PED/PEA-15 Protein, PCOS, Obesity, Insulin Sensitivity Indexes, Metformin, Oral Contraceptives
Overview[ - collapse ][ - ]
| Purpose | Insulin-resistance plays an important role in polycystic ovary syndrome (PCOS) physiopathology. The phosphoprotein enriched in the diabetes (PED/PEA-15), a 15 kDa protein related to insulin sensitivity, is over-expressed in type 2 diabetic patients and in PCOS women, independently of obesity. The effectiveness of oral contraceptives pills (OCP) or metformin (MET) in PCOS management is still uncertain. Aim of this pilot clinical study was to compare the effects of OCPs or MET on the expression of PED/PEA-15 in association with insulin sensitivity in obese PCOS women. Outcome measures: PED/PEA-15, BMI, plasma glucose and insulin, 1/HOMA-IR, homeostasis model assessment of insulin resistance; QUICKI, quantitative insulin sensitivity check index; ISI: whole-body insulin sensitivity index. Study design: twenty obese PCOS women (age: 24.7±18 yr; BMI: 30±2.4 kg/m2) were randomized according to insulin sensitivity to receive 30 µg ethinylestradiol plus 30 mg drospirenone 21 day/month or MET 1250 mg three times daily for 6 months. Results: At baseline, age and BMI were not different in the two groups; PED/PEA-15 protein expression was higher in MET than in OCP group (p=0.011), along with higher 1/HOMA-IR (p=0.004), and lower QUICKI and ISI (p=0.003 and p<0.001, respectively). After treatment, independently of body weight, only in MET group PED/PEA-15 decreased (p=0.004), along with insulin and 1/HOMA-IR (p<0.001), and QUICKI and ISI increased (p<0.001). Insulin sensitivity indexes improvement correlated significantly with PED/PEA-15 protein expression, but not with BMI. Conclusions: PED/PEA-15 protein over-expression in obese PCOS women with IR reduced after a six month treatment with MET, while remained unchanged in the OCP group. The reduction was independent of body weight, and correlated with insulin sensitivity indexes. This effect further supported MET as a more effective therapy than OCPs for obese PCOS women with IR, also when fertility is not required. |
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| Condition | Polycystic Ovarian Syndrome Insulin Sensitivity |
| Intervention | Drug: Metformin Drug: oral contraceptive |
| Phase | Phase 3 |
| Sponsor | Federico II University |
| Responsible Party | Federico II University |
| ClinicalTrials.gov Identifier | NCT00948402 |
| First Received | July 24, 2009 |
| Last Updated | October 13, 2009 |
| Last verified | October 2009 |
Tracking Information[ + expand ][ + ]
| First Received Date | July 24, 2009 |
|---|---|
| Last Updated Date | October 13, 2009 |
| Start Date | December 2006 |
| Estimated Primary Completion Date | January 2009 |
| Current Primary Outcome Measures | PED/PEA-15 protein expression [Time Frame: 6 months] [Designated as safety issue: No] |
| Current Secondary Outcome Measures | BMI, plasma glucose, plasma insulin, insulin sensitivity indexes (1/HOMA-IR, homeostasis model assessment of insulin resistance; QUICKI, quantitative insulin sensitivity check index; ISI, whole-body insulin sensitivity index). [Time Frame: 6 months] [Designated as safety issue: No] |
Descriptive Information[ + expand ][ + ]
| Brief Title | PED/PEA-15 Protein, PCOS, Obesity, Insulin Sensitivity Indexes, Metformin, Oral Contraceptives |
|---|---|
| Official Title | Effects of Metformin Versus Oral Contraceptives on PED/PEA-15 Protein Expression in Obese Women With Polycystic Ovary Syndrome |
| Brief Summary | Insulin-resistance plays an important role in polycystic ovary syndrome (PCOS) physiopathology. The phosphoprotein enriched in the diabetes (PED/PEA-15), a 15 kDa protein related to insulin sensitivity, is over-expressed in type 2 diabetic patients and in PCOS women, independently of obesity. The effectiveness of oral contraceptives pills (OCP) or metformin (MET) in PCOS management is still uncertain. Aim of this pilot clinical study was to compare the effects of OCPs or MET on the expression of PED/PEA-15 in association with insulin sensitivity in obese PCOS women. Outcome measures: PED/PEA-15, BMI, plasma glucose and insulin, 1/HOMA-IR, homeostasis model assessment of insulin resistance; QUICKI, quantitative insulin sensitivity check index; ISI: whole-body insulin sensitivity index. Study design: twenty obese PCOS women (age: 24.7±18 yr; BMI: 30±2.4 kg/m2) were randomized according to insulin sensitivity to receive 30 µg ethinylestradiol plus 30 mg drospirenone 21 day/month or MET 1250 mg three times daily for 6 months. Results: At baseline, age and BMI were not different in the two groups; PED/PEA-15 protein expression was higher in MET than in OCP group (p=0.011), along with higher 1/HOMA-IR (p=0.004), and lower QUICKI and ISI (p=0.003 and p<0.001, respectively). After treatment, independently of body weight, only in MET group PED/PEA-15 decreased (p=0.004), along with insulin and 1/HOMA-IR (p<0.001), and QUICKI and ISI increased (p<0.001). Insulin sensitivity indexes improvement correlated significantly with PED/PEA-15 protein expression, but not with BMI. Conclusions: PED/PEA-15 protein over-expression in obese PCOS women with IR reduced after a six month treatment with MET, while remained unchanged in the OCP group. The reduction was independent of body weight, and correlated with insulin sensitivity indexes. This effect further supported MET as a more effective therapy than OCPs for obese PCOS women with IR, also when fertility is not required. |
