A comparison of letrozole regimens

for ovulation induction in women with

polycystic ovary syndrome
Rachel S. Mandelbaum, M.D.,a Ravi Agarwal, M.D.,a Samuel Melville, M.D.,a Caroline J. Violette, M.D.,a
Sharon Winer, M.D.,a Donna Shoupe, M.D.,a Koji Matsuo, M.D., Ph.D.,b Richard J. Paulson, M.D.,a
and Molly M. Quinn, M.D.a
a
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Southern
California Keck School of Medicine, Los Angeles, California; b Division of Gynecologic Oncology, Department of Obstetrics
and Gynecology, University of Southern California, Los Angeles, California

Objective: To determine the optimal letrozole regimen for ovulation induction (OI) in women with polycystic ovary syndrome (PCOS)
Design: Retrospective cohort study.
Setting: Single academic fertility clinic from 2015–2022.
Patient(s): A total of 189 OI cycles in 52 patients with PCOS
Intervention(s): Patients were prescribed 1 of 4 letrozole regimens (group 1: 2.5 mg for 5 days, group 2: 2.5 mg for 10 days, group 3: 5
mg for 5 days, and group 4: 5 mg for 10 days).
Main outcome measure(s): The primary outcome was ovulation, and secondary outcomes included multifollicular development, and
clinical pregnancy rate, which were analyzed with binary logistic regression. Kaplan-Meier cumulative response curves and a Cox
proportional hazard regression model were used for time-dependent analyses.
Results: Mean age was 30.9 years (standard deviation [SD], 3.6) and body mass index was 32.1 kg/m2 (SD, 4.0). Group 2 (odds ratio
[OR], 9.12; 95% confidence interval [CI], 1.92–43.25), group 3 (OR, 3.40; 95% CI, 1.57-7.37), and group 4 (OR, 5.94; 95% CI, 2.48–14.23)
had improved ovulation rates after the starting regimen as compared with group 1. Cumulative ovulation rates exceeded 84% in all
groups, yet those who received 5 mg and/or 10 days achieved ovulation significantly sooner. Multifollicular development was not
increased in groups 2–4 as compared with group 1. Groups 2–4 also demonstrated improved time to pregnancy.
Conclusions: Ovulation rates are improved when starting with letrozole at 5 mg and/or a 10-day extended course as compared with the
frequently-used 2.5 mg for 5 days. This may shorten time to ovulation and pregnancy. (F S RepÒ 2024;5:170–5. Ó2024 by American
Society for Reproductive Medicine.)
Key Words: ovulation induction, letrozole, ovulation, polycystic ovary syndrome

L
etrozole is a selective, reversible, 5). Subsequent randomized controlled from the treatment of postmenopausal
competitive inhibitor of the aro- trials suggested that 2.5 mg was the women with hormone-sensitive breast
matase enzyme developed optimal dose in terms of breast cancer cancer, and administered letrozole be-
initially in the early 1990s for the treat- survival (5–8). tween days 3–7 of the menstrual cycle
ment of postmenopausal women with Mitwally and Casper (9) first as is typical with the clomiphene citrate
estrogen-sensitive breast cancer (1). described the off-label use of letrozole regimen. Since then, multiple high-
Initial phase I and II studies of letrozole for ovulation induction in women quality studies have suggested that
in postmenopausal women found that with polycystic ovary syndrome letrozole indeed may be superior to clo-
estrogen levels correlated with letrozole (PCOS) who had failed treatment with mid for ovulation induction in women
dose but that in this population doses clomiphene citrate. They used the with PCOS, in increasing ovulation
>0.5 mg led to extremely low- Food and Drug Administration– and live birth rates and decreasing
estrogen levels below assay limits (2– approved 2.5 mg dose, extrapolated risk of multiple gestation (10–14).
However, despite favorable data
Received October 26, 2023; revised March 22, 2024; accepted March 25, 2024.
Presented at the American Society for Reproductive Medicine Scientific Congress and Expo 2022, An- supporting the use of letrozole for
aheim, California, October 22–26, 2022. ovulation induction in women with
Correspondence: Rachel S. Mandelbaum, M.D., Division of Reproductive Endocrinology and Infertility,
Department of Obstetrics and Gynecology, University of Southern California, 2020 Zonal
PCOS, the ideal letrozole regimen re-
Avenue, IRD520, Los Angeles, CA 90033 (E-mail: rachel.mandelbaum@med.usc.edu). mains unknown and warrants evalua-
tion. Pharmacodynamic data in
F S Rep® Vol. 5, No. 2, June 2024 2666-3341
© 2024 The Authors. Published by Elsevier Inc. on behalf of American Society for Reproductive Med- postmenopausal women that underpin
icine. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ the commonly used 2.5 mg dose may
licenses/by-nc-nd/4.0/).
https://doi.org/10.1016/j.xfre.2024.03.004
not be valid in premenopausal

