1. An Introduction to Finasteride and DHT
2. Where and How is DHT synthesised?
3. How does Finasteride work?
4. DHT is Not a Typical Hormone
5. DHT is 10-fold More Potent Than Testosterone
6. The Role of 5-AR In The Brain
7. Spatial memory is enhanced by DHT, but not verbal memory:
8. DHT is neuroprotective: Implications for Alzheimer’s
9. DHT Facilities Sexual Desire, particularly through 3-alpha-Diol
10. The Cause of Post Finasteride Syndrome
11. The Evidence For Post Finasteride Syndrome
12. PFS is an Epigenetic disorder
13. How Can 5AR-2 Be Restored?
14. The ‘Gut-Brain’ Axis
15. Why does Finasteride Damage The Gut?
16. Restoring 5AR-2 Gene Expression
17. Valproate
18. Butyrate
19. References

Post-Finasteride Syndrome is the term used to describe the collection of lasting adverse symptoms that can persist long after discontinuation. These symptoms can be both physical and mental, since the hormonal target of Finasteride, Dihydrotestosterone (DHT) is central for male neurological health. In this post I detail the science underlying this chronic condition, and present evidence-based theories to explain its enduring nature.

1. An Introduction to Finasteride and DHT

Where and How is DHT synthesised?

The body synthesises only a tiny amount of DHT per day as compared to testosterone. An average male may produce as much as 6mg of testosterone, but approximately 0.3mg of DHT – representing approximately a 5% conversion rate. [1][2] The enzyme primarily responsible for synthesising DHT is 5-alpha-reductase (5AR), which can be subdivided into three different isoforms with different distributions in tissues:

• 5AR Type 1: The type 1 isoform is present in some areas of the brain, such as the cortex. As well as the liver, and non-genital skin. [3] It also contributes around one third of circulating DHT. [4]
• 5AR Type 2: This is the most highly expressed form of 5AR, being present in genital tissue, facial and chest hair follicles, liver and brain. Additionally, in contributes two thirds of circulating DHT. It is this isoform that is inhibited by Finasteride. [4]
• 5AR Type 3: Much less is known regarding the Type 3 isoform.  Some of its function is inferred from congenital deficiencies, where patients suffer from intellectual deficiencies and ocular defects. [5] It’s thought that it contributes to the folding and stability of proteins in the Endoplasmic Reticulum.

Whilst it’s true that Finasteride specifically inhibits 5AR-2 whilst leaving 5AR-1 largely unimpacted, it also inhibits 5AR-3 to the same degree as 5AR-2. [6] Finasteride is highly effective at inhibiting 5AR-2, with a 71% reduction in serum DHT after just 6 months – which reflects the total contribution of 5AR-2 to DHT in the blood. [7]

How does Finasteride work?

Finasteride is considered an anti-androgen, that potently inhibits 5AR-2 and 5AR-3. It is about 100-fold more selective for these isoforms, meaning that 5AR-1 activity is essentially unaffected. [8] The fact that 5AR-1 isn’t affected by Finasteride means that around 30% of serum DHT is maintained during treatment, unlike Dutasteride which inhibits all three isoforms of 5AR and thereby ablates serum DHT to only 1% of pre-treatment levels. [9] Finasteride works as competitive inhibitor, that reversibly binds to the active site of the 5AR-2 and 5AR-3 enzymes with a half life of around 5 hours. [10] Since DHT formation is inhibited, Finasteride treatment also gives a moderate boost to serum testosterone of around 10%. [11]

DHT is Not a Typical Hormone

Dihydrotestosterone (DHT) was the last of the primary sex hormones to be identified and in many ways is the most complex, only being identified following the discovery of the 5-alpha-reductase type II enzyme in 1974. [12] Unlike other sex hormones, it doesn’t primarily act through the endocrine system. The endocrine hormones are those which are secreted by an endocrine gland, such as the Testes, to secrete a hormone like Testosterone which travels in the blood stream to distant target organs to exert their effect. Instead, DHT is what is referred to as an ‘Intracrine’ hormone.

