Extended Clomiphene Citrate Regimen in Women With Polycystic Ovary Syndrome
Condition: Infertility
MeSH terms: Polycystic Ovary Syndrome; Infertility
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): clomiphene citrate; laparoscopic ovarian drilling (LOD)
Intervention type(s): Drug; Procedure
Intervention description(s): 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.; Laparoscopy was performed under general anesthesia, using three-puncture technique
Other intervention name(s): Clomid
Intervention MeSH terms: Clomiphene; Enclomiphene; Zuclomiphene
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment