Middle East Fertility Society Journal

Copyright Middle East Fertility Society

Vol. 13, No. 3, 2008

Letrozole - metformin versus clomiphene citrate - metformin in induction of ovulation in clomiphene citrate resistant patients with polycystic ovary syndrome (PCOS)
Usama M. F. Fouda, M.D. Adel F. El Bigawy, M.D. Hesham S. Elshaer, M.D. Ashraf A. Eldaly, M.D., M.R.C.O.G. Abdalla Y. Elkateb, M.D.

Department of Obstetrics and Gynecology, Cairo University, Cairo, Egypt

ABSTRACT
Objective: The aim of this study was to compare the effect of combined clomiphene citrate (150 mg) - metformin (1700mg) and combined letrozole (2.5mg) - metformin (1700 mg) on ovulation in clomiphene citrate resistant patients with PCOS. Design: Prospective quasi-randomized trial. Setting: University teaching hospital. Materials and methods: Infertile PCOS patients resistant to clomiphene citrate were randomized into letrozole metformin group (30 patients) and clomiphene citrate metformin group (30 patients). After two months of metformin administration, clomiphene citrate or letrozole was added to metformin on days 3-7 of menses. Main outcome measures: Number of follicles, endometrial thickness. Ovulation and pregnancy rates per cycle. Results: Ovulation occurred in 71.4% of the cycles (40/56) in clomiphene citrate - metformin group and 77.8% of the cycles (42/54) in letrozole - metformin group. The endometrial thickness was significantly higher in letrozole - metformin group; the number of mature follicles was significantly lower in the letrozole - metformin group. Pregnancy rate per cycle was 10.7% in clomiphene citrate-metformin group and 18.5% in letrozole - metformin group. Conclusion: Combined letrozole metformin is as effective as or even superior to combined clomiphene citrate metformin in ovulation induction in clomiphene citrate resistant patients with PCOS. Unlike clomiphene citrate, letrozole has no adverse effect on the endometrium, causes monoovulation in the majority of stimulation cycles. These advantages make combined letrozole metformin a better alternative than combined clomiphene citrate metformin in ovulation induction in clomiphene citrate resistant patients with PCOS. Key words: letrozole, clomiphene citrate, metformin, polycystic ovary syndrome, clomiphene citrate resistance, ovulation, conception

Polycystic ovary syndrome is the most common endocrinological disorder of women in reproductive age, with an incidence of 4% to 12% (1). The exact cause of polycystic ovary syndrome
Correspondence: Usama Mohamed Fikry Fouda, M.D., Cairo University, Faculty of medicine, Dept. of Obstetrics and Gynecology. E-mail: umfrfouda@yahoo.com.

is still not clear. However the association between the insulin resistance, compensatory hyperinsulinemia and PCOS is now well recognized. Hyperinsulinemia contributes to the two main pathological features of PCOS, which are hyperandrogenism and chronic anovulation. Hyperinsulinemia causes an increase in the ovarian androgen production and a decrease in sex hormone binding globulin synthesis from the liver,