170 VOL. 5 NO. 2 / JUNE 2024

 F S Rep®

reproductive-aged women who have active ovarian estrogen to catalyze follicular development and ovulation; however,
production, particularly women with PCOS who often have original grouping was unchanged in the analysis. Cycles
elevated body mass and chronic estrogen exposure. It is were considered separate events if they were separated by a
possible that higher doses may be beneficial in fertility pa- menstrual period or if >1 month time elapsed without inter-
tients for a greater degree of suppression of estrogen produc- vention in anovulatory patients with confirmation of ovarian
tion and resultant follicle-stimulating hormone rise. quiescence based on hormone levels and ultrasound before
Additionally, while usually administered for 5 days as with the next cycle.
clomiphene citrate, letrozole differs from clomiphene citrate
in its mechanism of action and half-life. Letrozole is an aro-
Primary outcomes
matase inhibitor with a shorter half-life of 2 days, whereas
clomiphene is an estrogen receptor antagonist with a half- The primary outcome of the study was response to the starting
life more than twice that. Thus, a 5-day course of letrozole letrozole regimen in that particular ovulation induction cycle,
may not be the ideal duration to support follicular growth. i.e., whether or not ovulation occurred. Secondary outcomes
The objective of this study was to compare 4 different were the rate of multifollicular development and clinical
starting doses of letrozole for ovulation induction in women pregnancy rate. Clinical pregnancy rate was determined by
with PCOS. a positive pregnancy test followed by the presence of fetal
cardiac motion on ultrasound.

