The following post is a deeper look into a potential theory I have been researching which links PAS to progesterone, this is of course just a theory based upon various studies I have looked at and read. I recommend reading the whole thing as it would be great to get some feedback. If you don’t have time I will try and briefly summarise it here but I recommend you read the full thing:
It is very possible that PAS and sexual dysfunction relate in some way to dysfunctional dopamine signalling in regions of the brain such as the reward system. Dopamine signalling in these regions play a significant role in motivation, reward seeking behavior, pleasure and sexual function. The questions is how has this dysfunction arisen? Many have blamed androgens and problems with androgen signalling such as changes in androgen receptor expression etc. which could be correct but it is possible these issues also relate to progesterone.
Progesterone plays a significant role in sexual function in both males and females. Progesterone also has a significant effect on dopaminergic signalling, progesterone receptors are expressed on dopaminergic neurons in the brains reward system, where they can alter the ability of dopaminergic neurons to function. A study of human glial cells found that retinoic acid (a metabolite of isotretinoin) specifically increased neurosteroids pregnenolone and progesterone, in addition there was a significant increase in enzyme expression ( 4.9, 5 and 50 fold respectively ) which seems to favour progesterone production. Glial cells are the most abundant cell type in the brain, they surround neurons and are known to release active metabolites which affect neuronal function. Given this study was conducted in human glial cells it offers very strong evidence for what may occur in the human brain during isotretinoin treatment.
In sufficient amounts, progesterone can be a potent inhibitor of 5AR activity, its metabolites also antagonise the androgen receptor and studies have found progesterone can reduce androgen receptor expression in certain parts of the brain. Notwithstanding, as mentioned before, progesterone can also directly effect the dopamine signalling in brain regions such as the striatum which is crucial to the brains reward system. Given these factors, could progesterone signalling be responsible for PAS?
Progesterone also helps to explain anomalies such as low blood results for FSH and LH reported by people with PAS, as well as a reason for why drugs such as L-Dopa which act directly on the dopaminergic system don’t seem to have an effect. It also explains random reports that the effect of dopaminergic drugs such as cannabis, adderall and ritalin seem to have changed before and after isotretinoin.
Given this, I think there is good reason to look into the possibility that PAS could be related to progesterone and thus look at potential protocols to deal with this. I haven’t seen many PAS people try protocols which specifically deal with progesterone as this is often not considered as important.
Flynn - The progesterone theory of PAS
PAS and most major issues associated with sexual dysfunction such as low libido are likely caused by changes in dopaminergic signalling in the brain, particularly the dopaminergic reward system. Androgens for example ultimately act on androgen receptors in the brain to stimulate dopaminergic signalling associated with reward seeking and reward processing pathways linked to sexual function. Therefore, issues with androgen signalling ultimately lead to issues with dopamine signalling and thus potentially to sexual dysfunction. However, what is not clear is whether these changes in dopamine signalling are directly or indirectly affected by isotretinoin. For example, if isotretinoin has affected androgen receptor expression or androgen signalling, this would be an indirect effect on dopaminergic signalling.
Here I outline what I consider to be a strong case for the involvement of progesterone in the development of PAS.
Progesterone and progestogens (natural or synthetic steroid hormones which interact with the progesterone receptor) are known to have an effect on sexual function in males and females. An interesting phenomena relates to the steroid deca-durabolin (nandrolone decanoate) which is used by body builders and has progestin activity. The use of this steroid can lead to a condition nicknamed “deca dick”, in which users develop sexual problems such as loss of libido, erectile dysfunction, genital numbness, loss of interest in sex and a loss of pleasure from orgasm as well as mental effects such as loss of motivation, emotional flatness and apathy. It is thought that these effects can be avoided by taking testosterone alongside deca however there are numerous online accounts of people who report developing “deca dick” despite using testosterone. Interestingly, users sometimes report sexual problems such as low libido persisting long after stopping Deca despite normal androgen levels (1). One user reported these problems persisting for over a year and included emotional flatness and him thinking that “the reward function in my brain has fucked,”. Another user claimed he had felt no improvement after 5 years. Another such steroid with similarly reported effects is Trenbolone also known as Tren. Both of these steroids have activity at the progesterone receptor (PR). Deca durabolin is regarded as a potent progestogen and binds the PR with 22% of the affinity of progesterone. Trenebolone also binds with high affinity to the PR. Coincidentally, of all steroids which are used and abused, the only steroids with long term sexual side effects such as these seem to all be progestogens.
What makes these cases so interesting is that they are examples of persistent sexual dysfunction (loss of interest in sex, low libido, loss of morning erections etc.) as well as loss of motivation, low mood, apathy and feelings of being disconnected from your normal self in spite of normal androgen and hormone levels, as is the case in PAS. Another progestogen called depo provera is also capable of reducing sex drive/libido and has even been suggested for use in sex offenders to reduce sex drive, this shows the powerful effect progestogens can have on sexual function (2).
