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Antagonists in Poor-Responder Patients

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Antagonists in Poor-Responder Patients FERTILITY AND STERILITY௡ VOL. 80, SUPPL. 1, JULY 2003 Copyright ©2003 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A. Antagonists in poor-responder patients Alan B. Copperman, M.D. Mount Sinai School of Medicine, New York, New York Objective: To review treatment options for poor-responding patients who are undergoing infertility treatment. Design: Review article and case studies. Results: A comprehensive determination of potential ovarian response for the poor-responding patient is important in the individualization of treatment options for these patients. Treatment options include both the microdose flare leuprolide acetate and GnRH antagonist stimulation protocols. For GnRH antagonist stimu- lation protocols, individualization of treatment includes use of oral contraceptive pretreatment and alterations in duration of gonadotropin stimulation and start day of antagonist administration. Conclusions: For poor-responding patients, the benefits of using GnRH antagonists for the suppression of premature LH surges plus the determination that stimulation protocols that include GnRH antagonists are at least as good as the microdose flare and provide better cycle outcomes than the long luteal leuprolide acetate down-regulation protocols have the potential to bring changes to the existing protocols for ovarian stimulation. (Fertil Steril௡ 2003;80(Suppl 1):S16–24. ©2003 by American Society for Reproductive Medicine.) Key Words: Ganirelix, GnRH antagonist, poor ovarian response, treatment options Individualization of stimulation regimens, ment modalities in COH, it is also important to prospective analysis of ovarian reserve, and have a clear understanding of inclusion criteria setting defined goals regarding ovarian re- for the poor-responder patient. sponse to stimulation are all necessary to ef- fectively perform controlled ovarian hyper- stimulation (COH). Management of the “poor DEFINITION OF A “POOR responder” is often quite challenging and re- RESPONDER” quires even more attention to achieve a good Received April 15, 2003; Characteristics that unquestionably catego- revised and accepted April reproductive outcome. rize a patient as a poor responder remain to be 15, 2003. Although most clinicians would agree to standardized. Historically, patients who were Presented at the classify patients who make few follicles in expected to respond poorly to gonadotropin symposium, “Real-Life Clinical Applications of response to adequate doses of gonadotropins as stimulation were given this classification be- GnRH Antagonists: poor responders, no uniform classification sys- cause they exhibited various criteria. The se- Individualization of Fertility tem exists. Moreover, few clinicians would lection of criteria used to categorize the poor- Treatment,” Seattle, Washington, October 16, agree on the best treatment modality for these responding patient has been extensively 2002 in conjunction with difficult patients. A variety of protocols exist, reviewed (1–3), with the most obvious criterion the American Society for therefore, allowing the clinician to attempt to being a previous poor-follicular response in an Reproductive Medicine 2002 annual meeting. individualize and optimize the treatment of the ovulation induction or IVF cycle (2). Supported by an poor responder. These protocols have led to At Reproductive Medicine Associates of unrestricted educational varying degrees of success and failure. grant from Organon Inc. New York (RMA of NY), we define a poor Reprints requests: Alan B. The objective of this review is to provide an responder to COH as someone who exhibited a Copperman, M.D., Mount update on the successful use of different treat- one- or two-follicle response or whose peak Sinai School of Medicine, ment protocols, including GnRH antagonists, serum E did not exceed 500 pg/mL by the 635 Madison Avenue, 10th 2 Floor, New York, New York in poor-responder patients. Because success in time of hCG administration (4). Patients who 10022. (FAX: 212-756-5770; these patients depends on adequate oocyte re- require an excessive amount or duration of E-mail: acopperman cruitment, I will discuss further the need for gonadotropin stimulation may also be classi- @rmaofny.com). carefully selected individualization of COH fied as poor responders (i.e., Ն450 IU to 0015-0282/03/$30.00 treatment protocols. In describing the advan- achieve more than three follicles). In addition, doi:10.1016/S0015-0282(03) 00765-9 tages and disadvantages of these different treat- poor responders may be identified by basal or S16 FIGURE 1 FIGURE 2 Relationship among age, declining pregnancy rates, and a Clinical pregnancy rates relative to ovarian response and age