Let’s start with the basics. What are ovaries and why do we need to
stimulate them for IVF ? Your ovaries are a pair of organs situated in the
pelvic region of females, one on each side. They act as the reservoir for our eggs.
Eggs are the cells which carry half of the information (genetic blue print)
necessary for creating a baby. Such precious egg cells are stored, nourished
and protected within specialized structures in ovaries called follicles. A female foetus at around 18-22 weeks of
gestation contains about 2,000,000 follicles in its ovaries and each follicle
contains one egg. The follicles which are carrying the eggs are lost
continuously (depleted) during the life time of a female and at around
menopause only less than 1000 follicles will remain. A woman releases approximately
400 eggs during her lifetime (one egg each month from the time of attaining
puberty until reaching menopause). A female ovary carries several immature
follicles (and hence several eggs!) but not all the follicles will become
mature enough to release a functional egg cell. This means that more than 99.9999
% of the follicles (and hence the eggs) are simply lost.
What causes the follicles to grow and attain maturity?
During the start of each menstrual cycle our hypothalamus (a part of our
brain) secretes a protein called gonodotrophin releasing hormone (GnRH). This
GnRH acts on special cells called gonodotrophs present in the anterior
pituitary gland which in turn secretes FSH and LH. FSH and LH are called gonodotropins.
Gonodotropins help in the growth of follicles. Follicles which are present in
an immature state within the ovary are called primordial follicles. After a woman
attains puberty, during the beginning of each menstrual cycle 15 to 20
primordial follicles develop into primary follicles. This process of selecting
15-20 follicles from the thousands of follicles present in the ovary is called the
phase of follicular recruitment. These primary follicles grow further and
become secondary follicles. The
secondary follicles further develop into antral follicles. These antral follicles are 2-8 mm in
diameter. When a vaginal ultrasound is performed during the initial days of
your menstrual cycle (for example on day 3) these antral follicles can be
counted and this count gives an indirect measure of your ovarian reserve. Women
with high ovarian reserve have high antral follicle counts and women with low
ovarian reserve will have a low antral follicle count. These antral follicles grow in response to FSH.
Growing antral follicles will also start secreting estrogen and inhibin which
inturn decreases the secretion of FSH from the pituitary gland. Follicles with
fewer FSH receptors fail to grow and eventually die (become atretic). The
follicle with the most number of FSH receptors grows quickly and becomes a dominant
follicle. This dominant follicle carries the egg which will be released during
ovulation ; and if all goes well, it will be fertilized by a sperm.
How does ovulation occur in humans?
During each menstrual cycle several follicles start growing in response
to the FSH secreted by our anterior pituitary and out of those several
recruited follicles only one follicle grows to maturity ( the dominant follicle).
The other follicles which fail to reach maturity are lost (die). When a
follicle reaches maturity it secretes increasing amounts of estrogen. This rise
in estrogen from the dominant follicle triggers the acute rise of another
pituitary hormone called Luteinizing hormone (LH). LH helps in the final
maturation of the egg present within the follicle, and also causes the follicle
to burst, thus resulting in the release of a mature egg. After the release of
egg from the follicle , LH also helps in the development of corpus luteum which
secretes a hormone called progesterone. Progesterone prepares the endometrium
for embryo implantation. During each menstrual cycle , a woman normally female
grows only one mature follicle and hence releases only one egg (very rarely 2
or more).
So how do doctors manage to grow several follicles to maturity and
retrieve so many eggs during an IVF treatment?
During IVF treatment , the doctor treats you with FSH injections. This huge
amount of FSH helps to rescue more of the follicles which were recruited during
that particular menstrual cycle. Remember, that in a natural menstrual cycle , only
one follicle out of 15-20 recruited follicles grows and becomes mature enough ,
while the others die. However, during IVF treatment , more of the recruited
follicles are grown to maturity (by using high concentrations of FSH) and each
mature follicle contains one mature egg . This is the reason why IVF
specialists are able to harvest several eggs during an IVF treatment. This is
also the reason why IVF treatment will not deplete your ovarian reserve (egg
reserve!). The follicles and eggs which would normally have been lost in any
case during that particular menstrual cycle are rescued during an IVF cycle. So,
during IVF treatment our ovaries are hyperstimulated in a “controlled” manner ,
thus overriding the natural biological process of the selection of a single dominant
follicle in women . ( Remember that this happens routinely in rabbits, who
routinely give birth to a litter of rabbits ! This is why they are so fertile.
)
Where does the FSH used for IVF treatment come from?
