ORIGINAL ARTICLES: REPRODUCTIVE ENDOCRINOLOGY

A randomized controlled trial of

combination letrozole and
clomiphene citrate or letrozole alone
for ovulation induction in women with
polycystic ovary syndrome
Rachel B. Mejia, D.O., Karen M. Summers, M.P.H., C.H.E.S., Jessica D. Kresowik, M.D.,
and Bradley J. Van Voorhis, M.D.
Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, Iowa City, Iowa

Objective: To evaluate whether a combination of letrozole and clomiphene citrate (CC) results in higher ovulation rates than letrozole
alone in infertile women with polycystic ovary syndrome (PCOS).
Design: Open-label randomized controlled trial.
Setting: Academic medical center using two clinic sites.
Patient(s): Women 18–40 years of age with a diagnosis of infertility and PCOS as defined by the Rotterdam criteria and no other known
cause of infertility.
Interventions(s): Participants were randomized in a 1:1 ratio, stratified by age and body mass index, to either 2.5 mg letrozole alone or
the combination of 2.5 mg letrozole and 50 mg CC daily on cycle days 3–7 for one treatment cycle.
Main Outcome Measure(s): Ovulation defined as mid-luteal serum progesterone concentration R3 ng/mL.
Result(s): Seventy patients were randomized: 35 to letrozole alone and 35 to letrozole and CC. Results were analyzed according to the
intention-to-treat principle. Women who received the combination of letrozole and CC had a statistically higher ovulation rate
compared with those who received letrozole alone (27 of 35 women [77%] vs. 15 of 35 women [43%]). There were no serious
adverse events or multiple-gestation pregnancies in either group. The side-effects profile was similar in the two treatment groups.
Conclusion(s): The combination of letrozole and CC was associated with a higher ovulation rate compared with letrozole alone in
women with infertility and PCOS. Further studies are needed to evaluate the effect on live birth rate.
Clinical Trial Registration Number: NCT02802865. (Fertil SterilÒ 2019;111:571–8. Ó2018 by American Society for Reproductive
Medicine.)
El resumen está disponible en Español al final del artículo.
Key Words: Letrozole, clomiphene citrate, infertility, polycystic ovary syndrome, combined therapy, ovulation induction
Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-
and-sterility/posts/41241-27023

P
olycystic ovary syndrome (PCOS) women and the most common cause of focuses on ovulation induction. Many
is the most common endocrine anovulatory infertility (1). The treatment treatment regimens have been used,
disorder in reproductive-age of infertility in patients with PCOS with varying success, to achieve ovula-
tion, pregnancy, and live birth.
Received September 20, 2018; revised October 25, 2018; accepted November 19, 2018; published Clomiphene citrate (CC) is a
online January 22, 2019. commonly prescribed pharmacologic
R.B.M. has nothing to disclose. K.M.S. has nothing to disclose. J.D.K. has nothing to disclose. B.J.V.V.
has nothing to disclose. agent used to induce ovulation in
Supported by the University of Iowa Department of Obstetrics and Gynecology, The Davis and The women with PCOS. It works as a selective
Henrietta Rose and Mary Ellen Molinaro-Blonigan Research Fund, University of Iowa College
of Medicine. The founding sources were not involved in development, conduct or analysis of estrogen receptor modulator by compet-
the results. The study protocol is available on request from the first author. itively attaching to nuclear estrogen re-
Reprint requests: Rachel B. Mejia, D.O., 31330 PFP, University of Iowa Hospitals and Clinics,
200 Hawkins Drive, Iowa City, Iowa 52242 (E-mail: rachel-mejia@uiowa.edu).
ceptors. As the negative feedback of
estrogen is reduced, secretion of gonad-
Fertility and Sterility® Vol. 111, No. 3, March 2019 0015-0282/$36.00 otropin hormones increases, inducing
Copyright ©2018 American Society for Reproductive Medicine, Published by Elsevier Inc.
https://doi.org/10.1016/j.fertnstert.2018.11.030 ovarian follicular growth. CC also has

