Does Spironolactone Normalize Sleep-wake Luteinizing Hormone Pulse Frequency in Pubertal Girls With Hyperandrogenism?

Inclusion Criteria:

• Mid- to late pubertal adolescent girls as signified by either (a) post-menarchealstatus (Tanner breast stages 2-5) or (b) Tanner breast stage of 4 or 5 (whetherpre-menarcheal or post-menarcheal) ages 10-17 years.

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

• General good health (excepting obesity, hyperandrogenism, PCOS, andadequately-treated hypothyroidism)

• 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)

• Age < 10 or > 17 years (this study is designed to elucidate mechanisms underlyingemerging PCOS in mid- to late pubertal adolescent girls

• Post-menarcheal by > 4 years

• Obesity resulting from a well-defined endocrinopathy, or genetic syndrome

• To ensure that blood withdrawal is within safe limits, weight < 21.5 kg is anexclusion criterion.

• Since underweight can alter pulsatile LH secretion, BMI-for-age percentile < 5 is anexclusion criterion.

• Positive pregnancy test or current lactation. Subjects with a positive pregnancytest will be informed of the result by the screening physician. Under Virginia law,parental notification is not required for minors. However, the screening physicianwill encourage the subject to tell her parent(s). We will counsel the adolescentabout the importance of appropriate prenatal care/counseling. We will offerappropriate follow-up at the Teen Health Clinic at UVA and/or encourage theadolescent to secure prompt care via their primary care physician's office.

• 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 > 300 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-hydorxyprogesterone > 300 ng/dl is confirmed on repeattesting, an ACTH stimulated 17-hydroxyprogesterone < 1000 ng/dl performed by thesubject's personal physician will be required for study participation.

• Any abnormal TSH concentration will trigger repeat testing. In many cases when TSHis initially abnormal, a repeat TSH will be normal. These subjects will be permittedto continue study. If TSH remains abnormal on repeat testing, the subject will bereferred to her primary medical provider. In some cases, a participant's primarymedical provider will elect to simply observe a mildly low (> 0.1) or mildlyelevated (< 10) if stable. In such cases, we will accept a TSH between 0.3 and 7 (inclusive) if it has remained stable for at least 6 months-such TSH values areexceedingly unlikely to influence the central reproductive axis or to influence therisks of the study. Notably, subjects with reasonably-treated primaryhypothyroidism-reflected by TSH values between 0.3 and 7-on a stable dose of thyroidhormone (i.e., same dose for at least 2 months) will not be excluded.

• Prolactin concentration > 30 ng/mL (confirmed on repeat). Mild prolactin elevationsmay be seen in adolescents and women with HA/PCOS or obesity.

• 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 hemoglobin < 11.5 g/dL for non-African American subjects; hemoglobin < 11.0 g/dL for African American subjects (confirmed on repeat). Importantly,documentation of a hemoglobin ≥ 11.0 g/dL for African American subjects or ≥ 11.5g/dL for non-African American subjects in the month prior to the CRU admission isrequired for frequent sampling protocol in the CRU.

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

• Previous diagnosis of diabetes, fasting glucose ≥ 126 mg/dl, or a hemoglobin A1c ≥ 6.5%

• Persistently abnormal sodium or potassium concentration. Bicarbonate concentrations < 20 or > 30.

• Liver test abnormalities, with two exceptions: (1) mild bilirubin elevations will beaccepted in the setting of known Gilbert's syndrome or when the subject's primarycare provider provides a presumptive diagnosis of Gilbert's syndrome and has noplans for further work-up; (2) mild transaminase (ALT, AST) elevations may be seenin obese/HA/PCOS girls, so stable elevations < 1.5 times the upper limit of normalwill be accepted in this group.

• Absolute contraindications to spironolactone use include history of allergy tospironolactone, anuria, acute renal insufficiency, significant impairment of renalexcretory function, hyperkalemia, primary adrenal insufficiency (Addison's disease),and concomitant use of eplerenone

• 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

• History of cancer diagnosis and/or treatment (with the exception of basal cell orsquamous cell skin carcinoma) unless they have remained clinically disease free (based on appropriate surveillance) for five years.