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Cited by 344Ovarian function and disordersReproductive Health and TechnologiesReproductive Biology and Fertility

Aromatase inhibition reduces gonadotrophin dose required for controlled ovarian stimulation in women with unexplained infertility

Mitwally, M.F.M.·2003·Human Reproduction
DOI 10.1093/humrep/deg311
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Abstract

BACKGROUND: Adding clomiphene citrate (CC) to FSH for controlled ovarian stimulation (COS) decreases FSH dose required for optimum stimulation. However, because of its anti-estrogenic effects, CC may be associated with lower pregnancy rates offsetting the FSH-dose reduction benefit. Previously, we reported the success of aromatase inhibition in inducing ovulation without antiestrogenic effects. METHODS: A prospective pilot study that included women with unexplained infertility undergoing COS and intrauterine insemination. Thirty-six women received the aromatase inhibitor letrozole + FSH, 18 women received CC + FSH and 56 women received FSH only. Each woman received one treatment regimen in one treatment cycle. All patients were given recombinant or highly purified FSH (50-150 IU/day) starting on day 3 to 7 until day of hCG. RESULTS: The FSH dose needed was significantly lower in letrozole + FSH and CC + FSH groups compared with FSH-only without a difference in number of follicles >1.8 cm. Pregnancy rate was 19.1% in the letrozole + FSH group, 10.5% in the CC + FSH group and 18.7% in the FSH-only group. Both pregnancy rate and endometrial thickness were significantly lower in CC + FSH group compared with the other two groups. Estradiol (E2) levels were significantly lower in the letrozole + FSH group compared with the other two groups. CONCLUSIONS: Similar to CC, aromatase inhibition with letrozole reduces FSH dose required for COS without the undesirable antiestrogenic effects sometimes seen with CC.

AI snapshot

Written from the paper’s full text.

TL;DR

In a non-randomized prospective pilot of 110 ovulatory women with unexplained or mild male factor infertility undergoing controlled ovarian stimulation and IUI, adding letrozole to FSH significantly reduced the total FSH dose required, similar to clomiphene citrate (CC) + FSH. Letrozole + FSH achieved this without the lower endometrial thickness and lower pregnancy rate seen with CC + FSH, although estradiol levels were significantly lower with letrozole.

Key findings

  • Total FSH dose/cycle was significantly lower in letrozole + FSH (465 ± 309 IU) and CC + FSH (619 ± 432 IU) versus FSH-only (1114 ± 393 IU), P < 0.001; letrozole + FSH and CC + FSH did not differ significantly from each other.
  • There was no significant difference among groups in number of follicles >18 mm, LH level on the day of hCG, or day of hCG. Letrozole + FSH had significantly lower estradiol on the day of hCG (1377 ± 184 pmol/l) and estradiol per mature follicle (530 ± 341 pmol/l) compared with FSH-only (2697 ± 1441; 1164 ± 668 pmol/l) and CC + FSH (3623 ± 1432; 1085 ± 497 pmol/l), P < 0.001.
  • Endometrial thickness was significantly lower in CC + FSH (0.8 ± 0.2 cm) than FSH-only (1.0 ± 0.2 cm), P < 0.01, while letrozole + FSH (0.91 ± 0.2 cm) was not significantly different from FSH-only.
  • Clinical pregnancy rate was reported inconsistently: the abstract states 19.1% for letrozole + FSH, 10.5% for CC + FSH, and 18.7% for FSH-only; the Results text states 22.2%, 11.1%, and 18.7%; tables report 22.2% for letrozole + FSH, 11.1% for CC + FSH, and 21.4% for FSH-only. CC + FSH pregnancy rate was significantly lower than the other groups (P < 0.05).

