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| ID | Type | Description | Link |
|---|---|---|---|
| HUM00008330 | Other Identifier | The University of Michigan IRBMED |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Normal Controls | No Intervention | Control subjects will have 5 visits (screening, oral glucose tolerance test (OGTT), neuropsychological testing, functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) as they will receive no treatment and will not have repeat studies. The baseline values obtained from the control subjects will be compared to the baseline values acquired from the PCOS affected subjects. | |
| PCOS Affected Women-Metformin Treatment | Experimental | Subjects with Polycystic Ovary Syndrome (PCOS) will be scheduled for 9 visits total: following the screening visit they will go through OGTT, neuro-psychological testing, fMRI and PET scan before and after 4 months of metformin use: 500mg tablets once daily with breakfast for 1 week, then increased to one tablet twice daily with breakfast & lunch for 1 week, then increased to one tablet three times daily with breakfast, lunch & dinner. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Metformin | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline and after 4 months |
| 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. | Baseline and after 4 months |
| 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.) | Baseline and after 4 months |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Yolanda R Smith, MD, MS | University of Michigan, Obstetrics and Gynecology | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Michigan, Michigan Clinical Research Unit | Ann Arbor | Michigan | 48109 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21486668 | Result | Berent-Spillson A, Love T, Pop-Busui R, Sowers M, Persad CC, Pennington KP, Eyvazaddeh AD, Padmanabhan V, Zubieta JK, Smith YR. Insulin resistance influences central opioid activity in polycystic ovary syndrome. Fertil Steril. 2011 Jun 30;95(8):2494-8. doi: 10.1016/j.fertnstert.2011.03.031. Epub 2011 Apr 12. | |
| 23557757 | Derived |
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Some potential subjects were excluded due to results of an oral glucose tolerance test (OGTT).
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)
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| ID | Title | Description |
|---|---|---|
| FG000 | Women Affected With PCOS - Metformin | The Polycystic Ovary Syndrome (PCOS) affected group is comprised of subjects with insulin resistant PCOS, defined as having irregular menstrual cycles and hyperandrogenism with other causes ruled out. Insulin resistance will be identified as fasting homeostasis model assessment insulin resistance (HOMA2-IR) of 60%S or less. |
| FG001 | Women Controls Without PCOS | Control group is comprised of subjects without PCOS. These women have normal menstrual cycles and no evidence of insulin resistance (fasting HOMA2 IR of 80%S or more). . Exclusion criteria: 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). |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Two controls were excluded from data analysis as they were later found to be insulin resistant.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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). |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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%. | Posted | Mean | Standard Deviation | ratio | Baseline and after 4 months |
|
Adverse events were followed in the course of 2 years.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Normal Controls | Women without PCOS |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| High Glucose During Oral Glucose Tolerance Test (OGTT) | Metabolism and nutrition disorders | Systematic Assessment | OGTT after 3 ½ months of Metformin. This event was unexpected as Metformin is prescribed to reduce the blood sugar levels and is a widely accepted anti-diabetic drug. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Yolanda Smith | University of Michigan | (734) 936-7401 | ysmith@umich.edu |
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| ID | Term |
|---|---|
| D011085 | Polycystic Ovary Syndrome |
| D007333 | Insulin Resistance |
| ID | Term |
|---|---|
| D010048 | Ovarian Cysts |
| D003560 | Cysts |
| D009369 | Neoplasms |
| D010049 | Ovarian Diseases |
