Hello again! I'm about 2 years on hrt, with unfortunately rather poor feminzation. I have been on monotherapy and have noticed some response to the CDG/Methylated B Vit/Magnesium supplement combo I see some people trying, however, not enough to actually get my transition moving in the direction I'd like.

About one month ago I reduced the amount of estrogen I was taking from 4mg of IM EV every 5 days, to 2mg. This was done due to hopefully reduce the amount of metabolites that were potentially accumulating in my system. While this reduction doesn't seemed to have meaningfully *harmed* my transition, I also haven't noticed any qualitative or quantitative shifts in feminization. I continue to be hopeful that there is a solution for why my transition has progressed how it has but I am beginning to suspect that metabolite clearance issues are not the culprit. At some point I'd like to get WGS and a DUTCH test done to get a better picture, as well as more properly examine metabolite clearance issues, but presently cannot afford them.

Does anyone have any idea what avenues might be worth exploring?

Guys why don't people with pssd talk more about this^

Pls let me know more about your experience with stimulants and dopaminergics!

This might seem paradoxical however two of my most prevalent PFS symptoms are the excessive need to urinate whilst also holding onto excessive amounts of water weight.

I seem to have to pass urine almost just after consuming fluids. It’s as though the water isn’t held or absorbed into cells. However with this level of water loss, you’d expect my water retention to be non-existent. However, this is the exact opposite.

Following on from Dr Powers’ theory, could it be that the high concentration of metabolites in cells is causing water imbalances. Perhaps the metabolites act similar to consuming lots of salt, which usually causes excessive urination. However due to metabolites being reabsorbed due to levels of specific gut bacteria and the high levels of metabolites within cells, existing water weight is excessively held simultaneously, even potentially outside the cells due to circulating metabolites (except no more water can be held upon drinking). In a way you could compare this to essentially having salty cells (metabolite overloaded cells), therefore we lose water but also hold water in the body as the metabolite levels never actually drop (whereas salt would) causing the body to constantly attempt to balance this out with water.

I’d be very curious to know Dr Powers thoughts on this and whether upping water intake would help flush out the metabolites or whether there is any other way to decrease water loss to support cells in excreting the metabolites cumulatively over time.

Guys I am 20. Its been 5 months after finasteride and my only side effects is erections. And ıt was getting better with time, I saw full erections, full orgasms. Maybe that was a window but I thought I recovered and I used topical Minoxidil 1ml to my scalp for 2 days, and I used ketoconazole 1 time for my scalp health because it was burning. I wake up today, with weak morning erections, cannot get full hard its like 5/10. I think it will turn normal , I HOPE. I didnt have problem minoxidil before finasteride. So if you considere taking finasteride, your hair and your penis will be bad together

Hello everyone,

*THIS IS NOT JUST ANOTHER PETITION*

The amazing Kim Witzciak recently launched a website serving as a petition for those with PSSD (and other SSRI injuries) to sign and document their experiences of harm with these medications.

It serves as a central place to show the volume of people being injured by these drugs. To convince those in power that these injuries are devastating a massive population size, deferring to Reddit groups won’t cut it/isn’t official enough. As such, this petition will be the MAIN SOURCE of reference when used to show the people we need to convince this is ruining/ending lives.

Please sign this, mention your experience and age if you can!!

We have SUCH power in numbers if we can all band together!

Hey guys,

I need your advice please.

Before HRT my T was around 9,..ng (high) and my SHBG was 68nmol (High for a T-dominated System). After HRT (first Gels, then Injections with EV, every 3 days), my E is around 450pg/ml and my SHBG is still 68nmol, my T is lower than 0,20 ng (undetectable)

My question: WTH? my LH/FSH is also pretty low.

Thank you and have a good start of the week <3

I have PSSD, and the worst symptoms are depression, anhedonia, and akathisia like symtoms, I feel internal agitation and an inability to relax, and I have dystonia like symtoms like a strong tightening of all the parts of my body, especially the neck and head.

My question is for those who have tried keto.

I started the keto diet 17 days ago. I experienced the keto flu during the first few days, and it has gradually started to subside, but I still don't feel well.

My agitation, muscle spasms, and the constant feeling of inner body tension have gotten worse. I also feel more fatigued, my face looks paler than usual, and my depression has become much worse.

The only thing I've noticed a slight improvement in is my anxiety, especially while walking. However, I still feel much more exhausted, and my depression feels deeper than before.

Should I keep going and give my body more time to adapt, or does this suggest that keto just isn't the right diet for me?

Introduction:

Hi there, I’m new to the subreddit here, and looking for help from anyone who has found themselves in a similar situation. Despite my extensive suffering over the last 5 years, I have spent very little time perusing the forums and exploring various protocols / therapeutic efforts - predominantly as I believed my phenotype was pathologically “different” to many of those inflicted with this torturous condition - I also believed that I had found a long-term solution, and I felt at the time that most hormonal / supplemental therapies would not be beneficial for me. I have recently tried to familiarise myself with the fantastic work of Dr. Will Powers, and his efforts have provided me with some hope that there may be a breakthrough imminently. Therefore, apologies in advance if I am unfamiliar with some of the recent updates or theories on the pathophysiology of this condition. 

This will be a lengthy post as I have never formally posted on any PFS forum to date, so I will attempt to be as detailed as possible, as this may help someone else avoid the potential pitfalls I have encountered. When sifting through this subreddit and other forums, I have previously found difficulty in ascertaining how various medications and treatments have helped patients, and therefore I am giving a thorough step-by-step account of my experience, in the hope that this may benefit patients / research in the future.

I appreciate that most of what I say is conjecture; and will be difficult to comprehend without the lived experience of this nightmare. I will refrain from extensively referencing the limited literature that is available, given the widespread uncertainty regarding the pathophysiology of this condition. I believe there are countless mechanisms at play which may account for the wide array of symptoms experienced by PFS patients. 

Reminder: Remember that this is an incredibly complex illness with immense variation between phenotypes. This is just my experience. 

TL;DR. 

I am a 28 year old doctor (previously well) with a 4-5 year history of very severe cognitive / neuropsychiatric sequelae of PFS, likely secondary to severe dysregulation / downregulation of GABA-A receptors, possibly as a consequence of impaired neurosteroid signalling (allopregnanolone + ?other neurosteroid modulators of GABA-A receptors). Previously have experienced a major deterioration in symptoms (in the long-term) after a trial of Zopiclone (GABA-A agonist) and to a lesser extent, alcohol (GABA-A activity); and partial recovery with strict long-term ketogenic diet and avoiding further GABA-A activation. 

I recently have had a further stepwise deterioration in symptoms despite continuing with the same protocol I have used for the last 4 years, and I cannot identify what has changed. Therefore, I am looking for anyone who has had any improvements with any therapeutic efforts exploring this potential pathological mechanism - which may be unique to me and a minority of the cohort here. 

Finasteride - 2019-2021. Stopped and restarted. 

As a 21 year old medical student, I first started noticing hair loss in 2019. This was on the background of a significant family history (on both sides). I started taking 1.25mg oral finasteride daily and applied topical minoxidil 5% twice daily. This was extremely effective at slowing my hair loss. At the time, I failed to recognise any potential side effects - but with the benefit of hindsight, can reflect and identify a significant personality change whilst on the drug at the time. I started to experience significant anxiety, became irritable and confrontational with friends / family and, ultimately after 13-14 months on the drug - developed severe insomnia that was refractory to any medical treatment / psychotherapy. This was also associated with an inability to reach a “euphoric state” from alcohol (which would have happened previously) despite drinking increasing quantities of alcohol (entirely irrelevant at the time but is now relevant when linking this with the potential pathophysiology). I did not experience any sexual side effects during this period - other than potential loss of libido secondary to my heightened sympathetic state. 

