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

Abstract

Finasteride (FIN) is the prototypical inhibitor of steroid 5α-reductase (5αR), the enzyme that catalyzes the rate-limiting step of the conversion of progesterone and testosterone into their main neuroactive metabolites. FIN is clinically approved for the treatment of benign prostatic hyperplasia and male baldness; while often well-tolerated, FIN has also been shown to cause or exacerbate psychological problems in vulnerable subjects. Evidence on the psychological effects of FIN, however, remains controversial, in view of inconsistent clinical reports. Here, we tested the effects of FIN in a battery of tests aimed at capturing complementary aspects of mood regulation and stress reactivity in rats. FIN reduced exploratory, incentive, prosocial, and risk-taking behavior; furthermore, it decreased stress coping, as revealed by increased immobility in the forced-swim test (FST). This last effect was also observed in female and orchiectomized male rats, suggesting that the mechanism of action of FIN does not primarily reflect changes in gonadal steroids. The effects of FIN on FST responses were associated with a dramatic decrease in corticotropin release hormone (CRH) mRNA and adrenocorticotropic hormone (ACTH) levels. These results suggest that FIN impairs stress reactivity and reduces behavioral activation and impulsive behavior by altering the function of the hypothalamus-pituitary-adrenal (HPA) axis.

https://www.ncbi.nlm.nih.gov/pubmed/31752360

6 Likes

Excellent find, @Sibelio.

Is really explains so much of what many PFS users find - emotional flatness.

I wish I could see the full text, or alternatively have @awor or @axolotl make sense of this (I assume they both have access).

1 Like

Yes, but I don’t think it explains it (although I haven’t read the full paper yet), it just demonstrates it. :slight_smile:

Just browsing the Wikipedia article on Corticotropin-releasing hormone (CRH) , it says,

  1. Increased CRH production has been observed to be associated with Alzheimer’s disease and major depression (One positive I suppose…)

  2. Recent research has linked the activation of the CRH1 receptor with the euphoric feelings that accompany alcohol consumption.

Reports on a lack of euphoric feeling from alcohol consumption may well be explained, at least partially through this mechanism.

2 Likes

Apparently levels of CRH and ACTH seem to be related to allopregnanolone levels.

https://www.ncbi.nlm.nih.gov/pubmed/11513484

Here’s the article - I’m currently doing my PhD so I have access to whatever you need.

5 Likes

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.

3 Likes

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.

4 Likes

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

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030330/

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

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831734/
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.

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?

1 Like

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.

2 Likes

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:

6 Likes

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.

1 Like

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.

3 Likes

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.

1 Like