Hum. Reprod. Advance Access originally published online on July 27, 2006
Human Reproduction 2006 21(11):2838-2844; doi:10.1093/humrep/del273
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Cost-effectiveness of aromatase inhibitor co-treatment for controlled ovarian stimulation
1 Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON, Canada 2 Department of Obstetrics and Gynecology, Assiut University, Assiut and 3 Cairo University, Giza, Egypt
4 To whom correspondence should be addressed at: Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Toronto, and Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Room 876, Toronto, ON, Canada M5G 1X5. E-mail: rfcasper{at}aol.com
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Abstract |
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BACKGROUND: To compare the clinical results and the cost-effectiveness of using the aromatase inhibitor, letrozole, in conjunction with FSH and FSH alone for controlled ovarian stimulation (COS) in patients undergoing intrauterine insemination (IUI) for a variety of indications. METHODS: Four hundred and thirty-two consecutive patients who underwent 872 IUI cycles were included. The study population was composed of two groups. Group I included 308 patients who underwent 589 IUI cycles with letrozole and FSH for the following indications: anovulation (143 cycles), male factor infertility (147 cycles), unexplained infertility (250 cycles), endometriosis (18 cycles) and combined indications (31 cycles). Group II included 124 patients who underwent 283 IUI cycles who received FSH only for the following indications: ovarian factor infertility (82 cycles), male factor infertility (66 cycles), unexplained infertility (114 cycles), endometriosis (13 cycles) and other indications (8 cycles). Main outcome measures included number of mature follicles >16 mm in diameter, dose of FSH used per cycle, clinical pregnancy rate and cost-effectiveness ratio per pregnancy. RESULTS: FSH dose required for ovarian stimulation was significantly lower when letrozole was used (P < 0.0001). Although a significantly higher number of follicles >16 mm and endometrial thickness at the day of hCG administration (P < 0.0001) were observed in Group II, pregnancy rate per started (14.4 versus 15.9%) and per completed cycles (15.77 versus 18.07%) was the same in Group I and Group II, respectively. IUI cancellation rate was significantly lower with letrozole treatment (P = 0.05%). The cost per cycle was significantly lower in Group I versus Group II (Can$468.93 ± 418.18 versus 1067.28 ± 921.43; P < 0.0001). The cost-effectiveness ratio was $3249.42 in the letrozole group and $6712.00 in the FSH-only group. CONCLUSION: A letrozole-FSH combination could be an effective ovarian stimulation protocol in IUI cycles. Such a protocol may be more cost-effective than FSH alone because of the difference of FSH dose and cost. A randomized controlled trial is needed to further substantiate this finding.
Key words: aromatase inhibitors/cost-effectiveness/intrauterine insemination/letrozole/ovarian stimulation
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Introduction |
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The number of US women using fertility services was estimated to be
9.3 million with 1.6 million women with ovulatory dysfunction. The US market for assisted reproduction technologies (ARTs) was estimated to be in the range of $6.5 billion in 2004 with an expected average annual growth rate of 8.6% to 2009 (http://www.cdc.gov/nchs/fastats/fertile.htm). Clomiphene citrate has become the standard front-line treatment for ovulation induction for many decades. Many women are non-responsive to clomiphene and require additional treatment using urinary or recombinant gonadotrophins. These treatments can cost thousands of dollars per cycle. Recently, aromatase inhibitors (letrozole and anastrozole) have been tested successfully as ovulation-inducing agents with an average cost of <$100 per cycle (Mitwally and Casper, 2001
). In many of these cases, a low-cost adjuvant like an aromatase inhibitor could reduce the gonadotrophin dose needed, thus eliminating the need for costly high doses of gonadotrophins.
About 25% of infertile couples are classified as unexplained infertility where no definite cause will be found after full investigations. In another 25% of patients, infertility is due to anovulation, secondary to polycystic ovary syndrome (PCOS) in most of the patients (Hull et al., 1985; Snick et al., 1997). In the management of both unexplained infertility and chronic anovulation, ovarian stimulation is used either alone or in conjunction with ARTs such as intrauterine insemination (IUI) or IVF-embryo transfer (Guzick et al., 1999).
