the case, there would be many
more genetically defective babies born. This is also
the reason why women who use their own eggs and who
are 35 years or older are encouraged to undergo amniocentesis
or chorionic villus sampling (CVS) to evaluate the fetus
for chromosomal abnormalities. Consequently, in women
of advancing age, not only is the pregnancy rate markedly
lower and the miscarriage rate significantly higher,
but the overall risk of chromosomal anomalies in the
few babies born is also dramatically increased. After
considering the above realities, you can see why there
is a dismally low probability of delivering a healthy
child, the ultimate goal, when using eggs from older
women in natural or assisted reproduction cycles. To
improve the odds, some reproductive endocrinologist
advocate older patients undergoing IVF with preimplantation
genetic diagnosis, PGD, where some genetic abnormalities
may be identified prior to embryo transfer and thus
only the "normal" embryos may be selected
for transfer. Unfortunately, sampling one cell from
a multi-celled embryo may not always reflect the genetics
found in all the other cells and this technique does
not correct for non-genetic age related defects in the
egg such as defects in the meiotic spindle fibers that
result in chromosomal misalignment or problems with
microtubular matrix composition.
The
problems of advancing age on eggs and subsequently on
embryo quality occur independently of a woman's proximity
to the menopause. The eggs of a younger woman who is
destined to undergo premature ovarian failure, let's
say in her late 20's, are just as capable of producing
a healthy baby as the eggs of a woman of the same age
who will enter the menopause in her late 50's. The converse
is also true, that a woman in her 40's who has entered
the peri-menopause, a time period of 5-10 years prior
to menopause and marks the advent of the accelerated
decline in ovarian function, will have a relatively
high percentage of chromosomally defective eggs. Thus,
growing older has a unique, irreversible, and devastatingly
negative effect on female fertility.
I
always remind younger patients suffering from infertility
that there is no abrupt change in fertility for any
given women at age 40, and therefore, this decline in
fertility may occur in younger women, although much
less often, even those in their late teens. This rate
of decline is on a continuum, from early and subtle
changes of hormone markers (FSH or inhibin B) to noticeable
impaired fertility to menopause, complete depletion
of eggs.
Other factors that contribute to age related female
infertility are the total number of eggs that a woman
is born with and her rate of loss of these eggs. Both
are genetically and uniquely predetermined. The rate
off egg loss can not be slowed or stopped; but, smoking,
medications, and surgery can accelerate it.
In
another words, the number of eggs available for possible
ovulation or medical intervention per menstrual cycle
is directly proportional to the unique number a woman
is born with, her age, and her proximity to menopause.
Although uterine pathology also increases with age,
it has little impact in comparison to the effect of
aging eggs.
Over
the last 15 years reproductive endocrinologists have
gained experience using various dynamic tests in order
to predict a woman's potential for pregnancy in both
natural and assisted reproduction. Qualitative "guestimations"
of fertility potential at a specific time in a woman's
life can be estimated through the performance of the
clomiphene citrate challenge test. This test of "ovarian
reserve" and possibly egg quality consists of simple
blood tests measuring a woman's blood levels of follicle
stimulating hormone (FSH) produced in the pituitary
and estrogen, produced in the ovaries from the developing
eggs before and after taking oral fertility medication,
clomiphene citrate. The clomiphene citrate challenge
test (CCCT) is performed by measuring day 3 FSH and
estradiol, administering clomiphene citrate 100mgs daily
from cycle days 5-9, and then measuring FSH on cycle
day 10. The test is considered abnormal if either FSH
value is above the laboratory's upper limit for the
follicular phase or the cycle day 3 estradiol is greater
than 80 pg/ml.
The
literature strongly suggests that women who have an
abnormal clomiphene citrate challenge test, regardless
of their chronological age, experience decreased response
to higher doses of gonadotropins, have higher cycle
cancellation rates, and suffer from poor reproductive
performance when using their own eggs, i.e., have a
poor probability of conception and delivery of a live
born baby with or without fertility treatments, around
5% per cycle. Thus, this provocative test predicts the
lack of success. A single elevated cycle day 3 FSH value
predicts a poor prognosis, even when normal values are
obtained during future cycle. However, if the test is
normal, it does not guarantee a woman's certainty of
conceiving or delivering a healthy baby, especially
in older women. The likelihood of an abnormal result
increases with increasing age. Patients are always cautioned
that no one test in medicine is 100% predictive of any
outcome, positive or negative. The rule of thumb is
that age is a better predictor of egg quality, and FSH
level is a better predictor of egg number. I also stress
to patients there is little if any literature related
to an abnormal clomiphene challenge test and the age
of onset of the menopause. Women still worry. The CCCT
is recommended for all unexplained infertile couples,
women > 34 years of age, and women < 35 with one
ovary, history of ovarian surgery, and exposure to chemotherapy
or radiation therapy.
Other
tests of ovarian reserve under investigation that are
not the standard of care due to conflicting data regarding
prognostic value include inhibin B levels, gonadotropin-releasing
hormone agonist test, and small antral follicle count
by transvaginal ultrasound.
The
most realistic options for women with an abnormal result,
especially women greater than 34 years of age, are in
vitro fertilization and embryo transfer using donor
egg, IVF with their own eggs possibly with assisted
hatching and PGD, controlled ovulation with gonadotropins
and IUI, (in decreasing order of success), adoption,
or to not expand their family. Of course most couples
are dismayed with these choices at first. Eventually
some couples take comfort in the fact that their prior
diagnosis of "unexplained infertility" has
been given a more definitive and impressive name, that
of diminished ovarian reserve, with an evolutionary
and biological explanation. Others are angered and frustrated
by yet another effect of time, the limitations of reproductive
science, and the misinformation preached to them by
the preceding generation.
The
baby boomer generation took their lead from their parents,
older friends and colleagues, and worldly teachers who
advised them to be responsible and learn from their
years of wisdom. This meant completing at least a college
education, obtaining a financially rewarding career,
finding a soul-mate to make and share a life, and once
thought to be emotionally and financially secure, to
embark on having children, their own genetic offspring,
in order to continue the life cycle of another generation.
Unfortunately, these well meaning mentors, trying to
better our lives from their hard-learned lessons never
carefully thought about evolution in regards to reproduction
and tested the female biological clock. Now it is our
responsibility to bestow on to the next generation conceived
in the laboratory with love our newfound enlightenment.
