Effects of Androgen Blockade on Sensitivity of the GnRH Pulse Generator to Suppression by Estradiol and Progesterone

Sponsor
University of Virginia (Other)
Overall Status
Terminated
CT.gov ID
NCT01428193
Collaborator
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
4
1
1
131
0

Study Details

Study Description

Brief Summary

The purpose of this study is to understand the effects of elevated male hormones in adolescent girls and how they effect the development of polycystic ovary syndrome (PCOS). If the investigators understand the effects of elevated male hormones levels in girls, the investigators may be able to better treat girls with elevated male hormone levels and perhaps even learn how to prevent the development of PCOS. Females with elevated levels of male hormones respond differently to estrace (estradiol) and progesterone than females with normal male hormone levels. The investigators will be giving you estrogen and progesterone to see how you respond after the male hormone has been blocked by a medication called flutamide.

Condition or Disease Intervention/Treatment Phase
N/A

Detailed Description

Similar to women with PCOS, girls with hyperandrogenemia have an increased frequency of LH pulses when compared to age matched controls. An ongoing study by our group is investigating whether the progesterone insensitivity of the GnRH pulse generator in adult women with PCOS is also seen in adolescent girls with hyperandrogenemia. Analysis of the data to date suggests that the hyperandrogenic adolescent girls have decreased hypothalamic progesterone sensitivity when compared to adolescent controls, with a subgroup (consisting of approximately half of the hyperandrogenic girls) having marked progesterone insensitivity similar to that seen in adult women with PCOS. These data have recently been published.

Given that androgens mediate hypothalamic progesterone insensitivity in adult women with PCOS, we hypothesize that androgens play a similar role in adolescent girls with hyperandrogenemia and that progesterone sensitivity can be restored with the use of the androgen receptor blocker flutamide.

Better understanding the effects of hyperandrogenemia in adolescence and its role in the development of PCOS will hopefully lead to improved prevention and treatment strategies for PCOS. This may prove increasingly important if the current epidemic in childhood obesity results in a growing number of girls with elevated androgen levels.

Study Design

Study Type:
Interventional
Actual Enrollment :
4 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Basic Science
Official Title:
Effect of Androgen Blockade on Sensitivity of the GnRH Pulse Generator to Suppression by Estradiol and Progesterone in Hyperandrogenic Adolescent Girls (JCM021)
Actual Study Start Date :
Sep 1, 2006
Actual Primary Completion Date :
Aug 1, 2017
Actual Study Completion Date :
Aug 1, 2017

Arms and Interventions

Arm Intervention/Treatment
Experimental: Flutamide, estrace, progesterone

For flutamide, subjects weighing > 50 kg will receive 250 mg orally twice a day, and subjects weighing < 50 kg will receive 125 mg orally twice a day for approximately 3 weeks. Subjects will be given oral estrace, 0.5-1 mg once a day for 7 days following the first overnight study admission. Subjects will be given oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days following the first overnight study admission.

Drug: Flutamide
Subjects weighing > 50 kg will receive 250 mg orally twice a day, and subjects weighing < 50 kg will receive 125 mg orally twice a day.

Drug: Progesterone
oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days

Drug: estrace
0.5-1 mg once a day for seven days
Other Names:
  • (estradiol)
  • Outcome Measures

    Primary Outcome Measures

    1. Slope of the Percent Change in Luteinizing Hormone (LH) Pulses as a Function of Day 7 Progesterone Level [3 weeks after flutamide treatment]

      The primary outcome variable for the study is the slope of the percent change in LH pulses as a function of day 7 progesterone level.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    13 Years to 17 Years
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Girls ages 13 to 17

    • Tanner IV or V stage of puberty

    • Post-menarche

    • Hyperandrogenemic (total testosterone > 0.4 ng/mL or free testosterone > 35 pmol/L) with or without hirsutism

    • Normal aspartate aminotransferase/alanine aminotransferase (AST/ALT) (AST < 35 U/L, ALT < 55 U/L)

    • Hemoglobin > 12 mg/dL or Hematocrit > 36%

    • Normal screening labs (with exception of the expected hormonal abnormalities inherent in hyperandrogenemia)

    • Sexually active subjects must agree to abstain or use double barrier contraception during the study

    • Subjects must agree not to take any other medications during the course of the study without approval by the study investigators

    Exclusion Criteria:
    • Abnormal screening labs (with the exception of the expected hormonal abnormalities inherent in hyperandrogenemia)

    • Elevated AST/ALT (AST > 35 U/L, ALT > 55 U/L)

    • Hemoglobin <12 mg/dL or hematocrit < 36%

    • Weight < 32 kg

    • History of liver disease, peanut allergy, deep venous thrombosis, breast cancer, endometrial cancer, or cervical cancer

    • Pregnant or breastfeeding

    • On medications known to affect the reproductive axis within 3 months of the study (including oral contraceptive pills, metformin, and spironolactone)

    • On medications known or likely to inhibit or induce CYP1A2 or CYP3A4 (please see "Restrictions on use of other drugs or treatments" section below for common examples of such drugs)

    • Are currently participating in another study or have been in one in the last 30 days.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Center for Research in Reproduction, University of Virginia Charlottesville Virginia United States 22908

    Sponsors and Collaborators

    • University of Virginia
    • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

