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Reproductive Sciences Division, Department of Obstetrics and Gynecology, University of Toronto, Toronto, Canada M5G 1X5
Address all correspondence and requests for reprints to: Robert F. Casper, M.D., Division of Reproductive Sciences, Fran and Lawrence Bloomberg Department of Obstetrics and Gynecology, University of Toronto, and Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Room 876, Toronto, Ontario, Canada M5G 1X5. E-mail: RFcasper{at}aol.com.
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Abstract |
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Methods: Two groups of women undergoing intrauterine insemination (IUI): group I (389 patients; mean age 35 ± 4.3 yr) underwent 630 IUI cycles stimulated with letrozole and FSH; and group II (134 patients; mean age 36.0 ± 4.6 yr) underwent 166 IUI cycles stimulated with FSH only. Each group was stratified into ovulatory and anovulatory cycles. Patients were monitored by ultrasound for folliculometry and blood sampling for hormonal assay on d 3, 7, 9, or 10 of the cycle, and on the day of human chorionic gonadotropin administration.
Results: Group I had a significantly lower follicular count greater than 10 mm on d 7, greater than 12 mm on d 9 or 10, and greater than 15 mm on the day of human chorionic gonadotropin administration compared to group II (P = 0.006, <0.001, and <0.001, respectively). After stratifying patients by diagnosis, this relationship was maintained only for patients with ovulatory infertility (P = 0.003, <0.001, and <0.001, respectively). Serum estradiol (E2) was significantly lower in the group I ovulatory and anovulatory at the last three monitoring visits (P < 0.001). However, the difference in E2 levels decreased in the preovulatory period with similar E2 levels per mature follicle. No premature preovulatory progesterone rise was observed in either group. However, significantly lower progesterone levels were observed in the second half of the follicular phase in group I (P = 0.02 and <0.001). Endometrial thickness was significantly lower in group I at the second and third visits (P < 0.001, 0.01) but was comparable to group II at the last monitoring visit. Although, the pregnancy rates were similar between the two groups, the multiple pregnancy rate was significantly higher in the FSH-only group (P = 0.039).
Conclusion: The addition of letrozole modifies the follicular, hormonal, and endometrial dynamics of FSH-stimulated cycles with possible positive effects on the overall cycle outcome.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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In addition, letrozole cotreatment was shown to be more cost-effective than FSH alone in patients undergoing controlled ovarian stimulation (COS) and intrauterine insemination (IUI) (2). Moreover, the safety of letrozole has been recently substantiated in a large multicenter study where the authors found no difference in the overall rates of major and minor congenital malformations among newborns from mothers who conceived after letrozole or CC treatments (3).
AI are believed to work through both a central mechanism at the level of the hypothalamic-pituitary axis and through a peripheral mechanism at the level of the ovary (1). The blockade of conversion of androgens to estrogens leads to reduction of serum estrogen levels and suppression of estrogen-negative feedback in the brain. AI also increase the intrafollicular androgen concentration with a concomitant increase in ovarian follicular FSH receptor mRNA (4). The ovarian mechanism of action of AI received further support when Garcia-Velasco et al. (5) unequivocally demonstrated an increase in the level of follicular fluid androgens in patients who received letrozole treatment as part of an in vitro fertilization (IVF) stimulation protocol compared with those who received FSH alone.
The effect of letrozole on different reproductive cycle parameters has been evaluated recently. Endometrial thickness and morphology was investigated in letrozole cycles and found to be comparable to the endometrium in natural cycles (6). In contrast, CC was previously shown to negatively affect the endometrium in both the follicular (7) and in the luteal phase (8).
In AI-treated cycles, preovulatory estradiol (E2) levels have always been shown to be lower in comparison to CC (9) or when compared with gonadotropin protocols (10). Low preovulatory E2 has been hypothesized to lead to an improvement of implantation with AI treatment because standard COS protocols often produce extremely high preovulatory E2 levels that could adversely affect the development of the endometrium, the follicles, and the embryo (11).
Generally, E2 levels have been studied at the time of ovulation, whereas data on the dynamics of other cycle hormones such as progesterone and LH in the follicular phase of AI-treated cycles are lacking. In addition, there is no information on the progression of follicular growth in the early and late parts of the follicular phase when letrozole cotreatment with FSH was used. The objective of the present study was to examine the modulatory effect of letrozole on FSH stimulation in the follicular phase of the cycle. We compared letrozole and FSH cotreatment compared with FSH alone on follicular phase dynamics in patients with ovulatory and anovulatory infertility.
