Our Love Life Needs You © Nina Otulakowski August 2022
RxISK regularly gets enquiries about what can be done to find an answer to the sexual dysfunctions following SSRIs, Finasteride and Isotretinoin – PSSD, PFS and PRSD.
RxISK and Sharks outlined the likely Endgame. This outcome would be terrible – especially as its highly likely there is someone out there who has the answer we need but doesn’t know we have the problem they have the answer to. At least four things can be done to help avoid this outcome.
First: We need someone to build a Wiki into which everyone can load leads. See below.
Second: We need you and others to load targets like the ones below and other targets that look suitable into the Wiki, along with the emails of the researchers listed in the articles.
Third: We need you to start emailing these researchers mentioning the RxISK Prize which you (yes you) can play a part in getting for them. Doesn’t matter if a researcher gets emails from 20 different people.
You should not think of the RxISK Prize as being owned byRxISK – the criteria for the Prize means that we in RxISK have to decide if a breakthrough merits the Prize but the Prize belongs to everyone with PSSD, PFS, PRSD or anyone linked to them or just interested in the issues.
Everyone one of you can bring it to the attention of anyone out there who might have the winning formula – we have no favorites or favorite answers, so if the person you find comes up with the breakthrough s/he wins.
You can also ask everyone you email if they know anyone working for instance on prokineticin, VEGF, p53, p63 or p73 or whatever other targets you or others identify. It would be great if you can then feed these back to the Wiki, along with the names of researchers who are willing to engage and their emails.
Fourth: We need links to epigeneticists who can locate other epigeneticists. Someone needs to be able to tell all of us what the Baylor Finasteride Epigenetics study means, what an earlier Citalopram Epigenetics study means and what isotretinoin studies reveal.
This needs epigeneticists who are not blinkered by being told to look for leads linked to the serotonin or dopamine or depression markers that PSSD folk have been focused on or the neurosteroids that those with PFS have felt certain must be involved.
We need to know where the biggest effects are seen (it will likely not be on serotonin or neurosteroids).
We need to know whether an epigeneticist can spot an effect that could be conceivably linked to a switch mechanism – some protein that might turn processes on or off, as the key to PSSD, PFS and PRSD is not just an effect on sexual function but on some on/off-switch.
All the targets below have come from people like you, usually with no background in research or healthcare – not from any high-powered (but blinkered) researchers or from anyone in RxISK. You out there are almost certainly better placed than you think to find the missing link.
What these targets have in common is that they are proteins or enzymes that come in genetic isoforms which might predispose some of us to have a semi-permanent knock-out effect where others of us can tolerate taking SSRIs or finasteride or isotretinoin just fine.
Prokineticin was mentioned in the Holy Grail post and in RxISK Prize and Research Fund, with links to the work of one group of researchers working on this and their emails.
There are almost certainly lots of other researchers working on this. Finding them will involve looking up articles on Prokineticin or PROKR-1 or PROKR-2 and tracking
This looks such a promising protein – it mediates the emotional aspect of touch that seems missing in PSSD, PFS and PRSD.
Can you add more prokineticin articles and researchers?
Angiotensin Converting Enzyme 2 – ACE-2 – was also mentioned in Holy Grail. This is also fascinating because it looks like one of those things that ties thalidomide, SSRIs and at least isotretinoin together, along with cancer, Covid and sexual dysfunction.
There is far more interaction between ACE systems and serotonin, even in the brain, than there is with dopamine or other systems. The same applies to isotretinoin. And we differ in the types of ACE-2 receptors we have.
