A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation
Open accessAbstract
Objective To compare the effects of the aromatase inhibitor letrozole (7.5 mg) and clomiphene citrate (CC; 100 mg) in women undergoing superovulation and IUI.Design Prospective randomized trial.Setting University teaching hospital.Patient(s) We studied a total of 238 cycles of superovulation and IUI in women with idiopathic infertility.Interventions Patients were randomized into treatment with 7.5 mg of letrozole daily (74 patients, 115 cycles) or 100 mg of CC daily (80 patients, 123 cycles).Main outcome measure(s) Number of follicles, endometrial thickness, pregnancy rate, and miscarriage rate.Result(s) The mean age, parity, and duration of infertility in both groups of patients were similar. There was no significant difference between the total number of developing follicles in the letrozole (5.7 +/- 3.7) and in the CC groups (4.8 +/- 2.5). The number of follicles of > or =14 mm and of >18 mm were 2.1 +/- 1.2 and 1.4 +/- 0.7 in the letrozole group, and 1.7 +/- 0.9 and 1.1 +/- 0.5 in the CC group, respectively. No difference was found in the endometrial thickness between the two groups (7.1 +/- 0.2 mm in the letrozole group, 8.2 +/- 5.9 mm in the CC group). The pregnancy rate per cycle was 11.5% in the letrozole group and 8.9% in the CC group. Four of the 11 pregnancies in the CC group resulted in a miscarriage (36.6%).Conclusion(s) Superovulation and IUI with letrozole and CC are associated with similar pregnancy rates, but the miscarriage rate is higher with CC. The ideal dose of letrozole remains unknown and further study is needed.
AI snapshot
Written from the paper’s full text.
TL;DR
In a randomized trial of 238 superovulation/IUI cycles, letrozole 7.5 mg and clomiphene citrate 100 mg produced similar pregnancy rates, but CC was associated with a higher miscarriage rate. The ideal letrozole dose remained unknown and further study was recommended.
Key findings
- Pregnancy rate per cycle was 11.5% with letrozole and 8.9% with CC.
- Miscarriage occurred in 4 of 11 CC pregnancies (36.6% in the abstract; 36.7% in the results) versus no miscarriages in the letrozole group; two ectopic pregnancies occurred with letrozole.
- Total follicle numbers and endometrial thickness did not differ significantly between groups, but mature follicle counts were higher with letrozole: Table 2 reports follicles >14 mm as 2.0 ± 0.1 vs 1.7 ± 0.1 and dominant follicles as 1.3 ± 0.1 vs 1.1 ± 0.1.
- Baseline age, parity, and duration of infertility were similar between groups.
Methods
- Prospective randomized trial at a university teaching hospital (Royal Victoria Hospital, McGill University Health Center) from July 2002 to September 2003, including 238 superovulation/IUI cycles in women with idiopathic infertility; inclusion required infertility ≥1 year, patent tubes on hysterosalpingogram, and normal semen analysis.
- Patients were randomized by computer-generated random table to letrozole 7.5 mg daily (74 patients, 115 cycles) or CC 100 mg daily (80 patients, 123 cycles) on days 3–7; hCG 10,000 U IM was given when the dominant follicle reached ≥18 mm, with IUI 24 and 48 hours later.
- Outcomes were total follicles, endometrial thickness, pregnancy rate, and miscarriage rate; analysis used Student’s t test, Wilcoxon rank-sum test, and a chi-square-type test for proportions, with P<.05 considered significant.
Limitations
- The paper states that the ideal dose of letrozole remains unknown and that further study is needed; it also states that a larger study is needed to clarify why more mature follicles in the letrozole group did not produce a higher pregnancy rate.
- Evident from the text: this was a small single-center trial with no blinding described, and the miscarriage comparison rests on small numbers (4/11 CC pregnancies vs 0/11 letrozole pregnancies).
- Evident from the text: reported values are inconsistent across sections, including total follicle counts, endometrial thickness, and the CC miscarriage percentage.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 16 cited sources checked · 0 supported · 0 flagged
- Findingown data
There was no significant difference in endometrial thickness between the letrozole and clomiphene citrate groups.
“No difference was found in the endometrial thickness between the two groups (7.1 Ϯ 0.2 mm in the letrozole group, 8.2 Ϯ 5.9 mm in the CC group).”
- Also stated in: § RESULTS · plain
“There was no significant difference in the endometrial thickness between the two groups.”
Quote in the paperNot a substantial claim - Also stated in: § RESULTS · plain
- Findingown data
There was no significant difference in the total number of developing follicles between the letrozole and clomiphene citrate groups.
“There was no significant difference between the total number of developing follicles in the letrozole (5.7 Ϯ 3.7) and in the CC groups (4.8 Ϯ 2.5).”
- Also stated in: § RESULTS · plain
“The total numbers of follicles during stimulation were similar between the two groups (5.5 Ϯ 0.4 in the letrozole group, 4.8 Ϯ 0.3 in the CC group).”
Quote in the paperNot a substantial claim - Also stated in: § RESULTS · plain
- Findingown data
The number of follicles >18 mm was significantly higher in the letrozole group than in the clomiphene citrate group.
“The number of follicles of Ն14 mm and of Ͼ18 mm were 2.1 Ϯ 1.2 and 1.4 Ϯ 0.7 in the letrozole group, and 1.7 Ϯ 0.9 and 1.1 Ϯ 0.5 in the CC group, respectively.”
- Also stated in: § RESULTS · plain
“The number of follicles Ն14 mm and Ͼ18 mm were significantly higher in the letrozole group (Table 2).”
Quote in the paperNot a substantial claim - Also stated in: § RESULTS · plain
- Findingown data
The number of follicles ≥14 mm was significantly higher in the letrozole group than in the clomiphene citrate group.
