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The Devastating Effects of Finasteride: Post-Finasteride Syndrome (PFS)
A quick google search for ‘prevent hair loss’ often reveals results for finasteride. A drug widely used by men and claimed by many corners of the internet to be ‘safe’. A quick google search for ‘finasteride side effects’ and we get a list (1):

Impotence,
Loss of interest in sex,
Trouble having an orgasm
Abnormal ejaculation
Swelling in your hands or feet
Swelling or tenderness in your breasts,
Dizziness,
Weakness
Feeling like you might pass out
Headache,
Runny nose or skin rash
But similarly all drugs carry the risk of various side effects and yet we’re fine after using them as directed, i.e. paracetamol. However, finasteride can be an exception & we’re going to dive into this.

Finasteride, also known as Proscar, is used to treat hair loss and benign prostatic hyperplasia in men. It’s a 5α-reductase inhibitor, aka an antiadrogen. 5α-reductase inhibitor is an enzyme primarily responsible for metabolising Testosterone to Dihydrogentestosterone (DHT), as shown below (2):

 

(Click for Full-Size Image)

 

If you look at the structure, it seems pretty similar right? All that’s happened is we’ve reduced Testosterone (took away an electron, which is visible from the first carbon ring at C4-5 – that extra line indicates an extra bond [double bond] – removing the electron turns it into a single bond). Let’s move away from organic chemistry – DHT is considerably more potent as an agonist of the androgen receptor. While we’re on this topic, there’s 3 isoenzymes (subtypes) of 5α-reductase; 5-AR1, 5-AR2, & 5-AR3 (3). Finasteride inhibits only the 2nd and 3rd isoenzyme (1st too to some extent), whereas dutasteride (another 5α-reductase inhibitor) inhibits only the 1st and 2nd isoenzyme (4). Dutasteride has a greater potency than finasteride for 5-AR2. Though both drugs provide some pretty nasty adverse side effects in those predisposed to it. This is still important as specific mutations in any of these isoenzymes genes could therefore alter the level of response to either dutasteride or finasteride.

DHT is involved in prostate growth, facial, axillary, pubic, and body hair growth, having metabolites which are neurosteroids that have antidepressant, anxiolytic, rewarding, anti-stress and pro-cognitive effects (5, 6) and increasing force production in fast contracting muscles (7). It’s also a selective agonist of the beta estrogen receptor. It basically makes you feel good, helps you grow hair, and can improve strength. Sadly it can also increase typical male pattern balding (MPB) in those predisposed to it (I am in this category, but I have more hair than Dr. Stevens! I hope this trend continues).

DHT effectively miniaturizes hair follicles in the scalp in those at risk to it. That ultimately pushes the hair out (. In men with an increased risk of MPB, there’s an increased sensitivity of scalp hair follicles to normal levels of circulating androgens, which activates genes responsible for follicular miniaturization aka hair loss. This is unfortunately genetic. Of course it’s clear that reducing the levels of DHT would stop hair loss in these men, ergo the use of finasteride. But, Post-finasteride syndrome (PFS) is no joke and affects many men. Let’s dive into it a bit deeper.

 

What is Post-Finasteride Syndrome?
Post-finasteride syndrome (PFS) is a condition that exhibits persistent sexual, neurological, physical, and mental adverse reactions in patients that have taken finasteride to treat hair loss.

It carries the following reported symptoms (9):

Decreased or completed loss of sex drive
Erectile dysfunction
Loss of morning and spontaneous erections
Sexual anhedonia (loss of pleasurable orgasm)
Decreased semen volume and force
Penis shrinkage and numbness
Scrotal shrinkage and numbness
Breast development and enlargement
Chronic fatigue
Myalgia, including muscle pain
Myopathy, including muscle weakness, cramps, stiffness and twitching
Rhabdomyolysis, including muscle atrophy
Creatine kinase elevation (due to muscle breakdown)
Decreased oil & sebum production
Dry & thinning skin
Melasma (brown patches which affect parts of the face)
Lipoatrophy (localised loss of fat)
Tinnitus (ringing in the ears)
Optic neuropathy (damage of optic nerve)
Retinopathy (disease of the retina)
Increased risk of obesity
Decreased body temperature
Reduced HDL, raised fasted blood glucose and triglycerides
Elevated rheumatoid factor
Suicidal ideation
Severe memory impairment
Slowed thought process
Impaired problem solving
Depression
Anxiety
Emotional flatness
Insomnia
Obstructive sleep apnea
The list is quite exhaustive and scary. However, the condition appears to not yet be recognized by the medical community, and some studies suggest it may be more likely to occur in those with a history of personality disorder (10) which brings the quote “I think of my body as a side effect of my mind”, by Carrie Fisher, to mind.

