Effect of High Testosterone on Sleep-associated Slowing of Follicular Luteinizing Hormone (LH) Frequency in Polycystic Ovary Syndrome (CRM004)

• Progesterone concentration [ Time Frame: One and two months ] [ Designated as safety issue: No ]
• Follicle stimulating hormone [ Time Frame: One and two months ] [ Designated as safety issue: No ]
• Testosterone concentration [ Time Frame: One and two months ] [ Designated as safety issue: No ]
• Estradiol concentration [ Time Frame: One and two months ] [ Designated as safety issue: No ]
• Liver panel (transaminases, bilirubin, alkaline phosphatase) [ Time Frame: 1 day, 14 days, 28 days, 42 days, and 56 days ] [ Designated as safety issue: Yes ]
• Pregnancy test [ Time Frame: 1 day, 14 days, 28 days, 42 days, and 56 days ] [ Designated as safety issue: Yes ]
• Red blood cell counts [ Time Frame: 1 day, 28 days, and 56 days ] [ Designated as safety issue: Yes ]
• Sleep study parameters (sleep stage, overnight ventilatory variables) [ Time Frame: One and two months ] [ Designated as safety issue: No ]

• Progesterone concentration [ Time Frame: Day 28 and day 56 of study (approximate) ] [ Designated as safety issue: No ]
• Follicle stimulating hormone [ Time Frame: Day 28 and day 56 of study (approximate) ] [ Designated as safety issue: No ]
• Testosterone concentration [ Time Frame: Day 28 and day 56 of study (approximate) ] [ Designated as safety issue: No ]
• Estradiol concentration [ Time Frame: Day 28 and day 56 of study (approximate) ] [ Designated as safety issue: No ]
• Liver panel (transaminases, bilirubin, alkaline phosphatase) [ Time Frame: At baseline; then day 14, 28, 42, and 56 of study (approximate) ] [ Designated as safety issue: Yes ]
• Pregnancy test [ Time Frame: Within one week of starting flutamide/placebo; then day 14, 28, 42, and 56 of study (approximate) ] [ Designated as safety issue: Yes ]
• Red blood cell counts [ Time Frame: At baseline; then day 28 and day 56 of study (approximate) ] [ Designated as safety issue: Yes ]
• Sleep study parameters (sleep stage, overnight ventilatory variables) [ Time Frame: Day 28 and day 56 of study (approximate) ] [ Designated as safety issue: No ]

The purpose of this study is to determine whether a testosterone receptor blocker (flutamide) will normalize sleep-wake luteinizing hormone pulse frequency relationships in women with polycystic ovary syndrome.

During the follicular phase of the normal menstrual cycle, luteinizing hormone (LH) pulse frequency decreases during sleep. These decreases may be important to support follicle stimulating hormone (FSH) synthesis and secretion. Polycystic ovary syndrome (PCOS) is associated with a persistently rapid gonadotropin hormone-releasing hormone (GnRH) pulse frequency, an abnormality that may account for many of the hormonal manifestations of PCOS. Although one prior study suggests that nocturnal LH frequency decreases slightly in PCOS, methodological issues limit interpretation. Our preliminary data suggest that nocturnal LH frequency does not decrease in untreated PCOS, but that nocturnal decreases of LH frequency are restored with androgen receptor blockade (flutamide) in women with PCOS. We have two hypotheses: (1) Prior to flutamide administration, sleep-associated slowing of LH pulse frequency is less pronounced in women with PCOS compared to that of normally-cycling women in the late follicular phase of the menstrual cycle; (2) After 4 weeks of flutamide administration, sleep-associated LH frequency reduction in women with PCOS is similar to that of normally-cycling women in the late follicular phase of the menstrual cycle. Women with PCOS and normally-cycling women will be studied. For each study participant, LH pulse frequency will be determined (from 1500 to 0700 h) after 4 weeks of flutamide and after 4 weeks of placebo. Flutamide and placebo will be given in random order (i.e., cross-over study). Sleep will be formally evaluated. Flutamide will then be given for 4 weeks prior to reassessment of LH pulse frequency. LH pulse frequency will be analyzed by way of hierarchical mixed effect models. We will use statistical analyses to determine: (a) whether the wake vs. sleep difference in LH frequency is the same for PCOS and normal controls prior to flutamide, and (b) whether the mean wake vs. sleep difference in LH frequency is the same for the two groups after flutamide.