rising prevalence of poor ovarian responsiveness. in IVF. Copperman. GnRH antagonist in poor-responding patients. Fertil Steril 2003. dynamic endocrine screening of ovarian response, including basal (cycle day 3) serum FSH and E2 levels and clomiphene citrate (CC)-stimulated serum FSH levels (5, 6). Baseline serum inhibin B levels (7) or more recently, day 5 inhibin B in down-regulated cycles (8), have also been used to predict ovarian response to gonadotropins. These and other endo- crine tests are reported to be predictive of ovarian reserve and IVF outcome (9–11). Although gonadotropin stimula- Copperman. GnRH antagonist in poor-responding patients. Fertil Steril 2003. tion tests (12) have been used to predict response, they are not widely used, as in effect, they merely demonstrate that patients with a poor ovarian response will be poor respond- Three-dimensional imaging has also changed the way that ers. we approach baseline transvaginal scans. This new technol- Patient age of Ն40 years may result in a designation of a ogy provides us with the opportunity to examine ovarian patient as a low or poor responder and most probably can be basal antral follicle number, ovarian volume, stromal area, attributed to a reduction in the number of ovarian follicles and ovarian stromal blood flow (17–19). Studies using three- available for recruitment (13) and declining oocyte quality dimensional imaging report that the best predictor of favor- (14) (see Figs. 1 and 2). Albeit, ovarian age is not an absolute able IVF outcome is total basal antral follicle count and that indicator of poor success in COH and setting a strict age this criterion provides a better prognosis of a poor response limit is debatable. In fact, older patients with a good re- than a patient’s chronologic age and current endocrine sponse to COH have a good prognosis for IVF treatment screening tests. In addition, combining the results of three- (15). Evaluating ovarian reserve by a number of predictors dimensional ultrasound imaging with other currently used may be a better indicator of treatment success than age. predictors provided a more stringent forecasting of a poor The sonographic appearance of the ovary may also have ovarian response (19) and success or lack in an IVF cycle value in identifying the poor responder. Ovarian volume (18). itself may very well be a simple predictor of ovarian reserve. Although total ovarian volume has been considered a good INDUCING AN OPTIMAL FOLLICULAR indicator of ovarian reserve, the volume of the smallest RESPONSE IN THE POOR RESPONDER ovary may be even more predictive (16). Most clinicians do Inducing a multifollicular response in a patient who is a not formally calculate ovarian volume as part of the routine known poor responder remains a challenge. When patients evaluation of every new patient, but it is part of the gestalt do not respond appropriately to the standard dose of gonad- that one has when one does a baseline transvaginal ultra- otropins (225–300 IU), the clinician is tempted to incremen- sound. Three-dimensional ultrasound has made assessment tally increase the dose. Unfortunately, administering more of volume significantly easier, thereby making some of the than 450 IU per day does not appear to add significantly to newer studies that document the importance of generating the ovarian response or to improve the reproductive outcome ovarian volume data even more significant. (11, 20). In fact, patients who require more than 450 IU of FERTILITY & STERILITY௡ S17 FIGURE 3 High-dose gonadotropins are associated with poor pregnancy outcomes after IVF. Copperman. GnRH antagonist in poor-responding patients. Fertil Steril 2003. gonadotropin probably have significantly diminished ovarian normally, so apparently the GnRH agonist does more than reserve and will have a poor outcome, no matter what dosage just prevent an LH surge. is administered. Although there have been some pregnancies For poor-responder patients, modifying the agonist treat- reported using 600 IU of gonadotropins, clinical pregnancy ment may result in improved IVF outcome. For example, in rates are inversely correlated with the amount of gonadotro- comparison to the long GnRH agonist suppression protocol, pins used to induce multifollicular development for IVF (11, the minidose GnRH agonist treatment results in higher E 21, 22) (Fig. 3). 2 levels, more follicles, shorter stimulations, and ultimately, It is unclear whether the addition of a GnRH agonist is improved implantation and pregnancy rates (23). Another advantageous or detrimental in the treatment of poor re- modification is to initiate gonadotropins and a GnRH agonist sponder patients. The addition of GnRH agonists has played together in the follicular phase (the so-called microdose flare a role in improving assisted reproductive
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