Article Letrozole versus human menopausal gonadotrophin in women undergoing intrauterine insemination

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1 RBMOnline - Vol 13. No Reproductive BioMedicine Online; on web 30 May 2006 Article Letrozole versus human menopausal gonadotrophin in women undergoing intrauterine insemination Dr Jamal was born in Lebanon and received his MD degree from the University of Istanbul in He completed his residency training in obstetrics and gynaecology there in 2001 and a fellowship in reproductive endocrinology and infertility in After completing his fellowship, Dr Jamal spent 2 years as a member of the medical staff at Eurofertil Reproductive Health Centre before moving to the Antalya IVF Center. His research interests include areas of assisted reproductive technologies, infertility and reproductive surgery. Dr Hashim Jamal Aynur Baysoy 1, Hasan Serdaroglu 1, Hashim Jamal 2,3, Emre Karatekeli 2, Hakan Ozornek 2, Erkut Attar 1 1 Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Istanbul University, Faculty of Medicine, Istanbul, Turkey 2 Eurofertil Reproductive Health Centre, Istanbul, Turkey 3 Correspondence: hashimjamal@hotmail.com Abstract This pilot study was conducted to compare the results of intrauterine insemination (IUI) under ovarian stimulation with either letrozole (Femara) or human menopausal gonadotrophin (HMG). A randomized controlled trial was conducted. Eighty women aged years with unexplained infertility of at least 2 years duration were randomized according to a computergenerated randomization list into the letrozole group and the HMG group. Letrozole was administered at 5 mg/day from day 3 to day 7 of the IUI cycle. HMG injections were started on day 3 at a dose of 75 IU for women under 30 years old and 150 IU for women over 30 years old and monitored periodically by vaginal ultrasound and oestradiol concentrations. The variables selected for analysis were clinical pregnancy rate, endometrial thickness, length of follicular phase and number of preovulatory follicles. No statistically significant difference in clinical pregnancy rates per cycle was found for patients in the letrozole or HMG group (18.4 versus 15.7%). Cost was significantly higher in the HMG stimulation cases (P < 0.001) and no injections were required in the letrozole group. In conclusion, letrozole offers a new treatment regimen in ovarian stimulation regimens for IUI that is cost effective, simple and convenient for the patients. Keywords: HMG, intrauterine insemination, aromatase inhibitors 208 Introduction Unexplained infertility affects 15% of couples presenting with infertility (Aboulghar et al., 2003). Proposed treatment regimens include ovulation induction with oral or injectable medications, combinations of intrauterine insemination (IUI) with ovulation induction, and assisted reproductive technologies. Ovulation induction combined with IUI is one of the oldest treatments for unexplained infertility, and couples with unexplained infertility should first be exposed to ovulation induction with IUI and be offered IVF only after the failure of these therapies (Homburg and Insler, 2002). Over the years, ovulation has been stimulated by the oral medication clomiphene citrate or injectable gonadotrophin treatment (human menopausal gonadotrophin; HMG or recombinant FSH) combined with intercourse or IUI. There have been relatively few alternatives for the treatment of infertile couples. The reported pregnancy rates per cycle of IUI in conjunction with ovulation induction have usually varied between 8 and 22% (Sunde et al., 1988; Dodson and Hane, 1991; Cohlen et al., 1998). Letrozole (Femara) is one of a new class of drugs known as aromatase inhibitors, which act by inhibiting aromatase activity and thereby suppressing systemic production of oestrone from androstenedione. Aromatase inhibitors have become an important part of ovulation induction protocols for the treatment of infertility (Vladimirov, 2004). Letrozole is a new orally active, potent and selective aromatase inhibitor first approved

2 for the hormonal treatment of advanced breast cancer in postmenopausal women (Roseman et al., 1997). Studies have shown that aromatase inhibitors are a successful method of inducing and augmenting ovulation (Metwally and Caspar, 2001). Aromatase inhibitors are also effective in the medical treatment of endometriosis (Fatemi et al., 2005). The evaluation of data from recent clinical trials has shown that transient inhibition of aromatase activity in the early follicular phase with the aromatase inhibitor letrozole results in stimulation of ovarian folliculogenesis similar to that seen with clomiphene citrate, with no apparent adverse effect on endometrial thickness or pattern at mid-cycle (Fisher et al., 2002). Both