VOL. 111 NO. 3 / MARCH 2019 571

ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY
an antiestrogenic effect on endometrial development and cervi-
cal mucus production, which has been suggested to contribute
to a relatively low pregnancy rate despite a high ovulation
rate (2, 3).
Letrozole is another commonly used oral ovulation
induction agent, with a different mechanism of action. It
works as a highly selective aromatase inhibitor, preventing
androgen-to-estrogen conversion. One proposed mechanism
is via suppressed estrogen production resulting in decreased
negative feedback on the hypothalamus and increased secre-
tion of FSH. An additional proposed mechanism of improved
ovulatory rates with the use of letrozole is increased follicular
sensitivity to FSH resulting from temporarily increased intra-
ovarian androgens (4). Letrozole may offer a benefit over CC
for ovulation induction because it does not block estrogen re-
ceptors in both central and peripheral target tissues, and
normal central feedback mechanisms remain intact. The
Pregnancy and Polycystic Ovary Syndrome (PPCOS) II trial,
a randomized controlled trial comparing letrozole and CC,
demonstrated that letrozole was associated with a higher
live birth rate (27.5% vs. 19.1%; P¼ .007; rate ratio 1.44,
95% confidence interval [CI] 1.10–1.87) and cumulative
ovulation rate (61.7% vs. 48.3%; P< .001) among women
with PCOS (5). Other than letrozole or CC for ovulation induc-
tion, there are few treatment options available to PCOS pa-
tients except proceeding to gonadotropin injections or
in vitro fertilization, both of which are associated with
increased cost and risk.
Because letrozole and CC have different mechanisms of
action, we postulated that the combination of these medica-
tions may result in an improved ovulatory rate over letrozole
alone. Because the combination of letrozole and CC had not
yet been studied in a prospective randomized fashion, we de-
signed a study to evaluate the ovulatory rate and effectiveness
of this combination treatment compared with letrozole alone.
If the combination results in a higher ovulatory rate, larger
studies evaluating the pregnancy and delivery rates with the
combined therapy would be indicated. Therefore, our aim
was to test the hypothesis that combined therapy of letrozole
and CC is effective and superior to the use of letrozole alone to
achieve ovulation in women with PCOS. Secondary objectives
included characterizing the side-effects profile and evalu-
ating mid-cycle ultrasonographic characteristics on this
treatment regimen.
MATERIALS AND METHODS
Study Overview and Design
We conducted a randomized controlled trial of oral letrozole
versus the combination of oral letrozole and CC for treatment
of infertility in patients with PCOS. Enrollment began in
September 2016 and was completed in March 2018 at two
clinic sites. Participants were enrolled after all eligibility
criteria were confirmed and informed consent completed.
Randomization occurred during the first 3 days of sponta-
neous menses or while taking medroxyprogesterone (10 mg/
d Provera for 10 days) to induce withdrawal bleed. Women
were randomly assigned to receive 2.5 mg letrozole daily or
a combination of 2.5 mg letrozole daily and 50 mg CC daily
572
on cycle days 3–7 for one treatment cycle. Participants
received the oral ovulation medication, one mid-cycle ultra-
sound, and two urine pregnancy tests at no charge. Additional
compensation was not provided.
Participants were provided with a calendar log to keep
track of bleeding, ovulation prediction kit (OPK) testing re-
sults, intercourse, side-effects, and use of other medications.
Participants started daily OPK testing on cycle day 11 until
a positive OPK result or until cycle day 21 if no positive result.
Couples were instructed to have regular intercourse, 2–3 times
per week and on the day of a positive surge and the following
day. A mid-cycle ultrasound was performed on cycle day
12–14. All images were reviewed by the principal investi-
gator. If the participant had a positive OPK test, serum proges-
terone level was obtained 7 days after the positive result. If
there was no positive OPK, serum progesterone level was
obtained on cycle day 21 or 22.
A urine pregnancy test was performed 7 days after an
ovulatory serum progesterone level with menses or on cycle
day 35 if no ovulation and no menses. Those with a positive
urine screening had serum hCG level determined. A repeated
hCG level was obtained 48 hours later, and those with a viable
pregnancy were followed according to routine during their
pregnancy. Pregnancy outcomes were tracked with follow-
up surveys and thorough chart review of maternal and infant
medical records.
Study Population and Eligibility Requirements
Women 18–40 years of age with PCOS and infertility and a
desire to become pregnant were screened. Enrollment criteria
were designed to identify women with PCOS and infertility
with no other identified cause. Eligibility criteria included:
diagnosis of infertility, defined as the inability of couple to
achieve a pregnancy after 12 months of regular timed unpro-
tected intercourse in women <35 years of age or after
6 months in women R35 years of age (6); diagnosis of
PCOS based on the Rotterdam criteria, including two of
the following three findings: oligomenorrhea or chronic
anovulation, hyperandrogenism (clinical or laboratory), and
polycystic ovary(ies) on ultrasound (7); normal sperm con-
centration of 15 million/mL and normal motility of >40%
(8); and English speaking. Exclusion criteria included: preg-
nancy; current hormonal contraception use; other known
cause of infertility; uncorrected thyroid disease; untreated
hyperprolactinemia; medical conditions not well controlled
or not recommended during pregnancy (i.e., uncontrolled
type 1 or 2 diabetes mellitus, hypertension, endometrial
hyperplasia/cancer); allergy or contraindications to letrozole
or CC; and clinical suspicion of other etiologies that mimic
PCOS warranting additional evaluation. After study enroll-
ment began, the eligibility criteria were modified as follows:
1) male partners with a history of fathering a pregnancy