Given that we reduce the production of DHT when using finasteride, we can expect side effects to occur. For one, there’s increased GABA activity in the brain with DHT, likely due to DHT metabolites modulating GABA-A receptors  (10, 11), which provides an anxiolytic effect (reduced anxiety). DHT may also modify circuitry in the brain by altering the number of excitatory spine synapses in a paracrine manner, which can therefore affect cognitive function (in a positive manner) of the brain (12). It’s been established that the risk of dementia is in fact greater for patients using 5α-reductase inhibitors (13), further demonstrating the need for DHT in the brain for adequate cognitive function and health. In male rats, it has been demonstrated that finasteride inhibits the brains dopaminergic system (involved in the reward system and sense of wellbeing) (14) which may well transfer to humans. It has even been suggested to use testosterone supplementation (note: within physiological levels) to improve cognition in older men, in part due to the neuroprotective and excitatory effects of DHT (12). Put simply, DHT is actually quite important for good mental health. It will reduce feelings of anxiety, improve feelings of wellbeing, and improve cognitive function.

Additionally, progesterone (another important steroid hormone) can be converted to allopregnanolone via 5α-reductase. Allopregnanolone is a potent ligand of the GABA-A receptor, which in normal circumstances will reduce the risk of anxiety, major depression, impulsive aggression, and negative symptoms in schizophrenia (15). So, that’s another thing lost to the use of finasteride. Though, one must bear in mind that balance is key – excess allopregnanolone can lead to tolerance at GABA-A receptors, leading to potentially increased risk of anxiety & depression. Balance is always key.

 

The Effects Of Post-Finasteride Syndrome On The Brain
You’ve probably seen the pictures of ‘this is your brain on drugs’, sometimes with the images of lesions present. While not quite as bad, it should be clear that a lack of DHT is detrimental to your brain health.

In the case of finasteride treatment, there have been observed significant and several alterations in the hippocampus (part of your brain), which is a part responsible for processing long-term memory and emotional responses, leading to depressive behaviour, reduced cognition, and neuroinflammation, plus alterations in gut microbiota (never good) (16). We’ve also observed finasteride inhibiting the brain’s dopaminergic system (14). Granted, this was in male rats – we appear to note similar clinical reports of negatively altered behaviour in humans. Human users of finasteride who were symptomatic reported major depression, impaired cognition/more cognitive complaints, reduced sexual arousal and fMRIs demonstrated abnormal brain circuitry with regard to sexual arousal (17). This appears to persist after drug cessation. Our own UK MHRA has reported reports of depression and suicidal ideation related to finasteride use (18).

It’s likely that the lack of DHT has similar effects in humans as it does in rats, ergo similar However, you may know someone with no side effects. I’ve certainly noted such anecdotal reports. That may be because of a difference in gene expression, especially in important biological pathways associated with the above adverse outcomes – in fact a recent Differential Gene Expression study proved just this (3). How will you find out if you have the mutant genes that increase the risk of PFS? Well for starters I wouldn’t rely on just these few genes being indicators as we may have epigenetic forces at play (altered gene expression due to environmental changes, can occur via methylation/acetylation due to a drug or some other stimuli).

 

Can We Resolve It?
Studies have observed that subjects still have symptoms following as long as 16 months. The effects of PFS appear to last for quite some time. This could be due to many reasons, oen including epigenetic modifications in cerebral tissue of SRD5A genes, causing downregulation of 5α-reductase in the brain (19). Unfortunately the literature is quite sparse on recovery, with no known treatment.

There have been anecdotal reports of recovery to near prior finasteride use over a period of 1 to 5 years following cessation of finasteride, but some report worsened psychological side effects (20). All we know is that with an increased duration spent on the drug, the worse the symptoms can be following cessation in those prone to PFS. Just another warning, dutaseride (Adovart) can also cause PFS as it is a 5α-reductase inhibitor.

I don’t want to scare anyone using finasteride. If you’ve not experienced these symptoms you may well be fine as you fall into the ‘does not get PFS’ category that some men will inevitably fall into due to their genetic makeup. But if you have fallen into it, you can get support from patient support forums, join patient support groups, and talk with a medical expert on the topic who can help you manage some of the symptoms.

For everyone else afraid of losing their hair, your best bet is to not take 5α-reductase inhibitors. It’s a gamble that’s not worth it. If you’re normotensive and not prone to hypotension, not on blood pressure medication, then you could try Minoxidil. You must always talk with your doctor first about this, though. Anecdotally, Minoxidil is a hit or miss. But for the hits, it works wonders to prevent further hair loss and sometimes grow hair back. However, it can become quite expensive, especially since you have to continue use as the hair growth is not permanent and stops following cessation. It’s also not side effect free, so again please consult your prescribing clinician first before considering such a thing.

 

Conclusion
Post-finasteride syndrome is an awful condition that affects many, but not every, man that uses finasteride or another 5α-reductase inhibitor. Sometimes its use is clinically indicated, but if you’re just using it for preventing hair loss, you are best off reconsidering. The symptoms of post-finasteride are no joke and prevention is the best thing to do here as there are no known ‘cures’. Means to manage some symptoms exist and will require extensive work and support with medical experts, groups, and more – but it’s best to not end up in that place in the first instance. Other hair regrowth methods exist, such as the use of Minoxidil if you are healthy and otherwise fit and under the go-ahead of a medical professional. But bear in mind that this is expensive and you have to continue its use to continue new hair regrowth. Just remember that one thing that’s more valuable than your hair and any money in the world is your mental wellbeing. Prevention is better than cure.

 

References
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By Joseph Hearnshaw BSc (Hons) DPS, MSc, FRSA, MRSB, MBCS November 16, 2021