Methods

  • Prospective, non-randomized pilot study conducted at University of Toronto–affiliated reproductive centres from January 2000 to March 2001; 110 ovulatory women with unexplained infertility or mild male factor infertility undergoing COS and IUI, none with polycystic ovarian syndrome or oligo-anovulation.
  • Treatment groups: letrozole 2.5 mg/day on cycle days 3–7 plus FSH (n = 36); CC 100 mg on cycle days 5–9 plus FSH (n = 18); FSH only (n = 56). FSH was given at 50–150 IU/day in the letrozole and CC groups and 50–225 IU/day in the FSH-only group until hCG (10,000 IU); IUI was performed 36 h after hCG if no endogenous LH surge.
  • Follicular monitoring used transvaginal ultrasound and serial estradiol/LH measurements; analysis used ANOVA, t-tests, chi-square, and Bonferroni tests, with P < 0.05 considered significant.

Limitations

  • The authors state the main limitation is the non-randomized design; they note their institutional research board would not have approved a randomized study without a preliminary observational pilot, and that it is difficult to draw definitive conclusions about pregnancy rates from non-randomized comparisons.
  • Evident from the text: the sample was small, especially the CC + FSH group (n = 18); treatment allocation was by patient/physician preference rather than randomization; each patient received only one treatment cycle; and subgroup analyses by endogenous LH surge status were performed without stated adjustment for multiple comparisons.
  • Evident from the text: pregnancy rate figures are inconsistent across the abstract, Results text, and tables, which limits confidence in the pregnancy-related conclusions.

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

Integrity signals

Registry

Crossref · 10.1093/humrep/deg311

Cites

74 of 74 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 34 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    There is no significant difference in total FSH dose required between letrozole + FSH and CC + FSH groups.

    “The total FSH dose/cycle was statistically signi®cantly lower (P < 0.05) in both study groups (letrozole + FSH group and CC + FSH group) when compared with the control group (FSH only) but not between the two study groups when compared with each other (Table II, Table III, Table IV).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The non-randomized treatment assignment did not introduce confounding that would invalidate the comparison of FSH dose and outcomes among groups.
    • Rests on an assumption: The FSH dose adjustment by physicians did not differ systematically among groups in a way that affects the FSH dose outcome.
  • Findingown data

    Endometrial thickness is significantly lower in the CC + FSH and letrozole + FSH groups compared with the FSH-only group throughout most of the follicular phase.

    “In the CC + FSH group and in the letrozole + FSH group, the endometrial thickness was signi®cantly (P < 0.05) lower than the FSH-only group throughout most of the follicular phase (Figure 2).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The non-randomized treatment assignment did not introduce confounding that would invalidate the comparison of FSH dose and outcomes among groups.
    • Rests on an assumption: The FSH dose adjustment by physicians did not differ systematically among groups in a way that affects the FSH dose outcome.
  • Findingown data

    CC + FSH reduces the total FSH dose required for controlled ovarian stimulation compared with FSH alone in women with unexplained infertility.

    “The total FSH dose/cycle was statistically signi®cantly lower (P < 0.05) in both study groups (letrozole + FSH group and CC + FSH group) when compared with the control group (FSH only) but not between the two study groups when compared with each other (Table II, Table III, Table IV).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The non-randomized treatment assignment did not introduce confounding that would invalidate the comparison of FSH dose and outcomes among groups.
    • Rests on an assumption: The FSH dose adjustment by physicians did not differ systematically among groups in a way that affects the FSH dose outcome.
  • Findingown data

    The pregnancy rate was 11.1% in the CC + FSH group.

    “The pregnancy rate was 22.2% in the letrozole + FSH group, 11.1% in the CC + FSH group and 18.7% in the FSH only group.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The non-randomized treatment assignment did not introduce confounding that would invalidate the comparison of FSH dose and outcomes among groups.
    • Rests on an assumption: The FSH dose adjustment by physicians did not differ systematically among groups in a way that affects the FSH dose outcome.
  • Findingown data

    In cycles without an endogenous LH surge, the same pattern of differences in cycle characteristics is observed as in all treatment cycles.

