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Home , Aromatase inhibitor, Unexplained infertility

Middle East Fertility Society Journal Vol. 11, No. 2, 2006  Copyright Middle East Fertility Society

Comparison of the use of and clomiphene citrate in regularly ovulating women undergoing intrauterine insemination

Robab Davar, M.D. Naeimeh Tayebi, M.D. Maryam Asgharnia, M.D. Abbas Aflatoonian, M.D.

Research and Clinical Center for , Shahid Sadoughi University, Yazd, Iran.

ABSTRACT

Objective: To compare the effects of letrozole 5mg and clomiphene citrate (CC) 100mg on total follicle number, endometrial thickness, hormone levels, pregnancy, miscarriage and OHSS rate in women undergoing superovulation and I.U.I. Material and methods: This study was done as a prospective randomized trial in Research and Clinical Center for Infertility (Shahid Sadoughi University) and Mother Hospital, Yazd, Iran. In this study, 115 patients with unexplained and mild male factor infertility were studied. Patients were randomized, using a computer-generated random table into two groups which were treated with 5 mg of letrozole daily (60patients, 60 cycles) or 100mg of CC daily (55 patients, 55 cycles) from day 3-7 followed by FSH on day 8 of the cycle. Then data were analyzed using student's T Test and chi- square. Results: The mean age and duration of infertility in both groups were similar. There was a significant difference in the total numbers of follicles during stimulation between two groups (5.45± 4.3 in CC group vs. 3.28± 2.5 in letrozole group) (p-value= 0.01). No significant difference was found in the endometrial thickness between two groups (letrozole group= 6.9±2.5, CC group= 7.6±1.8) .The mean level of LH (IU/L) and FSH (IU/L) in both groups were similar. (P-value of hormone levels between two groups were respectively: 0.33 and 0.47), but there was a significant difference in mean (pg/ml) levels between the groups (220.28±150.5 in letrozole group vs. 867.34±240.6 in CC group) (p-value=0.018). The mean number of used ampoule was the same in both groups. Chemical per cycle was 8.3% in the letrozole group and 5.5% in the CC group. Clinical pregnancy rate per cycle was 6.6%in the letrozole group and 1.8% in the CC group (p-value= 0.6).Two out of the three pregnancies in the CC group and one out of the five pregnancies in the letrozole group resulted in a miscarriage. One twin pregnancy occurred in the letrozole group and none in the CC group. Ovarian hyperstimulation syndrome (OHSS) has not occurred in any group. Conclusions: In spite of comparable pregnancy rate in clomiphene citrate and letrozole group, C.C. in these patients could be prescribed because of its lower cost. Keywords: letrozole, clomiphene citrate, superovulation, I.U.I

There are two main used for first line therapy because of its low cost and easy ovarian stimulation; an oral , administration (3, 4). Its use is associated with a clomiphene citrate (CC) and injectable high ovulation rate of 60%-80% but with a lower gonadotrophins (1). CC has a long half- life and pregnancy rate of about 50% (3) and some adverse accumulates in the body (2). In anovulatory side effects (1). This may be due to a detrimental women, the use of CC is widely accepted as the effect on the endometrium (an estrogen responsive site) and on the quality of cervical mucus (2). * Research and Clinical Center for Infertility, Mother Hospital, The endometrium is believed to be one of the Shahid Sadoughi University, Yazd, Iran most important targets for the antiestrogenic effect Correspondence: Robab Davar, Email: [email protected] of CC and may explain a large part of its low

