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

Overview[ - collapse ][ - ]

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.
ConditionPolycystic Ovary Syndrome
InterventionDrug: Metformin plus Placebo
Drug: Metfomin plus Simvastatin
PhasePhase 4
SponsorFasa University of Medical Sciences
Responsible PartyFasa University of Medical Sciences
ClinicalTrials.gov IdentifierNCT01021579
First ReceivedNovember 23, 2009
Last UpdatedNovember 27, 2009
Last verifiedNovember 2009

Tracking Information[ + expand ][ + ]

First Received DateNovember 23, 2009
Last Updated DateNovember 27, 2009
Start DateJanuary 2008
Estimated Primary Completion DateNovember 2009
Current Primary Outcome MeasuresSerum total testosterone [Time Frame: 6 weeks] [Designated as safety issue: No]
Current Secondary Outcome MeasuresLipid 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]

Descriptive Information[ + expand ][ + ]

Brief TitleEffects of Metformin Plus Simvastatin on Polycystic Ovarian Syndrome (PCOS): A Prospective, Randomized, Double-Blind, Placebo-Controlled Study
Official TitleNot Provided
Brief Summary
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.
Detailed DescriptionNot Provided
Study TypeInterventional
Study PhasePhase 4
Study DesignAllocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Outcomes Assessor), Primary Purpose: Treatment
ConditionPolycystic Ovary Syndrome
InterventionDrug: 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: Metfomin plus Simvastatin
Study Arm (s)
  • 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)
  • 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)

Recruitment Information[ + expand ][ + ]

Recruitment StatusCompleted
Estimated Enrollment84
Estimated Completion DateNovember 2009
Estimated Primary Completion DateMarch 2009
Eligibility 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.
GenderFemale
Ages16 Years
Accepts Healthy VolunteersNo
ContactsNot Provided
Location CountriesIran, Islamic Republic of

Administrative Information[ + expand ][ + ]

NCT Number NCT01021579
Other Study ID NumbersSUMS 84-258
Has Data Monitoring CommitteeYes
Information Provided ByFasa University of Medical Sciences
Study SponsorFasa University of Medical Sciences
CollaboratorsShiraz University of Medical Sciences
Investigators Not Provided
Verification DateNovember 2009

Locations[ + expand ][ + ]

Zainabieh Hospital
Shiraz, Fars, Iran, Islamic Republic of, 7173646199