After exploring other potential causes, I stopped taking finasteride at this point in 2020, and felt 100% again immediately - my sleep recovered to baseline, my anxiety significantly improved over the next week and I was left perplexed at how this all instantaneously resolved on cessation of finasteride (Insomnia was not a recognised adverse effect of finasteride at the time). This should be the end of my story. 

Alas, after an acceleration of hair loss in the following months, I decided to experiment again with 1.25mg oral finasteride and within a day, started experiencing profound insomnia. I had not heard of PFS at this point, and decided to continue taking 0.625mg every 2nd day - subtherapeutic for hair loss, but I was able to tolerate this without significant side effects. After a few weeks of this, I stopped taking finasteride in May 2021 due to a recurrence and progression of insomnia - I have not taken another dose of any 5-ARI since then, but have never recovered. Unfortunately, my symptoms have worsened considerably since. 

2021-2022:

Initially - my only symptom of PFS was insomnia. I experienced a very similar sleeping pattern in the months after cessation - to when I was on the drug. Early morning wakening was a hallmark (often pathognomonic of depression - ) and it felt like my quality of REM / Deep Sleep was significantly impaired. My sleep “architecture” as such appeared to be permanently damaged. This got progressively worse over a period of 8-9 months before I sought help. This coincided with my first clinical placements as a medical student and I tended to agree with the hypothesis that this insomnia was likely caused by stress and environmental factors as opposed to an iatrogenic cause. As the months progressed, my sleep pattern continuously deteriorated to the point where I would sleep 1-2 hours a night for weeks on end. I became increasingly anxious over these months, and would ruminate over everything. Interestingly, my sleep would drastically improve after drinking alcohol, and I would be considerably happier and more relaxed in the 1-2 days after drinking, before the poor sleeping cycle restarted. 

I trialled a variety of treatments for insomnia during this period and have summarised their effects below. These may be of some benefit to those suffering from PFS related insomnia. These are categorised in no particular order. 

CBT for Insomnia - No discernible benefit despite learning good sleep hygiene practices. 
Body scanning / meditation / breathwork: Relaxing effects but no improvement to sleep. 
Magnesium glycinate - mild improvement but not substantial enough to improve sleep by itself.  
Mirtazapine - some improvements to sleep, I personally experienced side effects such as dry mouth, increased appetite and possible ?akathisia-like symptoms - these all resolved on cessation of medication. It reportedly has effects on sleep architecture so some people may find benefit. 
Phenergan: I have actually used this in the long term for insomnia. Intermittently I have experienced drowsiness / hangover effect, but otherwise well tolerated and have experienced improvements to sleep with this. 
Melatonin: Minimal effect.
Amitriptyline: Very brief trial - did not experience benefit with this. 
Zopiclone / Zolpidem: see below. Very bad idea in the long term. 

TRT (Testogel): This was a short trial (3-4 weeks) after my initial consultation with an endocrinologist. It did nothing for my symptoms - but likely was too short a trial to draw a meaningful conclusion. This trial has not been repeated as I believe it doesn’t address the core pathology at play. I possibly noticed increased libido during this time, but was worried about the long term sequelae and self-ceased this. This was a year or so prior to the development of sexual symptoms (see below).
 
GABAergic supplements:  Taurine, Valerian Root, GABA, Lemon Balm - I believe these to be potentially safe options for sleep / anxiety in phenotypes similar to myself. These each demonstrate varying activity in GABAergic transmission and may / may not contribute to downregulation / tolerance at the receptor site. (Please refer to the first link in the discussion section). I did not trial these supplements during this phase but have since experienced significant short term benefit from these in recent years. 

Glycine: Have derived short term benefits from this at various timepoints - improves sleep and takes the “edge” off the all-consuming anxiety associated with this condition. 

2022: Major stepwise deterioration likely secondary to Zopiclone (likely further rapid downregulation of the previously dysfunctional GABA-A receptor).
 
Prior to this time, alcohol was the most effective agent in “improving symptoms” in the short term. I started to take Zopiclone (GABA-A agonist) nightly for sleep - in total for roughly 3 months straight. Immediately this substantially improved sleep, I noticed a significant improvement in anxiety and was feeling back to 100%. I tried to stop this after a two week period but immediately was unable to sleep again - similar to the previous 8-9 months, so I continued to take it every night - without realising the possible deleterious consequences I was about to incur. 

Within a few weeks of persistent once daily Zopiclone use, I developed a plethora of new symptoms seemingly on a weekly basis, some of which I did not believe were possible. This included constant panic attacks and sympathetic overdrive, severe cognitive dysfunction, significant memory loss, dissociation and depressive symptoms, neuropathic pain and parasthesia to name but a few. I had not experienced any of these symptoms prior to Zopiclone use. These occurred in a very distinct, discrete, stepwise fashion - given the presentation and precipitating factors - likely consistent with GABA-A receptors actively downregulating over a period of 3 months or so. This was the very definition of a nightmare - and thankfully - this “downregulation” stabilized on cessation of the Zopiclone - once I was able to identify what had taken place. After cessation, I did not experience any further deterioration in symptoms - but have been left in a state of significant cognitive dysfunction, experiencing brain fog, word-finding difficulties and profound memory loss since 2022 (see schematic below). I want to clarify that these symptoms are nothing like the minor cognitive dysfunction and memory issues one might experience after a period without restorative sleep. 

It was during this time that I began to research PFS as the likely cause and begin to explore therapeutic options. I attended a Psychiatrist and Endocrinologist during this time - who had previously seen 2-3 cases of PFS - and confirmed the underlying diagnosis. I began to explore GABAergic supplements (as recommended by patients with similar symptoms)- and saw considerable benefits with a variety of these in terms of controlling symptoms in the short term. However, I don’t believe these had any effect in relation to the long-term upregulation / downregulation of the GABA-A receptor, and the potential use of these may be a barrier to long-term recovery from this specific pathology. 

Ketogenic diet and partial recovery 2022-2025:

Immediately after this rapid deterioration of symptoms, I started the ketogenic diet. I was entirely skeptical of any elimination diet, but after multiple recommendations, and given the severity of my symptoms, I was open to trying anything. Within 7-10 days, I noticed a substantial alleviation of symptoms and can categorically say that it has been the most important intervention in my journey to date. I noticed significant improvement in the first 3 months and returned to a slightly more “functional” state - progressing upwards through some of the similar “stages” of symptoms (see associated schematic) to the point at which I have largely remained for the last 3-4 years. I don’t particularly want to expand on the sheer hell that this condition has wreaked on my life, but I believe that the diet has had positive long-term effects, and I feel that it should be one of the first line treatments for anyone with a similar presentation / phenotype. I acknowledge that other elimination diets / fasting may be equally efficacious. 

I have continued to see improvements after the initial 3 month period, but had to self-cease the diet on multiple occasions secondary to significant fatigue, lethargy and pre-syncopal symptoms (inadequate energy production). Initially, this was down to a poor understanding of the diet and the need for adequate fat consumption - however, despite attending a specific ketogenic dietician and correcting my calorie consumption - I still suffer from significant lethargy after the 6 month mark during every attempt of the diet - which has limited my long-term recovery. Supplemental daily electrolytes, a multivitamin and BHB salts have aided the process but not solved the energy issue. I have never attempted to avoid any particular 5-ARI food. 

