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Time Course of Waking vs. Sleep-associated LH Pulse Frequency Suppression in Response to Progesterone in Late Pubertal Girls With and Without Hyperandrogenemia

10 Years
17 Years
Open (Enrolling)

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Trial Information

Time Course of Waking vs. Sleep-associated LH Pulse Frequency Suppression in Response to Progesterone in Late Pubertal Girls With and Without Hyperandrogenemia

During early puberty, LH frequency increases during sleep; but in late puberty, LH frequency
decreases overnight. Nonetheless, nocturnal LH frequency is similar (~0.5 pulses per hour)
in early and late pubertal girls. Preliminary data in early pubertal girls suggests that
progesterone acutely slows waking LH frequency, but does not acutely change nocturnal LH
frequency. We hypothesize that daytime LH frequency is regulated primarily by sex steroid
negative feedback, while sleep-associated LH frequency is not; and that androgens interfere
with sex steroid suppression of daytime LH frequency. We propose to assess this further
using a protocol in which short-term Progesterone and placebo is given to late pubertal
girls (in a cross-over fashion), with subsequent assessment of LH pulse frequency (with
sampling occurring while awake and while asleep). We propose that any effect of Progesterone
will be blunted or absent in late pubertal girls with hyperandrogenemia.

Inclusion Criteria:

1. Late pubertal girls (Tanner breast stage 3, 4, or 5)

2. Postmenarcheal, but no more than 4 y postmenarcheal

3. Age 10-17 y

Exclusion Criteria:

1. Age < 10 or > 17 y

2. BMI-for-age < 5th percentile

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

4. Being a study of GnRH pulse regulation in adolescent girls with and without HA, boys
are excluded

5. Obesity associated with a diagnosed (genetic) syndrome (e.g., Prader-Willi syndrome,
leptin deficiency), obesity related to medications (e.g., glucocorticoids), etc.

6. Pregnancy or lactation

7. Virilization

8. Total testosterone > 150 ng/dl

9. DHEAS > upper limit of age-appropriate normal range (mild elevations may be seen in
adolescent HA, and elevations < 1.5 times the age-appropriate upper limit of normal
will be accepted in such girls)

10. 17-hydroxyprogesterone > 250 ng/dl, which suggests the possibility of congenital
adrenal hyperplasia (if postmenarcheal, the 17-hydroxyprogesterone will be collected
during the follicular phase, or >60 if oligomenorrheic). NOTE: If a
17-hydroxyprogesterone > 250 ng/dl is confirmed on repeat testing, an ACTH stimulated
17-hydroxyprogesterone < 1000 ng/dl will be required for study participation

11. History of premature adrenarche (i.e., appearance of pubic and/or axillary hair
before age 8)

12. A previous diagnosis of diabetes

13. Fasting glucose ≥ 126 mg/dl, or a hemoglobin A1c > 6.5% (confirmed on repeat)

14. Abnormal TSH (confirmed on repeat) (subjects with adequately treated hypothyroidism,
reflected by normal TSH values, will not be excluded)

15. Abnormal prolactin (confirmed on repeat) (mild elevations may be seen in HA girls,
and elevations < 1.5 times the upper limit of normal will be accepted in this group)

16. Evidence of Cushing's syndrome by history or physical exam (e.g., history of impaired
growth in children, striae)

17. Hematocrit < 36% and hemoglobin < 12 g/dl (specifically, documentation of a
hematocrit >= 36% or a hemoglobin >= 12 g/dl in the month prior to GCRC admission is
required for the frequent sampling protocol in the GCRC)

18. Significant history of cardiac or pulmonary dysfunction (e.g., known or suspected
congestive heart failure; asthma requiring intermittent systemic corticosteroids;

19. Persistent liver test abnormalities (confirmed on repeat), with the exception that
mild bilirubin elevations will be accepted in the setting of known Gilbert's syndrome

20. Persistently abnormal sodium, potassium, or elevated creatinine concentration
(confirmed on repeat)

21. Bicarbonate concentrations < 20 or > 30 (confirmed on repeat)

22. No medications known to affect the reproductive system, glucose metabolism, lipid
metabolism, or blood pressure can be taken in the 3 months prior to the first
inpatient GCRC study (or in the 2 months prior to screening). Such medications
include oral contraceptive pills, progestins, metformin, glucocorticoids,
psychotropics, and sympathomimetics/stimulants (e.g., methylphenidate). Patients
taking restricted medications will be excluded unless written permission (for the
subjects to discontinue the medication) is received from the subject's physician.

23. Weight < 22 kg is an absolute exclusion criterion (to ensure safe blood withdrawal)

24. Personal history of deep venous thrombosis (DVT)

25. Personal history of ovarian, endometrial, or breast neoplasia

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Supportive Care

Outcome Measure:

Luteinizing hormone pulse frequency

Outcome Time Frame:

Baseline and 2 months

Safety Issue:


Principal Investigator

Christopher R McCartney, M D

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Virginia


United States: Food and Drug Administration

Study ID:




Start Date:

June 2008

Completion Date:

December 2013

Related Keywords:

  • Hyperandrogenemia
  • hyperandrogenemia
  • pubertal
  • polycystic ovary syndrome
  • Polycystic Ovary Syndrome



University of Virginia Charlottesville, Virginia  22908