ACE-2 might explain the sexual dysfunction all three can cause along with the birth defects all three can cause. And it links to regulatory proteins like p63 below.
p53/p63/p73 in the epidermis in health and disease
Although p53 has long been known as the “guardian of the genome” with a role in tumor suppression in many tissues, the discovery of two p53 ancestral genes, p63 and p73, more than a decade ago has triggered a considerable amount of research into the role of these genes in skin development and diseases. In this review, we primarily focus on mechanisms of action of p53 and p63, which are the best-studied p53 family members in the skin. The existence of multiple isoforms and their roles as transcriptional activators and repressors are key to their function in multiple biological processes including the control of skin morphogenesis, regeneration, tumorigenesis, and response to chemotherapy. Last, we provide directions for further research on this family of genes in skin biology and pathology.
Proteins from the DNA Damage Response: Regulation, Dysfunction, and Anticancer Strategies
The genome is constantly harmed by spontaneous damage caused by endogenous factors produced by normal cellular physiological conditions such as bases alteration, aberrant DNA enzyme function or oxidation, and by a large variety of exogenous genotoxic factors . Cells have evolved a complex network of hundreds of proteins, named the DNA damage response (DDR), to ensure genome integrity and the expression of dedicated proteins to each cell type.
– in the last decade as part of anti-cancer therapy have been designed inhibitors of proteins that play a role as DDRs: DNA damage response inhibitors
– among these proteins, P53 plays a central role in managing cell proliferation, inducing cells with damaged DNA to apoptosis (death) and autophagy (eating parts of itself)
The Role of the p53 Protein in Stem-Cell Biology and Epigenetic Regulation
The p53 protein plays a passive and an active role in stem cells. The transcriptional activities of p53 for cell-cycle arrest and DNA repair are largely turned off in stem cells, but there is some indication that long-term stem-cell viabilitymay require other p53-regulated functions. When p53 is activated in stem cells, it stops cell division and promotes the commitment to a differentiation pathway and the formation of progenitor cells. In the absence of any p53 activity, stem-cell replication continues and mistakes in the normal epigenetic pathway occur at a higher probability. In the presence of a functionally active p53 protein, epigenetic stability is enforced and stem-cell replication is regulated by commitment to differentiation.
p53: key conductor of all anti-acne therapies
This review based on translational research predicts that the transcription factor p53 is the key effector of all anti-acne therapies. All-trans retinoic acid (ATRA) and isotretinoin (13-cis retinoic acid) enhance p53 expression. Tetracyclines and macrolides via inhibiting p450 enzymes attenuate ATRA degradation, thereby increase p53. Benzoyl peroxide and hydrogen peroxide elicit oxidative stress, which upregulates p53. Azelaic acid leads to mitochondrial damage associated with increased release of reactive oxygen species inducing p53. p53 inhibits the expression of androgen receptor and IGF-1 receptor, and induces the expression of IGF binding protein 3. p53 induces FoxO1, FoxO3, p21 and sestrin 1, sestrin 2, and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), the key inducer of isotretinoin-mediated sebocyte apoptosis explaining isotretinoin’s sebum-suppressive effect. Anti-androgens attenuate the expression of miRNA-125b, a key negative regulator of p53. It can thus be concluded that all anti-acne therapies have a common mode of action, i.e., upregulation of the guardian of the genome p53. Immortalized p53-inactivated sebocyte cultures are unfortunate models for studying acne pathogenesis and treatment.
– isotretinoin via increased p53 signalling apparently depletes the number and survival of p63-regulated sebocyte progenitor cells.
Isotretinoin treatment upregulates the expression of p53 in the skin and sebaceous glands of patients with acne vulgaris
Biopsies from back skin of patients taken before and after isotretinoin treatment show that the treatment significantly increased the nuclear expression of p53 in sebaceous glands, the p53 protein and gene expression significantly increased in the skin after isotretinoin treatment
– isotretinoin induces both p53-mediated autophagy as well as p53-induced apoptosis, depending on the dose and duration of isotretinoin exposure and the resulting magnitude of p53 expression.
– isotretinoin-induced expression of p53 not only promotes sebocyte apoptosis in human sebaceous glands as the predominant sebum-suppressive effect bit is also responsible for isotretinoin´s adverse effects [such as..]
