FERTILITY

ANDSTERILI~ Vol. 68, No. 6, December 1997

Copyright p 1997 American Society for Repmductive Medicine Printed on acid-free paper in U. S. A.

Published by Elsevier Science Inc.

The effects of clomiphene citrate on normally ovulatory women

Shunsaku Fujii, M.D. Akifumi Kagiya, M.D.

Atsushi Fukui, M.D. Shigemi Sato, M.D.
Yoshiyuki Fukushi, M.D. Yoshiharu Saito, M.D.

Department of Obstetrics and Gynecology, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan

Objective: To investigate the efficacy of clomiphene citrate (CC) on normally ovulatory

women who complained of infertility.
Design: A randomized study.
Setting: University Hospital.
Patient(s): Thirty-three normally ovulatory women with unexplained infertility.
Intervention(s): Eighteen women received CC at a 50-mg dosage. Fifteen women received
no ovulation-induction drugs.
Main Outcome Measures: The pregnancy rate (PR) per patient, the PR per cycle, and the
cumulative pregnancy rate.
Result(s): Seven patients in the CC group stopped taking CC, and observations were termi-
nated because of antiestrogenic effects. The pregnancy rate (PR) per patient and the PR per
cycle were significantly decreased (P <0.005) in the CC group (4 of 18 [22.2%1 and 4 of 66
[6.1%], respectively) than in the spontaneous group (11 of 15 [73.3%1 and 11 of 52 [21.2%1,
respectively). Kaplan-Meier tests showed that the cumulative pregnancy rate in the CC group
was significantly lower than in the spontaneous group (P ~0.05). Five of seven patients who
had stopped taking CC became pregnant in spontaneous cycles.
Conclusion(s): Administration of CC to normally ovulatory women is not efficacious in terms
of increasing the pregnancy rate. (Fertil Steril@ 1997;68:997-9. 0 1997 by American Soci-
ety for Reproductive Medicine.)

Key Words: Clomiphene citrate, ovulation induction, infertility

Clomiphene citrate (CC) is the most commonly
used drug in ovulation induction. However, it has
been established that pregnancy rates (PR) for
women who take CC are less than expected based
on ovulation rates. The causes of this discrepancy
between the PR and the ovulation rates have been
explained by the antiestrogenic effects of CC on es-
trogen-dependent tissues such as the cervical gland
and the endometrium (l-3).
Despite these adverse effects, CC therapy is so
simple and noninvasive that it is widely adminis-
tered to normally ovulatory women with the expecta-
tion of inducing multiple ovulation and increasing
the chances of conception relative to a spontaneous
cycle (4).
Received March 31, 1997; revised and accepted July 22, 1997.
Reprint requests: Shunsaku Fujii, M.D., Department of Obstet-
rics and Gynecology, Hirosaki University School of Medicine,
Zaifu-cho 5, Hirosaki, Aomori 036, Japan (FAX: 81-172-37-6842).
The purpose of this study was to assess whether
administration of CC to normally ovulatory women
is beneficial.
MATERIALS AND METHODS
Patients
Between April 1995 and March 1997,525 patients
were examined for infertility at Hirosaki University
Hospital and 33 patients were recruited for the
study. The study was approved by the ethics commit-
tee of Hirosaki University School of Medicine, and
all subjects provided written informed consent.
Patients who had been infertile for <2 years were
also included. The infertility evaluation consisted of
hormonal assays, including a LH-RH loading test and
a thyrotropin-releasing hormone (TRH) loading test,
confirmation of tubal patency (hysterosalpingography
and/or laparoscopy), a postcoital test, assessment of
ovulation by transvaginal ultrasound (US), endome-

