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Background: Polycystic ovary syndrome (PCOS) is associated with approximately 75% of women who suffer from infertility due to anovulation. Additionally, around 20- 25% of an ovulatory women with PCOS do not respond at all to clomiphene citrate and are considered to be 'clomiphene- resistant'. Aromatase inhibitors have been suggested as an alternative treatment to clomiphene as the discrepancy between ovulation and pregnancy rates with clomiphene citrate has been attributed to its anti-estrogenic action and estrogen receptor depletion.
Objective: The Present study is designed to compare Metformin - letrozole with Metformin - clomiphene citrate in clomiphene resistance PCO patients undergoing IUI.
Materials and Methods: In this single blind randomized trial, ovarian cycles were studied in 100 clomiphene- resistant patients with PCOS.The Inclusion criteria concerned PCOS patients who had failed to become pregnant after receiving 150 mg clomiphene citrate per day in3 months. The Patients were matched for their age, body mass index (BMI), and infertility period. They were randomly allocated to a metformin-letrozole group (n = 50) and a metformin- clomiphene citrate group (n = 50). Chemical and clinical pregnancies were assessed after IUI. Abortion rates were determined in both groups.
Results: Regarding pregnancy rate, there is no significant difference between the two groups. One miscarriage (2%) occurred in the metformin-clomiphene citrate group, whereas none was seen in the metformin- letrozole group.
Conclusion: There is no significant difference in pregnancy rate between clomiphene citrate and letrozole groups although it has been 2% in the former and 5% in the latter.
Keywords: Letrozole, Clomiphene Citrate, Ovarian stimulation, PCO, IUI, Metformin.
Polycystic ovary syndrome (PCOS) is associated with approximately 75% of women who suffer from infertility due to anovulation (1,2). The introduction of small amounts of FSH indirectly with clomiphene citrate
into the circulation is capable of inducing ovulation and pregnancy in a large number of anovulatory women with PCOS. (3). Ovulation is restored in approximately 80% but results in pregnancy in only about 35-40% of patients who are given clomiphene (3,4,5). Additionally, around 20- 25% of anovulatory women with PCOS do not respond at all to clomiphene citrate and are considered to be 'clomiphene resistant' (6,7). Patients who do not respond to clomiphene are likely to be more obese, insulin- resistant, and hyperandrogenic than those who do respond (7).
Numerous studies in women who were treated with Clomiphene Citrate and in various model systems have reported adverse effects on the quality or quantity of cervical mucus, endometrial growth, and maturation (8,9,10,11,12,13). It is generally believed that these effects are most apparent at higher doses or after longer durations of treatment with Clomiphene Citrate (9,10,11).
The endometrium is believed to be one of the most important targets of the antiestrogenic effect of Clomiphene Citrate and may explain a large part of the lower pregnancy rate and the possible higher miscarriage rate with Clomiphene Citrate. A reduction in endometrial thickness below the level thought to be needed to sustain implantation was found in up to 30% of women receiving Clomiphene Citrate (10). This observation has been confirmed by other studies such as Nelson et al, 1990 and Li et al, 1992. (12,13).
Aromatase inhibitors have been suggested as an alternative treatment to clomiphene as the discrepancy between ovulation and pregnancy rates with clomiphene citrate has been attributed to its anti-estrogenic action and estrogen receptor depletion. The aromatase inhibitors do not possess the adverse anti-estrogenic effects of clomiphene but, by suppressing estrogen production, mimic the central reduction of negative feedback through which clomiphene works.
Letrozole, the most prevalently used antiaromatase for this indication, has been shown to be effective, in early trials, in inducing ovulation and pregnancy in women with anovulatory PCOS and inadequate clomiphene response (14) and improving ovarian response to FSH in poor responders (15). Evidence from larger trials is still awaited, but some encouragement may be taken from the solidity of the working hypothesis and the success of the preliminary results. The Present study is designed to compare Metformin - letrozole with Metformin - clomiphene citrate in clomiphene resistance PCO patients undergoing IUI.
Material and methods
In this single blind randomized trial, 148 ovarian cycles were studied in 100 clomiphene- resistance patients with PCOS who were chosen among 250 PCOS patients attending the infertility research center of Shahid Sadoughi medical university in Yazd, Iran during the years 2007-2008 .The Study was approved by Yazd Medical University Ethical Board and was fully supported and funded by Yazd Medical University.
In this study, 50 people are needed in each group so as to gain a significant difference of 22% in pregnancy rate at a significant level of 5% and a power 80%. Randomization is conducted on the basis of random numbers table right after metformin administration. The major criteria for diagnosis of PCOS were oligo and /or anovulation, clinical or biochemical signs of hyperandrogenism, and polycystic ovaries, namely 10 or more follicles with 2 - 9 mm size) which are in accordance with the revised 2003 Rotterdom criteria of PCOS. Thyroid, liver, kidneys function, and prolactin level were checked for normal values. Samples without any of them were excluded from the study. Data were collected from the samples via questionnaires along with conversation and physical examination done by a medical researcher. Hysterosalpingo graphy and sperm analysis of our samples were normal.
