Effects of Metformin Plus Simvastatin on Polycystic Ovarian Syndrome (PCOS): A Prospective, Randomized, Double-Blind, Placebo-Controlled Study

This study has been completed.
Sponsor:
Collaborator:
Shiraz University of Medical Sciences
Information provided by:
Fasa University of Medical Sciences
ClinicalTrials.gov Identifier:
NCT01021579
First received: November 23, 2009
Last updated: November 27, 2009
Last verified: November 2009
  Purpose

Polycystic ovary syndrome (PCOS) is a common endocrinopathy affecting 6.5%-6.7% of women in reproductive age, and is commonly associated with obesity, menstrual irregularity, insulin resistance (IR), infertility, and clinical hyperandrogenism and/or hyperandrogenemia (1,2). PCOS is also associated with increased risk of abnormal lipoproteins and hypertension, as well as cardiovascular or cerebrovascular morbidity (3). The lipid and lipoprotein profile in androgenized women with poly cystic ovaries is similar to the made pattern with higher levels of cholesterol, low-density lipoprotein (LDL), and lower levels of high-density lipoprotein (HDL), and this abnormal pattern is independent of body weight (4). Insulin resistance is associated with reproductive abnormalities in women with PCOS. Improving insulin sensitivity through both lifestyle and pharmacological intervention can ameliorate these abnormalities. Insulin resistance in women with PCOS is common (up to 50%), both in obese and nonobese women (5), and disordered insulin action precedes the increase in androgen.

Treatment for PCOS subjects typically includes, implementation of lifestyle changes especially weight loss and adjuvant pharmaceutical intervention including oral contraceptives, anti-androgen therapy and insulin-lowering drugs (such as, metformin) (6). Metformin is a biguanide used extensively in type 2 diabetes. It inhibits hepatic glucose production and increases peripheral insulin sensitivity, but dose not cause hypoglycemia. Several studies have shown an increase in insulin sensitivity and pregnancy rate accompanied by decreased insulin and androgen levels in PCOS patients taking metformin (7).

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-COA) reductase inhibitors (statins) are the rate-limiting step in cholesterol biosynthesis, and inhibition of this enzyme decreases cholesterol synthesis and a compensatory increase in the expression of LDL receptors in the liver. Statins reduce plasma triglycerides in dose-dependent fashion and also have a modest HDL-raising effect which is not dose-dependent (8,9). Furthermore, statins pose other cardio-protective properties, including antioxidant and anti-inflammatory actions (10,11).

Some studies have reported that simvastatin decreases serum androgen levels in women with PCOS (12,13) by inhibiting proliferation and steroidogenesis of ovarian theca-interstitial cells (14). According to these previous findings, we hypothesized that combination therapy with simvastatin and metformin will result in lower androgen levels and cardiovascular risk factors in women with PCOS.


Condition Intervention Phase
Polycystic Ovary Syndrome
Drug: Metformin plus Placebo
Drug: Metfomin plus Simvastatin
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Outcomes Assessor)
Primary Purpose: Treatment

Resource links provided by NLM:


Further study details as provided by Fasa University of Medical Sciences:

Primary Outcome Measures:
  • Serum total testosterone [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Lipid profile BMI (kg/m2) Total Chol. (mg/dl) HDL (mg/dl) LDL (mg/dl) TG (mg/dl) Testosterone (ng/ml) LH (mIU/ml) FSH (mIU/ml) LH/FSH DHEAS (microgr/dL) Hirsutism score Prolactin (ng/dL) FBS (mg/dL) Fasting Insulin (μU/ml) QUICKI index [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 84
Study Start Date: January 2008
Study Completion Date: November 2009
Primary Completion Date: March 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Metformin plus Simvastatin
PCOS patients(n=42) will be assigned to the simvastatin (20mg/day) plus metformin (500mg three times a day, n=42; group 1)
Drug: Metfomin plus Simvastatin
Placebo Comparator: Metformin plus Placebo
PCOS patients(n=42) will be assigned to the placebo (once/day) plus metformin (500mg three times a day, n=42; group 2)
Drug: Metformin plus Placebo
PCOS patients(n=42) will be assigned to the placebo (once/day) plus metformin (500mg three times a day, n=42; group 2)

  Eligibility

Ages Eligible for Study:   16 Years to 45 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • All patients should have at least two of three following criteria: I) chronic anovulation, II) clinical and/or biochemical evidence of androgen excess and III) polycystic-appearing ovaries on transvaginal ultrasound.

Exclusion Criteria:

  • Patients with Cushing's syndrome, hyperprolactinemia, diabetes mellitus (DM), thyroid disease, adrenal hyperplasia and androgen-secreting tumors or other endocrinopathies, will be excluded from the study.
  • Patients with adrenal hyperplasia will be excluded by ACTH-stimulated 17-hydroxyprogesterone levels less than 10 ng/ml (15), and ACTH-stimulated 11-deoxycortisol levels less than 21 ng/ml [3-fold the 95th percentile (16) of a historical control group of 60 healthy women controls].
  • Those subjects who have kidney or liver diseases and those who were smoker or had breast cancer will also be excluded from the study.
  • None of the participants receive oral contraceptives (OCPs), steroid hormones or any medications that interfere with lipid metabolism, ovarian and pituitary and hypothalamic function, or insulin sensitivity in the last 3 months before study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01021579

Locations
Iran, Islamic Republic of
Zainabieh Hospital
Shiraz, Fars, Iran, Islamic Republic of, 7173646199
Sponsors and Collaborators
Fasa University of Medical Sciences
Shiraz University of Medical Sciences
  More Information

No publications provided

ClinicalTrials.gov Identifier: NCT01021579     History of Changes
Other Study ID Numbers: SUMS 84-258
Study First Received: November 23, 2009
Last Updated: November 27, 2009
Health Authority: Iran: Ministry of Health

Keywords provided by Fasa University of Medical Sciences:
Polycystic ovary syndrome
Metformin
Simvastatin

Additional relevant MeSH terms:
Polycystic Ovary Syndrome
Syndrome
Adnexal Diseases
Cysts
Disease
Endocrine System Diseases
Genital Diseases, Female
Gonadal Disorders
Neoplasms
Ovarian Cysts
Ovarian Diseases
Pathologic Processes
Metformin
Simvastatin
Anticholesteremic Agents
Antimetabolites
Enzyme Inhibitors
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Hypoglycemic Agents
Hypolipidemic Agents
Lipid Regulating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014