Background A common cause of anovulation is polycystic ovarian syndrome (PCOS). Clomiphene citrate (CC) is the first line of treatment in PCOS patients however approximately 25% of patients may be CC-resistant. This study aimed to evaluate the efficacy of adding dexamethasone (dex) to CC in CC-resistant PCOS patients with the intent to improve ovulation. Materials and Methods This randomized controlled trial study was performed on 60 infertile PCOS patients referred to our infertility research center from 2007 to 2009. Patients were randomly divided in two groups and stimulation performed with dex+CC or CC+placebo. Rates of ovulation, pregnancy and number of mature follicles were evaluated. Results Ovulation rate in the dex+CC group was 21 out of 30 (70%) and in the CC+placebo group it was 17 out of 30 (56.7%). The pregnancy rate was 5 (16.7%) in the dex+CC group and 3 (10%) in the CC+placebo group. There was no significant difference between rates of ovulation and pregnancy in both groups, but the number of follicles ≥18 mm were significant in the dex+CC group (p < 0.05). Conclusion Our results showed that addition of dex to CC significantly increased the number of matured follicles, however the ovulation and pregnancy rates were comparable between the two groups (Registeration Number: IRCT 138807041760 N2).
Polycystic ovarian syndrome (PCOS) has multiple
reproductive, metabolic and cardiovascular
components, with health implications across a
woman’s life span (1). Approximately 75% of
these women suffer from infertility due to anovulation
(2). The first line of treatment to induce
ovulation is Clomiphene citrate (CC) (3,
4) but about 20% of CC-treated women that fail
to ovulate are considered to be CC-resistant (5)
Although ovulation induction with gonadotropin
is successful in these patients (6), it is expensive
and extensive monitoring is necessary
because of the high sensitivity of polycystic
ovaries to exogenous gonadotropin, with a high
risk of ovarian hyperstimulation, cycle termination,
multiple pregnancies and abortion (7). Surgical
therapy with laparoscopic ovarian drilling
(LOD) may reduce the need for gonadotropins
but it is an invasive surgery with complications
(8). If anovulation persists or pregnancy does
not occur at a dosage level of 150 mg per day,
other medications may be added to the regime
to induce ovulation (9). There are a few limited
adjunctive therapies that can be attempted
before gonadotropin therapy or surgical intervention,
such as the use of corticosteroids (10).
Addition of oral dexamethasone (dex) to clomiphene
therapy has been advocated to improve
the chances of ovulation and pregnancy (10,
11) without any described side effects or serious
sequelae (12). Glucocorticoids may positively
affect GnRH pulsatility and increase follicle
stimulating hormone (FSH) release. This
effect causes the suppression of corticotrophin
releasing factor (CRF), which normally suppresses
GnRH release. Besides, glucocorticoids
reduce the level of circulating adrenal androgens
and thus release the ovary from inhibitory
androgenic affects (13, 14). Azziz et al. found
no differences in ovulatory response to dex
therapy between women with and without dehydroepiandrosterone sulfate (DHEAS) excess
(15). Parsanezhad et al. have reported improved
hormonal levels, follicular development and cumulative
pregnancy rates with the addition of
dex to CC in CC-resistant patients with PCOS
and normal DHEAS (16). Elnashar et al. noted
that the mean number of follicles >18 mm at the
time of human chorionic gonadotropin (hCG)
administration was significantly higher in the
dex group (high dose, short course) than the placebo
group (17).
There is a lack of studies in Iran on PCOS CCresistant
treatment modalities. A number of PCOS
CC-resistant patients that have referred to our
PCOS clinic in Babol, Northern Iran encouraged
us to investigate different types of dex treatment as
a cost effective drug.
This study aimed to evaluate the efficacy of adding
dex to CC in CC-resistant PCOS patients with the
intent to improve ovulation.
Materials and Methods
A total of 60 infertile women entered this randomized,
triple-blind placebo-controlled trial
study. Enrolled patients attended the Fatemeh-
Zahra Infertility and Reproductive Health Research
Center of Babol, Iran from 2008 to 2010.
Research Ethics Committee (REC) of Babol
University of Medical Science approved this
study. Following a description of the study, all
patients who agreed to participate signed informed
consents. Patients were diagnosed as
having PCOS according to the Rotterdam criteria
(18). Patients between the ages of 18 and
35 years, with a period of infertility >1/5 years
and normal DHEAS levels entered the study.
Patients diagnosed with hyperprolactinaemia,
or thyroidism, had a pelvic pathology or surgery,
or infertility factor other than anovulation
were excluded. All patients had previously received
CC and were diagnosed as CC-resistant
(failure of ovulation after three cycles of CC
that reached a dose of 150 mg daily from the
third to seventh cycle day). Patients underwent
no treatments during the previous three months
prior to the dex treatment. Sample size was calculated
by S-plus, version 2000 software. Patients
were randomly assigned to receive CC
and either dex or a placebo using a computergenerated
sequence concealed from the study
participants. Samples were blinded for the data
collector, patients, the doctor and a nurse who
administered the drugs.
The two groups were matched for age, duration
of infertility and body mass index (BMI).
Each patient had only one treatment cycle. All
patients underwent induction ovulation as follows:
on day 3, each had a baseline ultrasonographic
examination (Mylab40, Esaote, Italy).
Clomiphene citrate (Iran Hormone, Tehran,
Iran), 100 mg, was given from days 3 until 7.
Patients were then divided in two equal groups.
