letrozole protocol?

OVULATION INDUCTION Management of poor responders: can outcomes be improved with a novel gonadotropin-releasing hormone antagonist/letrozole protocol? William B. Schoolcraft, M.D., Eric S. Surrey, M.D., Debra A. Minjarez, M.D., John M. Stevens, B.S., and David K. Gardner, D. Phil. Colorado Center for Reproductive Medicine, Englewood, Colorado

Objective: To compare the efficacy of a microdose GnRH agonist flare (ML) with a GnRH antagonist/letrozole (AL) protocol before IVF-ET in poor responders. Design: Prospective controlled trial. Setting: Private assisted reproductive technology center. Patient(s): Five hundred thirty-four infertile women classified as past or potential poor responders based on clinicspecific criteria. Intervention(s): Poor responders were prospectively assigned to an ML or AL protocol in a 2:1 ratio, respectively. Main Outcome Measure(s): Results of controlled ovarian hyperstimulation and implantation and ongoing pregnancy rates. Result(s): Patient characteristics were similar between the two protocol groups. There were no significant differences in mean age, number of oocytes, fertilization rates, number of embryos transferred, or embryo score. Peak E2 levels were significantly lower in the AL group. Ongoing pregnancy rates were significantly higher in the ML group (52% vs. 37%). Trends toward increased implantation and lower cancellation rates were also noted, but these did not reach statistical significance. Conclusion(s): Quantitative results of stimulation between the ML and AL protocols were equivalent with the exception of peak E2 levels. However, the higher ongoing pregnancy rates and trend toward superior implantation rates would suggest that ML represents a preferred approach for the poor responder. An increased sample size would be necessary to verify these findings. (Fertil Steril 2008;89:151–6. 2008 by American Society for Reproductive Medicine.) Key Words: GnRH antagonist, letrozole, GnRH agonist, poor responder, in vitro fertilization, ovarian stimulation

The management of the poor-responder patient preparing for assisted reproductive technologies remains extremely controversial. Failure to respond adequately may result in suboptimal oocyte maturation and production as well as high cycle cancellation and poor pregnancy rates. The ideal controlled ovarian hyperstimulation (COH) protocol has not been clearly defined. A variety of regimens have been employed including the use of increased gonadotropin doses, decreased GnRH agonist (GnRH-a) doses, flare regimes, adjunctive growth hormone, GnRH antagonists, and microdose flare regimes (1).

strated improved ovarian responses and clinical outcomes (2–5). This approach takes advantage of the initial release of endogenous gonadotropins that is induced by low-dose GnRH-a administration in the early follicular phase in an effort to enhance response to the subsequent administration of exogenous gonadotropins.

Several studies have supported the use of a microdose GnRH-a flare protocol in this patient group, which demon-

More recently, GnRH antagonists have been administered to poor responders during gonadotropin stimulation with mixed results (6–13). The use of antagonists allows initiation of gonadotropin stimulation in the absence of prior pituitary gonadotropin down-regulation given that these agents are not typically added to the COH protocol until follicular maturation has already been initiated.

Received March 10, 2006; revised and accepted February 6, 2007. Presented in part at the 60th Annual Meeting of the American Society for Reproductive Medicine, Philadelphia, PA, October 16–20, 2004. Reprint requests: William B. Schoolcraft, 799 E. Hampden Ave., no. 300, Englewood, CO 80113 (FAX: 303-788-8310; E-mail: bschoolcraft@ colocrm.com).

The aromatase inhibitor letrozole has been employed as a novel approach to improving gonadotropin response. This agent acts by blocking E2 synthesis with a resulting decrease in negative feedback at the level of the pituitary. The resulting increase in endogenous gonadotropin secretion may enhance the ovarian response to exogenous gonadotropins in COH cycles (14–16). Therefore, the combination of a GnRH

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Fertility and Sterility Vol. 89, No. 1, January 2008 Copyright ª2008 American Society for Reproductive Medicine, Published by Elsevier Inc.

