CoChat
Sign Up
Cited by 801Ovarian function and disordersMenopause: Health Impacts and TreatmentsHypothalamic control of reproductive hormones

Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate

Open access
Mitwally, Mohamed F.M, Casper, Robert F·2001·Fertility and Sterility
DOI 10.1016/s0015-0282(00)01705-2
Open this paper in CoChat — free accountOpen PDF

Abstract

Objective To use aromatase inhibition for induction of ovulation in women in whom clomiphene citrate (CC) treatment was unsuccessful. Design Prospective trial in infertility patients treated with CC. Setting Two tertiary-referral infertility clinics associated with the Division of Reproductive Sciences, University of Toronto. Patient(s) Twelve patients with anovulatory polycystic ovary syndrome (PCOS) and 10 patients with ovulatory infertility, all of whom had previously received CC with an inadequate outcome (no ovulation and/or endometrial thickness of Intervention(s) The aromatase inhibitor letrozole was given orally in a dose of 2.5 mg on days 3-7 after menses. Main outcome measure(s) Occurrence of ovulation, endometrial thickness, and pregnancy rates. Result(s) With CC treatment in patients with PCOS, ovulation occurred in 8 of 18 cycles (44.4%), and all ovulatory cycles for the women included in this study had endometrial thickness of Conclusion(s) Oral administration of the aromatase inhibitor letrozole is effective for ovulation induction in anovulatory infertility and for increased follicle recruitment in ovulatory infertility. Letrozole appears to avoid the unfavorable effects on the endometrium frequently seen with antiestrogen use for ovulation induction.

Integrity signals

Registry

Crossref · 10.1016/s0015-0282(00)01705-2

Cites

43 of 43 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 23 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In ovulatory infertility patients, mean serum E2 concentration on the day of hCG administration was 719 pmol/L in letrozole cycles versus 3,003 pmol/L in CC cycles.

    “In ovulatory patients, the serum E 2 level was 719 pmol/L in letrozole treatment cycles versus 3,003 pmol/L in CC treatment cycles.”
    Quote in the paperSubstantial claim
  • Findingown data

    In ovulatory infertility patients, letrozole treatment resulted in a mean number of 2.3 mature follicles (>1.5 cm) on the day of hCG administration.

    “In the 10 patients with ovulatory infertility, letrozole treatment resulted in a mean number of 2.3 mature follicles and mean endometrial thickness of 0.8 cm.”
    • Also stated in: § RESULTS · plain
      “The mean number of follicles measuring Ͼ1.5 cm on the day of hCG administration was 2.3 (range, 1-4).”
    Quote in the paperSubstantial claim
  • Findingown data

    In women with PCOS, mean serum E2 concentration on the day of hCG administration was 962 pmol/L in letrozole cycles versus 1,638 pmol/L in CC cycles.

    “On the day of hCG administration in patients with PCOS, the mean serum E 2 concentration was 962 pmol/L in letrozole treatment cycles, versus 1,638 pmol/L in CC treatment cycles.”
    Quote in the paperSubstantial claim
  • Findingown data

    In ovulatory infertility patients, letrozole treatment resulted in a mean endometrial thickness of 0.89 cm on the day of hCG administration.

    “In the 10 patients with ovulatory infertility, letrozole treatment resulted in a mean number of 2.3 mature follicles and mean endometrial thickness of 0.8 cm.”
    • Also stated in: § RESULTS · plain
      “Mean endometrial thicknesses on the day of hCG administration in patients with PCOS and ovulatory patients was 0.81 and 0.89 cm with letrozole, compared with 0.62 and 0.52 cm in CC treatment cycles, respectively.”
    Quote in the paperSubstantial claim
  • Findingown data

    In women with PCOS, no pregnancy was achieved in any CC ovulatory cycle.

    “No pregnancy was achieved in any of the ovulatory cycles.”
    Quote in the paperSubstantial claim
  • May combine two claims. 10
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 8

  • May combine two claims.

    Findingown data

    At the time of writing, the three clinical pregnancies had resulted in a normal live birth and two ongoing singleton pregnancies.

    “At the time of writing, the three clinical pregnancies had resulted in a normal live birth and two ongoing singleton pregnancies.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    In ovulatory infertility patients, no pregnancy was achieved in CC cycles.

