Once a patient has chosen to undergo in vitro fertilization (IVF), a reproductive endocrinologist will recommend an IVF stimulation protocol specific to the patient's age, diagnosis and past response to ovarian stimulation, among other factors.
There are many protocol options — and many variations of each. Physicians should be familiar with luteal Lupron protocol, antagonist protocol and flare protocol as three of the most common.
IVF Stimulation: The Basics
In a normal menstrual cycle, the ovaries begin with multiple follicles. Guided by hormones, only one — occasionally two — becomes dominant and continues to grow. Both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) increase prior to ovulation. Around two to three days before ovulation, FSH dips and LH dramatically increases. At the time of ovulation when the follicle releases an oocyte, FSH increases once again and LH reaches its peak.
Reproductive endocrinologists use ovarian stimulation medication to mimic this process during an IVF cycle. Exogenous hormones, including FSH (Gonal-F or Follistim), human menopausal gonadotropin (HMG) or a combination of FSH and LH (Menopur), give physicians more control over the outcome and help with the goal of producing multiple oocytes.
Having more oocytes is critical because of attrition across the stages of the retrieval process. Not all follicles seen via 3D ultrasound immediately before a retrieval produce oocytes, and not all oocytes retrieved are mature. Not all mature oocytes fertilize, develop into morulas and continue developing into blastocysts. In other words, IVF stimulation is a numbers game that varies from patient to patient and cycle to cycle.
However, retrieving good- or high-quality oocytes also is important. After all, having more but poorer-quality oocytes likely does not improve the patient outcome over trying to conceive on their own.
The Luteal Lupron Protocol
A luteal Lupron protocol, also known as the long Lupron or agonist down-regulation protocol, is typically recommended for patients younger than 35 who have poor oocyte quality or a prior fair to poor response to ovarian stimulation, according to research published in Reproductive Biology and Endocrinology.
Leuprolide (Lupron) — a gonadotropin-releasing hormone (GnRH) agonist — temporarily inhibits the pituitary gland's ability to control the ovary, preventing ovulation. It does this by triggering the release of FSH and LH from the pituitary gland.
Hormonal suppression using Lupron takes approximately 10 days. This suppression coordinates follicles, reducing the likelihood of developing a lead follicle and making the ovaries more likely to respond to ovarian stimulation. Patients start Lupron in the luteal phase, typically on or around cycle day 21 of the previous cycle.
Lupron may be used in conjunction with birth control pills. If so, patients start pills on cycle day one of the previous cycle. Overlapping has several benefits, including preventing the development of ovarian cysts — which is common when taking Lupron and could result in a delayed or cancelled cycle — and managing and suppressing the body's natural hormones to synchronize the timing of exogenous hormones.
Prior to ovarian stimulation, a patient will stop taking oral contraceptives but continue with Lupron. The patient begins FSH and HMG injections to encourage follicle growth, hopefully at a relatively even pace and without the development of a lead follicle. Physicians frequently monitor follicle numbers and sizes and the thickness and appearance of the endometrial lining during this stage using 3D ultrasound.
Reproductive endocrinologists also test blood hormone levels of estrogen and progesterone throughout the cycle and adjust medication dosages accordingly. All follicles produce some estrogen, but mature follicles produce the most, helping to predict the number of mature oocytes prior to retrieval. Additionally, a patient's estrogen should not get too high or they will be at risk of developing ovarian hyperstimulation syndrome (OHSS).
All of this information together informs a reproductive specialist how well the cycle is going and when to time the trigger shot of human chorionic gonadotropin (hCG). Typically, when most follicles are mature (17 mm+), all injectable medications cease and a trigger shot tells the body to rapidly develop any remaining immature follicles and release a final LH surge. Approximately 36 hours later, reproductive endocrinologists retrieve oocytes from their follicles.
Antagonist Protocol
Antagonist protocols are typically recommended for patients who have unexplained infertility, according to research published in Frontiers in Endocrinology. The ideal patient population for this protocol also has not had prior injectable ovarian stimulation cycles and has had a fair or good response to ovarian stimulation using an estrogen receptor modulator (Clomid) or an aromatase inhibitor (Letrozole).
Similar to the luteal Lupron protocol, the antagonist protocol often begins in the luteal phase of the previous cycle with the patient taking oral contraceptives to ensure synchronous oocyte size at the beginning of ovarian stimulation. However, for patients who have poor-quality or reduced-quantity oocytes, a natural start might be the best choice due to the increased chance of over-suppression.
Ovarian stimulation again begins with FSH and HMG injections. Some physicians start at high doses of both to prompt a quicker initial ovarian response, then reduce the dose as the cycle progresses. Others start at low doses and increase over time.
This protocol usually involves monitoring patients through bloodwork and 3D ultrasound. Once the lead follicles reach 11 to 12 mm, notes research from the Middle East Fertility Society Journal, physicians introduce GnRH antagonist injections to prevent premature ovulation. The luteal Lupron protocol does not require a GnRH antagonist because Lupron serves the same function.
When most follicles are mature, the patient stops taking injections and takes the trigger shot — hCG, Lupron or a combination of both — followed by a retrieval. Like the luteal Lupron protocol, the specific trigger shot and dosage depend on the patient's estrogen level.
Flare Protocol
The flare protocol, also known as the microdose or short Lupron protocol, is typically recommended for patients of advanced reproductive age (38 years or older), with a prior poor response to ovarian stimulation. These patients may also have poor egg quality or have had a previous poor response to the luteal Lupron protocol.
Just like priming with birth control pills before an antagonist protocol, the luteal Lupron protocol over-suppresses some patients. Instead, they might benefit from beginning Lupron injections during the stimulation phase.
Lupron introduced at the beginning of the patient's menstrual cycle produces a strong initial boost, or flare, of natural FSH and LH production. Unlike the luteal Lupron protocol, Lupron doses are much smaller — five units per day rather than 10 to 20 — or diluted. This flare response lasts approximately three days, at which point the patient begins FSH injections and continues microdose Lupron to prevent premature ovulation.
Like other protocols, this procedure is followed by a trigger shot and retrieval, and the dosage depends on the patient's estrogen level.
Choosing a Protocol for an Individual Patient
The first IVF stimulation protocol is often an educated guess the reproductive endocrinologist makes based on information they have at the time. Although no patient wants to go through IVF more than once, data obtained from the first cycle can inform changes made during future cycles. Another possible consideration is minimal stimulation IVF versus conventional IVF, for example.
Physicians should thoroughly explain to patients why they are recommending a particular protocol and outline how it works, step by step. This conversation can help patients gain enough understanding to be an active part of the decision-making process.
