Venter Gerda, van der Berg Carien L, Jacobs Tarien, van der Westhuizen Francois H, Erasmus Elardus
Biomedical and Molecular Metabolism Research, Faculty of Natural and Agricultural Sciences, North-West University (Potchefstroom Campus), Potchefstroom, South Africa.
Department of Biochemistry, Faculty of Natural and Agricultural Sciences, North-West University (Mahikeng Campus), Mmabatho, South Africa.
Sci Rep. 2025 Aug 26;15(1):31468. doi: 10.1038/s41598-025-16892-8.
Combined oral contraceptives (COCs) are commonly prescribed for the prevention of pregnancy, as well as numerous other non-contraceptive health reasons. COCs act by suppressing the natural hormonal fluctuations of the menstrual cycle that result in ovulation. No studies have investigated the effects of COC use on endogenous estrogen biotransformation and the production of estrogen metabolites. This is important since imbalances in hormone biotransformation (e.g., inefficient methylation by catechol O-methyltransferases; COMT) are implicated in the initiation of breast cancer through the generation of genotoxic metabolites (i.e., estrogen quinones) and reactive oxygen species (ROS), and the depletion of vital antioxidants and metabolic cofactors. Here, we quantified the urinary levels of various estrogen precursors and metabolites in healthy young women who were using COCs containing drospirenone (DRSP) and ethinyl estradiol (EE) (n = 24) and controls (n = 25) via liquid chromatography-tandem mass spectrometry (LC‒MS/MS). In addition, we analysed several circulatory intermediates of the methylation cycle that are linked to the methylation of catechol estrogens via LC‒MS/MS. We found that free urinary estradiol (E2) and estrone (E1) were significantly lower, while 2-methoxyestrone (2-MeOE1) levels were significantly higher in COC users. Excretion of some metabolites including 16-hydroxylation pathway metabolites, glutathione conjugates, and DNA-adducts were also lower in COC users, although total hormone and metabolite excretion levels were not significantly different. Estrone metabolite ratios were higher in COC users, including 2&4-MeOE1:E1, 2&4-OHE1:E1, E1-3-sulphate: E1, and E1-3-glucuronide: E1. There was a positive correlation between 2-hydroxyestrogen and 2-methoxyestrogen levels in controls but not in COC users. In addition, the serum betaine and dimethylglycine (DMG) levels, as well as the betaine: choline ratio, were reduced in COC users, whereas the levels of choline and serine and the DMG: betaine ratio were significantly increased. DMG levels positively correlated with methoxyestrogens and methoxyestrogen: hydroxyestrogen ratios in COC users, while S-adenosylmethionine (SAM) negatively correlated with 2-MeOE2. Our data suggests that the use of EE/DRSP increases the flux of endogenous hormones into the hormone biotransformation pathway, resulting in increased conversion of estrogens (especially E1) into conjugated, catechol, and methylated estrogens but that the latter is limited by methyl-group donor availability. Interestingly, the increased oxidation of estrogens in COC users does not result in increased DNA-adduct formation.
复方口服避孕药（COCs）通常用于预防妊娠，以及基于许多其他非避孕的健康原因。COCs通过抑制导致排卵的月经周期自然激素波动发挥作用。尚无研究调查使用COCs对内源性雌激素生物转化及雌激素代谢产物生成的影响。这一点很重要，因为激素生物转化失衡（例如儿茶酚O - 甲基转移酶；COMT甲基化效率低下）通过产生基因毒性代谢产物（即雌激素醌）和活性氧（ROS）以及重要抗氧化剂和代谢辅助因子的消耗，与乳腺癌的发生有关。在此，我们通过液相色谱 - 串联质谱法（LC‒MS/MS）对使用含屈螺酮（DRSP）和炔雌醇（EE）的COCs的健康年轻女性（n = 24）及对照组（n = 25）尿液中各种雌激素前体和代谢产物的水平进行了定量分析。此外，我们通过LC‒MS/MS分析了甲基化循环中与儿茶酚雌激素甲基化相关的几种循环中间体。我们发现，COC使用者尿液中游离雌二醇（E2）和雌酮（E1）显著降低，而2 - 甲氧基雌酮（2 - MeOE1）水平显著升高。COC使用者中一些代谢产物（包括16 - 羟化途径代谢产物、谷胱甘肽结合物和DNA加合物）的排泄量也较低，尽管总激素和代谢产物排泄水平无显著差异。COC使用者中雌酮代谢产物比率较高，包括2&4 - MeOE1:E1、2&4 - OHE1:E1、E1 - 3 - 硫酸盐:E1和E1 - 3 - 葡萄糖醛酸苷:E1。对照组中2 - 羟基雌激素和2 - 甲氧基雌激素水平呈正相关，而COC使用者中并非如此。此外，COC使用者血清中甜菜碱和二甲基甘氨酸（DMG）水平以及甜菜碱:胆碱比率降低，而胆碱和丝氨酸水平以及DMG:甜菜碱比率显著升高。COC使用者中DMG水平与甲氧基雌激素及甲氧基雌激素:羟基雌激素比率呈正相关，而S - 腺苷甲硫氨酸（SAM）与2 - MeOE2呈负相关。我们的数据表明，使用EE/DRSP会增加内源性激素进入激素生物转化途径的通量，导致雌激素（尤其是E1）向结合型、儿茶酚型和甲基化雌激素的转化增加，但后者受到甲基供体可用性的限制。有趣的是，COC使用者中雌激素氧化增加并未导致DNA加合物形成增加。
