Pregnancy in Polycystic Ovary Syndrome II

Preliminary data are promising for the use of letrozole to induce ovulation in infertile
women with PCOS. However the true magnitude of the effect of letrozole is difficult to
discern from prior studies. Therefore we intend to determine the safety and efficacy of
letrozole, an aromatase inhibitor, compared to clomiphene citrate, a selective estrogen
receptor modulator, in achieving live birth in infertile women with PCOS.

Treatment- After progestin withdrawal, 750 women will be equally randomized to two different
treatment arms: A) clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), or B)
letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20
weeks. Dose will be increased in subsequent cycles in both treatment groups for non-response
or poor ovulatory response up to a maximum of 150 mg of clomiphene a day (x 5 days) or 7.5 mg
of letrozole a day (x 5 days).

Statistical Analysis- The primary analysis will use an intent-to-treat approach to examine
differences in the live birth rate in the two treatment arms.

Anticipated time to completion- A total of 4 years will be required to complete the study
after start up; 31 month enrollment period, 5 month treatment period, with 9 month additional
observation to determine pregnancy outcomes. This will be accomplished by enrolling ~3.45
women with PCOS per center per month over the enrollment period (N = 7 RMN sites).

Inclusion Criteria:

Key Inclusion Criteria (Must have ovulatory dysfunction and either hyperandrogenism or PCO)

1. Chronic anovulation or oligomenorrhea: defined as spontaneous intermenstrual periods
of ≥45 days or a total of ≤8 menses per year, or for women with suspected anovulatory
bleeding, a midluteal serum progesterone level < 3 ng/mL is indicative of chronic
anovulation. For women who have been on ovarian suppressive therapy or other
confounding medication (i.e. insulin sensitizing agents) within the last year prior to
the study, a history of ≤8 menses per year prior to the initiation of this prior
therapy will qualify as evidence of oligomenorrhea. For women with more regular
bleeding patterns, but who are suspected to be experiencing anovulatory bleeding, a
midluteal progesterone level < 3ng/mL will be evidence of ovulatory dysfunction and
qualify as anovulation. Undiagnosed persistent vaginal bleeding should be diagnosed
and treated prior to enrollment.

2. Hyperandrogenism (either Hirsutism or Hyperandrogenemia) or Polycystic Ovaries on
Ultrasound:

1. Hirsutism is determined by a modified Ferriman-Gallwey Score >8 at screening exam
(Hatch, Rosenfield et al. 1981 Aug 1). Subjects who have hirsutism do not need
local or core labs documenting elevated androgen levels.

2. Hyperandrogenemia can be determined from local labs. Local cutoffs will be
pre-determined by each site prior to study initiation. Hyperandrogenemia will be
defined as an elevated total testosterone, or free androgen index (FAI)(in our
lab at Penn State College of Medicine a total T > 50 ng/dL or a free androgen
index >5) will allow entry into the study (Legro, Driscoll et al. 1998). The FAI
is calculated from measurable values for total T and SHBG, as previously
described (Miller, Rosner et al. 2004), using the following equation: (FAI =
Total testosterone in nmol/L / SHBG in nmol/L) X 100. Outside lab values obtained
within the last year documenting elevated T or FAI levels are sufficient to meet
criteria of hyperandrogenemia.

3. Polycystic Ovaries on Ultrasound: We will use the revised Rotterdam criteria for
diagnosing polycystic ovaries (Balen, Laven et al. 2003). PCO will be defined as
either an ovary that contains 12 or more follicles measuring 2-9 mm in diameter,
or an increased ovarian volume (> 10 cm3) on one ovary for entry into the study.
If there is a follicle > 10 mm in diameter, the scan should be repeated at a time
of ovarian quiescence in order to calculate volume and area if the subject does
not otherwise qualify for the study. The presence of a single polycystic ovary
(PCO), either by volume or morphology, is sufficient to provide the diagnosis.

Exclusion Criteria:

We will exclude subjects with medical conditions that represent contraindications to CC,
aromatase inhibitors and/or pregnancy or who are unable to comply with the study
procedures. We will exclude subjects with poorly controlled Type I or Type II diabetes;
undiagnosed liver disease or dysfunction (based on serum liver enzyme testing); renal
disease or abnormal serum renal function; significant anemia; history of deep venous
thrombosis, pulmonary embolus, or cerebrovascular accident; uncontrolled hypertension,
known symptomatic heart disease; history of or suspected cervical carcinoma, endometrial
carcinoma, or breast carcinoma; undiagnosed vaginal bleeding, and use of other medications
known to affect reproductive function or metabolism (e.g., OCP, GnRH agonists and
antagonists, antiandrogens, gonadotropins, anti-obesity drugs, somatostatin, diazoxide, ACE
inhibitors, and calcium channel blockers). As in PPCOS we will allow a 2 months washout
period for subjects who desire to participate and discontinue exclusionary medications
(most commonly OCP, but also possibly metformin), and a period of observation or treatment
for correctable conditions.