| Detailed Description | Subjects: Twenty obese PCOS women (age: 24.7±18 yr; BMI: 30±2.4 kg/m2) were consecutively admitted to the Endocrinology Unit of the Department of Molecular and Clinical Endocrinology and Oncology of the Federico II University of Naples, and were enrolled in this clinical study. The diagnosis of PCOS was made according to the diagnostic criteria for PCOS At study entry the patients were randomized in two groups of treatment, according to insulin sensitivity. OCP group, 10 patients (BMI 29.7± 1.5 kg/m2) received 30 µg ethinylestradiol plus 30 mg drospirenone 21 day/month. MET group, 10 patients (BMI 30.4± 3.1 kg/m2), received metformin 1250 mg three times daily. The duration of follow-up was 6 months. The control group consisted of 10 healthy female volunteers, who were age matched. Methods: As all PCOS women were anovulatory, they underwent a progesterone challenge test (100 mg natural progesterone i.m.; Prontogest, Amsa, Rome, Italy), which induced uterine bleeding in all PCOS women. To exclude the presence of type 2 diabetes or abnormal glucose tolerance, the oral glucose tolerance test (OGTT) was performed and the normal glucose response to the OGTT was defined according to the 'Report of the Expert Committee on the diagnosis and classification of diabetes mellitus'. All anthropometric measurements were taken with subjects wearing only light clothes and without shoes. In each woman, weight and height were measured to calculate the BMI [weight (kg) divided by height squared (m2), kg/m2]. Height was measured to the nearest cm using a wall-mounted stadiometer. Body weight (BW) was determined to the nearest 50 g using a calibrated balance beam scale. Patients were given a standardized interview to obtain information about the duration of obesity, eating patterns, smok¬ing habits and physical exercise. In particular, subjects were also asked to make a daily record of the amount of physical activity (no exercise; ≤2-3 h/week; ≥2-3 h/week). Preadmission food intake and dietary history were assessed by a skilled dietitian who used a computer-assisted interview (Winfood 1.5, Medimatica srl, Martinsicuro, Italy). All PCOS women received a normo-caloric diet. Assays: Blood samples were obtained between 08.00 h and 09.00 h from an antecubital vein after an overnight fast, with the patient in the resting position. The OGTT was performed using 75 g dextrose. Blood samples were obtained at 0, 30, 60, 90, 120, min for plasma glucose and insulin measurements. Fasting plasma glucose (FPG) levels were determined by the glucose oxidase method immediately after the OGTT. Fasting plasma insulin (FPI) samples were promptly centrifuged, plasma was separated and stored at -20°C until assay. FPI was measured by a solid-phase chemiluminescent enzyme immunoassay using commercially available kits (Immunolite Diagnostic Products Co, Los Angeles, CA). 1/HOMA-IR, QUICKI and ISI were calculated. PED/PEA-15 protein was measured in white-blood cells (WBC) lysates obtained from 10 to 12 ml of freshly collected uncoagulated whole blood, after separation with dextran 6%, using Western blot analysis. For Western blot analysis WBC were solubilized at 4°C in TAT buffer, centrifuged at 500g for 20 min, and supernatant fractions were stored at -20°C until used. The amount of 50 μg of lysate proteins were heated at 100°C in Laemmli buffer. Proteins were separated by 15% SDS-PAGE and then transferred to 0•45-mm Immobilon-P membranes (Millipore, Bedfort, MA). Filters were probed with PED/PEA-15 antiserum at 1:2000 dilution, revealed by enhanced chemiluminescence and autoradiography. The protein bands were quantified by laser densitometry and expressed as percentage of pixels (arbitrary units). |
| Study Type | Interventional |
| Study Phase | Phase 3 |
| Study Design | Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment |
| Condition |
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| Intervention | Drug: Metformin metformin 1250 mg three times daily Other Names: BiguanidesDrug: oral contraceptive 30 µg ethinylestradiol plus 30 mg drospirenone 21 day/month. Other Names: estroprogestins |
| Study Arm (s) |
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Recruitment Information[ + expand ][ + ]
| Recruitment Status | Completed |
|---|---|
| Estimated Enrollment | 20 |
| Estimated Completion Date | January 2009 |
| Estimated Primary Completion Date | December 2006 |
| Eligibility Criteria | Inclusion Criteria: - female - premenopausal - obesity - PCOS. Exclusion Criteria: - pregnancy - type 2 diabetes or impaired glucose tolerance - hypothyroidism - hyperprolactinaemia - Cushing's syndrome - nonclassical congenital adrenal hyperplasia - previous (within the last 6 months) use of oral contraceptives - glucocorticoids - antiandrogens - ovulation induction agents - antidiabetic and antiobesity drugs, or other hormonal drugs. None of the subjects was affected by any neoplastic, metabolic, hepatic, and cardiovascular disorder or other concurrent medical illness (i.e. diabetes, renal disease, and malabsorptive disorders),acute and chronic inflammations based on medical history, physical examination, and routine laboratory tests, including measurement of oral temperature, white blood cell count and urinalysis. |
| Gender | Female |
| Ages | 21 Years |
| Accepts Healthy Volunteers | Accepts Healthy Volunteers |
| Contacts | Not Provided |
| Location Countries | Not Provided |
Administrative Information[ + expand ][ + ]
| NCT Number | NCT00948402 |
|---|---|
| Other Study ID Numbers | NeuroendoUnit-11 |
| Has Data Monitoring Committee | No |
| Information Provided By | Federico II University |
| Study Sponsor | Federico II University |
| Collaborators | Not Provided |
| Investigators | Principal Investigator: Annamaria Colao, MD PhD Department of Molecular and Clinical Endocrinology and Oncology Federico II University of Naples |
| Verification Date | October 2009 |