    “The same pattern of differences in the cycle characteristics was observed as in Table II (all treatment cycles).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The non-randomized treatment assignment did not introduce confounding that would invalidate the comparison of FSH dose and outcomes among groups.
    • Rests on an assumption: The FSH dose adjustment by physicians did not differ systematically among groups in a way that affects the FSH dose outcome.
  • May combine two claims. 18
  • Classified as probably not a substantial claim. 23

  • May combine two claims.

    Findingown data

    In cycles with an endogenous LH surge, there is no difference in endometrial thickness on the day of hCG or pregnancy rate per cycle among the three groups.

    “It is interesting that there was no difference in the endometrial thickness on day of hCG day or in the pregnancy rate per cycle among the three patient groups.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The non-randomized treatment assignment did not introduce confounding that would invalidate the comparison of FSH dose and outcomes among groups.
    • Rests on an assumption: The FSH dose adjustment by physicians did not differ systematically among groups in a way that affects the FSH dose outcome.

  • May combine two claims.

    Findingown data

    CC treatment is associated with significantly lower endometrial thickness despite significantly higher estrogen levels.

    “In contrast, CC treatment was associated with signi®cantly lower endometrial thickness despite signi®cantly higher levels of estrogen, demonstrating the antiestrogenic effect associated with CC treatment.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The non-randomized treatment assignment did not introduce confounding that would invalidate the comparison of FSH dose and outcomes among groups.
    • Rests on an assumption: The FSH dose adjustment by physicians did not differ systematically among groups in a way that affects the FSH dose outcome.

  • May combine two claims.

    Findingown data

    Endometrial thickness in FSH-only cycles is significantly greater than in clomiphene citrate + FSH cycles at all time points, and greater than in letrozole + FSH cycles from day -6 to day -2 inclusive (P < 0.05).

    “Endometrial thickness in FSH-only cycle is signi®cantly (P < 0.05) greater than CC + FSH cycles at all time points, and greater than letrozole + FSH cycles from day ±6 to day ±2, inclusive.”
    Quote in the paperNot a substantial claim

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

    Findingreasoning

    The day of hCG administration was later in the clomiphene citrate + FSH group.

    “The day of hCG administration was found to be later in the CC + FSH group.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Centrally, inhibition of estrogen synthesis by an aromatase inhibitor may release estrogenic negative feedback on the hypothalamus and/or pituitary, resulting in increased endogenous gonadotrophin secretion and enhanced ovarian follicular development.

    “Centrally, inhibition of estrogen synthesis by an aromatase inhibitor may release the estrogenic negative feedback on the hypothalamus and/or pituitary resulting in an increase in endogenous gonadotrophin secretion leading to enhancement of ovarian follicular development.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    There is a well-known discrepancy between high ovulation rates after CC treatment and a relatively low pregnancy rate.

    “However, there is a well-known discrepancy between the high ovulation rates after CC treatment and a relatively low pregnancy rate.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Co-treatment with CC during controlled ovarian stimulation has been proposed as a means to reduce the cost of gonadotrophin treatment.

    “Co-treatment with CC during COS has been proposed as a means to reduce the cost of gonadotrophin treatment (Dickey et al., 1993b).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dickey et al., 1993b

      Not checked in the free run.

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

    Premisecitation

    Decreased uterine blood flow, impaired placental protein 14 synthesis, and increased subclinical pregnancy loss have been suggested as contributing to lower pregnancy rates with CC treatment.

    “A decrease in uterine blood ¯ow (Hsu et al., 1995) and impairment of placental protein 14 synthesis (Johnson et al., 1993) in addition to the increased subclinical pregnancy loss (Shoham et al., 1990;Bateman et al., 1992;Saunders et al., 1992) have also been suggested as contributing to lower pregnancy rates with CC treatment.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Hsu et al., 1995

      Not checked in the free run.

