Serum Metabolome Changes in Relation to Prothrombotic State Induced by Combined Oral Contraceptives with Drospirenone and Ethinylestradiol

Abstract

The association between hypercoagulability and use of drospirenone (DRSP) and ethinylestradiol (EE) containing combined oral contraceptives (COCs) is an important clinical concern. We have previously reported that the two formulations of DRSP combined with EE (namely, DRSP/20EE and DRSP/30EE) bring about a prothrombotic state in hemostatic traits of female users. We report here the serum metabolomic changes in the same study cohort in relation to the attendant prothrombotic state induced by COC use, thus offering new insights on the underlying biochemical mechanisms contributing to the altered coagulatory profile with COC use. A total of 78 healthy women participated in this study and were grouped as follows: control group not using oral contraceptives (n = 25), DRSP/20EE group (n = 27), and DRSP/30EE group (n = 26). Untargeted metabolomics revealed changes in amino acid concentrations, particularly a decrease in glycine and an increase in both cysteine and lanthionine in the serum, accompanied by variations in oxidative stress markers in the COC users compared with the controls. Of importance, this study is the first to link specific amino acid variations, serum metabolites, and the oxidative metabolic profile with DRSP/EE use. These molecular changes could be linked to specific biophysical coagulatory alterations observed in the same individuals. These new findings lend evidence on the metabolomic substrates of the prothrombotic state associated with COC use in women and informs future personalized/precision medicine research. Moreover, we underscore the importance of an interdisciplinary approach to evaluate venous thrombotic risk associated with COC use.

Effect of Iron Depletion by Bloodletting vs. Observation on Oxidative Stress Biomarkers of Women with Functional Hyperandrogenism Taking a Combined Oral Contraceptive: A Randomized Clinical Trial

“…Glycine reduces superoxide anion radical release, protein carbonyl, and lipid peroxidation, and on the contrary, increases the biosynthesis of glutathione (GSH) [40]. This putative mechanism for COC-induced oxidative stress agrees with the changes observed in the metabolome of COC users [39].…”

“…Therefore, hydroxyl radicals from phase 1 metabolic activity would not be a major contributor to oxidative stress in COC users. Interestingly, the estrogen-induced phase 2 enzyme glycine N-acyltransferase increases glycine consumption [39]. Glycine reduces superoxide anion radical release, protein carbonyl, and lipid peroxidation, and on the contrary, increases the biosynthesis of glutathione (GSH) [40].…”

Mechanical and Physical Behavior of Fibrin Clot Formation and Lysis in Combined Oral Contraceptive Users

“…Another recent study from our group using untargeted metabolomics in the same cohort of DRSP/20EE and DRSP/30EE users, exhibited variation in oxidative stress markers along with changes in amino acid concentrations (Swanepoel et al, 2020). We attributed these quantifiable changes in the serum metabolome of the DRSP/EE users to specific biophysical changes visualized in the whole blood SEM micrographs due to spontaneous fibrin formation (Emmerson et al, 2018) Decreased amino acid concentration, as well as oxidative stress, could thus also account for changes in the fibrin network formation, lysis, and ultrastructure.…”

Health Status Is Affected, and Phase I/II Biotransformation Activity Altered in Young Women Using Oral Contraceptives Containing Drospirenone/Ethinyl Estradiol

“…Increased GLYAT activity will lead to increased glycine consumption. Interestingly, serum glycine levels are reduced in DRSP/EE COC users [71]. This may indicate that glycine availability is limited in COC users, which in turn may have biochemical consequences.…”