On evaluating the effectiveness of IUI, pregnancy rates were significantly higher in women who received gonadotrophins, compared with those who did not undergo ovarian stimulation (Hughes, 1997) before IUI with a pregnancy rates per cycle varying from 8 to 22% (Cohlen et al., 1998; Guzick et al., 1998). Reducing the dose of gonadotrophins without compromising the pregnancy rate would definitely reduce the overall costs and possibly improve the cost-effectiveness of IUI treatment. Stimulating endogenous gonadotrophins production with the concomitant use of lower doses of exogenous FSH for controlled ovarian stimulation (COS) has been extensively used with clomiphene citrate (Dickey et al., 1993). However, the reduction in FSH dose in this scenario was associated with lower pregnancy rates, possibly because of the anti-estrogenic effects of clomiphene citrate particularly at the level of the endometrium (Gonen and Casper, 1990) and cervix, (Gelety and Buyalos, 1993) as well as other possible targets (Hsu et al., 1995). We have shown earlier in a cohort study that the use of a letrozole-FSH combination can reduce the dose of FSH needed to achieve optimum ovarian stimulation in women undergoing IUI without compromising the pregnancy rate compared with FSH alone (Mitwally and Casper, 2004). In this study, we investigated the cost-effectiveness of such a combination versus FSH alone in patients undergoing IUI.
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Materials and methods |
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Each patient provided informed consent before enrolment into the study. The study was conducted in a private practice, Toronto Center for Advanced Reproductive Technology, affiliated with the Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Toronto, Canada. Patients were enrolled in the study from January 2003 to December 2005.
Patients’ recruitment
Patients with various infertility diagnoses (ovarian factor, male factor, unexplained and endometriosis related) presenting for ovarian stimulation and IUI were counselled for COS using the aromatase inhibitor, letrozole, in conjunction with FSH. Patients were fully informed regarding the rationale, mechanism of action and the experimental nature of letrozole. The off-label nature of this indication of aromatase inhibitors was thoroughly explained.
Participants who agreed received letrozole at a dose of 2.5–5 mg daily from cycle day 3 to 7, in conjunction with FSH injections started on day 7 of their stimulation cycle (Group I). The use of letrozole was solely based on the patient’s decision. Patients who opted not to use letrozole received FSH injections only (Group II). Withdrawal bleeding in amenorrhoeic women with PCOS was induced by administering medroxyprogesterone acetate 10-mg tablets daily for 10 days. The two study groups were comparable regarding their baseline parameters. All the study population had been trying to conceive for at least 1 year.
Four hundred and thirty-two consecutive patients who underwent 872 IUI cycles were included in this study. Group I included 308 patients who started 589 treatment cycles. The distribution of patients in Group I according to the diagnosis was as follows: ovarian factor infertility (n = 74), male factor infertility (n = 75), unexplained infertility (n = 130), endometriosis-associated infertility (n = 9) and for other indications (n = 20) who underwent 143, 147, 250, 18 and 31 treatment cycles, respectively. Group II included 124 patients who started 283 treatment cycles. The distribution of patients in Group II according to the diagnosis was as follows: ovarian factor infertility (n = 36), male factor infertility (n = 29), unexplained infertility (n = 47), endometriosis-associated infertility (n = 6) and for other indications (n = 4) who underwent 82, 66, 114, 13 and 8 treatment cycles, respectively. Diagnosis of PCOS was based on the National Institutes of Health (NIH) consensus criteria (Zawadzki and Dunaif, 1992). Unexplained infertility was based on the exclusion of known factors of infertility. Ovulation was documented with follicular monitoring by transvaginal ultrasonography (TVS) and serial measurements of serum estradiol (E2) and LH levels during a natural cycle and/or midluteal progesterone >15 nM associated with regular menstrual cycles. Tubal patency was confirmed by sonohysterography with Echovist (Scherring Health Care Ltd, Burgess Hills, Sussex, UK) contrast, hysterosalpingography and or pelvic laparoscopy. Male factor infertility was diagnosed according to the World Health Organization (WHO) criteria of normal semen. Endometriosis was diagnosed by pelvic laparoscopy.
COS
The choice of the stimulation protocol and the dose of medications were 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, USA) was given at a dose of 2.5–5 mg/day from day 3 to 7 of the menstrual cycle, followed by FSH injection starting at 50–150 IU/day beginning on day 7 until the day of hCG administration. The dose of FSH was adjusted according to the patient’s response to achieve two to three mature follicles (>16 mm) on the day of hCG administration.
In Group II, FSH injections were started on day 3 of the menstrual cycle beginning with a dose 50–150 IU/day. The FSH dose was then adjusted according to the patient’s response with the aim of obtaining two to three mature follicles (>16 mm) on the day of hCG administration. All patients received recombinant FSH (rFSH) (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 
16 mm.
Cycle monitoring and insemination
Follicular and endometrial dynamics were monitored by TVS. Serial hormonal assays of E2 and LH levels every 1 to 3 days during the follicular phase were performed as described by many others. The dose and duration of FSH treatment were adjusted during the monitoring of the follicular development according to the patient’s response, including the number of the growing follicles and E2 levels. IUI was performed 40 h after hCG administration if no endogenous LH surge occurred. If an endogenous LH surge was detected on the day of hCG administration, IUI was performed on the following 2 days. An LH surge was defined as an increase in LH level >100% over the mean of the preceding 2 days. The same three infertility specialists performed the IUI in all patients. Pregnancy was diagnosed by quantitative 
hCG assay, 2 weeks after the insemination. Clinical pregnancy was confirmed by observing fetal cardiac pulsation 4 weeks after positive pregnancy test by TVS.
End-points
Main outcome measures were number of follicles 16 mm, number of FSH IUs/cycle, clinical pregnancy rates, costs per cycle and cost-effectiveness ratio. Single and multiple pregnancies, spontaneous abortions, cases of ovarian hyperstimulation syndrome (OHSS) and cancelled cycles were all counted. All end-points underwent statistical comparison. A clinical pregnancy was determined by the visualization of an embryo with cardiac activity at 6–7 weeks of pregnancy. Spontaneous abortion was classified as the loss of the pregnancy before the 12th week of gestation.
Cost analysis
We determined the average cost of a single unit of rFSH to be Can$1.00 during the study according to the Canadian Formulary, 2005 Edition. The cost per cycle was calculated by multiplying the cost of a single IU with the mean number of FSH IU used per cycle. The cost of a single letrozole tablet was calculated to be $6.00 CDN. The cost-effectiveness ratio was calculated multiplying the cost per cycle by the total number of cycles performed in each group then dividing the result for the number of clinical pregnancies obtained in the group during the trial.
Statistical analysis
The various outcome measures are 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 (GEE) and on continuous variables using repeated measures mixed models. Groups were compared on rates of outcomes using events/trials logistic regression using GEE.
Normally distributed continuous variables were compared with the independent sample test. We used the non-parametric Mann–Whitney U-test to analyse 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, USA).
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Patient demographics and completed/cancelled cycles
Both groups were comparable regarding their baseline characteristics (Table I). The number of started, completed and cancelled IUI cycles according to the infertility diagnosis and ovarian stimulation protocol are displayed in Table II. Overall, there were significantly fewer cancelled cycles with letrozole treatment compared with FSH-only treatment (8.5 versus 12.1%; P = 0.05). The difference was also statistically significant among patients with ovarian factor and male factor infertility (P = 0.05; Table II).
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The major cause of IUI cancellations in both groups was inadequate response or failure to achieve one follicle
16 mm. We found that 37 of 50 (74%) IUI cancellations in Group I and 17 of 34 (50%) in Group II to be due to poor response (Table III). On the contrary, over response that led to the presence of too many mature follicles (>6 follicles 16 mm) was the second most frequent cause of cancellation in the FSH-only group (23.5%) but not in the letrozole and FSH group where only 3 of 50 (6%) cancellations were due to conversion to IVF (Table III). On-demand cancellation was requested by 16% (8/50) and 20.6% (7/34) of patients in both groups, respectively. Some of the cancelled IUI cycles were replaced with timed intercourse (16 cycles in the co-treatment group and 10 cycles in the FSH-only group). No pregnancies were achieved in any of these converted cycles. In patients with an excessive response, IUI was converted to IVF (three cycles in the co-treatment group and eight cycles in the FSH-only group). No pregnancy was achieved in the three converted cycles in Group I, whereas only one pregnancy was achieved in the eight converted cycles in Group II. There were other reasons for IUI cancellation in a few cycles, including anovulation in some women with PCOS, presence of ovarian cysts and failure to obtain a semen sample adequate for insemination. Table III details the various reasons for IUI cancellations according to the infertility diagnosis and treatment group.
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Cycle characteristics
Baseline levels of FSH, LH, E2 and progesterone were comparable between the two study groups (Table IV). However, total E2 levels at the day of HCG administration were significantly higher in the FSH-only group (P < 0.0001). Similarly, the FSH group had a significantly higher number of mature follicles >16 mm at the day of HCG administration. Although the endometrial thickness at the day of HCG administration was significantly greater in the FSH-only group compared with that of the letrozole and FSH group, it was above 0.8 cm in both groups, which is above the threshold needed to define normal endometrial thickness necessary for insemination.