Established a comprehensive mice model of persistent genital arousal disorder and investigated the mechanism of VEGF-ERK signal pathing in vaginal microvascular injury
These researchers believe they have obtained a valid model of PGAD on rats.
“Microvascular injury can significantly appeared in the model, and the VEGF-ERK signaling pathway is a possible mechanism involved”
Maybe this VEGF (Vascular endothelial growth factor, a signalling protein that promotes the growth of new blood vessels) is one of those things that would have something to do with anything
– is expressed and released by endothelial cells (the tissue that lines the inner surface of blood vessels)
– treatment target in cases of erectile dysfunction with vascular causes
– potential target for therapeutic intervention in depression
– overexpression of VEGF has been associated with tumor progression
– critical player in the neurovascular stem cell niche of the hippocampus
– SSRIs and SNRIs increase VEGF expression in the hippocampus
– Finasteride inhibits angiogenesis and expression of VEGF in human
– Retinoids are potent inhibitors of VEGF/VPF production by normal human Keratinocytes
– Thalidomide is a potent inhibitor of angiogenesis due to direct inhibitory action on VEGF secretion
– the two major isoforms of the p63 gene exert opposite effects on the VEGF gene expression
Off-Target Effects of Antidepressants on Vascular Function and Structure.
Impairment of the Retinal Endothelial Cell Barrier Induced by Long-Term Treatment with VEGF-A165 No Longer Depends on the Growth Factor’s Presence.
This seems to be a process to get to the bottom of what causes the persistence of an iatrogenic effect to the point of targeting a specific protein.
“The analysis of data from 3 studies describing serum leptin levels in PE patients before and after treatment with SSRIs showed that there was a significant decrease with leptin levels in PE patients after treatment”
There must be at least ten more plausible target proteins or enzymes like these out there.
We need someone to build a Wiki or maybe an APP that can help make all this happen. The gadget doesn’t need to be much more than a glorified spreadsheet with a user-friendly interface.
Something that makes it easy for anyone to find researchers to harass, places to upload articles, perhaps a place to comment back on responses from researchers or others, and a place to follow up researchers who have shown some interest – did they do anything, did it lead anywhere.
It would have sections for PSSD, PGAD, PFS and PRSD.
We need to be able to host articles on prokineticin or whatever. Ideally, this would be done in a way that has a high SEO so that people looking for prokineticin or leptin or p53 find us.
A place where researchers might also start coming off their own bat looking for evidence of links between things like p73, VEGF and serotonin or isotretinoin not easily found elsewhere.
The Wiki/APP would host a template message/letter giving details about PSSD, PFS and PRSD and the Prize that can be downloaded, modified and sent to researchers.
Please get in touch if you can build one of these.
Crikey now have to study all this. The only thing I know about The protein p63 is that it’s a Tumor Suppressor and p63 is mediated through ACE2 receptors and the Covid ‘vaccines’ spike protein binds to ACE 2 recepors. But I got thrown off this when Karen kingston said – to the effect – the whole mRNA vaccine being given to the public is not true – what people are getting is toxins via a nano lipid carrier and she certainly has shown a patent for this. Seems to me though, it’s still very much unclear what is in these ‘vaccines’ and therefore what is actually going on. Harms and terrible regulation issues, freedom of speech are certainly being shown in the Pfizer trial and FIOA documents. So are you saying this p63 is involved in erotic stuff as well as cancer?
Intermittent Fasting has been shown to successfully reverse diabetes, metabolic syndrome, and pharmaceutical drug and processed food damage.
I think the idea is that while the body isn’t busy digesting food, it can work on healing other parts.
It’s the type of approach that can be independently tested by the person themselves.
It doesn’t cost anything – but this could also be a problem.
Your donations are needed to fund scientific research into post-SSRI sexual dysfunction (PSSD) and other enduring sexual dysfunctions. The aim is to better understand the biology of these conditions and hopefully find treatments.
