Journal Logo

Research Article: Systematic Review and Meta-Analysis

Comparison of clomiphene and letrozole for superovulation in patients with unexplained infertility undergoing intrauterine insemination

A systematic review and meta-analysis

Qin, Fei MDa; Zhou, Yanqiong MDa; Huan, Lu MDb; Gui, Wenwu MDa,∗

Editor(s): Perovic., Milan

Author Information
doi: 10.1097/MD.0000000000021006
  • Open


1 Introduction

Infertility was defined as the failure to achieve a clinical pregnancy after 1 year of regular unprotected intercourse.[1] Intrauterine insemination (IUI) that was for treating couples with mild male factor infertility, minimal to mild endometriosis, and unexplained infertility IUI was implemented in. Compared with IUI alone, in addition, some randomized controlled trials those researchers considered that superovulation plus IUI increased pregnancy rates evidently, and there had been little controversy that ovarian hyperstimulation improved IUI outcome in couples with unexplained and mild male superiority compared with natural cycles.[2–4] However, which drug that promoted ovulation was considered as a first line treatment remained controversial.

Over several decades, clomiphene citrate (CC) had been the first line of treatment for ovulation disorders.[5,6] Nevertheless, it had fallacious results owing to its peripheral antiestrogenic effects.[7–10] Letrozole (LE), a specific aromatase inhibitor with the function of reducing oestrogen synthesis, had recently been applied as a potentially better alternative compared with CC. But in contrast with CC, LE was not associated with any antioestrogenic effects on endometrium, which was supported by some recent studies reporting adequate endometrial thickness during LE treatment.[11–13] Besides, compared with CC, LE was rapidly eliminated due to its shorter half-life, leading to late follicular rise in circulating oestrogen thereby enhancing endometrial development with subsequent increase in the chances of pregnancy.[14–16] The rising oestrogen levels might also result in a shorter FSH window (mimicking the physiological cycle) with subsequent mono-ovulation and a lower risk of multiple pregnancy.

On the basis of the work above, some RCTs[17,18] considered that LE had a superior efficacy as compared with CC in patients with unexplained infertility undergoing IUI. Otherwise, some RCTs[19,20] and a few retrospective studies[21,22] considered there were no significant differences between the 2 groups. Hence, Aromatase inhibitors that were originally developed and approved for treatment of breast cancer were currently being applied in alternatives to CC with an increased frequency, because it mimics the clomiphene action but without its peripheral antiestrogenic effect. However, there was even doubt that whether they can replace clomiphene as an ovulation inducer.

The primary outcome was the total rate of pregnancy, and the purpose of the present meta-analysis was to systematically assess the literature and identify the results of comparison studies to provide evidence for the effectiveness of LE compared with CC region for the induction of ovulation in patients with unexplained infertility IUI.

2 Materials and methods

Ethical approval or patient consent was not required since the present study was a review of previously published literature.

2.1 Searching strategy

We got the followed way to search all the literature. We used medical subject headings (MeSH) and keywords, such as IUI (Title/Abstract), CC (Title/Abstract), LE (Title/Abstract), LE “(Mesh). In addition, we used similar words about LE such as aromatase inhibitor that belonged to the same meaning with different description type. By this way we searched from the PubMed, EMBASE, and Cochrane library to confirm the related articles. The words were contacted by AND or OR. What is more we searched the relevant literature to assess whether was available to this study. (Fig. 1).

Figure 1
Figure 1:
Flow diagram showing the selection of including studies.

2.2 Study selection

Two people (Fei Qin and Yanqiong Zhou) screen the searching studies again and again, if they have divergences additional person (Wenwu Gui) reassesses the study. All the eligible studies should meet the following limitations:

  • 1. studies are comparison between LE and clomiphene for superovulation in patients with unexplained infertility undergoing IUI;
  • 2. the result included 1 of outcomes at least or more;
  • 3. maybe in some literature they do not use LE but the meaning is the same as it, we also adopt them;
  • 4. the patients must be at least one side of the unobstructed fallopian tube confirmed by hysterosalpingography (HSG) or laparoscopy;
  • 5. uterus is normal that is confirmed by laparoscopy, hysteroscopy, ultrasound, etc;
  • 6. semen detection is normal or mildly abnormal that is based on WHO Standard (1999).

