Great insight from the new book…Androgen receptor Genes cause of pfs and sensitivity varies side effects he explains how this works below…
The official name for the group of symptoms Kevin and Lars experienced is post-finasteride syndrome (PFS), and perhaps one of the most troubling aspects was that it seemed so permanent, with the effect often persisting years after discontinuation of the drug. One clue to why that might be comes from animal studies, which in this case also tell us more about the feed-forward relationship between testosterone and the androgen receptor. A group of Italian researchers gave finasteride to rats and noticed that the number of androgen receptors in their brains went up.75 Moreover, the effects persisted long after the drug had been discontinued. To follow up on this finding, they then called in men with PFS, took skin from the penis, and found that the density of androgen receptors in men with PFS was about twice that of those without.76 Now, remember the idea of the testosterone bell curve and damping effects (little testosterone, little growth, more testosterone, more growth, even more testosterone, reduced growth)? I think this is what we are seeing here. With a greater concentration of receptors, the organ becomes more sensitive to testosterone and at a certain point, paradoxically, that sensitivity may shut down.† The Italian researchers have subsequently demonstrated that patients with either very short or very long CAG repeats in the androgen receptor suffer these effects,77 reflecting the complexity of this chemistry as well as the plausibility of this mechanism. Did Lars’s brain adapt to the blockade of 5AR by amplifying androgen receptor levels and, in turn, its sensitivity to testosterone? It’s possible. It does look as if, in response to the 5AR blockade of finasteride, the brain produces more receptors in order to become sensitive to lower levels of the hormones. This is a familiar concept to those of us who treat prostate cancer, for this is the same adaptation that cancer makes to survive after testosterone is wiped away. As we’ve mentioned in previous chapters, it is possible that having greater androgen-receptor activity could make you not only more sensitive to testosterone—for instance, causing levels to skyrocket, as they did with Lars—but also more sensitive to its absence. All this said, there are plenty of men out there who swear by the drug. Why does it work fine for some and not others? It seems possible that something about the subtypes of 5AR in the brains of these men is responsible for the variability in their sensitivity to inhibition with finasteride. I am also struck by the fact that this syndrome tends to manifest itself in young men who are taking low-dose finasteride (1 mg) and not older men who take the higher dose of 5 mg to combat prostate enlargement. Perhaps the changes that occur with age, as discussed in the previous chapter, have something to do with this, or perhaps it is another bell curve. We’ve seen throughout the book that anytime you manipulate a piece of the testosterone system, you risk unexpected changes. The important difference, to me, is that in the case of using finasteride for baldness, this risk is not a necessary trade-off to treating a deadly disease like prostate cancer; it’s the cost of treating a receding hairline.