£17,036 raised of £50,000 goal
£13,925.15 to Professor Luisa Guerrini on 26 July 2022.
Transaction fee of £5 on 27 July 2022.
What I think you need is a template copy of the basic Wikipedia/Wikimedia software. This one:
MediaWiki 1.35.7 – current long-term support (LTS)
It is a wiki -that not surprisingly- looks like and operates exactly the same way as Wikipedia. Also, it is free to down load and use. No real building required, just a bit of customising.
It can be customised with your logo top left instead of the WP globe of letters. Editors can be password resricted. Trusted editors can be given Administrator passwords to do general house keeping etc. An important point is a lot of people already know how to use this type of wiki.
It must be a decade since I messed around with this software pakage and so can say with confidence that it is relitivly easy to do. Whoever looks after your website needs only to instal L.A.M.P. (also free) onto a server (or virtual server) and load MediaWiki on to it and you’re good to go.
I’m not in a position to customise it for you (such as replacing their logo with yours) but the thought has come to me that someone in the Wikipedia/Wikimedia community may be willing to help with these less obvious to accomplish tweeks ( I can link you to where they dwell). By and large they seem to score high in alturisum (they are volunteers after all) and alway willing to advise.
As an example of what other have done with this Wiki temple see:
Can you do this for us?
A Wiki is not something to be rushed into without some prior consideration about features, so I suggest an article first about determining what RxISK (and we as potential contributors) need.
Having an ‘open platform’ is great but too ’open’ can invite vandalism etc. So some control needs to be built in. It also needs to be relatively easy to maintain and administer. Reinventing the wheel and learning the hard way will ensure a short life to any half-baked wiki project. So I think there should be some sort of minimum specification or requirement put on paper for us to see first.
Although I am most familiar with the MediaWiki wiki, RxISK is a small orgainzation and an all-dancing-all-singing wiki may not be the best choice. Whilst starting with a blank sheet and building a wiki from scratch is not a practical nor realistic option.
So for those here interested in looking and considering alternitive off-the-shelf or turn-key Wiki engines I point them to this comparative list of features:
From the point of view of being able to customise it ourselves, the free version of the BlueSpice MediaWiki looks IMO to be best. For those that intend to help out with this project there are some
Video-Tutorials to give an indication of user friendliness. It looks easier to customise than my previous suggestion of MediaWiki 1.35.7
I’m very conscious of what is easy for me may not be easy for someone else and if it is not easy for contributors to RxISK to use it will just become another ”well it seemed like a good idea at the time” project.
Everything else one needs to know about the BlueSpice version can be found here:
For my part I would be happy to spend a few hours each week transferring content over and creating pages and so forth. I can also edit images and upload them. We could have Forum & Help Desk page with a ToDo List where such requests could be posted if the contributor can’t do it themselves.
I have only installed WikiMedia engines on desktops.
You need at least an IT professional who knows how to set up a server properly, located in a safe country (whose government won’t shut it down) with automatic backups. All the while ensuring you have control and own the domain name and so on. Then nominate someone to be the Main Administrator and gate keeper. This is because being open for anybody to edit means anybody can create havoc too. So someone will be needed to block IP address of any trouble makers. After that though, we should be able to do the rest…
This leaves me with three questions.
1) It would be interesting to know how many other people here already know how to edit, upload images etc., to Wikipedia and so feel they can hit the road running?
2) Would a Wikipedia style lay out be more familiar and so encourage more people to contribute?
3) Should we choose some other Wiki engine.
So what about a page on RxISK within WordPress
with a forum where people submit target proteins and papers and feedback on researchers contacted
which is moderated in order to avoid dud or spam material being added
and the plausible stuff is posted
I have no hands-on experience with WordPress, you will have to ask someone else. Would imagine though that it is far more user frendly.