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Patients and Methods |
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Patient recruitment and counseling
Patients with various infertility diagnoses (ovarian, male, endometriosis, unexplained, and other factors of infertility) undergoing COS-IUI were recruited to participate in this study. The use of letrozole cotreatment with FSH was offered to patients who were informed about the off-label nature of letrozole use as well as its mechanism of action to reduce the dose of FSH required. Patients who declined letrozole received FSH alone. We recruited 523 consecutive patients who underwent 796 IUI cycles. Patients were divided into two groups; group I received letrozole plus FSH, and group II received FSH injections only.
Group I included 389 patients who had 630 stimulation cycles. The numbers of patients/cycles for each diagnosis were anovulation (102/147), male (105/186), unexplained (150/240), endometriosis (14/25), and other factors (18/32), respectively. Patients/cycles in this group had ovulatory (287/483) or anovulatory (102/147) infertility, respectively. Group II included 134 patients who have had 166 stimulation cycles. The numbers of patients/cycles for each diagnosis were anovulation (33/41), male (26/23), unexplained (63/76), endometriosis (8/11), and other factors (4/6), respectively. Patients/cycles in this group had ovulatory (101/125) or anovulatory (33/41) infertility, respectively. Patients in both groups were treated concurrently.
Diagnosis of polycystic ovary syndrome (PCOS) was based on the Rotterdam consensus criteria (12). Tubal patency was confirmed by sonohysterography with contrast, hysterosalpingography, and or pelvic laparoscopy. Mild male factor infertility was diagnosed according to the World Health Organization (WHO) criteria for normal semen. Endometriosis was diagnosed by pelvic laparoscopy. Unexplained infertility was based on the exclusion of known factors of infertility.
Ovulation was documented with follicular monitoring by transvaginal ultrasonography and serial measurements of serum E2 and LH levels during a natural cycle and/or midluteal progesterone.
Medication protocol
The dose of medications was based on the clinical profile of the patient, including age, weight, and duration of infertility, as well as prior treatment cycles. In group I, letrozole (Femara; Novartis, East Hanover, NJ) was given at a dose of 2.5 mg/d from d 3–7 of the menstrual cycle, followed by FSH injection starting at 50–100 IU/d beginning on d 7 until the day of human chorionic gonadotropin (hCG) administration. The dose of FSH was adjusted according to the patient response to achieve two to three mature follicles (>15 mm) on the day of hCG administration. If patients had a poor response in cycle 1, the dose of letrozole was occasionally increased to 5 mg/d in subsequent cycles based on a previous dose response study (13). In group II, FSH injections were started on d 3 of the menstrual cycle beginning with a dose from 50–100 IU/d. The FSH dose was then adjusted on cycle d 7 according to the response of the patient with the aim of obtaining two to three mature follicles (>15 mm) on the day of hCG administration. All patients received recombinant FSH (Gonal-F; Serono, Oakville, Canada; or Puregon; Organon, Scarborough, Canada). hCG (Profasi, Serono; or Pregnyl, Organon) was given as a single injection of 10,000 IU to trigger ovulation when the mean diameter of at least two ovarian follicles was 15 mm or greater.
Cycle monitoring and insemination
All patients were monitored in the early and the late parts of the follicular phase. A monitoring transvaginal ultrasound (TVS) and serum sample was obtained on d 3 and 7 in the first half of the follicular phase for all patients. A third monitoring TVS and serum sample was obtained on either d 9 or 10 based on the patient response on d 7. Finally, the last monitoring TVS and serum sample was obtained on the day of hCG administration.
The endometrial thickness including the two layers of the endometrium was measured and recorded at all four visits. Similarly, all growing follicles were measured at the four time points. Serum hormonal assays included FSH on d 3 of the cycle only, and E2, LH, and progesterone on d 3, 7, 9, or 10, and day of hCG administration. An LH surge was defined as an increase in LH level greater than 100% over the mean of the preceding 2 d. IUI was performed 36–40 h after hCG administration if no endogenous LH surge occurred. If an endogenous LH surge was detected on the day of hCG administration, two IUIs were performed at 24 and 48 h. The same three infertility specialists performed the IUI in all patients. Pregnancy was diagnosed by quantitative ß-hCG assay 2 wk after the insemination. Clinical pregnancy was confirmed by observing fetal cardiac pulsation 4 wk after positive pregnancy test by TVS.
