Polycystic Ovary Syndrome
Conditions
Keywords
Polycystic Ovary Syndrome, Insulin resistance, Metformin, Brain function
Brief summary
The purpose of this study is to evaluate the effects of insulin resistance on brain function in women with Polycystic Ovary Syndrome (PCOS). PCOS affected women will be evaluated prior to and following 4-month treatment with Metformin. Additionally, brain function in women with PCOS will be compared to the brain activity in normal control subjects with regular menstrual cycles.
Detailed description
The pathogenesis of Polycystic Ovary Syndrome (PCOS), a reproductive and metabolic disorder, is associated with insulin resistance. The effects of insulin resistance on cognition, mood, opioid system and reproductive function in PCOS affected women are investigated in the current study. The identification of reversible changes in brain function and reproductive measures in insulin resistant PCOS patients would likely significantly influence treatment protocols for these young women. 1. Evaluate the differences in opioid tone in women with insulin resistant PCOS compared to normal controls. 2. Evaluate whether an oral hypoglycemic agent is capable of altering opioid tone in women with insulin resistant PCOS.
Interventions
DRUGMetformin
Following the baseline studies, PCOS affected women will be initiated on metformin at a dose of 500 mg orally after breakfast and the dose will be increased the following week to 500 mg twice daily (BID), adding a dose after lunch. On the third week, the dose will be increased to 500 mg three times daily (TID), adding a 500 mg tablet after supper. All subjects will be monitored for possible side effects such as nausea, vomiting, diarrhea, anorexia, and abdominal discomfort. These side effects tend to be mild, dose-related and improve with continued use of metformin. Hypoglycemia is rare and tends to occur in the setting of alcohol abuse or prolonged starvation. Malabsorption of vitamin B12 and folate occurs with long-term treatment, although it usually does not lead to anemia.
Sponsors
University of Michigan
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
21 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
* Insulin-resistant PCOS (Arm: PCOS Affected Women) * Irregular menstrual cycle (Arm: PCOS Affected Women) * Hyperandrogenism (Arm: PCOS Affected Women) * Regular menstrual cycles (Arm: Normal Controls) * Normal hormonal levels (Arm: Normal Controls) * Lack of hirsutism (Arm: Normal Controls) * Acne-free (Arm: Normal Controls) * Candidates are BMI-matched and screened for insulin resistance prior to inclusion. (Arm: Normal Controls)
Exclusion criteria
* Left handedness * Acute medical illness * Uncorrected thyroid disease * Diabetes renal * Cardiac or pulmonary insufficiency * Active liver disease * Neurological disease * Current psychiatric illness * Claustrophobia * Contraindications to MRI * Smoking * Use of hormones * Centrally acting or insulin sensitizing mediations * Allergy to any opioid medication * Substance abuse * Pregnancy * BMI \>35.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mu-opioid Binding Potential Measured in Left Nucleus Accumbens | Baseline and after 4 months | Mu-opioid binding potential in left nucleus accumbens is measured before and after 4 months of Metformin treatment. Mu-opioid binding potential is measured in vivo with C11-carfentanil positron emission tomography in women with PCOS before and after 4 months of metformin treatment. Binding Potential is measured by the ratio of Mu-opioid receptor concentration (Bmax)/Receptor radiotracer (C11-carfentanil) affinity (Kd.) Control group was measured at baseline only. |
| Mu-opioid Binding Potential Measured in Right Nucleus Accumbens | Baseline and after 4 months | Mu-opioid binding potential in right nucleus accumbens measured before and after 4 months of Metformin treatment. Mu-opioid binding potential is measured in vivo with C11-carfentanil positron emission tomography in women with PCOS before and after 4 months of metformin treatment. Binding Potential is measured by the ratio of Mu-opioid receptor concentration (Bmax)/Receptor radiotracer (C11-carfentanil) affinity (Kd.) Control group was measured at baseline only. |
| Mu-opioid Binding Potential Measured in Left Amygdala | Baseline and after 4 months | Mu-opioid binding potential in left amygdala measured before and after 4 months of Metformin treatment. Mu-opioid binding potential is measured in vivo with C11-carfentanil positron emission tomography in women with PCOS before and after 4 months of metformin treatment. Binding Potential is measured by the ratio of Mu-opioid receptor concentration (Bmax)/Receptor radiotracer (C11-carfentanil) affinity (Kd.) |
| Mu-opioid Binding Potential Measured in Right Amygdala | Baseline and 4 months | Mu-opioid binding potential in right amygdala measured before and after 4 months of Metformin treatment. Mu-opioid binding potential is measured in vivo with C11-carfentanil positron emission tomography in women with PCOS before and after 4 months of metformin treatment. Binding Potential is measured by the ratio of Mu-opioid receptor concentration (Bmax)/Receptor radiotracer (C11-carfentanil) affinity (Kd.) Control group was measured at baseline only. |
Countries
United States
Participant flow
Recruitment details
Volunteers between the ages of 21 - 40 years were recruited from reproductive endocrinology clinic and newspapers. Women were excluded according to protocol exclusion criteria (see protocol)
Pre-assignment details
Some potential subjects were excluded due to results of an oral glucose tolerance test (OGTT).