“The number of follicles of Ն14 mm and of Ͼ18 mm were 2.1 Ϯ 1.2 and 1.4 Ϯ 0.7 in the letrozole group, and 1.7 Ϯ 0.9 and 1.1 Ϯ 0.5 in the CC group, respectively.”
- Also stated in: § RESULTS · plain
“The number of follicles Ն14 mm and Ͼ18 mm were significantly higher in the letrozole group (Table 2).”
Quote in the paperNot a substantial claim - Also stated in: § RESULTS · plain
- Findingreasoning
The higher number of mature follicles in the letrozole group did not result in a higher pregnancy rate.
“The higher number of mature follicles in the letrozole group did not result in a higher pregnancy rate.”
Quote in the paperSubstantial claim
- Premisecitation
The ideal dose of letrozole for superovulation or ovulation induction remains unknown.
“The ideal dose of letrozole for superovulation or ovulation induction is still unknown.”
- Also stated in: § T A B L E 2 · plain
“The ideal dose of letrozole is still unknown and further study is required.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [8] Mitwally, 2001, Use of aromatase inhibitor for ovulation induction in patients with an inadequate response to clomiphene citrate, Fertil Steril source
Not checked in the free run.
- cites [9] Sammour A, Biljan MM, Tan SL, Tulandi T. Prospective randomized trial comparing the effects of letrozole and clomiphene citrate (CC) on follicular development, endometrial thickness and pregnancy rate in patients undergoing superovulation prior to intrauterine insemination [Abstract 291]. 57th Annual Meeting of the American Society for Reproductive Medicine, October 20–25, 2001, Orlando, FL. source
Not checked in the free run.
- Also stated in: § T A B L E 2 · plain
- Interpretationown data
Superovulation and IUI with letrozole and clomiphene citrate are associated with similar pregnancy rates.
“Superovulation and IUI with letrozole and CC are associated with similar pregnancy rates, but the miscarriage rate is higher with CC.”
- Also stated in: § T A B L E 2 · hedged
“The results of our study suggest that superovulation with letrozole and CC is associated with similar pregnancy rates, but the miscarriage rate is higher with CC.”
Quote in the paperSubstantial claim- Rests on an assumption: The study had sufficient statistical power to detect a difference in pregnancy rates between letrozole and clomiphene citrate.
- Also stated in: § T A B L E 2 · hedged
- Study design and conductown data
In women with idiopathic infertility undergoing superovulation and IUI, mean age, parity, and duration of infertility were similar between the letrozole and clomiphene citrate groups.
“The mean age, parity, and duration of infertility in both groups of patients were similar.”
- Also stated in: § RESULTS · plain
“The mean age, parity, and duration of infertility in both groups of patients were similar (Table 1).”
Quote in the paperNot a substantial claim - Also stated in: § RESULTS · plain
- Interpretationreasoning
Letrozole is potentially a new drug for ovulation induction or superovulation.
“Letrozole is potentially a new drug for ovulation induction or superovulation.”
Quote in the paperSubstantial claim - Premisecitation
Letrozole improves ovarian response to follicle-stimulating hormone in poor responder women.
“This is in agreement with the previous report (19) that letrozole improves ovarian response to FSH in poor responder women.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] Mitwally, 2002, Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders, Fertil Steril source
Not checked in the free run.
- Premisecitation
In a previous study, the addition of letrozole (5 mg daily for 5 days) to gonadotropin was associated with a thinner endometrium than gonadotropin alone.
“In our previous study, we reported that the addition of letrozole (5 mg daily for 5 days) to gonadotropin is associated with a thinner endometrium than gonadotropin alone (20).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Healey, 2003, Effects of letrozole on superovulation with gonadotropins in women undergoing intrauterine insemination, Fertil Steril source
Not checked in the free run.
- Premisecitation
Clomiphene citrate use is associated with endometrial thinning in 15%-50% of patients.
“The use of CC is associated with endometrial thinning in 15%-50% of patients (10 -12).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [10] Gonen, 1990, Sonographic determination of a possible adverse effect of clomiphene citrate on endometrial growth, Hum Reprod source
Not checked in the free run.
- cites [11] Yagel, 1992, The effect of ethinyl estradiol on endometrial thickness and uterine volume during ovulation induction by clomiphene citrate, Fertil Steril source
Not checked in the free run.
- cites [12] Dickey, 1993, Relationship of endometrial thickness and pattern to fecundity in ovulation induction cycles: effect of clomiphene citrate alone and with human menopausal gonadotropin, Fertil Steril source
Not checked in the free run.
- Premisecitation
Compared with clomiphene citrate, letrozole is associated with a thicker endometrium.
“Compared with CC, letrozole is associated with a thicker endometrium (8).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8] Mitwally, 2001, Use of aromatase inhibitor for ovulation induction in patients with an inadequate response to clomiphene citrate, Fertil Steril source
Not checked in the free run.
- May combine two claims. 7
- The quote only partly states this claim. 1
- Classified as probably not a substantial claim. 3
May combine two claims. The quote only partly states this claim.
Findingown dataThe miscarriage rate was higher in the clomiphene citrate group than in the letrozole group; 4 of 11 pregnancies (36.7%) in the CC group resulted in miscarriage, whereas no miscarriages occurred in the letrozole group.
“Four of the 11 pregnancies in the CC group resulted in a miscarriage (36.6%).”
- Also stated in: § T A B L E 2 · plain
“miscarriage rate was higher in the CC group.”
Quote in the paperSubstantial claim- Rests on an assumption: The observed difference in miscarriage rate between clomiphene citrate and letrozole groups is not due to chance.
- Also stated in: § T A B L E 2 · plain
May combine two claims.
Findingown dataThe pregnancy rate per cycle was 11.5% in the letrozole group and 8.9% in the clomiphene citrate group.
“The pregnancy rate per cycle was 11.5% in the letrozole group and 8.9% in the CC group.”
