Does short-term progesterone reduce waking LH pulse frequency in mid- to late-pubertal girls with and without hyperandrogenism?

Study to Assess Acute Progesterone Suppression of Wake vs. Sleep Luteinizing Hormone Pulse Frequency in Pubertal Girls With and Without Hyperandrogenism

We will see if short-term progesterone lowers waking LH pulse frequency in mid- to late-pubertal girls with and without hyperandrogenism.

Quick facts

• Phase: EARLY_PHASE1
• Study type: Interventional
• Enrollment: 36 (estimated)
• Ages: 10 Years to 17 Years
• Sex: Female
• Sponsor: University of Virginia (other)
• Locations: 1 site (Charlottesville, Virginia)
• Trial ID: NCT00929006 on ClinicalTrials.gov

What this trial studies

This randomized, placebo-controlled, double-blind crossover study gives mid- to late-pubertal girls oral micronized progesterone or placebo during two separate menstrual cycles with treatment order randomized. Each participant completes two 18-hour inpatient admissions during which progesterone or placebo is dosed at 07:00, 15:00, 23:00, and 07:00 and blood is sampled every 10 minutes from 18:00 to 12:00 to characterize pulsatile LH secretion and other hormones. The primary outcome is waking LH pulse frequency, with sleep-associated LH frequency as a key secondary endpoint. Responses in girls with biochemical or clinical hyperandrogenism are compared directly to those in girls without hyperandrogenism.

Who should consider this trial

Good fit: Ideal candidates are mid- to late-pubertal girls (at least Tanner breast stage 3 and within two years postmenarche) with or without biochemical or clinical hyperandrogenism who are in generally good health and willing to undergo inpatient monitoring and frequent blood draws.

Not a fit: Prepubertal girls, males, those more than two years postmenarcheal, individuals unwilling to have frequent blood sampling or to avoid pregnancy during the study, and those with major health issues are unlikely to be included or to benefit.

Why it matters

Potential benefit: If successful, the results could clarify hormone patterns that contribute to abnormal puberty and help guide future treatment or monitoring approaches for girls with hyperandrogenism.

How similar studies have performed: Previous work has shown acute progesterone suppression of waking LH pulses in pubertal girls without hyperandrogenism, while applying this protocol to girls with hyperandrogenism is a novel extension.

Eligibility criteria

Inclusion Criteria:

* Mid- to late pubertal adolescent girl (at least Tanner breast stage 3, but no more than 2 years postmenarcheal)
* For girls without hyperandrogenism: serum (calculated) free testosterone concentration within the Tanner stage-specific reference range and the absence of hirsutism
* For girls with hyperandrogenism: serum (calculated) free testosterone concentration greater than the Tanner stage-specific reference range and/or unequivocal evidence for hirsutism
* General good health (excepting overweight, obesity, hyperandrogenism, and adequately-treated hypothyroidism)
* Capable of and willing to provide informed assent (adolescents under age 16 years) and/or consent (adolescents over age 16 years; custodial parents or guardians of all adolescent volunteers)
* Willing to strictly avoid pregnancy with use of reliable non-hormonal methods during the study period

Exclusion Criteria:

* Inability/incapacity to provide informed consent
* Males will be excluded (hyperandrogenism is unique to females)
* Obesity resulting from a well-defined endocrinopathy or genetic syndrome
* Positive pregnancy test or current lactation
* Evidence for non-physiologic or non-PCOS causes of hyperandrogenism and/or anovulation
* Evidence of virilization (e.g., rapidly progressive hirsutism, deepening of the voice, clitoromegaly)
* Total testosterone \> 150 ng/dl, which suggests the possibility of virilizing ovarian or adrenal tumor
* DHEA-S elevation \> 1.5 times the upper reference range limit. Mild elevations may be seen in adolescent HA and in PCOS, and will be accepted in these groups.
* Early morning 17-hydroxyprogesterone \> 200 ng/dl measured in the follicular phase, which suggests the possibility of congenital adrenal hyperplasia (if elevated during the luteal phase, the 17-hydroxyprogesterone will be repeated during the follicular phase). NOTE: If a 17-hydroxyprogesterone \> 200 ng/dl is confirmed on repeat testing, an ACTH stimulated 17-hydroxyprogesterone \< 1000 ng/dl will be required for study participation.
* Abnormal thyroid stimulating hormone (TSH): Note that subjects with stable and adequately treated primary hypothyroidism, reflected by normal TSH values, will not be excluded.
* Hyperprolactinemia: Mild prolactin elevations may be seen in HA/PCOS, and elevations within 20% higher than the upper limit of normal will be accepted in this group.
* History and/or physical exam findings suggestive of Cushing's syndrome, adrenal insufficiency, or acromegaly
* History and/or physical exam findings suggestive of hypogonadotropic hypogonadism (e.g., symptoms of estrogen deficiency) including functional hypothalamic amenorrhea (which may be suggested by a constellation of symptoms including restrictive eating patterns, excessive exercise, psychological stress, etc.)
* Hematocrit \< 36% and hemoglobin \< 12 g/dl.
* Severe thrombocytopenia (platelets \< 50,000 cells/microliter) or leukopenia (total white blood count \< 4,000 cells/microliter)
* Previous diagnosis of diabetes, fasting glucose \> or = 126 mg/dl, or a hemoglobin A1c \> or = 6.5%
* Persistent liver panel abnormalities, with two exceptions. Mild bilirubin elevations will be accepted in the setting of known Gilbert's syndrome. Also, mild transaminase elevations may be seen in obesity/HA/PCOS; therefore, elevations \< 1.5 times the upper limit of normal will be accepted in such girls.
* Significant history of cardiac or pulmonary dysfunction (e.g., known or suspected congestive heart failure, asthma requiring intermittent systemic corticosteroids, etc.)
* Decreased renal function evidenced by GFR \< 60 ml/min/1.73m2
* A personal history of breast, ovarian, or endometrial cancer
* History of any other cancer diagnosis and/or treatment (with the exception of basal cell or squamous cell skin carcinoma) unless they have remained clinically disease free (based on appropriate surveillance) for five years
* History of allergy to micronized progesterone.
* Body mass index (BMI)-for-age percentile \< 5% (underweight)
* Due to the amount of blood being drawn, adolescent volunteers with body weight \< 25 kg will be excluded.
* Restrictions on use of other drugs or treatments: No medications known to affect the reproductive system, glucose metabolism, lipid metabolism, or blood pressure can be taken in the 2 months prior to the screening visit and in the 3 months prior to the start of the study medications. Such medications include oral contraceptive pills, progestins, metformin, systemic glucocorticoids, some antipsychotic medications, and sympathomimetics/stimulants (e.g., methylphenidate).

Where this trial is running

Charlottesville, Virginia

• University of Virginia — Charlottesville, Virginia, United States (RECRUITING)

Study contacts

• Principal investigator: Christine M Burt Solorzano, MD — University of Virginia
• Study coordinator: Melissa Gilrain

Conditions: Puberty, Hyperandrogenism, hyperandrogenemia, pubertal, polycystic ovary syndrome