5-alpha-reductase
Finasteride is a commonly used medication for treating androgen driven conditions such as male pattern baldness or benign prostatic hyperplasia. It inhibits the activity of the type II 5-alpha-reductase enzyme, which converts testosterone into the much more potent androgen Dihydrotestosterone (DHT). [1] The Type II isoform is expressed in the liver, skin, and prostate. Additionally, it is responsible for around two thirds of circulating DHT. [2]
Despite testosterone having the reputation of being the definitive male hormone, DHT is far more masculinising – with approximately double the binding affinity of testosterone for the Androgen Receptor. [3] On average oral Finasteride at 1mg/day decreases serum DHT by 70% after 1 year. [4]
DHT molecule. Fvasconcellos, Public domain, via Wikimedia Commons
By lowering the production of this powerful hormone, Finasteride essentially works as an ‘anti-androgen’. It’s therefore unsurprising that treatment with Finasteride poses the threat of developing side effects related to biological functions regulated by androgens, such as protein synthesis, sexual characteristics, and libido. [5] These side effects can often prompt patients to abandon treatment.
Troublingly, there’s an increasing recognition of the potentially enduring nature of these side effects, particularly in relation to libido and mood. These symptoms that persist after discontinuing Finasteride are colloquially referred to as ‘Post Finasteride Syndrome’. In a study of patients who developed sexual dysfunction following treatment with Finasteride, 96% found their symptoms were enduring when re-assessed up to 16 months later. [6]
Epigenetic effects
Researchers have posited various theories in an attempt to explain the lasting deleterious effects of Finasteride in some patients. One of the models with encouraging results centres on epigenetic modifications.
Epigenetics is the field of genetics that explains how gene expression can be altered without changing the underlying genetic code directly. Epigenetic mechanisms can essentially switch genes on and off in a lasting manner, and thereby influence an organism’s traits and behaviour. You can read more details on epigenetic processes in this article.
A small pilot study looking into these possible epigenetic changes took samples of cerebrospinal fluid from 16 patients suffering from PFS. From the samples they found an increase in DNA methylation at the 5AR type II promoter in 56% of PFS-sufferers, versus only 8% in the 20 controls. [7] Furthermore there was no difference in the DNA methylation of Type I promoter, which is relevant given that Finasteride targets the Type II isoform.
DNA methylation is a lasting form of epigenetic modification where methyl groups are bound to the promoter regions of genes, preventing the binding of transcription factors. [8] The result of this being a more compressed chromatin structure and less gene expression. In essence the gene (in this case 5AR type II) becomes less available.
DHT regulates 5AR expression
What could give rise to these changes in 5-alpha-reductase expression? One of these clues is the discovery that DHT induces the expression of 5-alpha-reductase in a feedforward mechanism.
A study in rats found that treatment with Finasteride resulted in an 87% decrease in 5 alpha-reductase enzyme activity. This reduction was matched a significant decrease in 5-alpha-reductase mRNA in the prostate. Treatment with DHT, but not Testosterone on its own, was able to restore 5-alpha-reductase activity and mRNA in a positive feedforward loop. [9]
Prostate cancer research has further revealed the mechanism that regulate 5-alpha-reductase activity. Audet-Walsh et al. (2017) demonstrated that Type I and Type II isoforms of 5AR are inversely correlated in prostate cancer progression. Significantly, they found that androgen stimulation induced the expression of Type I 5AR. They note the positive feedback loop of Type I to be relevant in understanding the progression of prostate cancer. [10]
A similar effect has been observed with the 3-beta-HSD1 enzyme, which is responsible for convert DHEA to androstenedione. This enzyme regulates the rate-limiting step in the production of DHT from DHEA. Like 5AR Type I, its activity is also positively regulated by Androgen Receptor activation in a feedforward relationship. [11] Other studies have confirmed the role DHT in regulating 5-alpha-reductase Type I, with other hormones such as testosterone, or progesterone having no effect. [12]
How does DHT regulate 5AR expression?
There hasn’t been a consensus as to how DHT enhances its own synthesising enzyme, but some work has been done on the possible role of IGF-1. Researchers have found that IGF-1 induced 5-AR activity 100 times greater than DHT. They found that applying monoclonal antibodies to block IGF-1 prevented DHT from inducing 5AR. [13] Another possible mechanism could be through directly influencing the enzymes involved in DNA methylation.
The primary enzyme involved in the methylation of Type II 5AR is DNA methyltransferase 1 (DNMT1). This enzyme represses the expression of 5AR by adding methyl groups to the promoter region of the gene on the DNA. [14] The age dependent reduction in the expression of Type II 5AR is likely on account of increased DNMT1 in old age.
Studies have found that treatment with anti-androgens triggers an increase in DNMT1 activity. Conversely, applying DHT significantly reduces DNMT. It could be through this mechanism, DHT is regulating the expression of 5-alpha-reductase.
Epigenetic Agents to induce 5-alpha-reductase expression
Given the evidence that 5-alpha-reductase expression can be repressed by DNA methylation, it might be reasonable to posit that de-methylating agents may in turn induce it. One of the approaches to de-methylating DNA, and thereby enhance gene expression, is to use HDACis (histone de-acetylase) inhibitors.