MATERIALS AND METHODS

Statistical analysis
Study participants and protocol
Patient baseline characteristics and demographics were
This was a retrospective study of patients diagnosed with
analyzed with c2 test for categorical variables or analysis of
PCOS by Rotterdam criteria between 2015 and 2022 in the
variance for continuous variables. Binary logistic regression
Los Angeles General Hospital Reproductive Endocrinology
was used to assess differences in ovulation rates, pregnancy
and Infertility Clinic. The study protocol was approved by
rates, and multifollicular development among the 4 groups.
the University of Southern California institutional review
For these analyses, group 1 was designated as the referent
board (HS-22-00197). The study clinic is a county-based
group; however, pairwise comparisons also were performed
fertility clinic that serves a predominantly Hispanic
to detect any differences between other groups. Results were
population.
confirmed with a generalized estimating equation controlling
Patients were prescribed a regimen of letrozole beginning
for repeated measures, as patients underwent multiple cycles
on day 2–3 of a spontaneous menstrual cycle or after a pro-
of ovulation induction in attempts to achieve pregnancy.
gestin withdrawal. Anovulatory patients confirmed to have
Given time to reach ovulation is relevant clinically for
low-serum estradiol and progesterone levels were allowed
patients with PCOS and patients may require redosing of
to ‘‘random start’’ letrozole. Baseline ultrasound in all patients
medication to achieve response in the same cycle, a time-
confirmed early follicular phase and no significant ovarian
dependent analysis was performed to assess letrozole
pathology. Patients were prescribed 1 of 4 different letrozole
response. The Kaplan-Meier method was used to assess cumu-
regimens based on provider preference: 2.5 mg for 5 days, 2.5
lative response curves with the log-rank test. A Cox propor-
mg for 10 days, 5 mg for 5 days, or 5 mg for 10 days. Patients
tional hazard regression model then was used to analyze
were excluded if they received clomiphene or if they were pre-
differences in letrozole response among the 4 groups control-
scribed a different letrozole regimen because of low numbers
ling for age, parity, body mass index, anti-m€ ullerian hormone
of patients in these groups.
levels, diabetes status, hypertension, hyperlipidemia, and met-
Patients were scheduled an appointment for an ultra-
formin use. The effect size of statistical significance was ex-
sound to determine response to letrozole around cycle days
pressed with hazard ratios and 95% confidence interval (CI).
10–12. Response to the initial letrozole regimen was deter-
All statistical analyses were based on 2-tailed hypotheses,
mined by the presence of a follicle R 14 mm on ultrasound.
and P value of < .05 was considered statistical significant.
Patients were instructed to begin ovulation predictor kits on
Statistical Package for Social Sciences (IBM SPSS, version
day 10 of their cycle. Ovulation was triggered either with
27.0, Armonk, NY) was used for the analysis. The STROBE
10,000 IU subcutaneous human chorionic gonadotropin in-
guidelines were consulted for the performance of this obser-
jection when R1 follicles were R 17–18 mm or was allowed
vational cohort study.
to proceed spontaneously with endogenous luteinizing hor-
mone surge based on patient and provider preference. If the
patient did not present for the scheduled ultrasound, response RESULTS
was determined by an ovulation predictor kit, midluteal pro- Of 144 patients with PCOS who presented for fertility treat-
gesterone R 3 ng/dL around cycle day 21, an appropriately ment during the study period, 52 underwent 189 ovulation in-
timed menses, or if the patient had a positive pregnancy duction cycles and were included in the study (Supplemental
test. If no method to determine response was available, the pa- Fig. 1, available online). There were 62 cycles (32.8%) in group
tient was determined as lost to follow-up and excluded from 1 (letrozole 2.5 mg for 5 days), 17 cycles (9.0%) in group 2
the analysis. If there was no response to the initial letrozole (letrozole 2.5 mg for 10 days), 57 (30.2%) in group 3 (letrozole
regimen, letrozole was represcribed per provider preference 5 mg for 5 days), and 53 (28.0%) in group 4 (letrozole 5 mg for
typically at a higher dose or for longer duration in attempts 10 days). Patient demographic variables are shown in Table 1

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ORIGINAL ARTICLE: ASSISTED REPRODUCTION

TABLE 1

Patient demographics
Group 1 Group 4
Variable 2.5 mg, 5 d Group 2 2.5 mg, 10 d Group 3 5 mg, 5 d 5 mg, 10 d P value
Age, y (mean, SD) 30.6 (3.6) 29.9 (3.7) 32.0 (3.8) 30.2 (3.1) .03
Hispanic (%) 96.8 100 100 96.2 445
Body mass index, kg/m2 (mean, SD) 32.1 (3.7) 30.2 (16) 31.2 (4.4) 32.5 (4.1) .09
Antimulterian hormone (mean, SD) 8.4 (5.8) 7.2 (4.3) 7.9 (38) 10.6 (5.6) .021a
Day 2-3 folicle-stimulating hormone -1.3 4.9 (16) 6.0 (1.0) 6.0 (16) .007a
(mean, SD)
Nuligravid (%) 64.5 82.4 36.8 71.7 .002a
Multiparity (%) 18.8 16.7 50.8 7.4 < .001a
Oligomenorrhea (%) 98.4 100 100 100 .560
Hyperandrogenism (%) 75.8 70.6 82.5 90.6 .133
Polycystic ovarian morphology (%) 88.7 100 94.7 96.2 .221
Prediabetes or diabetes mellitus (%) 40.3 5.9 47.4 41.5 .035a
Metformin use (%) 33.9 5.9 45.6 39.6 .025a
Hypertension (%) 97 0 12.3 1.9 .104
Hyperlipidemia (%) 32.3 29.4 43.9 17 .26
Mean (standard deviation) or percentage per column for each group is shown. Analysis of variance (ANOVA) was used for P value for continuous variables, and X2 test for categorical variables.
a
Significant P values.
Mandelbaum. Letrozole regimens for ovulation induction in PCOS. F S Rep 2024.