pregnancy rate and endometrial thickness were comparable when patients were co-treated with gonadotrophin and letrozole in order to reduce the FSH dosage required for ovarian stimulation (Healey et al., 2003). Another observed effect of aromatase inhibitors is a decrease in oestradiol production, with approximately a 50% diminution in oestradiol/mature follicles in peripheral blood on the day of human chorionic gonadotrophin (HCG) administration (Metwally and Caspar, 2001, 2002, 2003). As LH surge is induced by a late follicular rise in oestradiol concentrations that feeds back positively on the hypothalamo pituitary axis (Hoff, 1983), it is anticipated that letrozole delays the rise in LH. Letrozole not only lowers oestradiol but also the follicular protein(s) that antagonize(s) the LH surge (Metwally and Caspar, 2003). The primary objective of this pilot study was to assess pregnancy rate when using letrozole in IUI cycles, and whether it would be worthwhile to consider letrozole for clomiphene failures before going on to gonadotrophin treatment. The study was also designed to test the effects of the aromatase inhibitor letrozole on endometrial thickness, follicular phase length and premature luteinization compared with HMG treatment cycles. Materials and methods A total of 80 couples undergoing ovarian stimulation and IUI cycles were enrolled in this pilot study. The study was initiated to assess the usefulness of letrozole (a treatment of which the authors had no previous experience) in comparison with the treatment that was in use in the authors department. The sample size needed to detect a significant difference in pregnancy rates was not calculated. As the number of patients enrolled was small, the study was defined as a pilot study. All patients diagnosed as having unexplained infertility (lack of conception after at least 2 years of regular unprotected intercourse) had regular menstrual cycles of days duration, a pelvic ultrasound showing uterus and ovaries of normal size and structure, a hysterosalpingogram and/ or laparoscopy demonstrating tubal patency, thyroid and reproductive hormones within the normal range. The luteal progesterone concentrations were not measured. Semen analysis was performed at least twice with an interval of 3 months between tests and was acceptable according to the guidelines of the World Health Organization (WHO, 1999). All women in both groups had previously undergone at least one ovulation induction treatment cycle combined with intercourse but this was their first IUI cycle. The washout period between previous ovulation inductions and current treatments was not checked, there was no significant difference between the two groups in terms of previous ovulation induction treatments, and the average number of failed cycles in each group before moving on to IUI was 3 4 cycles. This pilot study was approved by the Ethics Committee of the hospital (Istanbul University, Faculty of Medicine). All couples were randomly assigned to one of two treatment groups according to a computer-generated randomization list. Only the specialist who had performed the IUI was blinded to group assignment. Patients were aware of the treatment allocation. Over the typical range of patient ages, letrozole dosage does not change, but the standard HMG protocol assigns a higher dosage to older patients. The intention was to compare letrozole with the standard HMG protocol. On day 3 of the treatment cycle, a baseline transvaginal ultrasound scan was performed. All sonograms were carried out by the same physician who performed the IUI. The endometrial stripe was measured at its maximum anteroposterior thickness along the longitudinal axis of the uterine body. When there was no ovarian cyst on the scan, in group A (letrozole, n = 40) stimulation began on day 3 with the administration of, 5 mg/day of letozole (Femara; Novartis Pharma AG, Switzerland) from day 3 to day 7 of the menstrual cycle. In group B (HMG, n = 40), 75 IU (<30 years) and 150 IU ( 30 years) of HMG (Menogon; Ferring, Germany) were given i.m. daily from day 3 onwards for 5 days. After this, the dose and duration of HMG treatment were adjusted during the monitoring of the follicular development according to the patient s response including the number of growing follicles and oestradiol concentrations. After day 7 of the menstrual cycle, all patients were evaluated every other day by transvaginal ultrasound and measurement of oestradiol and LH blood concentrations. To determine LH and oestradiol, a commercially available immunometric assay kit (Elecsys; Roche Diagnostics GmbH Mannheim, Germany) was used. HCG 10,000 IU (Pregnyl; Organon, Turkey) was given when the leading follicle was 17 mm in diameter. A single IUI was performed h after HCG administration if