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antagonist and letrozole in conjunction with gonadotropin COH may offer a new alternative to the microdose GnRHa flare protocol for poor responders preparing for IVF. The objective of this investigation is to compare these two regimes in a population of poor responders. MATERIALS AND METHODS Patients This investigation is a prospective controlled trial including 578 patients who were candidates for IVF and who were classified as poor responders as described below. All patients underwent precycle ovarian reserve testing, which included an assessment of cycle day 3 serum FSH and E2 levels and a measurement of ovarian volume and number of antral follicles measuring 4–8 mm by ultrasound evaluation during the follicular phase. Criteria for classification as a poor responder included at least one of the following: day 3 serum FSH level >10 mIU/mL, <6 total antral follicles, prior cycle cancellation, prior poor response to COH (peak E2 <500 pg/mL and/or <6 oocytes retrieved), and age >41. Patients were assigned in a 2:1 ratio to either a GnRH-a microdose flare (ML) or GnRH antagonist/letrozole (AL) protocol. Protocol assignment was made by the nursing staff based on the order in which the patient accessed the IVF program, without input by any of the investigators. Treatment Protocols A total of 355 patients were assigned to the ML protocol. All patients received 14–21 days of an oral contraceptive. Three days after the last oral contraceptive pill was taken, leuprolide acetate (Lupron, TAP Pharmaceuticals, Waukegan, IL) 40 mg SC twice daily was self-administered until the day of hCG administration. Two days after initiation of GnRH-a, gonadotropin stimulation consisting of recombinant FSH (Gonal-F, Serono, Rockland, MA) 300 IU and hMG (Pergonal, Serono) 150 IU daily was initiated. A schematic for this protocol is provided in Figure 1. A total of 179 patients were assigned to the GnRH AL protocol. Oral contraceptives were not used in this regimen. On day 3 of a spontaneous cycle, gonadotropin stimulation was initiated with recombinant FSH and hMG in the doses described above. Letrozole (Femara, Novartis, East Hanover, NJ) 2.5 mg per os daily was also initiated on day 3 and continued for 5 days. A GnRH antagonist, ganirelex acetate (Antagon, Organon, West Orange, NJ) or cetrorelix (Cetrotide, Serono) 0.25 mg SC daily was initiated once the lead follicle reached 14 mm in mean diameter. A schematic for this protocol is provided in Figure 2. Serial ultrasound examinations and evaluation of serum E2, LH, and P levels were used to assess follicular maturation. Gonadotropin doses were adjusted but not increased after 4 days of stimulation. Human chorionic gonadotropin (hCG) 10,000 IU IM was administered when at least two follicles achieved a mean diameter of 18 mm and serum E2 levels 152

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FIGURE 1 Schematic representation of the ML protocol.

Schoolcraft. Letrozole/antagonist for poor responders. Fertil Steril 2008.

were R500 pg/mL. Oocyte aspiration was performed 35 hours after hCG administration. Cycle cancellation was recommended when fewer than four developing follicles of an appropriate growth pattern were noted. Embryo Culture and Transfer Standard insemination or intracytoplasmic sperm injection (ICSI) was performed as clinically appropriate. Gametes and embryos were cultured in sequential G medium (Vitrolife, Englewood, CO) and incubated in 6% CO2, 5% O2, and 89% N2. Indications for day 5 ET have been described elsewhere (17). If embryos were transferred on day 3, assisted hatching was routinely used in this patient population. Embryo transfers were performed under ultrasound guidance using a Wallace catheter (Marlow, Willoughby, OK) as described elsewhere (18). Luteal support consisted of P in oil 50 mg IM initiated 2 days after oocyte retrieval and continued until the day of pregnancy testing. Transdermal E2 (Vivelle-Dot, Novartis,

FIGURE 2 Schematic representation of the AL protocol.

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Miami, FL) was administered starting 9 days after oocyte retrieval at a dose of 0.2 mg daily. After the documentation of pregnancy, estrogen and P supplementation was adjusted as necessary to maintain the appropriate serum level. Human chorionic gonadotropin levels were measured 14 days after oocyte retrieval. Pregnancies were confirmed by transvaginal ultrasound examination at 4.5 weeks from oocyte retrieval with the number of gestational sacs and cardiac activity noted. Ongoing pregnancy rates were defined as the presence of an intrauterine gestational sac with cardiac activity 4.5–5 weeks after oocyte retrieval. Data were analyzed by Student’s group t-test and c2 analysis as appropriate. P<.05 was considered statistically significant. Results are expressed as mean  SD unless otherwise specified. Informed consent as approved by the HealthONE Institutional Review Board was obtained. RESULTS Baseline clinical data are displayed in Table 1. There were no significant differences in age, number of prior failed IVF cycles, or ovarian reserve testing between the two groups. In addition, there were no differences in the distribution of indications for IVF between the treatment regimens. The indications for inclusion in this trial were also similarly distributed between the groups. The results of COH are displayed in Table 2. There were no differences in duration or doses of gonadotropins required, numbers of oocytes, or percentage of mature oocytes obtained. As would be expected, lower peak E2 levels were noted with AL, although this difference did not reach statistical significance. A trend toward higher cycle cancellation rates that did not reach statistical significance was experienced among patients assigned to AL as opposed to ML (9.0% vs. 4.3%) There were also no differences appreciated in the incidence of day 3 or 5 ET, use of ICSI, or assisted hatching. Cycle outcomes are displayed in Table 3. Fertilization rates and degree of day 3 embryo quality were similar between the two groups. The mean number of available embryos was also similar. As expected given the patients’ poorer prognosis and

