Objective: Obesity-associated hypogonadism is hypothesized to be due to the suppressive effect of high estradiol (from an increase in aromatase activity present in the abundant adipose tissue) on the hypothalamic-pituitary-gonadal unit resulting in low testosterone production. Although weight loss has been found to be effective in reducing estradiol and raising testosterone levels in studies of younger men, its effect in frail, obese older men is understudied. Thus, the objective of this study was to determine the effect of lifestyle intervention on hormone levels in frail, obese older men. Design: Randomized controlled trial of lifestyle intervention in frail, obese older men (>= 65 yo) for 1 year. Setting: University hospital. Methods: Forty frail, obese elderly men were randomized, for a 52-week study, to any of the following treatment groups: (1) control group, (2) diet-induced weight loss group (diet group), (3) exercise training group (exercise group), and (4) diet-induced weight loss and exercise training group (diet-exercise group). The objective was to achieve a similar to 10 % weight loss at 6 months and maintain this weight for an additional 6 months. Physical function was assessed by the modified physical performance testing (modified PPT). Estradiol was measured by radioimmunoassay, testosterone by automated immunoassay, and sex hormone-binding globulin by enzyme-linked immunoassay. Results: After 12 months of intervention, diet alone resulted in a weight loss of -10.1 +/- 1.9 kg in the diet group and -9.1 +/- 0.9 kg in the diet-exercise group. This resulted in a significant decrease (both p<0.05) in total estradiol compared to baseline among subjects in the diet (-2.5 +/- 1.3 pg/ml) and diet-exercise group (-2.2 +/- 4.0 pg/ml). Free estradiol index also significantly decreased (both p<0.05) in both the diet (-0.39 +/- 0.14 pmol/nmol) and diet-exercise (-0.52 +/- 0.12 pmol/nmol) group. Total testosterone significantly increased (p<0.05) in response to diet (71.0 +/- 21.0 ng/dl) and diet-exercise (49.9 +/- 15.5 pg/ml) resulting in values of 287.0 +/- 28.1 ng/dl in the diet and 317.6 +/- 33.1 ng/dl in the diet-exercise group. However, because there was a significant increase in sex hormonebinding globulin levels in both the diet and diet-exercise groups, free testosterone index and the changes in free testosterone index were not significant compared to baseline. Regardless of changes in hormonal levels, patients in the diet, exercise, and diet-exercise groups experienced significant improvements in the modified PPT from baseline. Conclusion: Weight loss from lifestyle intervention resulted in significant decreases in total and free estradiol levels in frail, obese older men, but this did not result in a clinically important increase in total testosterone nor a significant increase in free testosterone. Thus, alternative forms of treatment in addition to lifestyle intervention may be necessary to improve the hormonal profile among these patients. Nevertheless, whether further improvement in hormonal profile would result in better physical performance than what can be achieved by lifestyle alone in these subjects remains uncertain.