Middle East Fertility Society Journal Vol. 13, No.

1, 2008
Copyright © Middle East Fertility Society

A randomized trial of letrazole versus clomiphene

citrate in induction of ovulation in patients with
polycystic ovary syndrome (PCOS)

Adel F. El Bigawy, M.D.

Usama M. F. Fouda, M.D.
Hala A.E. Wahab, M.D.

Department of Obstetrics and Gynecology, Cairo university, Cairo, Egypt

ABSTRACT

Objective: The aim of this study was to compare the effect of letrazole (2.5mg) and clomiphene citrate (150mg) on
ovulation in patients with polycystic ovary syndrome.
Design: Prospective randomized trial.
Setting: University teaching hospital.
Materials and Methods: Sixty four consecutive patients with polycystic ovary syndrome were recruited. Thirty four
patients (70 cycles) were given clomiphene citrate and thirty patients (64 cycles) were given letrazole. Both drugs
were given orally on days 3-7 of menses. Letrazole, clomiphene citrate, ovulation induction, timed intercourse.
Main outcome measures: Number of follicles, endometrial thickness and pregnancy rates.
Results: The mean age, body mass index, and duration of infertility in both groups were similar. Ovulation occurred in
78% of the cycles (50 /64) in letrazole treated group and 73% of the cycles (51/70) in clomiphene citrate treaded
group. The endometrial thickness was significantly higher in letrazole group, the number of mature follicles was
significantly lower in the letrazole group. Pregnancy rate per cycle was 16% in the letrazole group and 13% in the
clomiphene citrate group.
Conclusion: Aromatase inhibitor letrazole is as effective as clomiphene citrate in induction of ovulation in patients with
polycystic ovarian syndrome, and may have a role as first line treatment for anovulatory patients with polycystic
ovary syndrome.
Key words: letrozole, clomiphene citrate, polycystic ovary, ovulation, conception

Polycystic ovary syndrome is an extremely peripheral antiestrogenic effect on endometrium

common disorder affecting 4% to 12% of women
of reproductive age (1). For more than 4 decades,
clomiphene citrate has been the main drug used in
treatment of patients with polycystic ovary
syndrome (2). Although clomiphene citrate is easy
to use and results in ovulation in most patients with
polycystic ovary syndrome, but pregnancy rates
were disappointing. This has been attributed to its
Correspondence: Adel Farouk, M.D., 25A El Dokki street, E-
mail: adel_farouk1@yahoo.com
and cervical mucous (3). Recently, Mitwally and
Casper published some data showing the success
of the aromatase inhibitor (letrazole) in
anovulatory women resistant to clomiphene citrate,
women with unexplained infertility, and in
addition with FSH to improve the ovarian response
in poor responders (4, 5).The aim of this
prospective randomized study is to determine
whether letrazole can be used as an alternative to
clomiphene citrate in induction of ovulation in
patients with polycystic ovary syndrome.