per group. Mean age of the entire cohort was 30.6 years (stan- ping’’ the dose did not significantly differ among the 4 groups
dard deviation [SD], 4.0) and body mass index was 32.0 kg/m2 (P>.05, all), and >84% of patients eventually ovulated in all
(SD, 4.1). The vast majority of patients were Hispanic, nulli- groups. However, time to ovulation was statistically signifi-
gravid, and obese. Antim€ ullerian hormone values were cantly longer for patients in group 1 as compared with the
elevated across all groups consistent with PCOS. Most pa- other 3 groups after adjusting for preselected covariates
tients met all 3 Rotterdam criteria for PCOS diagnosis. Group (Fig. 1, P< .001). Mean time to ovulation was 22.4 (SD,
2 patients had lower rates of prediabetes or diabetes mellitus. 11.0) days for group 1 as compared with 12.0 (SD, 3.8), 12.9
The mean number of cycles per patient was 3.8 (SD, 3.0). Of (SD, 5.9), and 14.3 (SD, 3.6) for groups 2, 3, and 4, respec-
the patients in the data set 29% underwent only 1 cycle, tively. In a time-dependent multivariable model, ovulation
whereas 60% underwent R3, and 23% underwent R6 cycles. was >3 times more likely for patients in groups 2, 3, or 4 as
The mean number of days between ovulation induction cycles compared with group 1 (Table 3). Increasing body mass index
in this study was 117 days (SD, 208). A new cycle was defined also was associated with lower likelihood of response.
in this study as a menstrual period if the patient was ovulatory Based on these results, a time-dependent analysis of cu-
the prior cycle, or in anovulatory patients, if at least 1 month mulative pregnancy rate was performed (Supplemental
time elapsed without intervention and there was confirmation Fig. 2 and Supplemental Table 1, available online). Patients
of early follicular phase based on serum hormone values and were censored if there was no follow-up or a lapse in treat-
ultrasound findings. These data reflect that many times pa- ment. Groups 2–4 were combined given low numbers of total
tients had nonconsecutive cycles because of either lapses in events and no difference between the groups in the primary
treatment or returning to treatment after pregnancy (either endpoint. Indeed, there was a significant difference in cumu-
birth or miscarriage) in attempts to conceive again. There lative pregnancy rates between groups 2–4 and group 1
was no significant difference in time between ovulation in- (P¼ .005), and in the multivariable Cox regression model,
duction cycles between groups. there was an increased hazard of pregnancy in groups 2–4
Outcomes after starting the letrozole regimen for ovula- as compared with group 1 (P¼ .006; Supplemental Table 1).
tion induction cycles are shown in Table 2. Group 1 had a sta-
tistically significantly lower ovulation rate after the starting
letrozole regimen than groups 2, 3, or 4. There was no statis- DISCUSSION
tical difference in pairwise comparisons between groups 2, 3, Results of this study suggest that a starting dose of letrozole
and 4. Rates of multifollicular development did not increase 2.5 for 5 days is associated with lower ovulation rates and a
with increased dose or duration of letrozole. Finally, the clin- longer time interval to reach ovulation as compared with
ical pregnancy rate was highest in group 3 (22%) and lowest starting at a 5 mg dose or for an extended 10-day course.
in group 2 (6.7%); however, differences in clinical pregnancy There was no increased likelihood of multifollicular recruit-
rates were not statistically significant with group 1 as the ment with a higher dose or longer duration in this study.
referent group nor with additional pairwise comparisons Most studies evaluating letrozole for ovulation induc-
(P>.05, all). There were no multiple gestations in the cohort. tion in PCOS have used a starting regimen identical to that
If a patient did not respond to the initial letrozole dose, as reported by Casper and Mitwally (9) in 2001 with
the dose was increased sequentially in a stair-step method un- sequential increases in dose if there was no response (10,
til ovulation was achieved. Overall response after ‘‘stair-step- 15, 16). The 2014 randomized controlled trial by Legro

