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Cited by 347Ovarian function and disordersReproductive Biology and FertilityReproductive Health and Technologies

A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women

Open access
Fisher, Stephanie A, Reid, Robert L, Van Vugt, Dean A, Casper, Robert F·2002·Fertility and Sterility
DOI 10.1016/s0015-0282(02)03241-7
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Abstract

Objective To evaluate the ovarian follicular dynamics of cycle modification with the aromatase inhibitor letrozole compared with clomiphene citrate in normal ovulatory women.Design Randomized double-blind controlled trial.Setting Tertiary care hospital.Patient(s) Nineteen ovulatory female volunteers, ages 18-35 years.Intervention(s) Subjects were monitored in one control cycle. Subjects then received either letrozole 2.5 mg daily or clomiphene citrate 50 mg daily on days 5-9 after menses.Main outcome measure(s) Number of mature follicles, endometrial thickness and endometrial pattern at ovulation, and follicular profiles of LH, FSH, and E(2).Result(s) The number of mature follicles at the LH surge in natural cycles was 1.0 with an exaggerated response seen for treatment both with clomiphene and letrozole. There was no difference in the endometrial thickness at midcycle during either the natural cycles or the medicated cycles. LH surges and spontaneous ovulation were documented in all natural and medicated cycles. When measured daily, follicular profiles of LH and FSH are similar between the groups in both the natural and medicated cycles. In the medicated cycles, clomiphene results in a significant increase in E(2) levels, while E(2) levels in letrozole-stimulated cycles appeared lower than in natural cycles.Conclusion(s) 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 midcycle.

AI snapshot

Written from the paper’s full text.

TL;DR

In a randomized double-blind pilot of normal ovulatory women, letrozole 2.5 mg/day and clomiphene citrate 50 mg/day on cycle days 5–9 both increased mature follicles at the LH surge compared with natural cycles, with comparable midcycle endometrial thickness and spontaneous ovulation. Letrozole produced lower E2 levels than clomiphene and natural cycles, but the authors conclude larger trials are needed.

Key findings

  • Sixteen participants completed both cycles. The mean (±SD) number of mature follicles (≥18 mm) at the LH surge was 2.2 (±0.67) in the clomiphene-treated group and 1.7 (±0.49) in the letrozole-treated group (P=.11); natural-cycle values were 1.0 in both groups.
  • Midcycle endometrial thickness was comparable: natural cycle 9.8 (±1.6) mm with clomiphene vs 9.9 (±2.4) mm with letrozole (P=.91); treatment cycle 10.1 (±2.2) mm vs 10.6 (±2.0) mm (P=.64). No within-group difference between natural and treated cycles.
  • Tri-laminar endometrium at midcycle was present in 100% (9/9) of letrozole natural cycles vs 56% (5/9) of clomiphene natural cycles; in treatment cycles it was 71% with letrozole (P=.46) and 44% with clomiphene (P=1.00). LH surges and spontaneous ovulation were documented in all natural and medicated cycles.
  • At the LH surge, mean (±SD) E2 was 686 (±388) pmol/L with clomiphene vs 560 (±193) pmol/L with letrozole in natural cycles, and 2,047 (±930) pmol/L vs 399 (±167) pmol/L in stimulated cycles; clomiphene significantly increased E2, while letrozole E2 appeared lower than natural cycles.

Methods

  • Randomized double-blind controlled pilot at Kingston General Hospital, October 1999–April 2000. Nineteen normal ovulatory women ages 18–35 who did not desire pregnancy were enrolled; inclusion required day 3 FSH ≤10 IU/L, normal hormonal profile, and reliable contraception.
  • Each participant was monitored through one natural cycle, then randomized to letrozole 2.5 mg/day or clomiphene citrate 50 mg/day on days 5–9 after menses. Monitoring included daily LH, FSH, and E2 and transvaginal ultrasound.
  • Primary outcome was number of mature follicles (≥18 mm) at the LH surge; additional outcomes included follicular E2/LH/FSH profiles, endometrial thickness and pattern 1 day after the LH surge, and spontaneous ovulation. Analysis used Student’s t-test and Fisher’s exact test, with P<.05 significant.