    “However, the endometrial thickness was Յ0.5 cm in all cycles, and no pregnancy was achieved.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Compared with CC, letrozole produced a significantly thicker endometrium on the day of hCG administration despite significantly lower E2 levels in both PCOS and ovulatory patients.

    “Compared with CC, letrozole produced a significantly thicker endometrium on the day of hCG administration despite the significantly lower E 2 levels in both patients with PCOS and the ovulatory patients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Aromatase inhibitors have potential as alternatives to, or replacements for, CC as first-line treatment for ovulation induction in anovulatory infertility and for augmentation of ovulation in ovulatory infertility patients.

    “Aromatase inhibitors have potential as alternatives to, or even replacements for, CC as a first-line treatment for ovulation induction in anovulatory infertility and for augmentation of ovulation in ovulatory infertility patients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Recent data support a stimulatory role for androgens in early follicular growth in primates, in contrast to the inhibitory effect observed in rodents.

    “Recent data support a stimulatory role for androgens in early follicular growth in primates, in contrast to the inhibitory effect observed in rodents (21).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Weil, 1998, Androgen receptor gene expression in the primate ovary, J Clin Endocrinol Metab source

  • May combine two claims.

    Premisecitation

    In women with PCOS, treatment with hMG or pure FSH is difficult to control and characteristically induces several ovulatory follicles, leading to the risk of multiple pregnancies and ovarian hyperstimulation syndrome (OHSS).

    “In women with polycystic ovary syndrome (PCOS), because of the high sensitivity of the ovaries to gonadotropin stimulation, treatment with hMG or pure FSH is difficult to control and characteristically induces several ovulatory follicles, leading to the risk of multiple pregnancies and ovarian hyperstimulation syndrome (OHSS) (12).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Kettel, 1993, Hypothalamic-pituitary-ovarian response to clomiphene citrate in women with polycystic ovary syndrome, Fertil Steril source

  • May combine two claims.

    Premisecitation

    Aromatase inhibitors have a relatively short half-life compared with CC and therefore would be eliminated from the body rapidly.

    “These aromatase inhibitors have a relatively short half-life compared with CC and therefore would be eliminated from the body rapidly (14,15).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Lipton, 1995, Letrozole (CGS 20267), Cancer source
    • cites [15] Iveson, 1993, Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in postmenopausal patients with advanced breast cancer, Cancer Res source

  • May combine two claims.

    Premisecitation

    Continuous administration of letrozole up to 5 mg/d produced marked suppression of E2, estrone, and estrone sulfate, with very few side effects.

    “Continuous administration of letrozole up to 5 mg/d produced marked suppression of E 2 , estrone, and estrone sulfate, with very few side effects (14,15).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Lipton, 1995, Letrozole (CGS 20267), Cancer source
    • cites [15] Iveson, 1993, Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in postmenopausal patients with advanced breast cancer, Cancer Res source

  • Classified as probably not a substantial claim.

    Premisecitation

    Androgen accumulation in the follicle may stimulate insulin-like growth factor, along with other endocrine and paracrine factors, which may synergize with FSH to promote folliculogenesis.

    “In addition, androgen accumulation in the follicle may stimulate insulin-like growth factor, along with other endocrine and paracrine factors, which may synergize with FSH to promote folliculogenesis (25)(26)(27).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites (25)(26)(27)

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Premisecitation

    The absolute systemic bioavailability of letrozole after oral administration was 100% compared with the same dose given IV.

    “The absolute systemic bioavailability of letrozole after oral administration was 100% compared with the same dose given IV (19).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Sioufi, 1997, Absolute bioavailability of letrozole in healthy post-menopausal women, Biopharm Drug Dispos source

  • May combine two claims.

    Premisecitation

    Testosterone was found to augment follicular FSH receptor expression in primates, which suggests that androgens promote follicular growth and estrogen biosynthesis indirectly by amplifying FSH effects.

    “Testosterone was found to augment follicular FSH receptor expression in primates, which suggests that androgens promote follicular growth and estrogen biosynthesis indirectly by amplifying FSH effects (22)(23)(24).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites (22)(23)(24)

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Premisecitation

    Some investigators have proposed combined CC and low-dose glucocorticoid therapy for the treatment of CC-resistant anovulation.

