Mutations to 5AR gene after Finasteride use causing phenotypic change?

General Discussion
#1

Has finasteride caused an adaptation and phenotypic change by mutating the 5alpha reductase gene? The stress on the cells would be enough to alter it and could explain the massive gene dysregulation that may just be a result of an upstream mutation and downstream effect being massive epigenetic changes.

“Organisms are often exposed to stressful environments. To cope, they have evolved responses based on the duration of the stress. For example, bacteria that are exposed to increased temperatures display a transient heat shock response, which involves upregulation of genes encoding heat stress proteins (Richter et al. 2010), followed by a period of phenotypic acclimation (Gunasekera et al. 2008).”

If the environmental stress is sustained over a long period of time, individuals may eventually accumulate mutations that result in long-term adaptation of the population.

One possible mechanism for adaptation to stressful conditions is genetic change that produces novel traits or new physiological functions.

“A significant finding of our study is that single mutations in RNAP led to either the direct or indirect alteration of GE for thousands of genes—most of which were differentially expressed during acclimation to 42 °C—and conferred large fitness advantages.“

#2

Researchers have found that evolution can never go backwards, because the paths to the genes once present in our ancestors are forever blocked. The findings come from the first rigorous study of reverse evolution at the molecular level.

The team used computational reconstruction of ancestral gene sequences, DNA synthesis, protein engineering and X-ray crystallography to resurrect and manipulate the gene for a key hormone receptor as it existed in our earliest vertebrate ancestors more than 400 million years ago. They found that over a rapid period of time, five random mutations made subtle modifications in the protein’s structure that were utterly incompatible with the receptor’s primordial form.

#3

PFS is not evolution.

I would guess PFS is something like discussed in this study done on SSRI.

https://www.sciencedirect.com/science/article/pii/S0306453021002389?dgcid=coauthor

Basically the SSRI they tried changed a lot of different enzymatic activities within the brain.

Most of PFS probably stem from the same issue. Good thing is enzymatic activity is very much plastic, bad part is there’s no way to know exactly what’s changed, and even if we did there would be no cure/medicine who target those areas.

1 Like
#4

“Consequently, any exposure to extreme stresses (e.g. heat or radiation, high inorganic salt concentrations, strong acids and bases) can disrupt a protein’s interaction and inevitably lead to denaturation.”

When a protein is denatured, secondary and tertiary structures are altered but the [peptide bonds of the primary structure between the amino acids are left intact. Since all structural levels of the protein determine its function, the protein can no longer perform its function once it has been denatured.

Most biological substrates lose their biological function when denatured. For example enzymes.

image
image2100×2791 548 KB

#5

Interesting read for sure. I think one thing is why the “crash” happens. The way I feel, every single one would’ve had to mutate basically overnight

#6

I also think blood tests would show if a 5alpha gene wasn’t working correctly I think?

#7

I think these substances we took are mutagenic and our bodies have underwent a phenotypic adaptation as a protection mechanism against the surge in hormones. I don’t think 5alpha reductase gene has been tested for mutagenises, post transcriptional modification or to check if it’s denatured.

#8

I think this is interesting. As you know I believe this is autoimmune. But mutagenesis can cause autoimmune reactions. So I’m highly interested. Biggest issues are 1. Why did this happen to some overnight. That’s a huge thing to suggest a whole body mutation occurred 2. Temporary windows / recoveries (I never experienced one). 3. I believe blood tests would suggest a change in 5 alpha.

The only blood tests I ever had come back abnormal were 3 separate high urinary cortisol tests on three separate occasions including at Mayo clinic

#9

Why do you believe it’s autoimmune? I’ve seen data suggesting the immune system for sure is involved, but I’m not sure if I’d call it autoimmune per se.

Anyone ever had their TNF-a and IL6 tested for example? I am thinking about testing my IL6, but it won’t be for quite some time. Can’t test for TNF-a in my country though. But TNF-a should impact CRP and my CRP is low.

And blood tests won’t show 5AR activity in specific tissues. Circulating DHT is mainly from the 5AR in the liver.

Even if liver 5AR is functioning, we have data suggesting that inside the brain, DHT is not synthesized. Since the same study showed high levels of T withing the brain, the conclusion must be that 5AR is not active.

We must remember how DHT is not a circulating hormone, but is rather site specific and it won’t cross the blood brain barrier very easy.

And according to the Baylor study, PFS patient have a harder time clearing cortisol out of the system. Now I see you have used Accutane, and there’s no way to know if the same is true for PAS.

1 Like
#10

I’ve been around with this for 4-5 years and have gathered info from all the forums, spoke with people, spoke with many doctors. That’s just my own conclusion. There was a guy who tested advanced inflammatory markers from pssd forum and they came back normal and said the professor suggested its more neurological in nature. However, inflammatory markers are not always abnormal in autoimmune diseases.

For me, the crash especially sometimes 2 weeks after and affecting the whole body immediately is characteristic of autoimmunity. I also crashed after having multiple vaccines, doing a weight cut, and having ebv. Ultimately, my opinion doesn’t mean anything. I’m interested in this topic because mutagenesis can cause autoimmune reactions. I’m commenting my opinion because if this is the case how do we reverse it, and giving reasons why hopefully it’s not the case.

#11

I also used accutane but recovered completely as a teenager, I took saw palmetto in a multivitamin and my world ended after like 4 pills

1 Like
#12

Drug resistance can arise by adaptation or by mutation. Adaptation is induced by drug and dependent on the continued presence of the drug; resistance is rapidly lost when the resistant cells are grown without drug. Mutations resulting in drug resistance can occur in the presence but also in the absence of drug. The mutant sub-population is selected by growth in presence of drug. As mutations are in principle irreversible, the resistance is retained if the cells are grown without drug.

Drugs may induce a change in cellular differentiation that is rather stable, but not associated with changes in DNA. There are also mutations that are fairly unstable; for instance, amplified DNA present as double minute chro- mosomes (see section on Gene amplification) is often lost rapidly when cells are grown without drug selection. To complicate matters further, not all alterations in DNA are mutations: gene expression may be stably repressed by methylation of DNA by cellular enzymes. Although re- placement of a DNA base by its methylated analogue formally changes the DNA sequence, such changes are usually called epigenetic, i.e. changes in differentiation state, rather than mutations, because they cannot be main- tained in dividing cells without a maintenance methylase that methylates hemi-methylated DNA after DNA replication.

#13

I was thinking today what if it was an accumulation of 5alpha reductase proteins that have build up in certain tissues that were causing insensitivity? If you think about it how can the proteins interact with a receptor if there’s a toxic build up with not enough receptors to support them. So perhaps protein aggregation is causing insensitivity in specific tissues? And when someone with PFS is exposed to further endocrine disruption these proteins can build up further causing a loss of function and worsening of their condition.

Protein aggregation
Loss of function