| D000291 |
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| ID | Term |
|---|---|
| D008687 | Metformin |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
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|
|
| Baseline and 4 months |
| Marsh CA, Berent-Spillson A, Love T, Persad CC, Pop-Busui R, Zubieta JK, Smith YR. Functional neuroimaging of emotional processing in women with polycystic ovary syndrome: a case-control pilot study. Fertil Steril. 2013 Jul;100(1):200-7.e1. doi: 10.1016/j.fertnstert.2013.02.054. Epub 2013 Apr 1. |
| BG001 | 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 |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Weight | Body weight measured in pounds (lbs) | Median | Inter-Quartile Range | pounds (lbs) |
|
| BMI (Body Mass Index) | lbs/inches squared (pounds over inches squared) | Median | Inter-Quartile Range | lbs/inch^2 |
|
| Waist Circumference | Waist circumference measured in cm | Median | Inter-Quartile Range | cm |
|
| Free Testosterone | Free testosterone measured in picograms over milliliters | Median | Inter-Quartile Range | pg/ml |
|
| Total Testosterone | Total Testosterone measured in nanograms over milliliters | Median | Inter-Quartile Range | ng/ml |
|
| Total Cholesterol | Total cholesterol measured in milligrams over deciliter | Median | Inter-Quartile Range | mg/dl |
|
| DHEAS | Dehydroepiandrosterone Sulfate (DHEAS)measured in micrograms/deciliter | Median | Inter-Quartile Range | ug/dl |
|
| HDL | High-density lipoprotein measured in milligrams/deciliter | Median | Inter-Quartile Range | mg/dl |
|
| Triglycerides | Triglycerides measured in measured in milligrams/deciliter | Median | Inter-Quartile Range | mg/dl |
|
| Fasting Insulin | Fasting Insulin measured in microunits/milliliter | Median | Inter-Quartile Range | uU/ml |
|
| Fasting Glucose | Fasting Glucose measured in milligrams/deciliter | Median | Inter-Quartile Range | mg/dl |
|
| Homeostatic Model Assessment (HOMA) | Homeostatic model assessment sensitivity reported in percentage | Median | Inter-Quartile Range | % - percentage |
|
| HOMA-IR | Homeostatic model assessment insulin resistance measured in milliunits per Liters | Median | Inter-Quartile Range | mU/L |
|
| OG001 | PCOS Affected Women Post-Metformin (After 4 Months) | PCOS will be defined as meeting the criteria of irregular menstrual cycles and hyperandrogenism (on physical exam or laboratory testing), with other causes ruled out. Subjects with insulin resistant PCOS must meet criteria for insulin resistance based on the 2 hr OGTT (Oral Glucose Tolerance Test). Insulin resistance will be defined as fasting HOMA2 IR of 60%S or less. |
| OG002 | Normal Controls | Normal controls will have HOMA2 IR of 80%S or greater, normal hormone levels, regular menstrual cycles (range 24 - 34 days), and lack hirsutism and acne. Control subjects are matched for age and education with the PCOS affected women. Control data is measured once (at baseline time frame) for the entire study. |
|
|
|
| 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. | All 7 PCOS women were included, 2 controls were excluded because repeat baseline HOMA2-IR %S was <80%. | Posted | Mean | Standard Deviation | ratio | Baseline and after 4 months |
|
|
|
|
| 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.) | Posted | Mean | Standard Deviation | ratio | Baseline and after 4 months |
|
|
|
|
| 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. | Posted | Mean | Standard Deviation | ratio | Baseline and 4 months |
|
|
|
|
| 0 |
| 5 |
| 1 |
| 5 |
| EG001 | PCOS Affected Women on Metformin | Women with PCOS and insulin resistance | 0 | 7 | 1 | 7 |
|
| Nausea from Carfentanil at PET | General disorders | Systematic Assessment |
|
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| Adnexal Diseases |
| D005831 | Genital Diseases, Female |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D000091662 | Genital Diseases |
| D006058 | Gonadal Disorders |
| D004700 | Endocrine System Diseases |
| D006946 | Hyperinsulinism |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| 95 |
| No |
| Superiority or Other |
| t-test, 2 sided | 0.038 | 95 | No | Superiority or Other |
| 95 |
| No |
| Superiority or Other |
| t-test, 2 sided | 0.606 | 95 | No | Superiority or Other |
| 95 |
| No |
| Superiority or Other |
| t-test, 2 sided | 0.190 | 95 | No | Superiority or Other |