The Steroidogenesis Inhibitor Finasteride Reduces the Response to Both Stressful and Rewarding Stimuli

What this seems to show, unsurprisingly, is that finasteride impaired the stress response of rats. The impaired stress response was demonstrated in both female rats and castrated male rats so it doesn’t seem like the impairment was related to deprivation of gonadal steroids (androgens). Probably more likely due to the inhibition of other metabolites of 5-AR like the neurosteroids.

For a while, I’ve wondered if PFS is a form of chemically induced PTSD. Although my sexual function is consistently impaired, my neurocognitive struggles seem to wax and wane along with external stressors.

If I may go out on a limb and offer some thoughts here, a healthy human responds to stress by releasing a cascade of chemicals such as allo, CRH, ACTH, and cortisol. Over time, if you are exposed to chronic stressors, your body will start to suffer longer term damage and you may even develop an autoimmune disorder because the system kind of breaks down. Without the ability to release these chemicals, we may be suffering the direct impact of stress without any kind of buffer which obviously is not good.

Dr. Robert Sapolsky is an academic neuroendocrinologist and has written a lot of books for the lay person on the physiology of stress. I read Behave, which I thought was fantastic, and parts of Why Zebras Don’t Get Ulcers. He only briefly mentioned allopregnanolone and neurosteroids, mainly because very little is known, but I definitely recommend both books for people who want to learn more. He has good tips for stress management as well which is obviously critical to improving your health. I emailed him a few years back about the stress response and PFS and he didn’t really know anything other than he had heard of PSSD and that little was known about it. He won the MacArthur Grant (AKA a genius prize) for his life’s work on the stress response so that should tell you a bit about how cutting edge this research is.

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Yes I have access to all publications. I think it’s always interesting that finasteride is interacting directly with these systems, but of course it doesn’t explain these elements of “PFS”. Rather, it shows a physiological interference in areas pertinent to PFS symptoms. It’s important to bear in mind the pattern of PFS on aggregate, and that many of our most severe cases completed suicides took very little of the drug and dramatically and progressively worsened following a crash hours, days, weeks later. And most importantly that millions are on this drug.

I have been interested in the PTSD overlap for a short while. I will maybe make a topic in a month or so. I spent some time looking into it a while ago after seeing a study (maybe @orthogs) posted. I’ve written a fair bit up in the literature review I’ve been doing and have found a lot I think people will be interested in reading. I don’t think it’s unreasonable to suggest as @frustrated has there may be some interesting symptomatic overlap and even potentially mechanistic. Certainly some amazing clinical stuff. Imo, this again highlights the mechanistic importance to medicine of this post-endocrine disruption syndrome.

In regard to this conclusion:

I don’t agree this experiment could support that conclusion if the androgen DHT is to be considered a gonadal steroid. To conclude this could be the case, it would have been important to conduct investigations into mRNA responses with administration of something like hydroxyflutamide. 5alpha reductase is a microsomal tissue-bound enzyme that allows for local synthesis site-specifically. It is also still very important in the female brain.

In terms of CRH, detailed mechanistic investigations currently in press (Heck and Handa, 2020) have demonstrated CHR mRNA is under the regulation of DHT, and evidence would suggest this is not due to gabergic neurosteroids.

key: GDX = gonadectomy, projections = neurons with axons projecting to other sites

As this mechanism was highly likely to be AR mediated, Heck and Handa investigated and described robust AR labeling within and outside of CRH neurons in the BNSTav, "a brain region well positioned to mediate the androgen regulation of the HPA axis. Anterior subdivisions of the BNST have neurons with AR expressing projections to the CRH containing parvocellular regions of the PVN (78). Additionally, the BNSTav includes substantial populations of PVN projecting CRH neurons that are functionally distinct from GABAergic neurons in the region and have been suggested to participate in the activation of the HPA axis (79–81). DHT may enhance the activity of these BNST CRH neurons to increase Crh gene expression in the PVN in the absence of GCs.