    • cites Johnson et al., 1993

      Not checked in the free run.

    • cites Shoham et al., 1990

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisereasoning

    Adding CC to FSH for controlled ovarian stimulation decreases the FSH dose required for optimum stimulation.

    “The value of adding CC during COS is to decrease the FSH dose required for optimum stimulation.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    In patients stimulated with clomiphene citrate for intrauterine insemination, no pregnancy was observed when endometrial thickness was 6 mm on the day of hCG administration, while all preclinical abortions occurred when endometrial thickness was 6±8 mm.

    “Dickey and Holtkamp (1996) reported that in patients stimulated with CC for IUI, no pregnancy was observed when the endometrial thickness was 6 mm on the day of hCG administration, while all preclinical abortions occurred when endometrial thickness was 6±8 mm.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dickey and Holtkamp (1996)

      Not checked in the free run.

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

    Premisereasoning

    The aromatase enzyme is a good target for selective inhibition because estrogen production is a terminal step in the biosynthetic sequence.

    “The aromatase enzyme is a good target for selective inhibition because estrogen production is a terminal step in the biosynthetic sequence.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Use of new aromatase inhibitors would be associated with no deleterious effects on the final stages of follicular development, oocyte maturation, or the early developing embryo.

    “Due to the much shorter half-life, in addition to the absence of any antiestrogenic effects, we believe that use of the new aromatase inhibitors (third generation) would be associated with no deleterious effects on the ®nal stages of follicular development and oocyte maturation or the early developing embryo.”
    Quote in the paperSubstantial claim

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

    Study design and conductreasoning

    The study was non-randomized and the choice of receiving an aromatase inhibitor was left to the patient.

    “Because of the experimental nature of the use of an aromatase inhibitor for augmentation of ovulation, the patients were not randomized for this preliminary clinical trial and the choice of receiving an aromatase inhibitor was exclusively left to the patient.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    Highly selective aromatase inhibitors including letrozole and anastrozole have been approved for use in post-menopausal women with breast cancer to suppress estrogen production.

    “Recently, a group of highly selective aromatase inhibitors (AI), including letrozole and anastrozole, has been approved for use in post-menopausal women with breast cancer to suppress estrogen production.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    IUI, by increasing the density of motile sperm available to oocytes, might further increase the monthly probability of pregnancy.

    “IUI, by increasing the density of motile sperm available to these oocytes, might further increase the monthly probability of pregnancy (Guzick et al., 1998).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Guzick et al., 1998

      Not checked in the free run.

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

    Premisecitation

    The rationale for controlled ovarian stimulation in women with unexplained infertility is to enhance the likelihood of pregnancy by increasing the number of oocytes available for fertilization and to overcome a possible subtle defect in ovulatory function not uncovered by conventional testing.

    “The rationale for COS in women with unexplained infertility, who by de®nition have regular ovulatory menstrual cycles, is to enhance the likelihood of pregnancy by increasing the number of oocytes available for fertilization and to overcome a possible subtle defect in ovulatory function not uncovered by conventional testing (Fisch et al., 1989).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fisch et al., 1989

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These aromatase inhibitors have a relatively short half-life (~48 h) compared with CC and would be eliminated from the body rapidly.

    “These AI have a relatively short half-life (~48 h) compared with CC, and therefore would be eliminated from the body rapidly (Siou® et al. 1997a;b).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Siouff et al. 1997a;b

      Not checked in the free run.

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

    Premisecitation

    Sequential CC and gonadotrophin therapy has become an increasingly utilized method of controlled ovarian stimulation for patients who fail CC treatment.

    “Recently, sequential CC and gonadotrophin (hMG or FSH) therapy has become an increasingly utilized method of COS for patients who fail CC treatment (Kemmann and Jones, 1983;Rose, 1992;Dickey et al., 1993b;Lu et al., 1996).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Kemmann and Jones, 1983

      Not checked in the free run.

