Post Finasteride Syndrome

What is Finasteride?

Finasteride is a medication that has garnered much attention owing to its ability to maintain a youthful hairline, making it particularly valued amongst actors and models. However, it has now taken a more prominent role in the aesthetic industry with online pharmacies issuing prescriptions after short questionnaires. As of 2024, market reports values it over $120 million in the USA with continual growth. [1] Finasteride is essentially a form of anti-androgen therapy which was historically confined for use in treating benign prostatic hyperplasia. [2]

It works by preventing the conversion of testosterone into the more potent androgen Dihydrotestosterone (DHT). It does so by functioning as a competitive inhibitor of an enzyme called type II 5-alpha-reductase (5AR). There a three isoforms of 5-alpha-reductase, however type II is most highly expressed in the liver, skin, and prostate gland. Type I is present in the sebaceous glands whilst type III is less well understood. [3] On average, 1mg of Finasteride per day is enough to lower serum DHT by 70% after one year. [4] This is owing to the fact that the Type II isoform is primarily responsible for circulating levels of DHT, contributing around two thirds.

Despite its value in maintain youthful hairlines in men of any age, it does come with some cost. DHT is a potent androgen, exerting a significantly more androgenic effect than its better-known precursor Testosterone. It possesses approximately double the binding affinity for the Androgen Receptor (AR) than testosterone and more strongly influences gene transcription. [5] The term Androgen refers the wide range of hormones that can bind to the Androgen Receptor, however DHT is the most potent of these naturally produced by the body. When these Androgens bind to the Androgen Receptor, they can begin to transcribe genes related to male sexual characteristics, such as body hair development, muscle growth and certain neurological functions.

What Are the Side Effects of Finasteride?

There are neurological functions that are specific to DHT that can’t be mimicked by Testosterone alone. Testing of memory faculties in Hypogonadal men treated with DHT found that boosts in spatial memory could only be achieved with DHT that were not achieved with Testosterone. [6] Given the strong Androgenicity of DHT, it’s hardly a surprise that its depletion is linked to a host of undesirable side effects in both the body and the brain. One of the functions of DHT is maintain the delicate balance between estrogenic (typically female hormone) activity in the body and androgenic activity. One of the consequences of disrupting this balance is the risk of developing female bodily characteristics, such as gynecomastia. [7]

Perhaps even more concerning that the risk of gynecomastia is the effect of Finasteride on neurological function including sexual function. Androgens are required for sexual desire by influencing the balance of neurotransmitters in the brain, such as by elevating Dopamine in the medial preoptic area. [8] This is an area of the Hypothalamus that integrates sensory stimuli from the genitalia and mediating feelings of sexual reward. Androgen Receptors are most abundant in regions of the brain linked to sexual reward such as the Amygdala and the Hypothalamus, and when DHT binds to these receptors it promotes Dopamine synthesis. When the Androgen-Receptor is ‘knocked-out’, male-typical sexual behaviours are lost. [9]

The rates of sexual dysfunction during treatment with Finasteride vary. The FDA label suggests that Finasteride increases the risk of sexual dysfunction by around 2%. [10] Some studies have found a higher risk, with around 4.5% of patients experiencing Erectile Dysfunction and 2.3% suffering from reduced libido. [11] Estimating the true rate of prevalence is challenging due to the sensitive nature of the topic and the risk of underreporting.

What is Post Finasteride Syndrome?

Due to the side effects of the treatment, there is a relatively high rate of discontinuation. Whilst for many side effects with resolve, for some they persist long after the drug has fully metabolised out of the body. [12] For these patients the symptoms of Erectile Dysfunction and reduced libido appear to last indefinitely. An analysis of 12,000 found approximately 1.4% falling into this category. For these unlucky individuals the symptoms are debilitating, and dramatically reduce quality of life. There have been almost 1400 product liability lawsuits levelled at Merck, resulting in a payout of $4.3 million. [13] How could Finasteride be continuing to diminish sexual function even years after treatment has ceased?

1. Epigenetic Changes

A small pilot study of patients complaining of Post Finasteride Syndrome found increased DNA methylation of the 5-alpha-reductase Type II gene in sample of cerebrospinal fluid. [14] Epigenetic modifications refer to alterations in how genes are expressed without changing the underlying genetic code. DNA methylation is a form of epigenetic modification by which the gene becomes less accessible to transcriptional machinery, which in essence means the gene is ‘switched off’. DNA Methylation is noted for being a particularly lasting form of epigenetic modification. The finding of this study is particularly insightful as the Type II isoform is the same as that targeted for inhibition by Finasteride. Intriguingly there’s evidence that DHT can stimulate its own synthesising enzyme in a positive feedback loop. It’s therefore possible that the supposedly temporary inhibition of 5-alpha-reductase by Finasteride can have a more lasting impact on gene expression. For the full details on this effect, you can read the article in full here.

2. Changes To Androgen Receptor Protein

Alterations in Epigenetic Status isn’t the only aberration identified in samples taken from PFS patients, in fact there’s also a modest elevation in Androgen Receptor protein too. It’s possible that a compensatory action takes place to boost Androgen Receptor gene expression in response to the reduction in androgenic activity during treatment with Finasteride. Whilst this may seem desirable, excessively elevated Androgen Receptor proteins can paradoxically be detrimental to gene transcription. This is most pertinent to individuals with specific mutations on the AR gene in a condition called Kennedy Syndrome.

There’s individual variability AR sensitivity based on the number of CAG (Cytosine Adenine Guanine) repeats on one of the binding domains of the Androgen Receptor, with more repeats making the receptor less sensitive. Patients suffering from Kennedy Sydrome have a pathologically high number of repeats, which leaves the androgen receptor significantly less active. In response, the AR protein becomes so elevated that it actually blocks proper functioning of the androgen receptor by over aggregation. This triggers a gain of toxic function feedback loop where the diminished androgen signalling further increase AR protein content. Pertinently, irregular CAG repeats are identified at a much higher rate in Post Finasteride Patients too. To read the full article, click here.

3. Dysbiosis and The ‘Gut-Brain’ Axis

The microbiome is the community of trillions of microorganisms that preside within the intestinal tract, including bacteria, viruses, and fungi. These microbiota play a vital role in the breakdown of food and the absorption of nutrients, as well as synthesising key neuroactive metabolites. It’s through these neuroactive metabolites that gut has a powerful regulatory role over mood and brain health, prompting the use of the term the ‘gut-brain’ axis. The gut also strongly influences epigenetic processes throughout the body through the formation of short-chain fatty acids such as butyrate, propionate and acetate. These small metabolites of the microbes in the gut can be transported through the blood to tissues throughout the body, including the brain. The most prevalent of these being Butyrate, which acts as Histone Deacetylase Inhibitor (HDACi).

A study of rats found that one month following treatment with Finasteride there was a significant change to composition of the gut microbiome. This change paralleled an increase in depressive-like behaviour. Other studies of patients treated with Finasteride have found similar reductions in diversity of the microbiome. Of particular interest was a decrease in the Ruminococcaceae family, which is the most important Butyrate producing family of bacteria in the gut. Reductions in this strain have been implicated in Hypoactive Sexual Desire Disorder in women, as well as Irritable Bowel Syndrome. To read more of this topic, click here.