Type-IIx
Well-known Member
To start, the markers of liver damage & bile duct obstruction are good proxies of hepatotoxicity.
I think that you have to view lethargy as, compound-dependently, merely associated with hepatotoxicity.
Now for a compound like Superdrol, I believe there is a strong association between lethargy & hepatotoxicity (I even believe there is likely causation). With Halo, by way of counterexample, it is not particularly hepatotoxic - yet it can induce lethargy, probably by its effects on cortisol & glucocorticoids (a weak association between lethargy vs. hepatotoxicity). Dbol, by its quite different effects on cortisol by way of ACTH, can also cause lethargy long-term (though it has less clear effects on glucocorticoids in the short term; and is even associated with promotion of well-being & vitality). Yet another interesting case is that of Winstrol, as it and its 16β-hydroxylated metabolite modulate glucocorticoid activity in the liver through negative allosteric modulation of LAGS (low-affinity glucocorticoid-binding site), with the result of this interaction yielding an effective increase in classical GR-signaling by increasing glucocorticoid availability to the cytosolic GR. So, if there is evidence of glucocorticoid effects by compounds, I immediately suspect some dissociation between lethargy & hepatotoxicity.
Aside from cortisol's morning rise being associated with wakefulness, glucocorticoids generally can be associated with lethargy as well (especially with chronic elevation; unlike cortisol's circadian rhythymicity). Take for instance, a case where a drug like Winstrol (certainly not particularly hepatotoxic) is causing one to feel lethargic. One should view the association between hepatotoxicity & lethargy here as a very weak one (with perhaps its effects on glucocorticoids considered more significant). Doubly so when GGT, ALT, AST are not significantly altered. To be clear, changes to GGT provides an excellent measure of AAS-induced hepatotoxicity (but should be viewed along with ALT, AST, ALP; with an understanding of what they represent [GGT is a mostly sensitive & specific measure from biliary epithelial cells; ALT, AST can be increased by intense training; ALP increases would be see the most pronounced elevation in cholestasis, etc.]). Of course, if we could practically, we might be more interested in directly measuring increases to liver CPT1 mRNA, the rate-limiting enzyme in mitochondrial β-oxidation that is increased by AR activation; or visually assessing the acuity of mitochondrial cristae in hepatocytes, as more direct measures.
Where the hepatotoxicity hypothesis (I'd be interested in hearing from @PeterBond on this) becomes interesting, is looking at an "edge" case like Proviron. Now, by all the Hershberger Assay (HA) & binding (e.g., Saartok) data, Proviron seems a likely candidate for possessing at least some significant potential for hepatotoxicity by being, apparently, a potent activator of AR. And yet, I suspect that Proviron is metabolized fairly extensively by 3α-HSD (though if I recall, it undergoes minor metabolism via 3β-HSD also). Given the prevalence of 3α-HSD isozymes in human skeletal muscle - I suppose what follows is that the analysis of potency to activate AR cannot be ascertained by mere reference to the literature for HA, rabbit [e.g., Saartok] binding affinities, etc; but we must consider the human metabolism). Of course, Dr. Bond has eviscerated the utility of HA data (and written an excellent eponymous article about Primobolan and its 3α-reduction), so I doubt he ever intended the rote application of HA data to the hepatotoxicity formula. I certainly would be keen to gain an understanding of how he would factually reason through his application of the hepatotoxicity hypothesis to the case of Proviron, though (noting any considerations about its metabolism in man), as I feel it could be enlightening.
I have a note to myself about this paper De Boer, D., de Jong, E. G., Maes, R. A. A., & van Rossum, J. M. (1992). The methyl-5α-dihydrotestosterones mesterolone and drostanolone; gas chromatographic/mass spectrometric characterization of the urinary metabolites. The Journal of Steroid Biochemistry and Molecular Biology, 42(3-4), 411–419. doi:10.1016/0960-0760(92)90146-a - that might give some better understanding of why Proviron lacks any significant AR potency in man. When I have time I'll do my best with it when I can find some time.
. I enjoy it. Maybe because I’ve taken an oral as intense as SuperDrol/halo that’s why I’m this impressed. That’s a tiny Win for my liver in my book haha