no endogenous LH surge occurred. An LH surge was defined as an increase in LH concentration 100% over the mean of the preceding 2 days (Metwally and Caspar, 2003). When LH surge occurred, insemination was performed on the following day, but that cycle was not taken into consideration. IUI was performed using an intrauterine catheter (Embryon EDL; Rocketmedical, UK) with a 1-ml syringe. The catheter was gently passed through the cervical canal and the sperm suspension expelled into the uterine cavity. Insemination volumes ranged from 0.5 to 1 ml. No luteal support was given. The patient was asked to rest in a supine position for 15 min after IUI and thereafter to resume her routine activities. IUI was performed by the same physician for all patients. If menstruation was delayed after IUI, transvaginal ultrasonography was performed 3 weeks later. Only clinical 209

3 pregnancies (viable fetus) that were diagnosed by transvaginal ultrasonography were considered in the current analysis. The variables selected for analysis were pregnancy rate, thickness of the endometrium, length of the follicular phase, premature LH surge frequency, number of pre-ovulatory follicles ( 14 mm in diameter) and complications of the two study protocols. Comparison between variables was performed by the Student s t-test, chi-squared test and Fisher s exact test. The sample size of 40 cases and 40 controls at probability = 0.05 has statistical power of about 6%. The power of the study was low, P < 0.05 being considered statistically significant. P-values for all other outcomes can be affected by multiple comparisons and are given only for context. Results A total of 80 patients (40 in each treatment group) were recruited to this pilot study. All the patients treated had primary infertility. The letrozole group (group 1) and the HMG group (group 2) were comparable with regard to demographic traits: age, mean basic diagnostic parameters and cause and duration of infertility (Table 1). Physical examination, hormone profiles, ultrasonography, semen analysis and hysterosalpingography were all normal in the two groups (Table 1). Comparison of the clinical results obtained in the two groups is given in Table 2. Pregnancy rates were not significantly different between the two groups. There were pregnancies in seven of the 38 letrozole IUI cycles (18.42%) and in six of the 38 HMG IUI cycles (15.78%). The number of follicles measuring 14 mm on the day of HCG administration was lower in the letrozole than in the HMG group (1.79 ± 1.3 and 3.21 ± 1.6 respectively). Also in the HMG group, the oestradiol concentrations on the day of HCG administration were considerably higher than those of the letrozole group ( ± 368 and ± 80 respectively). Although increased thickness of the endometrium was observed in the HMG group, there was no difference in endometrial pattern between the two groups. The triple-line endometrial pattern was found to be 92.10% in group A and 94.73% in group B. The 95% confidence intervals overlapped for the percentages with triple line appearance. When the length of the follicular phase in the patients receiving letrozole was compared with the follicular length in the HMG patients, there was a shortening among the HMG group. The length of stimulation was longer in the letrozole group (12.77 ± 1.9 versus ± 1.7 days). The mean dose of HMG (mean number of ampoules/cycle) was 15.5 ampoules/cycle. The dosage of letrozole was stable at 5 mg/day, 10 tablets/cycle. Letrozole cost US$43 per cycle, while HMG was more expensive at US$225 per cycle. LH concentrations were determined in peripheral blood on day 3 of the treatment cycles, then 5 days later and then every other day until HCG administration. The difference between the two groups was not statistically significant. There were four premature luteinizations (two in each group). In this pilot study, there was only one case of moderate ovarian hyperstimulation syndrome (OHSS) in the HMG group; for this case outpatient care was sufficient. There were two multiple pregnancies, one triplet in the letrozole group and one twin in the HMG group. Table 1. Comparison of demographic data and baseline hormonal parameters of the patients receiving letrozole (group A) or gonadotrophin (group B). Patient parameter Letrozole Gonadotrophin (group A) (group B) Age (years) ± ± 4.3 Duration of infertility (years) 5.31 ± ± 3.2 Day 3 FSH (IU/l) 6.41 ± ± 1.7 Day 3 LH (IU/l) 5.81 ± ± 2.1 Day 3 oestradiol (pg/ml) ± ± 13.4 Semen parameters before preparation for insemination Age of male partner (years) ± ± 5.9 Sperm count (10 6 /ml) 61 ± 17 (21 270) 63 ± 23 (23 189) Motile spermatozoa (%) 52 ± 11 (40 87) 56 ± 13 (42 69) Normal sperm forms (%) 42 ± 11 (33 67) 46 ± 12 (30 61) 210 Values are means ± SD; values in parenthesis are ranges.