- Also stated in: § RESULTS · plain
“The pregnancy rate per cycle was 11.5% in the letrozole group and 8.9% in the CC group.”
Quote in the paperSubstantial claim- Also stated in: § RESULTS · plain
May combine two claims.
PremisecitationClomiphene citrate treatment is associated with a discrepancy between ovulation and conception rates, and a higher incidence of miscarriage than in the general population.
“In addition, CC treatment is associated with a discrepancy between ovulation and conception rates, and the incidence of miscarriage is higher than in the general population (2)(3)(4)(5).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [2] Franks, 1985, Ovulatory disorders in women with polycystic ovary syndrome, Clin Obstet Gynecol
Not checked in the free run.
- cites [3] Kistner, 1965, Induction of ovulation with clomiphene citrate (clomid), Obstet Gynecol Survey source
Not checked in the free run.
- cites [4] Rabau, 1967, Current concepts in the treatment of anovulation, Br Med J source
Not checked in the free run.
May combine two claims.
PremisecitationLetrozole doses of 2.5 mg and 5 mg have been tested and produced similar responses.
“Two doses regimens have been tested (2.5 mg and 5 mg) with similar response (8,9).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [8] Mitwally, 2001, Use of aromatase inhibitor for ovulation induction in patients with an inadequate response to clomiphene citrate, Fertil Steril source
Not checked in the free run.
- cites [9] Sammour A, Biljan MM, Tan SL, Tulandi T. Prospective randomized trial comparing the effects of letrozole and clomiphene citrate (CC) on follicular development, endometrial thickness and pregnancy rate in patients undergoing superovulation prior to intrauterine insemination [Abstract 291]. 57th Annual Meeting of the American Society for Reproductive Medicine, October 20–25, 2001, Orlando, FL. source
Not checked in the free run.
May combine two claims.
PremisecitationIn a prior study, letrozole (2.5 mg daily for 5 days) induced ovulation in 9 of 12 cycles and 3 of 12 women with inadequate response to clomiphene citrate conceived.
“Mitwally and Casper (8) used letrozole (2.5 mg daily for 5 days) in 12 women with inadequate response to CC. Ovulation occurred in 9 of 12 cycles and 3 patients conceived.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] Mitwally, 2001, Use of aromatase inhibitor for ovulation induction in patients with an inadequate response to clomiphene citrate, Fertil Steril source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationLetrozole is an aromatase inhibitor that has been widely used in women with breast cancer.
“Letrozole is an aromatase inhibitor that has been widely used in women with breast cancer (7).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] Pfister, 2001, Effect of age and single versus multiple doses, pharmacokinetic of letrozole (Femara) in breast cancer patients, Biopharm Drug Dispos source
Not checked in the free run.
May combine two claims.
PremisecitationGonadotropin is associated with a higher risk of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies than clomiphene citrate.
“However, it is associated with a higher risk of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies (6).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6] Kettel, 1993, Hypothalamic-pituitary-ovarian response to clomiphene citrate in women with polycystic ovary syndrome, Fertil Steril source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenUltrasound examinations were performed by the same two ultrasonographers.
“The ultrasound examination was done by the same two ultrasonographers.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataRandomization was performed using a computer-generated random table.
“The randomization was done using a computer-generated random table.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The study had sufficient statistical power to detect a difference in pregnancy rates between letrozole and clomiphene citrate.
“The pregnancy rate per cycle was 11.5% in the letrozole group and 8.9% in the CC group.”
“Superovulation and IUI with letrozole and CC are associated with similar pregnancy rates, but the miscarriage rate is higher with CC.”
The paper relies on this without support.
The observed difference in miscarriage rate between clomiphene citrate and letrozole groups is not due to chance.
“miscarriage rate was higher in the CC group.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In a randomized trial of 238 cycles of superovulation in women with idiopathic infertility, pregnancy rates with 7.5 mg letrozole and 100 mg CC daily for 5 days were similar, but the miscarriage rate in the CC-treated cycles was higher.
“In another randomized trial of 238 cycles of superovulation in women with idiopathic infertility (75), we compared 7.5 mg of letrozole and 100 mg of CC daily for 5 days.The pregnancy rates in both groups were similar, but the miscarriage rate in the CC-treated cycles was higher.”
From A new era in ovulation induction (2006) · cites this paper as [75]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Total follicle counts differ between the abstract and results
MajorThe abstract reports 5.7 ± 3.7 follicles for letrozole and 4.8 ± 2.5 for CC, while the results report 5.5 ± 0.4 and 4.8 ± 0.3 for the same groups.
“There was no significant difference between the total number of developing follicles in the letrozole (5.7 Ϯ 3.7) and in the CC groups (4.8 Ϯ 2.5).”
“The total numbers of follicles during stimulation were similar between the two groups (5.5 Ϯ 0.4 in the letrozole group, 4.8 Ϯ 0.3 in the CC group).”
CC endometrial-thickness variability differs between the abstract and table
MinorThe abstract gives 8.2 ± 5.9 mm for the CC group, whereas the table gives 8.2 ± 0.6 mm at hCG.
“No difference was found in the endometrial thickness between the two groups (7.1 Ϯ 0.2 mm in the letrozole group, 8.2 Ϯ 5.9 mm in the CC group).”
“Endometrial thickness at hCG (mm) 7.1 Ϯ 0.2 8.2 Ϯ 0.6”
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Self-citationINDUCTIOS OF OVULATIOK WITH CLOAIIPHESE CITRATE (CLOAIID)
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“5 mg/day have been associated with thinning of the endometrium as seen with clomiphene citrate (67).”
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“, 2007) and three compared letrozole and clomiphene citrate (Al-Fozan et al., 2004; Barroso et al., 2006; Fatemi et al., 2003).”
