Comparison of the success rate of letrozole and clomiphene citrate in women undergoing intrauterine insemination

Abstract

BACKGROUND: This study was conducted to compare the success rate of daily administration of aromatase inhibitor letrozole at a dose of 5 mg when administrating clomiphene citrate (CC) 100 mg daily in women undergoing superovulation and IUI.
METHODS: This prospective randomized trial was done in Research and Clinical Center for Infertility (Shahid Sadoughi University), Yazd, Iran. Ninety-five patients with unexplained and mild male factor infertility were studied. Using a computer-generated random table, the patients were randomized into two groups, which were treated with 5 mg of letrozole daily (42 patients, 42 cycles) or 100 mg of CC daily (53 patients, 53 cycles). The data were analyzed using Student's t-test and chi square test.
RESULTS: The mean age and duration of infertility in both groups were similar. There was a significant difference between the two groups in the total numbers of follicles during stimulation (5.45 ± 4.2 in CC group vs. 3.07 ± 2.1 in letrozole group) (P = 0.01). No significant difference in the endometrial thickness was found between the two groups (letrozole group = 6.9 ± 2.2, CC group = 7.8 ± 1.8). The mean levels of LH and FSH in both groups were similar. P value of difference in hormone levels between two groups were 0.33 and 0.47, respectively, but there was a significant difference in mean E2 levels between the two groups (241.28 ± 167.537 in letrozole group vs. 867.34 ± 296.689 in CC group) (P = 0.018). The mean number of gonadotropin ampules used in both groups was the same. Pregnancy rate per cycle was 9.5% in the letrozole group and 5.7% in the CC group (P = 0.6). Two out of the three pregnancies in the CC group (66.6%) and one out of the four pregnancies in the letrozole group resulted in a miscarriage (25%). One twin pregnancy (33%) occurred in the letrozole group and none in the CC group. Ovarian hyperstimulation syndrome (OHSS) did not occur in either of the two groups.
CONCLUSIONS: In IUI, superovulation with clomiphene citrate and letrozole was associated with similar pregnancy rates, but the miscarriage rate was higher with clomiphene citrate.
KEY WORDS: IUI, letrozole, clomiphene citrate, superovulation.

Full text

Page 1

Received: 10.2.2006 Accepted: 8.11.2006
382 Journal of Research in Medical Sciences Nov & Dec 2006; Vol 11, No 6.
Original Article
Comparison of the success rate of letrozole and clomiphene citrate
in women undergoing intrauterine insemination

Robab Davar*, Maryam Asgharnia**, Mojgan Tayebi***
Abstract
BACKGROUND: This study was conducted to compare the success rate of daily administration of aromatase inhibitor
letrozole at a dose of 5 mg when administrating clomiphene citrate (CC) 100 mg daily in women undergoing superovu-
lation and IUI.
METHODS: This prospective randomized trial was done in Research and Clinical Center for Infertility (Shahid Sadoughi
University), Yazd, Iran. Ninety-five patients with unexplained and mild male factor infertility were studied. Using a
computer-generated random table, the patients were randomized into two groups, which were treated with 5 mg of le-
trozole daily (42 patients, 42 cycles) or 100 mg of CC daily (53 patients, 53 cycles). The data were analyzed using Stu-
dent's t-test and chi square test.
RESULTS: The mean age and duration of infertility in both groups were similar. There was a significant difference be-
tween the two groups in the total numbers of follicles during stimulation (5.45 ± 4.2 in CC group vs. 3.07 ± 2.1 in letro-
zole group) (P = 0.01). No significant difference in the endometrial thickness was found between the two groups (letro-
zole group = 6.9 ± 2.2, CC group = 7.8 ± 1.8). The mean levels of LH and FSH in both groups were similar. P value of
difference in hormone levels between two groups were 0.33 and 0.47, respectively, but there was a significant differ-
ence in mean E2 levels between the two groups (241.28 ± 167.537 in letrozole group vs. 867.34 ± 296.689 in CC
group) (P = 0.018). The mean number of gonadotropin ampules used in both groups was the same. Pregnancy rate per
cycle was 9.5% in the letrozole group and 5.7% in the CC group (P = 0.6). Two out of the three pregnancies in the CC
group (66.6%) and one out of the four pregnancies in the letrozole group resulted in a miscarriage (25%). One twin
pregnancy (33%) occurred in the letrozole group and none in the CC group. Ovarian hyperstimulation syndrome
(OHSS) did not occur in either of the two groups.
CONCLUSIONS: In IUI, superovulation with clomiphene citrate and letrozole was associated with similar pregnancy
rates, but the miscarriage rate was higher with clomiphene citrate.
KEY WORDS: IUI, letrozole, clomiphene citrate, superovulation.