    Investigators

    • Principal Investigator: Christopher R. McCartney, MD, University of Virginia

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    John Marshall, Principal investigator Center for Research in Reproduction, University of Virginia
    ClinicalTrials.gov Identifier:
    NCT01428193
    Other Study ID Numbers:
    • 12632
    • U54HD028934-18
    First Posted:
    Sep 2, 2011
    Last Update Posted:
    Jun 4, 2018
    Last Verified:
    May 1, 2018
    Keywords provided by John Marshall, Principal investigator Center for Research in Reproduction, University of Virginia
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Flutamide, Estrace, Progesterone
    Arm/Group Description For flutamide, subjects weighing > 50 kg will receive 250 mg orally twice a day, and subjects weighing < 50 kg will receive 125 mg orally twice a day for approximately 3 weeks. Subjects will be given oral estrace, 0.5-1 mg once a day for 7 days following the first overnight study admission. Subjects will be given oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days following the first overnight study admission. Flutamide: Subjects weighing > 50 kg will receive 250 mg orally twice a day, and subjects weighing < 50 kg will receive 125 mg orally twice a day. Progesterone: oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days estrace: 0.5-1 mg once a day for seven days
    Period Title: Overall Study
    STARTED 4
    COMPLETED 2
    NOT COMPLETED 2

    Baseline Characteristics

    Arm/Group Title Flutamide, Estrace, Progesterone
    Arm/Group Description For flutamide, subjects weighing > 50 kg will receive 250 mg orally twice a day, and subjects weighing < 50 kg will receive 125 mg orally twice a day for approximately 3 weeks. Subjects will be given oral estrace, 0.5-1 mg once a day for 7 days following the first overnight study admission. Subjects will be given oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days following the first overnight study admission. Flutamide: Subjects weighing > 50 kg will receive 250 mg orally twice a day, and subjects weighing < 50 kg will receive 125 mg orally twice a day. Progesterone: oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days estrace: 0.5-1 mg once a day for seven days
    Overall Participants 4
    Age (Count of Participants)
    <=18 years
    4
    100%
    Between 18 and 65 years
    0
    0%
    >=65 years
    0
    0%
    Age (years) [Mean (Full Range) ]
    Mean (Full Range) [years]
    15.5
    Sex: Female, Male (Count of Participants)
    Female
    4
    100%
    Male
    0
    0%
    Race/Ethnicity, Customized (Count of Participants)
    White
    4
    100%
    Region of Enrollment (Count of Participants)
    United States
    4
    100%

    Outcome Measures

    1. Primary Outcome
    Title Slope of the Percent Change in Luteinizing Hormone (LH) Pulses as a Function of Day 7 Progesterone Level
    Description The primary outcome variable for the study is the slope of the percent change in LH pulses as a function of day 7 progesterone level.
    Time Frame 3 weeks after flutamide treatment

    Outcome Measure Data

    Analysis Population Description
    One subject completed the study but had not taken the study medication so her data is unusable. The second subject completed the study. However, no data were formally analyzed. We were subsequently unable to recruit any additional subjects.
    Arm/Group Title Flutamide, Estrace, Progesterone
    Arm/Group Description For flutamide, subjects weighing > 50 kg will receive 250 mg orally twice a day, and subjects weighing < 50 kg will receive 125 mg orally twice a day for approximately 3 weeks. Subjects will be given oral estrace, 0.5-1 mg once a day for 7 days following the first overnight study admission. Subjects will be given oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days following the first overnight study admission. Flutamide: Subjects weighing > 50 kg will receive 250 mg orally twice a day, and subjects weighing < 50 kg will receive 125 mg orally twice a day. Progesterone: oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days estrace: 0.5-1 mg once a day for seven days
    Measure Participants 1
    Number [percentage of slope change]
    -0.55

    Adverse Events

    Time Frame Two weeks post study drug intervention, at time of last blood draw.
    Adverse Event Reporting Description
    Arm/Group Title Flutamide, Estrace, Progesterone
    Arm/Group Description For flutamide, subjects weighing > 50 kg will receive 250 mg orally twice a day, and subjects weighing < 50 kg will receive 125 mg orally twice a day for approximately 3 weeks. Subjects will be given oral estrace, 0.5-1 mg once a day for 7 days following the first overnight study admission. Subjects will be given oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days following the first overnight study admission. Flutamide: Subjects weighing > 50 kg will receive 250 mg orally twice a day, and subjects weighing < 50 kg will receive 125 mg orally twice a day. Progesterone: oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days estrace: 0.5-1 mg once a day for seven days
    All Cause Mortality
    Flutamide, Estrace, Progesterone
    Affected / at Risk (%) # Events
    Total 0/4 (0%)
    Serious Adverse Events
    Flutamide, Estrace, Progesterone
    Affected / at Risk (%) # Events
    Total 0/4 (0%)
    Other (Not Including Serious) Adverse Events
    Flutamide, Estrace, Progesterone
    Affected / at Risk (%) # Events
    Total 1/4 (25%)
    Social circumstances
    Mood change, sadness 1/4 (25%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Clinical Research Coordinator
    Organization University of Virginia
    Phone 434-243-6911
    Email pcos@virginia.edu
    Responsible Party:
    John Marshall, Principal investigator Center for Research in Reproduction, University of Virginia
    ClinicalTrials.gov Identifier:
    NCT01428193
    Other Study ID Numbers:
    • 12632
    • U54HD028934-18
    First Posted:
    Sep 2, 2011
    Last Update Posted:
    Jun 4, 2018
    Last Verified:
    May 1, 2018