BackgroundUse of letrozole in assisted reproduction: a systematic review and meta-analysis
Requena, A., Herrero, J. C., Landeras, J., Navarro, E., Neyro, J. L., Salvador, C., Tur, R., Callejo, J., Checa, M. Á., Farré, M., et al. (2008) · Human Reproduction Update · doi:10.1093/humupd/dmn033 · Cited by 197 · see citing works
“Al-Fozan et al. (2004) compared the effects of the letrozole (7.”
BackgroundInfluentialEvidence-based treatments for couples with unexplained infertility: a guideline
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A new era in ovulation induction
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RetractedUse of clomiphene citrate in infertile women: a committee opinion
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Bayar, Ü., Başaran, M., Kıran, S., Coşkun, A., & Gezer, Ş. (2006) · Fertility and Sterility · doi:10.1016/j.fertnstert.2006.04.026 · Cited by 100 · see citing works
Casper, R. F., & Mitwally, M. F. (2011) · Clinical Obstetrics & Gynecology · doi:10.1097/grf.0b013e3182353d0f · Cited by 99 · see citing works
“Doses higher than 5mg per day for 5 days could result in persistence of aromatase inhibition and estrogen levels too low for normal endometrial development by the time of ovulation.(27) We also published data on a single 20-mg dose of letrozole given on cycle day 3.”
BackgroundWeiss, N. S., van Vliet, M. N., Limpens, J., Hompes, P. G. A., Lambalk, C. B., Mochtar, M. H., van der Veen, F., Mol, B. W., & van Wely, M. (2017) · Human Reproduction · doi:10.1093/humrep/dex035 · Cited by 100 · see citing works
“reported pregnancy rates without defining the type of pregnancy, but since ultrasound findings were available we interpreted pregnancy outcomes as clinical pregnancy rates (Al-Fozan et al., 2004; Barroso et al., 2006; Akbary-Asbagh et al., 2007; Badawy et al., 2009, 2010).”
MethodOvulation Induction in Polycystic Ovary Syndrome
Vause, T. D. R., Cheung, A. P., Cheung, A. P., Sierra, S., Claman, P., Graham, J., Guillemin, J.-A., Lapensée, L., Steward, S., Vause, T. D. R., et al. (2010) · Journal of Obstetrics and Gynaecology Canada · doi:10.1016/s1701-2163(16)34504-2 · Cited by 97 · see citing works
Reproduction beyond cancer: A message of hope for young women
Maltaris, T., Boehm, D. U., Dittrich, R., Seufert, R., & Koelbl, H. (2006) · Gynecologic Oncology · doi:10.1016/j.ygyno.2006.08.003 · Cited by 97 · see citing works
Sohrabvand, F., Ansari, S., & Bagheri, M. (2006) · Human Reproduction · doi:10.1093/humrep/del020 · Cited by 97 · see citing works
“In the study performed by Al-Fozan et al. (2004), per-cycle pregnancy was 11.5% in the letrozole and 8.9% in the clomiphene citrate groups, which was not statistically significant.”
BackgroundInfluentialLetrozole vs. clomiphene citrate in patients with ovulatory infertility
Bayar, Ü., Tanriverdi, H. A., Barut, A., Ayoğlu, F. N., Özcan, O., & Kaya, E. (2006) · Fertility and Sterility · doi:10.1016/j.fertnstert.2005.09.045 · Cited by 93 · see citing works
Progesterone receptor modulators and the endometrium: changes and consequences†
Horne, F. M., & Blithe, D. (2007) · Human Reproduction Update · doi:10.1093/humupd/dmm023 · Cited by 93 · see citing works
Roy, K., Baruah, J., Singla, S., Sharma, J., Singh, N., Jain, S. K., & Goyal, M. (2012) · Journal of Human Reproductive Sciences · doi:10.4103/0974-1208.97789 · Cited by 95 · see citing works
“5 mg and compared with 100 mg of CC, there was no significant difference in ET.[3] In contrast, another study reported that the endometrial development was higher in letrozole group using 7.”
InfluentialBadawy, A., Shokeir, T. A., ALLAM, A. F., & Abdel‐Hady, H. (2008) · Acta Obstetricia Et Gynecologica Scandinavica · doi:10.1080/00016340802638199 · Cited by 90 · see citing works
Buckett, W. M., & Sierra, S. (2019) · Reproductive BioMedicine Online · doi:10.1016/j.rbmo.2019.05.023 · Cited by 85 · see citing works
A randomized trial of superovulation with two different doses of letrozole
Al-Fadhli, R., Sylvestre, C. V., Buckett, W. M., Tan, S. L., & Tulandi, T. (2006) · Fertility and Sterility · doi:10.1016/j.fertnstert.2005.07.1283 · Cited by 84 · see citing works
Self-citationGanesh, A., Goswami, S. K., Chattopadhyay, R., Chaudhury, K., & Chakravarty, B. (2009) · Journal of Assisted Reproduction and Genetics · doi:10.1007/s10815-008-9284-4 · Cited by 79 · see citing works
“Several smaller prospective randomized trials have also shown that letrozole may be an acceptable alternative to CC as an ovulation induction drug in women with PCOS [24–26].”
BackgroundBadawy, A., Mosbah, A., & Shady, M. (2008) · Fertility and Sterility · doi:10.1016/j.fertnstert.2007.05.010 · Cited by 76 · see citing works
RetractedLetrozole for ovulation induction and controlled ovarian hyperstimulation
Pritts, E. A. (2010) · Current Opinion in Obstetrics & Gynecology · doi:10.1097/gco.0b013e32833beebf · Cited by 76 · see citing works
Aromatase inhibitors in ovarian stimulation for IVF/ICSI: a pilot study
Verpoest, W., Kolibianakis, E. M., Papanikolaou, E. G. E., Smitz, J. E. J., Steirteghem, A. V., & Devroey, P. (2006) · Reproductive BioMedicine Online · doi:10.1016/s1472-6483(10)60611-6 · Cited by 70 · see citing works
“5 mg of letrozole versus 100 mg of clomiphene citrate daily for 5 days in women with idiopathic infertility did not show a difference in pregnancy rate; however, the miscarriage rate in the clomiphene citrate group was higher (Al-Fozan et al., 2004).”