Having mulled things over, I think RxISK’s target contributors
( we ) need not so much the best from a geeks point of view (which would need some oversight from a IT professional) but something very easy to use.
I’ve had a quick look at WordPress and there are now some Content Management System plugins available for small enterprises. For the non-technically minded, the main functional difference of a Small Enterprise Wiki is that they can’t be scaled up to support countless contributors. However, their smaller less complex engines allow their user interface to (sometimes) be made more user friendly.
Now, I have only just come across this Helpie Knowledge Base WordPress plugin but it appears to be capable of doing everything DH is envisioning on just one site- and it happens to be a wiki.
It can configured so that content added by new users needs to be approved by a moderator but trusted editors can work in real time and so grow and expand the site quickly. This gets over my concern that with open public platforms the moderators can get overwhelmed and feed up if they have no gate-keeping controls and editors get frustrated at having to sort out other peoples mess instead getting on building up the site.
Another advantage is that the Helpie team provide the tech support for all the software issues and of course WordPress has a good reputation as a reliable platform. Also, before any commitment is made, we can spend a week playing around with it to test its efficatousness. Here’s Helpie’s blurb about their plugin…
Helpie Knowledge Base is a self-hosted knowledge management software used as a plugin with WordPress CMS. It is a reliable and affordable tool for knowledge management for startups and small businesses. With Helpie, you can quickly create and share knowledge within an organization. It is also a great tool for creating a collaborative knowledge library for any use case like an internal team knowledge base, customer helpdesk, or a public facing wiki website.
It works with WordPress, which is beginner friendly platform. You can create your knowledge management website with Helpie and WordPress. Here are some resources to help you.
1. Create a WordPress website
2. Installing and using Helpie on your WordPress website
Best Features of Helpie Knowledge Management Tool for WordPress CMS
Content control and Access management – you can control who can add, edit, publish, and approve content. Access can be given to User Groups (roles) and individual Usernames.
Front-end editor – a text and media-rich visual editor like the one Medium.com has and with it you can add any type of content like text, images, GIFs, Video, etc.,
Revision System – can see the different versions of edited content and choose the best version to be published.
Advanced Styling and Branding – every part of Helpie knowledge base can be customized to match your brand.
Integrations -Since it uses WordPress, it leverages the ability to integrate with many other tools available.
* It is a fully collaborative knowledge management tool, and it promotes knowledge sharing.
* You get complete control of your knowledge repository.
* It is a very affordable solution
* Can have an unlimited number of agents and users
* Can be integrated and customized to fit any of the use cases and needs like a CRM, Ticketing system, HR system, etc.,
* Comes with all required knowledge base tools
* Pre-made demos for knowledge management system examples
People have inhibitions because it uses the WordPress platform. But using WordPress is actually an advantage.
Helpie Knowledge Base Pricing
Helpie Knowledge base has 3 pricing plans based on the number of sites you need. All 3 plans have full features.
There is a 7-days free trial for Helpie Knowledge base.
A Proposed plan.
Have a sysop at Data Based Medicine Global Limited instal WordPress on one of their servers.
Then instal the Helpie plugin.
Both of these tasks (unlike installing Wikimedia) are run-of-the-meal-jobs to a sysop.
After making copies of the master passwords he can give one to a RxISK volunteer who is willing to be an Administrator. He or she (the new admin) can then grant admin rights to other volunteers. [ I am willing to be an admin]
This involves mainly clicking boxes and so on.
Before the Wiki goes public, the legal stuff like TOC & Privacy polocies need to be cut & pasted , bespoken etc., and then locked so that only the System Administrator at Data Based Medicine Ltd can modify them.
Then the volunteer administrators can take over and give the wiki structure.
Set up the main page (home page) welcoming visitors and outline RxISK’s mission.
Set up some main categories into which like pages can be grouped.
So for instance, the sections and pages on PSSD, PFS, PRSD can be in a category of syndromes (for want of a better term).