    “Some investigators have proposed combined CC and low-dose glucocorticoid therapy for the treatment of CCresistant anovulation (28 -31).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [28] Lobo, 1982, Clomiphene and dexamethasone in women unresponsive to clomiphene alone, Obstet Gynecol
    • cites [29] Singh, 1992, Clomiphene-dexamethasone treatment of clomiphene resistant women with and without the polycystic ovary syndrome, J Reprod Med
    • cites [30] Daly, 1984, A randomized study of dexamethasone in ovulation induction with clomiphene citrate, Fertil Steril source
    • cites [31] Diamant, 1980, Induction of ovulation by combined clomiphene citrate and dexamethasone treatment in clomiphene citrate nonresponders, Eur J Obstet Gynecol Reprod Biol source

  • May combine two claims.

    Premisecitation

    Clinical data have revealed a discrepancy between ovulation and conception rates during CC treatment and a higher than expected incidence of miscarriage in conception cycles.

    “In addition, clinical data have revealed a discrepancy between ovulation and conception rates during CC treatment and a higher than expected incidence of miscarriage in conception cycles (3)(4)(5)(6).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites (3)(4)(5)(6)

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationown data

    Letrozole is an orally effective, inexpensive method for stimulating follicular development.

    “In summary, the results of this preliminary study suggest that the aromatase inhibitor letrozole is an orally effective, inexpensive method for stimulating follicular development.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The subsequent increase in gonadotropin secretion could stimulate ovarian follicle development, as reported previously in the Bonnet monkey.

    “The subsequent increase in gonadotropin secretion could stimulate ovarian follicle development, as reported previously in the Bonnet monkey (20).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Shetty, 1997, Effect of estrogen deprivation on the reproductive physiology of male and female primates, J Steroid Biochem Mol Biol source

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    A 2-month washout period before the letrozole cycles was used to eliminate any posttreatment effect of CC.

    “A 2-month washout period before the letrozole cycles was used to eliminate any posttreatment effect of CC.”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    Endometrial thickness was assessed as described previously and as performed routinely in the clinic for the last 10 years.

    “Endometrial thickness was assessed as we have described previously (9) and as performed routinely in our clinic for the last 10 years.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Gonen, 1990, Sonographic determination of an adverse effect of clomiphene citrate on endometrial growth, Hum Reprod source

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

    Premisecitation

    Other investigators have described the use of extended duration and higher doses of CC.

    “Other investigators have described the use of extended duration and higher doses of CC (32)(33)(34)(35).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites (32)(33)(34)(35)

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Identical criteria were used for administration of hCG in both the CC- and letrozole-treated cycles.

    “Identical criteria were used for administration of hCG in both the CC-and letrozole-treated cycles.”
    Quote in the paperSubstantial claim
19 of 19

  • The paper relies on this without support.

    20%-25% of women are resistant to CC and do not ovulate.

    “However, 20%-25% of women are resistant to CC and do not ovulate.”

  • The paper relies on this without support.

    Letrozole is a specific, reversible, nonsteroidal aromatase inhibitor that suppresses estrogen biosynthesis.

    “Letrozole (4,4Ј-[1H-1, 2, 4-triazol-1-ylmethylene]-bis-benzonitrile) is a specific, reversible, nonsteroidal aromatase inhibitor that suppresses estrogen biosynthesis.”

  • The paper relies on this without support.

    The disposition of letrozole in healthy postmenopausal women is characterized by steady-state plasma concentrations in 4-8 hours and a half-life of approximately 45 hours.

    “The disposition of letrozole in healthy postmenopausal women is characterized by steady-state plasma concentrations in 4 -8 hours and a half-life of approximately 45 hours.”

  • The paper relies on this without support.

    CC is the most commonly prescribed medication for ovulation induction.

    “CC is the most commonly prescribed medication for ovulation induction.”

  • The paper relies on this without support.

    Women with ovulatory disorders who are resistant to standard doses of CC generally become candidates for gonadotropin therapy.

    “Women with ovulatory disorders who are resistant to standard doses of CC generally become candidates for gonadotropin therapy.”

  • The paper relies on this without support.

    Severe OHSS and the high risk of multiple pregnancy are major disadvantages of gonadotropin treatment, especially in young women with PCOS.