The rate of long-term improvement slowed down considerably after the first 3 months, and was relatively slow (but consistent) between 2023 and early 2026. The most significant improvement was noted after a 15 month stint in long term ketosis, and this provided me with enough evidence to suggest that this was the long term “cure” for my condition. At that current trajectory, I estimated it was going to take a few more years to “recover” to my premorbid baseline. This is likely in the context of significant GABA receptor downregulation and I wouldn’t expect everyone to experience a similar trajectory or length of recovery pursuing this approach. 

I have largely avoided alcohol in the last few years (while this has conferred some immense short term benefits and temporarily improved all symptoms during my sporadic use (including brief improvements to cognition and memory, although I have never felt “drunk”) - I believe this likely has similar effects to Zopiclone (GABA-A downregulation) in the long term and should be avoided. Anecdotally, I noticed similar benefits while consuming non-alcoholic beers (bizarre considering the negligible alcohol content in these drinks but ?possibly possesses some GABA-A activity). I feel that even the sporadic use of alcohol likely slowed my recovery during this 4 year period. 

On a simplistic scale, I believe that the ketogenic diet addresses a GABA/Glutamate imbalance, and enhances the ability / makes it possible for the receptors to upregulate in the long term. I experience similar benefits in long-term ketosis as I would in the short term when taking a GABA-A agonist such as taurine. This is obviously entirely subjective - but is an experience shared by some who appear to have a similar phenotype to myself. I am not convinced that the ketogenic - associated BDNF and gut microbiome benefits had anything to do with the improvements I had seen. 

https://preview.redd.it/muqd23ykl0bh1.png?width=2048&format=png&auto=webp&s=cabb68084b012b8ee126cb55c94daca313ef5914

I appreciate this may be unique to me. This is the spectrum of symptoms I have experienced; each stage is discrete and may encompass a spectrum of symptoms from a “stage” either side. My hypothesis is that the specific symptoms I experience at a certain point in time are directly correlated to the likely percentage / degree of downregulation at the GABA receptor site. 

I have been “stuck” in stages 4-6 for the last 3-4 years. Each stage consists of a number of steps with associated minor changes to symptoms. This schematic is how I can personally identify when a potential treatment is improving / disimproving my clinical situation. This is a long term assessment but often can identify minor changes on a monthly basis. I believe that the vast majority of those in the neurological “arm” of PFS are stuck somewhere between stages 1-3 - the treatment for all of us should theoretically be the same - it may just take longer for me to recover to Stage 0 (full recovery) given the likely degree of downregulation. 

My recent deterioration has caused a rightward shift to re-enter Stage 6 (see below). I cannot identify what has precipitated this, and hence my concern.

2026: Further deterioration - unknown cause.

During my most recent stint on the diet in late 2025 / early 2026, I noticed limited benefits in the long run, which was alarming. (I usually would notice significant improvements at the 1, 5 and 9 month mark, which I did not experience on this occasion). I transitioned back to a normal diet as a break (ketogenic diet is labour and time intensive) and noticed a rapid deterioration in symptoms within a few weeks. This was a stepwise deterioration which followed the pattern of  the schematic I have provided and was very similar to the previous Zopiclone - induced deterioration seen in 2022. However, I have not identified any obvious trigger for this, which is concerning. Thankfully, transitioning back into ketosis has stabilised this deterioration for the moment, but I have not yet returned to my baseline (stage 4-5 of the last 4 years - (nor do I expect to in the short term given the trajectory of my condition). 

I believe that there has been further GABA-A receptor downregulation in recent weeks/months, but cannot identify what may have caused this. I have done previous stints off the ketogenic diet and have not experienced similar deteriorations so I am confident this is not the sole trigger. This period has rapidly negated most of the benefits I have witnessed in the last 4 years and would suggest there are alternate mechanisms at play now. 

The only other “variables” that I can identify within this timeframe was taking Cialis (tadalafil) on a few occasions. For those wondering, this slightly improved erectile quality, but I cannot fathom a potential link between these. I also suffered from recurrent viral infections during this period, which would cause significant fatigue for a week and likely has caused disruption to my gut microbiome (noting the Melcangi studies). These viral infections have had no impact on my neurological symptoms otherwise. I have not noticed any benefit with probiotic use at any point, despite using multiple strains at various timepoints

I want to clarify that this “stepwise deterioration” that I speak of is dissimilar to my understanding of the “crash” experienced by so many. The deterioration occurs usually over a period of 2-3 days, with a subsequent deterioration after 7-10 days and appears to be a pretty structured deterioration following a pattern such as the schematic provided. These stepwise deteriorations feel like a switch has flipped. I have experienced one “crash” as such which I have detailed below. 

Sexual symptoms post one dose of Silexan (Lavender oil). 2023. Recovery.

Whilst on the drug, or in the initial 2 or so years with the condition, I never experienced any of the common sexual symptoms reported by many patients. I failed to recognise the various phenotypes of the condition and due to a lack of sexual symptoms, I didn’t actually believe that I had PFS for a considerable period of time. In my attempts to find a long-term sleeping aid, I took one dose of Silexan, without recognising its potential anti-androgenic effects. 

The next day, I woke up with severe testicular pain and in the following days - noticed profound persistent erectile dysfunction and loss of libido, among other symptoms. While this would be catastrophic to most here, the neurological sequelae have been so all-consuming that this felt like a minor roadblock and has not influenced my aforementioned neurological trajectory in any way. I did not experience an exacerbation of “brain fog” or further cognitive decline during this period, nor did this contribute in a negative sense to any anxious / depressive symptoms in the long term. I have never experienced any of the skin wasting, atrophy, penile or muscle changes seen by many. 

Thankfully, I have seen a 80-90% recovery in this area over the last 3 years, and am now functional in this regard again. This has categorically not responded to the ketogenic diet or any other supplements which have improved the neurological symptoms. I have not explored any therapeutic efforts targeting any androgenic pathways and do not plan to do so, in fear of inducing any further symptoms in this area. I believe that time was likely the most important factor in this recovery. Given the timeline and contrasting precipitating factors, I feel that, in my unique case, the mechanism at play here is entirely discrete from the aforementioned GABAergic dysfunction. I also feel that I would have likely never suffered from any sexual symptoms had I avoided the obvious precipitant in this instance. 

Anecdotally, for anyone who intends to adhere to a long-term ketogenic diet, I personally have noted a decline in erectile quality as the months progress in ketosis (likely secondary to inadequate energy production). This immediately reverts to baseline on cessation of the diet. 

I am not an Endocrinologist, and have a limited understanding of the likely pathophysiology of the PFS-induced sexual symptoms, and will refrain from commenting on this. Dr. Powers appears to have made substantial progress in this area in recent times, and I would advise consulting his research and organising appropriate investigations with a specialist prior to experimenting with hormonal therapies. 

Research and Therapeutic efforts

I wanted to include an extensive analysis on the activity of allopregnanolone and various derivatives on the GABA-A receptor, but I cannot claim to fully grasp the intricacies of these neurosteroids and their direct effects. I could spend hours delving into the vast array of scientific papers I have consumed, as I know many of you have, but my recent deterioration in symptoms has shaken my confidence in my previously “reliable” theory. 

On a simplistic level, and as reported in literature, I believe the 5αR1 and 5αR2 inhibition has (at some point and maybe irreversibly) led to the reduced synthesis of allopregnanolone and likely  widespread dysregulation at the GABA-A receptor. This has led to possible hypersensitivity / tolerance issues at the specific receptor subunit sites. 

https://forum.propeciahelp.com/t/my-recovery-and-neuro-biological-disorder/43602

I recently came across this recovery post, and while the recovery has seemingly not been replicable to date, I independently have concluded that I likely have a similar underlying pathology. I do not fully comprehend the technicalities of GABA receptor subunits and their expressions within the CNS, but I feel that this is a route to pursue. He cites some important papers that I would encourage people to read in their own time. He poses a hypothesis in that his allopregnanolone production was not necessarily impaired, but its activity on the receptor site was altered. 

