IVF stimulation - How to choose a protocol

Most women produce just one mature egg per menstrual cycle, but during an IVF doctors prescribe drugs to be taken at the start of the cycle that trigger multi-follicular development, i.e. the growth of more ovarian follicles containing more eggs. 

‘Protocol’ in this sense refers to the combination of drugs and their dosage. It’s a complicated decision and so relies on you trusting your doctor to steer you in the right direction. Ultimately, there may be some trial and error as it’s not always easy to anticipate how a patient will react to different protocols. You can read more here about the practical aspects and potential side effects of this part of the treatment.

It’s frustrating but unavoidable that eggs and embryos will be lost as the IVF process progresses, and it is most likely to occur while the embryos are being grown in the lab. Consequently, the best scenario is to start off with as many eggs as possible. At least to an extent. Once about 15-20 eggs have been retrieved, your chances stop increasing while the risk of developing ovarian hyperstimulation syndrome (OHSS) becomes greater. Not only can OHSS be incredibly painful, but in some rare cases it can also prove life threatening. And so, the most important question to ask at this stage is: which protocol will result in the highest number of eggs without leading to OHSS?

Different types of protocols

When learning about the protocols, it might initially feel as though you are getting an information overload. Really they can be boiled down to three core options:

• Short protocol/Antagonist
• Long protocol/Long Agonist
• Flare protocol

The “Long Agonist” and “Antagonist” protocols, often just called long and short protocol, are the two most common ones, and it’s not always clear why one or the other is chosen. The “Flare” protocol is not used as often, only for patients with specific challenges (often poor responders).

There are two main differences between the protocols: how much of the drug that causes the follicles to grow (gonadotropin) is used, and what other drugs are used alongside it.

Gonadotropin is an injectable hormone that causes more follicles, and therefore more eggs, to grow simultaneously. The dose is important because too little gonadotropin means too few eggs, and too much may result in OHSS. The dose is commonly measured in International Units Per Day (IU) and can range from 0-900 IU with the majority of women prescribed 250-450 IUs per day.

Gonadotropin is the principal drug in most protocols, and will typically be prescribed alongside two other drugs. The purpose of the other drugs is to stop the eggs from maturing before the retrieval procedure and to force the eggs to mature so that they can be retrieved.

Which protocol is right for me?

At this stage, the question you will no doubt be asking yourself is: Which protocol is most likely to result in a pregnancy? When we look at general IVF statistics, they show that Antagonist and Long Agonist have a similar rate of success. However, when we break it down and look at sub-groups of the IVF population, it becomes clear that different protocols work better for some than others. It’s important to say that the choice of protocol should be done by your doctor, but to feel in control and to be able to ask better questions, understanding the difference between protocols can be good - especially if you belong to one of the groups below.

Patients with PCOS or a high AMH

The Antagonist protocol has proven to be comparatively successful for women with polycystic ovary syndrome (PCOS) or other patients with a high AMH that are at risk of ovarian hyperstimulation syndrome (OHSS). It lowers the risk for OHSS since, in the Antagonist protocol, the drug used to force the eggs to mature (known as the ‘trigger shot’) is one called Lupron instead of hCG (Human Chorionic Gonadotropin). As a result of Lupron’s properties, the chances of hyperstimulation are much lower. It isn’t possible to use Lupron in the Long Agonist protocol as it is already used elsewhere.

Poor responders

The Flare protocol has proven more successful for women with a diminished ovarian reserve, or those who have had a low number of eggs retrieved in past stimulation cycles. This protocol doesn’t use a Lupron trigger shot to prevent OHSS; however, poor responders don’t typically have a strong reaction to gonadotropins (as evidenced by previous low egg retrieval numbers) and so aren’t considered at risk of overstimulation.

The Flare protocol instead deploys Lupron (or another Gonadotropin-releasing hormone (GnRH)) on day two of the menstrual cycle in which the eggs will be retrieved, as opposed to a week before the onset of menses. This is to take advantage of the initial flare effect of the follicle-stimulating hormone (FSH) and luteinizing hormone (LH) released by the pituitary gland which typically occurs in the first three days of Agonist administration. If used for more than three days, Lupron temporarily suppresses the pituitary gland and lowers the output of FSH and LH.

The FSH product is started on day three in the hope that the Lupron has stimulated a large release of FSH and LH that accelerate the follicles (known as the ‘flare-up’). The intention is to enhance the response of the ovaries to grow more mature follicles and thus more eggs.

Birth control pills are commonly prescribed for the month before the Flare protocol begins to avoid a leftover cyst (corpus luteum) that could cause discomfort or more serious complications if reactivated by high LH levels at the start of the stimulation process.