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Pregnancy rate and cost-effectiveness analysis
Pregnancy rate was similar in letrozole plus FSH and FSH-only cycles per started IUI cycle (14.4 versus 15.9%) and per cycle completed (15.77 versus 18.07%). The cumulative pregnancy rate in both groups was 27.6 and 36.3%, respectively (Table V). The difference was not significantly different. The underlying cause of infertility did not influence the treatment outcome. On stratifying patients in both groups according to the diagnosis, the same relationship was maintained (Table VI). Both groups had comparable miscarriage and multiple pregnancy rates (Table V). However, the total dose of FSH used was significantly higher in the FSH-only group (P < 0.0001; Table V). The overall cost of medications per cycle started was significantly higher in the FSH-only group. Similarly, the mean cost per pregnant cycle was also significantly higher in the FSH-only group. The same relationship was maintained in cycles where pregnancy was not achieved and in cancelled cycles with the same level of significance (P = 0.0001). The cost-effectiveness ratio was $3249.42 in the letrozole group and $6712.00 in the FSH-only group. Consequently, the overall cost to achieve a single pregnancy in the letrozole-FSH group was almost one-half that of the FSH-only group with a cost saving of up to $3500. So far, 31 and 22 babies were delivered in Groups I and II, respectively. The birthweight was comparable between the two groups (Table V). One child was delivered with an extra finger on the right hand and extra toe on the right foot in the letrozole group. Otherwise no congenital anomalies were detected in either group.
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Discussion |
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During the past 5 years, the introduction of the aromatase inhibitor, letrozole, has added another option for the stimulation of follicle development in infertile women (Mitwally and Casper, 2001
). An aromatase inhibitor in combination with gonadotrophins has proved to be a safe and efficient preparation in ovarian stimulation with reduction of the total FSH dose used (Mitwally and Casper, 2004). However, reducing the dose of the gonadotrophins via the addition of aromatase inhibitors does not necessarily mean achieving better results in terms of efficacy. The higher medical costs of the gonadotrophins particularly the recombinant products motivated us to conduct this study and explore the efficacy and relative cost-effectiveness of alternative treatments in IUI cycles. To the best of our knowledge, there are no cost-effectiveness models available to reveal whether letrozole co-treatment in patients undergoing COS with rFSH preparation was associated with a better pregnancy rate and with lower costs in IUI cycles.
After failure of expectant management, the next-line treatment in young patients with a short duration of infertility and no severe male factor infertility or tubal factor is IUI. The efficacy of different treatment options in patients undergoing ART has been examined previously. Although IVF tended to be more effective on a per-cycle basis than IUI, the latter had a higher cumulative pregnancy rate at the end of the programmed treatment cycles in patients with idiopathic subfertility and male subfertility. This difference was mainly because of the lower drop-out rate (Goverde et al., 2000). Moreover, a meta-analysis showed that ovarian stimulation with gonadotrophins in IUI cycles has a better probability of conception than IUI alone (Hughes, 1997).
The present study analysed the clinical results and cost-effectiveness of letrozole and FSH versus FSH alone used in IUI cycles. The pregnancy rates were similar in the two groups of patients, and therefore, we decided to analyse the cost/benefit ratio for each treatment. This study could be criticized because it was not a prospective randomized controlled trial. We did not randomize our patients as the aromatase inhibitor was offered in an experimental setting and was not recommended by the manufacturer as an ovulation-inducing agent. This study was conducted as a pilot study so as to investigate the possible beneficial cost-effectiveness of letrozole in individuals undergoing IUI. It was executed using a pragmatic design and comparing the results of the experimental letrozole group to a control group of individuals who willingly decided not to be included in the letrozole group. For the purpose of this study, we feel it would not be beneficial to ascertain the costs undertaken by patients who underwent other treatment modalities other than IUI because it would be both retrospective at this point and may provide bias because we do not know the exact reasons for further treatment in the different patients.
The number of mature follicles and the cancellation rate are known as markers of drug bioactivity. Although the number of mature follicles in this study was higher in the FSH-only group, the pregnancy rate was comparable. On contrary, cancellation rate is an expression of an excessive or a poor response and was significantly lower when the letrozole-FSH combination was used. This suggests that the pharmacological stimulation of the ovaries was similar in both study groups. There were no differences in the efficiency of the treatments, as there were similar clinical pregnancy rates in the two groups.