    • cites Rose, 1992

      Not checked in the free run.

    • cites Dickey et al., 1993b

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Study design and conductreasoning

    It is difficult to draw definitive conclusions from the present data regarding pregnancy rates.

    “we believe it is dif®cult to draw de®nitive conclusions from the present data regarding pregnancy rates.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    Since no estrogen receptor down-regulation occurs with aromatase inhibitors, no adverse effects on estrogen target tissues as observed in CC-treated cycles would be expected.

    “In addition, since no estrogen receptor down-regulation occurs, no adverse effects on estrogen target tissues, as observed in CC-treated cycles, would be expected.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Aromatase is a cytochrome P-450 haemoprotein-containing enzyme complex that catalyses the rate-limiting step in the production of estrogens.

    “Aromatase is a cytochrome P-450 haemoprotein-containing enzyme complex that catalyses the rate-limiting step in the production of estrogens, i.e. the conversion of androstenedione and testosterone into estrogens (Cole and Robinson, 1990;Akhtar et al., 1993).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Cole and Robinson, 1990

      Not checked in the free run.

    • cites Akhtar et al., 1993

      Not checked in the free run.

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

    Premisecitation

    By depleting estrogen receptors, CC acts as an anti-estrogen on the central nervous system, increasing pulse frequency of FSH and LH, giving a moderate gonadotrophin stimulus to the ovary, and overcoming ovulatory disturbances and increasing the number of follicles reaching ovulation.

    “By depleting the estrogen receptors, CC acts as an anti-estrogen on the central nervous system.This increases the pulse frequency of FSH and LH, giving a moderate gonadotrophin stimulus to the ovary and, thus, overcoming ovulatory disturbances and increasing the number of follicles reaching ovulation (Adashi, 1984;Dickey and Holtkamp, 1996;Kousta et al., 1997).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Adashi, 1984

      Not checked in the free run.

    • cites Dickey and Holtkamp, 1996

      Not checked in the free run.

    • cites Kousta et al., 1997

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The occurrence of an endogenous LH surge might indicate release of the hypothalamus and/or pituitary from the anti-estrogenic effect of clomiphene citrate, allowing rising estrogen to exert positive feedback and trigger the LH surge.

    “The occurrence of an endogenous LH surge might indicate release of the hypothalamus and/or pituitary from the anti-estrogenic effect of CC allowing rising estrogen to exert its positive feedback and triggering the LH surge.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The pregnancy rate with aromatase inhibition is at least acceptable while achieving the advantage of reducing the FSH dose needed for controlled ovarian stimulation.

    “we conclude that the pregnancy rate with aromatase inhibition is at the least acceptable while achieving the advantage of reducing the FSH dose needed for COS.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The nonrandomized treatment groups are comparable in all characteristics that might affect pregnancy, including unmeasured characteristics.

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

    Interpretationreasoning

    Higher LH levels attained with letrozole treatment may indicate a more physiological LH surge due to the faster clearance of letrozole and the more physiological estrogen levels.

    “We believe that the higher LH levels attained with letrozole treatment may indicate a more physiological LH surge due to the faster clearance of letrozole and the more physiological estrogen levels.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    A significant drawback in the present clinical trial is the nonrandomized design of the study.

    “A signi®cant drawback in our present clinical trial is the nonrandomized design of the study.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Supraphysiological levels of estrogen attained during ovarian stimulation may explain the adverse effects of ovarian stimulation on the outcome of infertility treatment.

    “It is possible that supraphysiological levels of estrogen, attained during ovarian stimulation, may explain the adverse effects of ovarian stimulation on the outcome of infertility treatment (Paulson et al., 1990b;Hadi et al., 1994;Simo Ân et al., 1995).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Paulson et al., 1990b

      Not checked in the free run.

    • cites Hadi et al., 1994

      Not checked in the free run.