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leading to an increase in bioavailability of free androgens (2). Hyperinsulinemia could adversely affect folliculogenesis and ovulation by increasing ovarian androgen production, altering gonadotropin secretion or directly affecting follicular development (3). For more than 4 decades, clomiphene citrate has been the drug of choice used in treatment of patients with polycystic ovary syndrome (4). Although clomiphene citrate results in ovulation in 70%-80% of patients with polycystic ovary syndrome, only 40% of patients become pregnant. This has been attributed to its peripheral antiestrogenic effect on endometrium and cervical mucous (5). In addition 20%-30% of the patients are resistant to clomiphene citrate and fail to ovulate (6). Patients resistant to clomiphene citrate show greater insulin resistance compared to patients who respond to clomiphene citrate (7). Previous studies confirmed the effectiveness of metformin (insulin sensitizer), alone or in combination with clomiphene citrate, in induction of ovulation and improving biochemical features in clomiphene citrate resistant and nonresistant patients with polycystic ovary syndrome (8 ,9). In 2001, Mitwally and Casper introduced the use of letrozole (aromataze inhibitor) in anovulatory women resistant to clomiphene citrate (10). Subsequent studies confirmed the benefits of letrozole in clomiphene citrate resistant patients with PCOS, as an alternative to clomiphene citrate in patients with polycystic ovary syndrome, in patients with unexplained infertility and in addition with FSH to improve the ovarian response in poor responders (11). Although Sohrabvand et al compared the efficacy of combined letrozole metformin with that of combined clomiphene citrate metformin in PCOS patients who previously failed to become pregnant after three courses of 150 mg clomiphene citrate (12). However, no studies have yet compared their efficacy in clomiphene citrate resistant patients with PCOS. The aim of this prospective randomized study is to determine whether combined letrozole metformin can be used as an alternative to clomiphene citrate -metformin in clomiphene citrate resistant infertile women with PCOS.

MATERIALS AND METHODS This prospective randomized trial was performed in Cairo university hospitals, Cairo, Egypt. Sixty consecutive clomiphene citrate resistant patients with polycystic ovary syndrome were included in the study. Patients were diagnosed as having PCOS according to the Rotterdam revised criteria for polycystic ovary syndrome (13). Clomiphene citrate resistance was defined as failure to ovulate after clomiphene citrate treatment up to a daily dose of 150 mg from day 3 to 7 for at least four consecutive cycles. Our inclusion criteria were, age (18-35) years, period of infertility > 1 year, day 3 serum level of FSH < 12 IU/L. Exclusion criteria were edocrinological disorders as hypothyroidism, hyperprolactinemia, Cushing's syndrome, non classical congenital adrenal hyperplasia as detected by history, examination, or investigations. Other exclusion criteria were diabetes mellitus, liver, kidney, cardiovascular diseases or infertility factors other than anovulation, and recent use (within the last four months) of hormonal drugs or drugs which affect carbohydrate metabolism. Male factor of infertility and tubal factors of infertility were excluded by semen analysis, hysterosalpingography and /or laparoscopy respectively. Women in both groups were instructed to avoid any restrictive diet or any change in their physical activity during the study period. All the women included in this study were non smokers and non alcohol beverages drinkers. The study protocol was approved by the hospital research ethics board. Study participants were counseled, and informed consent was taken before randomization. Patients were divided into two groups, letrozole - metformin group (group I) (n = 30) or clomiphene citrate - metformin group (group II) (n = 30), a quasi-randomization method was used. Based on the attendance order, patients with odd numbers were prescribed letrozole metformin and those with even numbers were given clomiphene citrate - metformin. Neither the patients nor the doctors were blinded in any of the groups. Patients of both groups received metformin 1700 mg (Cidophage retard; CID, Giza, Egypt) a day (850 mg twice daily) for two months. If pregnancy occurred, the patient was excluded from the study. If pregnancy did not occur during this

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Table 1. Demographic and hormonal data of PCOS patients treated with letrozole metformin or clomiphene citrate metformin (Group 1) letrozole - metformin (29 patients, 54 cycles) Age (years) Mean infertility period (years) Body mass index(kg/m2) Basal hormones on day 3 FSH(mIU/ml) LH(mIU/ml) Prolactin (ng/ml) Total testosterone (ng/dl) 25.62 3.289 2.97 1.085 27.86 2.961 5.45 1.64 10.93 1.92 10.48 4.25 87.93 26.41 (Group II) Clomiphene citrate -metformin (30patients, 56cycles) 26.77 3.093 3.03 1.159 28.30 2.756 5.77 1.83 11.37 2.31 11.70 3.24 94.37 29.31 P value 0.173 0.818 0.559 0.48 0.43 0.22 0.38

