Impact of Metformin in Teens With Polycystic Ovary Syndrome (PCOS) on Oral Contraceptive Therapy

Study Overview
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Brief Summary
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Oral contraceptives are known to improve menstrual cycles and symptoms in PCOS, however may increase cholesterol. Metformin, a drug to improve insulin resistance, may benefit metabolic state. This study is to determine whether metformin added to oral contraceptive therapy in adolescent women with PCOS improves metabolic state.The study will also test a lifestyle improvement program to reduce weight.

Detailed Description
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Polycystic Ovary Syndrome (PCOS) is a heterogeneous condition characterized by chronic anovulation and androgen excess that occurs in 4-8% of unselected adult women. Although signs and symptoms of the disorder typically appear at the time of puberty, diagnosis is often delayed until adulthood. At least 50% of adult women with PCOS are obese, resulting in a more severe clinical picture. Obesity among adolescents has been increasing in recent years, with overrepresentation of females who show evidence of hyperandrogenism and irregular periods, suggesting an association of obesity and PCOS at an early age. Recent data, however, have drawn attention to the long-term risks of PCOS, including diabetes and cardiovascular disease. Insulin resistance plays a critical role in the pathophysiology of PCOS and is thought to be the metabolic abnormality most closely linked to an increased risk of diabetes and heart disease. Traditional treatments with oral contraceptives are associated with reduction in serum androgens and improvements in menstrual cycles in adolescents with PCOS, however these have not been well-studied in obese adolescents. Oral contraceptives may worsen the dyslipidemia seen in obese women with PCOS and do not address the insulin resistance. Metformin, an insulin sensitizing agent, has been shown to improve metabolic features of PCOS, but combination therapy with oral contraceptives has never been studied in the obese adolescent with PCOS. The major hypothesis of this proposal is that metformin will improve the metabolic profile of obese adolescent girls with PCOS treated with oral contraceptives. Additionally, a secondary hypothesis will be that compliance with a concurrent lifestyle modification program with be associated with the most significant improvements.

Official Title
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Metabolic Impact of Oral Contraceptives With or Without Metformin in Obese Adolescents With Polycystic Ovary Syndrome (PCOS)

Conditions
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Polycystic Ovary Syndrome

Intervention / Treatment
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* Drug: Metformin
* Drug: Oral Contraceptive Pill
* Behavioral: Lifestyle Management Program
* Behavioral: Quality of Life Questionnaire
* Procedure: Oral Glucose Tolerance Test
* Procedure: Blood work
* Procedure: Abdominal Ultra Sound
* Procedure: Dual-energy x-ray absorptiometry (DEXA scan)
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria:Age 12-18 years; Menstrual irregularity; Overweight; Must be able to swallow capsules; At lease 6 months since onset of first menstrual cycle. Exclusion Criteria:Diabetes; Kidney or Liver disease; Tobacco use; Depression or Bipolar Disease; Contraindication to exercise; Weight > 300 lbs.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>metformin | Drug: Metformin<br>* Metformin 500 mg. tabs 2 tabs BID for duration of study<br>* Other names: manufacturer: Mylan Pharmaceuticals, Morgantown, WV;Drug: Oral Contraceptive Pill<br>* Yasmin, drospirenone and ethinyl estradiol 28 tablets 1 tab daily for duration of study<br>* Other names: Manufacturer: Berlex, Montville, NJ 07045;Behavioral: Lifestyle Management Program<br>* Subjects and a parent/guardian will participate in a series of classes for training in diet, exercise & behavior modification skills on a regular weekly basis over the 24 week study<br>Behavioral: Quality of Life Questionnaire<br>* Quality of Life questionnaire designed for women with Polycystic Ovary Syndrome. Questions concern health and health related issues Performed twice during study, at baseline and conclusion<br>Procedure: Oral Glucose Tolerance Test<br>* Insulin response to a glucose challenge in an oral glucose tolerance test (OGTT), as measured by area under the curve (AUC). In this study we will administer an OGTT and calculate the AUC as a measure of insulin resistance. Performed twice during study, at baseline and conclusion<br>Procedure: Blood work<br>* Initial and conclusion blood draws include; comprehensive metabolic profile, CBC and platelet,hormonal assessment and lipids.<br>Procedure: Abdominal Ultra Sound<br>* transabdominal transducer, which contains integrated software for volume calculation will be used to assess ovarian volume. Performed twice during study, at baseline and conclusion<br>Procedure: Dual-energy x-ray absorptiometry (DEXA scan)<br>* Dual-energy x-ray absorptiometry (DEXA) will be used to assess percent body fat Performed twice during study, at baseline and conclusion<br>|
| Placebo Comparator: 0<br>placebo | Drug: Oral Contraceptive Pill<br>* Yasmin, drospirenone and ethinyl estradiol 28 tablets 1 tab daily for duration of study<br>* Other names: Manufacturer: Berlex, Montville, NJ 07045;Behavioral: Lifestyle Management Program<br>* Subjects and a parent/guardian will participate in a series of classes for training in diet, exercise & behavior modification skills on a regular weekly basis over the 24 week study<br>Behavioral: Quality of Life Questionnaire<br>* Quality of Life questionnaire designed for women with Polycystic Ovary Syndrome. Questions concern health and health related issues Performed twice during study, at baseline and conclusion<br>Procedure: Oral Glucose Tolerance Test<br>* Insulin response to a glucose challenge in an oral glucose tolerance test (OGTT), as measured by area under the curve (AUC). In this study we will administer an OGTT and calculate the AUC as a measure of insulin resistance. Performed twice during study, at baseline and conclusion<br>Procedure: Blood work<br>* Initial and conclusion blood draws include; comprehensive metabolic profile, CBC and platelet,hormonal assessment and lipids.<br>Procedure: Abdominal Ultra Sound<br>* transabdominal transducer, which contains integrated software for volume calculation will be used to assess ovarian volume. Performed twice during study, at baseline and conclusion<br>Procedure: Dual-energy x-ray absorptiometry (DEXA scan)<br>* Dual-energy x-ray absorptiometry (DEXA) will be used to assess percent body fat Performed twice during study, at baseline and conclusion<br>Drug: placebo<br>* placebo capsules, two capsules BID<br>* Other names: in size 3 capsules from Capsugel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction in Abdominal Fat as Measured by Waist Circumference. | Change in waist circumference measured in cms used as a measure of abdominal adiposity, pre minus post intervention | baseline and 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Weight Post Minus Pre Intervention. | Body mass index change in adolescents enrolled in lifestyle intervention program | baseline and 24 weeks | 
| Total Testosterone Change | Change in total testosterone post minus pre intervention | baseline and 24 weeks | 
| Change in Sex Hormone Binding Globulin (SHBG) | SHBG concentration post minus pre-intervention | baseline and 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Polycystic Ovary Syndrome, Overweight Adolescent Girls, Irregular Menstrual Cycles