4 Table 2. Comparison of the clinical results obtained in patients receiving letrozole (group A) or gonadotrophin (group B). Parameter Letrozole Gonadotrophin P-value (group A) (group B) Follicular phase (days) ± ± Follicle number (n) 1.79 ± ± 1.6 <0.001 Endometrial thickness (mm) 8.91 ± ± Trilaminar pattern (%) NS HCG day of oestradiol (pg/ml) ± ± 368 <0.001 Premature luteinization (n) 2 2 NS Pregnancy rate (%) 7/38 (18.42) 6/38 (15.78) NS Cost (US$) <0.001 Multiple gestation (n) 1 (triplet) 1 (twin) NS OHSS (n) 1 moderate NS Values are means ± SD. NS = difference not statistically significant. Discussion There are currently several hormonal treatment protocols for ovarian stimulation combined with IUI, but the optimal, most cost-effective method has not yet been determined. The use of gonadotrophins alone for ovarian stimulation is an established protocol in IUI treatment (Plosker et al., 1994). The average cycle fecundity range, according to the results of studies that have included women with various infertility aetiologies, is from 9 to 20% (Aboulghar et al., 1993). The expected baseline pregnancy rate with active control HMG in the authors department is 15 20% per cycle. Both gonadotrophins, HMG and recombinant FSH, yielded comparable results (Van Wely, 2003). In some studies, HMG administration was associated with lower treatment duration, gonadotrophin dose, cost, and clinical outcome compared with recombinant FSH-α (Filicori et al., 2003). The drawbacks of the gonadotrophins are their high cost (both for the medication and the extensive monitoring required), inconvenience, risk of high-order multiple gestations and perhaps most importantly, risk of the potentially life-threatening OHSS (Olivennes, 2003). The new generation aromatase inhibitor letrozole is now used in ovulation induction and in many infertility situations (Metwally and Caspar, 2001; Healey et al., 2003). Letrozole has been shown to improve outcome in IUI cycles combining injectable FSH with oral ovulation induction (Metwally and Caspar, 2004). Recent studies report that the combination of letrozole and FSH enhances follicular recruitment while reducing the amount of FSH needed for optimal stimulation, ultimately reducing the cost of the cycle (Metwally and Caspar, 2003, 2004). The use of aromatase inhibitors during assisted reproduction reduces the FSH dose needed to achieve optimum ovarian stimulation, improves ovarian response to FSH in poor responders, terminates the positive feedback loop and improves ovarian response to ovarian stimulation in infertile cases, improves implantation rates in assisted reproduction technology, and reduces oestrogen concentrations to diminish the risk of OHSS during ovarian stimulation (Fatemi et al., 2003; Vladimirov, 2004). Although low oestradiol concentrations and small numbers of mature follicles were obtained at the time of the LH surge in the letrozole group, pregnancy rate was highest in the letrozole group. It is difficult to draw definitive conclusions from the present data regarding pregnancy rates, but it can be said that a very good outcome in terms of achievement of pregnancy was obtained in the letrozole group. Another outcome noted was that the stimulation time (from day 3 of the menstrual cycle until at least one follicle reached 17 mm in diameter) lasted longer and the LH surge triggered later in the letrozole group than the HMG group. As other authors (Metwally and Caspar, 2003) have stated before, this longer time of stimulation may have beneficial effects on oocyte maturation and oocyte quality, which may be a reason why more pregnancies occurred in the letrozole group. In a comparison study in 2002 between letrozole and clomiphene, women who took letrozole had lower oestrogen concentrations than those taking clomiphene (Fisher, 2002). In the present study, despite significantly lower (P < 0.001) oestradiol concentrations in letrozole-treated women, endometrial development was unaffected, and endometrial thickness and pattern were acceptable in both groups. Letrozole has a very short half-life (~45 h), and is therefore quickly cleared from the body. For this reason, it is less likely to adversely affect the endometrium and cervical mucus (Metwally and Caspar, 2001; Cortinez et al., 2005). Serious complications (OHSS, multiple pregnancy) were rare in the two groups. Low oestradiol concentrations and small numbers of mature follicles at the time of the LH surge in the letrozole group may be a way to minimize and thereby avoid the complications of OHSS and multiple pregnancy. However, 211

