Sleep-wake Changes of Luteinizing Hormone Frequency in Pubertal Girls With and Without High Testosterone

Comparison of Sleep-wake LH Frequency in Peripubertal Girls With and Without Hyperandrogenemia

The purpose of this study is to determine whether sleep-wake changes of luteinizing hormone pulse frequency are different in early pubertal girls with high testosterone levels compared to early pubertal girls with normal testosterone levels.

During early puberty, luteinizing hormone (LH) pulse frequency normally increases during sleep. In contrast, preliminary data suggest that obese girls (who have high testosterone levels in general) demonstrate low LH frequency during the day and night during early puberty; but at mid puberty rapidly transition to a high LH frequency during the day and night. We hypothesize that in early pubertal girls with high testosterone levels, overnight increases of LH frequency are less prominent than those observed in early pubertal girls with normal testosterone levels. We will assess this using a frequent sampling protocol for assessment of LH pulse frequency (with sampling occurring while awake and while asleep) in early pubertal girls with and without high testosterone levels. Sleep will be formally evaluated.

Inclusion Criteria:

• Early to midpubertal girls (late Tanner 1 [i.e., estradiol > 20 pg/ml] to Tanner 3)
• Premenarcheal
• Approximate ages, 8-15 years

Exclusion Criteria:

• BMI-for-age < 5th percentile

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

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

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

• Pregnancy or lactation

• Virilization

• Total testosterone > 150 ng/dl (confirmed on repeat)

• DHEAS > upper limit of age-appropriate normal range (confirmed on repeat) (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)

• Follicular phase 17-hydroxyprogesterone > 250 ng/dl (for girls < 12 years old) or > 300 ng/dl (for girls 12 and older) (confirmed on repeat), which suggests the possibility of congenital adrenal hyperplasia. NOTE: If an elevated follicular 17-hydroxyprogesterone is confirmed on repeat testing, an ACTH stimulated 17-hydroxyprogesterone < 1000 ng/dl will be required for study participation

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

• A previous diagnosis of diabetes

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

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

• 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)

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

• Hematocrit < 36% and hemoglobin < 12 g/dl (confirmed on repeat)

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

• 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

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

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

• 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

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