Vol. 11, No. 2, 2006 Davar et al. Comparison of letrozole and clomiphene citrate 113 pregnancy rate and high miscarriage rate. Mitwally et al (2003) study, the combined use of Successful implantation requires a receptive inhibitors with gonadotropin injection endometrium, with synchronous development of was associated with improved ovarian response glands and stroma (5, 6). (18). The purpose of the present study was to In one study, CC was found to have a compare letrozole effect concerning pregnancy deleterious effect on the endometrium, as rate, in regularly menstruating women undergoing demonstrated by a reduction in glandular density IUI with clomiphene citrate. and an increase in the number of vacuolated cells (7). In addition, Gonen et al (1990) demonstrated a reduction in endometrial thickness, below the level MATERIALS AND METHODS thought to be needed to sustain implantation, in up to 30% of women receiving CC for ovulation The present study was performed at Yazd induction or for unexplained infertility (8). Research and Clinical Center for Infertility and Recently, it was suggested that letrozole, a specific Mother Hospital between October 2004 and reversible, aromatase inhibitor that September 2005. Informed consent was obtained suppresses estrogen biosynthesis (9), could from all the patients with unexplained and mild successfully replace CC in superovulation male factor infertility. Inclusion criteria were age treatment of patients with unexplained infertility or younger than 40 years, duration of infertility more polycystic ovarian syndrome in addition to the than 1 year, patent fallopian tubes on poor responder patients (10). hysterosalpingogram or laparoscopy and the The new third generation aromatase inhibitors presence of at least 10 million rapidly motile agents commercially available include two sperm/ml (17). Patients were randomized by using nonsteroidal preparations, and a computer-generated random table, into two letrozole and a steroidal agent, (11, groups which were treated with 5 mg of letrozole 12). Letrozole has a short half-life (around 2 days) daily (60patients, 60 cycles) or 100mg of CC daily and it clears rapidly from the body (13). This drug (55patients, 55cycles). Patients received either is a potent and highly specific nonsteroidal letrozole (Femara; Novartis pharmaceuticals, aromatase inhibitor that initially was approved for Dorval, Quebec, Canada) 5mg/day or clomiphene use in postmenopausal women with citrate 100mg/day from day 3-7 of their menstrual to suppress estrogen production (14, 15). cycle plus FSH (Gonal-F, Serono, Switzerland) Letrozole inhibits the aromatase by starting on day 8. The starting dose of competitively binding to the of the gonadotrophin in both groups was150IU/day. The subunit of the enzyme, resulting decision of combining FSH to letrozole or CC was in a blockade of conversion into based on previous study by authors (19). with subsequent increase in intraovarian Transvaginal ultrasonography scans were androgens (16). Letrozole can be administered performed on day 12 of the menstrual cycle and early in the follicular phase to induce ovulation by then daily until the mean diameter of the largest releasing the or pituitary from follicle reached 18 mm. One physician did all estrogen negative feedback on GnRH and ultrasound examination and she was blinded to the gonadotropin secretion, leading to an increase in group status. At ultrasonographic scan, the internal gonadotropin production which would stimulate diameter of each visible follicle was measured in ovarian follicular development (13) but unlike two dimensions and the average diameter was clomiphene citrate, it doesn’t lead to estrogen calculated. In addition, the endometrial thickness receptor depletion (17). By using letrozole, (mm) was measured at the greatest diameter intraovarian levels increase and this may perpendicular to the midsagittal plane in the fundal synergize with central effects of decreased region, including both layers of the endometrial estrogen to enhance ovarian response to cavity. The image was oriented so that the gonadotropin stimulation (1). In specifically endometrial canal and the cervical canal were defined subgroup of patients according to the visualized in the same plane to ensure measurement

114 Davar et al. Comparison of letrozole and clomiphene citrate MEFSJ Table1. Characteristics of patients undergoing superovulation including student's T Test and chi- square were with letrozole or clomiphene citrate (CC) used to compare the results, Which are expressed

Variable Letrozole CC p-value as mean and standard deviation .The differences were considered to be statistically significant if p No. of subjects 60 55 * value was<0.05. Mean (±SD) age of 28.7±2.9 25.7±3.8 NS women, years Mean (±SD) age of 33.88±4.3 32.66±4.01 NS men, years RESULTS Mean (±SD) duration 6.2±2.4 5.45±2.5 NS of infertility, years Causes of infertility All patients were included in the analysis. Our Male factor (%) 21.8 34.8 NS results showed that the causes of infertility, mean Unexplained (%) 78.2 65.2 NS age and duration of infertility in both groups were

* similar (Table1). The total numbers of follicles in NS= Not Significant the letrozole group were significantly lower than

those in the clomiphene citrate group (Table2).

There was no significant difference in the through the center of the endometrium (8). When endometrial thickness between the two groups the mean diameter of at least one follicle had (6.9±2.5 mm in the letrozole group, 7.6±1.8mm in reached 18mm, 10,000IU of HCG (Profasi; the CC group) (Table2). The mean number of Serono) was administered intramuscularly. Serum gonadotrophin ampules was the same in both FSH, LH and E levels were measured by the same 2 groups. (p-value=0.19) (Table 2). lab technician in all patients on day of HCG Hormones were measured on day of hCG administration by Elisa technical. Moreover, administration. The mean levels of LH (IU/L) and was prepared by swim down FSH (IU/L) in both groups were similar. (p-value procedure. of hormone levels between two groups were Intra uterine insemination (I.U.I) was respectively: 0.33, .0.47) but there was a performed 34 – 36 hours after administration of significant difference in mean E2 (pg/ml) levels HCG. Serum B hCG was measured two weeks between two groups (220.28±150.5 in letrozole after HCG administration. Chemical pregnancy group vs. 867.34±240.6 in CC group) (p- rate was calculated based on a positive result of value=0.018) (Table2). Chemical pregnancy rate serum BhCG (greater than 25mIU/ml) and clinical per cycle was 8.3% in the letrozole group and pregnancy rate was assessed by detection of fetal 5.5% in the CC group. Clinical pregnancy rate per heart beat on sonography. In addition, we cycle was 6.6%in the letrozole group and 1.8% in evaluated the total number of follicles, the number the CC group (p-value=0.6). Therefore, no of gonadotrophin ampules, and miscarriage rate. difference in the pregnancy rate between the two For statistical analysis, the data were entered into groups was noted (Table3). statistical package for social sciences (SPSS), PC version13. The appropriate statistical tests