It is very possible that PAS and sexual dysfunction relate in some way to dysfunctional dopamine signalling in regions of the brain such as the reward system. Dopamine signalling in these regions play a significant role in motivation, reward seeking behavior, pleasure and sexual function. The questions is how has this dysfunction arisen? Many have blamed androgens and problems with androgen signalling such as changes in androgen receptor expression etc. which could be correct but it is possible these issues also relate to progesterone.
Progesterone plays a significant role in sexual function in both males and females. Progesterone also has a significant effect on dopaminergic signalling, progesterone receptors are expressed on dopaminergic neurons in the brains reward system, where they can alter the ability of dopaminergic neurons to function. A study of human glial cells found that retinoic acid (a metabolite of isotretinoin) specifically increased neurosteroids pregnenolone and progesterone, in addition there was a significant increase in enzyme expression ( 4.9, 5 and 50 fold respectively ) which seems to favour progesterone production. Glial cells are the most abundant cell type in the brain, they surround neurons and are known to release active metabolites which affect neuronal function. Given this study was conducted in human glial cells it offers very strong evidence for what may occur in the human brain during isotretinoin treatment.
In sufficient amounts, progesterone can be a potent inhibitor of 5AR activity, its metabolites also antagonise the androgen receptor and studies have found progesterone can reduce androgen receptor expression in certain parts of the brain. Notwithstanding, as mentioned before, progesterone can also directly effect the dopamine signalling in brain regions such as the striatum which is crucial to the brains reward system. Given these factors, could progesterone signalling be responsible for PAS?
Progesterone also helps to explain anomalies such as low blood results for FSH and LH reported by people with PAS, as well as a reason for why drugs such as L-Dopa which act directly on the dopaminergic system don’t seem to have an effect. It also explains random reports that the effect of dopaminergic drugs such as cannabis, adderall and ritalin seem to have changed before and after isotretinoin.
Given this, I think there is good reason to look into the possibility that PAS could be related to progesterone and thus look at potential protocols to deal with this. I haven’t seen many PAS people try protocols which specifically deal with progesterone as this is often not considered as important.
Flynn - The progesterone theory of PAS
PAS and most major issues associated with sexual dysfunction such as low libido are likely caused by changes in dopaminergic signalling in the brain, particularly the dopaminergic reward system. Androgens for example ultimately act on androgen receptors in the brain to stimulate dopaminergic signalling associated with reward seeking and reward processing pathways linked to sexual function. Therefore, issues with androgen signalling ultimately lead to issues with dopamine signalling and thus potentially to sexual dysfunction. However, what is not clear is whether these changes in dopamine signalling are directly or indirectly affected by isotretinoin. For example, if isotretinoin has affected androgen receptor expression or androgen signalling, this would be an indirect effect on dopaminergic signalling.
Here I outline what I consider to be a strong case for the involvement of progesterone in the development of PAS.
Progesterone and progestogens (natural or synthetic steroid hormones which interact with the progesterone receptor) are known to have an effect on sexual function in males and females. An interesting phenomena relates to the steroid deca-durabolin (nandrolone decanoate) which is used by body builders and has progestin activity. The use of this steroid can lead to a condition nicknamed “deca dick”, in which users develop sexual problems such as loss of libido, erectile dysfunction, genital numbness, loss of interest in sex and a loss of pleasure from orgasm as well as mental effects such as loss of motivation, emotional flatness and apathy. It is thought that these effects can be avoided by taking testosterone alongside deca however there are numerous online accounts of people who report developing “deca dick” despite using testosterone. Interestingly, users sometimes report sexual problems such as low libido persisting long after stopping Deca despite normal androgen levels (1). One user reported these problems persisting for over a year and included emotional flatness and him thinking that “the reward function in my brain has fucked,”. Another user claimed he had felt no improvement after 5 years. Another such steroid with similarly reported effects is Trenbolone also known as Tren. Both of these steroids have activity at the progesterone receptor (PR). Deca durabolin is regarded as a potent progestogen and binds the PR with 22% of the affinity of progesterone. Trenebolone also binds with high affinity to the PR. Coincidentally, of all steroids which are used and abused, the only steroids with long term sexual side effects such as these seem to all be progestogens.
What makes these cases so interesting is that they are examples of persistent sexual dysfunction (loss of interest in sex, low libido, loss of morning erections etc.) as well as loss of motivation, low mood, apathy and feelings of being disconnected from your normal self in spite of normal androgen and hormone levels, as is the case in PAS. Another progestogen called depo provera is also capable of reducing sex drive/libido and has even been suggested for use in sex offenders to reduce sex drive, this shows the powerful effect progestogens can have on sexual function (2).