The FSH used in IVF treatment has different brand names like Menogon, Gonal
F, Menopur etc. hMG (human menopausal
gonadotrophin) refers to the FSH which is extracted and purified from human
menopausal female urine . This is cheaper. Menopur is a highly purified form of
hMG and is more expensive than hMG. Gonal F is manufactured using modern
recombinant DNA technology and is costlier. But all of them contain the same
ingredient FSH and serve the same purpose – helping the growth of follicles.
Scientific studies have failed to show the superiority of one FSH preparation over
the other. So it is wiser to use the cheaper version of FSH if you are
undergoing an IVF treatment.
Why do some women produce more eggs and some less during an IVF cycle?
To understand this, one must know what ovarian reserve is. Imagine our
ovary as an egg bank. Some women have more eggs in their egg bank and hence are
able to draw more eggs from it when required (for example, during an IVF cycle)
while some women have fewer eggs in their ovaries and hence cannot take withdraw
much from it. So the amount of eggs left in a female’s ovary determines her
ovarian reserve. But one more important point has to be emphasized when talking
about ovarian reserve - egg quality! Just because a women has more eggs it
doesn’t mean their quality is good enough to be used for making a much desired
baby! If the term ovarian reserve is used to indicate the reproductive capacity
of a woman, then ovarian reserve should be defined both by the quantity and
quality of eggs present in the ovaries. When a women has both good quantity and
good quality eggs , her chance of conceiving a baby is very high. Women who
have good ovarian reserve produce more eggs and women who have poor ovarian
reserve produce fewer eggs during an IVF treatment. The age of the woman is usually
a good indicator of their egg quality. Young women usually produce good quality
eggs ; and their egg quality declines as they age.
How will I know whether I have good ovarian reserve?
There are some tests which can give you an indirect measure of your ovarian
reserve.
1)
Blood levels of FSH
and E2 (estrogen level) measured on day 3 of your menstrual cycle.
2)
Blood levels of Anti
müllerian hormone (AMH) measured on any day of your menstrual cycle.
3)
Vaginal ultrasound to
count the number of antral follicles on your ovaries (usually done on day 2 - day
5)
These tests give a quantitative measure of a woman’s ovarian reserve. The best indicator of a woman’s egg quality
is how she actually performs during her IVF cycle – after all, the proof of the
pudding is in the eating !
How does controlled ovarian hyperstimulation during an IVF cycle work?
During controlled ovarian hyperstimulation (superovulation) , injectible
FSH is used to stimulate the synchronous growth of the follicles which have
been recruited during that particular menstrual cycle to maturity. This growth
of several follicles at a time causes the estrogen levels to rise and this can
trigger a premature LH surge. This LH surge can lead to premature ovulation,
which means that the eggs would be lost before they could be collected for
fertilization. To avoid this LH surge, GnRH agonists or antagonists are used. GnRH
agonists and antagonists suppress the pituitary’s ability to secrete gonodotropins
(FSH and LH) , and thus prevent premature surge of LH. Since the LH surge is
important for obtaining mature eggs , the doctor uses hCG hormone ( which is
similar in structure to LH ) as a trigger (in the form of injection) during the
final stages of ovarian stimulation , to induce final maturation of eggs . The mature
eggs are retrieved about 36 hours after the hCG trigger is given. It is very important that you take the hCG
trigger at the proper time , so that your doctor can retrieve eggs which are
mature enough to be fertilized.
What is an ovarian stimulation protocol?
During IVF, certain hormones and drugs (medications) are used to grow
several follicles in unison with an aim to retrieve many mature eggs at a time.
The medications are used in a variety of combinations called protocols. There are
several different ovarian stimulation protocols used in the field of ART. All of them are based on the following basic
principle:
1)
Use of gonodotropins
(FSH) to stimulate follicle growth.
2)
Use of GnRH agonist
or antagonist to suppress the ovaries prior to stimulation and to prevent
premature LH surge.
3)
Use of hCG trigger (or
in some cases, a GnRH agonist like lupron is used to the trigger the LH surge )
, to induce the final maturation of eggs.
The basic aim of any ovarian stimulation protocol is to collect many
mature eggs that can be fertilized to create good quality embryos , which will ultimately
develop into a healthy baby!
Does every woman respond well to ovarian stimulation protocols?
Depending on a woman’s ovarian response to injectible FSH, they can be
classified as hyper responders, normal responders and poor responders. Hyper
responders are women who develop several follicles when their ovaries are
stimulated with low doses of FSH . The doctor retrieves several eggs and their
estradiol levels exceed 3000 pg/ml on the day of hCG trigger. They are at risk
of developing OHSS - ovarian hyperstimulation syndrome. Poor responders are
women who develop less than 3 follicles when stimulated with a high dose FSH and
their estradiol level is less than 500 pg/ml on the day of hCG trigger. Normal
responders fall in between both these categories.
