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      Effect of adding letrozole to gonadotropin on in vitro fertilization outcomes: An RCT

      research-article
      , M.D. 1 , , M.D. 2
      International Journal of Reproductive Biomedicine
      Knowledge E
      Letrozole, Ovarian stimulation, Pregnancy.

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          Abstract

          Background

          Aromatase inhibitors prevent the aromatization of androgens into estrogens, which reduces the negative feedback of estrogen on the hypothalamic-pituitary axis. It is clear that increasing the secretion of follicle-stimulating hormones results in an increased follicular growth.

          Objective

          This study aimed to evaluate the effect of adding letrozole to gonadotropin on in vitro fertilization outcomes in normal responders.

          Materials and Methods

          In this randomized clinical trial, 100 normal responder women candidate for controlled ovarian stimulation were randomly enrolled in two groups (n = 50/each). In the case group letrozole was added to gonadotropin in the antagonist protocol. The control group received the conventional antagonist protocol. The main outcome was clinical and chemical pregnancy; and the second outcomes were the number of mature oocytes, the fertilization rate, estradiol level, and the total dose of gonadotropins.

          Results

          Basic clinical and demographic features were comparable between the groups. Estradiol level on the day of human-chorionic-gonadotropin administration and the total gonadotropin consumption were significantly higher in the control group than the case group (p = 0.045). In addition, the number of MII oocytes was higher (but not significantl) in the case group than the control group (p = 0.09). Moreover, the endometrial thickness was significantly lower in the case group. There were no significant differences in fertilization rate and chemical and clinical pregnancy rates between the two groups.

          Conclusion

          Although adding letrozole to gonadotropin in normal responders reduces the total dose of gonadotropin, it does not improve the pregnancy outcomes.

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          Most cited references19

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          The aromatase inhibitor letrozole increases the concentration of intraovarian androgens and improves in vitro fertilization outcome in low responder patients: a pilot study.

          To evaluate the impact of aromatase inhibitors as adjuvant treatment in IVF cycles on intraovarian androgens and cycle outcome. Observational, pilot study. University-affiliated IVF unit. One hundred forty-seven low responder patients with a previous canceled IVF cycle; 71 patients were treated with letrozole 2.5 mg plus a high-dose FSH/hMG-antagonist regimen, and 76 patients were similarly treated but letrozole was not employed. In vitro fertilization treatment with an antagonist FSH/hMG protocol with or without letrozole was administered during the first 5 days of stimulation; hormones were evaluated in both serum and follicular fluid. Number of oocytes retrieved, fertilization rate, implantation rate, and pregnancy rate; androstenedione, T, E2, and P values in serum and follicular fluid. Letrozole-treated patients showed significantly higher levels of follicular fluid T and androstenedione (80.3 vs. 43.8 pg/mL and 57.9 vs. 37.4 mg/mL, respectively). Similarly, these patients had a higher number of oocytes retrieved (6.1 vs. 4.3) and a higher implantation rate (25% vs. 9.4%) despite similar doses of FSH/hMG (3,627 vs. 3,804 IU). Adding 2.5 mg of letrozole to a high-dose FSH/hMG antagonist protocol increases intraovarian androstenedione and T concentration and improves IVF cycle outcome in poor responder patients.
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            Review: aromatase inhibitors for ovulation induction.