T
JRMS 2006; 11(6): 382-387
he principal medications available for
ovarian stimulation are oral antiestro-
gen, clomiphene citrate (CC), and in-
jectable gonadotropins and aromatase inhibitor
1. CC has a long half-life and accumulates in
the body 2. In anovulatory women, the use of
CC is widely accepted as the first line therapy

because of its low cost and easy administration
3, 13. Its use is associated with a high ovulation
rate of 60%-80%, but with a lower pregnancy
rate of about 50% 3and some side effects 1. This
may be due to a detrimental effect on the en-
dometrium (an estrogen responsive site) and
on the quality of cervical mucus

2. The
*Assistant Professor of Obstetric & Gynecology, Research and Clinical Center for Infertility, Shahid Sadoughi University, Yazd, Iran.
**Infertility Fellowship, Research and Clinical Center for Infertility, Shahid Sadoughi University, Assistant Professor of Obstetric & Gyne-
cology, Gilan University of Medical Sciences, Iran.
***General Practitioner, Research and Clinical Center for Infertility, Shahid Sadoughi University, Yazd, Iran.
Correspondance to: Dr Robab Davar, Assistant Professor of Obstetric & Gynecology, Research and Clinical Center for Infertility, Shahid
Sadoughi University, Yazd, Iran. e-mail: r_davar@yahoo.com

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Letrozole vs. clomiphene citrate in intrauterine insemination Davar et al
Journal of Research in Medical Sciences Nov & Dec 2006; Vol 11, No 6. 383
endometrium is believed to be one of the most
important targets for the antiestrogenic effect
of CC and may explain a large part of its low
pregnancy rate and high miscarriage rate. Suc-
cessful implantation requires a receptive en-
dometrium, with synchronous development of
glands and stroma 4, 5. In one study, CC was
found to have a deleterious effect on the en-
dometrium, demonstrated by a reduction in
glandular density and an increase in the num-
ber of vacuolated cells 6. In addition, Gonen et
al (1990) demonstrated a reduction in endo-
metrial thickness, below the level thought to be
needed to sustain implantation, in up to 30% of
women receiving CC for ovulation induction
or for unexplained infertility 7. Recently, it was
suggested that letrozole, a specific reversible,
nonsteroidal aromatase inhibitor that sup-
presses estrogen biosynthesis 8, could success-
fully replace CC in superovulation treatment
of patients with unexplained infertility or
polycystic ovarian syndrome and in poor re-
sponders 9. The new third generation aroma-
tase inhibitors agents commercially available
include two nonsteroidal preparations, ana-
strozole and letrozole and a steroidal agent,
exemestane 10,11. Letrozole has a short half-life
(around 2 days) and it clears rapidly from the
body 12. This drug is a potent and highly spe-
cific nonsteroidal aromatase inhibitor that ini-
tially was approved for use in postmenopausal
women with breast cancer to suppress estro-
gen production 13,14. Letrozole inhibits the
aromatase enzyme by competitively binding to
the heme of the cytochrome P450 subunit of
the enzyme, resulting in a blockade of andro-
gens conversion into estrogens with subse-
quent increase in intraovarian androgens 15.
Administering letrozole early in the follicular
phase induces ovulation by releasing the hypo-
thalamus or pituitary from estrogen negative
feedback on GnRH and gonadotropin secre-
tion, leading to an increase in gonadotropin
production which would stimulate ovarian fol-
licular development 12 but unlike clomiphene
citrate, does not lead to estrogen receptor de-
pletion 16. Letrozole increases intraovarian an-
drogen levels and may synergize with the cen-
tral effects of decreased estrogen to enhance
ovarian response to gonadotropin stimulation
1. The combined use of aromatase inhibitors
and gonadotropin injection was associated
with improved ovarian response 17.
The purpose of the present study was to
compare the effects of administrating 5 mg of
letrozole daily in women undergoing IUI with
these effects when administrating 100 mg of
CC.
Methods
In total, 95 patients with unexplained and mild
male factor infertility were studied at Yazd Re-
search and Clinical Center for Infertility. Inclu-
sion criteria were age younger than 40 years,
infertility of more than 1 year in duration, pat-
ent fallopian tubes on hysterosalpingogram or
laparoscopy and the presence of at least 10 mil-
lion rapidly motile sperm/ml (mild male fac-
tor) 16. Patients were randomized using a com-
puter-generated random table into two groups
which were treated with 5 mg of letrozole
daily (42 patients, 42 cycles) or 100 mg of CC
daily (53 patients, 53 cycles). In the letrozole
group, the patients were treated with letrozole
(Femara; Novartis pharmaceuticals, Dorval,
Quebec, Canada) 5 mg/day on days 3-7 of the
menstrual cycle and FSH (Gonal-F, Serono,
Ontario, Canada or puregon; organon) (150
IU/day) on day 8, while patients in CC group
were treated with clomiphene citrate 100
mg/day on days 5-9 of the menstrual cycle and
FSH (150 IU/day) from day 8. Ultrasound ex-
amination was started on day 12 and the fol-
lowing days when the diameter of the domi-
nant follicle reached 18 mm, HCG (10,000 IU)
was administrated for triggering ovulation fol-
lowed by IUI after 34-36 hours. We evaluated
the total number and size of the follicles, en-
dometrial thickness and type, the number of
gonadotropin ampules, mean LH, FSH and E2
levels, pregnancy rate (chemical and clinical)
and miscarriage rate. Data were analyzed us-
ing Student's t-test and chi-square test. Results
were expressed as mean and standard devia-
tion. P values below 0.05 were considered as
statistically significant.

