This is amazing information thanks for sharing
1 Like
This study reveals valuable information about mental and physical problems in PFS patients. If someone has problems with SRD5A2 then they have trouble creating the steroids that give us energy, confidence, focus, vitality, libido etc etc etc. Here is more on SRD5A2:
Reference: https://ghr.nlm.nih.gov/gene/SRD5A2
“The SRD5A2 gene provides instructions for making an enzyme called steroid 5-alpha reductase 2. This enzyme is involved in processing androgens, which are hormones that direct male sexual development. Specifically, the enzyme is responsible for a chemical reaction that converts the hormone testosterone to a more potent androgen, dihydrotestosterone (DHT), in male reproductive tissues.”
Although must of us suspected this, it is good to have science to back it up.
If what you said is true, it is very easy and very fast to check SRD5A2 status with all DNA and RNA testing technology that exist today.
What it is even more shameful is that RC Melcangi in Italy had done 2 studies and already published and Baylor study the first part is not even have been published yet
1 Like
(emphasis mine)
As far as I understand it, almost half of PFS patients did not have methylated SRD5A2 promoters. If that half also has horrible side effects, the mechanism behind PFS has to start somewhere else and the SRD5A2 might be a downstream effect for some. If 95% had an abnormality versus control and it explained physical symptoms we are onto the juicy stuff :).
If what I am saying is false, correct me. Just how I as a regular sufferer with no scientific background read the above summary.
I agree with you here. Another interesting takeaway from this study is this:
“Unmethylated controls compared to unmethylated SRD5A2
patients showed higher pregnenolone, dihydrotestosterone and dihydroprogesterone,
together with lower testosterone CSF levels.”
Even if you didn’t have methylation of the gene and had PFS, you still had lower preg, DHT, and dihydroprogesterone. From my interpretation, methylation isn’t the sole cause of lowered CSF concentrations of the chemicals I just mentioned. And in addition, “In PFS patients, neuroactive steroid CSF levels were not significantly related to the percentage of SRD5A2 gene promoter methylation.”
My TLDR:
- controls are less likely to be methylated in the 5ar2 gene.
- unmethylated controls have more of the neurosteroids mentioned.
- If you do have methylation, the amount of neurosteroids in your CSF is not related to the amount of methylation.
- symptomology (ED, depression, etc.) was not correlated with methylation amount.
- It’s impossible to tell if the methylation was a result of finasteride, or if we were born that way based on this study
- “If abnormal SRD5A2 promoter methylation is established prenatally, these subjects
could be predisposed to develop the PFS and alteration of neuroactive steroid levels in thebrain. In this case, treatment by finasteride might precipitate a dormant depressive
phenotype linked to such specific epigenetic pattern, resulting in the clinical picture
described previously.” - There were a low number of subjects in this study, so these results shouldn’t be taken as a universal proclamation.
2 Likes
Boys, please stop being scientists, because you are not! This publication is important, but it doesn’t help us. Unfortunately, it has not added important information. There is still a lot of work to do. You have been a scientist for 10 years, but you are not!
@Rb26dett I wouldn’t call this information unimportant. Any information is important, and it can tell us about our condition. Read my comment above for my “TLDR” that I believe highlights the important features of this study. Can you imagine if Melcangi discovered that 100% of the PFS subjects had methylation of the 5ar2 gene? We’d be freaking out here. I think his study had a good aim (to see if methylated gene sequences were the cause/effect of PFS), but it had shortcomings. I personally applaud Melcangi, although he is very focused on the 5ar2 byproducts and precursors. The more noise is made in PFS research, the better for us. I’m thankful Melcangi is taking a chance with us at least.
To me, an unimportant finding would be something like, “some finasteride users experience ED.”
3 Likes
If mohit “drag my feet” khera would finish his lolly gagging comparison of genes study for 6 years now we might actually see which ones are affected…
Apologies for being a bit off topic but since everyone’s discussing science, anyone got any idea what would cause the skin to become stretchy/lax and slow to repair?
Even if Khera was to determine which genes have been silenced, at this stage there’d be little we could do about it anyhow.
Collagen synthesis is dependent on sex hormones although not sure which ones.
1 Like
Hopefully it can return to normal or at least near normal if those hormones are restored. I expect some skin damage to persist like the deep stretch marks untill technology gets better, but even if it was firm again I’d be happy. Look like a pale ghost now lol but it could be worse I guess.
- The study shows that out of 16 PFS patients, close to 60% of them had issues with SRD5A2 - the gene that allows normal functioning of steroid synthesis in the body.
- Out of the controls studied (people who did not take PFS), only 7% showed problems with SRD5A2.
A few anecdotal conclusions can be drawn:
- Most PFS’ers have issues creating steroids due to alterations in the gene SRD5A2 (yes only 16 were studied, but there are not many people with PFS so when you consider that it’s actually a decent sample size percentage-wise)
- Whatever causes these issues with SRD5A2 can be caused by variables other than Finasteride since the same issue was seen in at least one of the non-Finasteride users.
