THEORY - PAS and FOXO theory - Very Unlikely/Disproved


Staff member
Feb 28, 2018
One purported hypothesis of PAS related to a set of transcription factors called forkhead box class O (FOXOs), these are transcription factors which regulate the expression of target genes. This theory was brought to light by Bodo C Melnik in the article linked below (note I will avoid using references as most info can be found in this article:


Put simply, it was thought that accutane usage may increase levels of FOXOs in the nucleus. These FOXOs would in turn alter gene expression leading a range of persisting side effects which remained beyond treatment. An interesting aspect of specific FOXOs, namely FOXO1 is that it regulates the androgen receptor (AR) by binding to it and acting as a co-repressor, thus suppressing AR transcriptional activity. One theory of PAS involves androgen resistance whereby the body is less receptive to actions of androgens either due to a reduce androgen production or changes in the androgen receptor. Note that androgen production is unlikely to be the problem as PAS sufferers have blood tests showing normal androgen levels and also report no improvement after artificially increasing androgen levels.

This would help to explain why many of the symptoms of PAS are identical/similar to the symptoms of hypogonadism such as low libido and erectile dysfunction. Essentially, ISO or Accutane usage ------> increases FOXOs such as FOXO1 ------> Increased FOXO1 reduces AR activity leading to PAS.

FOXOs also appear to have a range of other roles in the body including neurogenesis and the production of hormones associated with sexual desire such as alpha melanocyte stimulating hormone through their effects on Pro-opiomelanocortin. These effects would also contribute to PAS.

FOXO activity is repressed by growth factor signalling (PI3K/Akt pathway). Given this, hormones such as Insulin like growth factor-1 (IGF-1) work to remove FOXOs from the nucleus. Interestingly, ISO has also been shown the reduce the production of IGF-1. Thus a potential treatment may have been taking Growth hormone to artificially raise IGF-1 levels. However of the users with PAS who have tested their IGF-1 levels, the results showed normal levels. It could be assumed that overtime as IGF-1 levels normalised, so too should the levels of FOXO and a reversal of PAS.

This theory has now been largely debunked, as a recent paper showed that Accutane actually works by activating the the PI3K/Akt pathway and so is unlikely to involve FOXO's -

- Flynn
Apr 6, 2018
Thanks Flynn. I wasn't aware of the article you posted. It's shame the leading mechanistic theory was (largely) debunked, but I suppose it's a good thing. Any thoughts, now, on the mechanism behind ISO?

EDIT - found your other posts. These are fantastic.

EDIT - Recent literature to support this theory.
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