A first step for me would be actually identifying a low serum allopregnanolone level vs. progesterone / pregnenolone levels - which would reflect an issue with neurosteroid conversion vs. a potential issue at the receptor site. I am unsure if a urinary allopregnanolone level can be reliably tested / would even be beneficial? 

In an attempt to replicate the above, I have also trialled Bacopa in an attempt to upregulate GABA-A receptors - with no discernable benefit. I do not believe it either slowed / sped up my partial recovery on the ketogenic diet. I believe this patient’s extensive fasting likely mimics a ketogenic state - which is doing the vast majority of the work in this instance. I agree with his hypothesis that in theory this should work, and would encourage others to try, but I personally have not derived benefit from this. I would be hopeful that a substance that can effectively upregulate GABA-A receptors should theoretically lead to an improvement in my symptoms in the long-term. 

I have previously never seen a Neurologist - I had seen significant improvements with diet alone and wasn’t willing to pursue further consultations and investigations for a merely academic purpose (Lumbar puncture has some risks associated). This stance has obviously changed now so I intend to visit a private neurologist in an attempt to organise similar investigations to the above patient (Lumbar puncture with CSF analysis of allopregnanolone levels / GABA-A receptor subtypes) - which should glean some important information. 

If anybody has any recommendations for further investigations or neurologists who have experience dealing with the above, I would be forever grateful. I am happy to travel overseas if necessary as I feel that these niche investigations may be difficult to organise for myself without a clear indication. Despite being a doctor myself, I have had some lousy interactions with fellow work colleagues and friends and can only imagine the grief endured by many in consulting the medical profession. 

I will also organise appropriate investigations (DUTCH complete. etc) as recommended here. I live outside the USA, but have recently joined the waiting list for Dr. Powers. I acknowledge his excellent and progressive work in recent times, but I have yet to draw a conclusion on how his hypothesis fully links in with my lived experience. 

Laboratory results: 
An initial hormonal panel was done in 2022 when I first saw an Endocrinologist. I do not have the results to hand. Mildly raised serum cortisol. Every other result in the panel was within the normal range. Serum testosterone was in the low to normal range - hence the trial of TRT. 
Routine bloods have (on multiple occasions) been normal. There hasn’t been an indication to explore this further previously until now. 

Discussion:

I appreciate that there is a hesitancy in the community to recommend treatments to others (for good reason). Given my trajectory, I feel that my symptoms will continue to deteriorate in the upcoming weeks - months, and I need the scales to tip in the other direction. Therefore I am looking for advice - if anyone in this “neurological” cohort has had positive experiences with the below? I would appreciate a reference to previous posts /  scientific literature if deemed appropriate.

Lithium Orotate - Not pharmaceutical lithium carbonate. This is first on my list of potential treatments. I have recently seen the attached testimony who appears to have had considerable benefit with this in a similar scenario to myself, quoting a potential mechanism for his improvements. I am unsure if the framework and infrastructure included are essential, but it is something I will explore. 

https://www.reddit.com/r/DrWillPowers/comments/1tf4rq4/functional_pfs_recovery_5_years_neurological/

Etifoxine - theoretically has modulating abilities at the GABA-A receptor. I am wary of any medication with activity at the GABA-A site given my previous experiences and the unpredictable nature of the response. 

Bacopa monnieri - Properties as denoted above, I may try this again over an extended period. 

Zuranolone / Ganaxalone: allosteric modulators of GABA-A receptors. Their theoretical utility would depend on the serum allopregnanolone / steroid precursor results. I know that their use has been discussed in forums for decades.  

Progesterone / Pregnenolone: I gather that Dr. Powers has some experience prescribing these. Theoretically, this may lead to increased downstream allopregnanolone production, and therefore downstream activity on the GABA-A receptors. 

Faecal Microbiotal Transplant: Entirely clutching at straws here. As a potential reset to the gut microbiome. 

Various antidepressants / antipsychotics: I won’t cite individual agents but numerous agents reportedly increase serum allopregnanolone levels. Low dose fluoxetine for example, is said to increase serum allopregnanolone concentrations. I have always been against trialling the above classes given the potential side effects and unpredictability of these medications in inducing possible sexual dysfunction.

https://www.adxs.org/en/page/534/allopregnanolone#fn_48

Some interesting studies are included in the references here. I have read countless studies of various medications increasing / mimicking allopregnanolone - it is obviously a minefield to deduce if any would be beneficial in this instance.

Reflection:

The last few years of my life have been an unprecedented disaster, a nightmare which I have never woken up from. I acknowledge that, over time, the symptoms have become easier to deal with, but they have never reduced in severity. A “saving grace” (silver linings and all that) is the profound memory loss I have experienced, and the impaired ability to learn and consolidate new information. I wake up each day with a very hazy memory of the previous day, week and year, and therefore do not dwell on the five year misery I continue to endure. My memory pre 2022 is largely preserved in comparison, and drawing on this cognitive reserve has enabled me to somehow graduate with my best friends and work full-time as a junior doctor for the last 3 years, which has brought me immense joy and pride. This has been a major protective factor for me, despite the massive challenges this condition brings on a daily basis. 

The reality is, that despite being an optimist - I am not convinced I’ll have a positive long-term outcome given my recent trajectory. I have taken a step back from work to pursue researching my own condition, and therefore looking for help from the community. Unfortunately, my recent deterioration renders it more difficult to fully comprehend the latest research and therapeutic efforts and draw concise conclusions from these. I had always planned to engage in research in this field, once my symptoms had recovered sufficiently; however, I have never been in a position where I felt able to effectively do so. 

I want to acknowledge the great work done by the PFS community at large, and personally thank anyone who has advocated for use of the ketogenic diet previously. Some patients demonstrate incredible bravery when trialling new treatments without comprehending the potential deleterious sequelae of these efforts. These anecdotes have been incredibly useful for me over the years in deciphering which avenues to pursue. 

I could write so much more in this section, a few paragraphs cannot encapsulate the roller coaster of symptoms and emotions I have survived through. Every day has been a struggle, and I encourage everyone to keep fighting the hopelessness, exhaustion and uncertainty associated with this. With the increasing prevalence of the condition, coupled with recent discoveries, I do believe that the pendulum is beginning to swing in our favour. 

If anyone is experiencing similar issues, please reach out to me via DM. I cannot provide medical advice over text / over the phone, but am more than happy to answer any questions to the best of my ability. 

^

Hey dr powers my name is Lakshay my age is 20 and I've done the most brutal protocols in order to fix my pfs in the past,1 year ago

And I eventually fixed my pfs to some degree with the valproate and the dopamine did came back and I started responding to testosterone again but I wasn't fully cured but partially,I did .

But due to a breakup I took one snri again again(I didn't knew the pill was ssri i couldn't help myself and gone to psych to ask him give me a med to calm me down I even said the doc don't give me ssri he said okay but he still gave me one SNRI which is same as ssri,WOAH MF I WANT TO KILL HIM BUT THAT WONT FIX MY PSSD)

Back to the topic btw-

Right after taking that snri I forgot about my ex and got wierd veins in my penis with emotional loss and brutal libido loss,beard loss and all.

How can this happen with just one pill of pristiq/ deslavafaxine.

I don't know

But my question was I've seen people getting VERY SEVERE pssd after taking mirtazepine

And the new guy who had the recent post I've readed you're considering mirtazepine micro dose for his libido,i don't get it,it's a very risky drug.