Limitations

  • The paper states that no a priori power calculation was possible because letrozole had never been administered to premenopausal women; it was a small pilot designed before a larger trial in infertility patients. The authors also state that daily blood sampling may have been too infrequent to detect brief LH/FSH increases, and that whether lower E2 in letrozole cycles affects implantation or luteal function is unknown.
  • The paper states that a larger randomized trial is required to fully assess letrozole’s impact on endometrial development.
  • Evident from the text: only 16 of 19 enrolled women completed both cycles and were analyzed, and participants were normal ovulatory volunteers rather than infertile patients, so findings may not generalize to infertility or polycystic ovary syndrome populations.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/s0015-0282(02)03241-7

Cites

26 of 26 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 24 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Early follicular treatment with clomiphene and letrozole resulted in a comparable increase in the number of mature follicles at the LH surge.

    “Early follicular treatment with clomiphene and letrozole resulted in a comparable increase in the number of mature follicles at the LH surge.”
    Quote in the paperSubstantial claim
  • Findingown data

    In the treatment cycle, the mean midcycle endometrial thickness was 10.1 mm (±2.2 mm) in the clomiphene group and 10.6 mm (±2.0 mm) in the letrozole group (P=.64).

    “In the treatment cycle, the mean (ϮSD) midcycle endometrial thickness was 10.1 mm (Ϯ2.2 mm) in the clomiphene group and 10.6 mm (Ϯ2.0 mm) in the letrozole group (Pϭ.64,Student's t-test).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Despite significantly lower E2 levels in letrozole-treated women, endometrial development was unaffected in this study.

    “Despite significantly lower E 2 levels in letrozole-treated women, endometrial development was unaffected in this study.”
    Quote in the paperSubstantial claim
  • Findingown data

    During the natural cycle, the mean E2 levels on the day of the LH surge were 686 (±388) pmol/L for the clomiphene group and 560 (±193) pmol/L for the letrozole group.

    “During the natural cycle, the mean (ϮSD) E 2 levels on the day of the LH surge were 686 (Ϯ388) pmol/L for the clomiphene group and 560 (Ϯ193) pmol/L for the letrozole group.”
    Quote in the paperNot a substantial claim
  • Findingown data

    During the natural cycle, the mean midcycle endometrial thickness in the clomiphene group was 9.8 mm (±1.6 mm) and in the letrozole group it was 9.9 mm (±2.4 mm; P=.91).

    “During the natural cycle, the mean (ϮSD) midcycle endometrial thickness in the clomiphene group was 9.8 mm (Ϯ1.6 mm) and in the letrozole group it was 9.9 mm (Ϯ2.4 mm; Pϭ.91, Student's t-test).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 13
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Findingown data

    When expressed as E2 produced per follicle, clomiphene resulted in a slight increase in E2 level per follicle, while letrozole resulted in a slight decrease in E2 level per follicle compared with natural cycles.

    “When expressed as E 2 produced per follicle, clomiphene resulted in a slight increase in E 2 level per follicle, while letrozole resulted in a slight decrease in E 2 level per follicle compared with natural cycles (Fig. 4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The mean number of mature follicles in the clomiphene-treated group was 2.2 (±0.67), while that in the letrozole-treated group was 1.7 (±0.49) (P=.11).

    “The mean (ϮSD) number of mature follicles in the clomiphene-treated group was 2.2 (Ϯ0.67), while that in the letrozole-treated group was 1.7 (Ϯ0.49) (Pϭ.11,Student's t-test).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the medicated cycles, clomiphene resulted in a significant increase in E2 levels, while letrozole resulted in E2 levels lower than those in natural cycles.

    “In the medicated cycles, clomiphene resulted in a significant increase in E 2 levels, while letrozole resulted in E 2 levels lower than those in natural cycles.”
    • Also stated in: § Abstract · hedged
      “In the medicated cycles, clomiphene results in a significant increase in E 2 levels, while E 2 levels in letrozole-stimulated cycles appeared lower than in natural cycles.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    All women in the letrozole group had tri-laminar pattern endometrium at midcycle in the natural cycle (100%), while only 56% (5/9) of those in the clomiphene group had a tri-laminar pattern in the natural cycle.

    “While all women in the letrozole group had tri-laminar pattern endometrium at midcycle in the natural cycle (100%), only 56% (5/9) of those in the clomiphene group had a tri-laminar pattern in the natural cycle.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LH surges and spontaneous ovulation were documented in all natural and medicated cycles.

    “LH surges and spontaneous ovulation were documented in all natural and medicated cycles.”
    • Also stated in: § RESULTS · plain
      “LH surges and spontaneous ovulation were documented in all natural and medicated cycles.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Of three women with a thin endometrium at midcycle in the treatment cycle, two had received clomiphene (8 and 7.3 mm) and one had received letrozole (7.6 mm).