BackgroundFouda, U. M., & Sayed, A. M. (2011) · Reproductive Biology and Endocrinology · doi:10.1186/1477-7827-9-84 · Cited by 65 · see citing works
“On the other hand, other studies revealed that the endometrial thickness was comparable in patients treated with letrozole or clomiphene citrate [19,28].”
ResultBadawy, A., Elnashar, A., & Totongy, M. (2008) · Fertility and Sterility · doi:10.1016/j.fertnstert.2008.06.013 · Cited by 63 · see citing works
RetractedGonadal damage and options for fertility preservation in female and male cancer survivors
Maltaris, T., Koelbl, H., Seufert, R., Kiesewetter, F., Beckmann, M. W., Mueller, A., & Dittrich, R. (2006) · Asian Journal of Andrology · doi:10.1111/j.1745-7262.2006.00206.x · Cited by 61 · see citing works
Baruah, J., Roy, K. K., Rahman, S. M., Kumar, S., Sharma, J. B., & Karmakar, D. (2008) · Archives of Gynecology and Obstetrics · doi:10.1007/s00404-008-0714-4 · Cited by 59 · see citing works
Ovarian function and childbearing issues in breast cancer survivors
Gadducci, A., Cosio, S., & Genazzani, A. R. (2007) · Gynecological Endocrinology · doi:10.1080/09513590701582406 · Cited by 59 · see citing works
Badawy, A., Metwally, M., & Fawzy, M. (2007) · Reproductive BioMedicine Online · doi:10.1016/s1472-6483(10)61046-2 · Cited by 59 · see citing works
RetractedMcClamrock, H. D., Jones, H. W., & Adashi, E. Y. (2012) · Fertility and Sterility · doi:10.1016/j.fertnstert.2012.02.031 · Cited by 58 · see citing works
“Al-Fozan (70) 2004 115 74 Al-Fadhli (74) 2005 38 38 34 34 Badawy (71) 2009 400 205 Abu Hashim (72) 2011 220 69 Fouda (73) 2011 211 107”
Aromatase inhibitors for female infertility: a systematic review of the literature
Polyzos, N. P., Tzioras, S., Badawy, A., Valachis, A., Dritsas, C., & Mauri, D. N. (2009) · Reproductive BioMedicine Online · doi:10.1016/j.rbmo.2009.06.008 · Cited by 57 · see citing works
Jee, B. C., Ku, S., Suh, C. S., Kim, K. C., Lee, W. D., & Kim, S. H. (2006) · Fertility and Sterility · doi:10.1016/j.fertnstert.2006.02.070 · Cited by 57 · see citing works
Mitwally, M. F., Casper, R. F., & Diamond, M. P. (2005) · Reproductive Biology and Endocrinology · doi:10.1186/1477-7827-3-54 · Cited by 55 · see citing works
Hu, S., Yu, Q., Wang, Y., Wang, M., Xia, W., & Zhu, C. (2018) · Archives of Gynecology and Obstetrics · doi:10.1007/s00404-018-4688-6 · Cited by 53 · see citing works
“However, clomiphene has drawbacks, such as a long half-life (2 weeks) [5] that results in long-lasting adverse effects on cervical mucus [6] and endometrial development [7], leading to discrepancies in ovulation and pregnancy rates [6, 8, 9].”
BackgroundBarroso, G., Menocal, G., Felix, H., Ruiz, J. C. R., Arslan, M., & Oehninger, S. (2006) · Fertility and Sterility · doi:10.1016/j.fertnstert.2006.03.044 · Cited by 53 · see citing works
Clomiphene citrate and intrauterine insemination: analysis of more than 4100 cycles
Dovey, S. L., Sneeringer, R. M., & Penzias, A. S. (2008) · Fertility and Sterility · doi:10.1016/j.fertnstert.2007.10.057 · Cited by 53 · see citing works
Ray, P. B., Ray, A., & Chakraborti, P. S. (2011) · Archives of Gynecology and Obstetrics · doi:10.1007/s00404-011-2091-7 · Cited by 54 · see citing works
Diamond, M. P., Mitwally, M., Casper, R. F., Ager, J. W., Legro, R. S., Brzyski, R. G., Casson, P. R., Eisenberg, E., & Heping Zhang, D. (2011) · Contemporary Clinical Trials · doi:10.1016/j.cct.2011.07.009 · Cited by 49 · see citing works
“Recently, several descriptive reports have suggested that the use of aromatase inhibitors for ovarian stimulation may be an alternative to CC and gonadotropins, and that such use may be associated with monofollicular development, thereby reducing the rate of multiple gestation pregnancies.[5, 6, 7, 8, 9, 10] The latte…”
BackgroundKooshesh, L., Bahmanpour, S., Zeighami, S., & Nasr‐Esfahani, M. H. (2020) · Reproductive Biology and Endocrinology · doi:10.1186/s12958-020-00591-2 · Cited by 48 · see citing works
Wang, L., Lv, S., Li, F., Bai, E., & Yang, X. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.532692 · Cited by 48 · see citing works
“In addition to the side effects on cervical mucus (15), the main reason is that CC impaired endometrial development, which resulted in endometrial thinning and lower receptivity in PCOS women (16).”
