Polycystic Ovary Syndrome
Conditions
Brief summary
Our hypothesis is that hyperinsulinemia increases the renal clearance of D-chiro-inositol (DCI) in women with polycystic ovary syndrome (PCOS) and that this leads to a reduction in circulating insulin-stimulated D-chiro-inositol-containing inositol phosphoglycan (DCI-IPG) release. To assess the effects of a chronic reduction in circulating insulin on DCI metabolism, we propose to reduce circulating insulin in obese women with PCOS by improving insulin sensitivity with the drug pioglitazone. Pioglitazone is a thiazolidinedione that improves peripheral insulin sensitivity, presumably by activation of the peroxisome proliferator-activated receptor gamma (PPARγ) receptor. Administration of pioglitazone to women with PCOS has been shown to improve insulin sensitivity, reduce insulin secretion, and decrease both fasting and post-prandial serum insulin concentrations.
Detailed description
This protocol focuses on the hypothesis that a deficiency in a putative inositolphosphoglycan (IPG) mediator of insulin action, namely a D-chiro-inositol-containing IPG (DCI-IPG), contributes to the insulin resistance of some women with PCOS. Our interest in this area stems directly from our previous studies, which demonstrated that administration of the precursor, D-chiro-inositol (DCI), to both obese and lean women with PCOS improved glucose intolerance while reducing circulating insulin, and simultaneously improved ovulatory function and decreased serum androgens. These findings were recently confirmed in a large-scale study by an independent group. The findings of these three studies suggested that administration of DCI improved insulin sensitivity in PCOS, which then resulted in an improved hormonal and metabolic milieu.
Interventions
DRUGpioglitazone
pioglitazone 45 mg
DRUGPlacebo
placebo daily
Sponsors
Virginia Commonwealth University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
HEALTH_SERVICES_RESEARCH
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
1. Obese (Body Mass Index or BMI greater than or equal to 30 kg/m2) women with PCOS between 18-40 years of age: * oligomenorrhea (less than 8 menstrual periods annually) * biochemical hyperandrogenemia (elevated total or free testosterone) * normal thyroid function tests and serum prolactin; AND * exclusion of 21a-hydroxylase deficiency by a fasting 17a-hydroxyprogesterone less than 200 ng/dl.51, 2. acceptable health on the basis of interview, medical history, physical examination, and laboratory tests (Complete Blood Chemistry or CBC, Comprehensive Metabolic Panel denoted SMA20, urinalysis, negative pregnancy test). 3. Signed, witnessed informed consent. 4. Ability to comply with study requirements.
Exclusion criteria
1. Diabetes mellitus by fasting glucose or oral glucose tolerance test (OGTT), or clinically significant pulmonary, cardiac, renal, hepatic, neurologic, psychiatric, infectious, neoplastic and malignant disease (other than non-melanoma skin cancer). 2. Current use of oral contraceptives. 3. Documented or suspected recent (within one year) history of drug abuse or alcoholism. 4. Ingestion of any investigational drug within two months prior to study onset.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC DCI-IPG (%/Min) | Baseline | Change in the Area Under the Curve DCI-IPG measurements in blood samples taken at 15 minute intervals during the 2 hour OGTT before treatment with pioglitazone or placebo. Values reported as a percentage of bioactivity measured at time 0. Negative values indicate a decrease relative to the time 0 measurement. |
| Fasting Serum Insulin | baseline | Fasting serum insulin (uIU.min/ml) measured at 0, 60 and 120 minutes of a 2 hour OGTT before treatment with either pioglitazone or placebo |
| Fasting Serum Insulin (uIU/ml) | 6 months | Fasting serum insulin (uIU.min/ml) measured at 0, 60 and 120 minutes of a 2 hour OGTT following 6 months treatment with either pioglitazone or placebo |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Matsuda Index | Baseline | Whole body insulin sensitivity as determined by the Matsuda Index as calculated using the following formula: 10,000 divided by the square root of (FPI\* FPG) \* (xGPC\* xIPC) Where FPI is fasting plasma insulin expressed as uU/ml, FPG is fasting plasma glucose expressed as mg/dL, xGPC is mean plasma glucose concentration after the load and xIPC is the mean insulin concentration after the load. Values calculated on samples taken at 0, 30, 60, 90 and 120 minutes of a 2 hour OGTT. Values typically range from 0 to 12 units with higher scores indicating better insulin sensitivity. A value of 2.5 or less is indicative of insulin resistance. |
Countries
United States, Venezuela
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1/Pioglitazaone Treated Pioglitazone treated subjects
pioglitazone: pioglitazone 45 mg | 16 |
| 2/Placebo Placebo control to arm 1
Placebo: placebo daily | 16 |
| Total | 32 |
Baseline characteristics
| Characteristic | 1/Pioglitazaone Treated | 2/Placebo | 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 | 16 Participants | 16 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 9 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 7 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 14 Participants | 14 Participants | 28 Participants |
| Region of Enrollment Venezuela | 16 participants | 16 participants | 32 participants |
| Sex/Gender, Customized Females | 16 participants | 16 participants | 32 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 26 | 0 / 25 |
| serious Total, serious adverse events | 0 / 26 | 0 / 25 |
Outcome results
Primary
AUC DCI-IPG (%/Min)
Change in the Area Under the Curve DCI-IPG measurements in blood samples taken at 15 minute intervals during the 2 hour OGTT before treatment with pioglitazone or placebo. Values reported as a percentage of bioactivity measured at time 0. Negative values indicate a decrease relative to the time 0 measurement.
