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Cited by 132Reproductive Health and TechnologiesOvarian function and disordersReproductive Biology and Fertility

Effects of letrozole on superovulation with gonadotropins in women undergoing intrauterine insemination

Open access
Healey, Sarah, Tan, Seang Lin, Tulandi, Togas, Biljan, Marinko M·2003·Fertility and Sterility
DOI 10.1016/j.fertnstert.2003.03.001
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Abstract

Objective To investigate the effects of letrozole in patients undergoing superovulation with gonadotropins and IUI.Design Retrospective analysis.Setting Academic teaching hospital.Patient(s) Women younger than 40 years of age with patent fallopian tubes and infertility of more than 1 year in duration who were undergoing IUI and gonadotropin therapy.Intervention(s) Gonadotropins alone administered from day 3 or a combination of letrozole, 5 mg/d on day 3 to 7, and gonadotropins starting on day 5 of the menstrual cycle. Ultrasonography was performed before initiation of treatment, on day 9 of menstrual cycle, and as required thereafter until the dominant follicle reached 18 mm in diameter. Ovulation was triggered with 10,000 IU of hCG, and IUI was performed 24 and 48 hours later.Main outcome measure(s) Gonadotropin requirements, endometrial thickness, number of follicles, and pregnancy rate.Result(s) All 205 IUI treatment cycles conducted from March 2001 to March 2002 were included. Gonadotropins alone were used in 145 cycles and combination therapy was used in 60 cycles. Patients cotreated with letrozole required fewer gonadotropin administrations (median difference, 300 IU [95% confidence interval (CI), 225-375 IU]), developed more follicles larger than 14 mm (median difference, 1 follicle [95% CI, 1-2 follicles), and had a thinner endometrium (median difference, 1 mm [95% CI, 0.4-1.6 mm]). The pregnancy rate did not differ between patients using gonadotropin alone and those using gonadotropin plus letrozole (20.9% vs. 21.6%).Conclusion(s) The addition of letrozole to gonadotropins decreases gonadotropin requirements, increases the number of pre-ovulatory follicles and decreases endometrial thickness, without a negative effect on pregnancy rates.

AI snapshot

Written from the paper’s full text.

TL;DR

In this retrospective analysis of 205 IUI cycles, adding letrozole to gonadotropins reduced gonadotropin requirements and increased preovulatory follicles but decreased endometrial thickness, without changing pregnancy rate. The authors conclude that prospective randomized trials are needed to clarify letrozole’s role as a cotreatment in superovulation and IUI.

Key findings

  • Letrozole plus gonadotropins required less gonadotropin to reach follicular maturity than gonadotropins alone (mean 600.6 ± 405.7 IU vs. 940.6 ± 464.2 IU; P<.0001; median difference, 300 IU [95% CI, 225–375 IU]) and fewer days (7.6 ± 2.0 vs. 9.5 ± 3.0; P<.0001; median difference, −2 days [95% CI, −2 to 1 days]).
  • Letrozole cotreatment produced more follicles: follicles >14 mm at hCG administration (3.2 ± 1.2 vs. 2.2 ± 1.5; P<.001; median difference, 1 follicle [95% CI, 1–2]) and follicles >8 mm (5.7 ± 2.7 vs. 4.9 ± 4.3; P=.0008).
  • Endometrial thickness at hCG administration was thinner with letrozole (8.5 ± 2.6 mm vs. 9.4 ± 1.9 mm; P<.001; median difference, 1 mm [95% CI, 0.4–1.6 mm]).
  • Pregnancy rate per cycle started did not differ between groups (21.6% vs. 20.9%; NS in Table 1); no multiple pregnancies occurred in the letrozole plus gonadotropin group, whereas three twin pregnancies occurred in the gonadotropin-alone group.

Methods

  • Retrospective analysis at an academic teaching hospital, March 2001–March 2002; 107 patients and 205 IUI cycles were included, with 145 cycles using gonadotropins alone and 60 using letrozole plus gonadotropins. Inclusion criteria were age younger than 40 years, infertility >1 year, patent fallopian tubes, normal uterine cavity, and at least 10 million rapidly motile sperm/mL.
  • Gonadotropins alone began on day 3, or letrozole 5 mg/d was given on days 3–7 plus gonadotropins starting on day 5; the starting gonadotropin dose was 150 IU every 2 days and was modified as needed. hCG 10,000 IU was given when at least one follicle reached 18 mm, and IUI was performed 24 and 48 hours later.
  • Data were tested for normality with the Shapiro-Wilks test; because data were not normally distributed, Mann-Whitney tests were used, with chi-square and Fisher exact tests for proportions and 95% CIs reported; P<.05 was considered statistically significant.

Limitations

  • The authors state the study is limited by its retrospective nature and that treatment choice was based on physician preference, so some bias may have been introduced; they note the groups were similar in age, indications, and treatment history, and that two technicians performed all ultrasonographic scans and the same embryologist prepared IUI samples.
  • The authors note the anovulatory subgroup comprised only patients with PCOS, and not all underwent testing or treatment for insulin resistance, which may account for differences in ovarian sensitivity to gonadotropins.
  • Evident in the text: the pregnancy-rate result is internally inconsistent—the paper states no difference and Table 1 marks pregnancy rate NS, but also reports an odds ratio of 1.8 (95% CI, 1.1–3.2); the letrozole plus gonadotropin group was also much smaller (60 cycles) than the gonadotropin-alone group (145 cycles).