• Drug: Flutamide
  Flutamide, 250 mg capsule for oral administration, twice a day for 4 weeks (or menstrual cycle length in normally-cycling controls)
  Other Name: Eulexin
• Drug: Placebo
  Placebo, for oral administration, twice a day for 4 weeks (or menstrual cycle length in normally-cycling controls)

Inclusion Criteria:

Inclusion criteria for all participants:

• Subjects will be 18-35 years old; we use a cutoff age of 35 y because early menopause at this age is very rare.
• No significant health problems (other than PCOS and obesity).
• Subjects will be willing to strictly avoid pregnancy (using non-hormonal methods) during the time of study and must be willing and able to provide informed consent.

Inclusion criteria for normal controls:

• Controls will be healthy women with regular menstrual cycles and no evidence of hyperandrogenism.

Inclusion criteria for PCOS:

• PCOS will be defined according to NIH consensus criteria.

  • As such, subjects with PCOS will have hyperandrogenism, whether it is clinical (e.g., hirsutism) or biochemical (i.e., elevated plasma T).
  • Subjects with PCOS will also have oligo- or amenorrhea (i.e., < 7 periods per year) and no evidence for other endocrinopathies (e.g., hyperprolactinemia, Cushing's syndrome, etc.).

Exclusion Criteria:

• Being a study of GnRH pulse regulation in women with and without PCOS, men are excluded.
• Obesity associated with a diagnosed (genetic) syndrome, obesity related to medications (e.g., glucocorticoids), etc.
• Pregnancy or lactation.
• Virilization.
• A total testosterone > 150 ng/dl in women with PCOS (which suggests the possibility of a virilizing neoplasm) (confirmed on repeat).
• Elevated DHEAS (mild elevations may be seen in PCOS, and elevations < 1.5 times the upper limit of normal will be accepted in PCOS)(confirmed on repeat).

• Follicular 17-hydroxyprogesterone > 300 ng/dl, which suggests the possibility of congenital adrenal hyperplasia (if elevated during the luteal phase and there is a concern about the possibility of congenital adrenal hyperplasia, the 17-hydroxyprogesterone may be collected during the follicular phase, or >60 if oligomenorrheic).

  *NOTE: If a 17-hydroxyprogesterone > 300 ng/dl is confirmed on such repeat testing, an ACTH stimulated 17-hydroxyprogesterone < 1000 ng/dl will be required for study participation.

• A previous diagnosis of diabetes, a fasting glucose ≥ 126 mg/dl, or a hemoglobin A1c > 6.5%
• Abnormal TSH (subjects with adequately treated hypothyroidism, reflected by normal TSH values, will not be excluded; or, for a new diagnosis of hypothyroidism, further study will at the least be delayed pending appropriate treatment) (confirmed on repeat).
• Abnormal prolactin (mild elevations may be seen in PCOS, and elevations < 1.5 times the upper limit of normal will be accepted in this group) (confirmed on repeat).
• Evidence of Cushing's syndrome by history or physical exam.
• Hematocrit < 36% or hemoglobin < 12 g/dl (that is not reversed by iron treatment).
• Significant history of cardiac or pulmonary dysfunction (e.g., known or suspected congestive heart failure; asthma requiring intermittent systemic corticosteroids; etc.)
• Liver test abnormalities (confirmed on repeat), with the exception that mild bilirubin elevations will be accepted in the setting of known Gilbert's syndrome.
• Abnormal sodium or potassium (confirmed on repeat); bicarbonate concentration <20 or >30 (confirmed on repeat); or elevated creatinine concentration (confirmed on repeat).
• Due to the amount of blood being drawn in the study, subjects with body weight < 110 lbs will be excluded from the study.