Our findings show that GDX selectively decreases PVN Crfr1 expression when paired with ADX and support a role for CRH signaling in such androgen regulation of PVN Crh. Despite evidence for BNST to PVN CRH signaling, we cannot exclude the possibility that DHT inhibits the activity of GABAergic neurons in the BNSTav and other regions of the BNST that are not CRH expressing to increase PVN Crh expression following ADX. However, results of one study argued against such a mechanism of GABA disinhibition, as local DHT administration did not alter expression of GABA-synthesizing enzymes in the posterior BNST, a region thought to play an especially prominent role in the inhibition of the HPA axis (69)…Ultimately, the results of these studies have shown a sex difference in the regulation of PVN Crh that is revealed in the absence of GC-negative feedback and may depend on DHT actions outside of PVN CRH neurons in males. Our findings highlight the need for further systemic evaluation of central gonadal hormone effects on the HPA axis. Such studies will continue to advance our understanding of sex biases in the prevalence of stress-related pathologies."

Of interest for those aware of the curvilinear nature of androgen signaling: this study noted “the potentially dose-dependent, excitatory effect of DHTP observed in the current studies is not unprecedented, the possibility that DHT has opposing effects, if administered at high and low doses, is certainly intriguing”, noting dose dependent AR expression as a potential explanation for this paradox.

Seperately, supraphysiological androgen has been reported to predispose animals to depressive behaviour, causing a downregulation of AR in line with CRH mRNA. In the same study, orchiectomy caused a significant and correlated increase in AR and CRH (Ludwig et al 2019). Referencing animal and human studies of depression with supraphysiological androgens, they concluded “depression-like symptoms [may be] found on both ends of the spectrum…Altogether, it appears that long-term treatment with supraphysiological doses of testosterone induces depression-like symptoms in rats that were additionally exposed to uncontrollable stressors.”

Together, CRH is clearly under regulation of androgen signaling, and current evidence indicates this is AR mediated.

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Interesting read Axolotl!

This diagram does a good job depicting some of the link between androgens in sex and reward circuitry of the brain

Really good article. We do need more like this, some doctora are trying to undersand the pfs, and it is good news that not only Mecangli does.

I think ive said it before, there’s alot more studies on Accutane.

All- trans retinoic acid-induced hypothalamus–pituitary–adrenal hyperactivity involves glucocorticoid receptor dysregulation

Clinical reports have highlighted a role for retinoids in the etiology of mood disorders. Although we had shown that recruitment of the nuclear receptor retinoic acid receptor-α (RAR-α) to corticotropin-releasing hormone (CRH) promoter is implicated in activation of the hypothalamus–pituitary–adrenal (HPA) axis, further insight into how retinoids modulate HPA axis activity is lacking. Here we show that all- trans retinoic acid (RA)-induced HPA activation involves impairments in glucocorticoid receptor (GR) negative feedback. RA was applied to rats chronically through intracerebroventricular injection. A 19-day RA exposure induced potent HPA axis activation and typical depression-like behavior.

Keywords: all- trans retinoic acid, corticotropin-releasing hormone, depression, glucocorticoid receptor, hypothalamus–pituitary–adrenal axis, mifepristone (RU38486)

Rapid Action of Retinoic Acid on the Hypothalamic Pituitary Adrenal Axis


This study investigated the action of RA over 3 days on regulatory components of the HPA axis. Several key genes involved in glucocorticoid feedback pathways in the hippocampus, hypothalamus and pituitary were unchanged after 3-days exposure to RA. Key elements though in the adrenal gland involved in corticosterone and aldosterone synthesis were altered in particular with the Cyp11b2 gene downregulated in vivo and ex vivo . The rapid, 5 h, change in Cyp11b2 expression suggested this activation may be direct. These results highlight the adrenal gland as a target of short-term action of RA and potentially a trigger component in the mechanisms by which the long-term adverse effects of RA treatment occur.

The long-term influence of RA on the HPA axis has previously been examined from two perspectives; one as a treatment of Cushing’s disease (Vilar et al., 2016), and second as a possible contributor to depression (Cai et al., 2010, 2015; Hu et al., 2013). In the former, RA treatment over several months suppresses the HPA axis due to decreased ACTH secretion as a result of inhibition of pituitary gland POMC expression. The latter showed that approximately 3-weeks of RA exposure induces HPA activity, with increased CRH in the hypothalamic paraventricular nucleus (PVN) and decreased GR protein levels in the hypothalamus

im having problems with edits. my edits are disappearing. Stay! lol

Yes but it is very good notice that doctors/researchers are focusing also on Fin.
In fact, shoudn’t the foundation get in contact with these doctors?
Maybe they can share more info with us or want to work on some of our projects from other points of view.
We should learn from they as much as we can, and support them if needed.
Don’t you think?