Inclusion criteria covered PCOS patients who had failed to become pregnant after receiving 150 mg clomiphene citrate per day in 3 months that considered as clomiphene failure. In this study, however , the selected cases took the drug in just one treatment cycle Exclusion criteria concerned patients with a history of liver and kidney failure, cardiovascular disease, diabetes (based on the criteria set by the American Diabetic Association), or patients who had taken metformin or drugs affecting insulin secretion or clomiphene citrate in the previous 2 months.
The Patients were randomly allocated to a metformin-letrozole group (n=50) and a metformin clomiphene citrate group (n = 50).
All the patients of both groups received 1500 mg/day metformin for 6-8 weeks. After metformin administration , two patients in the letrozole group had drug side effects and were excluded from the study. If pregnancy occurred, the patient was excluded from the study. In case of pregnancy failure after the end of this period, the patients in the metformin- clomiphene group were given 100 mg clomiphene citrate for 5 days starting from the third day of their menstrual cycle, and those in the metformin-letrozole group received 5 mg letrozole for 5 days from the third day of their menstrual cycle. The drug administration continued in three cycles for all the included patients. Monitoring of follicular development was done by transvaginal sonography every other day from day 12 of the cycle by a single sonographist. A total of 10 000 IU of HCG was administered to those in whom at least one ovarian follicle was ≥18 mm in size. Endometrial thickness, number of mature follicles >18mm, estradiol level, and the ratio of chemical and clinical pregnancies were determined.
Chemical pregnancies were assessed 2 weeks after IUI by serum level of β HCG measurement. Existence of at least one gestational sac in ultrasonography was confirmed as a clinical pregnancy. Ongoing pregnancy was defined as the observation of at least one fetus with heart activity in sonography after the first trimester of pregnancy. Abortion rates were determined in both groups.
The sample is divided into two groups using the random allocation software. SPSS version 12.0 software was used for the statistical analysis. T-test, chi-square and Fisher exact tests were used when appropriate. P-values less than 0.05 were considered as statistically significant.
On the whole, 148 ovarian cycles were studied in 98 patients (70 cycles in 48 patients in the metformin - letrozole group and 78 cycles in 50 patients in the metformin - clomiphene citrate group).
Ninty eight PCO patients who were allocated to the two groups were included in the study. All the patients had at least 2 out of 3 Rotterdom criteria. No significant statistical difference was observed between the two groups with respect to the mean of demographic variables, including age, BMI, duration of infertility.
The total Mean estradiol on the day of HCG administration was significantly higher among the patients in the metformin- clomiphene group as compared with those in the metformin-letrozole group (175.01 ± 168.93 Vs 70.24 ± 138.32 pg /ml; P < 0.05) (Table I). Mean endometrial thickness was also significantly lower in the metformin- clomiphene group as compared to those in the metformin-letrozole group (0.9 ± 9.3 cm versus 1.03 ± 10.2 cm; P < 0.05) (Table I).
One miscarriage (2%) occurred in the metformin-clomiphene citrate group, whereas none were seen in the metformin- letrozole group. The clinical pregnancy rate was not significantly different between the two groups (4 patients (8.3%) in metformin-letrozole group as compared to 1 patient (2%) in metformin- clomiphene group; P > 0.05) (Table II). The rate of pregnancy in the cycles was 1% (1of 78 cycles) in the clomiphene-citrate group but 5% (4 of 70 cycles) in the letrozole group, which was not statistically significant.
Table I. Comparison of baseline parameters and different variables in the metformin-clomiphene citrate group and the metformin-letrozole group based on mean ± SD
Metformin clomiphene group
Metformin letrozole group
29.55 ± 3.47
28.54 ± 3.13
29.21 ± 2.92
28.98 ± 3.83
Endometrial thickness on day of hcg administration (mm)*
9.3 ± 0.9
10.2 ± 1.03
Duration of infertility
LevelE2Mean total (pg/ml) on day of HCG administration
168.93 ± 175.01
138.32 ± 70.24
Number of follicles > 18 mm in diameter
1.85 ± 0.27
1.80 ± 0.32
P-value: No difference was found between the two groups for the above parameters (by t-Test as appropriate).
Table II. Comparison of Pregnancy and miscarriage rate in the metformin-clomiphene citrate group and the metformin-letrozole group based on mean ± SD
Metformin clomiphene group
Metformin letrozole group
0.95 CI (0.5-34.5)
Regular menses after metformin
36 (72 %)
Chemical pregnancy rate
Clinical pregnancy rate
Intension to treat Analysis
P-value*: No difference was found between the two groups for the above parameters (by exact t-Test as appropriate).
