Oral Contraceptives in the Metabolic Syndrome

• Sponsor: Virginia Commonwealth University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00205504
• Collaborator: (none)
• Enrollment: 46
• Location: 1
• Arms: 3
• Duration (Months): 48
• Patients Per Site Per Month: 1

Study Details

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
• 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: Jun 1, 2005
• Actual Primary Completion Date: Jun 1, 2009
• Actual Study Completion Date: Jun 1, 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 [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 [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 [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 [Baseline and 6 months]

4. Changes in Waist-to-Hip Ratio Associated With OC Use Compared Among (1) Obese Women and (2) Lean Women [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 [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 [Baseline and 6 months]

7. Changes in Body Mass Index (BMI) Associated With OC Use Compared Among (1) Obese Women and (2) Lean Women [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 [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 [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

Criteria

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

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:

5. increased waist circumference > 35 inches,

6. hypertriglyceridemia ≥ 150 mg/dL,

7. low high-density lipoprotein (HDL) cholesterol < 50 mg/dL in women,

8. hypertension (≥ 130/≥ 85 mmHg),

9. 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

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Virginia Commonwealth University
• ClinicalTrials.gov Identifier: NCT00205504
• Other Study ID Numbers: HM4060
• First Posted: Sep 20, 2005
• Last Update Posted: Aug 8, 2018
• Last Verified: Jul 1, 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; Moxifloxacin; Norgestimate, ethinyl estradiol drug combination

Study Results

Participant Flow

Pre-assignment Detail	Although 46 completed informed consent, only 36 initiated the study. Among The participants who did not begin the study were lost to follow-up prior to beginning the protocol, were no shows, or withdrew from the study before beginning study procedures.

Arm/Group Title	Obese Women	Lean Women
Arm/Group Description	Women with Body Mass Index (BMI) >30 kg/m². Note: Only two arms were analyzed for the results. Women who were candidates for taking oral contraceptive pills and had the metabolic syndrome could not be recruited. That is because some inclusion criteria for metabolic syndrome are actually exclusion criteria for safe oral contraceptive use.	Women with Body Mass Index)BMI <25 kg/m²
Period Title: Overall Study
STARTED	21	15
COMPLETED	14	15
NOT COMPLETED	7	0

Baseline Characteristics

Arm/Group Title	Obese Women	Lean Women	Total
Arm/Group Description	Women with Body Mass Index (BMI) >30 kg/m². Note: Only two arms were analyzed for the results. Women who were candidates for taking oral contraceptive pills and had the metabolic syndrome could not be recruited. That is because some inclusion criteria for metabolic syndrome are actually exclusion criteria for safe oral contraceptive use.	Women with Body Mass Index)BMI <25 kg/m²	Total of all reporting groups
Overall Participants	21	15	36
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	21 100%	15 100%	36 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	25.3 (6.9)	21.4 (2.3)	23.4 (5.8)
Sex: Female, Male (Count of Participants)
Female	21 100%	15 100%	36 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	21 100%	15 100%	36 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Obese Women	Lean Women
Arm/Group Description	Women with Body Mass Index (BMI) >30 kg/m²	Women with Body Mass Index (BMI) <25 kg/m²
Measure Participants	14	15
Baseline Insulin sensitivity	4.36 (2.32)	6.62 (3.69)
6 months Insulin sensitivity	3.82 (3.12)	8.23 (3.30)

2. Secondary Outcome

Title	Changes in Lipid Profile Compared Associated With OC Use Among (1) Obese Women and (2) Lean Women
Description	The lipid profile is assessed through blood sample analysis for low-density lipoprotein (LDL), Triglycerides and high-density lipoprotein (HDL).
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Obese Women	Lean Women
Arm/Group Description	Women with Body Mass Index (BMI) >30 kg/m²	Women with Body Mass Index (BMI) <25 kg/m²
Measure Participants	14	15
Baseline LDL	95 (18.4)	84 (24.3)
6 months LDL	113 (25.2)	104 (26.1)
Baseline Triglycerides	72 (50.3)	72 (52.0)
6 months Triglycerides	83 (51.1)	106 (52.9)
Baseline HDL	51 (10.7)	53 (10.0)
6 months HDL	58 (12.4)	61 (12.8)