2.3 Data extraction

Data extraction which is based on a standardized collection is reviewed on 2 authors (Lu Huan and Fei Qin) and crosschecks. If the study compared the LE with clomiphene for patients with polycystic ovary syndrome (PCOS) or anovulation, we should exclude. Besides, if the patients had undergone related surgery, we did not include, either. The following data is our collection: the 6 trials characteristics which mainly contain the year of publication, the authors, the design of research, the number of patients in each control, study country, intervention, the interest outcomes (Dichotomous outcomes: total pregnancy rate, cycle pregnancy rate, miscarriage rate, multiple pregnancy; Continuous outcomes: dominant follicle, endometrial thickness). (Table 1).

Table 1
Table 1:
The characteristics of including studies.

2.4 Evaluation of quality

The current meta-analysis includes 4 RCTs[17–20] and 2 non-randomized controlled trials (NRCTs),[21,22] their evaluation of quality are judged by 2 methods, RCT is according to the Cochrane Handbook, NRCT is on the basis of the Newcastle–Ottawa Scale. In the Cochrane Handbook we use low, high or unclear to assess the quality in 7 fields which are consist of random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting and other sources of bias. In the NRCT we grade quality in 3 superior fields which include the selection of a research group, group's comparability, metrical results or exposure. (Table 2, Figs. 2 and 3).

Table 2
Table 2:
Assessable quality of including studies.
Figure 2
Figure 2:
Risk bias of graph. Each risk of bias item presented as percentages across all of the included trials, which indicated the proportion of different level risk of bias for each item.
Figure 3
Figure 3:
Risk bias of summary. Judgments about each risk of bias item for each included trials. Green indicates low risk of bias. Yellow indicates unclear risk of bias. Red indicates high risk of bias.

2.5 Data synthesis and statistical analysis

We utilized the Review Manager 5 soft-ware to complete data synthesis. In the outcomes of interest dominant follicle, endometrial thickness are continuous variable which were described as mean difference (MD) with 95% confidence interval, the others belong to dichotomous variables which is described as risk ratios (RRs) with 95% confidence interval. To test heterogeneity 2 researchers (Yanqiong Zhou and Lu Huan) independently affiliate data into RevMan, when the value I2 is beyond 50%, it means a high heterogeneity.[23] What is more, we exclude the including literature in sequence to check stability of the results. That we take the literature into subgroup is built on the design of the study. Owning to the number of including studies is lower than 10, there is no funnel plot.

2.6 Outcomes of interest

In the current meta-analysis, we include all the relevant literature and contain almost 3413 participants. The primary outcome is the total rate of pregnancy, secondary outcomes are pregnancy rate per cycle, total number of dominant follicles, miscarriage rate, multiple pregnancy, and endometrial thickness. Moreover, if there are two NRCTs at least in a pool, there will be a subgroup, where we compare the result based on RCTs and NRCTs.

2.7 Primary results

2.7.1 The total rate of pregnancy

Six studies that contain 3413 participants all reported the total rate of pregnancy. Study Akbarisene[21] and Khanna[22] belong to NRCTs, therefore, we set a subgroup to further analyze. The result suggested that there was no significant difference between the 2 groups (RR= 1.06, I2= 11%, P= .38). After removing every study, the result does not change at all, indicating the steady of result is fine. Four RCTs and 2 NRCTs in this pool suggest there was no significant difference (RR= 1.09, I2= 41%, P= .28, RR= 1.02, I2= 0%, P = .56, respectively). (Fig. 4).

Figure 4
Figure 4:
Forest plots of the total rate of pregnancy in infertility patients with LE versus those with CC administration.

2.8 Secondary results

2.8.1 Pregnancy rate per cycle

Considering only one NRCT was included, there was no subgroup in this pool. Five studies were included and there was no significant difference (RR= 1.09, I2= 7%, P= .32). Four RCTs in this pool suggested there were no worthwhile differences (RR= 1.09, I2= 30%, P= .34). The sensitive test presented there was no significant difference and the result was stable. (Fig. 5).

Figure 5
Figure 5:
Forest plots of pregnancy rate per cycle suggested there was no significant difference between the LE group and CC group.

