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

Study Description

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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	Not Applicable

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

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	11 participants
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 :	July 22, 2008
Estimated Primary Completion Date :	June 28, 2018
Estimated Study Completion Date :	December 2018

Arms and Interventions

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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 Name: Estrogen

Outcome Measures

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Primary Outcome Measures :

1. Change in LH pulse frequency before and after Metformin treatment. [ Time Frame: 12 weeks following start of metformin treatment ]
   The primary aim will be to compare the change in 11-hour LH pulse frequency between the 1st and the 2nd admissions (Δ(2-1)) to the change in the 11-hour LH pulse frequency between the 3rd and the 4th admissions (Δ(4-3)).

Eligibility Criteria

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Ages Eligible for Study:	10 Years to 17 Years (Child)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	No

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.

Contacts and Locations

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Locations

United States, Virginia
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

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Christine Burt Solorzano, Center for Research in Reproduction, University of Virginia
ClinicalTrials.gov Identifier:	NCT01427595 History of Changes
Other Study ID Numbers:	13789; U54HD028934-18 ( U.S. NIH Grant/Contract )
First Posted:	September 1, 2011
Last Update Posted:	January 23, 2018
Last Verified:	January 2018

Keywords provided by Christine Burt Solorzano, University of Virginia:

hyperandrogenemia

Additional relevant MeSH terms:

Polycystic Ovary Syndrome; Hyperandrogenism; Ovarian Cysts; Cysts; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Gonadal Disorders; Endocrine System Diseases; 46, XX Disorders of Sex Development; Disorders of Sex Development; Urogenital Abnormalities; Adrenogenital Syndrome; Congenital Abnormalities	Metformin; Estradiol; Estrogens; Polyestradiol phosphate; Progesterone; Estradiol 3-benzoate; Estradiol 17 beta-cypionate; Estradiol valerate; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progestins; Contraceptive Agents; Reproductive Control Agents