Variables are given as mean SD FSH=Follicle stimulating hormone, LH = luteinizing hormone

period. In group I, Letrozole (Femara; Novartis pharma AG, Basle, Switzerland) at the dose of 2.5mg on days 3-7 of menses was added to metformin. In group II, Clomiphene citrate (Clomid; Aventis pharma S.AE, Global Napi pharmaceuticals, Cairo, Egypt) at dose of 150 mg/day on days 3-7 of menses was added to metformin. Transvaginal ultrasound (Seimens, sonoline, prima) was performed on day 3 of the menstrual cycle before starting treatment; follicular development was monitored using transvaginal ultrasound from day 10 of the cycle. Human chorionic gonadotropin (Pregnyl; N.V. Organon, Oss, Holland) at dose of 10.000 IU was used to trigger ovulation when at least one follicle exceeding 18mm was noted. The patients were advised to have sexual intercourse 24 - 36 hours after HCG administration. Two days after HCG administration, transvaginal ultrasound was done to asses the signs of the release of egg (disappearance of the preovulatory follicle and the presence of fluid in the cul-de-sac).Serum progesterone was measured on cycle day 21 or one week after HCG administration and a concentration of 5 ng /ml was considered as confirmatory of ovulation. Endometrial thickness was assessed according to the method described by Goren and Casper (14), the endometrial thickness was measured at the greatest diameter perpendicular to the midsagittal plane in the fundal region, including both layers of the endometrial cavity, the image was oriented so that the endometrial canal and the cervical canal were visualized in the same plane to ensure measurement through the center of the endometrium.

Pregnancy was diagnosed by Bsubunit HCG performed 2 weeks from timed intercourse, and ultrasound was performed 2 - 4 weeks after a positive pregnancy test to confirm clinical pregnancy. Statistical methods Data were statistically described in terms of mean standard deviation ( SD), frequencies (number of cases) and relative frequencies (percentages) when appropriate. Comparison of quantitative variables between the study groups was done using Student t test for independent samples in comparing 2 groups when normally distributed and Mann Whitney U test for independent samples when not normally distributed. For comparing categorical data, Chi square (2) test was performed. Yates correction equation was used in stead when the expected frequency is less than 5. A probability value (p value) less than 0.05 was considered statistically significant. All statistical calculations were done using computer programs Microsoft Excel version 7 (Microsoft Corporation, NY, USA) and SPSS (Statistical Package for the Social Science; SPSS Inc., Chicago, IL, USA) statistical program for Microsoft Windows.

RESULTS One patient in letrozole - metformin group became pregnant after administration of metformin, and was excluded from the study. No difference in age, body mass index, mean infertility

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Table 2. Results of induction of ovulation in both groups (Group 1) Letrozole-metformin (29 patients)(54 cycles) Endometrial thickness(mm) Ovulation rate per cycle Number of follicles more than 18mm on the day of HCG administration Pregnancy rate per cycle 9.44 1.17 (42/54)(77.8%) 1.21 0.41 (10/54)(18.5%) (Group II) Clomiphene citrate --metformin (30patients)(56cycles) 6.57 1.33 (40/56)(71.4%) 1.6 0.59 (6/56)(10.7 %) P value <0.001 0.293 0.001 0.187

Pregnancy rate per cycle and ovulation rate per cycle are expressed as N (%), all other values are given as mean SD HCG : human chorionic gonadotropin

infertility period or any biochemical assay was observed between the two groups (Table 1). Ovulation occurred in 71.4 % of the cycles (40 /56) in clomiphene citrate - metformin group and 77.8% of the cycles (42/54) in letrozole - metformin group. The endometrial thickness was significantly higher in letrozole - metformin group; the number of mature follicles was significantly lower in the letrozole - metformin group. Pregnancy rate per cycle was 10.7% in the clomiphene citrate metformin and 18.5% in the letrozole - metformin group (Table 2). All the pregnancies in both groups were singleton pregnancies. One case of abortion occurred in each group, ectopic pregnancy did not occur in any group.