Semen analysis
Semen samples were collected after 2–3 d of sexual abstinence. Specimens were allowed to liquefy for up to 1 h after collection and the volume, appearance, pH, and semen viscosity were determined. Manual semen analysis was performed according to WHO guidelines to determine sperm concentration and motility (1). A 5-µl aliquot of liquefied semen was loaded on a microcell counting chamber (Conception Technologies, San Diego, CA) and examined under x200 magnification. Sperm concentration was expressed as x106/ml semen, whereas motility was expressed as a percentage. Progressive sperm motility was defined as grade A + B (rapid progressive and sluggish progressive). Smears of raw semen were prepared for sperm morphology assessment using WHO criteria. The smears were fixed and stained using the Diff-Quik kit (Baxter Healthcare Corporation, Inc., McGaw Park, IL). In this study, normal values were: sperm concentration equal to or greater than 20 x 106/ml semen, motility 50% or greater, and normal sperm forms 30% or greater.
Discontinuous density gradients were prepared by overlaying 1.5 ml of 80% Pure Sperm (Nidacon International, Gothenburg, Sweden) solution with 1.5 ml of 40% solution. Aliquots of 1.5 ml of the liquefied semen were carefully layered over the uppermost Pure Sperm layer. The gradient was centrifuged at 400 x g for 20 min at room temperature. The 80% layer was pooled, diluted in one volume of human tubal fluid and human serum albumin, and centrifuged at 300 x g for 7 min. The supernatant was discarded and the pellet was resuspended in 0.5 ml of human tubal fluid and human serum albumin for insemination. Postwash semen characteristics reported include sperm concentration, percent motility, total motile sperm count, and percent with normal morphology.
Hormone assay
Blood samples were collected using a serum separator tube (BD vacutainer, 5.0 ml, Franklin Lakes, NJ) starting from d 2 or 3 of patients’ cycle. Subsequent visits require additional blood monitoring for d 7, 9, 11, 12, or 13 of the patient’s cycle. The hormone assay included E2, LH, progesterone, and FSH (DPC Immulite; Diagnostic Products Corp., Los Angeles, CA).
The blood samples collected were then centrifuged for 15 min and the serum is collected and used to test the level of hormones required using the Immulite Automated Immunoassay Analyzer (DPC Immulite, Diagnostic Products Corporation). The Immulite system uses assay-specific antibody or antigen-coated plastic beads as the solid phase, alkaline phosphatase-labeled reagent, and a chemiluminescent substrate. The coated beads are housed in a plastic device called test units, which serves as a reaction vessel for the immune reaction, the incubation and washing processes, and signal development. The results for E2 and progesterone levels were reported as picomoles per liter and nanomoles per liter, respectively, and LH and FSH levels were reported in international units per liter.
Outcome parameters
Main outcome measures included the hormonal profile of the three hormones measured in the follicular phase (E2, LH, and progesterone), the number and size of growing follicles, and the endometrial thickness at different stages of the follicular phase in both groups. Pregnancy outcome was also investigated. The results of each group were further subgrouped according to whether the patient had ovulatory or nonovulatory infertility at the time of recruitment into the study.
Statistical analysis
The various outcome measures were expressed as mean ± SD. Because multiple cycles from the same patients were included, repeated measures models were employed for all analyses. Both groups were compared on binary outcomes with logistic regression using generalized estimating equations and on continuous variables using repeated measures mixed models. Rates of outcomes in the groups were compared by events/trials logistic regression using generalized estimating equations. Normally distributed continuous variables were compared with the independent samples test. We used the nonparametric Mann-Whitney U test to analyze continuous variables and the Fisher’s exact test and 
2 test for categorical variables. P < 0.05 was considered statistically significant. The statistical tests were performed with SPSS 13.00 for Windows (release 13.01; SPSS Inc., Chicago, IL). The figures were created using the Graph Pad Prism, version 4 (Graph Pad Software, San Diego, CA).
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Results |
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Both groups were similar in their baseline characteristics (Table 1
). The number of completed cycles according to the infertility diagnosis and ovarian stimulation protocol are displayed in Table 1. A total of 105 cycles were cancelled in both groups; 55 in the cotreatment group and 50 in the FSH-only group. The major cause of IUI cancellation in both groups was inadequate response or failure to achieve one follicle greater than 15 mm. We found that 22 of 55 cancelled cycles (40%) of IUI in group I and 12 of 50 cancelled cycles (24%) in group II to be due to poor response. In contrast, overresponse that led to the presence of too many mature follicles (more than six follicles > 15 mm) was the third most frequent cause of cancellation in the FSH-only group (11 of 50) (22%), but not in the letrozole and FSH group, where only five of 55 (9.1%) cancellations were due to conversion to IVF.
