This study demonstrates that the use of OCT could increase oxidative stress levels, as assessed by the d-ROMs test, in pre-menopausal women. It is notable that the difference in d-ROMs levels between the groups did not change when the analyses were adjusted for several well-established cardiovascular risk factors. Our findings are crucial, since oxidative stress may contribute to vascular complications.
The mechanisms responsible for the results of the present study are unclear, but there are several possible explanations. The behavior of molecules related to oxidative stress in circulating blood and at the cellular level can differ in the types and dosages of estrogen and progestin within the treatments may be important. Estrogens show various cardiovascular actions on the endothelium, increasing the bioability of NO via genomic and non-genomic activation of NO synthase.[10
] The most important difference between E2 and EE is that EE does not seem to protect endothelial function from oxidative stress.[11
] A previous study found that the NO production in human ECV304-endothelial cells was increased by E2 in a dose-dependent manner but not by EE.[11
] Similarly, the viability of endothelial cells after exposure to H2
was increased by E2 but not by EE, suggesting that EE does not protect endothelial cells from oxidative stress.[11
] Another investigation reported that basal NO and prostaglandin production increased in cultured aortic cells from ovariectomized rats treated with E2, whereas NO and prostaglandin production were reduced in cells from non-ovariectomized rats treated with EE.[12
] Moreover, a clinical study revealed that OCT significantly increased the plasma concentration of copper, selenium and lipid peroxides and decreased the levels of gamma-tocopherol and beta-carotene in women.[13
] Taken together, these findings indicate that OCT can increase oxidative stress, possibly leading to vascular complications.
The administration of progesterone has anti-atherosclerotic effects with preferable lipoprotein profiles. Furthermore, progesterone may reduce ROS formation and cause vascular relaxation in a tissue-specific fashion;[14
] however; progesterone antagonizes the vasoprotective effects of estrogen on anti-oxidant enzyme expression and function, and enhances NADPH oxidase activity and the production of ROS.[15
] In OCT, a progestogen-only contraceptive implant was reported to have no negative effects on cardiovascular risk factors (e.g., C-reactive protein, total/high-density lipoprotein cholesterol ratio and NO), suggesting progesterone does not negatively impact cardiovascular risk factors in healthy young women.[16
] The risk of venous thrombosis differs depending on the type of progestogen given in combination with EE, and the appropriate dose and type of progestin may reduce the adverse effects of OCT on cardiovascular risk factors.[17
] Recently, the MEGA study indicated that the risk of venous thrombosis with OCT could be increased by different progestin up to 3 to 7 fold.[18
] Thus, progestogen may also antagonize the beneficial effects of estrogen on vasodilation in OCT.
The present study has several limitations. The sample size was relatively small. The study design was cross-sectional, and cardiovascular outcomes were not evaluated. Furthermore, there was no measurement of blood levels of antioxidants, and oxidative stress markers other than d-ROMs. A prospective evaluation in a larger population with long-term follow-up and the measurement of additional markers is necessary to confirm the results of the present study.