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One of the most frustrating problems in IVF today is
that of poor ovarian response. This is also known as poor ovarian
function, poor ovarian reserve, occult ovarian failure, or the oopause. It’s well known that pregnancy rates
in IVF are directly dependent upon the quality and number of embryos
transferred, and the more the eggs a woman grows, the better the embryos
we can select from. This is why women with a good ovarian response have
much higher pregnancy rates than women with a poor ovarian response.
Usually, ovarian functions goes hand in hand with
age, and as a women becomes older, her ovarian response starts
declining. Every girl is born with a finite number of eggs, and their
number progressively declines with age. A measure of the remaining
number of eggs in the ovary is called the "ovarian reserve"; and as the
woman ages, her ovarian reserve gets depleted. The infertility
specialist is really not interested in the woman's calendar (or
chronological age), but rather her biological age - or how many eggs are
left in her ovaries.
Various tests have been described to measure
ovarian reserve. The commonest test measures the level of FSH ( follicle
stimulating hormone) in the blood - the basal
( day 3) FSH level. A high level suggests poor ovarian reserve; and a
very high level
( more than 20 mIU/ml, though this varies from lab to lab ) is
diagnostic of ovarian failure. A test that can provide earlier evidence
of declining ovarian function is the clomiphene citrate challenge test (
CCCT). This is similar to a " stress test " of the ovary; and involves
measuring a basal Day 3 FSH level; and a Day 10 FSH level, after
administering 100 mg of clomiphene citrate from Day 5 to Day 9. If the
sum of the FSH levels is more than 25, then this suggests poor ovarian
function, and predicts that the woman is likely to have a poor ovarian
response ( she will most probably grow few eggs, of poor quality) when
superovulated. Remember that a high FSH level does not mean that
you cannot get pregnant - it just means that your chances are
dropping because your egg quality is impaired.
Some women find it difficult to understand why FSH
levels are high in women with poor quality eggs. Intuitively, more is
better, so higher levels should mean better eggs, shouldn't it ? As one
patient asked me, " If FSH stands for Follicle Stimulating Hormone, and
I have high levels of FSH, then doesn't that mean that I have the
ability to stimulate lots of follicles ? A high FSH should mean that I
should have lots of eggs ! " I had to explain the basic biology to her.
Normally , FSH is produced by the pituitary, and this is the hormone
which is responsible for the growth of the egg from the ovary every
month. In young women with lots of good quality eggs, low levels of FSH
are enough to grow the eggs. However, as the woman grows older and
egg quality and quantity decline, the pituitary needs to produce more
and more FSH to stimulate egg growth, because the FSH has to work harder
to stimulate egg growth.
Another test which has been recently developed is the
measurement of the level of the hormone, inhibin B, in the blood. Low
levels of inhibin B ( which are produced by " good " follicles) suggest
a poor ovarian reserve. However, just because a test result is normal
does not mean that the quality or number of the eggs produced will be
good - the final proof of the pudding is always in the
eating ! This is
why one of the most useful ways of making a diagnosis of poor ovarian
reserve is when the patient gives a history of responding poorly to
medications used for superovulation in the past.
Along with using biochemical tests to assess ovarian
function, we can use biophysical markers to test these too. These
biophysical tests use ultrasound technology to image the ovaries and the
follicles. The most useful test is called an antral follicle
count ( AFC) , in which the doctor counts the number of antral follicles ( also
referred to as resting follicles) present in the ovary
on Day 3 using vaginal ultrasound scanning.
Antral follicles are small follicles ,
usually about 2-8 mm in diameter. The number of antral
follicles correlates well with ovarian response. A normal total antral
count is between 15 and 30. If the count is less than 6, the prognosis
is poor. You can read more about the antral follicle count and see
ultrasound images of these at the
advancedfertility.com website . The volume of the ovaries also
correlates with ovarian response. The volume of each ovary is
calculated using the formula ( length × width × height × 0.5 ) and the
normal ovarian volume of both ovaries combined is 10 ml. Women with
small ovaries ( volume of less than 4 ml) have a poor ovarian response.
While an older woman often expects to have poor
ovarian reserve, and is prepared for the fact that she may respond
poorly to superovulation, when a young woman finds out she is a poor
ovarian responder, this comes as a rude blow. Most young women
expect that their eggs will be fine,
because they are young and have regular cycles, but this is not always
true. Regular periods simply means that the eggs are good enough to
produce enough hormones to have normal menstrual cycles; however, this
does not mean that the egg quality is good enough to make a baby !
Ovarian reserve is a biological variable, and egg quantity and quality
in an individual woman can be average for her age, better than average,
or worse than average. Women with poor egg quality are said to have poor
ovarian reserve , poor ovarian function, or occult ovarian failure; and
Dr Jansen has coined the term , oopause, to describe this condition.
Many treatment strategies have been developed in
order to treat women with poor ovarian reserve. Because time is at a
premium for these women, treatment needs to be aggressive, in order to
help them conceive before their eggs run out completely. IVF is usually
their best option, as it offers the highest success rates.
Superovulating these women can be quite tricky, and this is where the
experience and the expertise of the doctor makes a critical difference !
They usually need much higher doses of gonadotropin
injections ( HMG) for superovulation. We have used upto 750 IU of HMG (
10 amp of 75 IU) daily for difficult women, in order to stimulate them
to grow eggs. Unfortunately, this is like scraping the bottom of the
barrel, and the quantity and quality of their eggs often still remains
poor.
Other clinics have tried using rec FSH ( recombinant
gonadotropins) or GnRH antagonists, but neither of these help. In the
past, doctors tried adding growth hormone injections ( because of the
“growth factors” this contained) , but this was of no use.
Interestingly, some doctors have gone back to using the natural cycle,
or trying gentle stimulation with clomiphene for these women, since they
don’t see any benefit in spending hundreds of dollars just to get 2-3
more eggs for IVF.
Interestingly, we see a lot of women who are
iatrogenic poor ovarian responders – who have a poor ovarian response
because they have been badly superovulated. These are typically women
who have PCOD ( polycystic ovarian disease), who are undergoing IVF in
clinics which don’t have much experience with treating such patients.
Because their doctors are so scared of ovarian hyperstimulation syndrome
( OHSS), in their anxiety to prevent this complication, they often
trigger off ovulation and egg retrieval too early. As a result of this
mis-timing of the HCG shot, most of the eggs retrieved are immature, and
fail to fertilise. These woman are then labeled as being poor ovarian
responders , when in reality it is their doctors who are poor ovarian
stimulators ! If they are superovulated properly in a good IVF clinic,
their pregnancy rates are excellent.
What happens if you are young and find that you have
a poor ovarian response in the middle of your first IVF cycle ? This is
a very difficult problem, because it was not anticipated, and you are
not emotionally prepared to deal with it. Options include: continuing
the cycle with an increased dose of injections; or canceling this cycle
and starting a new cycle later with a higher dose of injections.
However, the prognosis remains poor, and there is no certainty that you
will grow more eggs with a higher dose the next time around.
The option which offers the highest pregnancy rate
for women with a poor ovarian response is to use donor eggs. While this
is medically straight forward, it can be very hard for a young woman
with regular cycles to accept this option. Often, it’s worth doing one
cycle with your own eggs even if the chances are poor, so that you have
peace of mind that you did your best. This also may make it easier to
explore the option of donor eggs for the future.
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