Ovarian Contribution to Androgen Production in Adolescent Girls

Adolescent hyperandrogenemia can represent a forerunner to adult PCOS. Because adrenarche
leads to an increase in adrenal androgen production during early puberty and since early
puberty is associated with an overnight rise in testosterone that follows a similar time
course to cortisol, we hypothesize that the adrenal gland is a major source of androgens in
early puberty. On the other hand, the overnight rise in testosterone may reflect an ovarian
response to overnight increases of gonadotropin secretion in early puberty. However, the
ability of the ovaries to produce androgens (e.g., to respond to gonadotropin stimulation)
during early puberty has not been tested concurrently in these girls. The sources of excess
androgen production and the timing of their relative contributions across puberty are
important in understanding the mechanism of hyperandrogenemia in these individuals. In
addition, determination of the sources of hyperandrogenemia across puberty may have clinical
utility in the development of preclinical screening tests designed to reveal those girls at
greatest risk for PCOS and identification of potential therapeutic targets to prevent its
development.

Inclusion Criteria:

- Girls age 7-18 years

- Normal weight (BMI 5-85%-ile for age) or overweight (>85%-ile)

- With or without signs of excess androgen

- Screening labs within age-appropriate normal range, with the exception of a mildly low
hematocrit (see below) and the hormonal abnormalities inherent in obesity which could
include mildly elevated luteinizing hormone (LH), lipids, testosterone, prolactin,
DHEAS, E2, glucose, and insulin; and decreased follicle-stimulating hormone (FSH)
and/or sex hormone-binding globulin (SHBG)

Exclusion Criteria:

- Patients currently enrolled in another research protocol will be excluded, except for
those enrolled in IRB-HSR #12702/JCM022. This protocol is designed to allow subjects
enrolling in IRB-HSR #12702/JCM022 to simultaneously participate in this companion
protocol.

- Inability to comprehend what will be done during the study or why it will be done

- BMI-for-age < 5th percentile

- Weight < 27 kg if simultaneously participating in IRB-HSR #12702/JCM022 due to blood
volume limits

- Obesity associated with a diagnosed genetic syndrome (e.g. Prader-Willi syndrome)

- Since the study involves looking at ovarian function, boys will be excluded.

- Positive pregnancy test or lactation. Subjects with a positive pregnancy test will be
informed of the result by the screening physician. Under Virginia law, parental
notification is not required for minors. However, the screening physician will
encourage them to tell their parent(s) and counsel them about the importance of
appropriate prenatal care and counseling. We will arrange follow-up for them at the
Teen Health Clinic at the University of Virginia or their primary care physician's
office in a timely manner.

- Abnormal laboratory studies will be confirmed by repeat testing to exclude laboratory
error.

- Morning cortisol < 3 microgram/dL or history of Cushing syndrome or adrenal
insufficiency

- History of congenital adrenal hyperplasia or 17-hydroxyprogesterone > 300 ng/dL, which
suggests the possibility of congenital adrenal hyperplasia (if postmenarchal, the
17-hydroxyprogesterone will be collected during the follicular phase, or ≥ 40 days
since last menses if oligomenorrheic). NOTE: If a 17-hydroxyprogesterone >300 mg/dL is
confirmed on repeat testing, an adrenocorticotropic hormone-stimulated
17-hydroxyprogesterone <1000 ng/dL will be required for study participation.

- Total testosterone > 150 ng/dL

- Previous diagnosis of diabetes, fasting glucose ≥126 mg/dL, or a hemoglobin A1c >6.5%

- Abnormal thyroid stimulating hormone (TSH) for age. Subjects with adequately treated
hypothyroidism, reflected by normal TSH values, will not be excluded.

- Abnormal prolactin. Mild elevations may be seen in overweight girls, and elevations
<1.5 times the upper limit of normal will be accepted in this group.

- Persistent hematocrit <36% and hemoglobin <12 g/dL. Subjects with a mildly low
hematocrit (33-36%) will be asked to take iron in the form of ferrous gluconate for up
to 60 days. Subjects weighing ≤ 36 kg will take one 300-325 mg tablet oral ferrous
gluconate daily (containing 36 mg elemental iron); subjects weighing >36 kg will take
two 300-325 mg tablets oral ferrous gluconate daily (containing 36 mg elemental iron
each). They will return to the Clinical Research Unit (CRU) or alternate UVA clinical
unit after 30-60 days of iron therapy to have their hemoglobin or hematocrit rechecked
and will proceed with the remainder of the study if it is ≥12 g/dL or ≥36%,
respectively.

- Persistent liver test abnormalities, with the exception that mild bilirubin elevations
will be accepted in the setting of known Gilbert's syndrome. Mild elevations may be
seen in overweight girls, so elevations <1.5 times the upper limit of normal will be
accepted in this group.