Hyperandrogenism, Polycystic Ovary Syndrome
Conditions
Keywords
hyperandrogenemia
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).
Interventions
DRUGMetformin
500-2000 mg PO BID (X12 weeks)
DRUGProgesterone
oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days (X2)
DRUGestrace
oral estrogen (estrace, 0.5-1 mg once a day for seven days)- X2
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of Virginia
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
10 Years to 17 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Pre-assignment details
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).
Participants by arm
| Arm | Count |
|---|---|
| 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)
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 | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | Metformin, Progesterone , Estrace |
|---|---|
| Age, Categorical <=18 years | 10 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 15.3 years STANDARD_DEVIATION 1.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 25 |
| other Total, other adverse events | 12 / 25 |
| serious Total, serious adverse events | 0 / 25 |
Outcome results
Primary
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.
Time frame: 12 weeks following start of metformin treatment
Population: 12 subjects completed study but 2 subjects were excluded from analysis due to incomplete adherence to metformin, missing \> 10% of doses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin, Progesterone , Estrace | Change in Progesterone Sensitivity Index Before and After Metformin Treatment. | Before Metformin | -4.12 % change in LH pulses/day 7 P4 level | Standard Deviation 2.39 |
| Metformin, Progesterone , Estrace | Change in Progesterone Sensitivity Index Before and After Metformin Treatment. | After Metformin | -4.29 % change in LH pulses/day 7 P4 level | Standard Deviation 7.66 |