52 El Bigawy et al. Letrozole versus Clomid in PCOS MEFSJ

Table 1. Characteristics of patients undergoing ovulation with letrazole and with clomiphene citrate
Clomiphene citrate
(70 cycles)
Age (years) 27.41±3.7
Mean infertility period (years) 3.12±1.66
Body mass index (kg/m2) 32.16±4.18
Variables are given as mean ±SD
NS= not significant
MATERIAL AND METHODS
This prospective randomized trial was
performed in Cairo university hospitals, Cairo,
Egypt. Sixty four patients with polycystic ovary
syndrome according to the Rotterdam revised
criteria for polycystic ovary syndrome were
included in the study (6), all patients had a history
of oligomenorrhea or amenorrhea and ovaries with
at least 12 subcapsular cysts 2-9mm in diameter
and increased ovarian volume (>10 ml). Our
inclusion criteria were age (18-37) years, period of
infertility > 1 year, day 3 serum level of FSH < 12
IU/L, and serum prolactin level within normal
limits in early follicular phase. Exclusion criteria
were history of pelvic surgery or infertility factors
other than anovulation.
The study protocol was approved by the
hospital research ethics board. Study participants
were counseled, and informed consent was taken
before randomization. Patients were randomized to
clomiphene citrate (n = 34) or letrazole (n = 30), a
quasi-randomization method was used. Based on
the attendance order, patients with odd numbers
were prescribed letrazole and those with even
numbers were given clomiphene citrate. Neither
the patients nor the doctors were blinded in any of
the groups. Letrazole (Femara; Novertis pharma
AG, Basle, Switzerland) and Clomiphene citrate
(Clomid; Aventis pharma S.AE, Global Napi
pharmaceuticals, Cairo, Egypt) were given orally
in doses of 2.5mg/day and 150mg/day respectively
for five days beginning on day 3 of menstrual
cycle. Transvaginal ultrasound (siemens, sonoline,
prima) was performed on day 3 of the menstrual
cycle before starting treatment, follicular
development was monitored using transvaginal
Vol. 13, No. 1, 2008
Letrazole P value
(64 cycles)
26.33±3.72 0.250
2.87±1.8 0.565
31.26±4.2 0.394
ultrasound from day 10 of the cycle.
Human chorionic gonadotropin (Pregnyl ;N.V.
Organon, Oss, Holland) at dose of 10.000 IU was
used to trigger ovulation when at least one follicle
exceeding 18mm was noted. Endometrial thickness
was assessed according to the method described by
Goren and Casper (7), the endometrial thickness
was measured at the greatest diameter
perpendicular to the midsagittal plane in the fundal
region, including both layers of the endometrial
cavity, the image was oriented so that the
endometrial canal and the cervical canal were
visualized in the same plane to ensure
measurement through the center of the
endometrium. Pregnancy was diagnosed by β-
subunit HCG performed 2 weeks from timed
intercourse, and ultrasound was performed 2 - 4
weeks after a positive pregnancy test to confirm
clinical pregnancy.
Statistical methods
Data were statistically described in terms of
mean ± standard deviation (± SD), frequencies
(number of cases) and relative frequencies
(percentages) when appropriate. Comparison of
quantitative variables between the study groups
was done using Student t test for independent
samples. For comparing categorical data, Chi
square (X2) test was performed. Yates correction
was used in stead when the expected frequency is
less than 5. A probability value (p value) less than
0.05 was considered statistically significant. All
statistical calculations were done using computer
programs Microsoft Excel version 7 (Microsoft
Corporation, NY, USA) and SPSS (Statistical
Package for the Social Science; SPSS Inc., Chicago,
El Bigawy et al. Letrozole versus Clomid in PCOS 53
Table 2. Induction of ovulation with letrazole and clomiphene citrate
Clomiphene citrate
Day of HCG administration
Endometrial thickness(mm)
Ovulation rate per cycle
Number of follicles more than 18mm on the day of
HCG administration
Pregnancy rate per cycle
Pregnancy rate per cycle and ovulation rate are expressed as N (%), all other values are given as mean ±SD
HCG : human chorionic gonadotrophin
IL, USA) statistical program.
RESULTS
The mean age, body mass index, and duration
of infertility in both groups were similar (Table 1).
The duration to reach dominant was 13.06±0.89
days in the letrazole group and 12.73±0.93 days in
the clomiphene citrate group. Ovulation occurred
in 78.12% of the cycles (50 /64) in letrazole treated
group and 72.85% of the cycles (51/70) in
clomiphene citrate treaded group. The endometrial
thickness was significantly higher in letrazole
group. In the clomiphene citrate group the
endometrial thickness on the day of HCG
administration was more than 5 mm in 60 cycles
and less than 5mm in 10 cycles, pregnancy did not
occur in any of these ten cycles, the endometrial
thickness was more than 5 mm in all cycles with
letrazole. The number of mature follicles was
significantly lower in the letrazole group.
Pregnancy rate per cycle was 15.62% in the
letrazole group and 12.85 % in the clomiphene
citrate group (Table 2).One case of twin pregnancy
occurred in clomiphene citrate group. One case of
abortion occurred in each group, ectopic pregnancy
did not occur in any group.
DISCUSSION
Clomiphene citrate is the most commonly
prescribed medication for ovulation induction in
patients with polycystic ovary syndrome (2).
Clomiphene citrate initiates or augments ovulation
54 El Bigawy et al. Letrozole versus Clomid in PCOS
Letrazole P value
(70 cycles) (64 cycles)
12.73±0.93 13.06±0.89 0.072
6.43±1.85 9.44±1.81 < 0.001
(51/70)(72.85%) (50/64)(78.12%) 0.613
2.49±1.21 1.3±0.54 < 0.001
(9/70)(12.85%) (10/64)(15.62%) 0.833
by binding to estrogen receptors throughout the
body due to structural similarity to estrogen,
clomiphene citrate binding to estrogen receptors
occurs for prolonged periods i.e. weeks rather than
hours as with natural estrogen. This extended
binding ultimately depletes estrogen receptors
concentrations by interfering with the normal
process estrogen receptors replenishment (8).
Depletion of hypothalamic receptors prevent
correct interpretation of circulating estrogen levels,
estrogen concentration was falsely perceived as
low leading to reduced estrogen negative feedback
on GnRH production and subsequent increased
