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

NCT ID: NCT01427595

Last Updated: 2021-01-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 25 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-02-18
• Study Completion Date: 2015-01-17

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).

Conditions

Polycystic Ovary Syndrome; Hyperandrogenism

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

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)

Group Type: EXPERIMENTAL

Metformin

Intervention Type: DRUG

500-2000 mg PO BID (X12 weeks)

Progesterone

Intervention Type: DRUG

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

estrace

Intervention Type: DRUG

oral estrogen (estrace, 0.5-1 mg once a day for seven days)- X2

Interventions

Metformin

500-2000 mg PO BID (X12 weeks)

Intervention Type: 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)

Intervention Type: DRUG

estrace

oral estrogen (estrace, 0.5-1 mg once a day for seven days)- X2

Intervention Type: DRUG

Other Intervention Names

Estrogen

Eligibility Criteria

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.

• Minimum Eligible Age: 10 Years
• Maximum Eligible Age: 17 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

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

NIH

Sponsor Role: collaborator

University of Virginia

OTHER

Sponsor Role: lead

Responsible Party

Christine Burt Solorzano

Center for Research in Reproduction

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

John C. Marshall, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Virginia

Locations

Center for Research in Reproduction, University of Virginia

Charlottesville, Virginia, United States

Countries

United States

References

Lundgren JA, Kim SH, Burt Solorzano CM, McCartney CR, Marshall JC. Progesterone Suppression of Luteinizing Hormone Pulse Frequency in Adolescent Girls With Hyperandrogenism: Effects of Metformin. J Clin Endocrinol Metab. 2018 Jan 1;103(1):263-270. doi: 10.1210/jc.2017-02068.

Reference Type: DERIVED

PMID: 29095983 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

U54HD028934-18

Identifier Type: NIH

Identifier Source: secondary_id

View Link

13789

Identifier Type: -

Identifier Source: org_study_id