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

Integrity signals

Registry

Crossref · 10.1016/j.fertnstert.2003.03.001

Cites

36 of 36 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 6 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Letrozole plus gonadotropins decreases gonadotropin requirements compared with gonadotropins alone in women undergoing intrauterine insemination.

    “Patients cotreated with letrozole required fewer gonadotropin administrations (median difference, 300 IU [95% confidence interval (CI), 225-375 IU])”
    • Also stated in: § RESULTS · plain
      “Cotreatment with letrozole resulted in a decrease in the duration of time (median difference, Ϫ2 days [95% CI, Ϫ2 to 1 days]) and amount of gonadotropins (median difference, Ϫ300 IU [95% CI, Ϫ375 to 225 IU]) required to achieve follicular maturation.”
    • Also stated in: § DISCUSSION · plain
      “Gonadotropins to reach follicular maturity (IU) 940.6 Ϯ 464.2 600.6 Ϯ 405.7 Ͻ.0001”
    Quote in the paperSubstantial claim
  • Findingown data

    Letrozole plus gonadotropins decreases endometrial thickness at hCG administration compared with gonadotropins alone.

    “had a thinner endometrium (median difference, 1 mm [95% CI, 0.4 -1.6 mm])”
    • Also stated in: § RESULTS · plain
      “The endometrium at the time of hCG administration was significantly thicker in patients who received gonadotropins alone (median difference, 1 mm [95% CI, 0.4 -1.6 mm).”
    • Also stated in: § DISCUSSION · plain
      “Endometrial thickness on day of hCG administration (mm) 9.4 Ϯ 1.9 8.5 Ϯ 2.6 Ͻ.001”
    Quote in the paperSubstantial claim
  • Findingown data

    Letrozole plus gonadotropins increases the number of follicles 14 mm or larger at hCG administration compared with gonadotropins alone.

    “developed more follicles larger than 14 mm (median difference, 1 follicle [95% CI, 1-2 follicles)”
    • Also stated in: § RESULTS · plain
      “A higher number of follicles (median difference, 2 follicles [95% CI, 1-2 follicles]) and more follicles 14 mm or larger (median difference, 1 follicle [95% CI, 1-2 follicles) at the time of hCG administration were found in participants who received letrozole plus gonadotropins compared with those who received gonadotropins alone (Table 1).”
    • Also stated in: § DISCUSSION · plain
      “No. of follicles Ͼ14 mm on day of hCG administration 2.2 Ϯ 1.5 3.2 Ϯ 1.2 Ͻ.001”
    Quote in the paperSubstantial claim
  • Findingown data

    Pregnancy rate does not differ between letrozole plus gonadotropins and gonadotropins alone.

    “The pregnancy rate did not differ between patients using gonadotropin alone and those using gonadotropin plus letrozole (20.9% vs. 21.6%).”
    • Also stated in: § RESULTS · plain
      “No difference in the pregnancy rate between the two groups was noted (odds ratio, 1.8 [95% CI, 1.1-3.2]).”
    • Also stated in: § DISCUSSION · plain
      “Pregnancy rate per cycle started (%) 20.9 21.6 NS”
    Quote in the paperSubstantial claim
  • Findingown data

    Letrozole plus gonadotropins increases the total number of follicles at hCG administration compared with gonadotropins alone.

    “A higher number of follicles (median difference, 2 follicles [95% CI, 1-2 follicles]) and more follicles 14 mm or larger (median difference, 1 follicle [95% CI, 1-2 follicles) at the time of hCG administration were found in participants who received letrozole plus gonadotropins compared with those who received gonadotropins alone (Table 1).”
    • Also stated in: § DISCUSSION · plain
      “No. of follicles Ͼ8 mm on day of hCG administration 4.9 Ϯ 4.3 5.7 Ϯ 2.7 .0008”
    Quote in the paperSubstantial claim
  • May combine two claims. 7
  • Classified as probably not a substantial claim. 6

  • May combine two claims.

    Findingown data

    The effect of letrozole on reducing gonadotropin requirements is seen specifically in patients with unexplained or male factor infertility, but not in those with anovulation.

    “This effect was seen specifically in the patients with unexplained or male factor infertility, but not in those with anovulation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Three biochemical pregnancies occurred in the gonadotropin group and one in the letrozole plus gonadotropin group.

    “Three biochemical pregnancies occurred in the gonadotropin group and one occurred in the letrozole plus gonadotropin group.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    Both groups were treated at the same time and were similar in age, indications for treatment, and treatment history.

    “However, both groups of patients were treated at the same time and were similar in age, indications for treatment, and treatment history.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The discrepancy between our findings and previously published data may be attributable to differences in ovulation induction regimens.

    “The discrepancy between our findings and previously published data may be attributable to differences in ovulation induction regimens.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Two technicians performed all ultrasonographic scans and the same embryologist prepared the intrauterine insemination samples.

