Why Are There Different IVF Stimulation Protocols?
One of the more common questions we get asked by patients who are preparing to undergo IVF concerns which stimulation protocol is best for them. Many patients have learned about different protocols on the internet or from talking to friends, and they are very curious as to why we would choose one protocol over another.
As part of this discussion, we try to explain the rationale behind stimulation as well as why one protocol may be better than another in their particular situation.
The first thing to understand about ovarian stimulation is that it is a very complex process, and that there are many variables – most related to the patient herself – that can have a significant impact on the ultimate outcome. In a natural cycle, many oocytes begin to develop; the exact number depends on many factors including the patient’s age, her hormonal “status”, and the overall health of her ovaries.
As a rule, older patients have fewer remaining eggs than do younger patients, so they would be expected to develop fewer eggs. Similarly, patients who have abnormal production of the hormones that affect ovulation, such as prolactin, thyroid stimulating hormone, and testosterone, typically do not respond as well to stimulation as they would if their hormone levels were normal.
Finally, patients who have undergone previous ovarian surgery or those who have active ovarian disease, such as ovarian cysts or endometriosis, do not make as many eggs as they otherwise could.
Despite the fact that there are many differences between the more commonly used stimulation protocols, there are also many similarities. For example, almost all modern protocols start with 3-4 weeks of birth control pills (BCPs). Although this may sound counter-intuitive, there are actually several very good reasons for starting stimulation following a cycle of pills. The eggs in the ovaries of a typical reproductive age woman are in various stages of development. If one were to start stimulation without first taking BCPs, fewer of those eggs would actually develop. It has been shown by several investigators that BCPs actually help the eggs synchronize their development, so that when the pills are stopped and the stimulation medications are begun, more eggs are ready to respond. This results in a greater number of mature oocytes at the time of retrieval, as well as higher fertilization rates when compared to women who undergo stimulation without taking pills first.
In addition to BCPs, there are four other classes of medications that make up the foundation of a stimulation protocol:
Gonadotropins (or other medications) to cause the eggs to develop
A gonadotropin releasing hormone (GnRH) analog to prevent premature ovulation
A medication to cause the eggs to mature, and
A progesterone to support the uterine lining after embryo transfer
How these medications are administered defines the actual stimulation protocol itself.
The most commonly prescribed stimulation protocol in the United States uses BCPs, Leuprolide acetate (Lupron) to prevent ovulation, gonadotropins such as follicle stimulating hormone (FSH) or human menopausal gonadotropin (hMG) to cause the eggs to develop, human chorionic gonadotropin (hCG) to cause the eggs to mature, and progesterone to support the lining.
In this regimen, a patient will take BCPs for 3-4 weeks. Five days before her last BCP, she will start lupron. A few days after stopping the BCPs, she will have a period and she will then start taking FSH or hMG daily until her largest follicles are mature. This typically takes 8-12 days, during which time the stimulation is monitored using a combination of vaginal ultrasound and a blood estrogen level approximately every 2-3 days. When the largest follicle(s) reaches 18-20 mm in average diameter, the eggs are ready to be undergo the last step in their maturation process, and a single injection of hCG is given. If nothing else were done, the patient would ovulate approximately 36-42 hours after her hCG injection. In order to retrieve the eggs before they ovulate spontaneously, the patient is taken into the operating room and the eggs are removed non-surgically approximately 36 hours following hCG administration. Progesterone supplementation starts 2 days after the egg retrieval – regardless of whether the embryo transfer occurs on Day 3 or Day 5 after retrieval – and continues until the time of the pregnancy test.
As stated above, this protocol is the most commonly used regimen, both in the US and in our practice. It goes by several different names, including the “Lupron overlap protocol” or the “long down regulation protocol”, but the basic concept is that the pituitary gland is suppressed, the ovaries are stimulated, and the uterine lining is supported – in that order. While some practices make a big deal over the choice of gonadotropin (some use only “recombinant FSH”, such as Gonal F or Follistim while others primarily use urinary hMG drugs such as Bravelle or Menopur), most studies suggest that there is very little – if any – difference in pregnancy rates between the different medications.
Antagonist Protocol
Approximately ten years ago, a different type of GnRH analog was developed. Called GnRH “antagonists”, these medications work differently than the GnRH “agonists” like Lupron. Rather than slowly suppress the pituitary over 4-5 days like Lupron does, these newer medications – Cetrotide and Antagon – rapidly suppress the pituitary in a matter of hours. This concept has several theoretic advantages, not the least of which are fewer injections and the need to take less total gonadotropin. Unfortunately, however, most of the studies in our scientific literature suggest that pregnancy rates with the GnRH antagonists are not as good as those with the agonists. Therefore, this “antagonist” regimen is currently used mostly for egg donors, rather than for routine IVF patients.
Poor Responder Protocol (Microdose Flare or Low Dose Lupron Protocol)
If we believe that a particular patient will not respond well to stimulation medications, either because she is older, she has diminished ovarian reserve, or she has had previous ovarian surgery, we will frequently use our “poor responder protocol”. Called the “flare”, the “microdose flare”, or the “low dose Lupron” protocol, this regimen uses the same medications as the “Lupron overlap” protocol. The major difference is that, by cutting the dose of Lupron down to one sixth of the routine dose, and by giving it twice daily, the Lupron actually turns the pituitary gland “on” rather than “off”, producing major release of FSH. This “endogenous” or internal FSH acts directly on the patient’s ovaries and it is then reinforced with very high doses of “exogenous” (injections) FSH to cause the ovaries to respond as well as they possibly can.
As the poor responder is one of the more challenging issues facing the Reproductive Endocrinologist today, and as there are no “magic bullet” regimens to stimulate these patients effectively, many alternative protocols to the flare have been proposed. Some of these involve the use of oral medications, such as Clomid or Femara in addition to gonadotropins. Others involve newer supplements such as DHEA, and still others involve the use of injectable medications such as growth hormone. While many studies to evaluate the effectiveness of these additional medications have been conducted, there are unfortunately very few definitive conclusions that have been reached.
In summary, ovarian stimulation is a very complex process. Many different stimulation regimens have been developed and evaluated and it is therefore very important for you to discuss your options in detail with your physician. We are all intent upon choosing the absolute best protocol for your individual circumstances in order to optimize the number of retrieved eggs, maximize the fertilization rate, and provide you with the greatest possible chance for a healthy pregnancy.
Texas Fertility Center
- 6500 Mopac, Building 1 - Suite 1200
- Austin, TX 78731