In addition to CC, from days 5 to 14 of their
cycles, each patient was randomly selected to
receive the following: i. oral dex (Dexamethasone
0.5 mg, Tamin, Iran), 2 mg/day, in two divided
doses (group I), or ii. folic acid 1 mg/day
orally as placebo (group II). We choose dex 2.0
mg (high dose) because of the lack of side effects
and was more effective than 0.5 mg, according
to Beck (11). Transvaginal ultrasound
examination was performed the following day
after the end of CC and every other day according
to follicular size. hCG 10000 IU (Pregnyl;
Darou Pakhsh, Iran) was given intramuscularly
when at least one follicle measured 16-18 mm.
At 24–38 hours after hCG injection, timed intercourse
was advised. Two days after receiving
hCG, patients were assessed for signs of
ovulation (fluid in the cul-de-sac or corpus luteum
formation, or disappearance of dominant
follicle). Clinical pregnancy was diagnosed
when a gestational sac was detected on transvaginal
ultrasound examination 25 days after
hCG administration. Follicular development,
hormonal status, ovulation rate and pregnancy
rate were calculated.
Statistical analysis
Fisher’s exact test, t test, Chi-square and Mann
Whitney were used to analyze the data. P value of
<0.05 was considered significant.
Results
This study enrolled 60 PCOS patients. The numbers
of participants randomly assigned were 30
in each group. No patients withdrew from the
study after randomization.
Rates of ovulation and pregnancy were not significantly
higher in the dex + CC group compared
to the CC + placebo group, but the mean
number of follicles ≥18 mm were significantly
higher.
Also, as summarized in table 1, in a comparison
of the CC+placebo group and dex+CC group,
no significant differences with regards to age,
period of infertility, BMI, hirsutism, menstrual
regulation and hormonal levels were noted.
Dexamethasone was well tolerated and no patients
reported any side effects.
Demographic criteria and clinical outcomes in CC and dex groups
Variable
CC+Placebo (n=30)
Dex+CC (n=30)
Age (years)
23.1 ± 3.45
24.8 ± 3.56
Duration of infertility (years)
3.15 ± 1.45
2.98 ± 1.85
BMI (Kg/m2)
27.1 ± 2.96
27.56 ± 3.28
LH (IU/L)
5.68 ± 3.68
7.07 ± 3.98
FSH (IU/L)
4.81 ± 2.64
5.7 ± 3.29
Irregular Menstruation
22 (73.3%)
23 (76.7%)
Hirsutism
18 (60%)
22 (73.3%)
Ovulation rate
17 (56.7%)
21 (70%)
Number of Follicles >18mm
0.93 ± 1.04
1.8 ± 1.4*
Pregnancy rate
3 (10%)
5 (16.7%)
The values in above table are presented as Mean ± SD and n (%)
* Significant (p<0.05)
Discussion
Addition of dex to CC increased the number of mature
follicles in our study but ovulation and pregnancy
rates were comparable in the two groups.
In a Parsanezhad et al. study on 230 patients,
the ovulation rate was significantly higher in the
dex+CC group when compared to the CC alone
group. The pregnancy rate was also higher. Both
groups were treated for up to six cycles (17). The
dose and days of dex in our study was approximately
the same as the above study, although
their dose of CC was higher (200 mg). Another
difference was the sample size and number of
treatment cycles. Also, in a study by Elnashar et
al. (17), 80 patients were divided in two groups
and matched for age, duration of infertility and
BMI. The ovulation and pregnancy rates in their
dex group showed significant results which were
comparable to the Parsanezhad study, although
the dose of CC (100 mg) and the treatment days
with dex were less (five days) than the current
study and Parsanezhad (16). They treated patients
for only one cycle, as with our study, but a study
by Ashrafi et al. showed no significant statistical
difference in the number of retrieved oocytes and
transferred embryos in the dex group compared to
the placebo group in patients over 35 years of age
(19). Hence we are more in agreement with Lord
et al. that have suggested that the place for glucocorticoids
in therapy as well as CC has yet to
be established by further study and is still under
discussion. A well-designed randomized controlled
trial study is needed to clarify the value of
various days of dex therapy in women (20). Further
evaluation is needed to clarify whether it is
worthwhile to add dex to CC for the stimulation
of follicular development, ovulation and pregnancy
in CC-resistant PCOS before gonadotropins
or not. To clarify, further studies comparing
the various regimens (dose, days and treatment
cycles of dex) are required. One limitation to our
study was the lack of progesterone measurements
to assist with confirmation of ovulation.
Conclusion
Addition of dex to CC enhances the number of
mature follicles significantly but the ovulation and
pregnancy rate is comparable to CC alone.
Esmaeilzadeh, S., Amiri, M. G., Basirat, Z., & Shirazi, M. (2011). Does Adding Dexamethasone to Clomiphene Citrate Improve Ovulation in PCOS Patients? A Triple - Blind Randomized Clinical Trial Study. International Journal of Fertility and Sterility, 5(1), 9-12.
MLA
Seddigheh Esmaeilzadeh; Masoumeh Golsorkhtabar Amiri; Zahra Basirat; Mahin Shirazi. "Does Adding Dexamethasone to Clomiphene Citrate Improve Ovulation in PCOS Patients? A Triple - Blind Randomized Clinical Trial Study". International Journal of Fertility and Sterility, 5, 1, 2011, 9-12.
HARVARD
Esmaeilzadeh, S., Amiri, M. G., Basirat, Z., Shirazi, M. (2011). 'Does Adding Dexamethasone to Clomiphene Citrate Improve Ovulation in PCOS Patients? A Triple - Blind Randomized Clinical Trial Study', International Journal of Fertility and Sterility, 5(1), pp. 9-12.
VANCOUVER
Esmaeilzadeh, S., Amiri, M. G., Basirat, Z., Shirazi, M. Does Adding Dexamethasone to Clomiphene Citrate Improve Ovulation in PCOS Patients? A Triple - Blind Randomized Clinical Trial Study. International Journal of Fertility and Sterility, 2011; 5(1): 9-12.