Previous evidence suggests that the testicular negative feedback control of gonadotropin-releasing hormone-luteinizing hormone (LH) secretion may change as men age, and may thereby contribute to the hypogonadism that occurs as men grow older. To pursue this idea, we analyzed the results for 35 men with primary hypogonadism who were participants in an open-label multicenter study of testosterone replacement. LH, sex hormone-binding globulin (SHBG), and total and free testosterone and estradiol concentrations were measured in blood samples at baseline and after 2% testosterone gel was applied daily for 2 weeks. A 24-hour pharmacokinetic profile for testosterone and estradiol was obtained at the end of week 2. Age was a strong predictor of LH suppression during testosterone replacement (r = -0.46), and the effect could not be explained by obesity, SHBG, or higher levels of total or non-SHBG testosterone or estradiol during treatment. In fact, both LH and non-SHBG testosterone levels were lower (P < .05) in older men receiving testosterone treatment. In addition, the strongest association overall was between the percentage decline in LH and non-SHBG estradiol concentrations (r = -0.39). These data provide further evidence that suppression of LH secretion during testosterone treatment is greater as men age, and are consistent with the hypothesis that the hypogonadism of aging men is partly due to a change in gonadotropin negative feedback regulation. These results further suggest that estrogen receptor signaling might contribute to this effect.