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)
• Enrollment: 25
• Location: 1
• Arm: 1
• Actual Duration (Months): 70.9
• Patients Per Site Per Month: 0.4

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.

Condition or Disease	Intervention/Treatment	Phase
Polycystic Ovary Syndrome; Hyperandrogenism	Drug: Metformin; Drug: Progesterone; Drug: estrace	N/A

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

Arm	Intervention/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

	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: John C. Marshall, MD, PhD, University of Virginia

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 14, 2015
• Informed Consent Form - Dec 14, 2015

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: hyperandrogenemia
• Additional relevant MeSH terms: Polycystic Ovary Syndrome; Hyperandrogenism; Metformin; Progesterone; Estradiol; Estrogens

Study Results

Participant Flow

Pre-assignment Detail	25 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 Title	Metformin, Progesterone , Estrace
Arm/Group Description	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) 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
STARTED	25
COMPLETED	12
NOT COMPLETED	13

Baseline Characteristics

Arm/Group Title	Metformin, Progesterone , Estrace
Arm/Group Description	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) 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 Participants	10
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

Title	Change in Progesterone Sensitivity Index Before and After Metformin Treatment.
Description	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.
Time Frame	12 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 Title	Metformin, Progesterone , Estrace
Arm/Group Description	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) 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 Participants	10
Before Metformin	-4.12 (2.39)
After Metformin	-4.29 (7.66)

Adverse Events

Time Frame	From start of study procedures until 30 days post study drug.
Arm/Group Title	Metformin, Progesterone , Estrace
Arm/Group Description	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) 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
Total	0/25 (0%)
Serious Adverse Events
	Metformin, Progesterone , Estrace
	Affected / at Risk (%)	# Events
Total	0/25 (0%)
Other (Not Including Serious) Adverse Events
	Metformin, Progesterone , Estrace
	Affected / at Risk (%)	# Events
Total	12/25 (48%)
Cardiac disorders
SVT	1/25 (4%)	1
Eye disorders
Vision switched from near to farsighted	1/25 (4%)	1
Gastrointestinal disorders
diarrhea	2/25 (8%)	2
Acute Gastroenteritis	1/25 (4%)	1
vomitting	1/25 (4%)	1
General disorders
headache	1/25 (4%)	1
nausea	2/25 (8%)	2
fainting	1/25 (4%)	1
heartburn	1/25 (4%)	1
Infections and infestations
Infection	1/25 (4%)	1
UTI	3/25 (12%)	3
Skin and subcutaneous tissue disorders
rash	1/25 (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.