3. Secondary Outcome

Title	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
Description	Inflammatory markers are assessed through blood analysis for C-reactive protein (hs-CRP) and adiponectin.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Obese Women	Lean Women
Arm/Group Description	Women with Body Mass Index (BMI) >30 kg/m²	Women with Body Mass Index (BMI) <25 kg/m²
Measure Participants	14	15
Baseline Hs-CRP	4908.76 (5215.07)	2050.77 (4748.75)
6 months Hs-CRP	6207.76 (4566.8)	2266.02 (3443.3)
Baseline Adiponectin	17568.86 (5680.86)	21976.53 (8322.05)
6 months Adiponectin	18408.43 (4934.39)	22221.36 (11160.97)

4. Secondary Outcome

Title	Changes in Estrogen Metabolites (Plasma) Associated With OC Use Compared Among (1) Obese Women and (2) Lean Women
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Obese Women	Lean Women
Arm/Group Description	Women with Body Mass Index (BMI) >30 kg/m². Note: Only two arms were analyzed for the results. Women who were candidates for taking oral contraceptive pills and had the metabolic syndrome could not be recruited. That is because some inclusion criteria for metabolic syndrome are actually exclusion criteria for safe oral contraceptive use.	Women with Body Mass Index)BMI <25 kg/m²
Measure Participants	14	15
Baseline 16aE1	314.76 (179.73)	317.47 (159.8)
6 months 16aE1	421.6 (286.57)	383.39 (452.98)
Baseline 2ME1	25.92 (11.03)	32.39 (9.3)
6 months 2ME1	52.84 (54.29)	45.58 (23.83)
Baseline 4ME1	5.26 (3.58)	4.45 (3.13)
6 months 4ME1	6.1 (3.29)	7.42 (8.55)
Baseline 2ME2	1.48 (1.06)	0.91 (0.82)
6 months 2ME2	1.5 (1.11)	1.74 (2.15)
Baseline E1	217.23 (170.88)	245.99 (128.41)
6 months E1	315.03 (339.15)	227.4 (271.6)
Baseline 4ME2	0.73 (0.55)	0.59 (0.54)
6 months 4ME2	0.89 (0.79)	1.14 (1.41)
Baseline E2	34.11 (15.61)	36.796 (17.28)
6 months E2	74.73 (117.52)	47.32 (61.82)
Baseline 2OHE1	101.07 (126.04)	85.62 (48.08)
6 months 2OHE1	135.95 (220.24)	57.96 (70.02)
Baseline 2OHE2	9.81 (5.85)	8.01 (3.62)
6 months 2OHE2	11.55 (21.74)	6.05 (4.69)
Baseline 4OHE1	33.78 (16.52)	33.98 (25.86)
6 months 4OHE1	27.29 (25.65)	29.12 (15.08)
Baseline Total plasma	1068 (472.78)	1022.16 (295.61)
6 months Total plasma	1342.21 (1166.36)	1007.89 (977.81)

5. Secondary Outcome

Title	Changes in Waist-to-Hip Ratio Associated With OC Use Compared Among (1) Obese Women and (2) Lean Women
Description	Waist-to-hip ratio is assessed through calculated ratio of waist and hip circumference.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Obese Women	Lean Women
Arm/Group Description	Women with Body Mass Index (BMI) >30 kg/m²	Women with Body Mass Index (BMI) <25 kg/m²
Measure Participants	14	15
Baseline Waist-Hip Ratio	0.79 (0.059)	0.73 (0.027)
6 months Waist-Hip Ratio	0.81 (0.057)	0.73 (0.057)

6. Secondary Outcome

Title	Inflammatory Marker Changes (MCP-1) Associated With OC Use Compared Among (1) Obese Women and (2) Lean Women
Description	Inflammatory marker is assessed through blood analysis for Monocyte chemotactic protein-1 (MCP-1).
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Obese Women	Lean Women
Arm/Group Description	Women with BMI >30 kg/m²	Women with BMI >25 kg/m²
Measure Participants	14	15
Baseline MCP-1	209.56 (125.92)	156.14 (36.29)
6 months MCP-1	219.86 (159.85)	206.66 (76.15)