Well I know that risk is ok when you have to try new things,but that guy has pfs not pssd,

That can give him additional pssd.... considering I got pssd from just one dose of pristiq.

Btw thanks for your work sir,

I also want to tell you about valproate,which fully cured some of the friends I know,so pls look into the hdaci theory too!

I don't know more than you but I just thought this might help us.

Hello! I really think these instructions can help all Dr. Powers patients here. https://www.reddit.com/r/DrWillPowers/s/7q3H6NVuBf

But they are not comprehensive. That is why I am asking the Dr. Will Powers community to help me improve this instruction set. If you see something that could be improved or that is missing please let me know! Also big Thank you to both Dr Powers Community members that helped confirm that UGT2B7 variant

Basically title.

I’ve adjusted my estradiol valerate monotherapy dose to be 1.8mg taken every 4 days. This is the lowest dose I’ve had since starting, and I’m quite pleased with the benefits of not having my estrogen through the roof. I’ve definitely noticed my testosterone increasing (in a good way). My levels have always been under 10 ng/dL and have dealt with low energy levels for years.

I get my labs back next week, so we’ll see. But if my T is a bit above female levels, and my estrogen is fine, would I need to add a blocker like bicalutamide? Would this affect the positive changes I’ve experienced?

Does anyone have experience with this kind of thing?

I figured out how to run my VCF and TBI files through PharmaCAT, which took hours, but ended up giving me useful pharmacogenomic information that I was not able to pick up from my VCF and BAM alone.

The PharmaCAT output opens in any web browser. I also manually confirmed the genes marked with an asterisk against my BAM, so I’m comfortable treating those findings as reliable.

The biggest finding from my report is that I’m a CYP2C19 ultra-rapid metabolizer, while also being heterozygous for a CYP2D6 loss-of-function variant. I have not fully verified phase yet, but I strongly suspect that at least one of the other high-REVEL CYP2D6 variants I found may be on my remaining functional copy.

The reason I think this matters is because, in our group, we keep seeing CYP2D6 disruption show up again and again in PSSD genomes. Variants that either wipe out or significantly slow CYP2D6 seem way more common in the people we have looked at than I would have expected. Out of all the genes I’ve seen while helping people dig through their genomic data, CYP2D6 has been one of the loudest “something is going on here” signals.

I brought this up to Dr. Powers, and his response was:

“It just increases exposure to some SSRIs. Basically, 10mg can feel like 30 or 40 to these people.

Also it directly synths dopamine in the brain from tyrosine.

Aka, thank you, but I saw this awhile back. I am very aware of it.

It’s not ‘the answer’ but it’s a risk variable.”

That makes sense generally, but in my specific case, Zoloft is primarily metabolized through CYP2C19, and I am a CYP2C19 ultra-rapid metabolizer. So the simple “increased SSRI exposure” explanation does not seem like the cleanest fit for me personally.

What makes this more interesting is that CYP2D6 keeps showing up even in people whose original drug was not primarily metabolized by CYP2D6. That makes me wonder if its relevance is less about drug clearance alone and more about the second point Powers mentioned: CYP2D6’s role in dopamine/tyrosine-related brain chemistry, or possibly some other mechanism we have not explored yet.

Even more confusing, we are also starting to see CYP2D6-related findings in some PFS genomes, not just PSSD. I’m working on getting that data organized and posted separately.

I’m not saying CYP2D6 is “the answer,” but based on what we are seeing across multiple people, it is starting to look like a legitimate risk variable worth paying attention to.

24F from Canada.

I’m considering becoming a patient of Dr. Powers, but because I’d be traveling internationally and paying out of pocket, I’m trying to get a better sense of whether my case is something he has experience with.

For several years I’ve been dealing with what appears to be a complex estrogen-related disorder, although I still don’t have a definitive diagnosis. After consulting with specialists, one of the leading possibilities has been impaired estrogen signalling (or some form of altered estrogen sensitivity), because I consistently require much higher-than-expected estradiol levels to achieve normal physical and cognitive functioning and suppress debilitating symptoms. My levels are now in the pregnancy range as a result.

I understand the risks of supraphysiologic hormone levels, but every time I’ve attempted to reduce my dose, I’ve experienced significant functional decline across multiple areas of my life.

I’m looking for a physician who is comfortable investigating unusual endocrine presentations, willing to think outside the box when appropriate, and, if medically justified, willing to prescribe and monitor an unconventional regimen rather than dismissing it solely because the doses are atypical.

Does anyone know if Dr. Powers has expertise in estrogen signalling abnormalities, and whether he would be able to arrange an individualized hormone regimen (rather than routine HRT)?

Thanks!

Mine smells exactly like what I inject. Has the whole time I've been on T. I think I may have an idea of why that would happen. I just wanted to ask here, in case Dr. P or anyone else might know why that would happen with a FtM on T for all of the 8 years he's been injecting it mostly IM. (Handful of months subq before I had to switch back to IM because I seemingly metabolize it differently...long story.) I've asked the physicians on my medical team. I've basically just been shrugged at. They say they have no idea why. I have wonky hormone signaling stuff going on. Unsure if this is related, or just something that happens to everyone. Thanks in advance! Much appreciated!

For the BAM variants list, see https://www.reddit.com/r/DrWillPowers/s/jSOrCkJ75S

This will be a very long post of data. A special thank to u/Excellent-Push2833 for all the help. But before, a small AI summary that I suppose must be read with the usual caution.

Summary

CYP2D6 — heterozygous deletion confirmed by BAM (gene depth 19.86 vs flanking 38.93, ratio 0.51). Remaining allele carries *41 markers (rs28371725, rs16947, rs61731586). Genotype: *5/*41 — poor metabolizer. All 10 VCF variants hemizygous (0 ref reads), consistent with single copy.

Top 10 functional variants (VCF-confirmed, genes structurally intact on BAM):

CYP2D6 *5/*41 — poor metabolizer, ~10-25% capacity. Metabolizes ~25% of all prescribed drugs.

UGT2B7 — homozygous *2 (rs7439366, His268Tyr). Primary backup for UGT2B17 glucuronidation.

PAPSS2 — 68/88 variants homozygous ALT (77%). Produces PAPS, the universal cofactor for all sulfotransferases.

DBH — three heterozygous variants: rs1611115 (promoter, reduces expression), rs6271 (Arg549Cys, reduces function), rs1108580 (Ala318Thr). Dopamine-to-norepinephrine conversion impaired.

ABCC2 — two heterozygous loss-of-function variants: rs717620 (promoter) + rs2273697 (Val417Ile). Primary glucuronide efflux transporter.

CYP2C19 — *1/*2 heterozygous (rs4244285 + rs12769205). Intermediate metabolizer.

SLCO2B1 — 12/14 variants homozygous ALT (86%). Sulfated steroid transporter expressed in liver, gut, and brain.

SULT2A1 — 40/45 variants homozygous ALT (89%). Primary androgen sulfation enzyme.

KCNJ8 + ABCC8 — 100% and 78% homozygous ALT respectively. These encode the KATP channel subunits (Kir6.1 + SUR1), the direct pharmacological target of minoxidil. *In my case, penile application of Minoxidil is what made me a severe PFS case, instead of a mild one.*

CREBBP — 53/82 variants homozygous ALT (65%). Histone acetyltransferase and AR coactivator. Dr. Powers has identified CREBBP and NCOR as the most recurrent epigenetic gene findings across PFS and trans genomes.

