Managing and predicting low response to standard in vitro fertilization therapy: a review of the options.

Low responders remain a difficult group of patients to manage in an in vitro fertilization (IVF) program. Such patients have low peak estradiol concentrations (<500 ng/L) and few dominant follicles on the day of human chorionic gonadotropin administration (<5 to <2), and therefore have few retrieved mature oocytes (< or = 4 to < or = 6) with resultant lower pregnancy rates when stimulated with standard IVF therapy (daily gonadotropin dose 150-300IU [2-4 ampoules]). It is difficult to compare the various strategies that have been utilized to manage low responders because the definition of a low responder varies widely. Also, very few large prospective randomized trials have compared different protocols. Two stimulation protocols involving varying doses of leuprorelin and high doses of gonadotropins appear to be the most promising. The early gonadotropin-releasing hormone (GnRH) agonist cessation protocol involves routine pituitary desensitization with luteal phase start of leuprorelin 0.5 mg for 10-14 days. With the onset of gonadotropin treatment, there is cessation of leuprorelin. The 'microdose flare' protocol utilizes oral contraceptive priming followed by diluted doses of leuprorelin 50 microg given twice daily. Two days later, stimulation is started by adding high doses of gonadotropins. The microdoses of leuprorelin and the high doses of gonadotropins are then continued until the day of chorionic gonadotropin administration. Patients who do not respond to these protocols or those with severely diminished ovarian reserve are candidates for donor oocytes. The role of GnRH antagonists and the in vitro maturation of oocytes are potentially exciting strategies that are still being investigated. Ultrasound measurements of ovarian volume, baseline antral follicle counts, and Doppler measurement of ovarian stromal blood flow now make it possible to predict low response to IVF therapy. Low response can be expected if the smaller ovary has a volume <3 cm3, or the mean ovarian diameter in the two longest planes is <20 mm. Antral follicle counts of < or = 3 in each ovary are also associated with low response. Data on ovarian stromal blood flow are still unclear, but an ovarian peak systolic velocity of <10 cm/sec is associated with low response. If low response is anticipated based on baseline ultrasound scan, a switch to one of the two effective stimulation protocols should be initiated. This would reduce cancellation rates and improve pregnancy rates in the first cycle of IVF.