TY - JOUR
T1 - Proinflammatory cytokine infusion attenuates lh's feedforward on testosterone secretion
T2 - Modulation by age
AU - Veldhuis, Johannes
AU - Yang, Rebecca
AU - Roelfsema, Ferdinand
AU - Takahashi, Paul
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2016/2
Y1 - 2016/2
N2 - Context: 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. Objective: 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. 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, 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. 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.
AB - Context: 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. Objective: 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. 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, 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. 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.
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U2 - 10.1210/jc.2015-3611
DO - 10.1210/jc.2015-3611
M3 - Article
C2 - 26600270
AN - SCOPUS:84959356139
VL - 101
SP - 539
EP - 549
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0021-972X
IS - 2
ER -