CONTEXT:: In the experimental animal, inflammatory signals quench LHʼs feedforward drive of testosterone (T) secretion and appear to impair GnRH-LH output. The degree to which such suppressive effects operate in the human is not known. OBJECTIVE:: To test the hypothesis that IL-2 impairs LHʼs feedforward drive on T and Tʼs feedback inhibition of LH secretion in healthy men. SETTING:: Mayo Center for Translational Science Activities. PATIENTS OR OTHER PARTICIPANTS:: A total of 35 healthy men, 17 young and 18 older. INTERVENTIONS:: Randomized prospective double-blind saline-controlled study of IL-2 infusion in 2 doses with concurrent 10-minute blood sampling for 24 hours. MAIN OUTCOME MEASURES:: Deconvolution analysis of LH and T secretion. RESULTS:: After saline injection, older compared with young men exhibited reduced LH feedforward drive on T secretion (P < .001), and decreased T feedback inhibition of LH secretion (P < .01). After IL-2 injection, LHʼs feedforward onto T secretion declined markedly especially in young subjects (P < .001). Concomitantly, IL-2 potentiated Tʼs proportional feedback on LH secretion especially in older volunteers. CONCLUSION:: This investigation confirms combined feedforward and feedback deficits in older relative to young men given saline and demonstrates 1) joint mechanisms by which IL-2 enforces biochemical hypogonadism, viz, combined feedforward block and feedback amplification; and 2) unequal absolute inhibition of T and LH secretion by IL-2 in young and older men. These outcomes establish that the male gonadal axis is susceptible to dual-site suppression by a prototypic inflammatory mediator. Thus, we postulate that selected ILs might also enforce male hypogonadism in chronic systemic inflammation.