Optimal stimulation protocols for in vitro fertilization

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1 MODERN TRENDS Edward E. Wallach, M.D. Associate Editor Optimal stimulation protocols for in vitro fertilization Suheil J. Muasher, M.D., a,b,c,d Rony T. Abdallah, M.D., b,d and Ziad R. Hubayter, M.D. b,d a Muasher Center for Fertility and IVF, Fairfax, Virginia; b Department of Obstetrics and Gynecology, George Washington University, Washington, D.C.; c Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, Maryland; and d INOVA Fairfax Hospital, Fairfax, Virginia Objective: To update clinicians on different gonadotropin regimens for ovarian stimulation for IVF including the use of urinary and recombinant gonadotropins, the value of added LH to FSH in the stimulation regimen, the use of GnRH agonists and antagonists, and the role of minimal stimulation protocols. Design: Literature review and critical analysis of major articles during the last five years on ovarian stimulation for IVF. Conclusion(s): Urinary and recombinant gonadotropins, for ovarian stimulation for IVF, are probably equally safe and effective. The higher cost for recombinant products limits their worldwide use in IVF. Conflicting data exist regarding the benefit of adding LH to FSH in the stimulation regimens. The use of different GnRH-agonists, of varying potency, may account for different levels of LH suppression. Adding LH should be considered in severe situations of LH suppression such as with the use of potent GnRH-agonists or when GnRH-antagonists are introduced during the course of stimulation. GnRH-antagonists provide advantages to patients in terms of fewer injections, shorter stimulation days, and avoidance of adverse effects of agonists. The incidence of ovarian hyperstimulation syndrome is probably less with antagonists compared to agonists, with the option to use an agonist as a surrogate LH surge. Fixed and early start of the antagonist is probably more effective than an individualized and late start. The earlier reported lower pregnancy rates with antagonists compared to agonists is not fully understood and needs to be continually monitored. Minimal stimulation protocols using a combination of clomiphene citrate and gonadotropins are attractive and should be considered in some patients owing to lower costs and acceptable success rates. The optimal stimulation protocol for IVF should be an individualized regimen based on the patient s ovarian physiology and prior IVF experience, if any. (Fertil Steril 2006;86: by American Society for Reproductive Medicine.) Key Words: Ovarian stimulation, in vitro fertilization, gonadotropins, gonadotropin-releasing hormone agonists and antagonists, follicle-stimulating hormone, luteinizing hormone, human chorionic gonadotropin, clomiphene citrate, minimal stimulation Stimulation protocols for recruitment of multiple healthy fertilizable oocytes for the purpose of in vitro fertilization (IVF) have been constantly evolving over the last 25 years. Since the retrieval of a single oocyte during the preovulatory phase of the natural cycle was abandoned in the early 1980s in favor of using gonadotropins for the stimulation of multiple oocytes, the protocols used have been in a state of dynamic change depending on the availability of stimulatory agents. Human menopausal gonadotropin (hmg), extracted from the urine of postmenopausal women, was the only gonadotropin available on the market in the early 1980s when Elizabeth Carr, the first IVF baby in the United States, was born on December 28, Since that time, several gonadotropins have been introduced, and some withdrawn from the market, as well as GnRH agonists and antagonists in order to suppress a premature LH surge. Tables 1 and 2 list all the gonadotropins and GnRH-analogs that are available in the US market. The purpose of this review article is to update the clinician on the different stimulation protocols being used for IVF. No attempt will be made to list all published articles on this subject, which would be beyond the scope of this paper, but major articles and those of interest will be quoted to illustrate certain points. An attempt will be made to answer the following important questions: Received November 23, 2004; revised and accepted September 29, Reprint requests: Suheil J. Muasher, M.D., Muasher Center for Fertility and IVF, 8501 Arlington Boulevard, Fairfax, Virginia, (FAX: ; muashersj@mcfivf.com). 1. Are recombinant gonadotropins superior, in terms of efficacy and success, to urinary gonadotropins and should they replace them? 2. Should LH be added to FSH in the stimulation regimens? /06/$32.00 Fertility and Sterility Vol. 86, No. 2, August 2006 doi: /j.fertnstert Copyright 2006 American Society for Reproductive Medicine, Published by Elsevier Inc. 267

2 TABLE 1 Gonadotropins available in the U.S. market. Gonadotropin Brand name Manufacturer Urinary Human menopausal gonadotropin (hmg) Repronex Ferring Pharmaceuticals Highly purified hmg Menopur Ferring Pharmaceuticals Highly purified FSH Bravelle Ferring Pharmaceuticals Human chorionic gonadotropin (hcg) Novarel Ferring Pharmaceuticals Human chorionic gonadotropin (hcg) Pregnyl Organon Recombinant FSH Follitropin alfa Gonal-f Serono FSH Follitropin beta Follistim Organon LH Leuveris Serono hcg Ovidrel Serono Muasher. Optimal stimulation protocols for IVF. Fertil Steril Should GnRH-antagonists replace GnRH-agonists as the optimal method to suppress the LH surge? 4. Is there any role for simplified or minimal stimulation protocols in IVF? ARE RECOMBINANT GONADOTROPINS SUPERIOR, IN TERMS OF EFFICACY AND SUCCESS, TO URINARY GONADOTROPINS AND SHOULD THEY REPLACE THEM? A review and debate on the subject of whether urinary gonadotropins should be replaced by recombinant gonadotropins was published in 2002 (1). The potential risk of transmission of prion disease, such as bovine spongiform encephalopathy and Creutzfeldt-Jacob disease, was contrasted with a similar potential risk with recombinant products as they rely on bovine serum during the cell culture process. It is worth mentioning that no such diseases have been reported and attributed to the use of gonadotropins, recombinant or urinary. The review concluded that both products are probably equally safe and similar in efficacy, based on the available literature to date. An updated meta-analysis of recombinant versus urinary FSH, including 18 randomized clinical trials, concluded that the pregnancy rate per cycle started was better in favor of recombinant FSH (odds ratio [OR] 1.21, 95% confidence interval [CI] ) (2). The higher pregnancy rate was more pronounced when follitrophin alfa (Gonal-f; Serono, Rockland, MA) (OR 1.37) was used than when follitrophin beta (Follistim; Organon, Roseland, NJ) (OR 1.19) was given. The study concluded that one additional pregnancy was achieved for every 19 patients treated when recombinant products were used. In the same study, however, the use of follitrophin alfa did not have an advantage in patients with intracytoplasmic sperm injection (ICSI) compared with urinary products. Another published meta-analysis, comparing recombinant and urinary gonadotropins in published trials using a long protocol of GnRH-agonists, showed no advantage of one or the other (3). A randomized 22-center trial compared recombinant FSH versus highly purified hmg in over 700 patients using a long agonist protocol, concluding that there were no significant differences in the days of stimulation, ampules used, number of oocytes collected, and the clinical pregnancy rates between the two groups (4). Another similar 11-center randomized prospective trial compared the use of highly purified FSH, SC or IM, to follitrophin beta using a long agonist protocol and concluded that TABLE 2 GnRH-analog available in the U.S. market. GnRH-analog Brand name Manufacturer GnRH-agonists Leuprolide acetate Lupron TAP Pharmaceuticals Nafarelin acetate Synarel Searle Goserelin acetate Zoladex AstraZeneca GnRH-antagonists Ganirelix acetate Antagon Organon Cetrorelix acetate Cetrotide Serono Muasher. Optimal stimulation protocols for IVF. Fertil Steril Muasher et al. Optimal stimulation protocols for IVF Vol. 86, No. 2, August 2006

3 there were no significant differences in stimulation parameters or success rates among the three groups (5). A recent meta-analysis of six large randomized trials concluded that there was a higher clinical pregnancy rate with urinary hmg compared with recombinant FSH, but there were no significant differences in ongoing pregnancy rates or live births per women treated (6). A cost-effectiveness study was conducted in Europe (22 centers in six countries) comparing highly purified urinary hmg and recombinant FSH for IVF/ ICSI patients and concluded that there was no significant difference in ongoing pregnancy rates between the two groups but that there was a significant cost-saving advantage in favor of the urinary product (7). SHOULD LH BE ADDED TO FSH IN STIMULATION PROTOCOLS? A meta-analysis of all randomized controlled trials from 1985 to 1999 concluded that FSH-only protocols yielded better pregnancy results than hmg (FSH LH) protocols but only when GnRH-agonists where not used (8). Filicori, in an elegant review, reviewed the dynamics of follicular phase gonadotropins during the natural cycle (9). The early follicular phase is characterized by the presence of LH receptors on theca cells and the presence of FSH receptors on granulosa cells, with a prevalence of FSH activity. The middle-late follicular phase is characterized by the presence of LH receptors on both theca and granulosa cells, with a prevalence of LH activity and declining FSH levels. This leads to a selection of the dominant follicle and monofollicular ovulation. Filicori and his group tried to use these physiologic principles in a series of controlled ovarian stimulation protocols for IUI or IVF. In an elegant experimental protocol for IUI, patients were suppressed with a long GnRH-agonist protocol (triptorelin acetate, Decapeptyl; Ipsen, Slough, UK [not available in the U.S.]) and then stimulated with a fixed dose (150 IU daily) of FSH for the first 7 days. After 7 