Oral Contraceptives in the Metabolic Syndrome

• ClinicalTrials.gov Identifier: NCT00205504
• Recruitment Status: Completed
• First Posted: September 20, 2005
• Results First Posted: May 7, 2012
• Last Update Posted: August 8, 2018
• Sponsor: Virginia Commonwealth University
• Information provided by (Responsible Party): Virginia Commonwealth University

Study Description

Brief Summary:

Oral contraceptives (OCs) are the most widely used method of reversible birth control. However, the long-term cardiovascular safety of the widely used low-dose OCs (ethinyl-estradiol < 50 mcg) is still debated. Although cardiovascular events are rare in young women whether they use OCs or not, the risks of myocardial infarction and ischemic stroke are increased among users of OCs who have conventional cardiovascular risk factors such as use of tobacco, diabetes or hypercholesterolemia. However, the risk of cardiovascular events in OC users with emerging cardiovascular risk factors (such as obesity and the metabolic syndrome) have not been investigated. Recently, the metabolic syndrome has been linked with the risk of cardiovascular disease. The syndrome is a clustering of risk factors in a single individual, and its underlying cause may be insulin resistance. Whether the metabolic syndrome predicts a higher cardiovascular risk in OC users has not been studied. This is a critical problem because the metabolic syndrome is prevalent in 24% of adults. Until the cardiovascular risks in users of OC are clearly defined, the appropriate use of OC with the least harm would not be possible.

The investigator's long-term goal is to understand the best way to prevent and treat cardiovascular disease in women. The objective of this particular project is to obtain pilot data on the extent to which the metabolic syndrome and obesity affects glucose metabolism and cardiovascular risks in women taking OCs. The researchers hypothesize that women with metabolic syndrome and obese women will have worsened glucose metabolism and elevated cardiovascular risks associated with OC use, when compared to normal weight women without the metabolic syndrome. Results of this study will clarify the risk factors for cardiovascular events in women taking OCs, and will serve as pilot data for a National Institutes of Health (NIH) proposal. Once the cardiovascular risk factors of OC users are understood, clinicians can make better informed decisions about contraceptive choices for their patients.

Condition or disease	Intervention/treatment	Phase
Metabolic Syndrome X; Insulin Resistance; Obesity; Cardiovascular Diseases	Drug: Ortho Tri Cyclen	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 46 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Oral Contraceptives in the Metabolic Syndrome
• Study Start Date: June 2005
• Actual Primary Completion Date: June 2009
• Actual Study Completion Date: June 2009

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Obese women with metabolic syndrome	Drug: Ortho Tri Cyclen; Ortho Tri Cyclen, one tablet daily, for 6 cycles
Active Comparator: Obese women without metabolic syndrome	Drug: Ortho Tri Cyclen; Ortho Tri Cyclen, one tablet daily, for 6 cycles
Active Comparator: lean women without metabolic syndrome	Drug: Ortho Tri Cyclen; Ortho Tri Cyclen, one tablet daily, for 6 cycles

Outcome Measures

Primary Outcome Measures :

1. Changes in Insulin Sensitivity Associated With Oral Contraceptive (OC) Use Compared Among (1) Obese Women and (2) Lean Women [ Time Frame: Baseline and 6 months ]
   Insulin sensitivity was assessed by frequent sampling intravenous glucose tolerance test (FSIVGTT).

Secondary Outcome Measures :

1. Changes in Lipid Profile Compared Associated With OC Use Among (1) Obese Women and (2) Lean Women [ Time Frame: Baseline and 6 months ]
   The lipid profile is assessed through blood sample analysis for low-density lipoprotein (LDL), Triglycerides and high-density lipoprotein (HDL).
2. Inflammatory Marker Changes, High Sensitive C-reactive Protein (Hs-CRP) and Adiponectin, Associated With OC Use Compared Among (1) Obese Women and (2) Lean Women [ Time Frame: Baseline and 6 months ]
   Inflammatory markers are assessed through blood analysis for C-reactive protein (hs-CRP) and adiponectin.
3. Changes in Estrogen Metabolites (Plasma) Associated With OC Use Compared Among (1) Obese Women and (2) Lean Women [ Time Frame: Baseline and 6 months ]
4. Changes in Waist-to-Hip Ratio Associated With OC Use Compared Among (1) Obese Women and (2) Lean Women [ Time Frame: Baseline and 6 months ]
   Waist-to-hip ratio is assessed through calculated ratio of waist and hip circumference.
5. Inflammatory Marker Changes (MCP-1) Associated With OC Use Compared Among (1) Obese Women and (2) Lean Women [ Time Frame: Baseline and 6 months ]
   Inflammatory marker is assessed through blood analysis for Monocyte chemotactic protein-1 (MCP-1).
6. Changes in Blood Pressure Associated With OC Use Compared Among (1) Obese Women and (2) Lean Women [ Time Frame: Baseline and 6 months ]
7. Changes in Body Mass Index (BMI) Associated With OC Use Compared Among (1) Obese Women and (2) Lean Women [ Time Frame: Baseline and 6 months ]
   Body Mass Index is a calculation of height and weight: kg/m²
8. Changes in Waist Circumference Associated With OC Use Compared Among (1) Obese Women and (2) Lean Women [ Time Frame: Baseline and 6 months ]
9. Inflammatory Marker Changes, Soluble Vascular Cell Adhesion Molecule (sVCAM) and Soluble Intercellular Adhesion Molecule (sICAM), Associated With OC Use Compared Among (1) Obese Women and (2) Lean Women [ Time Frame: Baseline and 6 months ]
   These inflammatory markers are assessed through blood analysis of Soluble Vascular Cell Adhesion Molecule (sVCAM) and soluble intercellular adhesion molecule (sICAM).