Pages on proteins and enzymes can be added to the category ’Targets’
Direct links to these categories can be then added to the main page to aid first time visitors navigate quickly.
Activism, such as Emailing researchers and recording responces from emails sent, can all be grouped in a category.
I found organising information like this soon becomes instictive and thus gives the wiki systems the advantage over other collaborative information management systems.
Once we have a basic structure laid out it will be easier for editors to see where is the best place to add each of their contributions in an organised way and expand the structure themselves as the need arrises.
Two heads are better than one when it comes to structuring sensible in a way that going to makes sense to others.
Since there is no software coding to do, I think just a few of us could set up the wiki just using what we already know. Having several administrators also means that it will be easier to keep abreast of things as house keeping can be done whenever we have a few minutes spare thru out the week.
Anyway I’ve said enough and it is really up to the will of others as well, to help make this happen. A resource on this neglected area of medicine, one would all agree, is badly needed. I can see the possibility, that done well, this resource and knowledge base will develop it own momentum as word of its existence spreads exponentially through cyberspace, attracting a flood of visitors and hopefully more…
What do people think?
This has all been very helpful and a few of us are thinking about how to do it.
There does need to be some gatekeeping.
Noticed you have asked for help with a Wiki on twitter too, again without being specific.
Have you thought of seeking a ‘Wiki sysop’ (rather than just some help) on:
The LinkedIn Volunteer Marketplace: Connecting Professionals to Nonprofit Volunteer Opportunities
Or do it via VolunteerMatch
Dear Dr.Healy & Co.
Creating an “encyclopedia” on PFS/PSSD/PRSD is a good idea. At the moment, the information is scattered throughout the scientific literature and the Internet. This can be very confusing for a researcher because it can be an additional barrier for someone who wants to learn about this syndrome. However, I think we need to be very careful to avoid common pitfalls. As you mentioned in some of your blog posts, the PSSD/PFS/PRSD community is full of scammers trying to make money out of people’s desperation. If such a tool gains popularity, the vultures will start circling. Malicious people will leverage such a tool to gain credibility. For all these reasons, I think we need to keep a close eye on the content published on such a tool. Every piece of content should be reviewed by people we trust. If we can closely moderate the content, that would be a great idea.
I also wanted to share a potential lead. Maybe this lead has already been proposed. Let me know if it has. Below I describe the reasoning behind it. English is not my native language, so please bear with me if a wording is strange :
A GOOD APPROACH: ISOLATE/EXPLAIN
In one of your last blog posts, you presented a good approach of isolating a specific symptom and explaining it : to start with a specific symptom in order to explain the bigger picture. I agree this is the best way to avoid dispersion and establish a clear goal that everyone can focus on. One symptom you mentioned was genital numbness, as it offered us a very specific target. I agree that the explanation of genital numbness will lead us to a more comprehensive explanation. However, although the explanation of genital numbness is less complex than that of anhedonia or low libido, I still think that this specific symptom is very complex and can have a wide variety of causes. In fact, genital numbness can be caused by peripheral nerve damage, altered gene expression (e.g. the one that codes for prokineticin as you mentioned), central nervous system… Most importantly, genital numbness can be caused by the failure of different organs. Therefore, we have to take into account different organs in our reasoning, which adds a lot of complexity. Therefore, I think that genital numbness remains a very difficult symptom to study, while being less complex to study than anhedonia or low libido.
WHAT OTHER SYMPTOM COULD WE FOCUS ON?