    “However, severe OHSS and the high risk of multiple pregnancy are major disadvantages of gonadotropin treatment, especially in young women with PCOS.”
6 of 6

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?

  • Aromatase inhibitors were proposed as ovulation-inducing agents in 2001.

    “Aromatase inhibitors were proposed as ovulation-inducing agents in 2001. 236”

    From Assessment and management of polycystic ovary syndrome: Summary of an evidence-based guideline (2011) · cites this paper as [236]

  • Ovulation induction with letrozole is associated with an ovulation rate of 70%-84% and a pregnancy rate of 20%-27% per cycle.

    “Ovulation induction with letrozole is associated with an ovulation rate of 70%-84% and a pregnancy rate of 20%-27% per cycle.”

    From A new era in ovulation induction (2006) · cites this paper as [50]

  • In a small study of 12 PCOS patients with inadequate response to CC treated with letrozole, 9 (75%) ovulated, 3 conceived, and the mean endometrial thickness was 8.1 mm (6.2 mm with CC).

    “In a small study (50), 12 PCOS patients with inadequate response to CC were treated with letrozole.Of 12 patients, 9 (75%) ovulated, and 3 conceived; the mean endometrial thickness was 8.1 mm (6.2 mm with CC).”

    From A new era in ovulation induction (2006) · cites this paper as [50]

  • Letrozole can successfully replace clomiphene citrate in superovulation treatment of patients with unexplained infertility or polycystic ovarian disease and in poor responders.

    “Recently, it was suggested that letrozole, a specific reversible, nonsteroidal aromatase inhibitor that suppresses estrogen biosynthesis (16), can successfully replace clomiphene citrate in superovulation treatment of patients with unexplained infertility or polycystic ovarian disease and in poor responders (17,18).”

    From Effects of letrozole on superovulation with gonadotropins in women undergoing intrauterine insemination (2003) · cites this paper as [17]

  • Letrozole 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).”

    From A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation (2004) · cites this paper as [8]

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.

  • PCOS clomiphene endometrial measurements exceed the stated limit

    Major

    The results say all eight ovulatory clomiphene cycles in patients with PCOS had an endometrium no thicker than 0.5 cm. Table 1 reports a mean of 0.62 cm and a maximum of 1.2 cm for endometrial thickness on the day of hCG administration in those cycles.

  • Ovulatory-group clomiphene range exceeds the stated thickness limit

    Minor

    The results state that endometrial thickness was no more than 0.5 cm in every clomiphene cycle in the ovulatory group, but Table 2 gives a range extending to 0.6 cm.

2 of 2

Cites

Flagged first, then by citations

2 of the 45 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Shoham Z, Weissman A. Polycystic ovarian disease: obesity and insulin resistance. In: Kempers RD, Cohen J, Haney AF, Younger JB, eds. Fertility and reproductive medicine. Amsterdam, New York, Oxford, Shannon, Singapore, Tokyo: Elsevier, 1998:263–72.

Cited by

Sorted by citations

Related

Authors
Mitwally, M. F. M., & Casper, R. F.
Affiliations
  • Mount Sinai Hospital (CA)
  • University of Toronto (CA)
Corresponding author
Casper, Robert F
ORCID
Casper, Robert F
Venue
Fertility and Sterility
Publisher
Elsevier BV
Published
2001-02
Volume
75
Issue
2
Pages
305-309
ISSN
0015-0282 (ISSN-L)
DOI
10.1016/s0015-0282(00)01705-2
OpenAlex
W2165232862
Cited by
801
References
45
Citations by year
2026: 6 · 2025: 10 · 2024: 12 · 2023: 21 · 2022: 28 · 2021: 24 · 2020: 23 · 2019: 22 · 2018: 25 · 2017: 57 · 2016: 24 · 2015: 69 · 2014: 50 · 2013: 53 · 2012: 63
FWCI
29.17
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 › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Keywords
letrozole, aromatase inhibitors, ovulation induction, polycystic ovary syndrome, ovulatory infertility, anovulatory infertility, endometrial thickness, pregnancy rate
MeSH terms
Letrozole, Anovulation, Endometrium, Enzyme Inhibitors, Estradiol, Female, Chorionic Gonadotropin, Humans

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

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 ›

Are you an author, or do you see a problem with this page? Request a review