    “Moreover, two technicians performed all ultrasonographic scans and the same embryologist prepared the IUI samples.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The study is limited by its retrospective nature.

    “The study is limited by its retrospective nature.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The multiple pregnancy rate did not increase with letrozole despite a higher number of preovulatory follicles.

    “Similarly, despite the significantly higher number of preovulatory follicles in patients pretreated with letrozole, the pregnancy rate or multiple pregnancy rate did not increase.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    Because the study was not randomized and treatment choice was based on physician preference, some bias may have been introduced.

    “Because the study was not randomized and the choice of treatment was based on physician preference, some bias may have been introduced.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Letrozole's postulated mechanism of action is increased endogenous FSH production and possibly a local effect of increasing androgen concentration and ovarian sensitivity to FSH.

    “Its postulated mechanism of action is the increased endogenous production of FSH and, possibly a local effect of increasing androgen concentration and sensitivity of the ovaries to FSH (32).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Weil, 1998, Androgen receptor gene expression in the primate ovary, J Clin Endocrinol Metab source

      Not checked in the free run.

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

    Premisecitation

    The gonadotropin requirement can be significantly reduced by combining gonadotropin treatment with clomiphene citrate.

    “The gonadotropin requirement can be significantly reduced by combining this treatment with clomiphene citrate (9).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Kemmann, 1983, Sequential clomiphene citrate-menotropin therapy for induction or enhancement of ovulation, Fertil Steril source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted).

    Premisecitation

    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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Mitwally, 2001, Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate, Fertil Steril source

      Not checked in the free run.

    • cites [18] Mitwally, 2002, Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders, Fertil Steril source

      Not checked in the free run.

11 of 11

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 theoretically avoid adverse effects of clomiphene citrate as they do not affect oestrogen receptors centrally or thin the endometrium.

    “These agents theoretically avoid adverse effects of clomiphene citrate, 238,239 as they do not affect oestrogen receptors centrally or thin the endometrium. 237”

    From Assessment and management of polycystic ovary syndrome: Summary of an evidence-based guideline (2011) · cites this paper as [238]

  • The pregnancy rate for treatment with letrozole and FSH was similar to that for FSH alone.

    “The pregnancy rate for treatment with letrozole and FSH was similar to that for FSH alone.”

    From A new era in ovulation induction (2006) · cites this paper as [62]

  • The addition of letrozole to FSH treatment leads to a decreased FSH requirement.

    “The addition of letrozole to FSH treatment leads to a decreased FSH requirement.”

    From A new era in ovulation induction (2006) · cites this paper as [62]

  • In Healy et al., there was no significant difference in pregnancy rates between the gonadotropin-only and gonadotropin+letrozole groups (20.9% vs. 21.6%).

    “However, there was no significant difference in the pregnancy rates between the two groups (gonadotropin 20.9%, gonadotropin and letrozole 21.6%).”

    From A new era in ovulation induction (2006) · cites this paper as [62]

  • In Healy et al., patients treated with combined letrozole and gonadotropin required less gonadotropin and developed more follicles >14 mm but had thinner endometrium.

    “Patients treated with a combined regimen required less gonadotropin and developed more follicles Ͼ14 mm but had thinner endometrium.”

    From A new era in ovulation induction (2006) · cites this paper as [62]

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.

  • Pregnancy odds ratio contradicts the reported lack of a difference

    Major

    The reported 95% confidence interval for the odds ratio is 1.1-3.2, which excludes 1, yet the paper says the pregnancy rate did not differ and labels the comparison nonsignificant.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Buzdar, 2001, Howell A. Advances in aromatase inhibition, Clin Cancer Res, 7, 2620

Cited by

Sorted by citations

Related

Authors
Healey, S., Tan, S. L., Tulandi, T., & Biljan, M. M.
Affiliations
McGill University (CA)
Corresponding author
Healey, Sarah
ORCID
Venue
Fertility and Sterility
Publisher
Elsevier BV
Published
2003-12
Volume
80
Issue
6
Pages
1325-1329
ISSN
0015-0282 (ISSN-L)
DOI
10.1016/j.fertnstert.2003.03.001
OpenAlex
W2158299014
Cited by
132
References
36
Citations by year
2026: 1 · 2025: 1 · 2024: 3 · 2022: 8 · 2021: 1 · 2020: 5 · 2019: 1 · 2018: 5 · 2017: 5 · 2016: 1 · 2015: 7 · 2014: 5 · 2013: 7 · 2012: 7
FWCI
10.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Fertility and Sterility (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Reproductive Health and Technologies
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
Keywords
letrozole, superovulation, gonadotropins, intrauterine insemination, infertility, endometrial thickness, follicle count, pregnancy rate, ovulation induction, hCG trigger
MeSH terms
Letrozole, Adult, Enzyme Inhibitors, Female, Chorionic Gonadotropin, Hospitals, Teaching, Humans, Insemination, Artificial, Nitriles, Pregnancy, Pregnancy Outcome, Retrospective Studies, Superovulation, Triazoles, Aromatase Inhibitors

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