Time frame: Baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1/Pioglitazaone Treated | AUC DCI-IPG (%/Min) | 13162.06 % bioactivity at time 0 of OGTT | Standard Error 1240.6 |
| 2/Placebo | AUC DCI-IPG (%/Min) | 14054.17 % bioactivity at time 0 of OGTT | Standard Error 1373.1 |
Primary
AUC DCI-IPG (%/Min)
Change in the Area Under the Curve DCI-IPG measurements in blood samples taken at 15 minute intervals during the 2 hour OGTT following 6 months of treatment with pioglitazone or placebo. Values reported as a percentage of bioactivity measured at time 0. Negative values indicate a decrease relative to the time 0 measurement.
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1/Pioglitazaone Treated | AUC DCI-IPG (%/Min) | -412.22 % bioactivity at time 0 of OGTT | Standard Error 1295.7 |
| 2/Placebo | AUC DCI-IPG (%/Min) | -699.45 % bioactivity at time 0 of OGTT | Standard Error 1890.71 |
Primary
Fasting Serum Insulin
Fasting serum insulin (uIU.min/ml) measured at 0, 60 and 120 minutes of a 2 hour OGTT before treatment with either pioglitazone or placebo
Time frame: baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1/Pioglitazaone Treated | Fasting Serum Insulin | 15.04 uIU.min/ml | Standard Error 1.23 |
| 2/Placebo | Fasting Serum Insulin | 15.91 uIU.min/ml | Standard Error 1.32 |
Primary
Fasting Serum Insulin (uIU/ml)
Fasting serum insulin (uIU.min/ml) measured at 0, 60 and 120 minutes of a 2 hour OGTT following 6 months treatment with either pioglitazone or placebo
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1/Pioglitazaone Treated | Fasting Serum Insulin (uIU/ml) | -8.69 uIU.min/ml | Standard Error 1.23 |
| 2/Placebo | Fasting Serum Insulin (uIU/ml) | -0.24 uIU.min/ml | Standard Error 1.5 |
Secondary
Matsuda Index
Whole body insulin sensitivity as determined by the Matsuda Index as calculated using the following formula: 10,000 divided by the square root of (FPI\* FPG) \* (xGPC\* xIPC) Where FPI is fasting plasma insulin expressed as uU/ml, FPG is fasting plasma glucose expressed as mg/dL, xGPC is mean plasma glucose concentration after the load and xIPC is the mean insulin concentration after the load. Values calculated on samples taken at 0, 30, 60, 90 and 120 minutes of a 2 hour OGTT. Values typically range from 0 to 12 units with higher scores indicating better insulin sensitivity. A value of 2.5 or less is indicative of insulin resistance.
Time frame: Baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1/Pioglitazaone Treated | Matsuda Index | 3.36 units on a scale | Standard Error 0.18 |
| 2/Placebo | Matsuda Index | 3.05 units on a scale | Standard Error 0.15 |
Secondary
Matsuda Index
Whole body insulin sensitivity as determined by the Matsuda Index
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1/Pioglitazaone Treated | Matsuda Index | 4.29 units on a scale | Standard Error 0.36 |
| 2/Placebo | Matsuda Index | 0.29 units on a scale | Standard Error 0.17 |