Trial Information

Letrozole Versus Clomiphene Citrate Plus Metformin in the First Treatment of Infertility in Patients With Polycystic Ovarian Syndrome

The study will be in 200 patient diagnosed to have PCOS among those attending the Fertility
Outpatient Clinic at the Women's Health Center, Assiut University Hospitals.

The present study was prospective randomized controlled trial conducted over a period of 3
years from 1st of January 2009 to 1st of January 2012, at the Women's Health Center, Assiut
University hospital, Assiut, Egypt, after approval was received from the Ethics Committee of
faculty of medicine , Assiut University. Women referred to the infertility clinic in women's
health center were screened for PCO using Rotterdam consensus criteria for the diagnosis of
PCOS. The patients who were newly diagnosed as PCO and not treated previously were invited
to participate in our study. Written informed consent was obtained from each participant
after an information sheet had been provided. The patients had the right to refuse
participation in the study or to withdraw at any time without being denied their full
regular clinical care. All personal information and medical data were confidential and were
not made available to third parties. All participants met the Rotterdam consensus criteria
for the diagnosis of PCOS. At admission, a thorough medical history was taken and all women
underwent physical examination, which included anthropometric measurements and after
spontaneous menstruation or progestin induced withdrawal bleeding, basal endocrine
evaluation on day 3 of the cycle included measurement of the serum concentrations of
luteinizing hormone (LH), follicle-stimulating hormone (FSH),thyroid stimulating hormone(TSH
) and prolactin. Then vaginal sonographic examination were done to measure endometrial
thickness and exclude cases endometrial pathology or baseline ovarian cysts.

The participants were randomized to receive letrozole or clomiphene citrate plus metformin.
Randomization was performed using a computer-generated random numbers table, and allocation
concealment was achieved using serially numbered opaque envelopes that were only opened once
the interventions were assigned.

In the letrozole group, the ovaries were stimulated using 2.5mg/day letrozole (Femara;
Novartis Pharma, Basel, Switzerland) for 5 days,in the form of one tablet( 2.5 mg) per day
for 5 days from day 3 to day 7 of the menstrual cycle and if ovulation has occurred with
no pregnancy continue on the same dose for another 2 consecutive cycles ,but if no
ovulation increase the dose to 2 tablets per day(5 mg) for another 2 consecutive cycles in
the same manner .

The patients in the second group will take metformin (Cidophage tablets,500 mg per tablet;
CID, ARE, in an oral dose of 1,500 mg/d) 500mg three times daily for 3 months Plus
clomid(50-mg tablets twice daily; Global Napi Pharmaceuticals, Cairo, Egypt , Arab Republic
of Egypt) In the form of 50 mg twice daily (100mg /day) for 5 days from day 3 to day 7 of
menstrual cycle and to be repeated for 3 consecutive cycles in the same manner if no
pregnancy occur.

In both groups, endometrial thickness and mean follicular diameter were assessed by the same
investigator using transvaginal ultrasound on days 2 ,10, 12, and 14 of the menstrual
cycle, and 10 000 IU of human chorionic gonadotropin (hCG) (Pregnyl; Organon, Oss, The
Netherlands) were injected intramuscularly if there was at least 1 leading follicle
measuring 18 mm or more in diameter and endometrial thickness detected at that
time(endometrial thickness was determined at the greatest diameter perpendicular to the
midsagittal plane in the fundal region, including both layers of the endometrium). All
participants were advised to have intercourse 24-36 hours after the hCG injection. Two days
after being given Human chorionic gonadotropin, the patients were assessed for signs of
ovulation (disappearance of preovulatory follicle, fluid in the cul-de-sac, and/or corpus
luteum formation). Pregnancy will be diagnosed when positive pregnancy test in urine done or
a gestational sac was detected on transvaginal ultrasound examination 1week after the missed
period or serum β-hCG concentration 14 days after HCG injection if menses had not occurred.
A biochemical pregnancy was considered when the serum β-hCG concentration was 50 mIU/mL or
more in the absence of menstruation. All study medication were stopped when there was
positive pregnancy test.Pregnant patients then will be followed up until an ultrasound could
document the viability of pregnancy. A clinical pregnancy was defined as the presence of a
gestational sac with a beating fetal heart on transvaginal ultrasound. A spontaneous
abortion was defined as the spontaneous loss of a pregnancy before the end of the 20th week.