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Letrozole vs. clomiphene citrate in intrauterine insemination

Results
Our results show that the causes of infertility,
mean age and duration of infertility in both
groups of patients were similar (table 1). The
total numbers of follicles in the letrozole group
were lower than those in the clomiphene cit-
rate group. There was no significant difference
in endometrial thickness between the two
groups (6.9 ± 2.2 mm in the letrozole group, 7.8
± 1.8 mm in the CC group). The mean numbers
of gonadotropin ampules used in the two
groups were the same. (P = 0.19) (table 2).The
mean levels of LH and FSH in the groups were
similar. (P values for the difference in hormone

Table 1. Characteristics of patients undergoing superovulation with letrozole or clomiphene
citrate (CC).
Davar et al
384 Journal of Research in Medical Sciences Nov & Dec 2006; Vol 11, No 6.
levels between the two groups were 0.33 and
0.47, respectively). There was a significant dif-
ference in mean E2 levels between the groups
(241.28 ± 167.537 in letrozole group vs. 867.34 ±
296.689 in CC group) (P = 0.018) (table 2). The
pregnancy rate per cycle was 9.5% in the letro-
zole group and 5.7% in the CC group (P = 0.6).
One out of the four pregnancies in the letrozole
group (25%) and two out of the three pregnan-
cies in the CC group (66.6%) resulted in mis-
carriage (table 3). OHSS did not occur in either
of the two groups. One twin pregnancy (33%)
occurred in the letrozole group and none in the
CC group.
Characters Letrozole CC
N = 42 N = 53 P value
Mean (± SD) age of women, years 29 ± 2.9 25.7 ± 3.8 NS*
Mean (± SD) age of men, years 31.88 ± 4.3 30.66 ± 4.01 NS
Mean (± SD) duration of infertility, years 5.95 ± 2.4 5.23 ± 2.5 NS
Causes of infertility
Male factor (%) 23.8 34 NS
Unexplained (%) 76.2 66 NS
*NS = Not Significant
Table 2. Superovulation with letrozole or with clomiphene citrate (CC).


Letrozole CC
N = 42 N = 53 P value
Mean (± SD) number of total follicles 3.07 ± 2.1 5.45 ± 4.2 0.01
Mean (± SD) endometrial thickness (mm) 6.9 ± 2.2 7.8 ± 1.8 NS
Mean (± SD) of LH (IU/L) 8.07 ± 10.96 8.24 ± 7.8 NS
Mean (± SD) of FSH (IU/L) 6.39 ± 3.3 7.3 ± 4.4 NS
Mean (± SD) of E2 (pg/ml) 241.28 ± 167.537 867.34 ± 296.689 0.018
Mean (± SD) number of gonadotropin ampule 6.1 ± 2.4 7.7 ± 3.4 NS
*NS= Not Significant

Table 3. Outcome of letrozole or clomiphene
citrate in women undergoing IUI.
Letrozole CC
N = 42 N = 53 P value
Number of 4 (9.5%) 3 (5.7%) NS
pregnancies
Ongoing pregnancies 3 1 NS
Miscarriage 1 2 NS
*NS= Not Significant
Discussion
Clomiphene citrate is the most commonly pre-
scribed agent for ovulation induction. Unfor-
tunately, despite the high rates of ovulation,
pregnancy rates per cycle remain relatively
low. An antiestrogenic effect of clomiphene on
the endometrium has been postulated. Mit-
wally and Casper (2001) have shown that the
use of CC may be complicated owing to the