2.8.2 Total number of dominant follicles

Six studies were included in this pool and there was a subgroup, owing to 2 NRCTs were included. The result suggested that there was no significant difference between the 2 groups (MD= –0.49, I2= 100%, P= .06). After removing every study the result did not change at all, indicating the steady of the result was fine. Of interest, 4 RCTs and 2 NRCTs in this pool suggested there was a slight difference with higher heterogeneity. (MD= –0.56, I2= 100%, P= .04; MD= –0.39, I2= 73%, P= .0003, respectively). (Fig. 6).

Figure 6
Figure 6:
Patients receiving LE were more likely to Total number of dominant follicles than those with CC administration.

2.8.3 Multiple pregnancy

Considering only 1 NRCT was included, there was no subgroup in this pool. Five studies were included and there were no significant differences (RR= 0.79, I2= 0%, P= .46). Four RCTs in this pool suggested there was no significant difference (RR= 0.43, I2= 0%, P= .12). The sensitive test presented there was no significant difference and the result was stable. (Fig. 7).

Figure 7
Figure 7:
Forest plots of multiple pregnancy in infertility patients with LE vs those with CC administration and there was no significant difference between the 2 groups.

2.8.4 Miscarriage rate

Four studies were listed without subgroup. The result suggested that LE reduced the miscarriage rate in some extent. (RR= 0.61, I2= 0%, P= .03) 3 RCTs in this pool suggested there was no significant differences (RR= 0.64, I2= 27%, P= .22) with ascending heterogeneity. After eliminating the Fozan[18] or Akbari Sene[21] the result is according with the RCTs. However, that raised the heterogeneity. By changing the model the test of the result was also stable. (Fig. 8).

Figure 8
Figure 8:
The result of this Forest plots showed that LE could reduce the miscarriage rate.

2.8.5 Endometrial thickness

In this pool there were 5 studies. The result suggested there were no significant differences between the 2 groups with a high heterogeneity (MD= 0.01, I2= 100%, P= .98). Three RCTs in this pool suggest there was not any significant difference with the emergence of heterogeneity, either. (MD= –0.03, I2= 100%, P= 0.95). The sensitive test presented there were no significant differences and the result was stable. (Fig. 9).

Figure 9
Figure 9:
There was no difference in endometrial thickness for the infertility patients.

3 Discussion

Aromatase is a cytochrome P-450 hemoprotein-containing enzyme complex that catalyzes the conversion of androstenedione and testosterone into oestrogens.[24,25] It was postulated that blocking estrogen production by inhibiting aromatization in the ovary would release the hypothalamic/pituitary axis from estrogenic negative feedback. As a consequence, follicle-stimulating hormone (FSH) secretion increases, stimulating the development of ovarian follicles. Preliminary studies reported that aromatase inhibitors were helpful for inducing ovulation and in superovulation. Since no estrogen receptor down regulation occurs, no adverse effects on estrogen target tissues would be expected.

As presented in the current meta-analysis, we found, although, there was no significant difference in total rate of pregnancy, pregnancy rate per cycle and the number of dominant follicles, there was a tendency that LE had a little function to improve the number of dominant follicles owing to the result of subgroup. This was in agreement with the previous report[26] that LE improves ovarian response to FSH in poor responder women. In some preceding study, no difference was found in the pregnancy rate between the FSH group and the LE/FSH group (20.9% vs 21.6%).[27] The higher number of mature follicles in the LE group did not result in a higher pregnancy rate. Perhaps, this was related to inadequate quality of endometrium in the LE group.

Compared with CC, LE is associated with a thicker endometrium.[11] It suggests that LE has minimal effect on the endometrium. Perhaps, due to its rapid and reversible action on the endometrium allowing the endometrium to respond well to increasing endometrium in the late follicular phase. Such findings could be attributed to the mechanism of action of LE. As an aromatase inhibitor, it works by luring the conversion of androstenedione and endometrium in the ovary. The decrease in circulating E increases gonadotropin secretion.[28] What is more, the use of CC is associated with endometrial thinning in 15% to 50% of patients.[29] This could be due to prolonged E receptor depletion in the endometrium.[30] Compared with CC, LE is involved in a thicker endometrium.[11] It suggests that LE has minimal effect on the endometrium. However, in our present study we found there was no difference between CC group and LE group with a high heterogeneity, the reason for the heterogeneity was not only related to the choice of dose, but the mechanism of action of LE. A larger study is required to clarify this matter.