172 VOL. 5 NO. 2 / JUNE 2024

 F S Rep®

TABLE 2

Letrozole outcomes by group

Groups Ovulation rate Multifollicular development Clinical pregnancy rate
Group 1 45.2% 23.8% 14.8%
2.5 mg, 5 d Ref Ref Ref
Group 2 88.2% 20.0% 6.7%
2.5 mg, 10 d OR, 9.12 OR, 0.80 OR, 0.41
[95% CI, 1.92–43.25] [95% CI, 0.13–5.07] [95% CI, 0.04–4.06]
P¼ .005a P¼ .813 P¼ .446
Group 3 73.7% 21.9% 22.0%
5 mg, 5 d OR, 3.40 OR, 0.90 OR, 1.62
[95% CI, 1.57–7.37] [95% CI, 0.24–3.31] [95% CI, 0.44–5.90]
P¼ . 002 P¼ .869 P¼ .467
Group 4 83.0% 32.0% 13.6%
5 mg, 10 d OR, 5.94 OR, 1.51 OR, 0.91
[95% CI, 2.48–14.23] [95% CI, 0.41–5.58] [95% CI, 0.23–3.56]
P< .001a P¼ .540 P¼ .890
Binary logistic regression models were used for analysis between groups with group 1 as the referent group.
95% CI ¼ confidence interval; OR ¼ odds ratios.
a
Significant P values.
Mandelbaum. Letrozole regimens for ovulation induction in PCOS. F S Rep 2024.

et al. (10) comparing clomiphene 50 mg to letrozole 2.5 mg There is sparse high-quality literature examining higher
for ovulation induction in 750 patients with PCOS is doses and extended regimens of letrozole, but the studies
perhaps the most widely-cited evidence for letrozole use. that do exist report conflicting results. In terms of dose, higher
In that study, the dose was increased if no response was starting doses of letrozole have been studied with varying
observed. Interestingly, after letrozole 2.5 mg for 5 days success in the PCOS and unexplained infertility populations.
only, 28.6% of patients ovulated; the majority required Al-Fadhli, et al. (17) randomized patients with unexplained
dose increases to achieve response. Legro et al. (10) re- infertility to letrozole 2.5 or 5 mg on days 3–7 of the men-
ported time from study randomization to live birth, and strual cycle and found that the 5 mg dose led to significantly
they found that letrozole had a cumulative higher birth increased number of periovulatory follicles and pregnancy
rate, but time to pregnancy did not differ between the 2 rates. In contrast, a randomized controlled trial in patients
groups. Our study suggests that time to pregnancy theoret- with PCOS undergoing ovulation induction that compared a
ically could be improved with higher starting doses of le- 5 mg to a 7.5 mg dose did not find any statistical difference
trozole or extended duration. in outcomes (18). Similarly, another randomized trial
comparing 3 doses of letrozole (2.5, 5, and 7.5 mg) found
that a higher doses led to an increase in the number of perio-
vulatory follicles but that this did not translate to higher preg-
FIGURE 1 nancy rates (19). It appears that dose increases to even as high
as 12.5 mg may increase number of follicles but may not
translate to significantly improved pregnancy rates (20).
The first study to examine longer durations of letrozole
was in 2009 and found that women with PCOS who were ran-
domized to letrozole 2.5 mg for 10 days had an increased
number of follicles and a higher pregnancy rate per cycle
compared with those who received 5 mg for 5 days (21). There
was no significant difference, however, in the number of pa-
tients who achieved ovulation after the starting regimen
(65.7% vs. 61.8%, respectively). Another very recent study
also reported on a method to increase duration of letrozole
treatment sequentially at a 5 mg dose from 5 to 7 to 10
days should no response occur with a 5-day course (22).
This study reported that 70% of patients ovulated after a 7-
day cycle, which is similar to but slightly lower than the
Ovulation by starting letrozole group.
Kaplan-Meier survival analysis with log-rank test for P value. X-axis response rates in groups 2–4 in our study after the first start-
represents time to ovulation in days. Y-axis represents cumulative ing letrozole course. The referenced study only considered a
ovulation rate. subset of patients who were resistant to letrozole 5 mg for 5
Mandelbaum. Letrozole regimens for ovulation induction in PCOS. F S Rep 2024. days however, it validates the idea that a more aggressive
starting letrozole regimen may be an appropriate strategy.