Supporting findings:

COMT: Val/Val (rs4680 homozygous reference, high activity)

MAO-A: rs6323 T hemizygous (high activity haplotype)

ABCG2: 89% homozygous ALT (drug efflux at blood-brain barrier)

UGT2B15: rare missense p.Arg260Gln (rs371697004, gnomAD AF 0.0000526)

CYP3A5: *1/*3 heterozygous (intermediate metabolizer)

HIF1A: 70% homozygous ALT

SIRT1: 82% homozygous ALT

GCLC: 68% homozygous ALT (glutathione synthesis)

END of AI summary.

BAM deletions :

Deletion/copy-loss hits:

gene chrom start end gene_depth left_depth right_depth flank_mean gene_to_flank_mean gene_to_left gene_to_right call

CYP2D6 22 42126499 42130865 19.8649 40.1108 37.7526 38.9317 0.5103 0.4953 0.5262 POSSIBLE_PARTIAL_OR_HET_DELETION

VCF variants (NOTES/OTHER is also AI) :

Gene: ABCB1

Variant: SNP 7:87549888 T→A

Protein: not displayed (HGVS button not expanded)

rsID: not displayed

Zygosity: Het

Ref Allele: T

Alt Allele: A

Freq: gnomAD genomes v4 — 0.00; gnomAD exomes — 0.0

CADD: not available

REVEL: 0.671

NOTES/OTHER: Missense variant. Sufficient quality. Highly conserved (phyloP 5.04). 0 alt / 0 total in gnomAD. High cross-species conservation.

---

Gene: ABCB8

Variant: SNP 7:151028586 G→A

Protein: p.Arg24His (ENSP00000351717.4)

rsID: rs761485323

Zygosity: Het

Ref Allele: G

Alt Allele: A

Freq: gnomAD genomes v4 — 0.00000657; max ancestry — 0.0000241; gnomAD exomes — 0.00000137

CADD: not available

REVEL: 0.302

NOTES/OTHER: Missense variant. HGVSc: ENST00000358849.9:c.71G>A. Not conserved (phyloP −0.323). 1 alt / 152,240 total. 0 homozygotes.

---

Gene: ABCC5

Variant: SNP 3:183987742 A→T

Protein: intronic in canonical transcript; missense in ENST00000427120

rsID: rs140530675

Zygosity: Het

Ref Allele: A

Alt Allele: T

Freq: gnomAD genomes v4 — 0.000341; max ancestry — 0.000588; gnomAD exomes — 0.000335

CADD: not available

REVEL: not displayed

NOTES/OTHER: Intron variant (canonical transcript ENST00000334444.11:c.591+28T>A). Most severe impact in non-canonical transcript = missense. Marginally conserved (phyloP 0.401). 52 alt / 152,274 total. 1 homozygote.

---

Gene: ARID2

Variant: SNP 12:45905056 A→G

Protein: p.Lys1829Arg (ENSP00000335044.6)

rsID: not displayed

Zygosity: Het

Ref Allele: A

Alt Allele: G

Freq: gnomAD genomes v4 — 0.00; gnomAD exomes — 0.0

CADD: not available

REVEL: 0.023

NOTES/OTHER: Missense variant. HGVSc: ENST00000334344.11:c.5486A>G. Quality: "Poor evidence of alternate allele." Highly conserved (phyloP 2.542). 0 alt / 0 total. Gene-associated phenotypes: severe intellectual disability, generalized hypotonia.

---

Gene: ATP5F1B (variant 1)

Variant: SNP 12:56640166 C→A

Protein: not displayed (HGVS button not expanded)

rsID: not displayed

Zygosity: Het

Ref Allele: C

Alt Allele: A

Freq: gnomAD genomes v4 — 0.00; gnomAD exomes — 0.00

CADD: not available

REVEL: 0.621

NOTES/OTHER: Missense variant. Sufficient quality. Highly conserved (phyloP 9.124). 0 alt / 0 total. Gene-associated phenotypes: hyperleucinemia, hypervalinemia, polyphagia, AD inheritance.

---

Gene: ATP5F1B (variant 2)

Variant: SNP 12:56642557 G→C

Protein: p.Ile325Met (ENSP00000262030.3)

rsID: not displayed

Zygosity: Het

Ref Allele: G

Alt Allele: C

Freq: gnomAD genomes v4 — 0.00; gnomAD exomes — 0.0

CADD: not available

REVEL: 0.501

NOTES/OTHER: Missense variant. HGVSc: ENST00000262030.8:c.975C>G. Sufficient quality. Highly conserved (phyloP 9.129). 0 alt / 0 total. Two heterozygous missense variants on ATP5F1B (possible compound het?).

---

Gene: CAT

Variant: SNP 11:34456041 G→A

Protein: p.Glu248Lys (ENSP00000241052.4)

rsID: not displayed

Zygosity: Het

Ref Allele: G

Alt Allele: A

Freq: gnomAD genomes v4 — 0.00; gnomAD exomes — 0.0

CADD: not available

REVEL: 0.457

NOTES/OTHER: Missense variant. HGVSc: ENST00000241052.5:c.742G>A. Sufficient quality. Highly conserved (phyloP 4.226). 0 alt / 0 total. Gene-associated disease: acatalasemia (AR). Phenotypes: arteriosclerosis, parkinsonism, severe periodontitis.

---

Gene: CHD3

Variant: DEL 17:7884893 CGAG→C

Protein: not displayed (upstream gene variant in canonical; inframe deletion in non-canonical)

rsID: rs770383628

Zygosity: Het

Ref Allele: CGAG

Alt Allele: C

Freq: gnomAD genomes v4 — 0.000322; max ancestry — 0.000845; gnomAD exomes — 0.00694

CADD: not available

REVEL: not displayed

NOTES/OTHER: ClinVar: benign. Upstream gene variant in canonical transcript. Most severe impact in non-canonical transcripts: inframe deletion in ENST00000380358, ENST00000700753. Highly conserved (phyloP 2.282). 45 alt / 139,660 total. 0 homozygotes.

---

Gene: COMT

Variant: SNP 22:19962579 T→A

Protein: p.Leu18Gln (ENSP00000354511.6)

rsID: rs1439513393

Zygosity: Het

Ref Allele: T

Alt Allele: A

Freq: gnomAD genomes v4 — 0.00; gnomAD exomes — 0.00000213

CADD: not available

REVEL: 0.397

NOTES/OTHER: Missense variant. HGVSc: ENST00000361682.11:c.53T>A. Sufficient quality. Not conserved (phyloP −0.518). 0 alt / 0 total (genomes). This variant (p.Leu18Gln) is distinct from rs4680 (Val158Met / Val/Val) which was already documented. Very rare variant in the N-terminal region of COMT. Gene-associated phenotypes: bipolar affective disorder.

---

Gene: CYP21A2

Variant: SNP 6:32041127 G→A

Protein: p.Ser494Asn (ENSP00000496625.1)

rsID: rs6473

Zygosity: Het

Ref Allele: G

Alt Allele: A

Freq: gnomAD genomes v4 — 0.00566; max ancestry — 0.0182; gnomAD exomes — 0.00301

CADD: not available

REVEL: 0.076

NOTES/OTHER: ClinVar: benign (classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency). Missense variant. HGVSc: ENST00000644719.2:c.1481G>A. Marginally conserved (phyloP 0.828). 782 alt / 138,240 total. 0 homozygotes. Phenotype: hypoglycemia.

