Combined Letrozole and Clomid in Women With Infertility and PCOS

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.

Inclusion Criteria:

1. Willing to comply with all study procedures and be available for the duration of the
study

2. 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

3. Diagnosis of polycystic ovary syndrome based on Revised Rotterdam criteria

4. Ability to have regular intercourse during the ovulation induction phase of the study

5. 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:

1. Current pregnancy

2. 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

3. Other known cause of infertility: endometriosis, tubal factor, uterine abnormalities

4. Uncorrected thyroid disease

5. Untreated hyperprolactinemia.

6. Medical conditions in which avoiding pregnancy is recommended until under improved
control: poorly controlled Type 1 or Type 2 diabetes, poorly controlled hypertension

7. 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

8. Contraindications to letrozole: hypersensitivity to letrozole or any of its
components.

9. Use of medications known to affect reproductive function or metabolism or that are an
absolute contraindication during pregnancy within the past month.

10. 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).