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Ovarian Stimulation and Medication Protocols for IVF

Advanced Fertility Center of Chicago
In Vitro Fertilization Specialist Clinic
Gurnee & Crystal Lake, Illinois

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In order to maximize success rates with in vitro fertilization we need to get a good number of eggs from the woman. We prefer to get about 8-15 high-quality eggs at the egg retrieval procedure. IVF success rates are strongly correlated with the number of eggs retrieved with IVF.

The woman is stimulated with an injected medication that containing FSH hormone (follicle stimulating hormone) to develop multiple follicles (one egg develops in each follicle). These injections continue for about 7-12 days - until a "good" number of follicles (and eggs) are mature.

How many follicles are needed for IVF?

In most cases it is not difficult to get a sufficient number of follicles to develop to maturity. However, sometimes the response of the ovaries to the IVF medications is poor - a low number of follicles are seen on ultrasound. The minimum number of follicles needed to proceed with IVF treatment depends on several factors, including follicle size, age of the woman, results of any previous IVF stimulation attempts, and the willingness of the couple to proceed with the egg retrieval when it appears that there will be a relatively low number of mature eggs obtained. Some IVF doctors will say that you should have at least 5 follicles of 14mm or greater while others will be willing to proceed to egg retrieval with only 1 follicle. Most IVF programs in the US seem to want a minimum of about 3-4 mature follicles. In our experience, IVF success rates are quite low when less than 3 mature follicles are present.

See details about the subcutaneous injections and intramuscular injections used for IVF treatment

IVF stimulation protocols in the US generally involve the use of 3 types of drugs:

1. GnRH-agonist (gonadotropin releasing hormone agonist) or a GnRH-antagonist (e.g. Ganirelix) to suppress the LH surge and ovulation until the follicles are mature
2. FSH product (follicle stimulating hormone) to stimulate development of multiple follicles
3. HCG (human chorionic gonadotropin) to cause final maturation of the eggs in the follicles

The purpose of the GnRH-agonist (or antagonist) is to suppress release of LH (luteinizing hormone) from the woman's pituitary gland during the ovarian stimulation process. LH surges would cause premature ovulation (release) of the eggs.

The purpose of the FSH product is to stimulate development of multiple follicles (structures that contain eggs) in the ovaries.

Ultrasound of multiple follicles (black circles) in a stimulated ovary
Red cursors outline one mature follicle which is 17 mm diameter in this example
Most of the mature sized follicles (about 15-20 mm diameter) will usually yield mature eggs at the egg retrieval procedure

Ovarian Stimulation Protocols Using GnRH-agonists

There are 2 basic ways that we use the GnRH-agonist product (e.g. Lupron) in conjunction with the FSH product in ovarian stimulation protocols:

1. "Long protocols", also called "luteal Lupron", or "down regulation" protocols
2. "Flare" protocols, also sometimes called "short" protocols

Long Lupron Protocols - also called "down regulation" or "mid-luteal Lupron" protocols

Long protocols are more commonly used for most patients going through IVF. In general, pregnancy rates are thought to be better with the use of this type of stimulation. The Lupron is started about 7 days prior to the next expected menses (what we call mid-luteal), and the FSH product is started within the first 2-6 days after menses begins. The Lupron dose is usually reduced when the FSH product is started. The exact dose and "flavor" of GnRH-agonist (e.g. Lupron, Synarel) and FSH product (e.g. Follistim, Gonal-F, Repronex) will vary according to the individual biases of the physician and the specifics of the patient's case.

We prefer to get multiple follicles that are 17-20mm in average diameter - at which time the HCG injection is given that will induce egg maturation. The egg retrieval is planned for 34-35 hours after the HCG injection - just before the woman's body might start to release the eggs (ovulate).

Sample calendar of a typical IVF stimulation using the Long Lupron Protocol

Some women do not respond well to a long Lupron protocol and will not develop sufficient follicles to allow a reasonable chance for pregnancy from IVF. The ability of the ovary to stimulate well by developing numerous follicles can be predicted to some extent by an ultrasound test called an antral follicle count.

Women that are more likely to be low responders to ovarian stimulation would be those that have low antral follicle counts, or those women who are older than about 37, those with elevated FSH levels, or women with other signs of reduced ovarian reserve. 

Stop Lupron Protocol

Some women are "over-suppressed" by the standard long Lupron protocol, or are low responders for some other reason. A "stop Lupron" protocol is one possible way to get a better response to stimulation. The "flare-up" protocols are another option. Some reproductive endocrinologists will try a stop-Lupron protocol in the next attempt after a poor stimulation and others prefer to use a flare. To a great extent this is trial and error - we are never sure what the stimulation will be like until we do it.

