Effect of two oral contraceptives containing ethinylestradiol and levonorgestrel on serum and urinary surrogate markers of endothelial function.
OBJECTIVE
To investigate the effect of two oral contraceptives containing 0.02 mg ethinylestradiol and 0.1 mg levonorgestrel (Formulation A, Leios), and the other containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel (Formulation B, Stediril 30) on the serum and urinary concentrations of various markers reflecting the status of vascular tone and development of atherosclerosis. The adhesion molecules E-selectin, inter-cellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and homocysteine were included as serum markers and cGMP, prostacyclin and its antagonist thromboxane as urinary markers.


METHODS
In a comparative, double-blind, randomized, parallel group study, 34 women received formulation A and 33 women formulation B. Serum samples were collected before treatment and after 3, 6 and 12 cycles. Nocturnal urine was collected before treatment and during cyclic treatment after 3 and 12 cycles. Serum and urinary markers were measured by enzyme immunoassays.


RESULTS
E-selectin levels were significantly reduced by both contraceptives after 3, 6 and 12 months compared to pretreatment levels. A slight increase in ICAM concentrations was observed for both contraceptives after 6 cycles, but this fell to pretreatment levels after 12 cycles. VCAM values were significantly lowered after 3, 6 and 12 months by both contraceptives. No significant changes were found in serum levels of homocysteine. No significant differences were found between treatment groups for the serum markers. Both contraceptives significantly enhanced urinary cGMP excretion after 12 cycles. The prostacyclin metabolite remained unchanged in the case of both formulations, but the excretion of the thromboxane metabolite was significantly decreased after 12 cycles. Thus, the ratio of prostacyclin to thromboxane, decisive for the resulting effect on vascular tone, increased significantly.


CONCLUSIONS
These results indicate that the low-dose oral contraceptives can reduce the production of adhesion molecules which play a crucial role in the early stages of atherosclerosis. In addition, these contraceptives can shift the balance of vascular tone towards dominance of vasodilatory substances after 12 cycles of treatment. Thus, the positive influence of these contraceptives on the various markers investigated may improve vascular tone and impede development of atherosclerosis.
Seeger
H
H
Department of Obstetrics and Gynecology, University of Tübingen, Germany.
Petersen
G
G
Schulte-Wintrop
E
E
Teichmann
A T
AT
Mueck
A O
AO
D000328:Adult; D001161:Arteriosclerosis / Q000517:prevention & control*; D015415:Biomarkers / Q000032:analysis*; D015815:Cell Adhesion Molecules / Q000032:analysis*; D003280:Contraceptives, Oral, Synthetic / Q000008:administration & dosage / Q000494:pharmacology*; D004311:Double-Blind Method; D004727:Endothelium / Q000502:physiology*; D045166:Estradiol Congeners / Q000008:administration & dosage / Q000494:pharmacology*; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D016912:Levonorgestrel / Q000008:administration & dosage / Q000494:pharmacology*; D016482:Urinalysis
D015415:Biomarkers; D015815:Cell Adhesion Molecules; D003280:Contraceptives, Oral, Synthetic; D045166:Estradiol Congeners; D004997:Ethinyl Estradiol; D016912:Levonorgestrel