4-hydroxycatecholestrogen metabolism responses to exercise and training: Possible implications for menstrual cycle irregularities and breast cancer

Objective: To investigate the behavior of C4-substituted estrogens, the so-called catecholestrogens, in response to acute exercise and training. The 4-hydroxyestrogens are known to have both a strong estrogenic potency and affinity for catechol-O-methyltransferase (COMT), the enzyme that deactivates catecholamines. Design: A prospective trial covering three menstrual cycles: a control cycle, a moderate training cycle, and a heavy training cycle. Participant(s): Six untrained, healthy, eumenorrheic women (mean pretraining maximum oxygen uptake: 40.9 +/- 4.9 mL/kg per minute, body fat: 27.9% +/- 3.6%) volunteered for this study. Intervention(s): An incremental exercise test to exhaustion on a cycle ergometer, in the follicular and luteal phases, before and after a brief but exhaustive training program. Main Outcome Measure(s): Hormone measurements included follicular and luteal phase plasma E(2), LH, catecholamines, PRL, total unconjugated and conjugated estrogens, total 4-hydroxyestrogens (4-OHE), and 4-hydroxyestrogen-monomethylethers (4-MeOE). Result(s): Pretraining baseline 4-OHE levels were significantly higher in the luteal phase (66 +/- 9 pg/mL; mean +/- SEM) than in the follicular phase (51 +/- 7 pg/mL). Pretraining and post-training baseline 4-MeOE values were below minimal detection limits (<35 pg/mL). During incremental exercise, catecholamines, PRL, E(2) unconjugated and conjugated estrogens, 4-OHE, and 4-MeOE always increased (the increases in 4-OHE during exercise were more pronounced before training, contrary to the 4-MeOE being most increased after training). The baseline 4-MeOE:4-OHE ratio (a measure of catecholestrogen activity) significantly increased with progressive training. Conclusion(s): Because 4-OHE have been shown to be able to control the hypothalamic gonadotropin oscillator and to stimulate the luteolytic prostaglandin PGF(2 alpha), the acute exercise-induced increases of 4-OHE and their positive correlation with lactate levels may indicate a key process in the pathogenesis of exercise-associated menstrual irregularities. In addition, 4-OHE, when insufficiently O-methylated, are known to be capable of raising mutagenic superoxide free radicals and causing DNA damage that may lead to breast cancer. The results of the present study also may be of significance for the apparent protective effects of sports participation against cancer of the breast.