Unveiling the Pathology of PFS

Post-finasteride syndrome (PFS) is a condition in which individuals who have formerly taken finasteride experience a set of vague symptoms, usually over a long period of time. Commonly seen in these symptoms are loss of libido, anhedonia (lack of pleasure), and even suicidal ideology. Though some are convinced that PFS is psychological rather than neuropathological, I will explain precisely why they are wrong in this article.

Finasteride and its Mechanism

Finasteride is an inhibitor of the 5-alpha-reductase (5AR) enzyme - the enzyme that catalyzes the conversion of testosterone into dihydrotestosterone (DHT). By blocking 5AR systemically, one is able to reduce levels of DHT (by about 95% with finasteride), and thus decrease overall androgen-mediated hair loss that many males face.

This might seem like a miracle drug on paper, but in reality, the consequences for some can be life-altering.

Hypothesized Mechanism of PFS

Since individuals with PFS experience symptoms long after their last dose of finasteride, there are only two main ways that PFS could potentially manifest:

1. Permanent alteration of "negative" gene expression, forcing the user to become stuck in a state of expressing genes that lead to negative symptoms
2. Damaging or altering neural pathways in the brain due to chronically low androgenic signaling

I believe that PFS is a manifestation of the former - a state of altered gene expression. The latter doesn't make much sense, as testosterone itself should facilitate most of the androgenic signaling that would otherwise be mediated by DHT. DHT also does not play a critical role in the "upkeep" of neurological functions compared to other hormones, such as estrogen and progesterone.

The real mystery is not what exactly PFS is, but rather what genes become negatively expressed in such a manner that leads to these symptoms. The only issue in the way of exploring this topic is the sheer lack of clinical research done on the topic, considering this is a fairly new condition. To attempt to extrapolate the exact cause, I will briefly go over the most important data available.

In an attempt to uncover the long-term effects of finasteride on penile architecture, a study was conducted on rodents and discovered that inhibition of 5AR with finasteride causes both an atrophy in penile tissue and a deposition of scar tissue [3]. One human study found that individuals with sexual-related symptoms of PFS had a lower density of androgen receptors in their penile tissue compared to those who had not been previously exposed to any 5AR inhibitors [4]. This may indicate that finasteride potentially permanently downregulates androgen receptors in the penile tissue, which may explain one cause of the sexual-related symptoms of PFS.

To further support this claim, multiple studies loosely indicate that a decrease in receptor-specific androgenicity downregulates total androgen receptor expression (at least in some tissues - the data is not very robustly established on this topic).

In terms of neurological symptoms, the mechanism seems even more complex. I hypothesize that the neurological issues from PFS occur from dysfunction of neurosteroid expressing genes.

One human study [1] that measured the cerebrospinal fluid (CSF) of 16 PFS patients displayed a clear decrease in neurosteroids - specifically pregnenolone, progesterone and its metabolite (i.e., dihydroprogesterone), dihydrotestosterone and 17beta-estradiol. Furthermore, decreased levels of 5-alpha-reduced metabolites were observed, indicating that 5AR may permanently downregulate in some patients after finasteride treatment.

Some of these neurosteroids - such as progesterone and dihydroprogesterone - are particularly important for mood regulation. Progesterone metabolizes to dihydroprogesterone via 5AR, which then further gets metabolized into allopregnanolone by 3-alpha-hydroxysteroid dehydrogenase. Allopregnanolone is one of the main inhibitory chemicals in your brain, allosterically modulating the GABAA receptor and allowing endogenous GABAA agonists to bind with a higher affinity and efficacy [2]. By decreasing allopregnanolone in your brain, you essentially rid yourself of an important natural anti-depressant and anxiolytic. I believe that permanent downregulation of allopregnanolone synthesis may be the main contributor to depressive and anxious phenotypes displayed in PFS patients.

Potential Treatment Options

Since PFS is likely the result of being "stuck" in a dysfunctional neurosteroid gene expression, we must consider two types of treatment options that should be used concurrently with each other: one being a compound able to "unstick" or modify neurological gene expression permanently, and the other being a compound able to put one in a place of favorable neurosteroid gene expression.

For the former, we can consider both cerebrolysin and histone deacetylase (HDAC) inhibitors. Briefly put, cerebrolysin can upregulate neurogenesis and synaptic plasticity to a profound degree, allowing the user to form new neurons, neuronal pathways, and alter neurological gene expression seemingly permanently. You can read more about it in and how I reversed my neuropathology in my cerebrolysin article here if you'd like. Aerobic exercise also does something similar by upregulating neurotrophic factors, so one experiencing PFS might want to consider exercising regularly if they don't do so already.

HDAC inhibitors do not work this way directly. Rather, they work by increasing acetylation of histones that wrap DNA, which then affects how this DNA is expressed epigenetically. Theoretically, one could use both cerebrolysin and an HDAC inhibitor and a synergy may arise.

For the latter - a compound able to put one in a place of favorable neurosteroid gene expression - there are quite a few compounds and practices we can implement. Firstly, we can look at a compound called palmitoylethanolamide (PEA). PEA is an endogenously produced fatty amide that is able to speed up and increase the conversion of dihydroprogesterone into allopregnanolone.

Androgen therapy may also be a valid treatment, as supraphysiological amounts of androgens have been shown to upregulate androgen receptor expression and 5AR in some tissues.

If one used cerebrolysin or an HDAC inhibitor concurrently with other compounds, they could theoretically reverse themselves into a pre-PFS state, unsticking their brain from its dysfunctional epigenetic state.

Final Thoughts

While the exact cure for PFS still remains unknown, there is no doubt that it is a real and valid disorder. There are many ways to tackle it that have been shown successful. Ultimately, the cure may be individual dependant. My working theory of neurosteroids and epigenetics seems to be the most likely cause for PFS and its symptoms.

I hope you've taken something valuable from this article, and you can message me with any small questions you might have on instagram (linked at the top of website).

Interested in learning more about PFS or neurology in general? Book a consult with me here.

Sources

[1] Roberto Cosimo Melcangi et al. (2017) "Neuroactive steroid levels and psychiatric and andrological features in post-finasteride patients"

[2] Neurobiol. Stress (2020) "Allopregnanolone: From molecular pathophysiology to therapeutics. A historical perspective"

[3] Hyun Hwan Sung, Jiwoong Yu, Su Jeong Kang, Mee Ree Chae, Insuk So, Jong Kwan Park, Sung Won Lee (2019) "Persistent Erectile Dysfunction after Discontinuation of 5-Alpha Reductase Inhibitor Therapy in Rats Depending on the Duration of Treatment"

[4] Carla Di Loreto, Francesco La Marra, Giorgio Mazzon, Emanuele Belgrano, Carlo Trombetta, Sabina Cauci (2014) "Immunohistochemical evaluation of androgen receptor and nerve structure density in human prepuce from patients with persistent sexual side effects after finasteride use for androgenetic alopecia"