Oral Versus Patch Hormonal Contraceptive Effects on Metabolism, Clotting, Inflammatory Factors and Vascular Reactivity
Information source: University of Washington
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Contraception
Intervention: Ortho-Cyclen (R) (Drug); Ortho Evra (R) (Drug); extended use of Ortho Evra (R) (Drug)
Phase: Phase 2
Status: Active, not recruiting
Sponsored by: University of Washington Official(s) and/or principal investigator(s): Robert H Knopp, MD, Principal Investigator, Affiliation: University of Washington
Summary
The purpose of this study is to compare the effects of oral versus patch administration of
hormonal contraception on hormone sensitive proteins such as lipoproteins, clotting factors
and inflammatory proteins as well as blood sugar and insulin levels, antioxidant status and
flow-mediated dilation of arm and forearm vessels. The hypothesis is that oral
administration of contraceptive hormones will result in higher plasma levels of estrogen
sensitive proteins originating from the liver while patch administration of contraceptive
hormones will result in greater systemic effects of estrogen on vascular reactivity and
antioxidant status.
Clinical Details
Official title: Comparison of Oral and Patch Forms of Hormonal Contraception on Plasma Lipoproteins, Glycemia, Clotting Factors, Indices of Inflammation and Vascular Reactivity
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Glucose, insulin, lipoproteins, clotting factors, hormone levels and sex hormone binding globulininflammatory proteins, apoproteins and total antioxidant capacity vascular reactivity
Detailed description:
Study Rationale:
The metabolic effects of hormonal contraceptives differ when administered by oral or
systemic routes. The oral route magnifies the hepatic production of hormone sensitive
proteins including lipoproteins, clotting factors and inflammatory proteins such as CRP.
These effects are due to the first pass of hormone to the liver from the portal circulation.
The first pass hepatic effect also reduces the systemic exposure to orally administered
estrogen and progestin, due to glucuronidation and sulfation of sex hormones and excretion
in the bile. Systemic administration by the patch is more analogous to physiologic hormone
release from the ovary, as it avoids the first pass effect and the peripheral tissues are
exposed to higher hormone concentrations than with oral administration. Conversely, the
liver may have a lower exposure to hormone by patch administration than by oral
administration.
With respect to the extended cycle (2-month) patch contraception formulation under study,
similar questions may be asked about the metabolic, inflammatory and vascular effects of
this regimen compared to the one-month cycles.
The purpose of this research is:
1. to measure the plasma estrogen and progestin levels observed with each formulation and
the physiological parameters that affect vascular health including lipids, glucose and
insulin, redox state, clotting and inflammatory factors, and vascular reactivity; and
2. to study the relationships of hormones to physiological parameters among the three
regimens.
The underlying rationale is that the net effect of estrogen-progestin combinations is a
function of the dose and biological effect of each hormone and that these effects differ by
route of administration.
Study Design:
Three contraception regimens will be compared in an open label, randomized, crossover
design. The three regimens are Ortho-Cyclen® as the standard reference oral contraceptive,
Ortho Evra® patch formulation, and an investigational two month patch formulation. The two
month patch formulation will consist of applying Ortho Evra® for 7 weeks in a row with the
8th week off compared to 3 weeks of patch application with the 4th week off in the standard
patch cycle. Subjects will take each hormonal regimen for two months.
Eligible subjects will have an initial one-month run-in period on Ortho-Cyclen®. In
addition to washing out any previous hormone exposure, this washout will serve as a
compliance hurdle that will help in selecting subjects that are willing to undergo the
discipline of the study. Washouts between treatments will not be performed in order to
provide continuous contraception for the study subjects and facilitate compliance once
subjects are randomized into the study. As each treatment period will last two months, the
first month of each two-month treatment period will be considered as the washout from the
previous treatment protocol. The second month of each two-month treatment period will be the
investigative month.
Plasma hormones monitored in the second month of each two month period are ethinyl estradiol
and norelgestromin. Norelgestromin is the primary active metabolite of norgestimate
metabolism.
Clotting parameters to be measured are those monitored in our previous study of a
desogestrel (D) vs. levonorgestrel (L) contraceptive comparison at nearly equal estrogen
exposures over 9 months. In this study, PT and PTT increased equally from a pre-treatment
baseline, factor V decreased on (D) and increased on (L), and free protein S decreased on
(D) and did not change with (L). The impression from this study was that the changes were
internally compensating. PAI-1, an inhibitor of plasminogen activation, will also be
measured. These will be measured at 1, 7, 21 and 28 days of the investigative month.
