Combined Letrozole and Clomid in Women With Infertility and PCOS

Phase 4

Completed

Brief Summary: This study evaluates the addition of clomid to letrozole for the treatment of infertility in women with polycystic ovary syndrome. Half of the participants will receive letrozole and clomid in combination, while the other half will receive letrozole alone.

Detailed Description: Letrozole and Clomid are both used for ovulation induction, but they have different mechanisms of action. Letrozole has been shown to be superior to clomid in achieving live birth rates in women with infertility and polycystic ovary syndrome. However, the combination of these medications has not been studied. This is a pilot study to evaluate if the combination treatment has improved efficacy as measured by ovulation rate.

This is a randomized controlled trial of letrozole versus letrozole and clomiphene citrate (CC) for one menstrual cycle. Women will be randomized in a 1:1 ratio to receive letrozole 2.5 mg or combination of letrozole 2.5 mg and clomiphene 50 mg for 5 days on days 3-7 of menstrual cycle. The women and their partners will be instructed to have regular intercourse with the intent to conceive during the cycle. Patients will have an transvaginal ultrasound mid cycle and to evaluate number of follicles (\>15 mm), follicle size, endometrial thickness and pattern. Patients will have mid- luteal phase progesterone level drawn to evaluate ovulation. Side effect profile will also be monitored.

Recruitment & Eligibility

Inclusion Criteria

Willing to comply with all study procedures and be available for the duration of the study
Diagnosis of infertility: Inability of couple to achieve successful pregnancy after 12 months of regular timed unprotected intercourse in women less than 35 years of age; and after 6 months of regular intercourse without use of contraception in women 35 years and older
Diagnosis of polycystic ovary syndrome based on Revised Rotterdam criteria
Ability to have regular intercourse during the ovulation induction phase of the study
Normal sperm concentration of 15 million/mL and with normal motility of > 40% according to World Health Organization cutoff points, in at least one ejaculate during the previous year

Exclusion Criteria

Current pregnancy
Current use of hormonal contraception; use of any type of combined contraceptive or oral progestins within the past month; or use of hormonal implants or depo progestins within the past 3 months
Other known cause of infertility: endometriosis, tubal factor, uterine abnormalities
Uncorrected thyroid disease
Untreated hyperprolactinemia.
Medical conditions in which avoiding pregnancy is recommended until under improved control: poorly controlled Type 1 or Type 2 diabetes, poorly controlled hypertension
Contraindications to clomiphene citrate: hypersensitivity to CC or any of its components, history of liver disease or known liver disease, unknown cause of abnormal uterine bleeding, or intracranial lesion
Contraindications to letrozole: hypersensitivity to letrozole or any of its components.
Use of medications known to affect reproductive function or metabolism or that are an absolute contraindication during pregnancy within the past month.
If patients are suspected based on clinical findings for other etiologies that mimic PCOS, work up must be completed to exclude other etiologies prior to enrollment (i.e. Cushing's syndrome, androgen-secreting tumor).

Arm && Interventions

Group	Intervention	Description
Letrozole	Letrozole	Letrozole 2.5 mg orally for 5 days on cycle days 3-7
Letrozole + Clomiphene	Letrozole	Letrozole 2.5 mg orally for 5 days on cycle days 3-7 AND Clomid 50 mg orally for 5 days on cycle days 3-7
Letrozole + Clomiphene	Clomiphene	Letrozole 2.5 mg orally for 5 days on cycle days 3-7 AND Clomid 50 mg orally for 5 days on cycle days 3-7

Primary Outcome Measures

Name	Time	Method
Number of Participants Achieving Ovulation Measured by Mid-luteal Progesterone Level	7 days following LH surge or at cycle day 21 if no LH surge was detected	Ovulation: mid-luteal progesterone \> /=3 ng/mL. No ovulation: mid-luteal progesterone \<3ng/mL.

Secondary Outcome Measures

Name	Time	Method
Number of Developing Follicles	Cycle day 12-14	Number of follicles measuring \> 10mm on ultrasound
Size of Largest Developing Follicle	Cycle day 12-14	Size of largest follicle on ultrasound
Endometrial Thickness	Cycle day 12-14	Thickness of endometrial lining assessed by ultrasound
Conception	5 weeks after treatment	Conception: a positive serum or urinary test of hCG; No conception: Neither a positive serum or urinary test of hCG
Clinical Pregnancy	6-7 weeks after treatment	Clinical Pregnancy: an intrauterine pregnancy with fetal heart motion determined by ultrasonography; No Clinical Pregnancy: no intrauterine pregnancy with fetal heart motion determined by ultrasonography
Multiple Gestation	9-10 months after treatment	Multiple Gestation: an intrauterine pregnancy with multiple fetal heart rates determined by ultrasonography; No Multiple Gestation: either no intrauterine pregnancy, or an intrauterine pregnancy with a single fetal heart rate determined by ultrasonography
Live Birth	9-10 months after treatment	Live Birth: delivery of a live infant; No Live Birth: no delivery of a live infant
Pregnancy Loss	9-10 months after treatment	Pregnancy Loss: any pregnancy loss including biochemical pregnancy, ectopic pregnancy, and miscarriage; No Pregnancy Loss: no pregnancy loss including biochemical pregnancy, ectopic pregnancy, or miscarriage.