Participants by arm
| Arm | Count |
|---|---|
| PCOS Affected Women - Metformin Right handed women who don't smoke and who drink very little will be considered eligible. Women with the following conditions (exclusion criteria) may not participate: left handedness, acute medical illness, uncorrected thyroid disease, diabetes, neurological disease, current psychiatric illness, smoking within the last 6 months, use of hormones within the last 2 months, pregnancy within the last 6 months, current or past history of substance abuse, use of corticosteroids (such as cortisol and prednisone), history of lactic acidosis (condition caused by the buildup of lactic acid in the body), heart, lung and kidney problems, liver disease, use of intravenous dyes, current cimetidine (Tagamet) use, use of medications that affect the brain (for example, codeine, anti-depressants, anti-psychotics). | 7 |
| Normal Controls Normal controls are matched for age and education and screened for insulin resistance. Controls will have HOMA2 IR of 80%S or greater, normal hormone levels, regular menstrual cycles, and lack hirsutism and acne. Exclusion criteria: Left handedness, acute medical illness, uncorrected thyroid disease, diabetes, neurological disease, current psychiatric illness, claustrophobia, contraindications to MRI (including pacemakers, pumps, surgical clips or metallic surgical devices), smoking within the last 6 months, use of hormones or insulin sensitizing mediation within the last 2 months, pregnancy within the last 6 months, current or past history of substance abuse, use of corticosteroids, cardiac or pulmonary insufficiency, active liver disease and transaminases elevations \>2.5 X normal values, renal insufficiency (plasma creatinine level ≥1.4 mg/dl), use of centrally acting medications, allergy to any opioid medication, 300 lbs maximum weight limit (which is the max | 5 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | 2 controls were insulin resistant | 0 | 2 |
Baseline characteristics
| Characteristic | PCOS Affected Women - Metformin | Normal Controls | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 5 Participants | 12 Participants |
| Age, Continuous | 26.3 years STANDARD_DEVIATION 4 | 26.6 years STANDARD_DEVIATION 4 | 26.4 years STANDARD_DEVIATION 4 |
| BMI (Body Mass Index) | 35.3 lbs/inch^2 | 23 lbs/inch^2 | 29.5 lbs/inch^2 |
| DHEAS | 200 ug/dl | 189 ug/dl | 191 ug/dl |
| Fasting Glucose | 87 mg/dl | 89 mg/dl | 89 mg/dl |
| Fasting Insulin | 21.4 uU/ml | 8.1 uU/ml | 17.25 uU/ml |
| Free Testosterone | 1.5 pg/ml | .5 pg/ml | 1 pg/ml |
| HDL | 47 mg/dl | 76 mg/dl | 55.5 mg/dl |
| HOMA-IR | 2.7 mU/L | 1 mU/L | 2.150 mU/L |
| Homeostatic Model Assessment (HOMA) | 36.6 % - percentage | 95.4 % - percentage | 46.65 % - percentage |
| Region of Enrollment United States | 7 participants | 5 participants | 12 participants |
| Sex: Female, Male Female | 7 Participants | 5 Participants | 12 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Total Cholesterol | 157 mg/dl | 179 mg/dl | 174 mg/dl |
| Total Testosterone | .7 ng/ml | .36 ng/ml | .55 ng/ml |
| Triglycerides | 74 mg/dl | 72 mg/dl | 73 mg/dl |
| Waist Circumference | 102 cm | 72 cm | 92 cm |
| Weight | 203.9 pounds (lbs) | 123.7 pounds (lbs) | 170.48 pounds (lbs) |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 5 | 1 / 7 |
| serious Total, serious adverse events | 0 / 5 | 0 / 7 |
Outcome results
Primary
Mu-opioid Binding Potential Measured in Left Amygdala
Mu-opioid binding potential in left amygdala measured before and after 4 months of Metformin treatment. Mu-opioid binding potential is measured in vivo with C11-carfentanil positron emission tomography in women with PCOS before and after 4 months of metformin treatment. Binding Potential is measured by the ratio of Mu-opioid receptor concentration (Bmax)/Receptor radiotracer (C11-carfentanil) affinity (Kd.)
Time frame: Baseline and after 4 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PCOS Affected Women Pre-Metformin (Baseline) | Mu-opioid Binding Potential Measured in Left Amygdala | 2.28 ratio | Standard Deviation 0.17 |
| PCOS Affected Women Post-Metformin (After 4 Months) | Mu-opioid Binding Potential Measured in Left Amygdala | 2.08 ratio | Standard Deviation 0.19 |
| Normal Controls | Mu-opioid Binding Potential Measured in Left Amygdala | 2.03 ratio | Standard Deviation 0.07 |
p-value: 0.498t-test, 2 sided
p-value: 0.835t-test, 2 sided
p-value: 0.606t-test, 2 sided
Primary
Mu-opioid Binding Potential Measured in Left Nucleus Accumbens
Mu-opioid binding potential in left nucleus accumbens is measured before and after 4 months of Metformin treatment. Mu-opioid binding potential is measured in vivo with C11-carfentanil positron emission tomography in women with PCOS before and after 4 months of metformin treatment. Binding Potential is measured by the ratio of Mu-opioid receptor concentration (Bmax)/Receptor radiotracer (C11-carfentanil) affinity (Kd.) Control group was measured at baseline only.
Time frame: Baseline and after 4 months
Population: All 7 PCOS women completed the protocol and were included. 5 of 7 controls were included in this analysis. 2 controls were excluded from analysis because repeat baseline OGTT showed HOMA %S of \<80%.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PCOS Affected Women Pre-Metformin (Baseline) | Mu-opioid Binding Potential Measured in Left Nucleus Accumbens | 1.95 ratio | Standard Deviation 0.17 |
| PCOS Affected Women Post-Metformin (After 4 Months) | Mu-opioid Binding Potential Measured in Left Nucleus Accumbens | 1.65 ratio | Standard Deviation 0.27 |
| Normal Controls | Mu-opioid Binding Potential Measured in Left Nucleus Accumbens | 1.53 ratio | Standard Deviation 0.28 |
p-value: 0.143t-test, 2 sided
p-value: 0.9t-test, 2 sided
p-value: 0.133t-test, 2 sided
Primary
Mu-opioid Binding Potential Measured in Right Amygdala
Mu-opioid binding potential in right amygdala measured before and after 4 months of Metformin treatment. Mu-opioid binding potential is measured in vivo with C11-carfentanil positron emission tomography in women with PCOS before and after 4 months of metformin treatment. Binding Potential is measured by the ratio of Mu-opioid receptor concentration (Bmax)/Receptor radiotracer (C11-carfentanil) affinity (Kd.) Control group was measured at baseline only.
Time frame: Baseline and 4 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PCOS Affected Women Pre-Metformin (Baseline) | Mu-opioid Binding Potential Measured in Right Amygdala | 2.28 ratio | Standard Deviation 0.23 |
| PCOS Affected Women Post-Metformin (After 4 Months) | Mu-opioid Binding Potential Measured in Right Amygdala | 2.11 ratio | Standard Deviation 0.22 |
| Normal Controls | Mu-opioid Binding Potential Measured in Right Amygdala | 2.06 ratio | Standard Deviation 0.26 |
p-value: 0.118t-test, 2 sided
p-value: 0.581t-test, 2 sided
p-value: 0.19t-test, 2 sided
Primary
Mu-opioid Binding Potential Measured in Right Nucleus Accumbens
Mu-opioid binding potential in right nucleus accumbens measured before and after 4 months of Metformin treatment. Mu-opioid binding potential is measured in vivo with C11-carfentanil positron emission tomography in women with PCOS before and after 4 months of metformin treatment. Binding Potential is measured by the ratio of Mu-opioid receptor concentration (Bmax)/Receptor radiotracer (C11-carfentanil) affinity (Kd.) Control group was measured at baseline only.
Time frame: Baseline and after 4 months
Population: All 7 PCOS women were included, 2 controls were excluded because repeat baseline HOMA2-IR %S was \<80%.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PCOS Affected Women Pre-Metformin (Baseline) | Mu-opioid Binding Potential Measured in Right Nucleus Accumbens | 2.40 ratio | Standard Deviation 0.11 |
| PCOS Affected Women Post-Metformin (After 4 Months) | Mu-opioid Binding Potential Measured in Right Nucleus Accumbens | 2.11 ratio | Standard Deviation 0.21 |
| Normal Controls | Mu-opioid Binding Potential Measured in Right Nucleus Accumbens | 2.05 ratio | Standard Deviation 0.28 |
p-value: 0.049t-test, 2 sided
p-value: 0.717t-test, 2 sided
p-value: 0.038t-test, 2 sided