The term poor responder has been used to define women who require large doses of stimulation medications and who make less than an optimal number of eggs. There is no uniform definition of poor responders, but many authors have used a cutoff of less than four mature oocytes at the time of hCG or a peak estradiol of less than 500.
One may arrive at the diagnosis of poor response by having gone through an IVF cycle and achieving poor stimulation outcome. However, it is preferable to determine this problem ahead of time through ovarian reserve testing including basal FSH levels, and the clomiphene challenge test. In addition, the ultrasound assessment of the ovaries and the resting or antral follicle numbers allows for the prediction of a poor response to stimulation. Cycle day 3 blood levels of Inhibin B levels add little to the information gained from the above testing, and variability is problematic.
The first question facing patients who are poor responders is whether or not they should attempt IVF. Many studies are now illustrating that women with substantially elevated day 3 FSH levels during a clomiphene challenge test, have a poor prognosis for a successful IVF cycle. Furthermore, if there are fewer than four resting follicles available on a baseline ultrasound for recruitment, similar poor outcomes are seen. It is critical that women considering IVF have proper ovarian reserve testing to be sure that they are not wasting their time, money, or emotions by pursuing IVF when it has little or no hope of success.
Assuming that ovarian reserve tests predict an acceptable success rate, the next question facing patients is what stimulation protocol would optimize their chances for success.
The first and simplest approach to the poor responder is to simply increase the dose of gonadotropins. There may be a limited benefit to increasing FSH dose to a maximum of 6 ampules or 450 IU per day. However, doses beyond this amount yield little or no improvement in stimulation outcome. The type of gonadotropin preparation is an additional variable. Some trials have shown recombinant FSH to be more potent than urinary products. In the past, growth hormone has been added to stimulation regimens, but randomized trials have failed to clearly show a benefit to this adjunctive treatment.
GnRH agonists (lupron®) have been the standard for ovarian stimulation in IVF for the past 10 years. However, traditional "long" protocols where the agonist is administered for 10 days or longer, followed by gonadotropin stimulation, may be a poor choice for the poor responder. This initial pretreatment with agonist may remove endogenous gonadotropins from the system and "suppress" the response of the ovary so that adequate stimulation is impossible. Problems with this long protocol led to the so-called flare protocol whereby the agonist is started on the menstrual cycle concurrent with the use of gonadotropins. Unfortunately, standard doses of agonist result in elevated levels of androgens, LH, and progesterone, in the follicular phase, before ovulation. These effects are detrimental to oocyte quality and endometrial receptivity. A modification of the flare protocol by pretreating patients with birth control pills and lowering the doses of agonist to "microdoses" has eliminated the negative effects of the flare and resulted in a better recruitment of oocytes and indeed significant improvements in pregnancy rates.
A new approach to the poor responder involves the use of GnRH antagonists (Ganirelix Acetate Injection®, Cetrotide®). With this protocol, gonadotropin or FSH is started on the second or third day of the menstrual cycle with no birth control or agonist pretreatment. High doses of FSH are utilized to maximize egg numbers. When the lead follicle reaches an average of 13 to 14 mm in diameter, an antagonist is administered to avoid a premature LH surge while gonadotropins are continued. Some patients benefit by avoiding birth control pill pretreatment and/or agonist pretreatment and produce significantly better eggs on such antagonist protocols. Currently, however, this protocol should be considered investigational, as there are no randomized trials showing a benefit of antagonist protocols over the traditional approaches used for poor responders.
Assuming that the poor responder has achieved an adequate number of oocytes through a carefully chosen stimulation regimen, the next question is what to do with those oocytes in the laboratory that may be beneficial to the poor responder. Assisted hatching, first described a decade ago, has been shown in randomized prospective trials to improve the implantation rate per embryo in poor responders and specifically patients with elevated basal FSH levels. Indeed, implantation rates of 25% and ongoing pregnancy rates of 50% have been demonstrated with the combination of a microdose flare stimulation protocol and assisted hatching applied to day 3 embryos prior to transfer. Another laboratory adjunct that has been proposed is co-culture. Co-culture was first described more than a decade ago as well and was popular during its initial introduction. Most programs, however, have moved over the past five years to sequential culture systems. Indeed, a recent comparison of co-culture to sequential culture media showed an improved blastocyst formation rate and similar implantation rates with sequential media as compared with co-culture.
Other treatments for poor responders that are less proven include the use of baby aspirin and luteal phase support. In a recent trial from Argentina, 100 mg a day of aspirin improved ovarian responsiveness and oocyte number as well as implantation and pregnancy rates. With a limited number of follicles, the luteal function of poor responders may be impaired. Therefore, it is appropriate to supplement the luteal phase with progesterone. In addition, recent reports have suggested that luteal estrogen supplementation may further augment pregnancy rates.
In conclusion, patients who are labeled as poor responders certainly face a formidable challenge in achieving a pregnancy. It is critical to determine through ovarian reserve testing using FSH levels and the clomiphene challenge test as well as ultrasound assessment of the resting follicle numbers whether a patient is indeed a candidate for IVF treatment. Once this has been verified, it is critical to seek out a clinic where experience exists in the stimulation of poor responders so that an optimal protocol can be tailored to the patient's needs. The laboratory is also critical for success, particularly with regard to the use of an excellent culture system and the application of assisted hatching. There may be some marginal benefit as well to the adjunctive use of baby aspirin started prior to stimulation and luteal progesterone and estradiol support following oocyte retrieval. This holistic approach to poor responder care will serve to maximize ongoing pregnancy rates. Nevertheless, there is a portion of patients who may continue to fail due to depleted oocyte quality and may well benefit from consideration of oocyte (egg) donation treatment.
Information provided by Dr. William Schoolcraft is the founder and Medical Director of the Colorado Center for Reproductive Medicine.