7. Secondary Outcome

Title	Changes in Blood Pressure Associated With OC Use Compared Among (1) Obese Women and (2) Lean Women
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Obese Women	Lean Women
Arm/Group Description	Women with Body Mass Index (BMI) >30 kg/m². Note: Only two arms were analyzed for the results. Women who were candidates for taking oral contraceptive pills and had the metabolic syndrome could not be recruited. That is because some inclusion criteria for metabolic syndrome are actually exclusion criteria for safe oral contraceptive use.	Women with Body Mass Index)BMI <25 kg/m²
Measure Participants	14	15
Baseline Systolic Blood Pressure	121.1 (3.2)	105.7 (8.6)
6 months Systolic Blood Pressure	123.5 (11.7)	106.5 (12.2)
Baseline Diastolic Blood Pressure	74.4 (1.8)	68.0 (3.7)
6 months Diastolic Blood Pressure	73.4 (6.6)	66.5 (6.8)

8. Secondary Outcome

Title	Changes in Body Mass Index (BMI) Associated With OC Use Compared Among (1) Obese Women and (2) Lean Women
Description	Body Mass Index is a calculation of height and weight: kg/m²
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Obese Women	Lean Women
Arm/Group Description	Women with Body Mass Index (BMI) >30 kg/m²	Women with Body Mass Index (BMI) <25 kg/m²
Measure Participants	14	15
Baseline BMI	37.1 (6.7)	21.3 (1.8)
6 months BMI	37.6 (4.7)	21.4 (4.9)

9. Secondary Outcome

Title	Changes in Waist Circumference Associated With OC Use Compared Among (1) Obese Women and (2) Lean Women
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Obese Women	Lean Women
Arm/Group Description	Women with Body Mass Index (BMI) >30 kg/m²	Women with Body Mass Index (BMI) <25 kg/m²
Measure Participants	14	15
Baseline Waist circumference	100.0 (14.4)	70.2 (4.1)
6 months Waist circumference	101.0 (10.5)	70.9 (10.7)

10. Secondary Outcome

Title	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
Description	These inflammatory markers are assessed through blood analysis of Soluble Vascular Cell Adhesion Molecule (sVCAM) and soluble intercellular adhesion molecule (sICAM).
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Obese Women	Lean Women
Arm/Group Description	Women with Body Mass Index (BMI) >30 kg/m²	Women with Body Mass Index (BMI) <25 kg/m²
Measure Participants	14	15
Baseline sVCAM	905 (190.63)	1139.6 (159.57)
6 months sVCAM	880.14 (180.08)	1003.29 (256.62)
Baseline sICAM	163.34 (50.44)	182.11 (91.17)
6 months sICAM	163.2 (27.71)	160.21 (74.88)

Adverse Events

Arm/Group Title	Obese Women		Lean Women
Arm/Group Description	Women with Body Mass Index (BMI) >30 kg/m². Note: Only two arms were analyzed for the results. Women who were candidates for taking oral contraceptive pills and had the metabolic syndrome could not be recruited. That is because some inclusion criteria for metabolic syndrome are actually exclusion criteria for safe oral contraceptive use.		Women with Body Mass Index)BMI <25 kg/m²
All Cause Mortality
	Obese Women		Lean Women
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Obese Women		Lean Women
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/21 (4.8%)		0/15 (0%)
Gastrointestinal disorders
Gallstones removal	1/21 (4.8%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Obese Women		Lean Women
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/21 (9.5%)		2/15 (13.3%)
Injury, poisoning and procedural complications
Tiredness	0/21 (0%)		1/15 (6.7%)
Pain with venipuncture	0/21 (0%)		1/15 (6.7%)
Phlebitis due to catheter insertion	1/21 (4.8%)		0/15 (0%)
Dizziness due to Ortho Tricyclen	1/21 (4.8%)		0/15 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.