Changes in the adrenal and thyroid axes in critically ill patients are accentuated by increasing disease severity. However, the relationship of gonadal axis suppression to severity of illness is not well defined. We evaluated serial serum levels of LH, FSH, and testosterone (T) in 59 men and 42 postmenopausal women admitted to critical care units with a spectrum of disease severity. Patients were grouped according to severity of illness by the Acute Physiologic and Chronic Health Evaluation II (APACHE II) scores and by survival. Patients with surgery, renal or hepatic failure, alcohol abuse, endocrine disease, or head trauma were excluded to avoid these confounding factors. In men, mean admission serum T levels in all groups were lower than in healthy controls (P < 0.005). In addition, T levels in men with severe illness (APACHE > 15) were lower than in men with relatively mild (APACHE < 10; P < 0.01) or moderate illness (APACHE 10-15; P < 0.05). These differences were accentuated as hospitalization progressed. In postmenopausal women and men, nadir serum FSH but not LH levels during hospitalization were lower in patients with APACHE greater than 15 than in patients with APACHE scores of 10-15 or less than 15 (P < 0.05). Grouping patients by survival yielded similar results. Analysis of drug effects, age, and PRL did not explain these relationships. We conclude that the degree of both central and peripheral suppression of the reproductive axis in acute illness is related to disease severity. This suppression could not be attributed to other factors known to alter the reproductive axis independently from critical illness (e.g. age, drugs, head trauma, hepatic failure, etc.). These findings further document a general endocrine response to acute illness involving several axes which is graded according to disease severity.