    • cites Simón et al., 1995

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Controlled ovarian stimulation has a negative impact on implantation, independent of oocyte quality, as evidenced by sharing of oocytes between a donor undergoing controlled ovarian stimulation and a non-stimulated recipient.

    “However, there is evidence from sharing of oocytes between a donor undergoing COS and a non-stimulated recipient that COS has a negative impact on implantation, independent of oocyte quality (Check et al., 1995).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Check et al., 1995

      Not checked in the free run.

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

    Premisecitation

    One approach to improve treatment outcome has been to reduce the intensity of ovarian stimulation and subsequent estrogen levels, including minimal stimulation cycles or natural cycle IVF, and reducing the FSH dose (stepdown protocol) to improve endometrial receptivity.

    “One approach to improve treatment outcome has been to reduce the intensity of ovarian stimulation and subsequent estrogen levels.This approach includes minimal stimulation cycles or natural cycle IVF, and reducing the FSH dose (stepdown protocol) to improve endometrial receptivity (Simo Ân et al., 1998).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Simón et al., 1998

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a recent study, better pregnancy outcome was associated with the occurrence of an endogenous LH surge compared with hCG administration to trigger ovulation in the absence of an LH surge; this favourable outcome was most significantly seen with clomiphene citrate treatment.

    “In a recent study, we found a better outcome in terms of achievement of pregnancy associated with the occurrence of endogenous LH surge compared with when hCG was given to trigger ovulation in the absence of an LH surge.This favourable outcome was most signi®cantly seen with CC treatment (Mitwally et al., 2002).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mitwally et al., 2002

      Not checked in the free run.

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

    Interpretationreasoning

    The later day of hCG administration in the clomiphene citrate + FSH group might be due to patients starting treatment on day 5 of the menstrual cycle, whereas the other two groups started 2 days earlier on day 3.

    “This might be due to the fact that, in CC + FSH treatment, patients started to receive treatment on day 5 of the menstrual cycle while in the other two treatment groups, treatment was started 2 days earlier (on day 3 of the menstrual cycle).”
    Quote in the paperNot a substantial claim
31 of 31

  • The paper relies on this without support.

    The non-randomized treatment assignment did not introduce confounding that would invalidate the comparison of FSH dose and outcomes among groups.

    “Because of the experimental nature of the use of an aromatase inhibitor for augmentation of ovulation, the patients were not randomized for this preliminary clinical trial and the choice of receiving an aromatase inhibitor was exclusively left to the patient.”

  • The paper relies on this without support.

    The FSH dose adjustment by physicians did not differ systematically among groups in a way that affects the FSH dose outcome.

    “The dose and duration of FSH treatment were adjusted during the monitoring of the follicular development according to the patient's response including the number of the growing follicles and estradiol levels.”
    “The patient monitoring was performed, depending on the menstrual cycle start date, by one of ®ve physicians on call for 1 week rotations.”

  • The paper relies on this without support.

    Endometrial thickness is a clinically applicable method to monitor the antiestrogenic effects of treatment on the endometrium.

    “Because measuring the endometrial thickness is relatively simple, non-invasive and routinely applied during follicular monitoring, we considered it as a clinically applicable method to monitor the antiestrogenic effects on the endometrium.”

  • The paper relies on this without support.

    The nonrandomized treatment groups are comparable in all characteristics that might affect pregnancy, including unmeasured characteristics.

    “However, in the absence of any statistically signi®cant difference between the patient groups in characteristics that might affect the achievement of pregnancy, we conclude that the pregnancy rate with aromatase inhibition is at the least acceptable while achieving the advantage of reducing the FSH dose needed for COS.”
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?

  • 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 [61]

  • 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 [61]

  • In that study, the pregnancy rate per cycle in the CC and FSH group (10.5%) was significantly lower than in the letrozole and FSH group (19.1%) and the FSH-only group (18.7%).

