Dr. Amy Nett: Okay, these aren’t really opposite directions. In case three, we’re saying that high insulin favors cortisol over cortisone. So insulin resistance is associated with up-regulation of the 11β-HSD favoring cortisol over cortisone, and it’s also associated with up regulation of 5α-reductase increasing cortisol clearance. Right? Because case four as you’re describing and as is in the actual case, high total cortisol is seen but low free cortisol indicates increased clearance, which can be seen again with insulin resistance, overweight, and metabolic dysfunction. So these are not opposite directions. These are two different things. One is cortisol versus cortisone, and the other one is clearance, how quickly you’re clearing cortisol and cortisone.
So if you think about it, if insulin resistance up-regulates 11β-HSD, it favors cortisol over cortisone and it also up-regulates 5α-reductase, increasing clearance, this might actually be a protective mechanism that the body developed really since chronic high free cortisol, which can certainly occur with insulin resistance, would be harmful. Allowing increased clearance actually protects the body to some extent. So, I don’t know if this developed as a protective mechanism, but if you think it through, there’s actually some benefit to the body having an increased clearance in the setting where free cortisol over cortisone is favored. It’s going to be a little protective. If you sit through that and sort of work those out, it might make a little more sense, and then that goes to your next question, Justine.