Why there are so many different ovarian stimulation protocols used in the field of IVF?

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!