BackgroundBadawy, A., Mosbah, A., Tharwat, A., & Eid, M. (2009) · Fertility and Sterility · doi:10.1016/j.fertnstert.2008.04.065 · Cited by 45 · see citing works
RetractedNew advances in ovulation induction
Kafy, S., & Tulandi, T. (2007) · Current Opinion in Obstetrics & Gynecology · doi:10.1097/gco.0b013e3280c60c9a · Cited by 47 · see citing works
Self-citationDiamond, M. P., Legro, R. S., Coutifaris, C., Alvero, R. J., Robinson, R. D., Casson, P. R., Christman, G. M., Ager, J. W., Huang, H., Hansen, K. R., et al. (2015) · Fertility and Sterility · doi:10.1016/j.fertnstert.2014.12.130 · Cited by 44 · see citing works
Lazer, T., Dar, S., Shlush, E., Kudmani, B. S. A., Quach, K., Sojecki, A., GLASS, K. B., Sharma, P., Baratz, A. Y., & Librach, C. L. (2014) · International Journal of Reproductive Medicine · doi:10.1155/2014/581451 · Cited by 44 · see citing works
Lee, V. C. Y., Chan, C. C. W., Ng, E. H. Y., Yeung, W. S. B., & Ho, P. C. (2011) · Reproductive BioMedicine Online · doi:10.1016/j.rbmo.2011.05.012 · Cited by 44 · see citing works
“5 mg letrozole in intrauterine insemination showed a non-significantly higher number of follicles than using 100 mg clomiphene citrate in women with unexplained infertility (Al-Fozan et al. 2004).”
BackgroundMethodInfluentialQuaas, A. M., Gavrizi, S. Z., Peck, J. D., Diamond, M. P., Legro, R. S., Robinson, R. D., Casson, P. R., Christman, G. M., Zhang, H., & Hansen, K. R. (2020) · Fertility and Sterility · doi:10.1016/j.fertnstert.2020.07.030 · Cited by 44 · see citing works
Bao, S. H., Sheng, S. L., Peng, Y. F., & Lin, Q. D. (2008) · Fertility and Sterility · doi:10.1016/j.fertnstert.2007.11.024 · Cited by 43 · see citing works
Aromatase inhibitors for ovulation induction and ovarian stimulation
Lee, V. C. Y., & Ledger, W. J. (2011) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2011.04006.x · Cited by 42 · see citing works
IUI for unexplained infertility—a network meta-analysis
Danhof, N. A., Wang, R., van Wely, M., van der Veen, F., Mol, B. W., & Mochtar, M. H. (2019) · Human Reproduction Update · doi:10.1093/humupd/dmz035 · Cited by 41 · see citing works
Jirge, P. R., & Patil, R. S. (2008) · Fertility and Sterility · doi:10.1016/j.fertnstert.2008.10.009 · Cited by 39 · see citing works
“The observation may be clinically significant—requiring reconsideration of protocols for timed intercourse and IUI.”
BackgroundMethodBedaiwy, M. A., Abdel-Aleem, M. A., Hussein, M., Mousa, N. A., Brunengraber, L. N., & Casper, R. F. (2011) · Reproductive Biology and Endocrinology · doi:10.1186/1477-7827-9-83 · Cited by 38 · see citing works
Mehdinejadiani, S., Amidi, F., Mehdizadeh, M., Barati, M., Pazhohan, A., Alyasin, A., Mehdinejadiani, K., & Sobhani, A. (2018) · Biology of Reproduction · doi:10.1093/biolre/ioy187 · Cited by 36 · see citing works
ACOG Committee Opinion No. 738: Aromatase Inhibitors in Gynecologic Practice
(2018) · Obstetrics and Gynecology · doi:10.1097/aog.0000000000002640 · Cited by 36 · see citing works
The definition of unexplained infertility: A systematic review
Raperport, C., Desai, J., Qureshi, D., Rustin, E., Balaji, A., Chronopoulou, E., Homburg, R., Khan, K. S., & Bhide, P. (2023) · BJOG An International Journal of Obstetrics & Gynaecology · doi:10.1111/1471-0528.17697 · Cited by 41 · see citing works
A randomized trial of ovulation induction with two different doses of Letrozole in women with PCOS
Ramezanzadeh, F., Nasiri, R., Yazdi, M. S., & Baghrei, M. (2011) · Archives of Gynecology and Obstetrics · doi:10.1007/s00404-011-1951-5 · Cited by 33 · see citing works
Badawy, A., Aal, I. A., & Abulatta, M. (2008) · Fertility and Sterility · doi:10.1016/j.fertnstert.2007.08.034 · Cited by 34 · see citing works
RetractedDehbashi, S., Dehbashi, S., Kazerooni, T., Robati, M., Alborzi, S., & Shadman, A. (2009) · DOAJ (DOAJ: Directory of Open Access Journals) · Cited by 32 · see citing works
Liu, A., Zheng, C., Lang, J., & Chen, W. (2014) · Journal of obstetrics and gynaecology research · doi:10.1111/jog.12393 · Cited by 31 · see citing works
“Boa et al. reported that the markers of endometrial receptivity (HOXA10 and integrin alpha [v] beta [3]) in rats were suppressed by CC and not impacted by letrozole.8 Meanwhile, Dickey and Holtkamp discovered that in patients stimulated with CC for IUI, no pregnancy was observed when the endometrial thickness was 6 mm…”
BackgroundResultInfluentialGhasemi-rad, M., Hajishafiha, M., Dehghan, M., Kiarang, N., اسدی, ن., & Shayegh, S. N. (2013) · Drug Design Development and Therapy · doi:10.2147/dddt.s50972 · Cited by 31 · see citing works
Ibrahim, M. I., Moustafa, R. A., & Abdel-Azeem, A. A. (2012) · Archives of Gynecology and Obstetrics · doi:10.1007/s00404-012-2478-0 · Cited by 29 · see citing works
“Data from a previous study [16] showed that the clinical pregnancy rate was 8.”