Couple Inclusion Criteria

1. Sperm concentration of 14 million/mL in at least one ejaculate within the last year,
with at least some motile sperm.

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

3. At least one patent tube and normal uterine cavity as determined by sonohysterogram,
hysterosalpingogram, or hysteroscopy/laparoscopy within the last 3 years. An
uncomplicated intrauterine non-IVF pregnancy and uncomplicated delivery and postpartum
course resulting in live birth within the last three years will also serve as
sufficient evidence of a patent tube and normal uterine cavity as long as the subject
did not have, during the pregnancy or subsequently, risk factors for Asherman's
syndrome or tubal disease or other disorder leading to an increased suspicion for
intrauterine abnormality or tubal occlusion.

4. No previous sterilization procedures (vasectomy, tubal ligation) that have been
reversed. The prior procedure may affect study outcomes.

Specific Exclusion Criteria

1. Current pregnancy.

2. Patients on oral contraceptives, depo-progestins, or hormonal implants (including
Implanon). A two month washout period will be required prior to screening for patients
on these agents. Longer washouts may be necessary for certain depot contraceptive
forms or implants, especially where the implants are still in place. A one-month
washout will be required for patients on oral cyclic progestins.

3. Patients with hyperprolactinemia (defined as two prolactin levels at least one week
apart > 30 ng/mL or as determined by local normative values). The goal of eliminating
patients with documented hyperprolactinemia is to decrease the heterogeneity of the
PCOS population. These patients may be candidates for ovulation induction with
alternate regimens (dopamine agonists). A normal level within the last year or on
treatment is adequate for entry.

4. Patients with known 21-hydroxylase deficiency or other enzyme deficiency leading to
the phenotype of congenital adrenal hyperplasia. 21-hydroxylase deficiency will be
excluded in all patients by a fasting 17-hydroxyprogesterone (17-OHP) level <2 ng/mL
(Azziz, Hincapie et al. 1999 Nov). If relevant, this level should be determined in the
follicular phase, because the 17-hydroxyprogesterone level is likely to be elevated
beyond this range if the patient is in the luteal phase of an infrequent ovulatory
cycle. In the case of elevated fasting 17-OHP levels in the follicular phase, an ACTH
stimulation test will be performed. A 1-hour stimulated value > 10 ng/mL will be an
exclusion (Moran, Knochenhauer et al. 1998). As 21-hydroxylase deficiency is a
congenital condition, any normal level in the past of 17-hydroxyprogesterone allows
entry into this study.

5. Patients with menopausal levels of FSH (> 15 mIU/mL). A normal level within the last
year is adequate for entry.

6. Patients with uncorrected thyroid disease (defined as TSH < 0.2 mIU/mL or >5.5
mIU/mL). A normal level within the last year is adequate for entry.

7. Patients diagnosed with Type I or Type II diabetes who are poorly controlled (defined
as a glycohemoglobin level > 7.0%), or patients receiving antidiabetic medications
such as insulin, thiazolidinediones, acarbose, or sulfonylureas likely to confound the
effects of study medication; patients currently receiving metformin XR for a diagnosis
of Type I or Type II diabetes or for PCOS are also specifically excluded.

8. Patients with liver disease defined as AST or ALT > 2 times normal or total bilirubin
>2.5 mg/dL.

9. Patients with renal disease defined as BUN > 30 mg/dL or serum creatinine> 1.4 mg/dL.

10. Patients with significant anemia (Hemoglobin < 10 g/dL).

11. Patients with a history of deep venous thrombosis, pulmonary embolus, or
cerebrovascular accident.

12. Patients with known heart disease that is likely to be exacerbated by pregnancy.

13. Patients with a history of, or suspected cervical carcinoma, endometrial carcinoma, or
breast carcinoma. A normal Pap smear result within ACOG guidelines for Pap smear
frequency will be required for women 21 and over.

14. Patients with a current history of alcohol abuse. Alcohol abuse is defined as > 14
drinks/week or binge drinking.

15. Patients enrolled simultaneously into other investigative studies that require
medications, proscribe the study medications, limit intercourse, or otherwise prevent
compliance with the protocol. Patients who anticipate taking longer than a one month
break during the protocol should not be enrolled.

16. Patients taking other medications known to affect reproductive function or metabolism.
These medications include oral contraceptives, GnRH agonists and antagonists,
antiandrogens, gonadotropins, anti-obesity drugs, anti-diabetic drugs such as
metformin and thiazolidinediones, somatostatin, diazoxide, ACE inhibitors, and calcium
channel blockers. The washout period on all these medications will be two months and a
list is found in the appendix.

17. Patients with a suspected adrenal or ovarian tumor secreting androgens.

18. Patients with suspected Cushing's syndrome.

19. Couples with previous sterilization procedures (vasectomy, tubal ligation) which have
been reversed. The prior procedure may affect study outcomes, and patients with both a
reversed sterilization procedure and PCOS are rare enough that exclusion should not
adversely affect recruitment.

20. Subjects who have undergone a bariatric surgery procedure in the recent past (<12
months) and are in a period of acute weight loss or have been advised against
pregnancy by their bariatric surgeon.

21. Patients with untreated poorly controlled hypertension defined as a systolic blood
pressure ≥ 160 mm Hg or a diastolic ≥ 100 mm Hg obtained on two measures obtained at
least 60 minutes apart.