Progesterone Suppression of Nocturnal LH Increases in Pubertal Girls (JCM017)

We will recruit early pubertal, premenarcheal adolescent girls, since these stages are associated with the most prominent diurnal variations in LH pulsatility (13). Weight will be normal for height (i.e., BMI ≤ 85th and ≥ 5th percentile for age according to the CDC), and plasma testosterone will be < 40 ng/dl. We will recruit normal adolescent girls, or girls with idiopathic short stature (> 2 SD below mean height for age with no identifiable cause), from UVa Pediatric Clinics, local pediatric clinics, the Teen Health Center, and UVa Endocrine Clinics. Subjects will be late Tanner 1 (defined as having estradiol level > 20 pg/mL), Tanner 2, or Tanner 3. All potential subjects will undergo a screening history and physical prior to enrollment. These 60-90 min outpatient visits to the CRU or alternate UVA clinical unit will establish general health and developmental normality. Evaluation will include a complete personal and family medical history and physical examination (including height, weight, and pubertal stage determination using the Tanner scale). The goals and procedures of the study will be explained to potential subjects and their parents, and questions will be entertained. The volunteer and her parents will sign the assent and consent forms, respectively. Blood (20 ml) will then be drawn (at approx. 0800-0900 h) for the following tests: LH, FSH, P, E2, total testosterone, SHBG, DHEA-S, 17-OHP, beta-hCG, TSH, CBC, chemistry and liver panels, prolactin, insulin, Insulin-like Growth Factor 1 (IGF-1), and cytokines and adipokines (including adiponectin, leptin, resistin, PAI-1, IL-1b, IL-6, IL-8, TNFa, MCP-1, HGF and NGF). Subjects will need to fast for a minimum of 8 hours prior to screening blood draw. Bone age (plain x-ray of left hand and wrist) will also be performed as a marker of biological age, since pubertal stage generally correlates better with bone age than chronological age.

If the screening labs show a hemoglobin < 11.0g/dL for African American subjects or hemoglobin < 11.5 g/dL for non-African American subjects, iron therapy at a dose of 1-2 mg/kg will be encouraged for 60 days. Subjects weighing ≤ 36 kg will be given 300-325 mg oral ferrous gluconate daily (containing 36 mg of elemental iron); subjects weighing > 36 kg will be given 300-325 mg oral ferrous gluconate twice daily. Hemoglobin will then be rechecked in the CRU or clinical unit; if acceptable (hemoglobin ≥ 11 g/dL for African American subjects or hemoglobin ≥ 11.5 g/dL for non-African American subjects), the inpatient admission will be scheduled.

If the screening labs are normal, iron supplementation at a dose of 1-2 mg/kg for 30 days will be given to help prevent anemia from developing during the study. Subjects weighing ≤ 36 kg will be given 300-325 mg oral ferrous gluconate daily (containing 36 mg of elemental iron); subjects weighing > 36 kg will be given 300-325 mg oral ferrous gluconate twice daily.

If safety labs are abnormal during screening (e.g., abnormal liver tests, abnormal TSH), subjects will be asked to return once for repeat (confirmatory) labs to exclude lab error. Repeat testing will generally occur within one month of the original screening lab draw. If exclusionary lab values are confirmed on such repeat testing, subjects will be excluded from participation.

1-3 days before overnight admission: An outpatient blood sample will be obtained 1-3 d before overnight admission. Plasma P will be checked to exclude an unlikely luteal phase, with overnight admission cancelled if P exceeds 1.5 ng/ml. Hemoglobin will be obtained if these have not been obtained within 30 days of the overnight admission (subsequent overnight admission cancelled if hemoglobin < 11 g/dl for African American subjects or < 11.5 g/dL for non-African American subjects). Urine beta-HCG will be assessed to exclude pregnancy. If three months have elapsed between an overnight admission and the subject's most recent safety labs, then additional safety labs (chemistry and liver panel) will be obtained at this time.