Though, in the pool of total rate of pregnancy and pregnancy rate per cycle, there was no difference, compared with CC it was worth noting that LE had a lower miscarriage rate. Perhaps, this was due to the different mechanism of action between LE and CC. In previous study, the researchers reported that the addition of LE (5 mg daily for 5 days) to gonadotropin was associated with a thinner endometrium than gonadotropin alone.[27] In the present study, the endometrial thickness was the same in the LE group and in the CC group. Moreover, the drugs used in each of the subgroups included in the meta-analysis were the same, but the specific drug usage was different. In this study, different doses of LE were used including 2.5 mg/d or 5 mg/d or 7.5 mg/d, and the effect of different doses of LE was still currently controversial. A retrospective study by Portella showed that there was no statistical difference in the endometrial thickness and pregnancy rate between the 2.5 mg/d LE and the 5.0 mg/d LE when it is time to inject human chorionic gonadotropin;[31] a randomized controlled trial by Badawy A in 2007 showed that there was no significant difference in the pregnancy rate and abortion rate between the doses of LE 2.5 mg/d, 5 mg/d and 7.5 mg/d;[32] nevertheless, a randomized controlled trial of Fadhli showed: the pregnancy rate of 5 mg/d for 5 days is higher than 2.5 mg/d.[33] These might affect the reliability and applicability of current meta-analysis, but there was no heterogeneity that showed the different does of LE did not make a great influence on this result.

There are also some limitations in our study as following. Firstly, the quality of the original research methodology incorporated has their own limitations; Secondly, few studies based on patients with same characteristics and there is no one completely uniform medication regimen; Besides, the sample size is small; Ultimately, inadequate follow-up time leads to imperfect indicators.

4 Conclusion

Combined with the results of current systematic review and meta-analysis through subgroup analysis and sensitivity analysis, we can be cautious: in general, compared with CC LE is an effective treatment in the IUI cycle, has a likelihood to improve dominant follicles and reduces the miscarriage rate.

Author contributions

All authors’ contributions are equal.


