Although serum testosterone levels decrease acutely in critically ill patients, estrogen levels rise. We hypothesized that increased aromatization of androgens to estrogens underlie increases in serum estrogen. Eleven men and three women (aged 42-69 years) were studied before and again after elective coronary artery bypass graft surgery (CABG). Patients received priming doses of (¹⁴C)-androgen and (³H)-estrogen followed by peripheral infusions for 210 min. Eight men and three women received androstenedione (A4)/estrone (E1) and three men received testosterone (T)/estradiol (E2). Adipose tissue biopsies were obtained in another six men before and after CABG to evaluate levels of P450 aromatase mRNA. Serum T levels decreased postoperatively in all 17 men (P<0.001) while E1 levels rose (P=0.004) with a trend toward a rise in E2 (P=0.23). Peripheral aromatization rates of androgens to estrogens rose markedly in all fourteen patients (P<0.0001). Estrogen clearance rates rose (P<0.002). Mean serum A4 levels increased slightly postoperatively (P=0.04); A4 production rates (PRs) did not. T PRs decreased in two of three men while clearance rates increased in all three. Adipose tissue P450 aromatase mRNA content increased postoperatively (P<0.001). Conclusion: the primary cause of increased estrogen levels in acute illness is increased aromatase P450 gene expression resulting in enhanced aromatization of androgens to estrogens; a previously undescribed endocrine response to acute illness. Both increased T clearance and decreased T production contribute to decreased serum T. Animal studies suggest that these opposing changes in circulating estrogen and androgen levels may be important to reduce morbidity and mortality in critical illness.