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J Interferon Cytokine Res. 1999 Nov;19(11):1271-6.

Dose-dependent effects of recombinant human interleukin-6 on the pituitary-testicular axis.

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Developmental Endocrinology Branch, NICHD, NIH, Bethesda, MD 20892, USA.


Inflammatory cytokines are soluble mediators of immune function that also regulate intermediate metabolism and several endocrine axes. To examine the effects of interleukin-6 (IL-6), the main circulating cytokine, on the hypothalamic-pituitary-testicular axis in men, we performed dose-response studies of recombinant human IL-6 (rHuIL-6) in normal volunteers. Increasing single doses of IL-6 (0.1, 0.3, 1.0, 3.0, and 10.0 microg/kg body weight) were injected subcutaneously into 15 healthy male volunteers (3 at each dose) in the morning. We measured the circulating levels of testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex hormone binding globulin (SHBG) at baseline and then at 24 h, 48 h, and 7 days after the IL-6 injection. LH and FSH levels were also measured half-hourly for the first 4 h after the IL-6 injection. All IL-6 doses were tolerated well and produced no significant adverse effects. Mean peak plasma IL-6 levels achieved after IL-6 administration were 8 +/- 1, 22 +/- 5, 65 +/- 22, 290 +/- 38, and 4050 +/- 149 pg/ml, respectively for the five doses. We observed no significant changes in plasma testosterone levels after the two smaller IL-6 doses. The three higher IL-6 doses, however, caused significant decreases in testosterone levels by 24 h, which persisted at 48 h and returned to baseline by 7 days. The higher testosterone suppression was after the 3.0 microg/kg dose, making the dose-response curve bell-shaped. There also appeared to be small but not significant increases in LH levels after the three higher IL-6 doses, which were not acute and seemed to follow temporally the testosterone decreases. The concurrent plasma levels of FSH and SHBG were not appreciably affected by any IL-6 dose. In conclusion, subcutaneous IL-6 administration, which caused acute elevations in circulating IL-6 levels of a similar magnitude to those observed in severe inflammatory and noninflammatory stress, induced prolonged suppression in testosterone levels in healthy men without apparent changes in gonadotropin levels. This suggests that IL-6 might induce persistent testicular resistance to LH action or suppression of Leydig cell steroidogenesis or both, with potential adverse effects on male reproductive function.

[Indexed for MEDLINE]

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