As the name might suggest, an Intracrine hormone is synthesised and acts locally within the cell. DHT also has some Paracrine activity, meaning that it can also acts on adjacent cells within the same tissue. [13] This makes an understanding of its behaviour somewhat more complex than the comparatively simple endocrine hormone like Testosterone. For example, serum DHT doesn’t significantly contribute to the levels of DHT within androgenic tissues such as the prostate – even when enough exogenous DHT is administered trans-dermally (DHT gel) to raise serum DHT seven-fold. [14]

The reason for this being that the concentration of DHT within prostate cells is so much greater than that in the blood stream, that simple passive diffusion into cells isn’t sufficient to meaningfully contribute. In order to exceed intracellular concentrations in the prostate, serum DHT would likely need to exceed normal concentrations by at least 10-fold. [13] The same also applies to skin, which also possesses 5-alpha-reductase activity, with serum DHT not significantly contributing to acne. [15]

DHT is 10-fold More Potent Than Testosterone

DHT has a binding affinity for the Androgen receptor about 2-5 times greater than testosterone, but importantly it induces Androgen Receptor signalling about 10 times more potently. [16] Given that 5AR-2 is the most widely expressed isoform, genetic deficiencies in 5AR-2 leave individuals with under-virilisation. Virilisation is the process by which the body takes on male physical characteristics such as a deepening of the voice, body hair and the development of functioning male genitalia.

5AR-2 even contributes to the development of male characteristics prenatally (before birth), and so babies born with 5-AR2 deficiencies are left with ambiguous genitalia. In accordance with the mechanism of action of Finasteride, these individuals don’t suffer from Androgenic Alopecia in later life. Interestingly sebum production and the incidence of acne don’t differ from other males, as this is regulated by the activity of 5-AR1. [17]

2. The Role of 5-AR In The Brain

Spatial memory is enhanced by DHT, but not verbal memory:

The most direct way by which Finasteride can influence neurological function is by inhibiting the formation of DHT, which has a variety of unique effects on cognitive function and brain health. Just one example of the specific role of DHT in the brain is that on spatial memory. A battery of cognitive tests on older hypogonadal men treated with either testosterone or DHT found that whilst Testosterone was conducive to verbal memory, only DHT could boost spatial memory. [18] The researchers concluded that role of Testosterone in enhancing verbal memory was through aromatising into Estrogen (E2), based on prior studies in women.

The isoform 5-AR2 is present in the hippocampus, which is the region of the brain responsible for memory.  [19] Specifically 5-AR2 is abundant in the Medial Temporal Region which is involved in spatial memory, and so the elevated presence of DHT in this region would support the finding that it enhances spatial memory. [20] In the Cherrier et al. study (2013) DHT steadily improved spatial memory over the test period and reached statistical significance after 90 days. Given the opposing action of Finasteride on DHT synthesis, it’s reasonable to conclude that spatial memory may suffer deficits, but verbal memory could be unaffected.

DHT is neuroprotective: Implications for Alzheimer’s

One of the possible roles of DHT is in protecting neurons from cell death, which is of particular relevance to conditions like Alzheimer’s. There’s been growing scientific evidence to support the neuroprotective effect of androgens, with there possibly being a link between Hypogonadism and the development of Alzheimer’s. Supporting this androgens, and especially DHT, can prevent the reverse the accumulation of accumulation of beta-amyloid protein in rodent brains. [21] One of the enzymes involved in breaking down Amyloid plaques is NEP (Neprilysin), and DHT binding to the androgen receptor in hippocampal cells can induce the expression of this enzyme. [22]

DHT may have a further neuroprotective role by protecting the brain against the effects of kainate, an excitotoxin in the hippocampus. When neurons are over stimulated by excitatory neurotransmitters, they can become damaged and eventually die. Supplementation with DHT in androgen deficient rats can significantly counteract the loss of neurons in response to kainate. [23] Additionally DHT can modulate the MAPK/ERK signalling pathway to influence cell survival. By activating C6 glial cells, DHT can protect against cell death. [24] The obvious importance of DHT for neurological health would suggest that Finasteride could be linked to worsened neurological health in older populations.

DHT Facilities Sexual Desire, particularly through 3-alpha-Diol

The region of the brain best understood to influence sexual desire is the Medial Preoptic Area (MPOA) of the Hypothalamus. It takes inputs from hormonal signals and sensory information to mediate feelings of sexual motivation. Both Estrogen and Androgen Receptors are present in the MPOA and so both Estrogen and DHT can influence copulatory behaviour. By elevating dopamine signalling in the MPOA, DHT can support sexual desire. [25]

It’s important to recognise that DHT can be further metabolised into neurosteroids which have their own facilitative role on sexual desire. DHT can be converted into the weak androgen 3-alpha-Diol by the enzyme 3-alpha-HSD (hydroxysteroid dehydrogenase). 3-alpha-Diol can modulate sexual receptivity by acting as a positive allosteric modulator of the GABA-a receptor. [26]