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 40 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

1. Acceptable health based on interview, medical history, physical examination, and laboratory tests (comprehensive metabolic panel - SMA20, and complete blood count - CBC);
2. Have not taken oral contraceptives (OCs) in the past 3 months;
3. Ability to comply with the requirements of the study;

4. Ability and willingness to provide signed, witnessed informed consent. In addition, women with the metabolic syndrome must meet the National Cholesterol Education Program (NCEP) defined criteria of the metabolic syndrome, that is, having at least 3 of the 5 factors:

   1. increased waist circumference > 35 inches,
   2. hypertriglyceridemia ≥ 150 mg/dL,
   3. low high-density lipoprotein (HDL) cholesterol < 50 mg/dL in women,
   4. hypertension (≥ 130/≥ 85 mmHg),
   5. fasting glucose ≥ 100 mg/dL.

Obese women with or without the metabolic syndrome should have a Body Mass Index (BMI) > 30 kg/m2 and lean women should have a Body Mass Index BMI < 25 kg/m2.

Exclusion Criteria:

1. Diabetes mellitus by fasting glucose or a 2-hour oral glucose tolerance test (OGTT);
2. Clinically significant pulmonary, cardiac (including but not limited to ischemic heart disease, stable/unstable angina, and congestive heart failure), renal, hepatic, cholestatic, neurologic, psychiatric, infectious, and malignant disease (other than melanoma skin cancer);
3. History of thromboembolism, myocardial infarction, cerebrovascular accident, vascular disease, known coagulopathy, prolonged immobilization, or recent major surgery (within past 6 months);
4. Systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 100 mmHg (mild hypertension is not an exclusion criterion);
5. History of breast cancer, migraine headaches, or age ≥ 35 years and smoker of ≥ 20 cigarettes/day;
6. Use of metformin, thiazolidinediones, anti-hyperlipidemic drugs, anti-hypertensive drugs, glucocorticoids, or anti-androgens (spironolactone, flutamide, etc.) within 3 months;
7. Documented or suspected illicit drug abuse or alcoholism within one year;
8. Ingestion of any investigational drugs within 3 months prior to the study onset; and
9. Pregnancy or lactation (≤ 6 weeks postpartum);
10. Hematocrit < 33g/dL. These exclusion criteria are based on study requirements and also go beyond guidelines for OC use published by the World Health Organization.

Contacts and Locations

Locations

United States, Virginia

Virginia Commonwealth University General Clinical Research Center

Richmond, Virginia, United States, 23298

Sponsors and Collaborators

Virginia Commonwealth University

Investigators

• Principal Investigator: Kai I Cheang, Pharm.D.; Virginia Commonwealth University
• Study Director: John E Nestler, M.D.; Virginia Commonwealth University

More Information

Publications of Results:

Cheang KI, Essah PA, Sharma S, Wickham EP 3rd, Nestler JE. Divergent effects of a combined hormonal oral contraceptive on insulin sensitivity in lean versus obese women. Fertil Steril. 2011 Aug;96(2):353-359.e1. doi: 10.1016/j.fertnstert.2011.05.039. Epub 2011 Jun 15.

• Responsible Party: Virginia Commonwealth University
• ClinicalTrials.gov Identifier: NCT00205504
• Other Study ID Numbers: HM4060
• First Posted: September 20, 2005
• Results First Posted: May 7, 2012
• Last Update Posted: August 8, 2018
• Last Verified: July 2018

Keywords provided by Virginia Commonwealth University:

Inflammatory markers, oral contraceptions, obesity, metabolic syndrome X

Additional relevant MeSH terms:

Cardiovascular Diseases; Microvascular Angina; Metabolic Syndrome; Insulin Resistance; Syndrome; Disease; Pathologic Processes; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Angina Pectoris; Myocardial Ischemia; Heart Diseases; Vascular Diseases; Moxifloxacin; Norgestimate, ethinyl estradiol drug combination; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Physiological Effects of Drugs; Contraceptives, Oral, Combined; Contraceptives, Oral; Contraceptive Agents, Female; Anti-Bacterial Agents; Anti-Infective Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents