Hyperandrogenemia and Altered Day-night LH Pulse Patterns

Eligibility Criteria

• * Mid- to late pubertal adolescent girl (at least Tanner breast stage 3, but no more than 2 years postmenarcheal)
• * Hyperandrogenism, defined as a serum (calculated) free testosterone concentration greater than the Tanner stage-specific reference range and/or unequivocal evidence for hirsutism
• * General good health (excepting overweight, obesity, hyperandrogenism, and adequately-treated hypothyroidism)
• * Capable of and willing to provide informed assent (adolescents under age 16 years) and/or consent (adolescents over age 16 years; custodial parents or guardians of all adolescent volunteers)
• * 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 (hyperandrogenism is unique to females)
• * 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 adolescent HA and 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 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 adolescents and women with HA/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 \< 36% 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%
• * Persistent liver panel abnormalities, with two exceptions. Mild bilirubin elevations will be accepted in the setting of known Gilbert's syndrome. Also, mild transaminase elevations may be seen in obesity/HA/PCOS; therefore, elevations \< 1.5 times the upper limit of normal will be accepted in this group.
• * 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 any other cancer diagnosis and/or treatment (with the exception of basal cell or squamous cell skin carcinoma) unless they have remained clinically disease free (based on appropriate surveillance) for five years
• * History of allergy to micronized progesterone or spironolactone
• * Body mass index (BMI)-for-age percentile \< 5% (underweight)
• * Due to the amount of blood being drawn, adolescent volunteers with body weight \< 25 kg will be excluded.
• * Restrictions on use of other drugs or treatments: No medications known to affect the reproductive system, glucose metabolism, lipid metabolism, or blood pressure can be taken in the 2 months prior to the screening visit and in the 3 months prior to the start of the study medications. Such medications include oral contraceptive pills, progestins, metformin, systemic glucocorticoids, some antipsychotic medications, and sympathomimetics/stimulants (e.g., methylphenidate).