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Letrozole vs. clomiphene citrate in intrauterine insemination Davar et al

Journal of Research in Medical Sciences Nov & Dec 2006; Vol 11, No 6. 385
antiestrogenic effects on endometrial devel-
opment. For these reasons, a simple, inexpen-
sive and safe alternative to CC for use in nor-
mally ovulatory woman is required 18. The ad-
dition of IUI to Controlled Ovarian Hyper-
stimulation (COH) by CC or gonadotropins
was shown to be significantly more effective
than COH alone 19-21. Several authors found
combined COH and IUI treatment to be very
effective in unexplained and mild male infertil-
ity 22-24. Stephanie et al (2002) compared the
effect of clomiphene citrate and letrozole on
normal ovulatory women; profiles of both LH
and FSH were similar in natural and medi-
cated cycles with letrozole and CC, but E2
level was more than two times higher in
clomiphene-treated cycles 25. Despite signifi-
cantly lower E2 levels in letrozole-treated
women, endometrial development was unaf-
fected in this study. In a selected population of
women with endometrium (mean thickness of
5mm) after clomiphene treatment, letrozole
treatment in the early follicular phase resulted
in a significant increase in midcycle endo-
metrial thickness (mean thickness of 9 mm) 18.
These results were similar to our study. A lar-
ger randomized trial is required to fully assess
the impact of letrozole on endometrial devel-
opment. Al-Fozan et al 26, compared the effect
of CC and letrozole in women undergoing su-
perovulation. There was no difference in preg-
nancy rates or endometrial thickness between
the letrozole and the CC groups. Of interest,
the miscarriage rate was higher in the CC
group 26,27,28. This may have been due to the
different mechanisms of action of letrozole and
CC 26. In our study, there was no difference in
pregnancy rates or in endometrial thickness
between the groups. Mohamed F et al (2005)
showed the effect of an aromatase inhibitor for
ovarian stimulation on pregnancy outcome;
they found CC treatment to be consistently as-
sociated with development of more ovarian
follicles than with aromatase inhibitor and the
lowest multiple gestation rate was associated
with letrozole treatment 29. In our study, the
results of follicles development were the same,
but multiple-gestation rate was higher with
letrozole treatment. More studies on larger
numbers of multiple-gestation cases with le-
trozole are needed to confirm these findings.
Our results showed significantly lower estra-
diol concentrations in the letrozole group than
in the CC group and more follicles were ob-
served in cycles stimulated with 100 mg CC
from day 3 to 7 of the cycle than in the letro-
zole group. These results are similar to those of
Fatemi's research (2003) 30.
The estrogen levels in women on aromatase
inhibitors were found to be 2-3 times lower
than those reported in CC cycles, however, en-
dometrial thickness was greater in the aroma-
tase inhibitor cycles 2. In our study, estrogen
levels were higher in the CC group, but there
was no difference in the endometrial thickness
between the two groups. Letrozole, at doses of
1-5 mg/day, inhibits aromatase activity by
97%-99% 11. In all studies conducted so far, the
aromatase inhibitor letrozole was administered
as a 5-day regimen, usually from day 3 to 7 of
the menstrual cycle, at a dose of 2.5-7.5
mg/day 10,31. Even in one study 10 the new ap-
proach of a single-dose regimen of an aroma-
tase inhibitor for ovarian stimulation seems to
be as effective as the previously reported 5-day
regimen. In the present study, letrozole was
administrated at a dose of 5 mg/day from day
5 to 9 of the menstrual cycle. It was shown that
CC is associated with increased risk of severe
ovarian hyperstimulation syndrome and high
multiple pregnancies 1. In the present study,
OHSS did not occur in either of the two
groups. Mitwally and Casper (2004) proposed
that aromatase inhibitors would replace CC in
the future as the new primary treatment for
ovulation induction in PCO patients 11. Letro-
zole can be used for ovulation induction or
ovarian stimulation with higher pregnancy
rates compared with CC 18.
In summary, the results of this preliminary
study suggest that the aromatase inhibitor, le-
trozole, may be used as an alternative new
first-line treatment for ovulation induction in
ovulatory infertile patients. This research was
conducted before warnings of letrozole side
effects on the internet.

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Letrozole vs. clomiphene citrate in intrauterine insemination

Acknowledgments
This research was performed using a grant
from the Research and Clinical Center for In-
fertility, Shahid Sadoughi University, Yazd,

Davar et al
386 Journal of Research in Medical Sciences Nov & Dec 2006; Vol 11, No 6.
Iran. The authors extend their thanks to Ms.
Afsaneh Kermani-nejad and Habibeh Gheisari
for their cooperation.

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