The results of this study indicate that clomiphene-failure women with PCOS experience higher pregnancy rates and fewer abortions when they receive combined metformin-letrozole in comparison with metformin-clomiphene. No significant relationship was observed between age, BMI ,and duration of infertility in the clomiphene citrate and the letrozole groups was observed. Mean of endometrial thickness on the day of HCG administration was significantly less in patients that received clomiphene citrate than those who received letrozole. (Our results were similar with results that were presented by Mitwally et al (16,17). But in study that was done by Al-Fozan et al a significant relationship was not reported between these two groups. Fisher et al in their study believed that the cause of endometrial thickening in patients receiving letrozole is because of improved vascularization as compared with clomiphene citrate (18). Some studies showed that clomiphene citrate can cause inadequate endometrial thickness in 15-50% of patients (19) and the quality or quantity of the cervical and endometrial mucosa can affect(14). These side effects may be attributed to the anti-estrogenic effect and the relatively longer half-life of clomiphene citrate, thus decreasing endometrial thickness by its long-term effect in decreasing the number of estrogen receptors (14).
One miscarriage was happened in the metformin-clomiphene-citrate group whereas none were seen in the metformin- letrozol group. The clinical pregnancy rate between the two groups did not show significant difference. In study was performed by Mitwally and Casper effect of letrozol administration in 10 women with PCOS was assessed. They found that pregnancy occurred in 20% of women (14). Sammour et al in their study on efficacy of letrozole and clomiphen citrate in 49 women with idiopathic infertility showed that pregnancy rate was higher in patients receiving letrozole than clomiphene citrate group (16.7 versus 5.6%) (20). According to results of those studies; pregnancy rate is higher in patients receiving letrozole than clomiphene citrate group but is lower when compared with the current study. Moll et al in their study showed that in clomiphene citrate-resistant women, the combination of clomiphene plus metformin was the preferred treatment. Some studies reported that rate of miscarriage was higher than expected in clomiphene group. (In this study), There is one case of abortion in clomiphene group. This increase may be due to changes in peripheral estrogen level in the cervical and endometrial mucosa. Some evidence exists that assess the hazardous effects of clomiphene citrate accumulation during pregnancy and the initial stages of development in mouse and rabbit but has not been proved (21). We Hypothesize that clomiphene may have direct adverse effects on oocytes. Some studies reported that inadequate uterine blood flow during the early luteal phase was one of the probable causes of low pregnancy rate in patients who received clomiphen citrate. (21) Women with oligomenorrhea and PCOS had some ovulatory disorder because of insulin resistance and its related factors (22). Serum insulin level was main role in PCOS pathogenesis. Metformin can increase tissue sensitivity to insulin as well as decrease plasma insulin level and hepatic glucose production. In PCOS, metformin can decrease the level of L.H. and ovarian androgen level as well as correct hyperinsulinemia (23). Some clinical trials presented the effect of metformin on the activity of ovaries (22). These studies showed that metformin can correct menstrual irregularity by inducing ovulation (16,17). According to Nestler study, ovarian response to clomiphen was higher in obese women with PCOS (24).
Aromatase is the enzyme necessary for converting androstenedione to estrone and finally to E2 in peripheral tissues and Aromatase inhibitors can prevent peripheral estrogen production in patients that have higher peripheral estrogen production (25). According to noted mechanism, some of selective aromatase inhibitors such as letrozole are used to induce ovulation especially in infertile women with PCOS (21). They may also have direct action on the ovaries and increase follicular sensitivity to FSH. Women with PCOS may also have relatively low levels of ovarian aromatase. High androgen levels result in the formation of multiple small ovarian follicles. In addition, androgens increase the number of FSH receptors in the ovaries, which results in increasing FSH sensitivity. High exogenous FSH or low estrogen production because of aromatase inhibitors will lead to growth of one or more ovarian follicles (25,26).
Our Results show that letrozole is a suitable alternative to clomiphene citrate, especially in cases, who are (clomiphene failure), or it can be a first-line drug in ovarian stimulation and treatment of anovulation. It seems that letrozole and is a safe, reliable and cheap drug with therapeutic value (16,17). Serum clearance of letrozole is faster than clomiphene citrate (50h versus 4 weeks) and because letrozole does not decrease estrogen receptors, has no deleterious effects similar to that found with clomiphene citrate on the endometrium, and lead to higher pregnancy rates (4,12). Because we didn't have one optimum dosage for therapeutic effects of letrozole, Further studies are necessary for achieving that (16,17).Moreover I.U.I. had no favorable success and because I.U.I. wasnot considered as a therapeutic modality in recent references (Textbook of Assisted Reproductive Technologies, David K Gardner,etal 2009.), it should be better to do I.V.F. or ICSI in patients who donot respond to medical therapy.