A small pilot study of 16 patients purporting to have PFS against 20 controls identified an increase in DNA methylation of the 5AR type II promoter (56% versus 8% in controls). [1] 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. Methylated DNA further attracts enzymes such as HDAC (Histone Deacetylase) which modify the proteins around which DNA is wound called Histone. The result of this being a more compressed chromatin structure and less gene expression. In essence the gene (in this case 5AR type II) is switched off. [2] The researcher in this pilot study don’t present a mechanism which could explain this difference against controls however, there has been work by other scientists that could shed light onto this mystery.
[2] https://www.nature.com/articles/7310149
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. [1] 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. [2] The age dependent reduction in decrease 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.
[1] https://academic.oup.com/endo/article-abstract/133/2/447/3035051
[2] https://academic.oup.com/endo/article/152/12/4550/2457314
Valproate is mood stabiliser which also has strong HDACi and DNA de-methylating properties:
- “We observed the presence of DNA demethylation activity, which was increased in FC nuclear extracts from mice treated with valproate (VPA, 2.2 mmol/kg, twice a day for 3 days).
- VPA not only reduces anxiety, and cognitive deficits, and other symptoms in bipolar disorder (BP) disorder and schizophrenia (SZ) patients but also upregulates Reln and glutamic acid decarboxylase 67 (Gad67) mRNA/protein expression by reducing the methylation of their promoters.
- We believe that the identification of an enzyme in brain that facilitates DNA-demethylation and an understanding of how drugs induce DNA demethylation are crucial to progress in a new line of pharmacological interventions to treat neurodevelopment, neuropsychiatric, and neurodegenerative diseases.”
https://www.tandfonline.com/doi/abs/10.4161/epi.5.8.13053
Valproate induces 5-alpha-reductase activity in the brain:
- “In this study, VPA-induced acute metabolic alterations were investigated using liquid chromatography-tandem mass spectrometry in prepubertal mice brain.
- In VPA-treated (400 mg/kg in saline solution, intraperitoneal) mice, cortisol levels were increased (female: P < 0.004, male: P < 0.003) and 17β-estradiol levels were decreased (Both P < 0.03).
- Furthermore, in the VPA-treated male mice, dihydrotestosterone levels were increased (P < 0.02) and testosterone were decreased (P < 0.002).
- The 4-hydroxylase activity was upregulated in the female VPA-treated mice (P < 0.01) and the 5α-reductase activity was increased in the male VPA-treated mice (P < 0.003).
- These results indicate sex specific differences in VPA-induced steroid metabolism in the brain cortex.”
https://link.springer.com/article/10.1007/s11064-020-03065-4
Another HDAC inhibitor, Trichostatin A, also enhances 5-alpha reductase in neuronal tissue. https://link.springer.com/article/10.1007/s12031-009-9284-6
“In addition, progesterone and histone deacetylase (HDAC) inhibitors have also been reported to promote the glial cell differentiation with the enhancement of serotonin-stimulated brain-derived neurotrophic factor gene transcription through the production of 5α-reduced neurosteroids, thus suggesting that glial cell differentiation is probably implicated in the protection and survival of neuronal cells in the brain.
Therefore, the expression of 5α-R gene in glial cells seems physiologically important in maintaining the neural function in the brain, but little is known about the mechanism underlying the regulation of 5α-R gene transcription.
In the present study, the effect of a HDAC inhibitor trichostatin A (TSA) on 5α-R gene transcription in the glioma cells was examined, and TSA was shown to induce the elevation of 5α-R mRNA levels through the activation of the 5α-R promoter via a mechanism involving Sp1 and Sp3 transcription factors in a time- and concentration-dependent manner.”
Notably, Trichostatin A also induces DNA demethylation by inhibiting DNMT1.
https://www.tandfonline.com/doi/abs/10.1128/mcb.01304-10
https://www.sciencedirect.com/science/article/abs/pii/S0304383506001674