MethodRetractedPotential of Aromatase Inhibitors for Ovulation and Superovulation Induction in Infertile Women
Mitwally, M. F., & Casper, R. F. (2006) · Drugs · doi:10.2165/00003495-200666170-00001 · Cited by 29 · see citing works
Selim, M. F., & Borg, T. F. (2012) · Journal of Gynecologic Surgery · doi:10.1089/gyn.2012.0033 · Cited by 29 · see citing works
“21 In another study of CC-resistant women with PCOS, letrozole induction of ovulation was associated with an ovulation rate of 54.6% and a pregnancy rate of 25%.”
InfluentialWu, H., Wang, N. M., Cheng, M.-L., & Hsieh, J.-N. (2007) · Gynecological Endocrinology · doi:10.1080/09513590601137509 · Cited by 29 · see citing works
Ovulation Induction in Polycystic Ovary Syndrome
Vause, T. D. R., Cheung, A. P., Sierra, S., Claman, P., Graham, J., Guillemin, J., Lapensée, L., Steward, S., Vause, T. D. R., & Wong, B. C.-M. (2010) · International Journal of Gynecology & Obstetrics · doi:10.1016/j.ijgo.2010.07.001 · Cited by 28 · see citing works
Therapeutic strategies for ovulation induction in infertile women with polycystic ovary syndrome
Cristello, F., Cela, V., Artini, P. G., & Genazzani, A. R. (2005) · Gynecological Endocrinology · doi:10.1080/09513590500463360 · Cited by 27 · see citing works
“Letrozole has been proved effective also in a prospective randomized trial versus CC in women undergoing super-ovulation; the two drugs were associated with similar pregnancy rates, but the miscarriage rate was higher in the CC group [102].”
BackgroundAjaj, H. S., & Hassein, M. R. (2021) · Al-Kitab Journal for Pure Sciences · doi:10.32441/kjps.04.02.p2 · Cited by 26 · see citing works
Treatment of Unexplained Infertility With Aromatase Inhibitors or Clomiphene Citrate
Polyzos, N. P., Tzioras, S., Mauri, D., Tsappi, M., Cortinovis, I., Tsali, L., & Casazza, G. (2008) · Obstetrical & Gynecological Survey · doi:10.1097/ogx.0b013e31817d4e8d · Cited by 25 · see citing works
“Ectopic pregnancies, multiple pregnancies, and miscarriages were documented in only one trial (12); ectopic pregnancies occurred only in letrozole-treated women, whereas miscarriages and one multiple pregnancy (twin pregnancy) only in women treated with clomiphene.”
BackgroundInfluentialWessel, J. A., Danhof, N. A., van EEKELEN, R., Diamond, M. P., Legro, R. S., Peeraer, K., D’Hooghe, T., Erdem, M., Dankert, T., Cohlen, B. J., et al. (2022) · Human Reproduction Update · doi:10.1093/humupd/dmac021 · Cited by 27 · see citing works
“The authors of the remaining 18 studies were contacted, among which IPD of 11 studies (1278 couples) were not available, due to either no response (n1⁄4 9, 1009 couples) (Balasch et al., 1994; Nakajima et al., 1999; El Helw and El Sadek, 2002; Al-Fozan et al., 2004; Ozmen et al., 2005; Gregoriou et al., 2008; Fouda an…”
(2016) · Obstetrics and Gynecology · doi:10.1097/aog.0000000000001484 · Cited by 24 · see citing works
Sipe, C. S., Davis, W. A., Maifeld, M., & Voorhis, B. J. V. (2006) · Fertility and Sterility · doi:10.1016/j.fertnstert.2006.05.048 · Cited by 24 · see citing works
Samani, F. G., Farzadi, L., Nezami, N., Tarzamni, M. K., & Soleimani, F. (2008) · Archives of Gynecology and Obstetrics · doi:10.1007/s00404-008-0888-9 · Cited by 23 · see citing works
Akbari, S., Roozbahani, M. A., & Roozbahani, F. A. (2012) · PubMed Central · Cited by 23 · see citing works
Ombelet, W. U. A. M., Campo, R., Bosmans, E., & Nijs, M. (2008) · ESHRE Monographs · doi:10.1093/humrep/den165 · Cited by 23 · see citing works
“The aromatase inhibitor letrozole and CC are associated with similar PR in IUI (Al-Fozan et al., 2004).”
BackgroundLetrozole Compared With Clomiphene Citrate for Unexplained Infertility
Eskew, A. M., Bedrick, B. S., Hardi, A., Stoll, C. R. T., Colditz, G. A., Tuuli, M. G., & Jungheim, E. S. (2019) · Obstetrics and Gynecology · doi:10.1097/aog.0000000000003105 · Cited by 22 · see citing works
Bedaiwy, M. A., Shokry, M., Mousa, N. A., Claessens, A., Esfandiari, N., Gotleib, L., & Casper, R. F. (2008) · Fertility and Sterility · doi:10.1016/j.fertnstert.2008.03.020 · Cited by 22 · see citing works
Role of androgens in the treatment of patients with low ovarian response
Feigenberg, T., Simon, A., Ben‐Meir, A., Gielchinsky, Y., & Laufer, N. (2009) · Reproductive BioMedicine Online · doi:10.1016/j.rbmo.2009.09.012 · Cited by 21 · see citing works
Davar, R., Javedani, M., & Fallahzadeh, M. H. (2011) · PubMed Central · Cited by 20 · see citing works
Poor Endometrial Proliferation After Clomiphene is Associated With Altered Estrogen Action
Bressler, L. H., Fritz, M. A., Wu, S., Yuan, L., Kafer, S., Wang, T., DeMayo, F. J., & Young, S. L. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab381 · Cited by 18 · see citing works
Cantineau, A. E., Rutten, A., & Cohlen, B. J. (2021) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd005356.pub3 · Cited by 17 · see citing works
Bjelica, A., Trninić-Pjević, A., Mladenović-Segedi, L., Ćetković, N. B., & Petrović, D. (2016) · Srpski arhiv za celokupno lekarstvo · doi:10.2298/sarh1604146b · Cited by 17 · see citing works
Hembram, M., Biswas, R., & Jain, A. (2017) · Journal of Human Reproductive Sciences · doi:10.4103/jhrs.jhrs_120_16 · Cited by 15 · see citing works
“,([8]) in which ET in the CC group (8.”
