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

NCT01427595 | Completed Results

• 2 other identifiers: 13789U54HD028934-18
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

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.

Conditions

Polycystic Ovary Syndrome; Hyperandrogenism

Keywords

hyperandrogenemia

Outcome Measures

Primary Outcomes (1)

• 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

Study Arms (1)

Metformin, progesterone , estrace

EXPERIMENTAL

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; Drug: Progesterone; Drug: estrace

Interventions

Metformin DRUG

500-2000 mg PO BID (X12 weeks)

Metformin, progesterone , estrace

Progesterone DRUG

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

Metformin, progesterone , estrace

estrace DRUG

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

Also known as: Estrogen

Metformin, progesterone , estrace

Eligibility Criteria

• Age: 10 Years - 17 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

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

Study Sites (1)

Center for Research in Reproduction, University of Virginia

Charlottesville, Virginia, 22908, United States

Location

Related Publications (1)

• 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.

  PMID: 29095983 DERIVED

MeSH Terms

Conditions

Polycystic Ovary Syndrome; Hyperandrogenism

Interventions

Metformin; Progesterone; Estradiol; Estrogens

Condition Hierarchy (Ancestors)

Ovarian Cysts; Cysts; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Gonadal Disorders; Endocrine System Diseases; 46, XX Disorders of Sex Development; Disorders of Sex Development; Urogenital Abnormalities; Adrenogenital Syndrome; Male Urogenital Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Corpus Luteum Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progesterone Congeners; Gonadal Steroid Hormones; Estrenes; Estranes; Estradiol Congeners; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses

Results Point of Contact

• Title: Dr. Christine Burt Solorzano
• Organization: University of Virginia Center for Research in Reproduction

pcos@virginia.edu

4342436911

Study Officials

• John C. Marshall, MD, PhD

  University of Virginia

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Center for Research in Reproduction

Study Record Dates

• First Submitted: August 30, 2011
• First Posted: September 1, 2011
• Study Start: February 18, 2009
• Primary Completion: January 17, 2015
• Study Completion: January 17, 2015
• Last Updated: January 8, 2021
• Results First Posted: January 8, 2021

Record last verified: 2020-12

Locations

US (1)