0015-0282/97/$17.00 997
PI1 s0015-0282(97)00394-4
trial dating, and detection of serum progesterone level Table 2 Outcomes of Groups
at midluteal phase, and semen analysis according to
CC cycle Spontaneous cycle P
the World Health Organization criteria of 1992. The Variable (n = 18) (n = 15) value
LH-RH loading test and the TRH loading test were
No. of cycles observed 3.7 t 1.6 3.5 2 1.9 NS
performed in the morning to avoid the influences of No. of cycles until pregnancy 2.6 2 1.7 2.9 L 1.8 NS
exercise and diet. All patients recruited for the study No. of pregnancies/total no.
of patients (%) 4/18 (22.2) 11/15 (73.3) <0.005
had regular ovulatory cycles, and unexplained infertil- No. of pregnancies/total no.
ity was diagnosed in all cases. of cycles (%) 4/66 (6.1) 11/52 (21.2) <0.05
No. of abortions/total no. of
The selection of patients to whom the CC would pregnancies (%) l/4 (25.0) 3/11 (26.7) NS
be administered was determined by the patient’s No. of live births/total no. of
pregnancies (%) 314 (75.0) S/11 (73.3) NS
identification number. Patients with odd identifica-
tion numbers (n = 18) were chosen for CC-treated Note: Values are means ? SD unless otherwise indicated. NS = not
cycles, and patients with even identification num- significant.

bers (n = 15) were chosen for spontaneous cycles.

Study Cycles were confirmed in more than two cycles, CC adminis-

tration was stopped and observation of the patient
The CC-treated patients were prescribed 50 mg of
was terminated. The cycles before CC was discon-
the drug on days 5-9 of the menstrual cycle. All
tinued were included in the analysis.
patients in both groups attended clinic l-2 days be-
A clinical pregnancy was confirmed by an US visu-
fore the expected day of ovulation, as determined by
alization of a gestational sac or histologic evidence
their past few cycles.
of a trophoblast.
To estimate the day of ovulation, follicular develop-
ment and the endometrial thickness as determined
Statistics
by a transvaginal US, cervical mucus scores, and the
presence of an LH surge by urinary LH-kit (Gold-sign Results were analyzed by an unpaired t-test for
LH, Morinaga Nyugyo, Japan) were evaluated. If the comparison between two groups, Fisher’s exact test
mean diameter of the dominant follicles was z 18 mm for comparison of proportion, and Kaplan-Meier
or if the urinary LH was positive, 10,000 IU of hCG tests for comparison of cumulative pregnancy rates.
(hCG-Mochida; Mochida, Tokyo, Japan) was adminis- P <0.05was considered statistically significant.
tered IM to induce ovulation.
Sexual intercourse or treatment by IUI was timed RESULTS
to occur within 24 hours after confirmation of a posi-
The age, body mass index (BMI), and period of
tive urinary LH or hCG administration. Intrauterine
infertility were similar for both groups. Clinical di-
insemination was performed with the husband’s
agnoses, causes of infertility, and therapeutic meth-
sperm prepared with use of an 80% Percoll gradient
ods were similar for both groups (Table 1). In the
or by a swim-up technique. The luteal phase was
CC group, seven patients stopped taking CC and
supported by 10,000 IU of hCG on the seventh day
observations were terminated because of the marked
after ovulation.
antiestrogenic effects by CC. The mean number
If antiestrogenic effects, such as the decrease of
(&SD) of cycles until CC was discontinued was 3.7
cervical mucus or the thinning of the endometrium
2 2.1. The mean number of cycles observed and of
cycles until pregnancy were similar for both groups.
Table 1 Characteristics of 18 Infertile Patients Who Were
A total of 15 clinical pregnancies were obtained
Treated With CC and 15 Infertile Patients With during the observation period. The PR per patient
Spontaneous Cycles and the PR per cycle were significantly higher
cc cycle Spontaneous cycle P
(P<0.005 and P <0.05, respectively) in the sponta-
Variable (n = 18) (n = 15) V&e neous group than in CC group. The abortion rates
per pregnancy and the live birth rate per pregnancy
49 (Y) 31.4 + 5.2 31.4 2 2.8 NS
Body mass index 20.8 -c 2.2 21.4 2 1.9 NS was not significantly different between the two
Period of infertility (y) 4.8 2 3.2 3.7 5 1.8 NS groups (Table 2). Kaplan-Meier tests showed that
No. with diagnosis (%I NS
Primary infertility 13 (72.2) 11 (73.3) the cumulative pregnancy rate in the CC group was
Secondary infertility 5 (27.8) 4 (26.7) significantly lower than in the spontaneous group
No. with treatment (%) NS
Natural 13 (72.2) 11 (73.3) (P<0.05)(Fig. 1).
IUI 5 (27.8) 4 (26.7) In addition, five of seven patients who had discon-
Note: Values are means 2 SD unless otherwise indicated. NS = not
tinued CC became pregnant within a period of six
significant. spontaneous cycles after stoppage of CC. The mean