Table2. Superovulation with letrozole or with clomiphene citrate (CC).

Variable Letrozole CC p-value

No. of subjects 60 55 Mean(±SD) no. of total follicles 3.28±2.5 5.45±4.3 p= 0.01 Mean(±SD)Endometrial thickness(mm) 6.9±2.5 7.6±1.8 NS Mean(±SD) of L.H(IU/L) 8.17±4.9 8.24±7.8 NS Mean(±SD) of F.S.H (IU/L) 6.5±3.3 7.3±4.2 NS Mean(±SD) of E2 (pg/ml) 220.28±150.5 867.34±240.6 p=0.018 Mean(±SD) no. of Gonadotrophin Ampoule 6.8±2.4 7.4±3.4 NS

Vol. 11, No. 2, 2006 Davar et al. Comparison of letrozole and clomiphene citrate 115

Table 3. Outcome of letrozole or clomiphene citrate in women higher in the CC group (22). Perhaps, this is due to undergoing I.U.I. the different mechanism of action between

Variable Letrozole CC p-value letrozole and CC (22). In our study, there was no difference in pregnancy rates or in the endometrial No. of subjects 60 55 thickness between the groups. Mitwally et al Chemical pregnancy 5 (8.3%) 3 (5.5%) NS (2005), studied the effect of an aromatase inhibitor Clinical pregnancy 4 (6.6%) 1 (1.8%) NS for ovarian stimulation on pregnancy outcome, Miscarriage 1 2 NS their results indicated that CC treatment is consistently associated with development of more ovarian follicles than with aromatase inhibitor and One out of the five pregnancies in the letrozole the lowest multiple gestation rate is associated with group resulted in a miscarriage and two out of the letrozole treatment (23). In our study, there was a three pregnancies in the CC group resulted in a significant difference in the total numbers of miscarriage (Table3). One twin pregnancy follicles between two groups. The numbers of occurred in the letrozole group and none in the CC follicles were more in the CC group than those in group. OHSS has not occurred in any group. the letrozole group, but multiple gestation rate was higher with letrozole treatment. More studies are needed to confirm that letrozole is associated with DISCUSSION higher multiple gestation rate. Our results showed significantly lower Clomiphene citrate is the most commonly concentrations in the letrozole group than in the prescribed agent for CC group and more follicles were observed in .Unfortunately, despite high rates of ovulation, cycles stimulated with 100mg CC from day 3 to 7 pregnancy rates per cycle remain relatively low of the cycle than letrozole group. Fatemi et al (20). (2003) compared endocrinological environment of Mitwally et al (2001) have shown that the use cycles stimulated with CC or letrozole in patients of CC may be complicated because of undergoing I.U.I. Significantly lower estradiol antiestrogenic effects on endometrial development. concentration and follicles were observed in cycles Therefore, a simple inexpensive and safe stimulated with letrozole compared to CC (24). alternative to CC for use in normally ovulatory Sohrabvand et al (2006) compared the efficacy of woman is required (20). combined metformin-letrozole with metformin- Fisher et al (2002) compared the effect of clomiphene citrate in clomiphene resistant infertile clomiphene citrate and letrozole on normal women with polycystic ovarian disease. They ovulatory women , and found that profiles of both showed that the mean concentration of total E2 LH and FSH were similar in natural and medicated were significantly higher in CC without a cycles with letrozole and CC but E 2 level was more difference in mean number of follicle and than two times higher in clomiphene-treated cycles ovulation rate. In addition, endometrial thickness (21). Despite significantly lower E 2 levels in was significantly higher in letrozole group than CC letrozole-treated women, endometrial development group. Full term pregnancies were higher in was unaffected (21). In our study, CC resulted in a letrozole group (25). The estrogen level in women significant increase in E2 levels while there was no on aromatase inhibitors was found to be 2-3 times difference in the endometrial thickness at midcycle lower as well than that reported in CC cycles, but between two groups. Al-Fozan et al (2004) despite this, the endometrial thickness was greater compared the effect of CC and letrozole in women in the aromatase inhibitor cycles (2). In our study, undergoing superovulation, and found that there the estrogen level was greater in the CC group with was no difference in the pregnancy rates or in the a significant difference in the mean number of endometrial thickness between the letrozole and follicle than letrozole group, but there was no the CC group. Of interest, the miscarriage rate was difference in the endometrial thickness or