days, patients were randomized into four different groups: Group A continued with 150 IU FSH, group B with 50 IU FSH and 50 IU hcg (equivalent to 300 IU LH), group C with 25 IU FSH and 100 IU hcg (equivalent to 600 IU LH), and group D with 200 IU hcg (equivalent to 1,200 IU LH) alone. There were no significant differences among the groups in the days of stimulation, peak E 2 levels, and number of medium and large size follicles (10). The number of small follicles, however, significantly decreased as more LH activity and less FSH activity was used, suggesting a possible beneficial effect on decreasing the risk of ovarian hyperstimulation syndrome (OHSS). Another study compared highly purified FSH to hmg in IUI patients using a long agonist (triptorelin acetate) and stimulating with a fixed dose (150 IU daily for 14 days) of gonadotropins. The clinical pregnancy rate was the same between the two groups, but there were significant differences in shorter days of stimulation and fewer ampules used in favor of hmg (11). The number of smaller follicles was also significantly less in the hmg group. The same experimental design was used comparing recombinant FSH with highly purified hmg for IVF/ICSI patients. Similar conclusions were obtained in terms of shorter days of stimulation and lower number of ampules used in favor of highly purified hmg, but the pregnancy rate was the same between the two groups (12). It is noteworthy to mention again that a potent GnRH-agonist (triptorelin acetate), with a more profound degree of LH suppression, was used as well as a fixed dosage of gonadotropins in all the previous experiments, which could have explained the benefit of adding LH in that setting. Subsequent studies have shown a benefit of using a half-dose of depot triptorelin or stopping triptorelin at the start of gonadotropin stimulation (13, 14). Other studies have demonstrated conflicting data on the benefit of adding LH to FSH in stimulation protocols. A prospectiv,e randomized, placebo-controlled, multicenter study using a long GnRH-agonist protocol failed to show any benefit of adding LH (recombinant LH 75 IU daily when the leading follicle is equal to 14 mm) over placebo to FSH stimulation in terms of stimulation parameters and clinical pregnancy rates (15). Another study examined the effect of adding LH to FSH in oocyte donors suppressed with a GnRH-agonist (16). The study concluded that if the serum levels of LH were less than 1 IU/mL at the start of gonadotropin stimulation, the addition of LH resulted in an increase in the number of mature eggs, good-quality embryos, and implantation rates compared with FSH-only stimulation. However, if the serum LH levels were more than 1 IU/mL, the addition of LH resulted in an increase in the number of mature eggs but with impaired embryo morphology and implantation rates compared with FSH only stimulation. A large multicenter randomized prospective study, in patients suppressed with a minidose of GnRH-agonist (leuprolide acetate, Lupron; TAP Pharmaceuticals, Lake Forest, IL [less potent than triptorelin]), compared FSH-only stimulation with adding LH (recombinant LH at a fixed dose of 150 IU daily on stimulation day 6) to FSH (17). The study concluded that there were no significant differences in the days of stimulation, number of ampules of FSH, number of metaphase II oocytes, and clinical pregnancy rates between the two groups. A small subset of patients in the same study demonstrated a benefit of adding LH to FSH in patients 35 years. Cabrera et al. examined serum LH levels, on days 3 and 10 of the cycle, in consecutive patients suppressed with a GnRH-agonist (leuprolide acetate) and concluded that those levels did not correlate with stimulation characteristics or pregnancy rates, thus demonstrating that there was no need for exogenous LH in this clinical scenario (18). In recent years, accumulating evidence had demonstrated that hcg/lh receptors are expressed in extragonadal (endometrium) tissues and that this may improve implantation in assisted reproduction. Two very interesting studies, using the donor-recipient oocyte model, are worthy of presentation. Fertility and Sterility 269

4 One study demonstrated an enhancement of implantation by a single administration of a GnRH-agonist (0.1 mg triptorelin), thus stimulating a release of endogenous LH and FSH, over a placebo at the time of implantation in oocyte recipients (19). The other study showed a beneficial effect on endometrial thickness and implantation when oocyte recipients, suppressed with a GnRH-agonist (with suppressed LH levels), received 5,000 IU hcg (at the same time that the donor received hcg) compared with a placebo, but not in recipient patients who were menopausal (with high endogenous LH levels) (20). This potential benefit of hcg/lh on implantation is intriguing and worthy of further clinical trials. SHOULD GnRH-ANTAGONISTS REPLACE GnRH-AGONISTS AS THE OPTIMAL METHOD TO SUPPRESS THE LH SURGE? Agonists of GnRH have been incorporated in stimulation protocols for the past twenty years. The most common regimen is a long