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A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women
Open accessAbstract
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.
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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.
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Claims the paper makes
19 Own result · 15 Not checked yet · 10 Own method · 3 Own interpretation
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Early follicular treatment with clomiphene and letrozole resulted in a comparable increase in the number of mature follicles at the LH surge.”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > RESULTS
plaindirectn = 16- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > RESULTS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Despite significantly lower E 2 levels in letrozole-treated women, endometrial development was unaffected in this study.”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > RESULTS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > RESULTS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The number of mature follicles (Ն18 mm) at the LH surge in natural cycles was 1.0 in both the clomiphene and letrozole groups.”
- Also stated in: § Abstract · plain
“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.”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > RESULTS
plainn = 16- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Abstract · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Within each group, there was no difference in the mean endometrial thickness between the natural and treated cycles.”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > RESULTS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There was no significant reduction in the number of women with a midcycle tri-laminar pattern in either group during the treatment cycle (letrozole 71%, Pϭ.46, Fisher's exact test; and clomiphene 44%, Pϭ1.00, Fisher's exact test).”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > RESULTS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Endometrial thickness at midcycle was comparable between the groups during both natural cycles and treatment cycles.”
- Also stated in: § Abstract · plain
“There was no difference in the endometrial thickness at midcycle during either the natural cycles or the medicated cycles.”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > RESULTS
plainn = 19- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Abstract · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the stimulated cycle, the mean (ϮSD) E 2 levels on the day of the LH surge were 2,047 (Ϯ930) pmol/L for the clomiphene group and 399 (Ϯ167) pmol/L for the letrozole group.”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > RESULTS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“When measured daily, follicular profiles of LH (Fig. 1) and FSH (Figs. 2 and 3) were similar between the groups in both the natural and medicated cycles.”
- Also stated in: § Abstract · plain
“When measured daily, follicular profiles of LH and FSH are similar between the groups in both the natural and medicated cycles.”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > RESULTS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Abstract · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“During the natural cycles, a total of three women had midcycle endometrial thickness Յ8 mm, one in the clomiphene group (7.5 mm) and two in the letrozole group (7.2 and 6.8 mm).”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > RESULTS
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Prolonged endometrial estrogen receptor depletion (9 -11) results in the significant thinning of the endometrium (endometrium thickness Յ8 mm) that is associated with clomiphene cycles compared with natural cycles and in clomiphene/hMG cycles compared with hMG alone (9,10,12,13).”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > Abstract
What the sources say
- Not checked yetcites [9] Eden, 1989, The effect of clomiphene citrate on follicular phase increase in endometrial thickness and uterine volume, Obstet Gynecol
- Not checked yetcites [10] Gonen, 1990, Sonographic determination of a possible adverse effect of clomiphene citrate on endometrial growth, Hum Reprod source
- Not checked yetcites [12] Nakamura, 1997, Effects of clomiphene citrate on the endometrial thickness and echogenic pattern of the endometrium, Fertil Steril source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Similarly, non-trilaminar pattern endometrium at midcycle in clomiphene cycles has been shown to have a strong negative predictive value (90%) with respect to ongoing pregnancy (16).”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > Abstract
What the sources say
- Not checked yetcites [16] Gonen, 1990, Prediction of implantation by the sonographic appearance of the endometrium during controlled ovarian stimulation for IVF, J In Vitro Fertil Embryo Transfer source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“This endometrial thinning has been observed in 15%-50% patients on clomiphene (10,13,14).”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > Abstract
What the sources say
- Not checked yetcites [10] Gonen, 1990, Sonographic determination of a possible adverse effect of clomiphene citrate on endometrial growth, Hum Reprod source
- Not checked yetcites [13] Yagel, 1992, The effect of ethinyl estradiol on endometrial thickness and uterine volume during ovulation induction by clomiphene citrate, Fertil Steril source
- Not checked yetcites [14] Dickey, 1993, Relationship of endometrial thickness and pattern to fecundity in ovulation induction cycles, Fertil Steril source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“Dickey and Holtkamp (8) as well as Gonen and Casper (10) reported no pregnancies occurring in cycles with endometrial thickness Յ6 mm at midcycle (8,10)”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > Abstract
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Letrozole resulted in elevated FSH levels and a corresponding increase in the number of multiple mature follicles that were ovulated after administration of exogenous hCG (20).”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > Abstract
What the sources say
- Not checked yetcites [20] Shetty, 1997, Effect of estrogen deprivation on the reproductive physiology of male and female primates, J Steroid Biochem Molec Biol source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Given the short half-life of both LH (t 1 ⁄2 ϭ 20 minutes) and FSH (t 1 ⁄2 ϭ 3-4 hours), it is possible that daily blood sampling was too infrequent to identify a brief increase in the circulating concentrations of LH and FSH.”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Given that impaired endometrial development on clomiphene occurs in a minority of women, we would not expect to see a significant difference in this parameter because of the small sample size of this pilot study.”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > DISCUSSION