Inflammatory parameters will include highly sensitive C-reactive protein (hsCRP), which is
of hepatic origin, and serum amyloid A (SAA), which varies in parallel to CRP in the
metabolic syndrome but is transported almost entirely in HDL. SAA transport in HDL is
considered to be a barometer of impaired HDL function, which occurs in inflammatory states.
These measurements will be obtained at days 1 and 21.
Antioxidant status is related to inflammatory and metabolic stress and is of additional
interest in light of a current NIH NICHD study to examine the changes in oxidant stress
during the menstrual cycle. The primary parameter we will use is total antioxidant capacity
(TOAC). Several other parameters of plasma redox status can be measured if interesting
trends are detected. These parameters will also be measured at days 1 and 21 of the
respective cycles. We have previously described the antioxidant effects of estrogen and
prooxidant effects of progestins and differences among the progestins in in vitro systems.
The lipoprotein measures selected are the standard lipid profile consisting of triglyceride,
cholesterol, HDL cholesterol measured by precipitation and estimation of LDL by the
Friedwald algorithm. The HDL2 and HDL3 sub-fractions and apoproteins AI and AII are
sensitive measures of estrogen-progestin balance, as is sex-hormone binding globulin (SHBG).
Lipoprotein lipids, HDL sub-fractions and SHBG will be measured at 1, 7, 21 and 28 days. The
apoproteins will be measured at days 1 and 21.
We will measure vascular reactivity after arterial ischemia in two ways, by brachial artery
reactivity and by venous plethysmography. Both techniques are sensitive to nitric oxide
mediated vascular dilation. Both procedures will be done without the nitroglycerin step.
Differences in flow mediated dilation and arterial compliance have been described in the
normal menstrual cycle, and should be sensitive to differing biologic effects of estrogen
and progestin in the respective contraceptive cycles. We expect that the vasodilatory
response to ischemia will represent the net opposing biologic effects of estrogen and
progestin, as do the hormone-sensitive plasma proteins. These measurements will be made at
day 21 of the second month of each of the three treatment arms, as day 21 is the time of
maximum hormone exposure in all three regimens.
The subject's overall satisfaction with each hormonal regimen will be quantified in a daily
diary along with a record of menstrual history.
Eligibility
Minimum age: 18 Years.
Maximum age: 50 Years.
Gender(s): Female.
Criteria:
Inclusion Criteria:
1. Willing to participate in a crossover design study with biweekly or weekly clinic
visits in the second, fourth and sixth months.
2. Healthy women within the age range of 18 to 50 years inclusive who are sexually
active and at risk for pregnancy.
Exclusion Criteria:
1. Blood pressure above 140/90 mmHg
2. Glucose greater than 126 mg/dL or diabetes mellitus
3. Triglyceride greater than 300 mg/dL
4. Body mass index (BMI) greater than 30 kg/m2 or greater than 18. 5 kg/m2
5. Current or past history of thrombophlebitis, deep vein thrombosis or thromboembolic
disorders.
6. Current or past history of cerebrovascular or coronary artery disease.
7. Presence of valvular heart disease with complications.
8. Major surgery with prolonged immobilization.
9. Known or suspected carcinoma of the breast or personal history of breast cancer.
10. Carcinoma of the endometrium or other known or suspected estrogen-dependent
neoplasia.
11. Undiagnosed abnormal genital bleeding.
12. History of cholestatic jaundice during pregnancy or history of jaundice with prior
hormonal contraceptive use.
13. Acute or chronic hepatocellular disease with abnormal liver function. Hepatic
adenomas or carcinomas.
14. Any active liver or renal disease.
15. Untreated thyroid disease.
16. Migraine or headaches with focal neurological symptoms.
17. Known or suspected pregnancy or currently breast feeding.
18. Alcohol intake above one drink per day
19. Cigarette smoking
20. Depression or any psychiatric illness
21. Any lipid lowering or blood pressure lowering medication
22. Any illegal drug use
23. Non-steroidal anti-inflammatory drug (NSAID) or aspirin use for 5 days prior to
vascular reactivity studies.
24. Antioxidant supplements (stable multivitamin use allowed)
25. History of sensitivity or allergic reaction to any hormonal contraceptives.
26. Unwilling or unable to comply with the study protocol
Locations and Contacts
University of Washington, Northwest Lipid Research Clinic, Seattle, Washington 98104, United States
Additional Information
Starting date: February 2007
Last updated: February 10, 2011
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