Hyperandrogenemia and Altered Day-night LH Pulse Patterns

Inclusion Criteria:

• Mid- to late pubertal adolescent girl (at least Tanner breast stage 3, but no morethan 2 years postmenarcheal)

• Hyperandrogenism, defined as a serum (calculated) free testosterone concentrationgreater than the Tanner stage-specific reference range and/or unequivocal evidencefor hirsutism

• General good health (excepting overweight, obesity, hyperandrogenism, andadequately-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 alladolescent volunteers)

• Willing to strictly avoid pregnancy with use of reliable non-hormonal methods duringthe study period

Exclusion Criteria:

• 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/oranovulation

• Evidence of virilization (e.g., rapidly progressive hirsutism, deepening of thevoice, clitoromegaly)

• Total testosterone > 150 ng/dl, which suggests the possibility of virilizing ovarianor adrenal tumor

• DHEA-S elevation > 1.5 times the upper reference range limit. Mild elevations may beseen 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 duringthe luteal phase, the 17-hydroxyprogesterone will be repeated during the follicularphase). NOTE: If a 17-hydroxyprogesterone > 200 ng/dl is confirmed on repeattesting, an ACTH stimulated 17-hydroxyprogesterone < 1000 ng/dl will be required forstudy participation.

• Abnormal thyroid stimulating hormone (TSH): Note that subjects with stable andadequately treated primary hypothyroidism, reflected by normal TSH values, will notbe excluded.

• Hyperprolactinemia > 20% higher than the upper limit of normal. Mild prolactinelevations 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, adrenalinsufficiency, 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 eatingpatterns, excessive exercise, psychological stress, etc.)

• Persistent hematocrit < 36% and hemoglobin < 12 g/dl.

• Severe thrombocytopenia (platelets < 50,000 cells/microliter) or leukopenia (totalwhite blood count < 4,000 cells/microliter)

• Previous diagnosis of diabetes, fasting glucose > or = 126 mg/dl, or a hemoglobinA1c > or = 6.5%

• Persistent liver panel abnormalities, with two exceptions. Mild bilirubin elevationswill be accepted in the setting of known Gilbert's syndrome. Also, mild transaminaseelevations may be seen in obesity/HA/PCOS; therefore, elevations < 1.5 times theupper limit of normal will be accepted in this group.

• Significant history of cardiac or pulmonary dysfunction (e.g., known or suspectedcongestive 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 basalcell or squamous cell skin carcinoma) unless they have remained clinically diseasefree (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 < 25kg will be excluded.

• Restrictions on use of other drugs or treatments: No medications known to affect thereproductive system, glucose metabolism, lipid metabolism, or blood pressure can betaken in the 2 months prior to the screening visit and in the 3 months prior to thestart of the study medications. Such medications include oral contraceptive pills,progestins, metformin, systemic glucocorticoids, some antipsychotic medications, andsympathomimetics/stimulants (e.g., methylphenidate).