Infertility Clinical Trial
Official title:
Extended Clomiphene Citrate Regimen Versus Laparoscopic Ovarian Drilling for Ovulation Induction in Clomiphene Citrate-resistant Women With Polycystic Ovary Syndrome
One hundred and thirty six anovulatory women with CC-resistant PCOS were scheduled randomly into two equal groups. Group A (n=68); received CC (100 mg/day from cycle day 3 for 10 days) for up to six cycles. Group B (n=68) underwent LOD and followed up for 6 months. The primary outcome was the ovulation rate in each group; secondary outcomes were midcycle endometrial thickness and serum estradiol, midluteal serum progesterone, and the rates of clinical pregnancy and abortion.
This prospective randomized trial included 136 anovulatory women with CC-resistant PCOS
among those attending the Gynecology Outpatient Clinics of, Benha University Hospital, and
private practice settings, Alkalubia, Egypt from August 2012 to August 2014. The study
protocol was approved by the Local Ethics Committee and written informed consents were
obtained before the study commenced. Diagnosis of PCOS was based on the Rotterdam criteria
(18), whereby diagnosis of PCOS require the presence of two of three criteria after the
exclusion of other etiologies, i.e., oligomenorrhea and/or anovulation, clinical and/or
biochemical signs of hyperandrogenism, and/or polycystic ovaries on ultrasound. Inclusion
criteria: 1- Age: between 18-35 years. 2- Period of infertility > 2 years. 3- Serum level of
FSH <10 U/L in the early follicular phase. 4- All women were CC-resistant PCOS, as they
failed to ovulate with a dose of CC of 150 mg/day for 5 days per cycle for at least three
consecutive cycles. 5- All women had patent Fallopian tubes proved by hysterosalpingography
or laparoscopy and their partners satisfied the normal parameters of semen analysis
according to the modified WHO criteria (19). Exclusion criteria: 1- Infertility due to
causes other than CC- resistant PCOS or due to combined factors. 2- Body mass index (BMI)
≥35 Kg/m². 3- The use of metformin, gonadotropins, hormonal contraception or diet regimen
within the last 6 months. 4- Women with congenital adrenal hyperplasia, hyperprolactinaemia
or abnormal thyroid function. 5- Hypersensitivity or contraindications to Letrozole or
clomiphene treatment. 6- Previous LOD. The study was started two months after last CC
treatment cycle to eliminate any post-treatment effect of CC.
At admission, a thorough evaluation of all participants was carried out via history taking
and physical examination, which included anthropometric measurements. A baseline
transvaginal ultrasound examination was done using 7-10 MHZ probe (Voluson 730 PRO V, GE
Healthcare, USA) to measure endometrial thickness and exclude any pelvic pathology before
treatment. Basal hormonal assays were performed on day 3 of the spontaneous or progestin
induced cycle and included measurement of the serum concentrations of luteinizing hormone
(LH), follicle-stimulating hormone (FSH), and testosterone.
Randomization was done according to a computer generated random numerical table into two
equal groups. Treatment allocation was concealed by using sequentially numbered opaque
sealed envelopes. Envelopes were opened consecutively by a third person (study nurse), who
assigned patients to the extended Clomiphene Citrate group (Group A) or LOD group (Group B).
Once allocated, the treatment was revealed to both the investigator and the patient. Group A
(n =68) assigned to receive100 mg of clomiphene citrate (Clomid®; Hoechst Marion Russel,
Cairo, Egypt) daily starting on day 3 of spontaneous or progestin induced cycle for 10 days.
Group B (n =68) underwent LOD. Laparoscopy was performed under general anesthesia, using
three-puncture technique. Each ovary was cauterized perpendicular to its antimesenteric
border at four points, each for 4 seconds at 40 W with a mixed current, using a monopolar
electrosurgical needle (Karl Storz, ND, Germany). Each puncture was about 4 mm in diameter
and 6-8 mm in depth. The ovary was cooled by irrigation with normal saline solution. Any,
intraoperative or postoperative complication was reported. The follow-up was started from
the next cycle after ovarian drilling up to 6 months.
Starting from cycle day 9, ultrasound scans were repeated daily to monitor follicle growth
(number and mean diameter). Ultrasound examination was done by the same doctor to avoid
interobserver variability and he was blinded to the treatment groups. When the optimal
follicle size was reached (i.e. mean follicular diameter ≥ 18 mm), HCG 10,000 IU (Epifasi,
EPICO, Egypt) was given intramuscular to trigger ovulation. No HCG was given and protected
sexual intercourse was advised, if there were ≥ 3 follicles with a diameter ≥16mm to avoid
the risk of ovarian hyperstimulation syndrome and multiple gestations. Intrauterine
insemination was performed 36 - 40 hours after HCG injection using soft tip catheter.
Serum E2 and the endometrial thickness were measured on the day of HCG administration. The
endometrial thickness was measured in a sagittal plane in the fundus of the uterus (point of
maximal thickness) from the echogenic interface at the junction of the endometrium and
myometrium Ovulation was confirmed when midluteal (day 21of the cycle) serum progesterone
was ≥ 5 ng/mL. Serum β-hCG was determined 2 weeks after HCG injection for diagnosis of
biochemical pregnancy. Sonographic evidence of an intrauterine gestational sac at 6 weeks
gestation was considered an evident of a clinical pregnancy.
Treatment continued for up to six months. Patients were counseled for further lines of
treatment if there was no ovulation as confirmed by midluteal serum progesterone level less
than 5 ng /ml within 3 months.
The primary outcome was the ovulation rate in each group. Secondary outcomes were the
endometrial thickness and serum estradiol (pg/ml), on the day of the hCG injection,
midluteal serum progesterone (ng/ml) and the rates of clinical pregnancy and first trimester
spontaneous abortion. The ovulation rate was calculated as the percentage of ovulatory
cycles per total observed cycles. The cumulative pregnancy rate was defined as the number of
pregnant patients to the total number of patients. The abortion rate was defined as the
percentage of miscarriage during the first 12 weeks of gestation per total pregnancies,
while the biochemical miscarriage was considered if pregnancy loss occurred in any confirmed
biochemical pregnancy without ultrasound evidence of intrauterine pregnancy.
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Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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