ORIGINAL ARTICLE East J Med 25(3):427-433, 2020 DOI: 10.5505/ejm.2020.24993 Comparison of The Efficacy of Letrozole and Gonadotropin Combination Versus Gonadotropin Alone In Intrauterine Insemination Cycles In Patients With Unexplained Infertility Süleyman Cemil Oğlak1*, Mehmet Nafi Sakar2, Serhat Ege1, Serap Mutlu Özçelik Otçu1, Mehmet Obut3, Bekir Kahveci4, İsmail Yıldız5 1Health Sciences University, Diyarbakır Gazi Yaşargil Training and Research Hospital, Department of Obstetrics and Gynaecology, Diyarbakır, Turkey 2Memorial Diyarbakır Hospital, Department of Obstetrics and Gynecology, Diyarbakır, Turkey 3Etlik Zübeyde Hanım Women's Health Training and Research Hospital, Ankara, Turkey 4Çukurova University School of Medicine, Department of Obstetrics and Gynaecology, Adana, Turkey 5Dicle University School of Medicine, Department of Biostatistics, Diyarbakır, Turkey ABSTRACT This study aimed to determine the outcomes of combined treatment of letrozole (LTZ) with recombinant follicle - stimulating hormone (rFSH) in comparison with rFSH alone in intrauterine insemination (IUI) cycles. This study consisted of 86 patients who experienced 106 IUI cycles. Patients were classified into two treatment groups: group I underwent a combination of LTZ plus rFSH, and group II received rFSH alone. Ovulation was triggered with human chorionic gonadotropin (hCG), and IUI performed 36 hours later. The number of follicles ≥18 mm, endometrial thickness, required dose of FSH, duration of ovulation induction (OI), clinical pregnancy rates, multiple pregnancy rates, spontaneous abortion rates, and live birth rates were evaluated. The total required rFSH dose during the OI was significantly lower in the LTZ-rFSH combination group than the rFSH alone group (401.2±177.1 IU and 770.1±345.8 IU, respectively, p<0.001). The days of stimulation with rFSH were also lower in the LTZ co-treatment group than the rFSH-alone group (5.2±1.3 days and 10.1±3.0 days, respectively, p<0.001). Clinical pregnancy rate was 17.0% in LTZ-rFSH group, and 15.2% in rFSH group (p>0.05). The combined use of LTZ with rFSH resulted in a lower required dose of rFSH, a similar and ac ceptable endometrial thickness at the day of hCG administration, and comparable pregnancy rate compared with rFSH alone. Key Words: Letrozole, gonadotropin, ovulation induction, intrauterine insemination Introduction couples with infertility (1,3). Also, there are conflicts among clinicians on the appropriate Intrauterine insemination (IUI) is frequently ovarian stimulation protocol in an IUI cycle. practiced as first-line treatment for couples with Clomiphene citrate (CC) has been accepted as a unexplained or mild male-factor infertility standard treatment for ovarian hyperstimulation in worldwide because it is considered to increase the unexplained infertility for many years (4,5). pregnancy rates while simple to perform and to be Clomiphene citrate increases the release of FSH comparatively low-cost (1). It is possible to from the pituitary by blocking estrogen negative perform the IUI procedure in patients' natural feedback effect, and thus increases the follicle cycles (2). But, it was found that pregnancy and development (6). However, CC has disadvantages live birth rates in IUI cycles were significantly in treatment, and the prevalence of CC resistance higher with ovulation induction (OI) cycles using is 15-40% (7). Clomiphene citrate depletes medications compared with no stimulation for estrogen receptors and has a long half-life (2 *Corresponding Author: Süleyman Cemil Oğlak, Health Sciences University, Diyarbakır Gazi Yaşargil Training And Research Hospital, Department Of Obstetrics And Gynaecology, Diyarbakır, Turkey E-mail: [email protected], Phone: 90 (506) 402 11 57 ORCID ID: Süleyman Cemil Oğlak: 0000-0001-7634-3008, Mehmet Nafi Sakar: 0000-0002-3260-1041, Serhat Ege: 0000-0001-5430- 602X, Serap Mutlu Özçelik Otçu: 0000-0001-5124-9031, Mehmet Obut: 0000-0002-6925-4784, Bekir Kahveci: 0000-0002-8729-1669, İsmail Yıldız: 0000-0001-5505-838x Received: 12.03.2020, Accepted: 25.05.2020 Oğlak et al / rFSH vs LTZ-rFSH Combination in IUI Cycles weeks), inducing unfavorable effects on IUI. The Ethics Committee of Gazi Yaşargil endometrial thickness and cervical mucus (8,9). Training and Research Hospital approved the This effect leads to a pregnancy rate of 8.5-10% study. per cycle with the combination of CC and IUI, Before the treatment, all couples received a despite the high ovulation rate with CC (10). regular infertility assessment that involved In gonadotropin-stimulated IUI cycles, the transvaginal ultrasonography (US), a baseline pregnancy rates were in the range of 15-17% per hormone levels that included FSH, LH, estradiol, cycle (11,12). Nevertheless, the use of PRL, and