5 212 to compare such an outcome, a large study including a very large number of patients would be required. The results support the efficacy of letrozole. A very acceptable clinical pregnancy rate was obtained and no injection was required with letrozole. Overall, ovarian stimulation with letrozole is cost effective, simpler and more convenient than HMG. References Aboulghar M, Mansour R, Serour G, Al-Inany H 2003 Diagnosis and management of unexplained infertility: an update. Archives of Gynecology and Obstetrics 267, Aboulghar M, Mansour R, Serour G et al Ovarian superstimulation and intrauterine insemination for the treatment of unexplained infertility. Fertility and Sterility 60, Cohlen B, te Velde E, van Kooij R et al Controlled ovarian hyperstimulation and intrauterine insemination for treating male subfertility: a controlled study. Human Reproduction 13, Cortinez A, De Carvalho I, Vantman D et al Hormonal profile and endometrial morphology in letrozole-controlled ovarian hyperstimulation in ovulatory infertile patients. Fertility and Sterility 83, Dodson W, Haney A 1991 Controlled ovarian hyperstimulation and intrauterine insemination for treatment of infertility. Fertility and Sterility 55, Fatemi HM, Al-Turki HA, Papanikolaou EG et al Successful treatment of an aggressive recurrent post-menopausal endometriosis with an aromatase inhibitor. Reproductive BioMedicine Online 11, Fatemi H, Kolibianakis E, Tournaye H et al Clomiphene citrate versus letrozole for ovarian stimulation: a pilot study. Reproductive BioMedicine Online 7, Filicori M, Cognigni G, Pocognoli P et al Comparison of controlled ovarian stimulation with human menopausal gonadotropin or recombinant follicle-stimulating hormone. Fertility and Sterility 80, Fisher S, Reid R, Van Vugt D, Casper R 2002 A randomized doubleblind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women. Fertility and Sterility 78, Healey S, Tan S, Tulandi T, Biljan M 2003 Effects of letrozole on superovulation with gonadotropins in women undergoing intrauterine insemination. Fertility and Sterility 80, Homburg R, Insler V 2002 Ovulation induction in perspective. Human Reproduction Update 8, Metwally M, Casper R 2004 Aromatase inhibition reduces the dose of gonadotropin required for controlled ovarian hyperstimulation. Journal of the Society for Gynecologic Investigation 11, Metwally M, Casper R 2003 Aromatase inhibition reduces gonadotrophin dose required for controlled ovarian stimulation in women with unexplained infertility. Human Reproduction, Metwally M, Casper R 2002 Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders. Fertility and Sterility 77, Metwally M, Casper R 2001 Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertility and Sterility 75, Olivennes F 2003 Patient-friendly ovarian stimulation. Reproductive BioMedicine Online 7, Plosker S, Jacobson W, Amato P 1994 Predicting and optimizing success in an intra-uterine insemination programme. Human Reproduction 9, Roseman B, Buzdar A, Singletary S 1997 Use of aromatase inhibitors in postmenopausal women with advanced breast cancer. Journal of Surgical Oncology 66, Sunde A, Kahn J, Molne K 1998 Intrauterine insemination: a European collaborative report. Human Reproduction 3, Van Wely M 2003 Human menopausal gonadotropin versus recombinant follicle stimulation hormone for ovarian stimulation in assisted reproductive cycles. Cochrane Database System Reviews 1, CD Vladimirov I 2004 Aromatase inhibitors is it a new opportunity in the treatment of infertility? Akusherstvo i Ginekologiia 43, World Health Organization 1999 WHO Laboratory Manual for the Examination of the Human Semen and Sperm Cervical Mucus Interaction, 4th edn. Cambridge University Press, Cambridge, UK. Paper based on contribution presented at the 21st Meeting of the European Society of Human Reproduction and Embryology (ESHRE 2005), Denmark. Received 13 March 2006; refereed 29 March 2006; accepted 8 May 2006.