Proinflammatory Cytokine Infusion Attenuates LH's Feedforward on Testosterone Secretion: Modulation by Age

In the experimental animal, inflammatory signals quench LH's 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.

To test the hypothesis that IL-2 impairs LH's feedforward drive on T and T's feedback inhibition of LH secretion in healthy men.

Mayo Center for Translational Science Activities.

A total of 35 healthy men, 17 young and 18 older.

Randomized prospective double-blind saline-controlled study of IL-2 infusion in 2 doses with concurrent 10-minute blood sampling for 24 hours.

Deconvolution analysis of LH and T secretion.

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, LH's feedforward onto T secretion declined markedly especially in young subjects (P < .001). Concomitantly, IL-2 potentiated T's proportional feedback on LH secretion especially in older volunteers.

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.