were not required to obtain semen analysis; and 2) women
who were anovulatory were not required to wait the full
year to obtain an infertility diagnosis. These changes were
made to aid in recruitment and are consistent with our clinical
management in this patient population.
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Outcome Measures
The primary outcome measure was ovulation, defined as a
mid-luteal progesterone level >3 ng/mL. This was tested
7 days after a positive OPK test or on cycle day 21 if no surge
was detected.
Secondary outcomes included: 1) conception: a positive
serum or urinary test of hCG; 2) clinical pregnancy: an intra-
uterine pregnancy with fetal heart motion determined by
ultrasonography; 3) live birth; 4) singleton birth; 5) preg-
nancy loss, including biochemical, miscarriage, ectopic; 6)
size and number of developing follicles on cycle day 12–14
ultrasound; 7) endometrial thickness on cycle day 12–14 ul-
trasound; and 8) adverse events related to the study medica-
tions. Adverse events were defined as any side-effects that the
subject recorded on her daily calendar log during the study
cycle. Serious adverse events (SAEs) were defined as events
that were fatal or immediately life threatening or required
inpatient hospitalization. SAEs, pregnancy complications,
and congenital anomalies were assessed to determine relation
to study treatment.
Sample Size
Thirty-one subjects per group were required to obtain 80%
statistical power to demonstrate a clinically meaningful
33% absolute difference in ovulation rate between treatment
groups, assuming a 50% rate for letrozole with the use of the
Pearson chi-square test with a two-sided significance level of
0.05. The sample size was increased to 35 per arm to allow for
a dropout rate of 10%. We selected a benchmark of 33% dif-
ference between groups based on the PPCOS II trial, in which
2.5 mg letrozole had an ovulation rate of 50% after one treat-
ment cycle (5), and a prospective cohort study, in which com-
bined letrozole and CC had follicular development in 83% of
cycles (9).
Randomization
Randomization occurred in a ratio of 1:1 and was stratified by
age (<35 vs. R35 years) and body mass index (BMI; <30 and
R30 kg/m2). Stratification was used because both age and
BMI are strongly associated with infertility treatment success
and with a relatively low sample size we wanted to ensure
similar age and BMI across treatment groups. The randomiza-
tion scheme was generated by a statistician via a computer
program using a minimization technique with a random
element to maintain balance in stratifying factors and main-
tain random allocation. The allocation scheme was not dis-
closed to the investigators. Participant treatment group
assignment was obtained at randomization by logging into
a secure network computer program and entering the partic-
ipant stratification information.
Statistical Analysis
The intention-to-treat (ITT) analysis included all randomized
participants, and the per-protocol (PP) analysis included those
who took the allocated treatment. In both analyses, partici-
pants were analyzed within the treatment group they were
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Fertility and Sterility®
assigned to at randomization. For the ITT analysis, the outcome
was recorded as ‘‘ovulatory’’ for participants who became preg-
nant before taking the study medication and ‘‘not ovulatory’’
for participants whose outcome was unknown.
For categoric variables, either chi-square or Fisher exact
test was used at a two-sided significant level of 0.05 for
testing differences between the two treatment groups. For
continuous variables, the mean  SD in each group is re-
ported and differences between groups were analyzed with
the use of independent-sample t tests when appropriate. In
the case of skewed data, the median and interquartile range
are reported and Mann-Whitney U tests were applied. A sub-
group analysis was performed to assess fecundity and ultra-
sound characteristics among those who ovulated.
Treatment side-effects reported by two or more partici-
pants (>2%) and adverse events were categorized and the
percentage of patients experiencing adverse events in each
treatment group were compared with the use of chi-square
tests. All analyses were performed with use of SPSS software
(10).
Trial Registration and Approval
This study was reviewed and approved by University of Iowa
Institutional Review Board (20160806). Each participant gave
written informed consent for herself and to obtain records
on any infants born if pregnancy resulted during the study
treatment cycle. The trial was registered at Clinicaltrials.gov
(NCT02802865).
Adverse events and side-effects profiles were submitted
to an independent physician researcher every 6 months to
monitor study safety.
The study is reported following the CONSORT and
IMPRINT guidelines (11).
RESULTS
Characteristics of the Participants
A total of 73 participants were enrolled. Of these, three became
ineligible before randomization (two because of pregnancy
and one because of endometrial cancer). Of the remaining 70
participants, 35 were randomized to the letrozole-only group
and 35 to the letrozole and CC group. After randomization,
three participants became ineligible before starting treatment
medication (two because of pregnancy and one because
of tuberculosis), leaving 67 participants that took the allocated
treatment. Supplemental Figure 1 (available online at
www.fertstert.org) presents a Consolidated Standards of Re-
porting Trials flow diagram for this study (12). The first enroll-
ment was in September 2016 and the last enrolled participant
finished the study medication in March 2018. Follow-up for
the study cycle outcomes was completed in April 2018. Base-
line participant characteristics in the two groups are summa-
rized in Table 1. There were no significant differences in
baseline characteristics between the two groups.
Primary Outcome
Women who received letrozole and CC had a higher ovulation
rate than women receiving letrozole alone in both the ITT and
573
ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY

TABLE 1

Baseline characteristics of participants.

