Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression by Estradiol and Progesterone

Sponsor
University of Virginia (Other)
Overall Status
Completed
CT.gov ID
NCT01427595
Collaborator
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
25
Enrollment
1
Location
1
Arm
70.9
Actual Duration (Months)
0.4
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Many, but not all, girls with high levels of the male hormone testosterone go on to develop polycystic ovary syndrome (PCOS) as adults. Women with PCOS often have irregular menstrual periods, excess facial and body hair, and weight gain. PCOS is also a leading cause of difficulty becoming pregnant. The investigators do not understand why some girls with high hormones develop PCOS and others do not. In a previous study by our group, some girls with high levels of male hormones had abnormalities in the secretion of another hormone, called luteinizing hormone (LH), that are often seen in women with PCOS. However, another group had normal LH secretion. The girls with the abnormal LH secretion had higher levels of another hormone, called insulin, than the girls with normal LH secretion. The investigators will test whether metformin, an insulin-sensitizing agent, changes the effects of high male hormone levels in adolescent girls, specifically by looking at their LH secretion response following metformin treatment.

Detailed Description

A better understanding of the factors that make adolescent girls more or less susceptible to the adverse neuroendocrine effects of elevated androgens will hopefully lead to improved prevention and treatment strategies for PCOS. In this study, we propose to explore the role of hyperinsulinemia on neuroendocrine function in hyperandrogenic adolescent girls by assessing the effect of the insulin sensitizer Metformin on hypothalamic progesterone sensitivity. Other differences between the progesterone sensitive and progesterone insensitive subgroups, including racial and ethnic differences between the two populations and a trend towards older gynecologic age in the progesterone insensitive population, are being pursued through other ongoing studies (IRB-HSR# 8588 and 12160).

Study Design

Study Type:
Interventional
Actual Enrollment :
25 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Basic Science
Official Title:
Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression by Estradiol and Progesterone in Hyperandrogenemic Adolescent Girls (JCM025)
Actual Study Start Date :
Feb 18, 2009
Actual Primary Completion Date :
Jan 17, 2015
Actual Study Completion Date :
Jan 17, 2015

Arms and Interventions

ArmIntervention/Treatment
Experimental: Metformin, progesterone , estrace

12 weeks Metformin oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days (2X) oral estrace, 0.5-1 mg once a day for seven days (2X)

Drug: Metformin
500-2000 mg PO BID (X12 weeks)

Drug: Progesterone
oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days (X2)

Drug: estrace
oral estrogen (estrace, 0.5-1 mg once a day for seven days)- X2
Other Names:
  • Estrogen
  • Outcome Measures

    Primary Outcome Measures

    1. Change in Progesterone Sensitivity Index Before and After Metformin Treatment. [12 weeks following start of metformin treatment]

      The progesterone (P4) sensitivity index is defined as the percent change in 11-hour LH pulse frequency before and after P4 and estradiol administration for 7 days, divided by the day 7 mean serum P4 concentration. We compared the P4 sensitivity index after metformin administration to the baseline P4 sensitivity index, using Wilcoxon signed-rank test.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    10 Years to 17 Years
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Girls ages 10 to 17

    • Hyperandrogenemic (free testosterone greater than 2.5 standard deviations above the mean for normal control subjects of the same Tanner Stage)

    • Creatinine clearance > 90 ml/min as calculated by the Cockcroft-Gault equation

    • 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)

    • Creatinine clearance less than 90 ml/min as calculated by Cockcroft-Gault equation

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

    • Abnormal liver function tests, including Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Bilirubin, Albumin, and Alkaline Phosphatase

    • Weight < 34 kg

    • History of renal dysfunction, liver dysfunction, congestive heart failure, deep venous thrombosis, breast cancer, endometrial cancer, or cervical cancer

    • Pregnant or breast feeding

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

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

    • Subjects using restricted medication (see restrictions below) are excluded unless the subject's primary care provider approves stopping the medication.

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Center for Research in Reproduction, University of VirginiaCharlottesvilleVirginiaUnited States22908

    Sponsors and Collaborators

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

    Investigators

    • Principal Investigator: John C. Marshall, MD, PhD, University of Virginia

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Christine Burt Solorzano, Center for Research in Reproduction, University of Virginia
    ClinicalTrials.gov Identifier:
    NCT01427595
    Other Study ID Numbers:
    • 13789
    • U54HD028934-18
    First Posted:
    Sep 1, 2011
    Last Update Posted:
    Jan 8, 2021
    Last Verified:
    Dec 1, 2020
    Keywords provided by Christine Burt Solorzano, Center for Research in Reproduction, University of Virginia
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail25 subjects enrolled in this study. 7 subjects completed screening procedures only (these 7 subjects were withdrawn from study prior to being assigned to an arm of intervention).
    Arm/Group TitleMetformin, Progesterone , Estrace
    Arm/Group Description12 weeks Metformin oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days (2X) oral estrace, 0.5-1 mg once a day for seven days (2X) Metformin: 500-2000 mg PO BID (X12 weeks) Progesterone: oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days (X2) estrace: oral estrogen (estrace, 0.5-1 mg once a day for seven days)- X2
    Period Title: Overall Study
    STARTED25
    COMPLETED12
    NOT COMPLETED13