prior history, a higher number of embryos were transferred than would be anticipated for age-matched controls. Ongoing pregnancy rates in the AL group were significantly lower than in the ML group. A trend toward lower implantation rates, which did not achieve statistical significance, was also noted in this group. DISCUSSION In this trial, we have evaluated a large series of proven or presumed poor responders based on ovarian reserve testing, advanced maternal age, and/or prior cycle response. A unique stimulation protocol involving the use of an aromatase inhibitor initiated in the early follicular phase along with gonadotropin stimulation and subsequent GnRH antagonist suppression was compared with a more standard ML GnRH-a regime. Quantitative results of stimulation were similar between the two protocols as judged by the number of mature oocytes obtained as well as the stimulation parameters (Table 2). Lower mean peak E2 levels were appreciated in the group receiving the GnRH antagonist, which was presumed to be due to aromatase inhibition induced by letrozole (15). Superior ongoing pregnancy rates and a trend toward higher implantation rates in the ML group would suggest a difference in oocyte and embryo quality. A difference in endometrial receptivity cannot be ruled out as an alternative explanation for these results. One of the difficulties in critically evaluating various COH protocols is the lack of a single universally accepted definition of the poor responder (1). A variety of criteria have been used alone or in combination as inclusion criteria for proposed protocols. The current investigation has not relied on a single criterion but rather on the evidence of prior poor response, advanced maternal age, or presumed poor response based on standard evaluations of ovarian reserve (19– 21). There is no question that it would be advantageous to predict which patients will respond poorly and tailor an appropriate protocol in advance rather than allowing them to fail to respond to more standard regimens before introducing a more appropriate stimulation regime during a second cycle. It would have been ideal to evaluate a more homogenous population in a truly randomized trial. However, the similar distribution of inclusion criteria in baseline characteristics between the groups would belie the potential of selection

TABLE 1 Patient characteristics.

Protocol AL ML

n

Age, % >41 years

Day 3 FSH, % >10 mIU/mL

Prior failed completed IVF cycles, % of patients

Antral follicle count, % with <6

179 355

38  3.75 38.0  4.0

7.9  2.1 8.0  3.9

1.16  0.6 1.1  0.6

9.0  3.6 9.0  3.5

Note: P ¼ NS for all data. Schoolcraft. Letrozole/antagonist for poor responders. Fertil Steril 2008.

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TABLE 2 Stimulation results.

Protocol AL ML P

Gonadotropin dose, 75 IU ampules

Duration of stimulation, days

Peak E2, pg/mL

Oocytes retrieved

% Metaphase II oocytes

56.3  9.9 52.5  13 NS

9.9  1.3 10.1  1.6 NS

1,403  965 3,147  1,189 < .05

12  6 13  5.3 NS

70  20 79  15 NS

Schoolcraft. Letrozole/antagonist for poor responders. Fertil Steril 2008.

bias. It is possible that results may differ with the application of more strict criteria for this patient group. However, the definitions for poor responders employed in this trial are consistent with those employed in our previously published evaluation of an ML regime (3). Microdose GnRH-a flare regimes have been generally shown to be effective therapy for poor responders. Traditional flare regimes in which higher-dose GnRH-a is administered with minimal delay before initiation of gonadotropin COH are associated with significant increases in follicular-phase serum P and androgen levels, which may exert deleterious effects on follicular development and oocyte quality (22, 23). In an effort to minimize this effect, while maintaining the benefit of stimulating endogenous gonadotropin release, the administration of lower doses of GnRH-a was proposed. Four separate trials employing lower daily doses of leuprolide acetate ranging from 40 to 80 mg in appropriately selected poor responders have demonstrated significant benefit over more traditional regimes with regards to improved ongoing pregnancy rates and decreased cancellation rates (2–4, 24). It is interesting to note that no significant changes in follicular-phase serum P or androgen levels were noted by Surrey et al. when this regime was employed (4). Schoolcraft and coworkers reported no evidence of premature luteinization or LH surges and reported a 50% ongoing pregnancy rate in 28 of 32 patients with prior poor response who proceeded to oocyte aspiration using an ML regimen supplemented with growth hormone (3). Several investigators have evaluated the role of GnRH antagonist protocols in the treatment of poor responders. Craft et al. reported a significant reduction in cycle cancellation

