Testosterone suppresses the response of the hypothalamic-pituitary-adrenal axis to interleukin-6

Endotoxin and the inflammatory cytokines interleukin (IL)-1 and IL-6 are potent activators of the hypothalamic-pituitary-adrenal (HPA) axis. Previous studies in the rodent and in the primate have shown that the responses of the HPA axis to endotoxin and to IL-1 were enhanced by gonadectomy and attenuated by testosterone or estradiol replacement. The mechanisms underlying these observations are unclear, but there is evidence that gonadal steroids have direct inhibitory effects on IL-6 synthesis and release. Since endotoxin and IL-1 both stimulate IL-6, the question arises as to whether the sex-steroid-induced suppression of the HPA response to endotoxin and IL-1 results solely from decreased IL-6 release, or whether other mediators are involved.

We have therefore examined the ACTH and corticosterone responses to IL-6 in intact and castrated male rats with and without testosterone replacement. Animals were castrated 2 weeks prior to study; testosterone was replaced by subcutaneous Silastic capsules. Four days prior to study, an indwelling right atrial catheter was implanted. Blood samples for ACTH and corticosterone radioimmunoassays were collected through the catheter 0, 20, 40, 60, 120 and 180 min after intravenous injection of recombinant human IL-6 (500 ng).

IL-6 stimulated ACTH and corticosterone release in all groups, with peak stimulation occurring within the first hour. The release of both ACTH and corticosterone was significantly attenuated in the intact (n = 9) and testosterone-replaced (n = 5) animals compared to the castrated animals without replacement (n = 7). Peak ACTH levels were 340 +/- 58 and 133 +/- 41 pg/ml in the intact and testosterone-replaced animals versus 678 +/- 170 pg/ml in the castrated animals (p < 0.02). Peak corticosterone levels were 29 +/- 4.7 and 30 +/- 4.2 microg/dl in the intact and testosterone-replaced animals versus 47 +/- 5.8 microg/dl in the castrated animals (p < 0.05).

We conclude that testosterone attenuates the response of the HPA axis to IL-6 in the rat. This would indicate that other mechanisms, in addition to the inhibition of IL-6 release, are responsible for restraining the HPA response to inflammatory stimuli in the presence of gonadal steroids.