Pyrogenicity of etiocholanolone and interleukin-1 in New and Old World Monkeys

Etiocholanolone (5beta-androstan-3alpha-ol-17-one; designated E) is one of the major products of metabolism of testosterone and androstenedione (androst-4-ene-3,17-dione) in many mammalian species, including humans. E and several other 5beta-reduced steroids have been found to induce fever in humans. The pyrogenic effect of these steroids has been shown to be due to the release of interleukin-1 (IL-1) from the leukocytes that are mobilized in response to the steroid injections. Old World Monkeys such as Rhesus monkeys (Macaca mu/atta), metabolize androgens similarly to humans, and E is a normal metabolite. However, New World Monkeys such as Squirrel monkeys (Saimiri sciureus), lack hepatic 5alpha- and 5beta-steroid reductases and excrete androgens primarily in an unaltered state; E is not produced. Therefore, we postulate that Squirrel monkeys likewise may have lost the ability to respond to 17-ketosteroids such as E. To test this hypothesis, adult male Rhesus and Squirrel monkeys were treated with E, and their rectal temperatures were recorded over a 24-hr period. Rhesus monkeys exhibited a rise of up to 3 degrees F following E injection. Squirrel monkeys, on the other hand, did not exhibit any increase in rectal temperature over the 24-hr period, even when doses up to 250 times the effective human dose were used. However, both species responded to injected IL-1alpha with a robust increase in rectal temperature. The data show that E is pyrogenic in Rhesus, but not Squirrel monkeys. The findings support the notion that injected E may induce release of IL-1 in Rhesus monkeys, but not in Squirrel monkeys.