Characteristic Letrozole group (n [ 35) Letrozole D CC group (n [ 35)
Age, y 31  3.9 30  4.4
BMI, kg/m2 33  8.7 34  7.0
Weight, kg 94  29.6 94  22.5
Race or ethnic group
White 29 (83) 30 (86)
Black 2 (6) 1 (3)
Asian 1 (3) 1 (3)
Hispanic or Latino 2 (6) 2 (6)
Mixed race 1 (3) 1 (3)
Current tobacco use 1 (3) 3 (9)
Study site
Site 1 22 (63) 21 (60)
Site 2 13 (37) 14 (40)
Insurance coverage
Full coverage 10 (29) 15 (43)
Partial coverage 9 (26) 10 (29)
No coverage/unsure 16 (46) 10 (29)
PCOS diagnosis
Polycystic ovaries according to modified Rotterdam criteria 35 (100) 32 (91)
Hyperandrogenism (clinical or laboratory) 20 (57) 21 (60)
Oligomenorrhea 34 (97) 33 (94)
Fertility history
Previous live birth 14 (40) 11 (31)
Duration of time attempting to conceive, mo 30  29.6 28  18.5
Previous use of letrozole 10 (29) 17 (49)
Max dose of letrozole, mg 5 (2.5, 7.5) 5 (2.5, 7.5)
Ovulation on max dose of letrozole (n/no. reported previous 4/10 (40) 7/16 (44)
use of letrozole)
Letrozole use >6 mo before 6/10 (60) 10/16 (63)
Previous use of Clomid 17 (49) 23 (66)
Max dose of Clomid, mg 150 (100, 150) 150 (100, 150)
Ovulation on max dose of Clomid (n/no. reported previous 9/16 (56) 8/23 (35)
use of Clomid)
Clomid use >6 mo before 7/16 (44) 14/23 (61)
Previous use of both letrozole and Clomid 8 (23) 14 (40)
Resistance to both letrozole and Clomid (n./no. reported previous 4/8 (50) 7/14 (50)
use of both medications)
Metabolic glucose status
Metformin current use 14 (40) 15 (43)
Metformin previous use/not currently 6 (17) 10 (29)
Never use 15 (43) 10 (29)
HbA1c 5.3  0.47 (n ¼ 23) 5.3  0.73 (n ¼ 23)
Fasting blood glucose, mg/dL 95  6.7 (n ¼ 6) 90  10.6 (n ¼ 9)
2-h GTT, mg/dL 103  18.5 (n ¼ 6) 114  23 (n ¼ 9)
Note: Values are presented as mean  SD, n (%), or median (interquartile range). P values were calculated with the use of chi-square or Fisher exact test for categoric data and t or Mann-Whitney
U test for continuous data; none of the P values reached significance. Clomid ¼ clomiphene citrate; GTT ¼ glucose tolerance test; HbA1c ¼ glycosylated hemoglobin.
Mejia. Clomiphene citrate and letrozole combination. Fertil Steril 2018.

PP analyses (ITT: 27 of 35 women [77%] vs. 15 of 35 women
[43%], P¼ .0068, rate ratio for ovulation with combination
treatment 1.80, 95% CI 1.18–2.75; PP: 25 of 33 women
[76%] vs. 14 of 34 women [41%], P¼ .009, rate ratio for
ovulation with combination treatment 1.84, 95% CI 1.178–
2.873; Table 2).
those who conceived, the rates of pregnancy loss were similar
in the two treatment groups (Table 2).
Cycle characteristics are presented in Table 3. Among the
participants who ovulated there was no significant difference
in endometrial thickness, median number of follicles
>15 mm, largest follicle size, or serum progesterone level.

Secondary Outcomes Adverse Events

There were no statistically significant differences in concep-
tion, pregnancy, and live birth between the two groups in
the PP analysis. A much larger sample size would be needed
to detect differences in these outcomes (Table 2). There were
no multiple-gestation pregnancies in either group. Among
No SAEs related to the treatments occurred during the
study. Two hospitalizations occurred, one for gallstones
and cholecystectomy (letrozole group) and one for appen-
dicitis with appendectomy on cycle day 1 after completion
of the study (letrozole þ CC group). Participants in both

574 VOL. 111 NO. 3 / MARCH 2019

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TABLE 2

Reproductive outcomes, n (%).

