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

Study Overview
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Brief Summary
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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
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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).

Official Title
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Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression by Estradiol and Progesterone in Hyperandrogenemic Adolescent Girls (JCM025)

Conditions
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Polycystic Ovary Syndrome, Hyperandrogenism

Intervention / Treatment
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* Drug: Metformin
* Drug: Progesterone
* Drug: estrace


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin, progesterone , estrace<br>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<br>* 500-2000 mg PO BID (X12 weeks)<br>Drug: Progesterone<br>* oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days (X2)<br>Drug: estrace<br>* oral estrogen (estrace, 0.5-1 mg once a day for seven days)- X2<br>* Other names: Estrogen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Progesterone Sensitivity Index Before and After 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. | 12 weeks following start of metformin treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hyperandrogenemia