            For the last 40 yr, the first line of treatment for anovulation in infertile women has been clomiphene citrate (CC). CC is a safe, effective oral agent but is known to have relatively common antiestrogenic endometrial and cervical mucous side effects that could prevent pregnancy in the face of successful ovulation. In addition, there is a significant risk of multiple pregnancy with CC, compared with natural cycles. Because of these problems, we proposed the concept of aromatase inhibition as a new method of ovulation induction that could avoid many of the adverse effects of CC. The objective of this review was to describe the different physiological mechanisms of action for CC and aromatase inhibitors (AIs) and compare studies of efficacy for both agents for ovulation induction. We conducted a systematic review of all the published studies, both controlled and noncontrolled, comparing CC and AI treatment, either alone or in combination with gonadotropins, for ovulation induction or augmentation, identified through the Entrez-PubMed search engine. Because of the recent acceptance of the concept of using AIs for ovulation induction, few controlled studies were identified, and the rest of the studies were pilot or preliminary comparisons. Based on these studies, it appears that AIs are as effective as CC in inducing ovulation, are devoid of any antiestrogenic side effects, result in lower serum estrogen concentrations, and are associated with good pregnancy rates with a lower incidence of multiple pregnancy than CC. When combined with gonadotropins for assisted reproductive technologies, AIs reduce the dose of FSH required for optimal follicle recruitment and improve the response to FSH in poor responders. Preliminary evidence suggests that AIs may replace CC in the future because of similar efficacy with a reduced side effect profile. Although worldwide experience with AIs for ovulation induction is increasing, at present, definitive studies in the form of randomized controlled trials comparing CC with AIs are lacking.
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              Comparison of ovarian stimulation response in patients with breast cancer undergoing ovarian stimulation with letrozole and gonadotropins to patients undergoing ovarian stimulation with gonadotropins alone for elective cryopreservation of oocytes†.

              The primary objective of this study is to compare the oocyte yield in breast cancer patients undergoing controlled ovarian stimulation (COS) using letrozole and gonadotropins with patients undergoing COS with standard gonadotropins for elective cryopreservation of oocytes. Odds ratios (OR) for the number of mature oocytes were estimated. Pregnancy outcomes for breast cancer patients undergoing frozen-thawed 2-PN embryo transfers (FETs) after oncologic treatment were also noted. 220 and 451 cycles were identified in the breast cancer and the elective cryopreservation groups, respectively. Patients in the former group had lower peak estradiol levels [464.5 (315.5-673.8) pg/mL] compared to the latter [1696 (1058-2393) pg/mL; p < 0.01]. More oocytes were retrieved in the breast cancer group (12.3 ± 3.99) compared to the elective cryopreservation group (10.9 ± 3.86; p < 0.01). The odds for mature oocytes with letrozole and gonadotropins was 2.71 (95% CI 1.29-5.72; p = 0.01). Fifty-six FETs occurred in the breast cancer group. The clinical pregnancy and live birth rates per FET cycle were 39.7%, and 32.3%, respectively. Our findings suggest that COS with letrozole and gonadotropins yield more mature oocytes at lower estradiol levels compared to COS with gonadotropins alone. Breast cancer patients undergoing FET after oncologic treatment have live birth rates comparable to age-matched counterparts.
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                Author and article information

                Journal
                Int J Reprod Biomed (Yazd)
                Int J Reprod Biomed (Yazd)
                IJRM
                International Journal of Reproductive Biomedicine
                Knowledge E
                2476-4108
                2476-3772
                April 2020
                30 April 2020
                : 18
                : 4
                : 287-294
                Affiliations
                1deptResearch and Clinical Center for Infertility, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
                2deptAfzalipour Hospital, Kerman University of Medical Science, Kerman, Iran.
                Author notes
                *Lida Saeed; Afzalipour Hospital, Kerman University of Medical Science, Kerman, Iran. Postal Code: 7616914111 Tel: (+98) 9131991748 Email: lsaeed6@yahoo.com
                Article
                10.18502/ijrm.v13i4.6891
                7218674
                aec5550f-881c-4efa-8988-d272de97a7d1
                Copyright © 2020 Eftekhar et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 16 March 2019
                : 23 October 2019
                : 27 November 2019
                Page count
                Figures: 1, Tables: 3, References: 20, Pages: 8
                Categories
                Research Article

                letrozole, ovarian stimulation, pregnancy.
                letrozole, ovarian stimulation, pregnancy.

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