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ORIGINAL ARTICLE: ASSISTED REPRODUCTION

e.g., some patients received trigger injections or had addi-

TABLE 3
tional monitoring ultrasounds while others preferred sponta-
Multivariable model for cumulative ovulation
neous ovulation and at-home testing. Furthermore,
individual patients underwent multiple cycles in this analysis.
Adjusted HR
Study groups [95% CI] P value Although we accounted for repeated measures, patients’ his-
tory undoubtedly impacted prescribing practices in subse-
Age, y 1.04 [0.9–1.11] .165
Body mass index, kg/m2 0.92 [0.87–0.97] .001a
quent cycles. There also were low numbers of patients
Antimullerian hormone 0.99 [0.95–1.03] .522 particularly in group 2 and for pregnancy data, which limits
Multiparity 1.24 [0.65–2.36] .524 further analysis among individual groups 2–4. A small num-
Prediabetes/diabetes mellitus 1.12 [0.70–1.80] .627 ber of patients also were lost to follow-up, and the outcomes
Hypertension 1.36 [0.69–2.68] .380
Hyperlipidemia 1.32 [0.81–2.14] .268 of these cycles (i.e., whether they ovulated) are unknown but
Letrozole group Group 1 Referent may have influenced results.
Group 2 4.60 [2.35–9.00] < .001a
Group 3 3.69 [2.35–5.77] < .001a
Group 4 3.84 [2.41–6.14] < .001a CONCLUSION
Cox proportional hazard regression model for analysis for P value adjusted for preselected Based on this study, it appears that a starting dose of 2.5 mg
covariates as shown. Adjusted hazard ratios with 95% confidence intervals are reported.
Significant P values are italicized and in bold font. Abbreviations: CI ¼ confidence interval; for 5 days may lead to inferior response rates for ovulation in-
HR ¼ hazard ratio. duction, and consideration should be given to starting pa-
a
Significant P values.
Mandelbaum. Letrozole regimens for ovulation induction in PCOS. F S Rep 2024.
tients with PCOS undergoing ovulation induction at a
higher dose or administering letrozole for an extended dura-
tion. Ultimately, after patients who did not respond to the
initial letrozole regimen were re-dosed or ‘‘stair-stepped,’’
Of course, the concern with higher doses or duration of
ovulation and pregnancy rates did not differ between groups
ovulation induction medication is that of multifollicular
in this study, but patients who started their cycle at the 2.5 mg
development resulting in multiple gestation or adverse ef-
dose for 5 days required more time to reach those endpoints.
fects. This is, indeed, true with clomiphene citrate when
This study also shows that reducing time to ovulation may
used at high doses or for repeated cycles; its long half-life
translate to reduced time to pregnancy, and this may be
leads to drug accumulation and high rates of multiple ovula-
because patients can complete more cycles within a given
tion as well as antiestrogenic effects on the endometrium (23).
time period.
Unlike clomiphene, letrozole has a short half-life, which
reduces the possibility of drug accumulation and does not
have active metabolites (24). Our study did not show CRediT Authorship Contribution Statement
increased rates of multifollicular development with higher Rachel S. Mandelbaum: Writing – review & editing, Writing
letrozole doses or extended regimens. There were no cases – original draft, Visualization, Validation, Software, Project
of multiple gestation, although larger scale studies are needed administration, Methodology, Investigation, Formal anal-
to assess this further given low numbers of patients who ysis, Data curation, Conceptualization. Ravi Agarwal:
achieved pregnancy in this cohort. Other studies also have Writing – review & editing, Methodology, Investigation,
shown that letrozole is associated with reduced or similar Data curation, Conceptualization. Samuel Melville: Writing
rates of multiple pregnancy as compared with clomiphene – original draft, Data curation. Caroline J. Violette: Writing
and that increased doses do not seem to increase the risk of – review & editing, Investigation, Data curation, Conceptual-
multiple gestation (10, 11, 17, 25). Endometrial thickness ization. Sharon Winer: Writing – review & editing, Method-
also does not to appear to be affected detrimentally with letro- ology, Conceptualization. Donna Shoupe: Writing – review
zole even at high doses (20). Finally, studies also have shown & editing, Supervision, Investigation, Conceptualization.
no increase in the incidence of congenital anomalies with Koji Matsuo: Writing – review & editing, Formal analysis,
letrozole (26–28). Conceptualization. Richard J. Paulson: Writing – review &
Strengths of the current study include the analysis of editing, Supervision, Conceptualization. Molly M. Quinn:
several different combinations of letrozole regimens, in dose Writing – original draft, Supervision, Formal analysis,
and duration. Existing studies have compared either Conceptualization.
increasing dose or duration but not both. Homogeneity of
the population minimizes confounding variables but also Declaration of Interests
limits generalizability of findings to other populations R.S.M. has nothing to disclose. R.A. has nothing to disclose.
because this population consists predominantly of Hispanic S.M. has nothing to disclose. C.J.V. has nothing to disclose.
nulligravid women of low socioeconomic status who experi- S.W. has nothing to disclose. D.S. has nothing to disclose.
ence significant barriers in access to fertility treatments. Other K.M. has nothing to disclose. R.J.P. has nothing to disclose.
limitations include the possibility for selection bias because M.M.Q. has nothing to disclose.
providers chose the letrozole regimen, and possible patient
factors may have influenced this choice that were not known. REFERENCES
There also was heterogeneity in clinical practice patterns 1. Bhatnagar AS, H€ausler A, Schieweck K, Lang M, Bowman R. Highly selective
given aforementioned health care barriers in this patient pop- inhibition of estrogen biosynthesis by CGS 20267, a new non-steroidal aro-
ulation to additional medications, laboratory tests, or visits; matase inhibitor. J Steroid Biochem Mol Biol 1990;37:1021–7.