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The two groups were comparable regarding baseline ovarian reserve as evidenced by an almost identical mean d 3 FSH and a very close SD. In addition, patients in both groups had the same duration of infertility. Both groups received the hCG trigger around the same day in the preovulatory period. In other words, letrozole cotreatment did not alter the duration of stimulation. However, the FSH-only (group II) patients needed a significantly higher dose of gonadotropins compared with group I (P < 0.001).
On stratifying the study population by ovulatory status, 287 patients with ovulatory infertility in group I underwent 483 IUI cycles compared with 101 patients and 125 cycles in group II. In contrast, the 102 patients with anovulatory infertility in group I underwent 147 IUI cycles compared with 33 anovulatory patients undergoing 41 cycles in group II. Patients with ovulatory and anovulatory infertility had comparable baseline characteristics irrespective of the stimulation protocol (Table 1
). Significantly higher doses of FSH were needed in both ovulatory and anovulatory subgroups when FSH-only stimulation was implemented (P < 0.001).
Cycle characteristics: hormonal dynamics
E2.
Serum E2 levels were the same on d 3 in both groups (Table 2 and Fig. 1). However, letrozole cotreatment was associated with significantly lower E2 levels at the next three visits (P < 0.001 at all time points). Of interest, the E2 level per mature follicle on the day of hCG administration was similar in both groups. Figure 1 clearly demonstrates the gap in the E2 curves between the two groups. The gap gets narrower close to the day of hCG administration.
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Progesterone.
Serum progesterone concentration was the same on d 3 and continued to be comparable in both groups (Table 3 and Fig. 2) on d 7 of the follicular phase. However, letrozole cotreatment was associated with significantly lower progesterone levels at the next two visits (P < 0.001 on the third visit, and P < 0.003 on the day of hCG administration). Figure 2 demonstrates the difference between the progesterone level in the two groups. Contrary to the estrogen curves, the gap in the progesterone levels gets wider close to the periovulatory period. The same relationship was maintained in patients with ovulatory infertility (P < 0.001 and P < 0.03 on monitoring visits three and four, respectively) and patients with anovulatory infertility (P < 0.002 and P < 0.02 on monitoring visits three and four, respectively).
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and Fig. 3). On the third monitoring visit and on the day of hCG administration, the LH levels were again comparable between the two groups. Except for the increase of LH on d 7 for patients who received letrozole cotreatment, the LH curves in both groups were comparable. The same increase in the LH level in the cotreatment group at d 7 was observed in patients with ovulatory (P = 0.05) and anovulatory infertility (P < 0.001). After discontinuation of letrozole in the cotreatment group, LH level became comparable to that of the FSH group.
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The baseline endometrial thickness was comparable between the two groups on d 3 of the follicular phase. However, on d 7 of the follicular phase, endometrial thickness was significantly lower when letrozole was used (0.46 ± 0.37 cm) compared with FSH only (0.64 ± 0.22 cm; P < 0.001; Table 5 and Fig. 4). The difference was decreased at the third monitoring visit (0.66 ± 0.44 vs. 78 ± 0.23, respectively) but was still statistically significant (P = 0.019). By the day of hCG administration, endometrial thickness was comparable between the two groups and was above 0.8 cm in both groups.
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Follicular dynamics
We found that letrozole cotreatment was associated with a significantly lower number of follicles greater than 10 mm on d 7, greater than 12 mm on d 9 or 10, and greater than 15 mm on the day of hCG administration when compared with the FSH-only group (P < 0.006, <0.001, and <0.001, respectively). The mean number of follicles greater than 15 mm on the day of hCG administration in the letrozole group was approximately two thirds that of the FSH-only group (Table 6 and Fig. 5). On stratifying both groups by ovulatory status, patients with ovulatory infertility had a significantly higher number of follicles of all sizes on the second, third, and fourth monitoring visits when stimulated by FSH alone compared with letrozole and FSH (P = 0.003, <0.001, and <0.001, respectively). Surprisingly, patients with anovulatory infertility had the same number of follicles of all sizes at the second, third, and fourth monitoring visits, whether stimulated by FSH alone or by letrozole and FSH cotreatment (P = 0.7, 0.3, and 0.08, respectively). Consequently, the increased number of follicles in the FSH-only group was restricted to patients with ovulatory infertility.