A symptom reported by people with PFS/PSSD/PRSD that has been evaluated in an observational study might be a good symptom to focus on. Many people have reported oligospermia, especially early in the syndrome. They commonly refer to this symptom as “watery semen” because oligospermia usually manifests itself as a different semen texture (notably less white). A reduction in sperm count has been observed in patients taking SSRIs and finasteride during intake (DOI: 10.1016/j.fertnstert.2013.07.2000). Interestingly, this symptom was described in an observational study in patients with PFS : androgen levels and semen parameters among former users (doi:10.1001/jamadermatol.2014.3234). Despite the obvious limitations of this study (no control group, selection bias …), it gave interesting results: 16% of patients with PFS had severe oligospermia. The study did not have a control group and therefore compared this percentage to data from a WHO study that assessed sperm count in the general population. 3% of the general population has oligospermia. A problem with sperm motility was also observed in this study among former finasteride users. Despite the limitations of this study, and given the frequency with which this symptom was reported in the PFS/PSSD/PRSD community, we can assume that it is a symptom of PFS/PSSD/PRSD.
WHY IS THIS SYMPTOM RELEVANT?
What is interesting about this symptom is that oligospermia mainly involves one specific organ: the testis. However, semen does not only come from one organ, as the prostate is also involved, spermatozoon production involves the testis as this is where spermatogenesis takes place. Of course, spermatogenesis is also regulated by endocrine pathways. The secretion of FSH will induce the secretion of Inhibin by the sertoli cells which will in turn reduce the secretion of FSH. As you can see, the process of spermatogenesis is controlled by a feedback loop involving the hypophysis and sertoli cells. I have simplified the mechanism that controls spermatogenesis here, there are other hormones involved in spermatogenesis other than FSH or inhibin but these are the main ones. If you complain to a doctor about infertility, FSH is normally the first hormone he will check. A decrease in FSH compared to a control group has been observed in patients taking finasteride or SSRIs (Finasteride: DOI: 10.1016/s0039-128x(98)00005-1 / SSRI: DOI: 10.1097/JCP.0b013e31817e6f80). This could be an explanation for the decrease in sperm count observed in SSRI or finasteride users while taking them (DOI: 10.1016/j.fertnstert.2013.07.2000). Unfortunately I could not find any observational study evaluating FSH and LH in patients with PFS/PSSD/PRSD compared to a control group. I have only found forum reports of patients with low FSH and LH, but due to the obvious selection bias, it is difficult to infer whether this is a common hormonal marker of PFS/PSSD/PDSP. It would be interesting to have such data from a cohort of PFS/PSSD/PRSD patients compared with healthy patients. I am not saying that PFS/PSSD/PRSD is due to a deficiency of FSH or any other hormone, but rather that explaining why some patients experience oligospermia after discontinuation of treatment may help us understand the overall picture, just as explaining genital numbness would help us understand the underlying mechanism that leads to PFS/PSSD/PRSD.
WHAT TARGET COULD CAUSE SUCH SYMPTOMS?
We can look for a target that could explain both the “emotional” symptoms and the oligospermia, assuming that this problem does not originate from the endocrine pathway (e.g. low FSH). By looking for proteins that are both expressed in the organs that can trigger such symptoms: the brain and the testis. I used the following tool: the Human Protein Atlas (https://www.proteinatlas.org/). The Human Protein Atlas is a project that aims to map all proteins in cells, tissues and organs. It allows to identify gene expressions shared between different organs. For example, we can search for a gene expressed in the brain and in the testis. Among all the genes expressed in the brain and testis, some seem to be “genes of interest”: KISS1, GPR54. The KISS1 gene encodes the Kisspeptin protein while the GPR54 gene encodes a G protein receptor that binds to Kisspeptin.
WHAT ARE THE KNOWN FUNCTIONS OF KISSPEPTIN IN OUR BODY?
Kisspeptin is involved in several reproductive processes. The best known role of Kisspeptin is to control the secretion of GnRH by increasing its concentration. Kisspeptin “activates” the GnRH neuron, which leads to the release of GnRH that induces the release of FSH and LH from the hypophysis. A role for Kisspeptin has also been established in the initiation of puberty. Mutation of the gene coding for the Kisspeptin G protein receptor leads to a syndrome called hypogonadotropic hypogonadism. These examples are far from an exhaustive illustration of the role of Kisspeptin in the human body but highlight the endocrine role of Kisspeptin. Kisspeptin receptors have been found (using immunological tools) in several regions of the brain, suggesting a broad role for this protein.