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Despite the relatively short duration of letrozole treatment, the reduction in E 2 levels per follicle suggests a persistent reduction of aromatase activity, which lasts to midcycle.”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > DISCUSSION
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, this pilot study has demonstrated that the aromatase inhibitor letrozole is equivalent to clomiphene for stimulation of follicular growth in normal ovulatory women.”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > DISCUSSION
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Several recent publications support a role for androgens in the stimulation of follicular growth in primates through amplification of FSH receptor gene expression (22)(23)(24).”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > DISCUSSION
What the sources say
- Not checked yetcites [22] Weil, 1999, Androgen and follicle stimulating hormone interactions in primate ovarian follicle development, J Clin Endocrinol Metab source
- Not checked yetcites [23] Vendola, 1999, Androgens promote oocyte insulin-like growth factor I expression and initiation of follicle development in the primate ovary, Biol Reprod source
- Not checked yetcites [24] Vendola, 1998, Androgens stimulate early stages of follicular growth in the primate ovary, J Clin Invest source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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In the paper
“In a selected population of women with a thin endometrium (mean, 5 mm) after clomiphene treatment, letrozole treatment in the early follicular phase resulted in a significant increase in midcycle endometrial thickness (mean, 9 mm) (21).”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > DISCUSSION
What the sources say
- Not checked yetcites [21] Mitwally, 2001, Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate, Fertil Steril source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“In another study, women undergoing IUI who received letrozole in addition to FSH required significantly lower total FSH doses (45%-56%) per cycle than those women receiving FSH only (26).”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > DISCUSSION
What the sources say
- Not checked yetcites [26] Mitwally, 2001, Aromatase inhibition decreases FSH dose needed during controlled ovarian hyperstimulation, J Soc Clin Invest
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In these women, addition of letrozole to the stimulation protocol resulted in a significant increase in the number of mature follicles at midcycle (3.5 vs. 1.9).”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > DISCUSSION
What the sources say
- Not checked yetcites [25] Mitwally, 2001, Aromatase inhibition improves ovarian response to FSH, Fertil Steril source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 13
- Probably not a substantial claim. 13
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > RESULTS
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > RESULTS
plainn = 16- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > RESULTS
plaindirectn = 19- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § Abstract · hedged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > RESULTS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > Abstract
plainn = 19- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § RESULTS · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > RESULTS
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > RESULTS
plaincorrelationaln = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Clomiphene results in a 60%-85% ovulation rate and a 10%-20% pregnancy rate per cycle (2)(3)(4)(5)(6)(7)(8).”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > Abstract
What the sources say
- Not checked yetcites [2] Dickey, 1996, Incidence of spontaneous abortion in clomiphene pregnancies, Hum Reprod source
- Not checked yetcites [3] Garcia, 1977, The use of clomiphene citrate, Fertil Steril source
- Not checked yetcites [4] Gorlitsky, 1978, Ovulation and pregnancy rates with clomiphene citrate, Obstet Gynecol source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Clomiphene citrate has been widely used in the treatment of infertility since its introduction into clinical practice in the 1960s (1).”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > Abstract
What the sources say
- Not checked yetcites [1] Greenblatt, 1961, Induction of ovulation with MRL/41, JAMA source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“and a significantly higher rate of biochemical pregnancies when the endometrial thickness was 6 -8 mm (15).”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > Abstract
What the sources say
- Not checked yetcites [15] Dickey, 1993, Relationship of biochemical pregnancy to preovulatory endometrial thickness and pattern in ovulation induction patients, Hum Reprod source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > Abstract
What the sources say
- Not checked yetcites [17] Lamb, 1998, Letrozole, Drugs source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > MATERIALS AND METHODS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“A total of 16 participants completed both cycles of the study and were included in the final analysis of data.”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > RESULTS
plainn = 16- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > MATERIALS AND METHODS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Also stated in: § Abstract · plain
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > MATERIALS AND METHODS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > Abstract
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“A single daily dose of 2.5 mg/day has been shown to achieve optimal suppression of serum estrogen levels in postmenopausal women (18).”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > Abstract
What the sources say
- Not checked yetcites [18] Dowsett, 1995, In vivo measurement of aromatase inhibition by letrozole (CGS 20267) in postmenopausal women with breast cancer, Clin Cancer Res
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > RESULTS
plainn = 2- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > MATERIALS AND METHODS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
In the paper
“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).”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > Abstract
What the sources say
- Not checked yetcites [19] Sinha, 1998, Effect of CGS 20267 on ovarian aromatase and gonadotropin levels in the rat, Breast Cancer Res Treat source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > MATERIALS AND METHODS
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Samples from the control and stimulation cycle of each subject were always assayed in the same LH and FSH assay.”