    Baseline Characteristics

    Arm/Group TitleMetformin, Progesterone , Estrace
    Arm/Group Description12 weeks Metformin oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days (2X) oral estrace, 0.5-1 mg once a day for seven days (2X) Metformin: 500-2000 mg PO BID (X12 weeks) Progesterone: oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days (X2) estrace: oral estrogen (estrace, 0.5-1 mg once a day for seven days)- X2
    Overall Participants10
    Age (Count of Participants)
    <=18 years
    10
    100%
    Between 18 and 65 years
    0
    0%
    >=65 years
    0
    0%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    15.3
    (1.2)
    Sex: Female, Male (Count of Participants)
    Female
    10
    100%
    Male
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    0
    0%
    White
    8
    80%
    More than one race
    2
    20%
    Unknown or Not Reported
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    10
    100%

    Outcome Measures

    1. Primary Outcome
    TitleChange in Progesterone Sensitivity Index Before and After Metformin Treatment.
    DescriptionThe progesterone (P4) sensitivity index is defined as the percent change in 11-hour LH pulse frequency before and after P4 and estradiol administration for 7 days, divided by the day 7 mean serum P4 concentration. We compared the P4 sensitivity index after metformin administration to the baseline P4 sensitivity index, using Wilcoxon signed-rank test.
    Time Frame12 weeks following start of metformin treatment

    Outcome Measure Data

    Analysis Population Description
    12 subjects completed study but 2 subjects were excluded from analysis due to incomplete adherence to metformin, missing > 10% of doses.
    Arm/Group TitleMetformin, Progesterone , Estrace
    Arm/Group Description12 weeks Metformin oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days (2X) oral estrace, 0.5-1 mg once a day for seven days (2X) Metformin: 500-2000 mg PO BID (X12 weeks) Progesterone: oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days (X2) estrace: oral estrogen (estrace, 0.5-1 mg once a day for seven days)- X2
    Measure Participants10
    Before Metformin
    -4.12
    (2.39)
    After Metformin
    -4.29
    (7.66)

    Adverse Events

    Time FrameFrom start of study procedures until 30 days post study drug.
    Adverse Event Reporting Description
    Arm/Group TitleMetformin, Progesterone , Estrace
    Arm/Group Description12 weeks Metformin oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days (2X) oral estrace, 0.5-1 mg once a day for seven days (2X) Metformin: 500-2000 mg PO BID (X12 weeks) Progesterone: oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days (X2) estrace: oral estrogen (estrace, 0.5-1 mg once a day for seven days)- X2
    All Cause Mortality
    Metformin, Progesterone , Estrace
    Affected / at Risk (%)# Events
    Total0/25 (0%)
    Serious Adverse Events
    Metformin, Progesterone , Estrace
    Affected / at Risk (%)# Events
    Total0/25 (0%)
    Other (Not Including Serious) Adverse Events
    Metformin, Progesterone , Estrace
    Affected / at Risk (%)# Events
    Total12/25 (48%)
    Cardiac disorders
    SVT1/25 (4%) 1
    Eye disorders
    Vision switched from near to farsighted1/25 (4%) 1
    Gastrointestinal disorders
    diarrhea2/25 (8%) 2
    Acute Gastroenteritis1/25 (4%) 1
    vomitting1/25 (4%) 1
    General disorders
    headache1/25 (4%) 1
    nausea2/25 (8%) 2
    fainting1/25 (4%) 1
    heartburn1/25 (4%) 1
    Infections and infestations
    Infection1/25 (4%) 1
    UTI3/25 (12%) 3
    Skin and subcutaneous tissue disorders
    rash1/25 (4%) 1

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT 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/TitleDr. Christine Burt Solorzano
    OrganizationUniversity of Virginia Center for Research in Reproduction
    Phone4342436911
    Emailpcos@virginia.edu
    Responsible Party:
    Christine Burt Solorzano, Center for Research in Reproduction, University of Virginia
    ClinicalTrials.gov Identifier:
    NCT01427595
    Other Study ID Numbers:
    • 13789
    • U54HD028934-18
    First Posted:
    Sep 1, 2011
    Last Update Posted:
    Jan 8, 2021
    Last Verified:
    Dec 1, 2020