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

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

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.

Study Overview

• Status: Completed
• Conditions: Polycystic Ovary Syndrome
• Intervention / Treatment: Drug: Metformin; Drug: ethinyl estradiol and cyproterone acetate

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.

• Study Type: Interventional
• Enrollment (Actual): 101
• Phase: Phase 4

Contacts and Locations

Study Locations

• India
  • Odisha
    • Cuttack, Odisha, India, 753007
      • Department of Obstetrics & Gynecology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: OCP only arm; 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; Oral Contraceptive Pill
Active Comparator: Metformin arm; Metformin 500mg bid in morning and evening after meals to be taken for 6 months.	Drug: Metformin

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

Collaborators and Investigators

• Sponsor: S.C.B. Medical College and Hospital
• Investigators: Principal Investigator: Mahija Sahu, MD, S.C.B. Medical College and Hospital; Principal Investigator: Priyadarshini Tripathy, MD, S.C.B. Medical College and Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 15, 2016
• Primary Completion (Actual): April 20, 2017
• Study Completion (Actual): August 1, 2017

Study Registration Dates

• First Submitted: August 4, 2016
• First Submitted That Met QC Criteria: August 12, 2016
• First Posted (Estimate): August 15, 2016

Study Record Updates

• Last Update Posted (Actual): April 20, 2018
• Last Update Submitted That Met QC Criteria: April 18, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Endocrine System Diseases; Disease; Ovarian Cysts; Cysts; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Polycystic Ovary Syndrome; Syndrome; Hypoglycemic Agents; Physiological Effects of Drugs; Antineoplastic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Hormone Antagonists; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Hormonal; Androgen Antagonists; Contraceptive Agents, Male; Estradiol; Metformin; Ethinyl Estradiol; Cyproterone Acetate; Cyproterone
• Other Study ID Numbers: OG/2016/13

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes