The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index; none of the 15 sources its claims cite is checked for support yet.
Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders
Open accessAbstract
Objective To examine the use of the aromatase inhibitor letrozole with FSH for ovarian stimulation in poor responders undergoing ovarian superovulation and IUI.Design Observational cohort study as a prospective clinical trial in patients with unexplained infertility and a low response to ovarian stimulation with FSH.Setting Two tertiary referral infertility clinics associated with the Reproductive Sciences Division, University of Toronto.Patient(s) Twelve patients with unexplained infertility undergoing IUI who received FSH alone in 25 prior cycles with poor response (less than three dominant follicles).Intervention(s) Patients were offered letrozole, 2.5 mg/day from day 3-7 of the menstrual cycle with FSH (50-225 IU/day) starting on day 5-7. hCG (10,000 IU) was given when two leading follicles were >/=2 cm followed by IUI.Main outcome measure(s) Number of mature follicles (>1.8 cm), FSH dose, endometrial thickness, and pregnancy rate.Result(s) Improved response to FSH stimulation with letrozole co-treatment was evidenced by the significantly lower FSH dose associated with significantly higher number of mature follicles. During letrozole plus FSH stimulation cycles, clinical pregnancy was achieved in three cycles (21%).Conclusion(s) In this preliminary report, we demonstrate a potential benefit of aromatase inhibition for improving ovarian response to FSH in poor responders.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
In 12 poor responders with unexplained infertility, adding letrozole to FSH improved ovarian response compared with prior FSH-only cycles. Letrozole plus FSH produced more mature follicles, required less FSH, and yielded three clinical pregnancies (21%), with no pregnancies in FSH-only cycles.
Key findings
- Letrozole plus FSH cycles had significantly more mature follicles (>1.8 cm) than FSH-only cycles: 3.3 ± 1.8 vs 1.9 ± 0.6 (P = .003).
- Total FSH per cycle was significantly lower with letrozole plus FSH: 616 ± 454 IU vs 1590 ± 708 IU (P = .0001), and stimulation days were fewer: 6.57 ± 1.95 vs 9 ± 3.42 (P = .026).
- E2 per mature follicle on hCG day was significantly lower with letrozole plus FSH: 626 ± 302 pmol/L vs 1324 ± 485 pmol/L (P = .0001), while E2 on hCG day, endometrial thickness, and LH on hCG day were not significantly different.
- No pregnancies occurred in FSH-only cycles; during letrozole plus FSH cycles, four patients achieved pregnancy, including three clinical pregnancies (21%) and one chemical pregnancy.
Methods
- Observational cohort study conducted as a prospective clinical trial in 12 patients with unexplained infertility and poor response to FSH in at least two prior cycles, defined as fewer than three follicles >1.8 cm on the day of LH surge or hCG administration.
- Patients received FSH alone in 25 prior cycles and letrozole 2.5 mg/day from day 3–7 plus FSH 50–225 IU/day in 14 cycles; hCG 10,000 IU was given when two leading follicles reached >2 cm, followed by IUI.
- Outcomes were compared between 20 completed FSH-only cycles (excluding canceled cycles) and 14 letrozole plus FSH cycles using t-tests with GraphPad Prism Version 3.
Limitations
- The paper states this preliminary report includes a small number of patients and used a nonrandomized, nonplacebo-controlled design.
- The paper states that possible effects of a short course of letrozole on pregnancy outcome are unknown and should be addressed in counseling and pregnancy follow-up.
- The text makes evident that the comparison relies on prior FSH-only cycles rather than concurrent randomized controls, and that five canceled FSH-only cycles were excluded from the outcome comparison.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Statistics
Verification
Claims the paper makes
12 Own result · 7 Not checked yet · 7 Own interpretation · 2 Own method
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
“Although there was no difference in the level of E 2 on the day of hCG administration, the amount of E per mature follicle was significantly lower with letrozole treatment.”
- Also stated in: § DISCUSSION · plain
“E2/mature follicle on hCG day (pmol/L) 1324 Ϯ 485 626 Ϯ 302 .0001”
- Also stated in: § DISCUSSION · plain
“Letrozole treatment was associated with a significantly lower amount of E per mature follicle but still within phys-iologic levels seen during natural cycles.”
§ Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders > RESULTS
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.
- Also stated in: § DISCUSSION · 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
“Stimulation days/cycle 9 Ϯ 3.42 6.57Ϯ 1.95 .026”
§ Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders > DISCUSSION
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.
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
“We have preliminary data to support this mechanism of action in the form of increased FSH and LH during letrozole treatment (data not shown).”
§ Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders > 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 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 difference between FSH-only or letrozole plus FSH on the day of hCG administration, LH level, or endometrial thickness on the day of hCG administration”
- Also stated in: § DISCUSSION · plain
“Day of hCG administration 11.6 Ϯ 2.27 11.78 Ϯ 0.939 NS”
§ Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders > 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: § DISCUSSION · 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 letrozole plus FSH stimulation cycles, clinical pregnancy was achieved in three cycles (21%).”
- Also stated in: § RESULTS · plain
“Three had clinical pregnancies (21%) and one had a chemical pregnancy.”