The Lupron is started at the same time in the cycle, but usually at a lower dose, e.g. at 5 units daily instead of 10 units. The Lupron is then stopped completely after the woman gets her period and the FSH product is started.

The LH suppressing ability of this protocol is not as complete as with the standard "long" Lupron protocol. However, the risk for a premature LH surge is still low, and blood tests can be done during the cycle to watch for any LH increases.

Flare Protocol

In this type of stimulation, the Lupron (or other GnRH agonist) is started on cycle day 2 in the same menstrual cycle that we will retrieve the eggs - instead of starting it a week prior to the start of menses. We are trying to take advantage of an initial "flare-up" response of FSH and LH release from the woman's own pituitary gland that usually occurs in the first 3 days of Lupron administration. Continuing Lupron for more than 3 days temporarily suppresses the pituitary gland so that it has very low output of FSH and LH.

The FSH product (e.g. Follistim, Gonal-F, Repronex) is then started on the following day (day 3). The idea is that the Lupron will stimulate release of a large amount of FSH (and LH) that will jump-start (flare-up) the follicles so that we might have a better ovarian stimulation with more mature follicles and more eggs to utilize with IVF.

Birth control pills are usually given for the month before the flare so that there will not be a leftover cyst (corpus luteum) that could become reactivated by the high LH levels at the onset of the flare stimulation.

An example of one flare protocol is given below - there are many variations on the theme.

1. Birth control pills for 1 month
2. Stop birth control pills - no meds for 2 days
3. Start Lupron on the third pill free day. We use a 50ug dose of Lupron twice daily -AM and PM- for these flare cycles.
50ug is a very small dose as compared to the usual Long Lupron protocol dose of 0.5mg (500ug). The Lupron needs to be diluted by the pharmacy or the doctor's office in order to be able to inject such a low dose.
4. Start injections of the FSH product (once or twice daily) on the day after starting Lupron
5. The Lupron is usually continued at the same dose until the HCG trigger shot is given.

Some women do not respond well to a flare protocol (or any other protocol) and will not be able to develop sufficient follicles to allow a reasonable chance for pregnancy from IVF with their own eggs. These women are good candidates for egg donation.

Learn more about IVF cycle cancellation

Ovarian Stimulation Using GnRH-antagonists

Ganirelix acetate, also called Antagon, became available in the U.S. in the spring of 2000. It has been used in Europe for much longer.  Cetrorelix acetate (Cetrotide) is another GnRH-antagonist that is now available in the U.S. 

Ganirelix and Cetrotide - as well as Lupron - prevent the woman from having an LH surge. However, Ganirelix and Cetrotide are antagonists  instead of agonists. Ganirelix works by competing with native GnRH molecules at their binding sites in the pituitary - while Lupron works by "down regulating" the pituitary's ability to produce the LH surge. This distinction is not important to understand. The bottom line is that both kinds of drugs, antagonists and agonists, prevent LH surges (in different ways).

Ganirelix or Cetrotide are usually started on (about) the sixth day of giving the FSH product that stimulates the development of follicles in the ovary. They are commonly given subcutaneously once daily and continued until HCG is given. Cetrotide can also be be used as a single shot (in a higher 3mg dose), rather than as daily injections of the lower 0.25mg dose. When the single 3mg dose is given, Cetrotide is supposed to give 4 days of suppression (no LH surge for 96 hours). If the patient needs more days of stimulation beyond the 96 hours, the daily 0.25mg Cetrotide injections are given until the stimulation is completed and HCG is given.

Use of Ganirelix results in less total number of shots being taken during the stimulation cycle than with the use of Lupron. However, there is some evidence from the published literature that there are slightly fewer eggs retrieved (on average), slightly less embryos available on the day of transfer (on average), and slightly lower pregnancy rates than with the use of Lupron. However, this is when all patients are given the same protocol (Lupron vs. Ganirelix). Pregnancy rates are excellent with Ganirelix when used properly in selected patients. We use it for almost all of our egg donation cases and see excellent pregnancy and live birth rates with it in the donors. More studies are needed to further clarify this important issue.

Some clinics are reporting that women who are low responders to ovarian stimulation protocols that involve use of Lupron might be able to stimulate better if an antagonist such as Ganirelix is used instead. This deserves careful study in randomized controlled trials of previous low responders to see whether it will be a viable alternative to the other ovarian stimulation regimens for low responders such as the "stop Lupron" and flare protocols.