Rate ratio in
Absolute difference between combination
Outcome Letrozole Letrozole D CC groups (95% CI)c group (95% CI) P valued
Intention-to-treat analysis/
primary outcomea
Ovulation 15 (42.9) 27 (77.1) 33.8 (9.31 to 54.25) 1.80 (1.18 to 2.75) .007

Per-protocol analysis/
primary outcomeb
Ovulation 14 (41.2) 25 (75.8) 34.6 (8.9–54.9) 1.84 (1.18–2.87) .009
Secondary outcomes
Pregnancy
Conception 3 (8.8) 4 (12.1) 3.3 (14.7 to 21.5) 1.37 (0.33–5.67) .709
Clinical pregnancy 1 (2.9) 3 (9.1) 6.2 (9.5 to 22.8) 3.09 (0.34–28.23) .356
Singleton pregnancy 1 (2.9) 3 (9.1) 6.2 (9.5 to 22.8) 3.09 (0.34–28.23) .356
Twin pregnancy 0 0 0.000 – –
Singleton live birth 1 (3) 3 (9.1) 6.2 (9.5 to 22.8) 3.09 (0.34–28.23) .356
Pregnancy loss among 2/3 (67) 1/4 (25) 41.7 0.38 (0.06–2.45) .486
those who conceived
Fecundity among those
who ovulated
Conception 3/14 (21) 4/25 (16) 5.4 (34.6 to 21.6) 0.75 (0.19–2.87) .686
Live birth 1/14 (7) 3/25 (12) 4.9 (27.2 to 26.3) 1.68 (0.19–14.66) 1.00
a
Letrozole, n ¼ 35; letrozole þ CC, n ¼ 35.
b
Letrozole, n ¼ 34; letrozole þ CC, n ¼ 33.
c
Differences are expressed as percentage points for all outcomes.
d
P values were calculated with the use of chi-square or Fisher exact test.
Mejia. Clomiphene citrate and letrozole combination. Fertil Steril 2018.

groups reported similar acceptability of side-effects. All (Table 4). There was no significant difference in the side-
participants stated they would take the allocated medica- effects profile between the two groups. The most commonly
tion again, except one person in the combination group reported side effects in the letrozole group included head-
who stated that the mood irritability was not tolerable ache (41%), fatigue (22%), and abdominal pain or

TABLE 3

Cycle characteristics.
Characteristic Letrozole group (n [ 34) Letrozole D CC group (n [ 33) P value
Progestin withdrawal 18 (53) 17 (52) 1.00
Ultrasound cycle day 13  0.9 13  1.0 .975
Reported LH surge 18 (53) 25 (76) .143
Cycle day of LH surge 16  3.7 16  1.9 .960
No. of follicles >10 mm 0 (0–1) 1 (0–3) < .001b
No. of women with follicles >15 mm 9 (27) 19 (58) .020
No. of follicles >15 mm 0 (0–1) 1 (0–1) .004b
Largest follicle size, mm 10.00 (8.75–15.25) 16.00 (10.00–19.00) .004b
Endometrial lining thickness, mm 6.2  2.2 8.3  3.6 .006
Cycle day progesterone level obtained 23.4  2.7 23.6  2.8 .742
Progesterone level, ng/mL 0.5 (0.3–8.9) 9.7 (2.5–19.4) .002b
Cycle characteristics among those who ovulated (n ¼ 14) (n ¼ 25)
Progestin withdrawal 6 (43) 11 (44) 1.00
Ultrasound cycle day 13  1.1 13  1.0 .873
Reported LH surge 11 (79) 22 (88) .647a
Cycle day of LH surge 16  3.9 16  1.9 .886
No. of follicles >10 mm 1 (0–1) 2 (1–4) .002b
No. of women with follicles >15 mm 7 (50) 18 (72) .305
No. of follicles >15 mm 0.5 (0–1) 1 (0–1.5) .081b
Largest follicle size, mm 15.5 (10.0–18.3) 17.0 (13.5–19.5) .228b
Endometrial lining thickness, mm 7.4  2.3 8.6  3.9 .286
Cycle day progesterone level obtained 24  2.6 24  2.7 .355
Progesterone level, ng/mL 10.95 (5.07–14.30) 13.30 (9.45–25.70) .093b
Note: Values are presented as n (%), mean  SD, or median (interquartile range).
a
Fisher exact test.
b
Mann-Whitney U test.
Mejia. Clomiphene citrate and letrozole combination. Fertil Steril 2018.

