Acute Progesterone Suppression of Wake vs. Sleep Luteinizing Hormone Pulse Frequency in Pubertal Girls With and Without Hyperandrogenism (CRM003)

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

The purpose of this study is two-fold. (1) We will determine if in mid- to late pubertal girls without hyperandrogenism (HA), progesterone (P4) acutely reduces waking luteinizing hormone (LH) frequency to a greater extent than sleep-associated LH frequency. (2) We will determine if in mid- to late pubertal girls with HA, P4 will acutely suppress waking LH frequency to a lesser degree than it does in girls without HA.

Study Overview

• Status: Recruiting
• Conditions: Hyperandrogenism; Puberty
• Intervention / Treatment: Drug: Placebo; Drug: Micronized progesterone suspension

Detailed Description

This is a randomized, placebo-controlled, double-blinded crossover study to test the following hypotheses: (1) In normal mid- to late pubertal girls without hyperandrogenism (HA), progesterone acutely suppresses waking LH pulse frequency more than sleep-associated LH pulse frequency; and (2) compared to normal mid- to late pubertal girls without HA, acute progesterone suppression of waking LH pulse frequency is impaired in mid- to late pubertal girls with HA. Studies will be performed in mid- to late pubertal girls (at least Tanner breast stage 3 but no more than 2 years postmenarcheal). Subjects will complete two 18-hour Clinical Research Unit (CRU) admissions in separate menstrual cycles. Immediately before and during the first CRU admission, either oral micronized progesterone (0.8 mg/kg/dose) or placebo (randomized) will be given at 0700, 1500, 2300, and 0700 h. During the CRU admission, blood will be obtained every 10 minutes through an indwelling iv catheter from 1800 to 1200 h. This will allow full characterization of pulsatile LH secretion in addition to other hormone measurements. A second CRU admission (performed at least 2 months later given blood withdrawal limits) will be identical to the first except that placebo will exchanged for progesterone or vice versa (treatment crossover). The primary endpoint is LH pulse frequency while awake. (LH pulse frequency while asleep is an important secondary endpoint.) Results in pubertal girls without HA were recently published (Kim et al, J Clin Endocrinol Metab 2018;103:1112-1121). Data from girls with HA will be compared to recently-published results in girls without HA. Mean LH pulse frequency while awake will be analyzed via a hierarchical linear mixed model (HLMM). HA status (HA vs. non-HA), sleep status (wake vs. sleep), and treatment (progesterone vs. placebo) will represent fixed-effects, along with all associated interactions. Random effects will be used to account for hierarchical variance-covariance structure of the crossover study design. With regard to hypothesis testing, the association between HA status and wake LH pulse frequency will be evaluated via linear contrasts of HLMM least squares pulse frequency means. The differential impact of exogenous progesterone on wake LH pulse frequency in pubertal girls with and without HA (primary analysis) will be evaluated via the same testing method. Using published and preliminary data, we determined that, if 16 pubertal girls with HA complete both admissions, we should have at least an 80% chance of detecting a 0.2 pulse/hour differential effect of P4 on wake LH pulse frequency between the HA and the non-HA groups with a two-sided false positive rejection rate of no more than 0.05.

• Study Type: Interventional
• Enrollment (Anticipated): 36
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • Recruiting
      • University of Virginia
      • Principal Investigator: Christopher McCartney, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Micronized progesterone suspension; Micronized progesterone 0.8 mg/kg at 0700, 1500, 2300 and 0700 h. Progesterone is a natural hormone.	Drug: Micronized progesterone suspension; Micronized progesterone 0.8 mg/kg at 0700, 1500, 2300 and 0700 h. Progesterone is a natural hormone.; Other Names: Progesterone
Placebo Comparator: Placebo; Placebo contains only inert ingredients and is not expected to exert any direct physiological effects.	Drug: Placebo; Placebo contains only inert ingredients and is not expected to exert any direct physiological effects

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Luteinizing hormone (LH) pulse frequency	LH pulse frequency while awake vs. while asleep pulse frequency	During first CRU admission and during the second CRU admission (which occurs at least 2 months after the first)

Collaborators and Investigators

• Sponsor: University of Virginia
• Collaborators: National Institutes of Health (NIH)
• Investigators: Principal Investigator: Christopher R McCartney, M D, University of Virginia

Publications and helpful links

General Publications

• Kim SH, Lundgren JA, Bhabhra R, Collins JS, Patrie JT, Burt Solorzano CM, Marshall JC, McCartney CR. Progesterone-Mediated Inhibition of the GnRH Pulse Generator: Differential Sensitivity as a Function of Sleep Status. J Clin Endocrinol Metab. 2018 Mar 1;103(3):1112-1121. doi: 10.1210/jc.2017-02299.

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Anticipated): December 1, 2024
• Study Completion (Anticipated): December 1, 2024

Study Registration Dates

• First Submitted: June 23, 2009
• First Submitted That Met QC Criteria: June 24, 2009
• First Posted (Estimate): June 26, 2009

Study Record Updates

• Last Update Posted (Actual): May 18, 2022
• Last Update Submitted That Met QC Criteria: May 16, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: polycystic ovary syndrome; hyperandrogenemia; pubertal
• Additional Relevant MeSH Terms: Endocrine System Diseases; Gonadal Disorders; 46, XX Disorders of Sex Development; Disorders of Sex Development; Urogenital Abnormalities; Adrenogenital Syndrome; Congenital Abnormalities; Hyperandrogenism; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progestins; Progesterone
• Other Study ID Numbers: 13717

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: Data from this study will be deposited in the NICHD Data and Specimen Hub "DASH." We will also provide raw study data (de-identified) as supplementary materials in manuscripts (e.g., see Kim SH, et al. Progesterone-mediated inhibition of the GnRH pulse generator: differential sensitivity as a function of sleep status. J Clin Endocrinol Metab 2018; 103: 1112-1121 [PMCID in process]).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No