    “Of three women with a thin endometrium at midcycle in the treatment cycle, two women had received clomiphene (8 and 7.3 mm) and one had received letrozole (7.6 mm).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    All of the women with a thin endometrium during the treatment cycle had greater endometrial thickness in the natural cycle.

    “Of interest, all of the women with a thin endometrium during the treatment cycle had greater endometrial thickness in the natural cycle (clomiphene group, 9.5 and 11.7 mm; letrozole group, 8.7 mm).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Clomiphene results in a 60%-85% ovulation rate and a 10%-20% pregnancy rate per cycle.

    “Clomiphene results in a 60%-85% ovulation rate and a 10%-20% pregnancy rate per cycle (2)(3)(4)(5)(6)(7)(8).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [2] Dickey, 1996, Incidence of spontaneous abortion in clomiphene pregnancies, Hum Reprod source

      Not checked in the free run.

    • cites [3] Garcia, 1977, The use of clomiphene citrate, Fertil Steril source

      Not checked in the free run.

    • cites [4] Gorlitsky, 1978, Ovulation and pregnancy rates with clomiphene citrate, Obstet Gynecol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Clomiphene citrate has been widely used in the treatment of infertility since its introduction into clinical practice in the 1960s.

    “Clomiphene citrate has been widely used in the treatment of infertility since its introduction into clinical practice in the 1960s (1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Greenblatt, 1961, Induction of ovulation with MRL/41, JAMA source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There is a significantly higher rate of biochemical pregnancies when endometrial thickness is 6-8 mm.

    “and a significantly higher rate of biochemical pregnancies when the endometrial thickness was 6 -8 mm (15).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Dickey, 1993, Relationship of biochemical pregnancy to preovulatory endometrial thickness and pattern in ovulation induction patients, Hum Reprod source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Letrozole is a potent, reversible oral aromatase inhibitor.

    “Letrozole (Femara; Novartis Pharmaceuticals, Dorval, Que ´bec, Canada) is a potent, reversible oral aromatase inhibitor that has recently been tested in phase 3 trials as a chemotherapeutic agent in postmenopausal women with metastatic breast cancer (17).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Lamb, 1998, Letrozole, Drugs source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The study protocol was approved by the Queen's University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board, and informed consent was obtained before randomization.

    “The Queen's University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board approved the study protocol.Study participants were counseled, and informed consent was obtained before randomization.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    A total of 16 participants completed both cycles of the study and were included in the final analysis of data.

    “A total of 16 participants completed both cycles of the study and were included in the final analysis of data.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The study was performed as a randomized double-blind controlled investigation.

    “This pilot study was performed as a randomized doubleblind controlled investigation between October, 1999 and April, 2000 at Kingston General Hospital, Kingston, Ontario.”
    • Also stated in: § Abstract · plain
      “Design: Randomized double-blind controlled trial.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Randomization was performed by choosing the next sequentially numbered opaque envelope prepared by the hospital pharmacy according to random number tables with randomization in blocks of four.

    “Randomization was performed by choosing the next sequentially numbered opaque envelope prepared by the hospital pharmacy according to random number tables with randomization in blocks of four.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Transient inhibition of aromatase activity in the early follicular phase with 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 midcycle.

    “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 midcycle.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A single daily dose of letrozole 2.5 mg/day achieves optimal suppression of serum estrogen levels in postmenopausal women.

    “A single daily dose of 2.5 mg/day has been shown to achieve optimal suppression of serum estrogen levels in postmenopausal women (18).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Dowsett, 1995, In vivo measurement of aromatase inhibition by letrozole (CGS 20267) in postmenopausal women with breast cancer, Clin Cancer Res

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    One woman from the clomiphene group voluntarily withdrew after completing the control cycle, and two women from the letrozole group failed to complete the study.

    “One woman from the clomiphene group voluntarily withdrew from the study after completing the control cycle.Two women from the letrozole group failed to complete the study: 1 woman failed to ovulate in the control cycle and was withdrawn after randomization, and 1 woman voluntarily withdrew from the study before completion of the control cycle for personal reasons.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    Blinding was accomplished by preparing identical capsules, and study investigators, radiologists, ultrasound technicians, and participants were unaware of study group allocation.

    “To accomplish blinding of the medications, the required daily doses of both letrozole and clomiphene were prepared by the hospital pharmacy in identical capsule form before randomization.Study investigators, radiologists, ultrasound technicians, and participants were unaware of study group allocation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In normally cycling female rats, letrozole resulted in greater than 80% suppression of ovarian E2 levels and caused a marked increase in LH and FSH, with a 35% increase in ovarian weights within 1 week of treatment.