BackgroundAl-Shaikh, S. F., Al-Mukhatar, E. J., Al-Zubaidy, A. A., Al-Rubaie, B. J. U., & Al-Khuzaee, L. M. (2016) · Middle East Fertility Society Journal · doi:10.1016/j.mefs.2016.12.003 · Cited by 15 · see citing works
Eftekhar, M., Mohammadian, F., Davar, R., & Pourmasumi, S. (2014) · Europe PMC (PubMed Central) · Cited by 14 · see citing works
No. 362-Ovulation Induction in Polycystic Ovary Syndrome
Smithson, D. S., Vause, T. D. R., & Cheung, A. P. (2018) · Journal of Obstetrics and Gynaecology Canada · doi:10.1016/j.jogc.2017.12.004 · Cited by 14 · see citing works
Huang, H., Clancy, K. B. H., Burhance, C., Zhu, Y., & Madrigal, L. (2015) · American Journal of Human Biology · doi:10.1002/ajhb.22723 · Cited by 13 · see citing works
“They also tend to support ovulation without suppressing endometrial function, a common side effect of other ovulation induction methods (Al-Fozan et al., 2004; Atay et al., 2006; Badawy et al., 2009; Healey et al., 2003; Nahid and Sirous, 2012).”
BackgroundRahmani, E., Ahmadi, S., Motamed, N., & Maneshi, H. O. (2012) · Obstetrics and Gynecology International · doi:10.1155/2012/758508 · Cited by 13 · see citing works
“Letrozole induced fewer mature follicles that can decrease multiple-pregnancy rate and risk of ovarian hyperstimulation syndrome.”
Management of Infertility in Women with Polycystic Ovary Syndrome
Stadtmauer, L., & Oehninger, S. (2005) · Treatments in Endocrinology · doi:10.2165/00024677-200504050-00002 · Cited by 13 · see citing works
ElKattan, E. A. (2013) · Middle East Fertility Society Journal · doi:10.1016/j.mefs.2012.07.008 · Cited by 12 · see citing works
Ghomian, N., Khosravi, A., & Mousavifar, N. (2015) · PubMed Central · doi:10.22074/ijfs.2015.4204 · Cited by 12 · see citing works
“5 mg LTZ for 5 days was compared to 150 mg CC that was proved to be more efficacious in terms of ovulation and pregnancy rates (14).”
MethodBahadur, G. A., Homburg, R., & Al‐Habib, A. (2016) · The Journal of Obstetrics and Gynecology of India · doi:10.1007/s13224-016-0928-5 · Cited by 12 · see citing works
Grabia, A., Papier, S. D., Pesce, R. I., Mlayes, L., Kopelman, S., & Sueldo, C. E. (2006) · Fertility and Sterility · doi:10.1016/j.fertnstert.2006.03.034 · Cited by 11 · see citing works
Anastrozole versus clomiphene citrate: which is better for ovulation induction?
Tredway, D. R., & Schertz, J. C. (2011) · Fertility and Sterility · doi:10.1016/j.fertnstert.2010.07.1094 · Cited by 10 · see citing works
Arya, S., Kupesic-Plavsic, S., Mulla, Z. D., Dwivedi, A. K., Crisp, Z., Jose, J., & Noble, L. S. (2017) · European Journal of Obstetrics & Gynecology and Reproductive Biology · doi:10.1016/j.ejogrb.2017.09.023 · Cited by 10 · see citing works
Topipat, C., Choktanasiri, W., Jultanmas, R., Weerakiet, S., Wongkularb, A., & Rojanasakul, A. (2008) · Gynecological Endocrinology · doi:10.1080/09513590801895609 · Cited by 10 · see citing works
“However, there were no detrimental effects on implantation and pregnancy, given that the pregnancy rates were similar when the two groups were compared [24,25,31,37,38].”
BackgroundResult
- Authors
- Al-Fozan, H., Al-Khadouri, M., Tan, S. L., & Tulandi, T.
- Affiliations
- McGill University (CA)
- Corresponding author
- Tulandi, Togas
- Venue
- Fertility and Sterility
- Publisher
- Elsevier BV
- Published
- 2004-12
- Volume
- 82
- Issue
- 6
- Pages
- 1561-1563
- ISSN
- 0015-0282 (ISSN-L)
- OpenAlex
- W2086050129
- Semantic Scholar
- e113a1ca52d9245e3be8fa8ca22e265b6332f548
- Cited by
- 174
- References
- 19
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 4 · 2022: 2 · 2021: 14 · 2020: 10 · 2019: 7 · 2018: 10 · 2017: 5 · 2016: 8 · 2015: 8 · 2014: 3 · 2013: 5 · 2012: 11
- FWCI
- 12.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Fertility and Sterility (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Health Sciences › Medicine › Reproductive Medicine › Reproductive Health and Technologies
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Keywords
- letrozole, clomiphene citrate, superovulation, intrauterine insemination, unexplained infertility, aromatase inhibitors, pregnancy rate, miscarriage rate, folliculogenesis, endometrial thickness
- MeSH terms
- Abortion, Spontaneous, Letrozole, Adult, Clomiphene, Endometrium, Female, Fertility Agents, Female, Ovarian Follicle, Humans, Infertility, Female, Insemination, Artificial, Nitriles, Pregnancy, Prospective Studies, Superovulation, Triazoles, Ultrasonography, Incidence, Pregnancy Rate, Aromatase Inhibitors
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Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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