rates and oocyte production in a mixed group of patients with poor response or failed cycles during prior standard GnRH-a down-regulation cycles (6). Nevertheless, only an 11.8% live birth rate per completed cycle was achieved. Akman and colleagues compared responses to a GnRH antagonist protocol and to gonadotropin stimulation alone in a group of poor responders (8). No significant differences in outcome were reported, although trends toward higher implantation (13.3% vs. 3.4%) and ongoing pregnancy (20% vs. 6.25%) rates were noted. In contrast, Akman et al. in a prospective randomized trial noted a trend toward lower pregnancy and implantation rates with the antagonist (24). Takahashi and coworkers reported an improvement in blastocyst quantity in comparison with standard down-regulation protocols (25). Several studies comparing antagonist with more traditional protocols reported no difference in implantation or clinical pregnancy rates, although the number of embryos available for transfer was higher with the antagonist (10, 12). In contrast, Malmusi et al., in a prospective randomized trial of 54 poor responders, noted that although pregnancy rates were similar, fertilization rates, numbers of mature oocytes retrieved, and high-quality embryos transferred were higher with a traditional flare regime (9). We are aware of a single prospective randomized trial that compared an ML regime with a protocol employing the antagonist ganirelex acetate. This pilot study evaluated 48 poor responders (26). Cancellation rates were similar but extremely high (over 40%) in both groups. Of those patients who completed therapy, no significant differences in pregnancy rates were appreciated.

TABLE 3 Treatment outcome.

AL ML P

Fertilization, %

Day 3 embryo score

Embryos transferred

Implantation rate, %

Ongoing pregnancy rate, %

71 73 NS

3.48  0.27 3.47  0.28 NS

3.5  1.3 3.7  1.3 NS

15 21 NS

37 52 < .05

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Although the use of an antagonist eliminates the effect of excessive pituitary gonadotropin suppression induced by a GnRH-a in a standard long protocol, poor responders may benefit from additional stimulation of endogenous gonadotropin release in the early follicular phase. D’Amato et al. employed a protocol including clomiphene citrate, highdose gonadotropins, and delayed antagonist administration to a group of poor responders and compared results with patients undergoing a long protocol in a prospective nonrandomized trial (26). Although cancellation rates were significantly decreased, no significant differences in pregnancy rates were noted. Once again, low implantation rates (13.5%) were noted. Some possible causes for this phenomenon may be the antiestrogenic effects of clomiphene on the endometrium and potential deleterious effects on oocytes (27, 28). The aromatase inhibitor letrozole acts to increase endogenous gonadotropin release but does not deplete estrogen receptors at the level of the endometrium and could theoretically serve as an ideal alternative to clomiphene citrate in this model (29). Two studies have demonstrated that the addition of letrozole to gonadotropins in poor-responder patients undergoing COH improved follicular response and lessened gonadotropin requirements (15, 16). Garcia-Velasco and colleagues reported the results of an observational pilot trial designed to assess the effects of the addition of letrozole to an antagonist-gonadotropin regimen in a group of poor responders (30). No enhancement of pregnancy rates was noted, but implantation rates were improved. In the current investigation, we report that gonadotropin requirements, oocyte number, and embryo quality were similar between the two treatment groups assigned to either AL or ML protocols. However, both implantation and ongoing pregnancy rates were higher and cycle cancellation rates were lower among those who received the ML regime. One possible explanation for the poorer outcome in the AL group may be that letrozole increases follicular fluid androgen levels, which may have a deleterious effect on oocyte quality (30, 31). Surrey et al. previously reported that the ML regime did not induce aberrant rises in serum androgen levels during the early stages of follicular recruitment (4). A second possibility lies in the fact that a brief course of oral contraceptives administered as part of the ML regime was not used in the AL protocol. The use of this agent may have reduced the potential for corpus luteum rescue with ML but not during letrozole and gonadotropin administration during the early follicular phase (32, 33). A recent study has shown that a luteal-phase E2 patch may improve response in antagonist cycles also by potentially eliminating a preexisting corpus luteum (34). Recent controversy has surrounded the subject of the overall safety of letrozole therapy. A published abstract has suggested a possible increased risk in birth defect rates with letrozole use, which is a source of additional concern (35). However, a larger retrospective trial evaluating 911 newborns Fertility and Sterility

who were conceived after administration of this agent to mothers as infertility therapy found no greater overall rates of major or minor malformations than in those who were conceived after administration of clomiphene citrate (36). In conclusion, therefore, we note no advantage in treating poor responders with an LA COH regime before IVF. Pending the results of larger-scale prospective randomized trials, it would appear that the ML regime remains the ovarian stimulation regime of choice for the appropriately selected poor responder. Acknowledgments: The authors thank the embryology and nursing staffs of the Colorado Center for Reproductive Medicine for their contributions and extraordinary care.

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