998 Fujii et al. CC effects on normally ovulatory women Fertility and Sterility@
s-
lrJG ..” ..-. spn~eo~
c -
gpJup
ccgroup Y,
6
8 ..
~ II
%
e ~ ._,.,...........
/
E xl-
I I
0 1 2 3 4 5
No. of cycles
Figure 1 The cumulative pregnancy rate for the spontaneous
group versus the CC group (P<O.O5).
number (+SD) of spontaneous cycles before concep-
tion was 2.6 ? 2.1.
DISCUSSION
In infertile patients with irregular menstrual cy-
cles, CC is useful to regulate cycles and to make it
easier to predict the day of ovulation. Clomiphene
citrate is recognized as a primary therapy for anovu-
latory infertility because CC is easy to use, inexpen-
sive, and has no major general side effects. Recently,
the applications for CC have expanded to include
infertile patients without ovulation disorders (5).
The purpose of CC treatments for normally ovula-
tory women has been to induce multiple ovulations
and to increase the chances of conception. The
expansion in the use of CC has allowed us to admin-
ister CC to infertile women without close investiga-
tion.
At the same time, a discrepancy apparently exists
between the ovulation rates and the PR in CC-
treated women. Various factors have been suggested
to account for this discrepancy. It has been well
known that CC sometimes causes adverse antiestro-
genie effects, e.g., a decrease in the quantity and
quality of cervical mucus (l-31, a thinning of the
endometrium (6, 7), or an increase in “out-of-date”
endometrium (8). Gelety and Buyalos (1) reported
that the incidence of an unfavorable cervical mucus
score is 48.1% in patients receiving 50 mg of CC. It
has also been reported that CC-induced cycles result
in a high incidence of chromosomal aberrations (9),
luteinizing unruptured follicles (lo), or subclinical
pregnancy loss (11).
We conducted this study because pregnancies
sometimes occur directly after discontinuation of CC
and the effects of administering CC to normally ovu-
latory women have remained unclear. As we could
not find a reliable study on this subject, we per-
formed this randomized study to investigate
whether the administration of CC to normally ovula-
Vol. 68, No. 6, December 1997
tory women is beneficial. There were statistically
significant differences in the PR per patient or the
..__............
1 PR per cycle between the CC group and the sponta-
neous group, and the cumulative pregnancy rate was
significantly decreased in the CC group as compared
I to the spontaneous group. These results suggest that
CC treatment has adverse effects in normally ovula-
tory women trying to achieve pregnancy.
It is noteworthy that five of seven CC-treated pa-
1 tients got pregnant within a period of six spontane-
6 7 8 ous cycles after administration of CC was stopped.
It will be necessary to continue a study recruiting
more patients with unexplained infertility.
In conclusion, administering CC to normally ovu-
latory women appears to be useless because of the
significant decrease in the PR per patient, the PR
per cycles, and the cumulative pregnancy rate.
Therefore, it is imperative that the causes of infertil-
ity be investigated before choosing a suitable thera-
peutic method. In addition, the effects of administer-
ing CC to women who are trying to get pregnant
should be thoroughly investigated.
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Fujii et al. CC effects on normally ovulatory women 999