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So you’re telling me that soyface is just a meme

I posted last week about possibly trying an SGB shot for us with the neuro issues. Thats supposed to make a huge improvement with people with PTSD.

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Hi @Tomas, we and the foundation are already aware of the work of these scientists on this issue and in contact with some.

Two of the authors of this paper had previously published an attempt to standardise symptom reports available on propeciahelp.com, clearly demonstrating the need for researchers to have an accessible data set regarding the clinical picture of the patients we support (and this is apparent for these scientists specifically).

The survey was designed with thorough regard to good practice standards after review of all published literature on PFS and all patient anecdotes on our site. It was thousands of hours of work. All ad-hoc symptoms included are clearly reported here, and it additionally contains a number of validated instruments widely used and understood by clinicians and scientists. It was beta tested with dozens of patients and feedback was implemented.

Given this is now the largest dataset in existence, there’s an easy way to support any PFS researchers: Pressing the bar graph icon on the top right of the screen on a laptop or desktop. Thanks :slight_smile:

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Thanks, I didn’t realize this treatment existed.

This is another hunch as well, but I wonder that if we do have some kind of PTSD, I think there could be different many versions of the problem. Maybe each version requires their or treatment or set of treatments. All well-functioning complex systems should mostly resemble each other but there are a million reasons they can collapse or breakdown or fail.

Sometimes complex systems do have the ability to reset and heal but maybe we have to push ourselves back into a position where we reset to equilibrium. IDK if this will be possible. It does make me wonder if there is something to the few guys who have recovered after taking a million different supplements but it is like alchemy. We’ll never really know why they got better and it might not work on others. There are risks to trying a lot of these things too.

Just making sure you don’t miss this, @Tomas.

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Of course not. I have seen the results showed on bars and at the end itbis presented as i suspected: in a very simple way, yes or not.
As said, I do not agree on some of the questions from the survey, because fornexample it is not possible to explain the crash, what I consider a key factor on PFS. Therefore, until this is well solved I am not going to complete mine, because qrong data would be used.

I hope you don’t miss this neither @Greek :slight_smile:

That’s easy to “solve” as it is mistaken. We agree with you that is a key feature that needs appreciation, and designed it specifically to account for the crash in standardised data throughout. It is disingenuous or a misunderstanding to say that is how it is “described”: The yes/no graph you mention isn’t describing the crash, it’s a tally showing one data point: How many people experience a crash - defined as an exacerbation or development of symptoms following cessation. Immediately below is graph dividing the experiences of remissions (or the lack of) amongst patients between quitting and the crash, so even on that single page it isn’t “described” as a yes/no. As well as across every symptom, we issued the standardised questionnaires across progressive time frames. Every one supports the existence of the post-drug worsening in some patients (see Quality of Life Impact ). We illustrate it with hundreds of other data points across the entire survey (including symptoms by time frame), and where that isn’t enough we include a text box to describe the onset of symptoms in patients own words.

It’s important to note what you are claiming is demonstrably untrue as this was a key aim for the year of design work going into this, and although I think this is more of an objection because you’ve made your mind up than any tangible reason, if this concern was genuine it’s worth attempting to clear this up. This data is now the only standardised data on PFS demonstrating the crash, and will be used to ensure greater appreciation that this is a frequent occurrence. This doesn’t preclude scientists further exploring the crash - simply, it asserts it exists. We met with a professor during the design phase who was also concerned the crash had not even been appreciated in medical literature after this long.

It surprises me you are personally unwilling to participate to help demonstrate this, yet are enthusiastic about publications like this and their theories which do not take the crash, or its existence as a feature of the syndrome, into account. Appreciation of the crash, which we can illustrate now thanks to those who have done, is important to counter many faulty assertions and assumptions found in many papers, including this.

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Aside from favouring indirect evidence over current direct evidence, it’s very troubling to see at the outset they are tying a “high nocebo effect” from Mondiani’s paper to PFS. This keeps happening and is entirely faulty. What they are referring to was a single study associating some degree of ED, decreased libido, and ejaculation disorders with prior information of the risk of these as a side effect. These were measured by self report at 6 and 12 months of use in a BPH cohort while on 5mg finasteride. This has nothing to do with PFS, a condition in which the majority (young men not in this cohort) experience a worsening and enduring effects after the drug, with many of the most severe cases having been on it weeks or much less yet experience progressive health problems.