116 Davar et al. Comparison of letrozole and clomiphene citrate MEFSJ pregnancy rate between two groups. Letrozole, at 4. Homburg R, Insler V. Ovulation induction in perspective. doses of 1-5 mg/day, inhibits of the 97%-99% Hum Reprod update 2002, 8: 449-462. aromatase activity (11).In all studies reported so 5. Hammond MG, Halme JK, Talbert LM. Factors affecting the pregnancy rate in clomiphene citrate induction of far, the aromatase inhibitor letrozole was ovulation. Obstet Gynecol 1983, 62: 196202. administered as a 5day regimen, usually from day 6. Carpenter SE. Implantation: In: Reproductive Medicine and 3 to 7 of the menstrual cycle, at a dose of 2.5- Surgery. Edited by Wallach EE, Zacur HA, St Louis. 7.5mg/day (26). Even in one study (12), the new Mosby, 1995: 158-165. approach of a single-dose regimen of an aromatase 7. Sereepapong W, Suwajanakorn S, Triratanachat S, Sampatanukul P, Pruksananonda K, Boonkasemsanti W, inhibitor for ovarian stimulation seems to be as Reinprayoon D. Effects of clomiphene citrate on the effective as the previously reported 5- day endometrium of regularly cycling women. Fertil regimen. Al-Fadhli et al (2006) showed that 5mg 8. Steril 2002, 73:287-291. daily for 5 days is a preferable letrozole dose for 8. Gonen Y, Casper RF. Sonographic determination of an superovulation (27). adverse effect of clomiphene citrate on endometrial growth. Hum Reprod 1990, 5: 670-4. In the present study, letrozole was 9. Geisler J, Haynes B, Anker G, Dowsett M, Lonning PE. administrated at a dose of 5mg/day from day 3 to7 Influence letrozole and anastrozole on total body of the menstrual cycle. It was shown that CC is and plasma estrogen levels in postmenopausal associated with increased risk of ovarian breast cancer patients evaluated in randomized, cross-over hyperstimulation syndrome and high multiple study. J Clin Oncol 2002, 20:751-7. 10. Mitwally MF, Casper RF. Aromatase inhibition improves pregnancies (1).In the present study, O.H.S.S has ovarian response to follicle-stimulating hormone in poor not occurred in any group. Mitwally et al (2004) responders. Fertil Steril 2002, 77:776-80. proposed that aromatase inhibitors would replace 11. Mitwally MF, Casper RF. Aromatase inhibitors in ovulation CC in the future as the new primary treatment for induction. Semin Reprod Med 2004, 22: 61-78. ovulation induction in P.C.O patients (11). 12. Mitwally MF, Casper RF. Single- dose administration of an Letrozole can be used for ovulation induction or aromatase inhibitor for ovarian stimulation. Fertil Steril 2005, 83: 229-231. ovarian stimulation with higher pregnancy rates 13. Mitwally MF, Casper RF. Aromatase inhibition for ovarian compared with CC (20), but in our study the stimulation: Future avenues for infertility management. pregnancy rate between two groups was the same. Current Opin Obstet and Gynecol 2002, 14:255-263. 14. Winer EP, Hudis C, Burstein HJ, Chlebowski RT, Ingle JN, Edge SB, Mamounas EP, Gralow J, Goldstein LJ, Pritchard KI, Braun S, Cobleigh MA, Langer AS, Perotti J, Powles TJ, ACKNOWLEDGMENTS Whelam TJ, Browman GP. American society of clinical oncology technology assessment on the use of aromatase This research was granted by Research and inhibitors as adjuvant therapy for women with hormone Clinical Center for Infertility, Shahid Sadoughi receptor positive breast cancer: status report 2002. J Clin University and Mother Hospital, Yazd, Iran. The Oncol 2002, 20:3317-27. 15. Pfister CU, Martoni A, Zamagni C, Lelli G, De Braud F, authors express their thanks to Ms Afsaneh Souppart C , Duval M, Hornberger U. Effect of age and Kermani nejad and Habibeh Gheisari for their single versus multiple doses, pharmacokinetic of cooperation. letrozole(Femara) in breast cancer patients. Biopharm Drug Dispos 2001 ,22:191-7.

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118 Davar et al. Comparison of letrozole and clomiphene citrate MEFSJ