Treatment strategies for IVF poor responders

While in vitro fertilization (IVF) helps thousands of women get pregnant every year, not everyone is successful.

Who is a poor responder?

Doctors have not agreed upon universal criteria for poor responders, but this term is generally used to describe women who produces fewer oocytes than expected during ovarian stimulation treatment, especially if she has received a higher dosage of stimulating medications. Commonly cited criteria to identify a poor responder are fewer than four mature follicles at collection time and/or a peak estradiol level below 500 on the day of optimal egg maturity. A history of failed IVF cycles is another indicator that a patient could be a poor responder.


Can poor responders be predicted prior to IVF?

Identification of a potential poor responder prior to attempting IVF treatment is ideal. Ovarian reserve testing informs patients and doctors about the quantity of remaining eggs in the ovaries, and can help to predict the likelihood of IVF success. Follicle counts via vaginal ultrasound provide an accurate assessment of how many follicles remain in a patient’s ovaries. Measurements of basal follicle-stimulating hormone (FSH) levels followed by a clomiphene challenge test indicate how much FSH a woman is producing naturally, and are good predictors of stimulation response. Assessment of Inhibin B levels are often unnecessary, as this test provides little additional information and can be misleading.


Should potential poor responders attempt IVF?

Given the strain IVF can place on a woman’s body, emotions, time, and finances, ovarian reserve testing is an essential first step when considering IVF. Multiple studies have indicated that a successful IVF cycle is unlikely in situations where less than four resting follicles are identified during ultrasound or when FSH levels are highly elevated from baseline during a clomiphene challenge test. These tests also identify women who are likely to be poor responders to normal treatment protocols, but may benefit from modified strategies. Knowing that a patient is likely to respond poorly to treatment can help set realistic expectations for IVF results and direct treatment strategies to maximize potential for success.


What IVF strategies are available for poor responders?

Strategies for follicle stimulation

A common approach to treating poor responders involves increasing levels of gonadotropins, the group of hormones (including FSH) that direct reproductive tract activities. Some women benefit from an increased dosage of FSH, up to 6 ampules or 450 IU a day, but doses higher than this are not effective. Studies have indicated that the source of FSH may also influence treatment outcomes; recombinant FSH may be more effective than urine-derived products.

Through the past decade, the standard ovarian stimulation protocol has been prolonged treatment with a gonadotropin-releasing hormone (GnRH) agonist. GnRH agonists stimulate the body to release its naturally occurring FSH and then suppress further gonadotropin production. They are commonly administered for periods of 10 days or longer to suppress ovulation, after which a dose of gonadotropins is given to encourage multiple follicles to mature at once. However, in poor responders this “long” agonist treatment can backfire and completely suppress ovulation. This issue has led to a variation in treatment called the “flare” protocol, during which doses of GnRH agonists are given in conjunction with gonadotropins for a shorter period of time, encouraging the body to release its own FSH without shutting down natural production. Large flares of agonist can be detrimental to egg quality, so current variations of this procedure involve pre-treatment with birth control pills and a lower dose of agonist. The modified flare protocol significantly improves success rates in poor responders.

A recent strategy for follicle stimulation in poor responders utilizes GnRH antagonists, compounds that prevent the body from releasing its own gonadotropins.

A high dose of FSH is administered in conjunction with the natural menstrual cycle, encouraging the maturation of many oocytes at once. Once follicles begin to reach 13 mm in diameter, a dose of GnRH antagonist prevents the body from releasing luteinizing hormone (LH), a gonadotropin that causes mature follicles to release eggs into the fallopian tubes. Some patients respond well to antagonist protocols and produce higher quality eggs; however, due to their recent development, antagonist treatments are not as well studied as agonist treatments. Further clinical trials are necessary to determine if poor responders would benefit from antagonist treatment over more traditional strategies.


Strategies for embryo culture and implantation

Following a follicular stimulation treatment that leads to successful egg collection, further measures may be taken in the lab to improve pregnancy rates for poor responders. The traditionally recommended procedure for poor responders has been co-culture, where fertilized eggs are cultured in media with purified cells from the maternal uterine lining. That said, due to recent advances in the understanding of embryonic development, sequential culture media is now available that performs as well or better than co-culture, and many laboratories now prefer sequential culture media.

Another post-fertilization procedure that improves pregnancy rates in poor responders is assisted hatching. During normal development the embryo must hatch out of a layer of protein called the zona pellucida, a process that is sometimes difficult for IVF embryos. During assisted hatching, a technician creates a small hole in the zona pellucida just prior to transfer to the uterus, making it easier for the embryo to break through. Poor responders demonstrate significant increases in pregnancy rates when this procedure is utilized.

A few additional treatments for poor responders show potential, though clinical evidence is limited. A recent study demonstrated improvement in both follicle response and pregnancy rates in IVF patients who took 100mg of aspirin daily. Poor responders may also benefit from progesterone and estrogen supplementation to support healthy luteal function following induced ovulation.


Care for poor responders

With ovarian reserve testing it is possible to assess a patient’s potential to benefit from IVF treatment and identify potential poor responders. By tailoring follicle stimulation and embryo culture procedures to a patient’s needs, doctors can develop a strategy to maximize the potential for a successful IVF pregnancy, even for poor responders.