Progesterone Suppression of Nocturnal LH Increases in Pubertal Girls
Condition: Female Puberty
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to learn more about how gonadotropin-releasing hormone (GnRH)
      and luteinizing hormone (LH) pulses are controlled during puberty. In this study, the
      investigators aim to discover whether or not giving 2 small doses of progesterone to early
      pubertal girls will prevent the nighttime increase of GnRH and LH pulses. From the
      information gathered in this study, the investigators may be able to learn more about how
      menstrual cycles are normally established in girls during puberty. Ultimately, if these
      normal processes can be understood, the investigators may be able to better understand
      abnormalities of puberty.
    

Detailed description: 
      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.

      Inpatient Admission: Subjects will be admitted to the CRU, alternate UVA hospital unit, or
      off-site hotel at 1400 h. In general, parents are welcome to stay with their child at the
      off-site hotel if they wish. If the overnight portion of the study is to be done at an
      off-site hotel, the subject may stay without a parent or legal guardian, as long as two CRU
      staff are present. Whether or not a parent needs to remain during the overnight admission
      will be discussed when the visit is scheduled. An i.v. line with be placed in the forearm
      vein (this may be facilitated by EMLA cream), on the same side as the dominant hand if
      possible. Subjects will take 25-50 mg oral micronized P or placebo at 1600 h and again at
      2000 h. P dosing will be based on weight, with 25 mg administered to girls < 42 kg and 50 mg
      given to those ≥ 42 kg; with P administration, we aim to produce mean P concentrations of
      approximately 2-3 ng/ml. Frequent blood sampling will begin at 1900 h and continue for 14 h
      as follows: LH every 10 min (1 ml); and FSH every 10 min (no additional blood required); P,
      E2, T, DHEA and cortisol every 30 min (1 ml). An additional 0.3 cc sample will be drawn at
      0700 to test for fasting glucose. Fasting insulin, SHBG, estrone, androstenedione, DHEA-S
      will be performed on pooled samples from 05:00-07:00.

      Lights will be extinguished at 2200 h to facilitate sleep, which will be carefully recorded
      by trained observers. During blood sampling, activity (e.g. awake, sleeping) will be recorded
      by the nurse every 10 minutes. Additionally, periods of sleep will be estimated using wrist
      actigraphy (Motionlogger Basic-L; Ambulatory Monitoring, Inc.) The Motionlogger Basic-L is a
      watch-like device (that includes an accelerometer) that will be worn on the non-dominant
      wrist by the research participant during the overnight admission. There will be an overnight
      fast from 22:00 until 07:00. Subjects will be awakened at 0700 h. Sampling will cease at 0900
      h.

      During the admission, ~150 ml of blood will be drawn (including 0.25 ml discarded with each
      sample). The total amount of blood that will be drawn during the study, including the
      screening, outpatient P sampling, and inpatient admission is ~170 ml. One of the parents will
      be allowed to stay overnight with the subject during the admission. After the last sample is
      taken, volunteers will be discharged on oral iron supplementation to be taken for 30 d.

      Follow-up:

      We will advance every effort to follow subjects (via outpatient CRU or clinic visits) at 6-
      to 12-month intervals for up to 3 y to assess progression of puberty, onset and frequency of
      menses, and development of signs of hyperandrogenism (e.g., hirsutism). We will obtain blood
      for LH, FSH, E2, P, and T during these follow-up visits. These follow-up visits will be
      encouraged, but not mandatory.
    

Intervention name(s): Progesterone; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Subjects will take 25-50 mg oral micronized progesterone at 1600 h and again at 2000 h. Progesterone dosing will be based on weight, with 25 mg administered to girls < 42kg and 50 mg given to those or = to 42 kg.; Subjects will take oral placebo suspension at 1600 h and again at 2000 h.
Intervention MeSH terms: Progesterone
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Single (Participant)
Primary purpose: Basic Science