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ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY

were similar between the two groups, although this study was
TABLE 4
underpowered to detect significant between-group differ-
Tolerability and adverse events.
ences for these outcomes. We acknowledge that the ideal pri-
mary outcome would be live birth when studying a fertility
Letrozole Letrozole D P
Event group CC group value treatment, but given the absence of prospective randomized
data on the combination of letrozole and CC, we found that
Side-effects acceptable .156
Yes 17/33 (52) 22/32 (69)
the most practical and feasible first step was to assess the
No 0/33 (0) 0/32 (0) ovulation rate in a randomized controlled trial.
No side-effects 16/33 (49) 10/32 (31) Mechanistically, the combination treatment may have an
Would take the medication 33/33 (100) 31/32 (97)b .492a additive effect on ovulation induction. Letrozole works
regimen again (yes)
Hospitalized or seek any 3/33 (9)c 2/32 (6)d 1.00a locally at the level of the ovary to block estrogen synthesis,
additional care during and CC exerts its effect centrally by antagonizing the negative
the treatment month feedback of estrogen on the hypothalamus and down-
(yes)
Side-effects during treatment month (before conception)
regulating estrogen receptors. These different mechanisms
Serious adverse events 0/35 (0) 0/35 (0) – of action may provide complementary effects to provide
Reported side-effects 21/32 (66) 19/32 (59) .796 improved ovulation rates compared with the use of letrozole
Headache 13/32 (41) 9/32 (28) .430 alone.
Hot flashes 4/32 (13) 10/32 (31) .131
Abdominal bloating 2/32 (6) 0/32 (0) .492a Only one other study has published the use of the combi-
Abdominal pain 6/32 (19) 6/32 (19) 1.00 nation of letrozole and CC (9). That prospective cohort study
including cramps enrolled 100 patients resistant to letrozole alone (four cycles)
Nausea 3/32 (9) 3/32 (9) 1.00a and CC alone (six cycles) and demonstrated a follicular devel-
Mood changes 1/32 (3) 4/32 (13) .355a
Fatigue 7/32 (22) 4/32 (13) .508 opment rate of 82.9% (213 of 257 cycles) based on develop-
Back pain 1/32 (3) 1/32 (3) 1.00a ment of a dominant follicle with the use of 5 mg letrozole
Dizziness 2/32 (6) 1/32 (3) 1.00a plus 100 mg CC daily for 5 days (9). In addition, patients
Breast discomfort 3/32 (9) 2/32 (6) 1.00a
Diarrhea 2/32 (6) 1/32 (3) 1.00a
received an FSH injection on day 11 if a dominant follicle
Night sweats 1/32 (3) 2/32 (6) 1.00a was present and then received hCG trigger when the follicle
Sleep disturbances 1/32 (3) 2/32 (6) 1.00a was R18 mm in size, followed by intrauterine insemination
including insomnia 36–38 hours later. That study provided initial interesting find-
Adverse events of ongoing pregnancies
1st trimester 0/1 0/3 ings regarding the use of combination treatment with letro-
2nd trimester to delivery 0/1 (0) 1/3 (33)e zole and CC, but follicle size alone is not necessarily a
Delivery 0/1 0/3 reliable or accurate way to confirm ovulation. Furthermore,
Diagnosis of congenital 0/1 (0) 0/3 (0)
birth defects
the study was not randomized and used a limited population
Note: Two participants did not complete the end of treatment questionnaire. Six participants
of PCOS women resistant to both CC alone and letrozole
did not turn in their calendar logs documenting possible side-effects (three in each group).
a
alone. It is possible that the combination treatment may be
Fisher exact test.
b
One participant stated that she would not take the medication regimen again because the useful for patients resistant to letrozole alone and/or to CC
CC caused mood irritability. alone, although our data demonstrate that the combination
c
Hospitalization/additional care details for letrozole treatment group: participant 35: chole-
cystectomy and endoscopic retrograde cholangiopancreatography for gallstones; participant treatment offers a superior ovulatory rate compared with le-
34: pilonidal cyst; participant 50: urinary tract infection (received antibiotics).
d
Hospitalization/additional care details for combination letrozole and CC treatment group: trozole alone in a general infertile PCOS population and could
participant 4: appendicitis on cycle day (CD) 1 after treatment cycle (hospitalized and under- be considered as a first-line treatment.
went appendectomy); participant 15: urinary tract infection on CD35, seen at local
obstetrics-gynecology clinic. It is important to note that the side-effects profiles of
e
Complications for combination letrozole and CC treatment group: echogenic bowel and
small head on ultrasound, infant born healthy with no birth defects.
these two treatments in the present study were very similar.
Mejia. Clomiphene citrate and letrozole combination. Fertil Steril 2018. Only one participant out of 32 said they would not take the
combination regimen again, owing to irritability. Further-
more, there were no SAEs related to the study treatments in
cramping (19%). The most commonly reported side effects either group. Although the study was not powered to assess
in the letrozole and CC group included: hot flashes (31%), a difference between groups for congenital birth defects, we
headache (28%), and abdominal pain or cramping (19%; can report that among the four live births there were no
Table 4). congenital birth defects.
There were no adverse events during pregnancy. There One of the limitations of this study is that participants and
were no congenital birth defects (Table 4). investigators were not blinded to the treatment after random-
ization. Allocation concealment was maintained with the in-
vestigators not aware of the treatment assignment until
DISCUSSION participant information was entered into the secure computer
The results of this study support our hypothesis that a combi- system. We acknowledge the possibility of bias from an open-
nation of letrozole and CC is superior to letrozole alone for label trial. The outcome we have chosen is an objective one
achieving ovulation in women with infertility and PCOS. (ovulation assessed by mid-luteal progesterone level) and
This study found that the combination of letrozole and CC should minimize any bias introduced from lack of blinding.
had a higher ovulatory rate, with a 34% absolute difference Another limitation was that only one cycle per participant
noted. Conception, pregnancy, pregnancy loss, and live birth was performed and there was not a stair-step approach for