174 VOL. 5 NO. 2 / JUNE 2024

 F S Rep®

2. Lipton A, Demers LM, Harvey HA, Kambic KB, Grossberg H, Brady C, et al. 15. Rahmani E, Ahmadi S, Motamed N, Maneshi HO. Dosage optimization for
Letrozole (CGS 20267). A phase I study of a new potent oral aromatase in- letrozole treatment in clomiphene-resistant patients with polycystic ovary
hibitor of breast cancer. Cancer 1995;75:2132–8. syndrome: a prospective interventional study. Obstet Gynecol Int 2012;
3. Iveson TJ, Smith IE, Ahern J, Smithers DA, Trunet PF, Dowsett M. Phase I 2012:758508.
study of the oral nonsteroidal aromatase inhibitor CGS 20267 in postmen- 16. Thomas S, Woo I, Ho J, Jones T, Paulson R, Chung K, et al. Ovulation rates in
opausal patients with advanced breast cancer. Cancer Res 1993;53:266–70. a stair-step protocol with letrozole vs clomiphene citrate in patients with
4. Iveson TJ, Smith IE, Ahern J, Smithers DA, Trunet PF, Dowsett M. Phase I polycystic ovarian syndrome. Contracept Reprod Med 2019;4:20.
study of the oral nonsteroidal aromatase inhibitor CGS 20267 in healthy 17. Al-Fadhli R, Sylvestre C, Buckett W, Tan SL, Tulandi T. A randomized trial of
postmenopausal women. J Clin Endocrinol Metab 1993;77:324–31. superovulation with two different doses of letrozole. Fertil Steril 2006;85:
5. Cohen MH, Johnson JR, Li N, Chen G, Pazdur R. Approval summary: letro- 161–4.
zole in the treatment of postmenopausal women with advanced breast can- 18. Ramezanzadeh F, Nasiri R, Sarafraz Yazdi M, Baghrei M. A randomized trial
cer. Clin Cancer Res 2002;8:665–9. of ovulation induction with two different doses of Letrozole in women with
6. Gershanovich M, Chaudri HA, Campos D, Lurie H, Bonaventura A, Jeffrey M, PCOS. Arch Gynecol Obstet 2011;284:1029–34.
et al. Letrozole, a new oral aromatase inhibitor: randomised trial comparing 19. Badawy A, Metwally M, Fawzy M. Randomized controlled trial of three
2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal doses of letrozole for ovulation induction in patients with unexplained infer-
women with advanced breast cancer. Letrozole International Trial Group tility. Reprod Biomed Online 2007;14:559–62.
(AR/BC3). Ann Oncol 1998;9:639–45. 20. Pritts EA, Yuen AK, Sharma S, Genisot R, Olive DL. The use of high dose le-
7. Buzdar A, Douma J, Davidson N, Elledge R, Morgan M, Smith R, et al. Phase trozole in ovulation induction and controlled ovarian hyperstimulation. ISRN
III, multicenter, double-blind, randomized study of letrozole, an aromatase Obstet Gynecol 2011;2011:242864.
inhibitor, for advanced breast cancer versus megestrol acetate. J Clin Oncol 21. Badawy A, Mosbah A, Tharwat A, Eid M. Extended letrozole therapy for
2001;19:3357–66. ovulation induction in clomiphene-resistant women with polycystic ovary