agonist protocol, where the agonist is started in the midluteal phase of the preceding menstrual cycle, followed by gonadotropin stimulation after the onset of menstruation, when suppression of endogenous LH and FSH has occurred. The main advantages of the agonist are prevention of a premature LH surge and recruitment of a larger cohort of follicles. The main disadvantages include the development of ovarian cysts owing to the stimulatory effects of the agonist, signs and symptoms of estrogen deprivation, including headaches, hot flushes, and vaginal dryness, and increased costs of treatment owing to longer stimulation days and higher dosages of gonadotropins. Antagonists of GnRH have been used in clinical trials for IVF since the late 1990s. The main advantages of the antagonists include avoidance of the adverse effects of agonists, such as ovarian cysts and estrogen deprivation, and potentially a more friendly stimulation protocol for the patient. Dose-finding studies with ganirelix acetate (Antagon; Organon, Roseland, NJ) were conducted in the middle to late 1990s and concluded that the higher the dosage of the antagonist used the higher the degree of LH suppression achieved, but the lower the implantation rate with dosages 0.25 mg/d (21). As such, a 0.25 mg dosage was eventually used for clinical studies, but the adverse effect of higher dosages on implantation rates was never fully understood. Prospective randomized studies were conducted in North America, Europe, and the Middle East, comparing a long agonist protocol with an antagonist protocol for IVF (22 24). With all three large multicenter studies, it was concluded that the number of injections of the analog was significantly less with the antagonist compared with the agonist, the number of days of stimulation and dosage of gonadotropins used were significantly less with the antagonist, and the peak E 2 was also significantly less with the antagonist. The number of oocytes obtained, number of embryos, clinical pregnancy rates, and implantation rates were better with the agonist compared with the antagonist. These studies hinted that the lower pregnancy rates with the antagonist were possibly due to a lack of experience with the antagonist compared with the agonist in some of the centers. A meta-analysis of randomized studies comparing two different antagonists, ganirelix acetate and cetrorelix acetate (Cetrotide; Serono, Rockland, MA), to a long agonist protocol for IVF concluded that the pregnancy rate was lower with ganirelix acetate but not with cetrorelix acetate (compared with the agonist) and that the incidence of OHSS was lower with cetrorelix acetate but not with ganirelix acetate (25). It is noteworthy to mention that the studies conducted with ganirelix acetate used FSH-only stimulation protocols and the studies conducted with cetrorelix acetate used hmg (FSH LH) for stimulation. A Cochrane review of five randomized studies concluded that the pregnancy rate and OHSS were lower with the antagonist compared with the agonist protocols (26). The GnRH-antagonist protocol was compared with the microdose flare agonist protocol in a small but prospective and randomized study in poor responders (27). The study concluded that the two protocols were similar in efficacy and pregnancy rates. Another similar, but retrospective, study concluded that the days of stimulation and the peek E 2 levels were lower in the antagonist protocol, but the number of eggs obtained and the pregnancy rates were similar in the antagonist compared with the microdose flare agonist protocol (28). A randomized prospective study compared an antagonist protocol with a long agonist protocol in poor responders and concluded that there were no significant differences in the cycle cancellation rates, duration of stimulation, dosage of gonadotropins (a fixed dose was used), and mean numbers of mature follicles, oocytes, and embryos obtained (29). The implantation rates were similar but the pregnancy rate was higher, though not statistically significant, in the antagonist group. The question of whether LH addition to FSH is required for stimulation in antagonist protocols is not resolved. In one study using the donor-recipient oocyte clinical model, the addition of LH in donors stimulated with FSH and antagonist resulted in significantly higher E 2 levels, fertilization rate, percentage of mature oocytes obtained, and pregnancy rate in recipients compared with donors stimulated with FSH and antagonist only (30). Two other studies failed to reveal any significant advantage of adding LH to FSH in antagonist protocols, in terms of numbers of oocytes obtained, pregnancy, and implantation rates (31, 32). Another incompletely resolved issue is when to start the antagonist during the course of ovarian stimulation. The earlier studies with both ganirelix and cetrorelix all used a fixed start of the antagonist (on stimulation day 6). Some studies tried to use a flexible start (when dominant follicles 14 mm) to increase the number of mature eggs obtained and to lower cost (33). A multicenter randomized study compared a fixed with a flexible start of the antagonist and concluded that the number of mature oocytes was the same but the clinical pregnancy rates were higher with the fixed start (34). 270 Muasher et al. Optimal stimulation protocols for IVF Vol. 86, No. 2, August 2006

