Aggressive IVF Stimulation Protocols

By Sy Q Le, M.D.

Not all patients will benefit from the standard IVF stimulation protocols. While Lupron and birth control pill (BCP) help recruit multiple follicles by preventing natural selection of a single dominant follicle, each can suppress ovarian response, especially when used together during the pre-stimulation phase.  Patients with low ovarian reserve will do better using regimens that minimize the inhibitive effects of Lupron and BCP. At IVFMD we use a variety of aggressive protocols to optimize ovarian response. When choosing a protocol for patients with low egg reserve, the experience, creativity, and flexibility of the physician contribute greatly to the chance of success. Listed below are the protocols that we have used effectively over the years:

1.  Micro-Lupron Flare Protocol

Lupron binds to the pituitary to cause the release of FSH and LH to eventually exhaust the pituitary of these hormones so that the brain and pituitary can no longer regulate the function of the ovaries. Once the natural selection mechanism is removed, ovarian stimulation to recruit multiple follicles can begin.

In the classic protocol, Lupron and BCP are used for at least 10 days before stimulation. In some patients, this combination can be a potent suppressor of ovarian response. In contrast, the micro-Lupron regimen uses a very small amount of Lupron (1/20 the usual dose) just 3 days before ovarian stimulation in order to release LH and FSH from the pituitary. Thus during the first 2-3 days of micro-Lupron, the ovaries are stimulated by pituitary FSH and LH (the flare effect). On the third day of micro-Lupron, medications containing FSH and LH are added to further augment the stimulation. After a week, the pituitary finally is exhausted of its LH and FSH and can no longer interfere with the stimulation process by either selecting the dominant follicle or causing ovulation.

The micro-Lupron protocol was one of  the first aggressive protocols introduced and over the years has helped many patients with low ovarian reserve to conceive their own children without resorting to donor eggs. Its main disadvantage is that LH is also released along with FSH, which theoretically can negatively impact egg development. However, several studies have demonstrated that some early LH is necessary for optimal development of follicles. The other disadvantages are the increased risk of premature ovulation near the end of the stimulation process due to minimal pituitary suppression, and the potential inhibition of BCP on ovarian response in patients with very low egg reserve (AMH < 0.5 ng/ml).

2.  Estrogen (E2)-primed Low Lupron protocol

The E2-primed Low Lupron protocol was introduced to address the problem of early LH release seen in the micro-Lupron flare protocol. Unlike the classic Lupron protocol, no BCP is used in the pre-stimulation cycle. Lupron is started about a week after ovulation, its dose is halved at menses, and further halved when stimulation begins. Estrogen is added on day 3 of menses and is continued throughout the stimulation phase.

As  in the classic Lupron protocol, this regimen uses extended Lupron pretreatment to eliminate any potential negative effect of LH during the initial phase of stimulation. The sequential decrease of Lupron dose aims to offset the suppression side effect of the medication. Estrogen also provides a beneficial hormonal milieu for follicular development. The main disadvantage of the E2-Lupron protocol is that the prolonged pituitary inhibition with Lupron, albeit a reduced doses, can lead to pronounced suppression of ovarian response in patients with AMH <0.5 ng/ml. In addition, ovarian cyst can form from  Lupron-induced release of FSH, which may necessitate longer use of Lupron and can further delay stimulation. In our experience, the stimulation duration for this protocol tends to be protracted and the medication requirement can be very high.

3.  Estrogen-primed Luteal Antagonist Protocol

In this protocol, the pretreatment cycle is a natural cycle (no BCP). About a week after ovulation, estrogen and an GnRH antagonist (Ganirelix or Cetrotide) are started to prevent premature release of FSH that can cause size discrepancy in the developing follicles. Pretreatment with estrogen provides the young follicles a beneficial environment to develop. Ovarian stimulation begins on day 3 of menses and the antagonist is used again added later to prevent premature ovulation.

At IVFMD, this is currently our favorite protocol for patients with very low egg reserve (AMH <0.5 ng/ml or total antral follicle count of 5 or less. It avoids the suppressive effect of Lupron and BCP on the ovaries. In addition, the use of estrogen during the pretreatment cycle prevents premature recruitment of follicles that can reduce the number of follicles available for stimulation. Studies have shown that this protocol allows more gradual and coordinated growth of follicles resulting in improvement of embryo quality and quantity. The main disadvantage of this protocol is the lack of flexibility in planning the cycle since ovarian stimulation can occur on any day.

4.  Estrogen-primed Micro-Lupron Flare Protocol

We recently introduced this protocol to improve on the micro-Lupron flare protocol. We reserve this protocol for patients who do not respond well to the E2-Antagonist program. The pretreatment phase is a natural cycle in which estrogen is given for 7 days a week after ovulation. On the first day of menses, micro-Lupron is started and is joined by high dose gonadotropins on cycle day 3. The E2-microlupron protocol avoids the use of BCP that can suppress the ovaries, while utilizing the beneficial effects of luteal phase estrogen- preventing  premature follicle recruitment and sensitizing follicles to stimulation- as well as the flare effect of micro-Lupron. At IVFMD several patients with AMH of 0.1-0.3 ng/ml who conceived using this special protocol.

5.  Femara-Antagonist Protocol

And finally, a protocol for patients who had failed to respond to all previous protocols due to extremely low egg reserve (AMH of < 0.3 ng/ml but with at least 3 antral follicles). In this protocol, there is no pretreatment cycle. As soon as the baseline sonogram shows at least 3 antral follicles, ovarian stimulation begins immediately using a combination of Femara and high dose gonadotropins (FSH and HMG). Femara indirectly induces pituitary of FSH and LH release by blocking the synthesis of E2. The combination of pituitary and medication LH and FSH provides very potent ovarian stimulation. After 5-6 days of stimulation, an antagonist is added to prevent ovulation until the day of HCG trigger.

The disadvantage of this protocol is the delayed endometrial growth caused by 5 days of Femara but this effect can be overcome quickly with vaginal estrogen supplementation on the last day of Femara. Another disadvantage is the lack of flexibility in cycle planning as there is no way to plan ahead the start of ovarian stimulation. However, for a patient who desires a last chance to use her own eggs, this protocol gives her a final opportunity before closure and moving on to donor eggs.

The above protocols have helped many patients at IVFMD with low ovarian reserve to conceive their biological children. Each regimen has its own advantages and limitations, and patients respond differently to them. The physician must be flexible, creative, and willing to change treatment whenever necessary. The patient must remember that no protocol can allow her to make more eggs than her ovaries can provide in a cycle, and that a minimum of 3 antral follicles is required before she can proceed with the process. Finally, she must also know that no protocol can reverse the negative impact of time on the quality of her eggs.

The main advantages and disadvantages of the aggressive protocols are summarized in the following table:

This entry was posted on Monday, May 7th, 2012 at 1:31 am and is filed under IVF. You can follow any responses to this entry through the RSS 2.0 feed. Responses are currently closed, but you can trackback from your own site.