Androgen Blockade and Progesterone Augmentation of Gonadotropin Secretion

Eligibility Criteria

• * Post-pubertal (\> 4 years post-menarche) adult woman aged 18-30 years
• * PCOS, defined as clinical and/or laboratory evidence of hyperandrogenism (hirsutism and/or elevated serum \[calculated\] free testosterone concentration) plus ovulatory dysfunction (irregular menses, fewer than 9 per year), but without evidence for other potential causes of hyperandrogenism and/or ovulatory dysfunction
• * General good health (excepting overweight, obesity, hyperandrogenism, PCOS, and adequately-treated hypothyroidism)
• * Capable of and willing to provide informed consent
• * Willing to strictly avoid pregnancy with use of reliable non-hormonal methods during the study period
• * Inability/incapacity to provide informed consent
• * Males will be excluded (PCOS is unique to females)
• * Age \< 18 years or \> 30 years (ovarian reserve may decrease beyond age 30)
• * Obesity resulting from a well-defined endocrinopathy or genetic syndrome
• * Positive pregnancy test or current lactation
• * Evidence for non-physiologic or non-PCOS causes of hyperandrogenism and/or anovulation
• * Evidence of virilization (e.g., rapidly progressive hirsutism, deepening of the voice, clitoromegaly)
• * Total testosterone \> 150 ng/dl, which suggests the possibility of virilizing ovarian or adrenal tumor
• * DHEA-S elevation \> 1.5 times the upper reference range limit. Mild elevations may be seen in PCOS, and will be accepted in these groups
• * Early morning 17-hydroxyprogesterone \> 200 ng/dl measured in the follicular phase, which suggests the possibility of congenital adrenal hyperplasia (if elevated during the luteal phase, the 17-hydroxyprogesterone will be repeated during the follicular phase). NOTE: If a 17-hydroxyprogesterone \> 200 ng/dl is confirmed on repeat testing, an ACTH stimulated 17-hydroxyprogesterone \< 1000 ng/dl performed by the subject's personal physician will be required for study participation.
• * Abnormal thyroid stimulating hormone (TSH): Note that subjects with stable and adequately treated primary hypothyroidism, reflected by normal TSH values, will not be excluded.
• * Hyperprolactinemia \> 20% higher than the upper limit of normal. Mild prolactin elevations may be seen in women with PCOS, and elevations within 20% higher than the upper limit of normal will be accepted in this group.
• * History and/or physical exam findings suggestive of Cushing's syndrome, adrenal insufficiency, or acromegaly
• * History and/or physical exam findings suggestive of hypogonadotropic hypogonadism (e.g., symptoms of estrogen deficiency) including functional hypothalamic amenorrhea (which may be suggested by a constellation of symptoms including restrictive eating patterns, excessive exercise, psychological stress, etc.)
• * Persistent hematocrit \< 37% and hemoglobin \< 12 g/dl
• * Severe thrombocytopenia (platelets \< 50,000 cells/microliter) or leukopenia (total white blood count \< 4,000 cells/microliter)
• * Previous diagnosis of diabetes, fasting glucose \> or = 126 mg/dl, or a hemoglobin A1c \> or = 6.5%
• * Given that this study involves flutamide use, any liver panel abnormality will be grounds for exclusion
• * Significant history of cardiac or pulmonary dysfunction (e.g., known or suspected congestive heart failure, asthma requiring intermittent systemic corticosteroids, etc.)
• * Decreased renal function evidenced by GFR \< 60 ml/min/1.73m2
• * A personal history of breast, ovarian, or endometrial cancer
• * History of allergy to micronized progesterone, flutamide, or transdermal estradiol
• * BMI \< 18 or \> 40 kg/m2
• * Due to the amount of blood being drawn, volunteers with body weight \< 110 pounds must be excluded