    “When administered to normally cycling female rats, letrozole resulted in greater than 80% suppression of ovarian E 2 levels and caused a marked increase in LH and FSH, with a 35% increase in ovarian weights within 1 week of treatment (19).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Sinha, 1998, Effect of CGS 20267 on ovarian aromatase and gonadotropin levels in the rat, Breast Cancer Res Treat source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    At the beginning of the study, the dose of letrozole required to achieve suppression of ovarian aromatase and the clinical effect of the chosen dose could not be predicted, which precluded an a priori power calculation.

    “At the beginning of this study, letrozole had never been administered to premenopausal women, and neither the dose required to achieve suppression of ovarian aromatase nor the clinical effect of the chosen dose could be predicted.This precluded an a priori power calculation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Samples from the control and stimulation cycle of each subject were always assayed in the same LH and FSH assay.

    “Samples from the control and stimulation cycle of each subject were always assayed in the same LH and FSH assay.”
    Quote in the paperNot a substantial claim
22 of 22

  • The paper relies on this without support.

    Letrozole does not cause estrogen receptor depletion.

    “Because letrozole is more rapidly eliminated than clomiphene and does not cause estrogen receptor depletion, it is likely that letrozole may not cause the adverse endometrial effects observed with clomiphene, ultimately resulting in improved pregnancy rates.”

  • The paper relies on this without support.

    Letrozole is more rapidly eliminated than clomiphene.

    “Because letrozole is more rapidly eliminated than clomiphene and does not cause estrogen receptor depletion, it is likely that letrozole may not cause the adverse endometrial effects observed with clomiphene, ultimately resulting in improved pregnancy rates.”

  • The paper relies on this without support.

    Clomiphene citrate is the current standard oral treatment for ovulation induction.

    “The efficacy of letrozole was compared with clomiphene citrate, rather than placebo, to establish its equivalence to the current standard oral treatment for ovulation induction.”

  • The paper relies on this without support.

    Normal ovulatory women are an appropriate model for evaluating letrozole before testing it in infertile women.

    “This small pilot study was designed to evaluate the potential of letrozole as an ovulation induction agent before embarking on a larger trial involving infertility patients.”
4 of 4

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 superovulation, letrozole is associated with few developing follicles and thick endometrium.

    “In superovulation, letrozole is associated with few developing follicles and thick endometrium.”

    From A new era in ovulation induction (2006) · cites this paper as [53]

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Mitwally, 2001, Aromatase inhibition decreases FSH dose needed during controlled ovarian hyperstimulation, J Soc Clin Invest, 8, 85A

Cited by

Sorted by citations

Related

Authors
Fisher, S. A., Reid, R. L., Van Vugt, D. A., & Casper, R. F.
Affiliations
  • Queen's University (CA)
  • University of Toronto (CA)
Corresponding author
Reid, Robert L
ORCID
Venue
Fertility and Sterility
Publisher
Elsevier BV
Published
2002-08
Volume
78
Issue
2
Pages
280-285
ISSN
0015-0282 (ISSN-L)
DOI
10.1016/s0015-0282(02)03241-7
OpenAlex
W2029278810
Semantic Scholar
1a3a5d4d0b6f3798f147b32266da94b97f987fe1
Cited by
347
References
26
Citations by year
2025: 2 · 2024: 4 · 2023: 2 · 2022: 2 · 2021: 5 · 2020: 4 · 2019: 5 · 2018: 6 · 2017: 37 · 2016: 8 · 2015: 41 · 2014: 35 · 2013: 28 · 2012: 38
FWCI
8.74
Type
journal article
Language
en
Open access
Licence
Locations
  • Fertility and Sterility (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
  • Health Sciences › Medicine › Reproductive Medicine › Reproductive Health and Technologies
Keywords
clomiphene citrate, letrozole, aromatase inhibitors, ovulation induction, ovarian follicle development, endometrial thickness, luteinizing hormone surge, follicle-stimulating hormone, estradiol
MeSH terms
Letrozole, Adolescent, Adult, Clomiphene, Double-Blind Method, Estrogen Antagonists, Fertility Agents, Female, Follicle Stimulating Hormone, Humans, Middle Aged, Nitriles, Ovulation, Pilot Projects, Triazoles, Aromatase Inhibitors

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