- Also stated in: § DISCUSSION · plain
“In addition, three clinical pregnancies were achieved in the letrozole and FSH cycles.”
§ Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders > Abstract
plainn = 4- 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: § 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
“significantly higher number of mature follicles.”
- Also stated in: § RESULTS · plain
“During FSH plus letrozole stimulation cycles, the mean number of mature follicles was 3.3, which was significantly higher than in the FSH-only stimulation cycles (1.9 follicles).”
- Also stated in: § DISCUSSION · plain
“No. of mature follicles (Ͼ1.8 cm) 1.9 Ϯ 0.6 3.3 Ϯ 1.8 .003”
§ Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders > Abstract
plaindirectn = 12 ·- 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: § 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
“whereas four patients achieved pregnancy during letrozole plus FSH treatment cycles.”
§ Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders > RESULTS
plainn = 4- 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
“Although there was no difference in the level of E 2 on the day of hCG administration”
- Also stated in: § DISCUSSION · plain
“E2 on hCG day (pmol/L) 2471 Ϯ 1113 1786 Ϯ 898 NS”
§ Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders > 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: § DISCUSSION · 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
“There was no significant difference between FSH-only or letrozole plus FSH on the day of hCG administration, LH level, or endometrial thickness on the day of hCG administration indicating the absence of any antiestrogenic effects of letrozole on the endometrium.”
- Also stated in: § DISCUSSION · plain
“Endometrial thickness on hCG day (cm) 0.89 Ϯ 0.1 0.88 Ϯ 0.09 NS”
§ Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders > 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.
- Also stated in: § DISCUSSION · 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
“Improved response to FSH stimulation with letrozole co-treatment was evidenced by the significantly lower FSH dose associated with significantly higher number of mature follicles.”
- Also stated in: § RESULTS · plain
“The amount of FSH required was significantly lower in the letrozole plus FSH cycles than the FSH-only cycles.”
§ Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders > Abstract
plaindirectn = 12- 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: § RESULTS · plain
- Probably not a substantial claim. 3
- It may state two separate claims as one. 4
None of the sources cited for this claim have been checked yet.
In the paper
“In addition, androgen accumulation in the follicle may stimulate insulin-like growth factor I (IGF-I), and other endocrine and paracrine factors, which may synergize with FSH to promote folliculogenesis (29 -31).”
§ Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders > DISCUSSION
What the sources say
- Not checked yetcites [29] Adashi, 1993, Intraovarian regulation, Ann NY Acad Sci source
- Not checked yetcites [30] Giudice, 1992, Insulin-like growth factors and ovarian follicular development, Endocr Rev
- Not checked yetcites [31] Yen, 1993, Interface between extra- and intra-ovarian factors in polycystic ovary syndrome (PCOS), Ann NY Acad Sci source
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.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Markedly elevated E levels have been reported to have deleterious effects on the embryo or the endometrium and jeopardize the chance of achieving pregnancy (32,33).”
§ Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders > DISCUSSION
What the sources say
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.
None of the sources cited for this claim have been checked yet.
In the paper
“We have reported the success of aromatase inhibition by letrozole in inducing ovulation in anovulatory women with polycystic ovary syndrome (PCOS) (11)(12)(13)(14) and augmenting ovulation in ovulatory women (13,14).”
§ Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders > Abstract
What the sources say
- Not checked yetcites [11] Mitwally, 2000, The use of an aromatase inhibitor for induction of ovulation in cases of clomiphene citrate failure
- Not checked yetcites [12] Mitwally, 2000, Aromatase inhibition, Reprod Technol
- Not checked yetcites [13] Mitwally, 2000, The aromatase inhibitor, letrozole: a promising alternative for clomiphene citrate for induction of ovulation
boosteddirect- 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
“Aromatase is a cytochrome P-450 enzyme complex that catalyzes the rate-limiting step in the production of estrogens (E), that is, the conversion of the androgens, androstenedione and testosterone, to estrone (E 1 ) and E 2 (9).”
§ Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders > Abstract
What the sources say
- Not checked yetcites [9] Akhtar, 1993, Mechanistic studies on aromatase and related C-C bond cleaving P-450 enzymes, J Steroid Biochem Mol Biol 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.
Probably not a substantial claim. 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
“This preliminary clinical report includes a small number of patients treated in a nonrandomized, nonplacebo controlled design.”
§ Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders > 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.
Probably not a substantial claim. It may state two separate claims as one.
The paper relies on this without support.
The prior FSH-only cycles and the letrozole+FSH cycles are comparable enough that the observed differences in ovarian response can be attributed to letrozole.
“This preliminary clinical report includes a small number of patients treated in a nonrandomized, nonplacebo controlled design.”
The paper relies on this without support.
Multiple follicle development during gonadotropin stimulation correlates positively with pregnancy outcome.
“Achievement of multiple follicle development during gonadotropin stimulation has been found to correlate positively with the outcome of infertility management in terms of achievement of pregnancy.”
The paper relies on this without support.
Endometrial thickness on the day of hCG administration is a valid marker of antiestrogenic effects of letrozole on the endometrium.
