Etiocholanolone (Test Metabolite) and the Test Flu

[The Anonymizer]

An abstract showing most likely the main cause of the Test flu. (Etiocholanolone)
A search will find several articles about the test flu and etiocholanolone, including the monkey abstract. You can find a discussion of the phenomenon in most good pharmacology texts, like Goodman & Gilman.

Any how Why some people experience this reaction and others don't is what's always puzzled me. Of course injecting straight etiocholanolone would doubtless make anyone ill. But etiocholanolone represents only about 20% of the metabolites of testosterone in people. Very well could be that folks who experience this reaction to testosteone have particularly high levels of 17 beta hydroxysteroid dehydrogenase, the enzyme that converts testosterone into etiocholanolone. Or an isoform of the enzyme that makes the conversion more efficient. Kind of like people (commonly asians) who have certain isoforms of the enzymes alcohol dehydrogenase and/or aldehyde dehydrogenase that interfere with the metabolism of ethanol. These people get drunk and sick from alcohol pretty easily.

Etiocholanolone is believed to produce fever and flu-like aches and pains because it induces the systemic release of Interleukin-1, a powerful proinflammatory cytokine:

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

Steinetz BG, Randolph C, Werner R, Mahoney CJ.

New York University Medical Center, Laboratory for Experimental Medicine and Surgery in Primates, Tuxedo 10987, USA. steinetz@charlotte.med.nyu.edu

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.