Simply put, HDAC is an enzyme that removes acetyl marks on histone tails, which makes some genes less transcriptionally active. By inhibiting HDAC, genes can become more transcriptionally active, and around 2% of mammalian genes are affected in this way. [15]
modified from original byAnnabelle L. Rodd, Katherine Ververis, and Tom C. Karagiannis, CC BY-SA 4.0, via Wikimedia Commons
Modifications to histone tails are more transient than DNA methylation, which is a more persistent modification. However, histone are connected to DNA and HDAC inhibitors can also encourage DNA de-methylation. [16][17] A particularly potent HDAC inhibitor is a mood stabilising medication called Valproate.
It’s been found that Valproate can induce significant changes in steroid metabolism in the brain cortex of mice. Of particular interest is the dramatic induction of 5-alpha-reductase, resulting in an increase in Dihydrotestosterone (DHT) content in the brain. [18] It’s possible this effect can be attributed Valproate enhancing gene expression by the removal of repressive methyl marks.
Valproate isn’t the only HDAC inhibitor to have this effect. A related medication called Trichostatin A is used to inhibit class I and class II histone deacetylase enzymes. Epigenetic agents are often used to investigate possible cancer treatments, with the goal of differentiating stem cell-like cancer cells.
HDAC inhibitors aren’t alone in forcing glial cell differentiation, in fact the 5-alpha-reduced neurosteroids can also trigger this process. Futhermore, Serotonin is therefore also implicated in glial differentiation, as it’s been found that binding to the the 5-HT2A receptor raises 5-alpha-reductase mRNA. [18]
In short, by upregulating 5-alpha-reductase expression in glioma cells, serotonin encourages the synthesis of 5-alpha-reduced neurosteroids and therefore promotes glial cell differentiation. Research by Her et al. (2010) revealed that Trichostatin A can potently enhance this effect of serotonin. [19]
Treating glioma cells with Trichostatin A gave way to a considerable boost in 5-alpha-reductase mRNA. This was found to be driven by the transcription factors Sp1 and Sp3 binding at the gene promoter of 5-alpha-reductase. This finding led the authors of the study to conclude that 5-alpha-reductase is vital to glial cell health by promoting the synthesis of neuroactive steroids which are in turn involved in neuroprotection.
Article Summary
- Finasteride Use: Finasteride is commonly prescribed for androgen-related conditions like male pattern baldness and benign prostatic hyperplasia. It inhibits the Type II 5-alpha-reductase enzyme, reducing the conversion of testosterone into dihydrotestosterone (DHT). Finasteride reduces DHT levels by around 70% after one year, leading to anti-androgen effects that may result in side effects affecting protein synthesis, sexual characteristics, and libido.
- Post Finasteride Syndrome (PFS): Some patients experience long-lasting side effects, particularly related to libido and mood, even after stopping treatment, referred to as Post Finasteride Syndrome (PFS). 96% of affected patients report persistent symptoms.
- Epigenetic Mechanism Hypothesis: Research suggests Finasteride may induce epigenetic changes, such as increased DNA methylation of the 5AR Type II promoter, leading to reduced expression of the 5-alpha-reductase enzyme, which may contribute to lasting side effects.
- DHT and Feedforward Mechanism: DHT can induce the expression of 5-alpha-reductase in a feedforward loop, enhancing its own synthesis. Studies in rats and prostate cancer research support this mechanism.
- DNA Methylation and DNMT1: Increased DNMT1 activity, particularly in older individuals, leads to higher DNA methylation of 5AR Type II, reducing its expression. DHT can inhibit DNMT1 activity, thereby increasing 5AR expression.
- Potential Treatments: HDAC inhibitors, like Valproate and Trichostatin A, may upregulate 5-alpha-reductase by removing repressive methyl groups, potentially offering a way to reverse Finasteride’s epigenetic effects.
Related articles
References
Click Arrow to Show References
[1] https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006015.pub3/full
[2] https://www.drugs.com/monograph/finasteride-hair-growth.html
[3] https://www.ncbi.nlm.nih.gov/books/NBK557634/
[4] https://www.drugs.com/monograph/finasteride-hair-growth.html
[5] https://escholarship.org/uc/item/24k8q743
[6] https://academic.oup.com/jsm/article-abstract/9/11/2927/6886761
[8] https://www.nature.com/articles/7310149
[9] https://www.pnas.org/doi/abs/10.1073/pnas.88.18.8044
[10] https://academic.oup.com/endo/article/158/4/1015/2939508
[11] https://academic.oup.com/endo/article/159/8/2884/5005852
[12] https://pubmed.ncbi.nlm.nih.gov/10562469/
[13] https://academic.oup.com/endo/article-abstract/133/2/447/3035051
[14] https://academic.oup.com/endo/article/152/12/4550/2457314
[15] https://www.sciencedirect.com/science/article/pii/S0022316622161043?via%3Dihub
[16] https://www.ingentaconnect.com/content/ben/cmcaca/2003/00000003/00000003/art00002
[17] https://www.sciencedirect.com/science/article/abs/pii/S0006295207000068 [18] https://pubmed.ncbi.nlm.nih.gov/32601984/
[18] https://www.sciencedirect.com/science/article/abs/pii/S0169328X05002342
[19] https://www.sciencedirect.com/science/article/abs/pii/S0169328X05002342
Leave a Reply