What determines a woman’s response to ovarian stimulation?
Hyper responders are usually women with an endocrine disorder called
PCOD ; or young women. These women have a large number of antral follicles ( over
25). Their response to FSH is excessive (even
low doses of FSH are able to stimulate the growth of several follicles). They
have a very good pregnancy rate when undergoing IVF since they produce more
eggs and hence will get many embryos which are good enough to be transferred to
their uterus. However, they are at risk of developing OHSS, and need to be
handled with care and respect !
Normal responders are young women who have a decent amount of antral
follicles (10-20) in their ovaries. Their ovaries need medium doses of FSH to
stimulate the growth of follicles. Their overall pregnancy rate is good too.
Poor responders are women with fewer antral follicles in their ovaries. Women
with poor ovarian reserve and older women come under this category. They need larger
amounts of injectible FSH to stimulate the growth of follicles. Their egg yield
will be less and their chances of success with IVF is lower when compared to
women of the other two groups.
Why are there so many different ovarian stimulation protocols?
Protocols vary in the type, dosage and timing of gonodotropins, GnRH
agonists and GnRH antagonists used. Normal responders and hyper responders are
easy to superovulate – and pretty much any protocol will work well for them ! The
probable reason for the existence of so many different IVF stimulation
protocols is to help doctors manage poor ovarian responders , who are challenging patients to treat. A
poor response to gonodotropins during IVF can lead to cycle-cancellations; the
availability of fewer embryos or embryos of poor quality for embryo transfer ; and
decreased pregnancy rates. This has led to the search for protocols which could
either increase their yield of eggs ; or increase their chances of pregnancy ,
even with the meagre number of eggs retrieved from them. But until now no particular protocol has been
identified as a successful method for treating poor responders (PMID:
17253503).
Poor responders usually have poor ovarian reserve with a low antral
follicle count. Since antral follicles are the ones which respond to injectible
FSH, in a poor responder the use of high concentration of FSH often will not
increase the number of growing follicles. The sad truth is that if your egg
bank (ovary) in on the verge of bankruptcy, it simply will not allow you to
draw an overdraft on it. This is why a poor responder doesn’t necessarily grow
more follicles even if the doctor increases the dosage of FSH .
Let me explain using an analogy. Consider an apple tree (ovaries) with
lots of apples (follicles) closely packed together. You want to get a good
amount of apples from the tree. You decide to throw a stone (ovarian
stimulation protocol) at it so that some ripe apples fall down. The amount of
apples you want to get will be directly proportional to the force (dosage of
FSH) with which you throw the stone. The
more the force you apply, the more strongly the stone will hit a branch , and
hence more apples will fall down (growth of more follicles). This is why if an ovary
(apple tree) has good ovarian reserve or good amount of resting follicles
(apples) , any protocol (any stone) works well ! But what will happen if there are only two or
three apples (follicles) present in a big tree (ovary)? Even if you hit the tree with high force
(increase the dose of FSH) , the yield of apples will not change and you have
to really struggle to get those apples off the tree , because even if you use
different stones, (different protocol) it’s only if you hit that particular
branch (the follicles which are capable of responding to FSH), will the apples
fall down. The probability of this happening is low; you may have to try
several times before you succeed. However, there is one more way to get those
apples-just wait for one to ripen and fall down on its own! The same applies to
an ovary with a poor ovarian reserve. Scientific
studies have also failed to show any improvement as regards the number of eggs retrieved
or in the pregnancy rate with the use of different protocols. This is why mini-IVF
or natural cycle IVF has become a popular option for poor responders. This is
just like waiting for the apple to fall down on its own! In a mini IVF cycle, the
follicle that grows naturally during each menstrual cycle is monitored closely
and the single egg present in it is collected for fertilization and the
resulting embryo is transferred to the uterus. Although the success rate is not
as high with such a strategy, it prevents the futile attempt of stimulating the
ovary with a very high dose of expensive FSH! Since FSH is costly and conventional
IVF is expensive , this kind of natural IVF for poor responders is becoming
increasingly popular. After all, at the end of the day, you just need one
winning lottery ticket to hit the jackpot !
So the moral is, different IVF protocols are just different ways of
doing the same thing – after all, there are many ways to skin a cat ! In that
case, why not use the same protocol for everyone? This is because different REs
prefer working with different protocols - and some REs just try to hype and
promote their own regime ( often calling it with a catchy acronym) to impress patients
! Many patients fall for the fancy names some IVF clinics use for their different
protocols. This is especially true for poor responders who are frantically
searching for ways to use their own eggs to get their baby!