It has been shown that the economic effectiveness of a drug depends less on its costs but rather on the clinical outcomes associated with its use (Silverberg et al., 2002). Our results are in agreement with this statement as we obtained a comparable pregnancy rate using the letrozole-FSH combination at a much lower cost compared with the pregnancy rate achieved in the FSH-only group. In this study, we demonstrated that the cost per cycle and the cost per pregnancy were 120 and 106%, respectively, higher when the recombinant products were used alone. The results of this study, therefore, demonstrated an improved cost-benefit ratio for the letrozole-FSH combination protocol for ovulation induction in IUI cycles. The main limitations of this study are i) its non-randomized nature and ii) the cost was calculated based on a single IU of FSH. However, with the different commercial preparations, usually some of the IUs remain without use.
Recently, a concern about the safety of letrozole to the fetus was raised in an abstract presentation at the 2005 American Society for Reproductive Medicine (ASRM) meeting (Biljan et al., 2005). The authors reported the outcome of 170 infants of which 20 were lost to follow-up. As a result, 150 babies from 130 pregnancies were compared with a control group of over 36 000 infants born from low-risk pregnant women in a community hospital. The control population was younger [mean age (SD) 30.5 ± 1.2 years] than the letrozole group (35.2 ± 4.7 years). The authors reported that the incidence of cardiac and ‘bone’ anomalies were higher in the letrozole group than in the control group. The cardiac anomalies comprised of two cases of aortic stenosis in the 150 babies, which the authors calculated to be statistically higher than the rate of cardiac anomalies in the 36 000 babies born from low-risk pregnancies. Similarly, there were three different bone abnormalities in the letrozole babies resulting in an apparent relative risk. We believe both these differences are solely related to type I error.
On the basis of that study, Tulandi et al. (in press) evaluated the incidence and type of congenital malformation among offspring of mothers who conceived with letrozole compared with a control group of infertile women conceiving with clomiphene citrate. They studied 911 newborns from women who conceived following clomiphene or letrozole treatment at five fertility centres in Montreal, Quebec and London and Toronto, Ontario. They used the WHO definition of congenital malformation, deformations and chromosomal abnormalities. Congenital malformations and chromosomal abnormalities were found in 14 of 514 newborns in the letrozole group (2.4%) and in 19 of 397 newborns in the clomiphene citrate group (4.8%). The major malformation rate in the letrozole group was 1.2% (6/514) and in the clomiphene citrate group was 3.0% (12/397). One newborn in the letrozole group was found to have a ventricular septal defect (0.2%) compared with four newborns in the clomiphene citrate group (1.0%). In addition, the rate of all congenital cardiac anomalies was significantly higher (P = 0.02) in the clomiphene citrate group (1.8%) compared with the letrozole group (0.2%). The authors concluded that there was no difference in the overall rates of major and minor congenital malformations among newborns from mothers who conceived after letrozole or clomiphene treatments. However, it appears that congenital cardiac anomaly is less frequent in the letrozole group. The concern that letrozole use for ovulation induction could be teratogenic is unfounded based on the data (Tulandi et al., in press). We believe that further data collection regarding pregnancy outcome is warranted for both letrozole and clomiphene citrate.
In conclusion, we believe that aromatase inhibitor co-treatment with FSH could be cost-effective for IUI. When compared with FSH alone for COS and IUI, the cost-effectiveness ratio was less than half for the letrozole-FSH combination. These data suggest that treatment with an aromatase inhibitor followed sequentially by FSH injections may be effective in mild ovarian stimulation protocols for ART like IUI. Before firm conclusions regarding the cost-effectiveness of co-treatment with aromatase inhibitors can be drawn, a properly designed randomized controlled trial is mandatory. Further research is also needed to demonstrate whether aromatase inhibitors are superior to clomiphene citrate for this indication. In addition, pregnancy outcome from clomiphene citrate and aromatase inhibitor cycles needs to be carefully followed to establish safety profiles for both drugs.
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Footnotes |
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Presented in part at the 61th annual meeting of the American Society for Reproductive Medicine and the Canadian Andrology and Fertility Society, October 15–20, 2005, Montreal, Canada.
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Submitted on February 7, 2006; resubmitted on April 16, 2006; resubmitted on May 24, 2006; resubmitted on June 5, 2006; accepted on June 13, 2006.
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