§ A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women > MATERIALS AND METHODS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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.”
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 the citing paper
“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]
Citations
Cites
Mitwally, M. F. M., & Casper, R. F. (2001) · Fertility and Sterility · doi:10.1016/s0015-0282(00)01705-2 · Cited by 800
Self-citationAndrogens stimulate early stages of follicular growth in the primate ovary
Vendola, K. A., Zhou, J., Adesanya, O. O., Weil, S. J., & Bondy, C. A. (1998) · Journal of Clinical Investigation · doi:10.1172/jci2081 · Cited by 712
Androgen and follicle stimulating hormone interactions in primate ovarian follicle development
Weil, S., Vendola, K., Zhou, J., & Bondy, C. A. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.8.5929 · Cited by 592
Induction of Ovulation with MRL/41: Preliminary Report
Greenblatt, R. B. (1961) · JAMA · doi:10.1001/jama.1961.03040410001001 · Cited by 343
Vendola, K., Zhou, J., Wang, J., Famuyiwa, O. A., Bievre, M., & Bondy, C. A. (1999) · Biology of Reproduction · doi:10.1095/biolreprod61.2.353 · Cited by 324
Gonen, Y., & Casper, R. F. (1990) · Journal of In Vitro Fertilization and Embryo Transfer · doi:10.1007/bf01135678 · Cited by 307
Self-citationEffect of estrogen deprivation on the reproductive physiology of male and female primates
Shetty, G., Krishnamurthy, H., Krishnamurthy, H. N., Bhatnagar, A. S., & Moudgal, R. N. (1997) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/s0960-0760(97)80008-8 · Cited by 306
Gysler, M., March, C. M., Mishell, D. R., & Bailey, E. J. (1982) · Fertility and Sterility · doi:10.1016/s0015-0282(16)46033-4 · Cited by 270
Dowsett, M., Jones, A. L., Johnston, S. R. D., Jacobs, S., Trunet, P. F., & Smith, I. E. (1995) · PubMed · Cited by 238
Garcia, J., Jones, G. S., & Wentz, A. C. (1977) · Fertility and Sterility · doi:10.1016/s0015-0282(16)42670-1 · Cited by 233
Research works printed but not linked: 1
- Mitwally, 2001, Aromatase inhibition decreases FSH dose needed during controlled ovarian hyperstimulation, J Soc Clin Invest, 8, 85A
Cited by
Sorted by citations
Goodman, N. F., Cobin, R. H., Futterweit, W., Glueck, J. S., Legro, R. S., & Carmina, E. (2015) · Endocrine Practice · doi:10.4158/ep15748.dscpt2 · Cited by 366
Clomiphene citrate—end of an era? a mini-review
Homburg, R. (2005) · Human Reproduction · doi:10.1093/humrep/dei042 · Cited by 332
“A direct comparison of letrozole with 50mg/day of CC in ovulatory women in an RCT showed similar effects on stimulation of folliculogenesis, whilst endometrial thickness was maintained by letrozole despite much lower estradiol concentrations than with CC at mid-cycle (Fisher et al., 2002).”
BackgroundAromatase Inhibitors for Ovulation Induction
Casper, R. F., & Mitwally, M. F. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-1923 · Cited by 272
Self-citationOktay, K., Büyük, E., Davis, O., Yermakova, I. S., Veeck, L. L., & Rosenwaks, Z. (2003) · Human Reproduction · doi:10.1093/humrep/deg045 · Cited by 270
“Nevertheless, aromatase inhibitor drugs have recently been used in ovulation induction (Fisher et al., 2002), and we are conducting a prospective study to test their value for fertility preservation in breast cancer patients as they may not result in a rise in estradiol levels.”
BackgroundClomiphene citrate versus letrozole for ovarian stimulation: a pilot study
Fatemi, H. M., Kolibianakis, E. M., Tournaye, H. J., Camus, M., Steirteghem, A. V., & Devroey, P. (2003) · Reproductive BioMedicine Online · doi:10.1016/s1472-6483(10)62070-6 · Cited by 253
“In a randomized study, Fisher et al. (2002) compared the administration of CC and letrozole for IUI.”
Background
Metadata
- 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
- Venue
- Fertility and Sterility
- Publisher
- Elsevier BV
- Published
- 2002-08
- Volume
- 78
- Issue
- 2
- Pages
- 280-285
- ISSN
- 0015-0282 (ISSN-L)
- 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
- bronze
- doi.org
- Licence
- Locations
- Fertility and Sterility (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Health Sciences › Medicine › Reproductive Medicine › Reproductive 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
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.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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.
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