Cabergoline & Letrozole Versus Letrozole in Ovulation Induction in PCOS

After obtaining approval of Institutional Review Board, this RCT will be conducted. Women with polycystic ovary syndrome wants fertility, attending the OPD of Reproductive Endocrinology and Infertility department at BMU will be the study population.

After fulfilling the inclusion and exclusion criteria participants will be allocated to experimental group ( group A : combined cabergoline and letrozole) or comparator group( group B : letrozole only). Randomization will be done between group A and group B. The random sequence generation will be done by permuted blocks randomized with computer generated random numbers. Allocation concealment will be done by serially numbered opaque sealed envelope. Each envelop will be labeled with a serial number and will have a card inside noting the intervention type. Allocation will never be changed after opening the closed envelops.

First Cycle :

Purpose and procedure of study will be discussed with the participant and informed written consent (Appendix II) will be obtained to participate in the study. Detailed socio-demographic data, history, clinical examination and investigations will be recorded in a predesigned data sheet.

Treatment will be started from the 2nd day of menstruation/withdrawal bleeding after the baseline visit and investigations. Experimental group participants will receive tab cabergoline 0.5 mg (1 tablet at night) on day 2 and day 9 of cycle plus letrozole 5 mg/day ( 2 tablet at night)for consecutive 5 days starting from the day 2 of menstrual cycle or withdrawal bleeding. Participants in the comparator group will receive only letrozole 5 mg/day (2 tablet at night) for consecutive 5 days starting from the day 2 of menstrual cycle or withdrawal bleeding. All participants will be instructed not to take any medications during the trial except after consultation with primary investigator.

Ovarian response of both groups will be assessed by transvaginal monitoring of follicle growth(presence of pre ovulatory follicles \& largest follicle size) on12th day of cycle done by same operator. Responders will be defined as participants who will develop pre ovulatory follicles of ≥ 14 mm. The participants will then be advised to test for ovulation by urinary LH kit daily until positive. She will inform the investigator over cellphone and will do timed intercourse next two days. Confirmation of ovulation will be done by measuring mid-luteal (day 21) serum progesterone measurement.She will again come to our department for serum progesterone estimation and then I will collect 5ml of blood in EDTA mixed test tube at morning time \& will send it to biochemistry lab for estimation. Serum progesterone ≥ 3 ng/ml will be considered as ovulation. At least four follow up visits will be needed each month, one visit for baseline assessment, one for ovulation induction, one visit for folliculometry and one for serum progesterone estimation to confirm ovulation. Further visits will be needed after missed period for serum β-hCG estimation for confirmation of pregnancy. If pregnancy test is positive she will do an USG for fetal cardiac motion around 7-8 weeks.

Second cycle :

Assessment of clinical profile, compliance with drug and side effects. If participant can tolerate Experimental group will receive tab cabergoline 0.5 mg 1 tablet at night on day 2 and day 9 of cycle plus letrozole 5 mg/day(2 tablet at night) for consecutive 5 days starting from the day 2 of menstrual cycle Comparator group will receive only letrozole 5 mg/day ( 2 tablet at night) for consecutive 5 days starting from the day 2 of menstrual cycle Further procedure will follow as same as first cycle. If participant cannot tolerate ,will be considered as drop out.

Third cycle :

Assessment of clinical profile, compliance with drug and side effects If participant can tolerate Experimental group will receive tab cabergoline 0.5 mg 1 tablet at night on day 2 and day 9 of cycle plus letrozole 5 mg/dayat night for consecutive 5 days starting from the day 2 of menstrual cycle Comparator group will receive only letrozole 5 mg/day at night for consecutive 5 days starting from the day 2 of menstrual cycle Further procedure will follow as same as first cycle. If participant can not tolerate ,will be considered as drop out.

For each and every subject separate clinical record form will be prepared. Data will be collected from the patients on different visits on variables of interest using interview, observation, clinical examination, investigations and from the history sheet of the patients. The cumulative data will be subjected to analysis.

• Presence of preovulatory follicle on D12 of cycle [Time frame: assessed by TVS within 12 days after each ovulation induction cycle ,upto 12 weeks]
• Largest follicle size on D12 of cycle [Time frame: Assessed by TVS,within 12 days of each ovulation induction cycle ,upto 12 weeks]
• Pregnancy [Time frame: assessed if missed period occur after each ovulation induction cycle ,for upto 12 weeks]