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The overall pregnancy rate was similar in letrozole plus FSH and FSH-only cycles per completed IUI cycle (17.94 vs. 16.87%, respectively, P = 0.8). The cumulative pregnancy rate in group I and group II was 30.05 and 22.04%, respectively (Table 7). The difference was not statistically significant. The underlying cause of infertility did not influence the treatment outcome. On stratifying patients in both groups according to ovulatory status, the same relationship was maintained in patients with ovulatory infertility vs. patients with anovulatory infertility as the two COS protocols led to similar pregnancies per cycle and per patient.
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). In contrast, FSH-only stimulation was associated with a significantly higher multiple pregnancy rate compared with letrozole cotreatment, 34.78 vs. 20.21%, respectively (P = 0.039). The majority of multiple pregnancies in the letrozole group were twins (18%), with a triplet rate of 3.4%. In the FSH-only group, there were 21.7% twins, 4.3% of triplets, and two sets of quintuplets. The same relationship was maintained on stratifying the pregnancy outcome according to ovulatory status with a marginally higher incidence of multiple pregnancies in patients with anovulatory infertility receiving FSH only (P = 0.06). In patients with ovulatory infertility, the multiple pregnancy rate in the FSH-only group was 31.3% compared with 22.5% in the letrozole cotreatment group (P = 0.7). |
Discussion |
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Contrary to CC, letrozole-only treatment is associated mostly with monofollicular ovulation when the 2.5 mg dose was used from d 3–7 (1). This effect was attributed to the short half-life (
45 h) of letrozole (14, 15) and the absence of estrogen receptor depletion as seen with CC (16). Consequently, normal central feedback mechanisms in the hypothalamus and the anterior pituitary remain intact. With the growth of the dominant follicle and the rise of the estrogen levels, normal negative feedback occurs centrally, resulting in suppression of endogenous FSH release and atresia of the smaller growing follicles. In turn, a single dominant follicle should occur in most cases of letrozole administration for ovulation induction. In contrast, a recent randomized dose-response study demonstrated that a letrozole dose of 5 mg/d for the same duration could produce more follicles and higher pregnancy rate (13).
In the present study, the addition of either 2.5 or 5 mg/d of letrozole for 5 d, before adding FSH, modulated folliculogenesis in patients with ovulatory infertility, reducing the number of the developing follicles by approximately one third at all time points of the follicular phase. However, patients in this study with anovulation (mostly PCOS) produced the same number follicles at all time points of the follicular phase irrespective of the COS protocol. Given the lower cost of the letrozole-FSH combination (2), our results provide further support to adding letrozole to protocols of COS in patients with ovulatory or anovulatory infertiliy undergoing IUI.
In patients who received letrozole, E2 levels were significantly lower at all time points compared with the FSH-only group in our study. Our findings related to serum estrogen concentrations are supported by previous studies that looked at the periovulatory E2 levels with letrozole treatment compared with natural cycles, CC-stimulated cycles, or letrozole cotreatment with FSH compared with FSH-only cycles. Fisher et al. (17), in a randomized double-blind controlled trial, found that the E2 levels in letrozole-stimulated cycles appeared lower than in natural cycles or CC cycles. Another more recent study compared letrozole- to CC-stimulated cycles and found the same relationship regarding estrogen (9).
Of interest, there was a gradual narrowing of the gap in serum E2 levels between the two groups. On d 7, when letrozole is expected to have exerted its maximum effect, the serum E2 level is lowest in the cotreatment group compared with the FSH-only group. The mean serum E2 level in the FSH-only group was almost seven times the level in the cotreatment group. On the third monitoring visit (2–3 d later), the serum E2 level in group II was three times the level in group I. On the day of hCG administration, the gap in serum E2 concentrations was the narrowest with an E2 ratio of 1:1.5 for groups I and II, respectively. This observation indirectly demonstrates a prompt decline of the letrozole effect upon discontinuation as evidenced by the rebound in the circulating serum estrogen level.
This low estrogen level associated with letrozole treatment throughout the follicular phase may have implications for fertility preservation in breast cancer patients. Recently developed ovarian stimulation protocols using letrozole can be used to increase the margin of safety in these patients by reducing serum estrogen levels during COS (18). The same observation was confirmed by a recent publication from the same group (19).
Serum progesterone levels were comparable between both of our study groups on d 7. However, the mean serum progesterone concentration became statistically significantly lower with letrozole cotreatment both on d 9 or 10, and on the day of hCG administration. The same relationship was maintained when both groups were stratified by ovulatory status. It is important to point out that the mean progesterone values in both groups were still below the levels accepted for the definition of premature luteinization (20). Nevertheless, the fact that the serum progesterone level was significantly lower in the second half of the follicular phase in the cotreatment group could have positive implications for prevention of premature luteinzation in some cycles, which might negatively affect egg quality or implantation rates.
The mean serum LH concentration was significantly increased on d 7 when letrozole was given. This increase in LH was expected secondary to the release of the anterior pituitary from the negative feedback of E2. The rise in LH was not sufficient to fulfill the definition of an LH surge as described in Patients and Methods and by others (20). Other investigators who used letrozole alone for ovulation induction have also observed this increase in LH (6). The LH level in our study started to decrease immediately after discontinuation of letrozole and was comparable to the LH level in the FSH-only group, only 2–3 d later and on the day of hCG administration. The absence of a premature LH rise in the letrozole cotreatment group is reassuring because the main drawback of COS regimens is the frequent occurrence of premature LH rises and luteinization (21).
The slower development of the endometrium in the first half of the follicular phase in the letrozole cotreatment group was expected because of the low estrogen production as a result of aromatase inhibition. After discontinuation of letrozole and the start of FSH injections, the endometrium grew faster in the second half of the follicular phase in patients with ovulatory infertility compared with patients with anovulation. However, in both groups, the endometrial thickness matched the thickness of FSH-only stimulated cycles by the day of hCG administration. This rapid endometrial growth could be explained by up-regulation of endometrial estrogen receptor in response to estrogen withdrawal (22) resulting from aromatase inhibition. As a result, one could speculate that the endometrium was more sensitive to resumption of estrogen production once the letrozole was discontinued, resulting in more rapid proliferation of endometrial epithelium and stroma and improved blood flow to the uterus and endometrium (23). Consequently, normal endometrial development and thickness should occur by the time of follicular maturation, despite the significantly lower E2 concentrations in letrozole-treated cycles. The comparable pregnancy rates in groups I and II support the concept that the endometrial thickness in both groups is above the threshold required for pregnancy.
The pregnancy rates observed in our study population are consistent with the pregnancy rates of similar previous studies. Healey et al. (24) performed a retrospective analysis of 205 IUI cycles comparing cotreatment with letrozole and gonadotropins vs. gonadotropins alone. These investigators found that the pregnancy rate did not differ significantly between the 2 groups (20.9% vs. 21.6%, respectively) (24) and also found a lower incidence of multiple pregnancies in the letrozole-FSH group, in keeping with the results of the present study and that of Mitwally et al. (25).
Our study has the limitations of all nonrandomized studies. However, both groups were comparable regarding all demographic variables tested. In addition, subgroup analysis within each group according to ovulatory status further confirmed the homogeneity and the comparability of the study population. Moreover, upon reviewing the literature, we observed that our data are still the first exploration of cycle dynamics with respect to the hormonal, endometrial and follicular changes in a large infertility population receiving letrozole cotreatment for COS in IUI cycles.
We conclude that patients stimulated with the AI, letrozole, in conjunction with FSH, recruited a significantly lower number of preovulatory follicles and had lower mean serum E2 levels throughout the follicular phase. Letrozole addition does not lead to a premature rise in LH or progesterone in the preovulatory period. The endometrium was thinner in the first part of the follicular phase, but the endometrial thickness caught up rapidly upon discontinuation of letrozole. Although the overall pregnancy rates were not affected by letrozole treatment before FSH stimulation, this COS protocol is associated with lower multiple pregnancy risk than FSH-only treatment. Therefore, we have shown that the addition of letrozole modulates the follicular, hormonal, and endometrial dynamics of FSH-treated cycles without a negative effect on the occurrence of pregnancy.
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Footnotes |
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Disclosure: M.A.B., N.A.M, R.F., and N.E. have nothing to declare. R.F.C. has a licensing agreement with Ares-Serono.
First Published Online December 27, 2006
Abbreviations: AI, Aromatase inhibitor; CC, clomiphene citrate; COS, controlled ovarian stimulation; E2, estradiol; hCG, human chorionic gonadotropin; IUI, intrauterine insemination; IVF, in vitro fertilization; PCOS, polycystic ovary syndrome; TVS, transvaginal ultrasound.
Received August 2, 2006.
Accepted December 18, 2006.
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