Here is the interesting part. A recent study highlighted the involvement of kisspeptin in sexual behavior. According to the study, “kisspeptin administration increases limbic brain activity specifically in response to sexual and couple stimuli”. A cohort of 29 healthy patients were evaluated when given kisspeptin versus no kisspeptin. When given Kisspeptin, participants showed a higher response to sexual and couple-bonding stimuli. In addition, “Kisspeptin enhancement of limbic brain structures correlated with psychometric measures of reward, drive, mood, and sexual aversion, providing functional significance”. Full study: kisspeptin modulates sexual and emotional brain processing in humans (https://doi.org/10.1172/JCI89519). A video where one of the lead authors, Waljit S. Dhillo, presents the methods and results of the study can be found here: https://www.youtube.com/watch?v=nMtSSCV1yvY . What is interesting about their finding is that kisspeptin appears to be involved in “romantic love”, as couple-bonding stimuli are enhanced when kisspeptin is administered. The lack of ability to feel love or form emotional bonds has been widely reported in individuals with PFS/PSSD/PRSD.
Interestingly, kisspeptin receptors have also been identified in the testes using immunological tools (immunocytochemistry), suggesting a role in testicular function. Waljit S. Dhillo and colleagues have also published a paper on the role of kisspeptin in the testis (http://dx.doi.org/10.3390/ijms21082958). However, there is some evidence that kisspeptin is involved in sperm function, but its exact role is a matter of debate. One observational study found a correlation between semen quality and kisspeptin in seminal fluid (https://doi.org/10.1155/2019/5129263). We can speculate that the decrease in semen quality observed in PFS/PSSD/PRSD may be due to a dysfunctional mechanism involving Kisspeptin.
Reading the above will certainly leave readers with more questions than answers. My knowledge in these areas is limited and an informed opinion would be welcome. The main symptoms of PFS/PSSD/PRSD are: low libido, decreased genital sensation, erectile dysfunction, weak or pleasureless orgasms, abnormal semen, flat emotion or anhedonia. Some of these symptoms seem to correlate with the role played by Kisspeptin in our body. Perhaps a damaged mechanism involving Kisspeptin may be a cause of all of the symptoms exhibited by people with PFS/PSSD/PRSD. There are many hypotheses: conformational change of a receptor, desensitization of a receptor, a subset of neurons undergoing death, an autoimmune reaction targeting an antigen involved in a Kisspeptin mechanism… Anything that someone can imagine. A starting point could be to assess the level of kisspeptin in serum and semen of patients with PFS, PSSD, or PRSD and compare them to a control group. An informed opinion might be of interest.
Thanks for these thoughts. Kisspeptin is a great addition to the proteins and other targets we should be checking out. And you’ve also outlined some great ideas for people interested to chase other leads
Thank you so much for suggesting keeping an open mind about the etiology of PSSD/PRSD/PFS. As most of the time discoveries are surprising and unexpected!
Google Docs seems to have a suggestion feature which would let others add to documents after you accept their changes
I’m in a couple of desk based research groups, putting out literature reviews concerned with mRNA LNP pathology. There aren’t many receptors these don’t bind or initiate pathologies on.
We are particularly interested in tumor suppressor depletion like p53 and p63 & BRCA1, il16, th17 & VEGF stimulation.
But quite often our frequently TCM based therapeutics are very good for your circulation, eg recovery from ischaemic strokes. And all your circulation at that. My forthcoming review is about icariin and the biochem & signalling, dosing etc.
Aka horny goats rue, helps the herd…
Subscribe and watch this space.
If I find anything for ssri seratonin repair etc then will let you know!
Thanks for this – would be great to get