5 Clinicians using a delayed start of the antagonist should be cautioned about the possibility of premature luteinization even with follicles less than 14 mm in diameter. One study addressed the issue of a delay of hcg (2 days after the dominant follicles reached a diameter of 17 mm) administration in antagonist cycles. The study concluded that a delay in hcg resulted in lower pregnancy and implantation rates compared to an earlier hcg (dominant follicles 17 mm), possibly owing to an adverse effect on the endometrium (35). A great potential advantage of antagonist compared with agonist protocols is the use of an agonist as hcg trigger in patients at risk for OHSS. An original study reported on the use of triptorelin (0.2 mg) as a single dose to achieve an endogenous LH surge in eight patients at risk for OHSS (mean E 2 on day of triptorelin 3,675 pg/ml, range 2,980 7,670 pg/ml) stimulated with an antagonist protocol (36). The study reported a 50% pregnancy rate and a 0% OHSS rate. A multicenter prospective randomized study compared 10,000 IU hcg with two different agonists (0.2 mg triptorelin and 0.5 mg leuprolide) as hcg triggers in antagonist cycles and concluded that all three agents were similar in efficacy in terms of number of oocytes obtained, fertilization rate, and clinical pregnancy and implantation rates (37). A recent study compared hcg with a GnRH-agonist (0.5 mg buserelin; Suprefact; Hoechst, Frankfurt, Germany [not available in the U.S.]) as an ovulation trigger in patients stimulated with an antagonist protocol. The study concluded that the number of mature oocytes obtained was higher with the agonist, but the implantation, clinical, and ongoing pregnancy rates were significantly lower with the agonist compared with hcg, possibly owing to a luteal phase deficiency (38). In that study, patients were supplemented with micronized progesterone vaginally, 90 mg/d, and E 2 orally, 4 mg/d, starting on the day following oocyte retrieval. It would be of interest to study if an earlier start of progesterone (the day of oocyte retrieval or the day before) or a different form of progesterone administration would make a difference in antagonist cycles using an agonist as an ovulation trigger. The issue of the reported lower clinical pregnancy and implantation rates in the earlier studies comparing antagonist and agonist protocols is still not resolved. This issue was examined in two studies using the donor recipient oocyte model as a way of addressing whether any adverse effects of the antagonist were related to the oocyte or the endometrium. One study randomized oocyte donors to an agonist or an antagonist protocol and concluded that there were no differences in the number of mature oocytes obtained, fertilization rate, and clinical pregnancy and implantation rates between the two protocols (39). The other study randomized 148 donor IVF cycles to an agonist or antagonist protocol and reached similar conclusions in terms of clinical pregnancy and implantation rates (40). These studies are very suggestive that any adverse effect of the antagonist, if any, probably occurs at the level of the endometrium and not at the oocytes or embryos. Similarly, the outcomes of cryopreservationthaw embryo cycles are the same whether the frozen embryos came from cycles stimulated with GnRH-agonists or GnRH-antagonists (41). IS THERE ANY ROLE FOR SIMPLIFIED OR MINIMAL STIMULATION PROTOCOLS IN IVF? Minimal stimulation protocols, using a combination of clomiphene citrate and gonadotropins, with or without the addition of a GnRH-antagonist, have been proposed in recent years to make the stimulation process more friendly to patients. In one study, 100 mg/d clomiphene citrate orally was given on cycle days 3 to 7 and 150 IU/d gonadotropins SC was started on cycle day 9. This protocol was compared with a control group, in a nonrandomized manner, who used a long agonist protocol. The mean number of ampules used was significantly less (5.7 vs. 25) in the minimal stimulation protocol as was the number of mature oocytes obtained, but the pregnancy rate per transfer was similar between the two groups (42). Three other similar studies, using a combination of clomiphene citrate and gonadotropins, reported similar results (43 45). All the previous studies reported a similar pregnancy rate for fresh transfer in the minimal stimulation protocol compared with the long agonist protocol at the expense of obtaining a lower number of mature oocytes and a lower chance of freezing excess embryos. A prospective controlled study compared a minimal stimulation protocol (clomiphene citrate, recombinant FSH, and antagonist) with a long agonist protocol in poor responders with elevated basal FSH levels. The study concluded that the number of mature oocytes was significantly less with the