The Effects of OCP and Metformin on Clinical, Hormonal, Metabolic and Ultrasonographic Characteristics in PCOS

Study Overview
=================
Brief Summary
-----------------
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorder in women of reproductive age and is a leading cause of infertility due to anovulation. Oral contraceptive pills (OCPs) are considered as first line medical therapy to regularize menses in woman with PCOS. However they may worsen the metabolic profile of patients by elevating insulin resistance which is already deranged in PCOS. As there is higher prevalence of insulin resistance in Indian women with PCOS, insulin sensitisers like metformin may be more beneficial. Hence this study is undertaken to compare the combined effect of metformin and OCPs on the clinical, hormonal, metabolic and ovarian ultrasonographic characteristics in patients with PCOS and to evaluate whether this combination of drugs is more advantageous than OCPs or metformin alone in improving the clinical and metabolic profile.

Detailed Description
-----------------
We aim to enroll about 120 patients fulfilling the Rotterdam diagnostic criteria for PCOS in our study. Patients will have a baseline clinical examination (Body weight, Body mass index, Waist circumference, Hirsutism score), hormonal profile (FSH, LH, fasting Insulin/glucose ratio, DHEAS, testosterone levels), metabolic profile (fasting and 2 hour post prandial plasma glucose, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides level), ultrasound examination (ovarian volume and subcapsular follicle count, stromal echogenicity) and doppler blood flow study (ovarian stromal velocity, Pulsatility index, Resistivity index, Systolic/Diastolic ratio and stromal vascularization index). Patients will be then randomized using a computer generated randomization program into two groups according to BMI (<25 and >25). The randomization will be stratified in order to achieve a homogenous distribution of PCOS patients in both arms of the study with respect to age and body mass index. Each group will be further subdivided into three treatment arms. 1st treatment arm will receive OCP containing 35 microgram ethinyl estradiol and 2 mg cyproterone acetate cyclically (21 days regimen) daily; 2nd treatment arm will receive OCP containing 35 microgram ethinyl estradiol and 2 mg cyproterone acetate cyclically (21 days regimen) while the 3rd treatment arm will receive OCP plus metformin 500 mg twice daily for a period of six months. Each patient will be asked to keep a diary of her menstrual periods over the study period. The patients will be followed up at 3 and 6 months of treatment to evaluate the changes in the above mentioned parameters. Analysis of the data will be done through descriptive and perceptive statistical methods by using Statistical Package for the Social Sciences (SPSS) software.

Official Title
-----------------
The Effects of Treatment With Oral Contraceptive Pill Containing Ethinyl Estradiol-Cyproterone Acetate and Metformin on Clinical, Hormonal, Metabolic and Ultrasonographic Characteristics in Polycystic Ovarian Syndrome

Conditions
-----------------
Polycystic Ovary Syndrome

Intervention / Treatment
-----------------
* Drug: Metformin
* Drug: ethinyl estradiol and cyproterone acetate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients will be included into study who fulfill the Rotterdam diagnostic criteria (2003) for PCOS. Exclusion Criteria: Current or previous use of oral contraceptives, glucocorticoids, antiandrogens, ovulation induction agents, antidiabetic and anti-obesity drugs or other hormonal drugs. Medical or surgical treatment of PCOS during the previous 3 months Presence of other endocrinopathies; except treated hypothyroidism on stable replacement doses of thyroid hormone Pregnancy, breastfeeding or desire for pregnancy during study interval (6 months) Inability to understand the proposal of the study precluding effective informed consent

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: OCP only arm<br>OCP containing 35 microgram ethinyl estradiol and 2 milligram cyproterone acetate to taken from the first day of the menstruation, oral administration of one pill daily for 21 days consecutively, then discontinue using the pill for seven days, and on the eighth day, restart taking the pill. OCP to be taken for 6 months. | Drug: ethinyl estradiol and cyproterone acetate<br>* Oral Contraceptive Pill<br>|
| Active Comparator: Metformin arm<br>Metformin 500mg bid in morning and evening after meals to be taken for 6 months. | Drug: Metformin<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in menstrual cycle pattern | All the participants will be asked to maintain a menstrual calendar and fill a questionnaire before and at the end of study. The questionnaire will include menstrual cycle dates, duration and amount from which improvement of menstrual pattern will be assessed. | 6 months | 
| Change in Abdominal Fat as measured by Waist Circumference in centimeter |  | 6 months | 
| Change in weight as measured in kg |  | 6 months | 
| Improvement in hirsutism measured by Modified Ferriman and Gallwey scores |  | 6 months | 
| Improvement in glucose tolerance (measured by of fasting plasma glucose and 2-hour post prandial plasma glucose) |  | 6 months | 
| Change in waist-to-hip ratio |  | 6 months | 
| Change in Body mass index (kg/m2) |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lipid profile (Cholesterol, LDL, HDL and Triglyceride) improvement | The serum levels of Cholesterol, LDL, HDL and Triglyceride were measured in mg/dl before and after of treatment in both groups. | 6 months | 
| Change in blood level of luteinizing hormone [LH] (mIU/ml) |  | 6 months | 
| Change in blood level of follicle stimulating hormone [FSH] (mIU/ml) |  | 6 months | 
| Change in blood level of Testosterone (nmol/L) |  | 6 months | 
| Change in blood level of Sex hormone binding globulin (SHBG) (ng/ml) |  | 6 months | 
| Change in Free androgen Index (FAI) | Free Androgen Index or FAI is a ratio used to determine abnormal androgen status. The ratio is the total testosterone level divided by the sex hormone binding globulin (SHBG) level, and then multiplying by 100. | 6 months | 
| Change in Dehydroepiandrosterone sulfate (DHEAS) level (microgram/dl) |  | 6 months | 
| Changes in fasting serum insulin levels (mIU/L) |  | 6 months | 
| Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) | Homeostatic model assessment (HOMA) is a method for assessing β-cell function and insulin resistance (IR) from basal (fasting) glucose and insulin concentrations. HOMA-IR = (Glucose x Insulin) / 405; Glucose is expressed in mg/dl and Insulin is expressed in mIU/L | 6 months | 
| Ovarian Stromal artery Pulsatility index |  | 6 months | 
| Ovarian Stromal artery Resistivity index |  | 6 months | 
| Chang in ovarian Follicle number by Ultrasonography (USG) | Largest cross-sectional plane of the ovary will be evaluated for follicle number | 6 months | 
| Change in ovarian Follicle diameter (in mm) by USG | Largest cross-sectional plane of the ovary will be evaluated for follicle diameter | 6 months | 
| Change in Ovarian volume (in cc) by USG | Ovarian volume, estimated according to the formula 1/2 (A x B x C), where A is the longitudinal diameter, B the anteroposterior diameter, and C the transverse diameter of the ovary | 6 months | 
| Change in Endometrial thickness (in mm) |  | 6 months | 
| Change in ovarian stromal/total area ratio (S/A) | Ovarian area, evaluated by outlining with the caliper the external limits of the ovary in the maximum plane section. Ovarian stromal area, evaluated by outlining with the caliper the peripheral profile of the stroma, identified by a central area slightly hyperechoic with respect to the other ovarian area. | 6 months |