DISCUSSION Letrozole is a third generation non steroidal aromataze inhibitor that suppresses estrogen synthesis by blocking the action of the aromataze enzyme which catalyze the rate limiting step in the production of estrogen, that is, the conversion of androstenedione and testosterone via three hydroxylation steps to estrone and estradiol respectively (15). Letrozole administration in the early part of the menstrual cycle will block systemic estrogen (produced by ovaries and by peripheral conversion of androgens in fat) and locally produced estrogen by aromatization of androgens in the brain, this will release the pituitary-hypothalamic axis from estrogenic negative feedback. The resultant increase in gonadotropin secretion will stimulate growth of ovarian follicles. In addition, letrozole acts locally on the ovaries, preventing the

conversion of intraovarian androgens into estrogen, leading to temporary accumulation of androgens, which in turn increases the sensitivity of the ovarian follicles to gonadotropin stimulation by enhancing follicle stimulating hormone receptor gene expression (16). In women with polycystic ovary syndrome, there is an increase in the ovarian androgen production which is converted to estrogen by aromatization in the brain, leading to relative oversuppression of FSH. Letrozole suppresses the estrogen production in both the ovaries and the brain. Therefore, letrozole increases FSH release and stimulates the growth of ovarian follicles. (17). The present study revealed that the endometrial thickness was significantly higher in letrozolemetformin group than in clomiphene citrate metformin group, in addition all cycles in the letrozole-metformin group had endometrial thickness more than 5 mm while in clomiphene citrate-metformin group the endometrial thickness was less than or equal 5 mm in ten cycles. This indicated that clomiphene citrate has adverse effect of on the endometrium and that letrozole has no adverse effect on endometrium. The results of this study agree with results of Mitwally and Casper and Atay et al (10) (18). On the other hand, another study revealed that there was no significant difference in endometrial thickness when letrozole or clomiphene citrate was used for ovulation induction (19). Peripheral antiestrogenic effects of clomiphene citrate are frequently suggested as the possible explanation for the discrepancy between the high ovulation rate and relatively lower pregnancy rate with clomiphene citrate treatment (5). Clomiphene citrate causes long lasting estrogen receptor

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depletion, in addition the long half life of clomiphene citrate isomer (zu-clomiphene) (several days to weeks) leads to its accumulation in the body and persistence of its antiestrogenic effect. As a result clomiphene citrate have a delirious effect on the cervical mucous and the endometrium (20). Compared with natural cycles, endometrial thinning has been observed in 30% of cycles on clomiphene citrate. Gonen and Casper reported no pregnancies occurring in cycles with endometrial thickness < 6mm at midcycle and a significantly higher rate of biochemical pregnancy when the endometrial thickness was 6-8 mm (14).On the other hand, letrozole causes upregulation of the estrogen receptors in the endometrium due to suppression of estrogen concentration in the circulation and the peripheral target tissues in the early part of the menstrual cycle. This will increase the sensitivity of the endometrium to the estrogen resulting in more rapid proliferation of the endometrium as soon as estrogen level rises after cessation of letrozole administration (21). The present study revealed that the number of mature follicles was significantly higher in clomiphene citrate metformin group than in letrozole -metformin group. In contrast to clomiphene citrate, letrozole has short half life (45 hours) and doesn't deplete estrogen receptors, therefore normal negative feedback occurs centrally as the dominant follicle grows and estrogen levels increase. This results in FSH suppression, atresia of smaller follicles and monoovulation in most cases (18). In the present study, monoovulation occurred in 78.5% of the ovulatory cycles of letrozole metformin group. The limited number of stimulated mature follicles decreases the risk of ovarian hyperstimulation syndrome, multiple pregnancy, and makes letrozole metformin an appropriate treatment modality for patients with polycystic ovary syndrome who are at higher risk for ovarian hyperstimulation syndrome and multiple pregnancy with other medications used for ovulation induction. The incidence of multiple pregnancy is approximately 9% with clomiphene citrate and 20%-30% with gonadotropins (22). In the study performed by Mitwally et al, letrozole (2.5 mg and 5 mg) was used for induction of