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Be clear that I am not critiziting the work done. This is very helpful and I said already thank you for this. It seems that all of you admins take this too much personally, and you shouldn’t. I do think, however, that there is something that i do not agree with, and would prefer you to inderstand my point, but if you don’t, you may accept my comment and stop demanding me to fullfil the survey im every post, like if i was obligated to.
We are in democracy and I do want to think that people here is also free to say what we think, always inside of some moral limits.

Regarsing the point i do mot agree, is mot the same that you are reffering to. It is relared qith the questions of our symptoms one month later cessation. I had the crash one month after, should i put that i was feeling myself great like a god? Or like a shit? Because results are totally different and this will make results very confusing.
I am sure more people are in the same situation so i do prefer this to be solved before adding my data. If not, i have no any problem, but i won’t fullfil it.
I hope this is clear now, but i assume you won’t accept it, will keep pushing me, and at some point maybe until you consider me to be banned. What I hope this is not happening for the health of this site. Opinions should be respected.

You made a specific point regarding a simplistic yes/no presentation that I addressed. I do not take it personally - I would not bother replying if I was personally antagonised or you were breaking the rules. If you were excluded it would not be for not taking the survey and I have made no such demands - I’ve suggested it’s a way to help. I don’t know what you mean by we’re in a democracy but this is a private website provided by the staff’s effort and money to patients, not a country. If you were to be banned in the future it would not be for not personally choosing to take the survey, though. Asking people to take the survey (a major objective of the continued existence of this site), and trying to address stated concerns, is what we have spent a lot of time doing and will continue to. Certainly, not being able to suggest that, when there’s evidence that these authors tried to gain standardised data from this site, would be remiss in reply to supporting scientists efforts -especially when they are not currently appreciative of something apparent to both you and I.

Besides there being no grounds to, editing the survey after issue would invalidate the results. No standardised surveying the tailoring can ever be exact to every patient, or it would not be standardisation. For example, the IIEF (included in our survey and in PFS publications) is the gold standard of urological assessment for male erectile function, but has been criticised as it is not fully suited to someone who is not sexually active at all. Nevertheless, it is used widely in research and patients can make their closest estimation of an answer.

As we ask about a remission between cessation and the crash, you could select that you felt even better than before while going on to list your crash symptoms in the month time frame after cessation. If you state you felt even better than before in the multiple choice regarding remission, you give a pre-fin per-symptom assessment, and then state your crash symptom in the month-following window, I don’t see how that does not capture what you are describing while capturing the crash. I do appreciate a low percentage of cases are significantly outside this time frame, but they still have the pre, during and now timeframe that will clarify a broad progression, as well as stating they have experienced a crash and providing data on that at the outset. It is therefore not gathering incorrect data if a crash doesn’t fall in that time frame - it just means that isn’t when your crash was. One day out is not going to somehow break the aggregate picture in your personal case however. Some allowances have to be made for standardising an extremely complex situation into fixed research-agreeable time frames (predominantly 4 weeks).

Anyway, those concerns are now as addressed as they can be so it’s up to you. It would help us advocate, however - trust me.

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If I might make a suggestion @Tomas, perhaps you could think of filling out the survey as a way of acknowledging the vast amount of time spent working on maintaining the forum, running the projects that are making a difference and the time spent liasing with the scientific community and the costs involved in those things.

Refusing to take the survey based on a technicality when the importance and benefit is so great feels at best self defeating.

I don’t pretend to understand all of the details, but when the most knowledgeable that we have are advocating for a course of action, I think it’s worth doing it.

Please join us in trying to help. It is an hour of your time.

Possibility.

Effects of histamine H1 receptor signaling on glucocorticoid receptor activity

https://www.nature.com/articles/srep17476
“our results show a dual regulation of GR activity by the H1R”

Relevant cell types where the signaling convergence identified in our work may be relevant should express both H1R and GR, such as endothelial cells, dendritic cells, monocytes, neutrophils, T and B cells and microglia39,40. The existence of these cell types co-expressing both receptors suggests that our findings may have implications for regulation of inflammation in several systems, such as lung, skin and brain.

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You’re saying we’re soyjacks? How depressing

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Taking fin and developing PFS because r/tressless said not to worry is the ultimate soyjak moment.