Metabolic and Neuro-Endocrine Effect of Treating PCOS in Adolescents

Study Overview
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Brief Summary
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To exam in the effect of a combination of low dose Metformin and Spironolactone on functional brain MRI, menstrual regulation and metabolism in adolescents with PCOS.

Detailed Description
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Polycystic Ovarian Syndrome (PCOS) is the most common endocrinopathy in adolescent females and also one of the most complex. Patients experience an exaggerated ovarian/adrenal androgen production in response to physiologic and supra-physiologic elevations in insulin. The hormonal dysregulation is not only associated with acne, hirsutism, and menstrual irregularity, but also with perpetuated insulin resistance, central adiposity, and clinical depression. In the proposed study, we aim to treat a hormonally and metabolically well-defined group of adolescent girls with PCOS with a combination of two pharmacological agents: metformin (insulin sensitizer) and spironolactone (anti-androgen) for 6 months. Although hyperandrogenism is a fundamental component of PCOS and responsible for the perpetuation of insulin resistance, adiposity and anovulation, there are few pediatric studies that have examined the benefits of treating both insulin resistance and hyperandrogenism simultaneously. Preliminary studies in adults, however, suggest synergistic effect of both spironolactone and metformin (spiro-met) with near normalization of the metabolic and ovulatory dysfunction. Therefore, we hypothesize that spiro-met will improve adolescent metabolism, body composition, ovarian morphology/function. We anticipate that our study will generate key pilot data for further randomized, double blind placebo controlled trials using both agents. We also plan to examine functional brain MRI before and after the spiro-met intervention. This will allow us to inspect the effects of the hyperinsulinemic/androgenic hormonal milieu in PCOS on structural and functional brain MRI. We hypothesis, that the hormonal environment in PCOS affects centers of appetite and mood.

Official Title
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Metabolic and Neuro-Endocrine Effect of Treating PCOS in Adolescents

Conditions
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PCOS

Intervention / Treatment
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* Drug: Metformin and Spironolactone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Generally healthy Meeting Androgen Excess Society (AES) diagnostic criteria of PCOS: Menstrual Dysfunction or PCO ovaries on ultrasound AND clinical or biochemical hyperandrogenism Normal liver and kidney function No chronic illnesses except for stable, treated hypothyroidism Exclusion Criteria: Use of metformin and/or spironolactone within the last 6 months Currently on either oral hormonal contraception or other forms of hormonal contraception such as Depo-Provera, NuvaRing Current or past pregnancy Currently sexually active Psychiatric disorder based on self/parental report Type 2 diabetes (blood glucose > 200mg/dl on OGTT) Anemia (Hct < 35) Impaired kidney function (Baseline creatinine > 1.0 mg) Abnormal liver transaminases > 2 x the upper limit of normal range Potassium elevated outside the reference range (in non-hemolyzed blood sample)

Ages Eligible for Study
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Minimum Age: 13 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Overall Study<br>Treatment with Metformin and Spironolactone | Drug: Metformin and Spironolactone<br>* Oral Metformin tablet (500 mg/tablet) twice daily for 6 months. Oral Spironolactone tablet (50 mg/tablet) once daily for 6 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oral Glucose Tolerance Test | Measurement of glucose and insulin at baseline and 2 hours after 75g of glucola. | Change Measures: Baseline & 6 Months | 
| Total Testosterone | Total Testosterone measured in ng/dL | Change Measures: Baseline & 6 Months | 
| Free Testosterone | Free Testosterone measured in ng/dL | Change Measures: Baseline & 6 Months | 
| Dehydroepiandrosterone Sulfate (DHEAS) | DHEAS measured in mcg/dL | Change Measures: Baseline & 6 Months | 
| Body Mass Index (BMI) | Body Mass Index measured in kg/m2 | Change Measures: Baseline & 6 Months |