Rhonda Zwingerman
Rhonda Zwingerman
Rhonda Zwingerman, MD MSc FRCSC (GREI), Co-Founder, Medical Director & Fertility Specialist at Twig Fertility

IVF Protocols Explained

IVF cycles use different types of medications in order to help the ovaries produce multiple mature eggs that can be retrieved and fertilized in the IVF laboratory. IVF protocols refer to the specific ways in which these medications are combined. This article will first review the most common types of medications followed by some of the most commonly used protocols.

Pills for IVF

IVF medications

1) Gonadotropins
Gonadotropins are hormones that are made by the part of the brain called the pituitary gland. They play a critical role in the regulation of the menstrual cycle. There are two main gonadotropins: follicle stimulating hormone (FSH) and luteinizing hormone (LH). These hormones can also be synthesized or purified in a laboratory and given by injection as fertility medications. FSH, either alone or together with LH, is used in IVF cycles to stimulate the ovaries to produce multiple large follicles in a given cycle. (A follicle is a fluid filled sac within the ovary that contains an immature egg.)

2) GnRH Antagonists
GnRH antagonists are medications that block the release of GnRH (gonadotropin releasing hormone) from the brain in order to prevent ovulation. 

They are used in IVF cycles to prevent large follicles from ovulating and releasing eggs before the egg retrieval procedure.

3) GnRH Agonists
GnRH Agonists are medications that, depending on their dose and when an IVF cycle they are used, can serve a number of different purposes. Sometimes they act just like GnRH antagonists – to prevent ovulation before the egg retrieval procedure. Other times they are used to help stimulate egg growth or to trigger egg maturation and the start of the ovulation process (known as the trigger shot). They work by acting on the brain so that the brain releases its own gonadropins.

4) Human chorionic gonadotropin (hCG), a.k.a. the pregnancy hormone
hCG is most frequently used in IVF cycles to trigger egg maturation and the start of the ovulation process just prior to the egg retrieval procedure (the trigger shot). Sometimes it is also used after embryo transfer to support the developing embryo and early pregnancy.

5) Progesterone
Progesterone is a hormone that is normally produced by the ovary after ovulation. In IVF cycles, extra progesterone or a similar type of hormone (called a progestin) is usually given. It can be administered orally, vaginally or by injection into the muscle. It helps support the developing pregnancy until the placenta can take over. This is often referred to as luteal support.

The Antagonist Protocol

With this protocol, people start taking gonadotropins at the start of their cycle to stimulate follicles to grow. Approximately 4 to 6 days later, they also start taking a GnRH antagonist to prevent all those follicles from ovulating. Once the follicles have reached their target size, either a GnRH agonist or hCG is used to trigger final egg maturation. It usually takes between 8 and 12 days of gonadotropins for the largest follicles to reach the correct size for trigger. The egg retrieval procedure is usually performed 36 hours after the trigger shot.
This protocol is appropriate for most people regardless of their ovarian reserve. It is particularly useful for those at high risk of ovarian hyperstimulation syndrome (OHSS).

Example of an Antagonist Protocol

The Long Agonist Protocol (a.k.a The Long Protocol, The Long Down-Regulated Protocol)

With this protocol, people start taking a GnRH Agonist around 1 week before their expected cycle start, in the mid-luteal phase of the menstrual cycle. The purpose of this is to turn off the body’s production of reproductive hormones from the brain and to prevent premature ovulation later on in the IVF cycle. (Premature ovulation is when eggs ovulate and are released into the body before they can be retrieved through an egg retrieval procedure.) About 1 week after the start of the GnRH Agonist, when their next cycle begins, people start taking gonadotropin injections just like in the antagonist protocol above. They continue to take the GnRH Agonist as well, at a reduced dose. Both medications are continued until the trigger shot is given – the GnRH Agonist acting as the brake and the gonadotropins as the gas. The egg retrieval procedure is usually performed 36 hours after the trigger shot.

Example of a Long Agonist Protocol

The Microdose Flare Protocol (a.k.a. The Flare Protocol, The Short Protocol, The Microflare Protocol)

This protocol uses the same medications as the Long Agonist Protocol above. The differences are that the GnRH Agonist is given at a lower dose and that it is started on the first day of the cycle and then, 1 or 2 days later in the same cycle, gonadotropins are started. The total amount of time that the GnRH Agonist is used for is shorter compared to a traditional Long Agonist Protocol, which is why it is sometimes referred to as the short protocol.
The theory behind this protocol is that the GnRH Agonist can be used for 2 purposes – at the start of the cycle, together with gonadotropins, to stimulate follicles to grow (the flare effect), and then later in the stimulation phase of the cycle to prevent premature ovulation.
This protocol is generally used for people with a low ovarian reserve or a history of a poor response (low number of eggs retrieved) with a previous IVF cycle or protocol; however, it can be used for anyone. This protocol should be used with caution in people at high risk of OHSS.

The Minimal Stimulation Protocol (a.k.a. The Mini-IVF Protocol)

This protocol is almost identical to the Antagonist protocol with one exception. The dose of gonadotropins used is intentionally low. Sometimes, oral fertility medications are used alone or in combination with gonadotropins.
This protocol is generally used for people with a low ovarian reserve or a history of a low number of eggs retrieved despite using high doses of gonadotropins in a previous cycle. In these groups of people, there is evidence that an intentionally low dose approach leads to just as good outcomes as a high dose strategy.

4. The Minimal Stimulation Protocol (a.k.a. The Mini-IVF Protocol)
Schedule the timing of cycles is important

Priming

Regardless of the protocol used, some physicians will recommend that people take birth control pills or estrogen pills in the days or weeks leading up to the start of their cycle. This is referred to as priming. It is used primarily as a way to schedule the timing of cycles.

Luteal Support

Luteal support is required in all cycles where a fresh embryo transfer is being planned. As described above, this usually means taking oral, vaginal and/or intramuscular progesterone in the days leading up to the embryo transfer procedure and continuing until the results of the pregnancy test are known. After a positive pregnancy test, luteal support medications are generally prescribed for another 3 to 6 weeks until the placenta can fully take over the job of supporting the developing pregnancy.

Conclusions

There are numerous ways in which different IVF protocols, together with options for priming and luteal support, can be combined. And new medications and ways to prescribe these medications are constantly being developed and studied. If you are planning an IVF cycle, you should speak with your fertility specialist about which option is right for you, based on your individual characteristics.