---

Gene: DBH (variant 1)

Variant: SNP 9:133657152 C→T

Protein: p.Arg549Cys (ENSP00000376776.2)

rsID: rs6271

Zygosity: Het

Ref Allele: C

Alt Allele: T

Freq: gnomAD genomes v4 — 0.0475; max ancestry — 0.0700; gnomAD exomes — 0.0629

CADD: not available

REVEL: 0.182

NOTES/OTHER: ClinVar: benign (orthostatic hypotension 1). Missense variant. HGVSc: ENST00000393056.8:c.1645C>T. Highly conserved (phyloP 3.609). 7,229 alt / 152,278 total. 239 homozygotes. Known functional variant — associated with reduced serum DBH activity.

---

Gene: DBH (variant 2)

Variant: SNP 9:133639992 A→G

Protein: p.Glu162= (synonymous) (ENSP00000376776.2)

rsID: rs1108580

Zygosity: Het

Ref Allele: A

Alt Allele: G

Freq: gnomAD genomes v4 — 0.533; max ancestry — 0.666; gnomAD exomes — 0.515

CADD: not available

REVEL: not applicable (synonymous)

NOTES/OTHER: ClinVar: benign (orthostatic hypotension 1). Splice region variant + synonymous variant. HGVSc: ENST00000393056.8:c.486A>G. Highly conserved (phyloP 9.321). 80,984 alt / 152,062 total. 22,686 homozygotes. Common variant, but splice region positioning confers functional interest.

---

Gene: DBH (variant 3)

Variant: SNP 9:133635393 T→C

Protein: not applicable (upstream gene variant)

rsID: rs1611115

Zygosity: Het

Ref Allele: T

Alt Allele: C

Freq: gnomAD genomes v4 — 0.796; max ancestry — 0.829; gnomAD exomes — 0.0

CADD: not available

REVEL: not applicable

NOTES/OTHER: ClinVar: "Not provided" (orthostatic hypotension 1). Upstream gene variant (promoter). Not conserved (phyloP −0.298). 120,899 alt / 151,818 total. 48,324 homozygotes. Known −1021C>T variant — the C allele (alt) is a major negative regulator of DBH expression, associated with reduced plasma DBH activity.

---

Gene: DRD4

Variant: SNP 11:640099 A→C

Protein: p.Ser284Arg (ENSP00000176183.5)

rsID: rs34662058

Zygosity: Het

Ref Allele: A

Alt Allele: C

Freq: gnomAD genomes v4 — 0.000572; max ancestry — 0.00439; gnomAD exomes — 0.000803

CADD: not available

REVEL: 0.043

NOTES/OTHER: Missense variant. HGVSc: ENST00000176183.6:c.850A>C. Sufficient quality. Not conserved (phyloP −1.067). 55 alt / 96,084 total. 2 homozygotes. Gene-associated phenotype: hyperactivity.

---

Gene: HDAC9

Variant: SNP 7:18954219 T→C

Protein: p.Ile1004Thr (ENSP00000509161.1)

rsID: rs138163349

Zygosity: Het

Ref Allele: T

Alt Allele: C

Freq: gnomAD genomes v4 — 0.00209; max ancestry — 0.00334; gnomAD exomes — 0.00256

CADD: not available

REVEL: 0.051

NOTES/OTHER: ClinVar: benign (not provided). Missense variant. HGVSc: ENST00000886413.1:c.3011T>C. Marginally conserved (phyloP 0.848). 318 alt / 152,234 total. 4 homozygotes.

---

Gene: HTR1D

Variant: SNP 1:23193766 C→A

Protein: p.Ala152Ser (ENSP00000363748.1)

rsID: rs142643700

Zygosity: Het

Ref Allele: C

Alt Allele: A

Freq: gnomAD genomes v4 — 0.000440; max ancestry — 0.000544; gnomAD exomes — 0.000441

CADD: not available

REVEL: 0.121

NOTES/OTHER: ClinVar: uncertain significance (VUS). Missense variant. HGVSc: ENST00000374619.2:c.454G>T. Sufficient quality. Not conserved (phyloP −3.894). 67 alt / 152,202 total. 0 homozygotes. Serotonin receptor 1D.

---

Gene: KAT6B

Variant: SNP 10:74843533 G→A

Protein: intronic in canonical; missense in ENST00000648539, ENST00000650434

rsID: rs138782403

Zygosity: Het

Ref Allele: G

Alt Allele: A

Freq: gnomAD genomes v4 — 0.0104; max ancestry — 0.0175; gnomAD exomes — 0.0152

CADD: not available

REVEL: not displayed

NOTES/OTHER: ClinVar: likely benign (not provided). Intron variant (ENST00000287239.10:c.621+55G>A). Marginally conserved (phyloP 0.469). 1,591 alt / 152,290 total. 8 homozygotes. Gene-associated disease: genitopatellar syndrome (AD).

---

Gene: KDM6B

Variant: SNP 17:7853303 G→T

Protein: p.Ala1611Ser (ENSP00000412513.2)

rsID: rs141627015

Zygosity: Het

Ref Allele: G

Alt Allele: T

Freq: gnomAD genomes v4 — 0.0000591; max ancestry — 0.000118; gnomAD exomes — 0.0000788

CADD: not available

REVEL: 0.071

NOTES/OTHER: ClinVar: likely benign (inborn genetic diseases). Missense variant. HGVSc: ENST00000448097.7:c.4831G>T. Moderately conserved (phyloP 1.113). 9 alt / 152,324 total. 0 homozygotes. Gene-associated phenotypes: epilepsy, motor delay, hypotonia, global developmental delay.

---

Gene: MFN2

Variant: SNP 1:12014474 A→G

Protein: downstream gene variant in canonical; missense in ENST00000675298

rsID: rs143440477

Zygosity: Het

Ref Allele: A

Alt Allele: G

Freq: gnomAD genomes v4 — 0.00280; max ancestry — 0.00550; gnomAD exomes — 0.0

CADD: not available

REVEL: not displayed

NOTES/OTHER: ClinVar: likely benign (not provided). Downstream gene variant in canonical transcript. Not conserved (phyloP −0.765). 401 alt / 143,404 total. 2 homozygotes. Gene involved in mitochondrial fusion.

---

Gene: MT-ATP6

Variant: SNP MT:8860 A→G

Protein: p.Thr112Ala (ENSP00000354632.2)

rsID: rs2001031

Zygosity: Hom

Ref Allele: A

Alt Allele: G

Freq: gnomAD genomes v4 — 249 alt, 0 ref (near-fixed)

CADD: not available

REVEL: not displayed

NOTES/OTHER: ClinVar: benign (Leigh syndrome). Mitochondrial missense variant. HGVSc: ENST00000361899.2:c.334A>G. Highly conserved (phyloP 3.819). Near-fixed mitochondrial DNA variant — constitutes the revised Cambridge Reference Sequence (rCRS) polymorphism. Gene-associated diseases: Leber hereditary optic neuropathy, NARP syndrome, familial isolated hypertrophic cardiomyopathy, isolated ATP synthase deficiency.

---

Gene: MT-CYB

Variant: SNP MT:15326 A→G

Protein: p.Thr194Ala (ENSP00000354554.2)

rsID: rs2853508

Zygosity: Hom

Ref Allele: A

Alt Allele: G

Freq: gnomAD genomes v4 — 248 alt, 0 ref (near-fixed)

CADD: not available

REVEL: not displayed

NOTES/OTHER: ClinVar: benign (Leigh syndrome, mitochondrial disease, familial breast cancer). Mitochondrial missense variant. HGVSc: ENST00000361789.2:c.580A>G. Marginally conserved (phyloP 0.228). Like MT-ATP6 rs2001031, near-fixed variant — rCRS polymorphism.