576 VOL. 111 NO. 3 / MARCH 2019


increasing the dose in either treatment group. Additional
cycles would have allowed for cumulative ovulation to be as-
sessed and provided a means to evaluate different combina-
tions of doses. However, the present study design offered
both a timely, cost-effective, and responsible means to obtain
initial ovulation data on this combination treatment.
It is possible that the difference in ovulatory rates be-
tween the two arms could be explained by a dosing effect.
The lowest initial doses for letrozole and CC were chosen to
use the lowest effective doses for each medication. By using
2.5 mg letrozole in both arms of the study, the only difference
between the two treatment groups was the addition of CC. The
ovulatory rate with the use of letrozole alone in this study was
43%, which is similar to other studies for women with PCOS at
this dose and for one cycle (5). The cumulative ovulation over
five cycles for letrozole alone (including doses of 2.5, 5.0, and
7.5 mg) in the PPCOS II trial was 61.7% (834 of 1,352 cycles)
(5). The ovulation rate in our combination-treatment group
was higher than the rates reported in the PPCOS II trial for cu-
mulative ovulation and cycle ovulation for letrozole doses
5.0 mg and 7.5 mg, suggesting that there may be a synergistic
effect of the combination of these medications (5). It will be
important in future studies to compare cumulative ovulatory
rate and live birth rate between letrozole alone and the com-
bination of letrozole and CC with the use of multiple cycles
and dosing regimens.
The present study did include participants who were tak-
ing metformin. A systematic review and network analysis
found that CC and metformin combined had higher ovulation
rates (odds ratio 1.55, 95% CI 1.02–2.36) but similar live birth
rates compared with CC alone (13). In our study, the use of
metformin was similar in both arms (Table 1), and therefore
randomization likely eliminated any treatment bias. To
confirm this, we performed a chi-square post hoc analysis
and found that ovulation rates were similar between women
who were concurrently using metformin and those who
were not (PP: 17 of 29 women [59%] vs. 22 of 38 women
[58%]; P ¼ 1). However, our study was not powered to detect
a difference in these subgroups nor were these subgroup an-
alyses defined a priori. In addition, this study did not require
every participant to take progestin to induce menses, and
some participants chose to await a spontaneous menses. Pro-
gestin use in the index cycle was evenly distributed between
both treatment arms after randomization, so any treatment
bias due to progestin use would likely have been eliminated.
A chi-square post hoc analysis did not find a difference in
the ovulation rates between women who used progestin and
those who did not during the study cycle (PP: 17 of 35 women
[49%] vs. 22 of 32 women [69%]; P¼ .154). We performed lo-
gistic regression analysis controlling for Provera, and the as-
signed treatment remained a significant predictor of
ovulation: odds ratio 4.33, 95% CI 1.499–12.488). This was
a post hoc analysis, and the study was not designed to
compare progestin use versus no progestin use in this cohort
so it may be underpowered to detect a difference.
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Fertility and Sterility®
One of the strengths of this study is the pragmatic
approach in the eligibility criteria, providing results for a pa-
tient population that is likely similar to that in other reproduc-
tive endocrine clinics. Patients were similar on the level of a
PCOS and infertility diagnosis, although they had varied
reproductive history, including type of infertility, recent use
of fertility treatment, and previous exposure to letrozole or
CC. Although this increases variability among participants,
it also improves the generalizability of these findings.
CONCLUSIONS
The present study showed that the combination of letrozole
and CC was superior to letrozole alone for inducing ovula-
tion in the setting for infertility treatment in women with
PCOS. These novel results suggest that this combination
therapy may be an alternate low-risk, low-cost infertility
treatment that offers superior ovulation rates. Additional
randomized clinical trials are needed to determine if preg-
nancy and live birth rates are higher with the combination
of letrozole and CC.
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577
ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY

Ensayo controlado aleatorio de letrozol y citrato de clomifeno combinados o letrozol solo para la inducci

on de la ovulaci

on en mujeres
con síndrome de ovario poliquístico
Objetivo: Evaluar si una combinaci
on de letrozol y citrato de clomifeno (CC) produce mayores tasas de ovulaci

on que el letrozol solo en
mujeres inf
ertiles con síndrome de ovario poliquístico (SOP).
~o: Ensayo controlado aleatorio abierto.
Disen
Lugar: Centro m
edico acad
emico utilizando dos clínicas.
Paciente (s): Mujeres de 18 a 40 a~nos de edad con diagn

ostico de infertilidad y SOP, seg

un lo definen los criterios de Rotterdam y sin
ninguna otra causa de infertilidad conocida.
Intervenciones: Las participantes se asignaron al azar en una proporci
on de 1:1, estratificadas por edad e índice de masa corporal, se les
administr
o 2,5 mg de letrozol solo o la combinaci

on de 2,5 mg de letrozol y 50 mg de CC diariamente en los días 3 a 7 del ciclo para un
ciclo de tratamiento.
Principales medidas de resultado: La ovulaci

on se defini

o como la concentraci

on s
erica de progesterona en la mitad de la fase l

utea
superior o igual a 3 ng / ml.
Resultado (s): Setenta pacientes fueron aleatorizados: 35 con letrozol solo y 35 con letrozol y CC. Los resultados fueron analizados
un el principio de ‘‘intenci

seg
on de tratar’’. Las mujeres que recibieron la combinaci

on de letrozol y CC tuvieron una tasa de ovulaci
on
estadísticamente m
as alta en comparaci
on con las que recibieron letrozol solo (27 de 35 mujeres [77%] frente a 15 de 35 mujeres [43%]).
No hubo efectos adversos graves o embarazos de gestaci
on m
ultiple en ning

un grupo. El perfil de efectos secundarios fue similar en los
dos grupos de tratamiento.
Conclusi
on (es): La combinaci

on de letrozol y CC se asoci

o con una tasa de ovulaci
on m
as alta en comparaci
on con letrozol solo en
mujeres con infertilidad y PCOS. Se necesitan estudios adicionales para evaluar el efecto sobre la tasa de reci
en nacidos vivos.

mero de registro de ensayo clínico: NCT02802865.
Nu

578 VOL. 111 NO. 3 / MARCH 2019

 Fertility and Sterility®

SUPPLEMENTAL FIGURE 1

Enrollment

Pre-screened (n=127) Excluded (n=54)

♦ Did not meet inclusion criteria (n=36)
♦ 16 - no records to confirm eligibility
♦ 10 - other causes of infertility including
abnormal partner semen analysis
♦ 7 - pregnant prior to enrollment visit
♦1 - no PCOS diagnosis
♦2 - other
♦ Declined to participate (n=18)
Consented (n=73) ♦ 5 Desired alternate treatment
♦ 4 did not want to be randomized to control
♦ 3 Logistical issues
♦ 6 Other / reason not provided

Excluded (n=3)
♦ 2 - pregnant prior to randomizaon
♦ 1 - endometrial cancer

Randomized (n=70)

Allocation

Allocated to Letrozole 2.5 mg (n=35) Allocated to Letrozole 2.5 mg + Clomid 50 mg (n=35)

♦ Received allocated intervention (n=34) ♦ Received allocated intervention (n=33)
♦ Did not receive allocated intervention (n=1) as ♦ Did not receive allocated intervention (n=2) as
became ineligible (1 pregnancy) became ineligible (1 pregnancy and 1 with
tuberculosis)

Follow-Up

Lost to follow-up (n=0) Lost to follow-up (n=0)

Discontinued intervention (n=0) Discontinued intervention (n=0)

Analysis

Analysed ITT (n=35) Analysed ITT (n=35)

Analysed PP (n=34) Analysed PP (n=33)
♦ Excluded from analysis (n=1 ♦ Excluded from analysis (n=2
subject became ineligible and did not subjects became ineligible and did not
take treatment) take treatment)

Participant flow diagram.

Mejia. Clomiphene citrate and letrozole combination. Fertil Steril 2018.

VOL. 111 NO. 3 / MARCH 2019 578.e1