*edit 7/22/2019 - After reading the full study I’ve changed my opinion - 100% of the non-pfs SRD5A2 controls had UN-Methylated SRD5A2 (normal) levels (there was one who had methylated SRD5A2 but he suffered from normotensive hydrocephalus (a condition which has symptoms like difficulty concentrating and urinary issues) and should have been excluded from the “healthy” controls.
I was looking for a stronger correlation and after seeing the fully study this looks to be a very strong correlation.
5 Likes
Yes, a few things, but mainly cortisol.
1 Like
Yes, as with every other symptom, site specific over-expression of the AR, which importantly is already established in 100% of symptomatic dermal prepuce tissue across cell lines in PFS. The prevalence of the symptom you mention and this important primary finding already disproves the hypothesis of effects localised to the CNS.
Androgen signalling has a determinant role in skin maintenance, epithelialisation, collagen deposition and inflammation. AR signalling is inhibitory of skin healing. (1-7)
- Gilliver, Regulatory roles of androgens in cutaneous wound healing, 2002
- Ashcroft and Mills, Androgen receptor-mediated inhibition of cutaneous wound healing, 2002
- Gilliver et al, 5alpha-dihydrotestosterone (DHT) retards wound closure by inhibiting re-epithelialization, 2009
- Ashcroft et al, Topical estrogen accelerates cutaneous wound healing in aged humans associated with an altered inflammatory response, 1999
- Fimmel and Zouboulis, Influence of physiological androgen levels on wound healing and immune status in men, 2005
- Lai et al Monocyte/macrophage androgen receptor suppresses cutaneous wound healing in mice by enhancing local TNF-alpha expression, 2009
- Gilliver et al, Androgens influence expression of matrix proteins and proteolytic factors during cutaneous wound healing, 2007
…As such antiandrogenic substances are increasingly considered as potential therapeutic angles to aid healing - including finasteride, quercetin and flutamide (8, 9, 10):
- Toraldo et al, Topical androgen antagonism promotes cutaneous wound healing without systemic androgen deprivation by blocking β-catenin nuclear translocation and cross-talk with TGF-β signaling in keratinocytes, 2012
- Liu, Quercetin suppresses glomerulosclerosis and TGF‑β signaling in a rat model, 2019
- Wang et al, Androgen actions in mouse wound healing: Minimal in vivo effects of local antiandrogen delivery, 2016.
This is likely part of a pleiotropic picture as increased androgen signalling has been demonstrated to be inhibitory of healing following injury to androgen target tissues such as the heart and endometrium. Finasteride has recently been suggested as potentially therapeutic in heart failure due to marked improvement in animal models.
Hopefully I can clear this up, as this is obviously coming up a lot: What Melcangi has done is not on remotely the same scale. While more confirmation of epigenetic differences is very good to have (I gave a large personal donation to this particular study and was hopeful it could provide some fast evidence of methylation in PFS patients), 5ar deficiency is not a plausible driver of PFS as @awor has stated for many years, and this result should make clear. The practicality of this will lie in more evidence for a direction towards epigenetic involvement, again as @awor said.
This present study, at least in organisation terms, got underway at the end of 2017. It looked at two genes in serum and CSF. I think it’s therefore simple to understand that it is much more of an undertaking to look at those, plus 19998 more, in tissue biopsy of a larger control-matched cohort, with what we hope is the potential to provide insight into possible driving factors of previously established AR deregulation. We expect a variably significant picture of altered expression depending on the severity of case, and disentangling the volume of data is not easy.
I do not know the quality of report that will ultimately be produced or factors that may influence that. However, that a narrowly-focused study is quick does not make it “shameful” that the important things inherently take longer. It is not in the same ball park.
7 Likes
Does anyone know anything about Melcangi’s other ongoing PFS study, on the gut micriobiome, and how would we evaluate the significance of that?
i think melcangi is the only one that can help us. i have no hopes in baylor
4 Likes
@awor, @axolotl Do you guys think that the fact that not only all of the pfs sufferers showed srd5a2 hypermethylation proves that srd5a2 hypermethylation is not the root cause of the problem, and from now on it would be better to focus on androgen receptor’s expression?
Although is important to understand what the gene’s hypermethylation could imply because the difference is strongly statistically significant.
1 Like
What I would expect is the more genes they look at a pattern like this should start emerging showing a variance of genes that are affected and at different percent in different patients…So a whole host of genes affected but at different degrees in different people could explain why some get crippled, some get fat, some lose weight, some recover more etc…Why yes, its likely they could not do anything right now I suppose about it but wouldn’t you finally like to know the cause and see this proven?? So people would quit coming up with all these outlandish theories…
1 Like