[1]. Zegers-Hochschild F, Adamson GD, Dyer S, et al. The International Glossary on Infertility and Fertility Care, 2017. Hum Reprod 2017;32:1786–801.
[2]. Guzick DS, Carson SA, Coutifaris C, et al. Efficacy of superovulation and intrauterine insemination in the treatment of infertility. National Cooperative Reproductive Medicine Network. N Engl J Med 1999;340:177–83.
[3]. Arici A, Byrd W, Bradshaw K, et al. Evaluation of clomiphene citrate and human chorionic gonadotropin treatment: a prospective, randomized, crossover study during intrauterine insemination cycles. Fertil Steril 1994;61:314–8.
[4]. Cohlen BJ, Vandekerckhove P, te Velde ER, et al. Timed intercourse versus intra-uterine insemination with or without ovarian hyperstimulation for subfertility in men. Cochrane Database Syst Rev 2000;3:CD001838.
[5]. Kistner RW. Induction of ovulation with clomiphene citrate (clomid). Obstet Gynecol Surv 1965;20:873–900.
[6]. Adashi EY. Clomiphene citrate: mechanism(s) and site(s) of action-a hypothesis revisited. Fertil Steril 1984;42:331–44.
[7]. Gonen Y, Casper RF. Sonographic determination of a possible adverse effect of clomiphene citrate on endometrial growth. Hum Reprod 1990;5:670–4.
[8]. Eden JA, Place J, Carter GD, et al. The effect of clomiphene citrate on follicular phase increase in endometrial thickness and uterine volume. Obstet Gynecol 1989;73:187–90.
[9]. Nakamura Y, Ono M, Yoshida Y, et al. Effects of clomiphene citrate on the endometrial thickness and echogenic pattern of the endometrium. Fertil Steril 1997;67:256–60.
[10]. Randall JM, Templeton A. Cervical mucus score and in vitro sperm mucus interaction in spontaneous and clomiphene citrate cycles. Fertil Steril 1991;56:465–8.
[11]. Mitwally MF, Casper RF. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril 2001;75:305–9.
[12]. Al-Omari WR, Sulaiman WR, Al-Hadithi N. Comparison of two aromatase inhibitors in women with clomiphene-resistant polycystic ovary syndrome. Int J Gynaecol Obstet 2004;85:289–91.
[13]. Atay V, Cam C, Muhcu M, et al. Comparison of letrozole and clomiphene citrate in women with polycystic ovaries undergoing ovarian stimulation. J Int Med Res 2006;34:73–6.
[14]. Lipton A, Demers LM, Harvey HA, et al. Letrozole (CGS 20267). A phase I study of a new potent oral aromatase inhibitor of breast cancer. Cancer 1995;75:2132–8.
[15]. Sioufi A, Gauducheau N, Pineau V, et al. Absolute bioavailability of letrozole in healthy postmenopausal women. Biopharm Drug Dispos 1997;18:779–89.
[16]. Young SL, Opsahl MS, Fritz MA. Serum concentrations of enclomiphene and zuclomiphene across consecutive cycles of clomiphene citrate therapy in anovulatory infertile women. Fertil Steril 1999;71:639–44.
[17]. Fouda UM, Sayed AM. Extended letrozole regimen versus clomiphene citrate for superovulation in patients with unexplained infertility undergoing intrauterine insemination: a randomized controlled trial. Reprod Biol Endocrinol 2011;9:84–184.
[18]. Al-Fozan H, Al-Khadouri M, Tan SL, et al. A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation. Fertil Steril 2004;82:1561–3.
[19]. Elnashar A, Badawy A, Totongy M. Clomiphene citrate or aromatase inhibitors for superovulation in women with unexplained infertility undergoing intrauterine insemination: a prospective randomized trial. Hum Reprod 2011;26: (Suppl 1): P-308.
[20]. Badawy A, Elnashar A, Totongy M. Clomiphene citrate or aromatase inhibitors for superovulation in women with unexplained infertility undergoing intrauterine insemination: a prospective randomized trial. Fertil Steril 2009;92:1355–9.
[21]. Akbari Sene A, Ghorbani S, Ashrafi M. Comparison of the pregnancy outcomes and the incidence of fetal congenital abnormalities in infertile women treated with letrozole and clomiphene citrate. J Obstet Gynaecol Res 2018;44:1036–41.
[22]. Khanna SC, Kumar A, Joy SG, et al. Is letrozole superior to clomiphene for ovarian stimulation prior to intrauterine insemination? Arch Gynecol Obstet 2013;287:571–5.
[23]. Higgins JPT, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ 2003;327:557–60.
[24]. Cole PA, Robinson CH. Mechanism and inhibition of cytochrome P-450 aromatase. J Med Chem 1990;33:2933–42.
[25]. Akhtar M, Njar VC, Wright JN. Mechanistic studies on aromatase and related C-C bond cleaving P-450 enzymes. J Steroid Biochem Mol Biol 1993;44:375–87.
[26]. Mitwally MFM, Casper RF. Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders. Fertil Steril 2002;77:776–80.
[27]. Healey S, Tan SL, Tulandi T, et al. Effects of letrozole on superovulation with gonadotropins in women undergoing intrauterine insemination. Fertil Steril 2003;80:1325–9.
[28]. Vendola KA, Zhou J, Adesanya OO, et al. Androgens stimulate early stages of follicular growth in the primate ovary. J Clin Invest 1998;101:2622–9.
[29]. Dickey RP, Olar TT, Taylor SN, et al. Relationship of endometrial thickness and pattern to fecundity in ovulation induction cycles: effect of clomiphene citrate alone and with human menopausal gonadotropin. Fertil Steril 1993;59:756–60.
[30]. Opsahl MS, Robins ED, O’Connor DM, et al. Characteristics of gonadotropin response, follicular development, and endometrial growth and maturation across consecutive cycles of clomiphene citrate treatment. Fertil Steril 1996;66:533–9.
[31]. Noriega-Portella L, Noriega-Hoces L, Delgado A, et al. Effect of letrozole at 2.5 mg or 5.0 mg/day on ovarian stimulation with gonadotropins in women undergoing intrauterine insemination. Fertil Steril 2008;90:1818–25.
[32]. Badawy A, Metwally M, Fawzy M. Randomized controlled trial of three doses of letrozole for ovulation induction in patients with unexplained infertility. Reprod Biomed Online 2007;14:559–62.
[33]. Al-Fadhli R, Sylvestre C, Buckett W, et al. A randomized trial of superovulation with two different doses of letrozole. Fertil Steril 2006;85:161–4.

clomiphene; intrauterine insemination; letrozole; superovulation; unexplained infertility

Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.