ovulation in 410 patients. The incidence of multiple pregnancy was 4% (23). Although the teratogenic potential of letrozole was shown in animal studies (24).Several recent well designed clinical studies showed that the use of letrozole to induce ovulation was not associated with increased rates of minor or major malformations compared to general population (25) (26). The administration of letrozole in the early follicular phase and its short half life result in clearance of the drug before implantation of the embryo (27). Metformin is a biguanide which is commonly used in the treatment of patients with non insulin dependent diabetes mellitus. Metformin suppresses hepatic gluconeogenesis, reduces glucose absorption from the gastrointestinal tract, enhances peripheral insulin action and therefore reduces plasma insulin level. Moreover, metformin decreases serum cholesterol, triglycerides and blood pressure. In patients with PCOS, metformin restores normal LH secretion, decreases ovarian androgen production, enhances SHBG syntheses and therefore decreases free androgens (28). Metformin is not an accelerant of ovarian follicular recruitment or growth, it causes resumption of normal ovarian function by gradual damping of inappropriate cellular growth stimuli chiefly mediated by tonically elevated insulin level (29). The data from randomized controlled studies demonstrated that the addition of metformin to clomiphene citrate increased the ovulation rate and the pregnancy rate particularly in clomiphene citrate resistant patients with PCOS(8). Thus we postulated that the addition of metformin to letrozole could enhance the response to letrozole in clomiphene citrate resistant patients with PCOS who often have greater insulin resistance compared to patients who respond to clomiphene citrate (7). Although pregnancy rate per cycle was higher in letrozole- metformin group than in clomiphene citrate metformin group (18.5% versus 10.7%), that difference was not statistically significant. In the study performed by Mitwally et al, which included patients with PCOS, unexplained infertility and mild factor of male infertility, the pregnancy rate per cycle was 8% in 994 clomiphene citrate stimulation cycles, 16.4% in 164 letrozole (2.5 mg) stimulation cycles and

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19.8% in 432 letrozole (5 mg) stimulation cycles (23).In another study by Atay el al, the pregnancy rate was higher in patients with PCOS receiving letrozole than those receiving clomiphene citrate (21.6% versus 9.1%) (18). In the study performed by Sohrabvand et al, which included PCOS patients who failed to become pregnant after three courses of clomiphene citrate, the pregnancy rate per cycle was 18.8% in patients receiving letrozole metformin and 7.4% in patients receiving clomiphene citrate -metformin (12). According to the results of these studies, it seems that the pregnancy rate is higher in patients with PCOS receiving letrozole (alone or combined with metformin) than in those receiving clomiphene citrate (alone or combined with metformin). In contrast to these findings, Badawy et al compared the efficacy of letrozole and clomiphene citrate in 438 patients with PCOS, the pregnancy rate per cycle was 15.1% in the letrozole group and 17.9% in the clomiphene citrate group without statistically significant difference between both groups. (30). Our study has the limitations of all non controlled non blinded studies. However, both groups were comparable regarding the clinical and hormonal variables tested. This indicated the homogeneity and the comparability of the studied population. Moreover, upon reviewing the literature, we observed that our study is still the first study which examined the effect of combined letrozole-metformin on ovulation in clomiphene citrate resistant patients with PCOS. In summery, this prospective quasi-randomized trial demonstrates the advantages of the use of letrozole-metformin in clomiphene citrate resistant patients with PCOS, which are monoovulation, absence of antiestrogenic effect on endometrium. These properties make letrozole-metformin an acceptable alternative to clomiphene citratemetformin in clomiphene citrate resistant patients with PCOS. The pregnancy rate per cycle was non significantly higher in letrozole metformin group than in clomiphene citrate metformin group (18.5% versus 10.7%). The small sample size could be a reason for the failure to find a statistically significant difference between both groups. Further large scale, double blinded, controlled studies are needed to clarify this issue.

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Received on June 30, 2008; revised and accepted on August 27, 2008

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