8. Thu €rlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, syndrome: a novel protocol. Fertil Steril 2009;92:236–9.
et al. A comparison of letrozole and tamoxifen in postmenopausal women 22. Zhu X, Fu Y. Extending letrozole treatment duration is effective in inducing
with early breast cancer. N Engl J Med 2005;353:2747–57. ovulation in women with polycystic ovary syndrome and letrozole resistance.
9. Mitwally MF, Casper RF. Use of an aromatase inhibitor for induction of Fertil Steril 2023;119:107–13.
ovulation in patients with an inadequate response to clomiphene citrate. 23. Schenker JG, Yarkoni S, Granat M. Multiple pregnancies following induction
Fertil Steril 2001;75:305–9. of ovulation. Fertil Steril 1981;35:105–23.
10. Legro RS, Brzyski RG, Diamond MP, Coutifaris C, Schlaff WD, Casson P, et al. 24. Lønning P, Pfister C, Martoni A, Zamagni C. Pharmacokinetics of third-
Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. generation aromatase inhibitors. Semin Oncol 2003;30:23–32.
N Engl J Med 2014;371:119–29. 25. Diamond MP, Legro RS, Coutifaris C, Alvero R, Robinson RD, Casson P, et al.
11. Tsiami AP, Goulis DG, Sotiriadis AI, Kolibianakis EM. Higher ovulation rate Letrozole, gonadotropin, or clomiphene for unexplained infertility. N Engl J
with letrozole as compared with clomiphene citrate in infertile women Med 2015;373:1230–40.
with polycystic ovary syndrome: a systematic review and meta-analysis. 26. Sharma S, Ghosh S, Singh S, Chakravarty A, Ganesh A, Rajani S, et al.
Hormones (Athens) 2021;20:449–61. Congenital malformations among babies born following letrozole or clomi-
12. Franik S, Eltrop SM, Kremer JA, Kiesel L, Farquhar C. Aromatase inhibitors phene for infertility treatment. PLoS One 2014;9:e108219.
(letrozole) for subfertile women with polycystic ovary syndrome. Cochrane 27. Akbari Sene A, Ghorbani S, Ashrafi M. Comparison of the pregnancy out-
Database Syst Rev 2018;5:Cd010287. comes and the incidence of fetal congenital abnormalities in infertile women
13. Franik S, Le QK, Kremer JA, Kiesel L, Farquhar C. Aromatase inhibitors (letro- treated with letrozole and clomiphene citrate. J Obstet Gynaecol Res 2018;
zole) for ovulation induction in infertile women with polycystic ovary syn- 44:1036–41.
drome. Cochrane Database Syst Rev 2022;9:Cd010287. 28. Tulandi T, Martin J, Al-Fadhli R, Kabli N, Forman R, Hitkari J, et al.
14. Roque M, Tostes AC, Valle M, Sampaio M, Geber S. Letrozole versus clomi- Congenital malformations among 911 newborns conceived after infer-
phene citrate in polycystic ovary syndrome: systematic review and meta- tility treatment with letrozole or clomiphene citrate. Fertil Steril 2006;
analysis. Gynecol Endocrinol 2015;31:917–21. 85:1761–5.

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