TSH in the early follicular stage, a gonadotropin significantly boosts the cost of semen analysis, and assessment of tubal patency treatment and increases the risk of ovarian by hysterosalpingogram or laparoscopy. Ovulation hyperstimulation syndrome and multiple documented by serum progesterone on day 21. pregnancies (13). With the combination of The determination of unexplained infertility was gonadotropin and CC in IUI cycles, the required based on eliminating female and male factor gonadotropin dose and treatment cost decrease infertility. The inclusion criteria were as follows: compared to gonadotropin use alone, but the aged <40 years, infertility of at least one-year pregnancy rates are low with this combination due continuance, at least one patent fallopian tube, a to the anti-estrogenic effects of CC (14). healthy uterine cavity, and at least 15 million of Letrozole (LTZ), an aromatase inhibitor, inhibits motile sperm/mL with ≥32% of progressive the conversion of androgens to estrogens in motility and ≥4% of normal morphology in the ovarian follicles, resulting in a decrease in spouses' semen analysis. The exclusion criteria circulating and local estrogens and an increase in were as follows: oligo/anovulation, bilateral tubal intraovarian androgens (9). The reduction in pathology, other endocrine disorders, and male estrogen levels causes the discharge of the factor infertility. Canceled cycles were also hypothalamic-pituitary axis from the negative excluded. feedback of estrogen. This effect leads to an Study Groups: This study consisted of 86 women increase in FSH release, which results in follicular who underwent 106 IUI cycles. None of the growth (9). Unlike CC, LTZ has no anti-estrogenic women had treated with LTZ before. Patients impact and has a short (45 hour) half-life (15). were informed entirely about the mechanism of Due to these effects, LTZ does not cause an effect and the experiential essence of LTZ. The unfavorable effect on cervical mucus and off-label indication of LTZ was wholly explained. endometrial thickness, and therefore, LTZ The use of LTZ was based on the couple's choice. correlated with higher pregnancy rates (9). Participants were classified into two treatment letrozole and gonadotropin combination can groups: group I received a combination of LTZ diminish the required dose of FSH for ovarian (Femara; Novartis, Basel, Switzerland) plus rFSH stimulation without jeopardizing the pregnancy (Gonal-F; Merck, Aubonne, Switzerland), and rate compared with FSH alone and result in a low group II received rFSH (Gonal-F; Merck, occurrence of multiple gestations and ovarian Aubonne, Switzerland) alone. Group I included 34 hyperstimulation syndrome (OHSS) (16). patients who had 47 OI cycles. Group II included This study aimed to examine the effectiveness of 52 patients who had 59 OI cycles. All women LTZ-gonadotropin combination to gonadotropins experienced a maximum of two cycles of IUI. The as an ovulation induction therapy for unexplained initial dose of gonadotropins was determined on infertility couples in IUI cycles. the clinical characteristics of women, including age, BMI, duration of infertility, and prior treatment cycles. In group I, LTZ was given 5.0 Material and Methods mg/day from day 3 to 7 of the menstrual cycle, followed by the rFSH dose beginning at 50-150 Patients: This retrospective study included 86 IU/day starting on day seven until the day of the women with unexplained infertility ranging in age hCG administration. In group II, rFSH treatment from 20 to 40 years who admitted to Gazi Yaşargil was begun on day 3 of the menstrual period with Training and Research Hospital Infertility an initial dose of 50-150 IU/day until the day of policlinic between February 2017 and March 2018. the hCG treatment. Both of the groups, the dose The clinical data were recorded from our clinical of rFSH was adjusted depending on the ovarian database. All the patients had unexplained response to achieve mature follicle (≥18 mm). infertility and experienced ovarian Follicle growth (the number and the diameter of hyperstimulation with recombinant FSH (rFSH) follicles) was monitored with transvaginal alone or combined with LTZ (5.0 mg/day) for East J Med Volume:25, Number:3, July-September/2020 428 Oğlak et al / rFSH vs LTZ-rFSH Combination in IUI Cycles ultrasound by gynecologists from day 7 to day 10 Results of the cycle, and then performed every two days based on the follicle growth. When the diameter A total of 86 patients experienced 106 IUI cycles. of at least one follicle had reached 18mm, a All participants diagnosed with unexplained subcutaneous injection of 6500 IU of hCG infertility. There were no statistically significant (Ovitrelle; Merck, Modugno, Italy) was used to differences