“There was no significant difference between FSH-only or letrozole plus FSH on the day of hCG administration, LH level, or endometrial thickness on the day of hCG administration indicating the absence of any antiestrogenic effects of letrozole on the endometrium.”
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
“Recently, it was suggested that letrozole, a specific reversible, nonsteroidal aromatase inhibitor that suppresses estrogen biosynthesis (16), can successfully replace clomiphene citrate in superovulation treatment of patients with unexplained infertility or polycystic ovarian disease and in poor responders (17,18).”
From Effects of letrozole on superovulation with gonadotropins in women undergoing intrauterine insemination (2003) · cites this paper as [18]
In the citing paper
“This is in agreement with the previous report (19) that letrozole improves ovarian response to FSH in poor responder women.”
From A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation (2004) · cites this paper as [19]
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
Insulin-Like Growth Factors and Ovarian Follicular Development*
Giudice, L. C. (1992) · Endocrine Reviews · doi:10.1210/edrv-13-4-641 · Cited by 521
Efficacy of Superovulation and Intrauterine Insemination in the Treatment of Infertility
Guzick, D. S., Carson, S. A., Coutifaris, C., Overstreet, J. W., Factor-Litvak, P. R., Steinkampf, M. P., Hill, J. A., Mastroianni, L., Buster, J. E., Nakajima, S. T., et al. (1999) · New England Journal of Medicine · doi:10.1056/nejm199901213400302 · Cited by 521
Toner, J. P., Philput, C. B., Jones, G. S., & Muasher, S. J. (1991) · Fertility and Sterility · doi:10.1016/s0015-0282(16)54249-6 · Cited by 495
Weil, S. J., Vendola, K., Zhou, J., Adesanya, O. O., Wang, J., Okafor, J., & Bondy, C. A. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.7.4917 · Cited by 359
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
Assisted conception following poor ovarian response to gonadotrophin stimulation
Keay, S. D., Liversedge, N., Mathur, R., & Jenkins, J. M. (1997) · BJOG An International Journal of Obstetrics & Gynaecology · doi:10.1111/j.1471-0528.1997.tb11525.x · Cited by 241
Cantab, M. D. (1972) · PubMed · Cited by 222
Research works printed but not linked: 2
- Mitwally, 2000, Aromatase inhibition, Reprod Technol, 10, 244
- Russell, 1995, Pre-cycle estrogen treatment and poor responders, Assist Reprod Rev, 5, 82
Cited by
Sorted by citations
Items 401–407 of 407
Chowdhury, S. B. (2013) · Bangladesh Journal of Obstetrics & Gynaecology · doi:10.3329/bjog.v26i1.13750
Shoham, Z., & Howles, C. M. (2012) · Informa Healthcare eBooks · doi:10.3109/9781841849737.037 · Cited by 1
Begum, M. R., Ehsan, M., Quadir, E., Ehsan, N., Hossain, I., & Sharif, A. B. (2024) · Journal of South Asian Federation of Obstetrics and Gynaecology · doi:10.5005/jp-journals-10006-2476
Mitwally, M., & Casper, R. F. (2025) · Springer eBooks · doi:10.1007/978-3-031-77255-9_3
Self-citationLin, Q.-X., Zeng, J.-J., Wen, H., Yin, J.-W., & Sun, Y. K. (2026) · Reproductive and Developmental Medicine · doi:10.1097/rd9.0000000000000155
Çeliksoy, H. Y., Baştu, E., Balcı, B. K., Yaşa, C., Dural, Ö., & Buyru, F. (2020) · DergiPark (Istanbul University)
Mesfin, T. (2026) · Gynecological Endocrinology · doi:10.1080/09513590.2026.2646774
Metadata
- Authors
- Mitwally, M. F. M., & Casper, R. F.
- Affiliations
- Mount Sinai Hospital (CA)
- Corresponding author
- Casper, Robert F
- ORCID
- Casper, Robert F
- Venue
- Fertility and Sterility
- Publisher
- Elsevier BV
- Published
- 2002-04
- Volume
- 77
- Issue
- 4
- Pages
- 776-780
- ISSN
- 0015-0282 (ISSN-L)
- OpenAlex
- W2023963334
- Semantic Scholar
- c28960882fbca4247ecf3e0ab20c305b14652355
- Cited by
- 407
- References
- 30
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 2 · 2022: 6 · 2021: 6 · 2020: 8 · 2019: 4 · 2018: 6 · 2017: 36 · 2016: 11 · 2015: 42 · 2014: 45 · 2013: 30 · 2012: 41
- FWCI
- 13.53
- 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
- aromatase inhibitors, letrozole, poor ovarian responders, follicle-stimulating hormone, ovulation induction, superovulation, intrauterine insemination, unexplained infertility, clinical pregnancy rate
- MeSH terms
- Letrozole, Endometrium, Enzyme Inhibitors, Estradiol, Female, Follicle Stimulating Hormone, Chorionic Gonadotropin, Ovarian Follicle, Humans, Insemination, Artificial, Menstrual Cycle, Nitriles, Ovulation Induction, Pregnancy, Prospective Studies, Triazoles, Cohort Studies, Aromatase Inhibitors
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