minimal stimulation protocol, but the clinical pregnancy and implantation rates were similar between the two protocols (46). Another retrospective study compared a minimal stimulation protocol with a long agonist protocol in patients of advanced age (more than 40 years) and pointed to the tremendous cost-saving advantage of the minimal stimulation protocol compared with the long agonist protocol that usually requires a very large dosage of gonadotropins in patients with advanced age and/or poor ovarian reserve (47). Simplified protocols, using gonadotropins only, have also been proposed with good success rates. One study compared a long agonist protocol with a fixed dose of gonadotropins (225 IU/d) and only 1 day of monitoring with the usual long agonist protocol and concluded that the two protocols yielded similar results in terms of oocytes obtained and clinical pregnancy rates (48). Such protocol yielded considerable cost-saving advantages to the patients owing to fewer days of monitoring (with ultrasound and E 2 levels) and a lower number of gonadotropin ampules used. The protocol also provided for less stress for the patients and was thus more friendly and acceptable than the usual protocols. A simplified protocol, using a modification of the natural cycle and consisting of administration of recombinant FSH and a GnRH-antagonist in the late follicular phase (when the dominant follicle is equal to 14 mm), was recently reported (49). The cumulative ongoing pregnancy rate after three cycles Fertility and Sterility 271

6 with this protocol was 34% and the live birth rate per patient was 32%. Considering the lower costs and risks and the patient-friendly nature of such protocols, minimal or simplified protocols provide an acceptable alternative option for some patients. CONCLUSION After thorough review of the current literature, we have concluded that urinary and recombinant gonadotropins are probably equally safe and effective. The lower worldwide cost of urinary products makes them attractive for use for ovarian stimulation for IUI or IVF. With respect to the value of adding LH to FSH in the stimulation regimens, we have found that conflicting data exist in the current literature. The use of GnRH analogs, agonists of varying potency and antagonists, account for different degrees of LH suppression and probably explains the need for LH in severely suppressed endogenous LH situations such as with the use of potent GnRH-agonists before gonadotropin stimulation or when GnRH-antagonists are introduced during the course of stimulation. The potential benefit of hcg/lh on implantation is intriguing and worthy of further investigation. With respect to the use of GnRH-analogs, we have concluded that GnRH-antagonists provide significant advantages over GnRH-agonists in terms of fewer injections, fewer days, and avoidance of the adverse effects of the agonists, including cyst formation and signs and symptoms of estrogen deprivation. The reported lower pregnancy rates with the antagonists compared with the agonists, in earlier randomized studies, are not fully understood but need to be carefully monitored. The incidence of OHSS is probably less with antagonists compared with agonists, with the option to use agonists as an ovulation trigger in patients at higher risk for OHSS. The question of when to start the antagonist during the course of stimulation is not fully resolved, but it seems from the available randomized studies that a fixed and early start is probably more successful than a late and individualized start. The issue of whether LH addition to FSH is required for stimulation in antagonist protocols is also not resolved, and conflicting data exist in this matter. Minimal or simplified stimulation protocols, using clomiphene citrate and or fixed gonadotropin stimulation regimens, are attractive options for some patients, owing to a lower cost and more patient-friendly stimulation, in terms of decreased monitoring visits for serum E 2 and ultrasound measurements, compared with the standard protocols. The pregnancy rates, from fresh transfers, seem to be comparable in patients using either minimal stimulation protocols or standard protocols, based on the available literature in recent years. Minimal stimulation protocols seem to have a tremendous cost-saving advantage in low responders and/or patients with advanced maternal age compared with the standard protocols that usually require a very large dosage of gonadotropins in such patients. In conclusion, the optimal stimulation protocol is one that maximizes the recruitment of fertilizable oocytes and minimizes the risks and is administered and monitored in an acceptable and friendly manner to the patient. REFERENCES 1. Matorras R, Rodriguez-Escudero FG. Debate. Bye-bye urinary gonadotropins? Hum Reprod 2002;17: Daya S. Updated meta-analysis of recombinant follicle stimulating hormone (FSH) versus urinary FSH for ovarian stimulation in assisted reproduction. Fertil Steril 2002;77: Al-Inany H, Aboulghar M, Mansour R, Serour G. 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