gonadotropin (FSH and LH). The rise of FSH
promotes the growth of ovarian follicles and
ovulation in anovulatory women (9). Ovulation is
restored in 70 % – 80 % but will lead to pregnancy
in only about 30 % - 40 % (10). Peripheral
antiestrogenic effect of clomiphene citrate on the
endometrium and cervix are frequently suggested
as the possible explanation of such discrepancy, in
addition the accumulation of the isomers of
clomiphene citrate (zu-clomiphene) in the body
due to its long half life (several days to weeks) add
to persistence of this antiestrogenic effect
(11).While depression of cervical mucous, occur in
about 15% of patients, may be overcome by
intrauterine insemination, suppression of the
endometrial proliferation, unrelated to dose or
duration of treatment but apparently idiopathic
(12). Prolonged endometrial estrogen receptor
depletion results in significant thinning of the
endometrium. Compared with natural cycles, this
endometrial thinning has been observed in 15% to
50% on clomiphene citrate (13). Gonen and Casper
reported no pregnancies occurring in cycles with
MEFSJ
endometrial thickness < 6mm at midcycle and a
significantly higher rate of biochemical pregnancy
when the endometrial thickness was 6-8 mm (7).
Letrazole is a third generation non steroidal
aromatase inhibitor licensed for treatment of breast
cancer. Letrazole exerts its function through
binding to the hemomoiety of the aromatase
enzyme, which is a member of the cytochrome
P450 hemoprotein containing enzyme complex
superfamily that catalyze the rate limiting step in
the production of estrogen, that is, the conversion
of androstendione and testosterone via three
hydroxylation steps to estrone and estradiol
respectively (14).
The proposed mechanisms of ovarian
stimulation by letrazole are a central effect on
releasing the pituitary-hypothalamic axis from
estrogenic negative feedback, therefore increases
gonadotropin secretion and resulting ovarian
follicular development. This indicates that letrazole
lead to the same action of clomiphene citrate
without depletion of estrogen receptors, or
antiestrogenic effect on cervical mucous or
endometrium.
In women with polycystic ovary syndrome,
there is relative aromatase deficiency in the ovary,
resulting in increase in the ovarian androgen
production (15) which is converted to estrogen by
aromatization in the brain, leading to relative
oversuppression of FSH. Letrazole suppress the
estrogen production in both the ovaries and the
brain therefore resulting in increase in FSH release
and subsequent follicle stimulation and ovulation.
In addition to the central effect on the pituitary-
hypothalamic axis letrazole acts locally on the
ovaries, preventing the conversion of intraovarian
androgens into estrogens, leading to temporary
accumulation of androgens and enhances follicle
stimulating hormone receptor gene expression
leading to an increase in the sensitivity of the
ovarian follicles to gonadotropins stimulation (16).
The present study reveals that the induction of
ovulation with letrazole is associated with limited
number of mature follicles compared to
clomiphene citrate, because letrazole doesn't
deplete estrogen receptors and have short half (45
hours), unlike clomiphene citrate, normal negative
feedback occurs centrally as the dominant follicle
grows and estrogen levels increase, this results in
Vol. 13, No. 1, 2008
FSH suppression and atresia of small follicles, and
midcycle mono-ovulation occurs in most patients
(17).The result of the present study highlights the
main advantage of letrazole in induction of
ovulation in patients with polycystic ovary
syndrome which is mono-ovulation, patients with
polycystic ovary syndrome are often hyper-
responders to gonadotropins and at higher risk for
ovarian hyperstimulation syndrome.
One case of twin pregnancy occurred in
clomiphene citrate group and all the pregnancies in
the letrazole group were singleton, this is attributed
to mono-ovulation which occurred in 70% of
patients in letrazole group. Mitwally et al reported
that the use of aromatase inhibitor letrazole is
associated with significantly lower multiple
pregnancy rates compared with other methods of
ovarian stimulation, they explained this results by
the fact that letrazole induce limited number of
mature follicles compared to other methods of
induction of ovulation (18).
Higher endometrial thickness was reported on
the day of HCG administration with the letrazole
group compared with clomiphene citrate, in
addition all cycles in the letrazole group had
endometrial thickness more than 5 mm while in
clomiphene citrate group the endometrial thickness
was less than 5 mm in ten cycles. This indicates
the adverse effect of clomiphene citrate on the
endometrial growth that is thought to be due to
depletion of the endometrial receptors, and
indicates that letrazole has no adverse effect on
endometrium (19).These results agrees with the
results of Mitwally and Casper and Atay et al (4)
(20). On the other hand another study revealed that
there is no significant difference in endometrial
thickness (21).
Although the pregnancy rate per cycle was
higher in the letrazole group (15.62%) than in
clomiphene citrate group (12.85%), that difference
is not statistically significant. In a prospective
randomized study the pregnancy rate per cycle was
nearly similar between two groups of patients with
polycystic ovary syndrome treated with letrazole or
clomiphene citrate (22). In contrast to our finding,
other randomized study comparing the use of
letrazole or clomiphene citrate in patients with
polycystic ovary syndrome, pregnancy rate per
cycle was significantly higher in patients in
El Bigawy et al. Letrozole versus Clomid in PCOS 55
letrazole group (21% versus 9.1%) (20).
In summery, this prospective randomized study
has demonstrated the advantages of use of letrazole
in patients with polycystic ovary syndrome, which
is mono ovulation and absence of antiestrogenic
effect on endometrium, and higher pregnancy rate
per cycle. These properties make letrazole a viable
alternative to clomiphene citrate in patients with
polycystic ovary syndrome.
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Received on August 13, 2007; revised and accepted on September 2, 2007
MEFSJ