    “The pregnancy rate per cycle in the CC and FSH group (10.5%) was significantly lower than in the letrozole and FSH group (19.1%) and the FSH-only group (18.7%).”

    From A new era in ovulation induction (2006) · cites this paper as [61]

  • In a prospective nonrandomized study, compared with the FSH-only group, the required amount of FSH was significantly lower in the letrozole and FSH and in the CC and FSH groups.

    “Compared with the FSH-only group, the required amount of FSH was significantly lower in the letrozole and FSH and in the CC and FSH groups.”

    From A new era in ovulation induction (2006) · cites this paper as [61]

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.

  • Abstract pregnancy rates differ from the Results

    Major

    The abstract reports different pregnancy rates for the letrozole and CC groups than the Results section does.

  • Figure cycle counts exceed the stated study groups

    Major

    Figure 1 describes 42 letrozole and 91 FSH-only cycles, whereas the study describes 36 and 56 women in those groups, respectively, with one treatment cycle per woman.

  • FSH-only follicular estradiol maximum differs across all-cycle tables

    Minor

    Tables II and III give different maxima, 3431 and 1431 pmol/l, for the same FSH-only group and outcome across all treatment cycles.

  • FSH-only pregnancy rate differs between Results and tables

    Minor

    The Results give an FSH-only pregnancy rate of 18.7%, whereas Tables II and III give 21.4%.

  • CC no-surge subgroup exceeds the entire CC group

    Minor

    Table IX lists 36 CC-treated cycles without an LH surge, but the entire CC + FSH group contains only 18 women, each contributing one cycle.

  • Reported CC FSH-dose mean exceeds its maximum

    Minor

    For CC cycles with an LH surge, Table VI reports a mean total FSH dose of 629 IU but a maximum of 600 IU.

  • Abstract FSH-dose range excludes the control protocol

    Minor

    The abstract says all patients received 50-150 IU/day of FSH, while the methods specify up to 225 IU/day for the FSH-only control group.

  • Letrozole subgroup estradiol maximum exceeds the overall maximum

    Minor

    The letrozole group's maximum estradiol on the hCG day is 2910 pmol/l for all cycles in Table II, but reaches 3420 pmol/l in the no-LH-surge subset in Table VIII.

8 of 8

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Authors
Mitwally, M. F. M.
Affiliations
Mount Sinai Hospital (CA)
Corresponding author
Mitwally, M.F.M.
Venue
Human Reproduction
Publisher
Oxford University Press (OUP)
Published
2003-08-01
Volume
18
Issue
8
Pages
1588-1597
ISSN
  • 0268-1161 (ISSN-L)
  • 1460-2350
DOI
10.1093/humrep/deg311
OpenAlex
W2143080753
Semantic Scholar
8920651561fa9a175b8dd186f6a5a23dc35684ab
Cited by
344
References
74
Citations by year
2025: 3 · 2024: 4 · 2023: 1 · 2022: 2 · 2021: 4 · 2020: 4 · 2019: 3 · 2018: 5 · 2017: 37 · 2016: 6 · 2015: 47 · 2014: 37 · 2013: 27 · 2012: 41
FWCI
13.18
Type
journal article
Language
en
Open access
closed
Locations
  • Human Reproduction (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
aromatase inhibition, letrozole, clomiphene citrate, controlled ovarian stimulation, unexplained infertility, pregnancy rate, endometrial thickness, estradiol levels, antiestrogenic effects, intrauterine insemination
MeSH terms
Letrozole, Adult, Clomiphene, Enzyme Inhibitors, Estradiol, Female, Fertility Agents, Female, Ovarian Follicle, Humans, Infertility, Female, Luteinizing Hormone, Nitriles, Ovulation Induction, Pilot Projects, Pregnancy, Prospective Studies, Triazoles, Ultrasonography, Follicle Stimulating Hormone, Human, Aromatase Inhibitors

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 ›

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