---

Gene: NSD1

Variant: SNP 5:177212121 G→C

Protein: p.Ser1241Thr (ENSP00000395929.2)

rsID: rs138641637

Zygosity: Het

Ref Allele: G

Alt Allele: C

Freq: gnomAD genomes v4 — 0.000670; max ancestry — 0.00308; gnomAD exomes — 0.000761

CADD: not available

REVEL: 0.049

NOTES/OTHER: ClinVar: likely benign (Sotos syndrome, Weaver syndrome, inborn genetic diseases). Missense variant. HGVSc: ENST00000439151.7:c.3722G>C. Not conserved (phyloP −0.071). 102 alt / 152,134 total. 0 homozygotes.

---

Gene: SLC22A13

Variant: SNP 3:38275953 C→T

Protein: p.Thr365Met (ENSP00000310241.3)

rsID: rs765934579

Zygosity: Het

Ref Allele: C

Alt Allele: T

Freq: gnomAD genomes v4 — 0.0000394; max ancestry — 0.000576; gnomAD exomes — 0.0000315

CADD: not available

REVEL: 0.376

NOTES/OTHER: Missense variant. HGVSc: ENST00000311856.9:c.1094C>T. Sufficient quality. Not conserved (phyloP −5.666). 6 alt / 152,224 total. 0 homozygotes. Organic cation transporter — relevant to renal clearance of endogenous substrates.

---

Gene: SLCO3A1

Variant: SNP 15:92104454 A→C

Protein: p.Arg307Ser (ENSP00000320634.6)

rsID: rs72655652

Zygosity: Het

Ref Allele: A

Alt Allele: C

Freq: gnomAD genomes v4 — 0.0115; max ancestry — 0.0168; gnomAD exomes — 0.0139

CADD: not available

REVEL: 0.086

NOTES/OTHER: Missense variant. HGVSc: ENST00000318445.11:c.921A>C. Sufficient quality. Highly conserved (phyloP 6.031). 1,758 alt / 152,250 total. 19 homozygotes. OATP family transporter — potentially relevant for conjugated steroid transport.

---

Gene: SOD2

Variant: SNP 6:159692745 G→C

Protein: not displayed (HGVS button not expanded)

rsID: not displayed

Zygosity: Het

Ref Allele: G

Alt Allele: C

Freq: gnomAD genomes v4 — 0.00; gnomAD exomes — 6.84e-7

CADD: not available

REVEL: 0.083

NOTES/OTHER: Missense variant. Sufficient quality. Highly conserved (phyloP 7.494). 0 alt / 152,186 total. 0 homozygotes. Extremely rare variant on mitochondrial superoxide dismutase.

---

Gene: STAT3

Variant: SNP 17:42329523 C→T

Protein: intronic in canonical; missense in ENST00000677421

rsID: rs112644937

Zygosity: Het

Ref Allele: C

Alt Allele: T

Freq: gnomAD genomes v4 — 0.00121; max ancestry — 0.00307; gnomAD exomes — 0.00151

CADD: not available

REVEL: not displayed

NOTES/OTHER: ClinVar: likely benign (not provided). Intron variant (ENST00000264657.10:c.1233+31G>A). Marginally conserved (phyloP 0.629). 185 alt / 152,328 total. 0 homozygotes. Gene-associated diseases: acute promyelocytic leukemia, chronic lymphoproliferative disorder of natural killer cells.

---

Gene: TBP

Variant: DEL 6:170561958 ACAG→A

Protein: p.Gln95del (ENSP00000375942.2)

rsID: rs752404282

Zygosity: Het

Ref Allele: ACAG

Alt Allele: A

Freq: gnomAD genomes v4 — 0.00403; max ancestry — 0.00513; gnomAD exomes — 0.00574

CADD: not available

REVEL: not applicable (inframe deletion)

NOTES/OTHER: ClinVar: benign. Inframe deletion. HGVSc: ENST00000392092.7:c.279_281del. Marginally conserved (phyloP 0.29). 578 alt / 143,364 total. 4 homozygotes. Gene-associated phenotype: cerebellar atrophy.

---

Gene: TET2

Variant: SNP 4:105234042 C→T

Protein: p.Leu34Phe (ENSP00000369351.4)

rsID: rs111948941

Zygosity: Het

Ref Allele: C

Alt Allele: T

Freq: gnomAD genomes v4 — 0.0138; max ancestry — 0.0189; gnomAD exomes — not displayed

CADD: not available

REVEL: 0.037

NOTES/OTHER: ClinVar: benign (not provided). Missense variant. HGVSc: ENST00000380013.9:c.100C>T. Highly conserved (phyloP 4.571). 2,100 alt / 152,276 total. 30 homozygotes. Gene-associated diseases: primary myelofibrosis, polycythemia vera, acquired idiopathic sideroblastic anemia.

---

Gene: UGT2B15

Variant: SNP 4:68868134 C→T

Protein: p.Arg260Gln (ENSP00000341045.5)

rsID: rs371697004

Zygosity: Het

Ref Allele: C

Alt Allele: T

Freq: gnomAD genomes v4 — 0.0000526; max ancestry — 0.0000735; gnomAD exomes — 0.0000322

CADD: not available

REVEL: 0.307

NOTES/OTHER: Missense variant. HGVSc: ENST00000338206.6:c.779G>A. Sufficient quality. Marginally conserved (phyloP 0.443). 8 alt / 152,046 total. 0 homozygotes. Androgenic glucuronidation enzyme — directly relevant to androgen metabolite clearance (UGT2B cascade).

---

Structural Variants / CNV (Transcript Ablation / Amplification)

---

Gene: ABCC1

Variant: Transcript ablation (CNV)

Protein: not applicable

rsID: not applicable

Zygosity: indeterminate (structural)

Ref Allele: not applicable

Alt Allele: deletion / ablation

Freq: not displayed

CADD: not available

REVEL: not applicable

NOTES/OTHER: chr16:15,949,138–16,143,257. Aliases: GS-X, MRP, MRP1. MANE transcript: ENST00000399410.8. 1 variant identified (proband). Classified under "High or moderate impact" as transcript ablation. Phenotypes: AD sensorineural deafness (DFNA), tinnitus, morphological abnormality of the inner ear. ABC transporter — exports glutathione, glucuronide, and sulfate conjugates. Directly relevant to conjugated androgen clearance (ABCC2 was already documented in the PFS profile).

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Gene: CYP2E1

Variant: Transcript amplification (CNV)

Protein: not applicable

rsID: not applicable

Zygosity: indeterminate (structural)

Ref Allele: not applicable

Alt Allele: amplification

Freq: not displayed

CADD: not available

REVEL: not applicable

NOTES/OTHER: chr10:133,520,406–133,561,220. Alias: CYP2E. MANE transcript: ENST00000252945.8. 1 variant identified (proband). Classified under "High or moderate impact" as transcript amplification. CYP2E1 metabolizes ethanol, fatty acids, and certain xenobiotics; amplification could increase phase I metabolic activity through this CYP.

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Gene: GUSB

Variant: Transcript amplification (CNV)

Protein: not applicable

rsID: not applicable

Zygosity: indeterminate (structural)

Ref Allele: not applicable

Alt Allele: amplification

Freq: not displayed

CADD: not available

REVEL: not applicable

NOTES/OTHER: chr7:65,960,684–65,982,215 (reverse strand). MANE transcript: ENST00000304895.9. 0 point variants identified. Classified under "High or moderate impact" as transcript amplification. Lysosomal β-glucuronidase — catalyzes hydrolysis of glucuronides. Potential relevance: increased GUSB activity could prematurely deconjugate glucuronidated androgens (DHT-G, 3α-ADG), partially counteracting UGT2B function.

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Gene: HDAC1

Variant: Transcript amplification (CNV)

Protein: not applicable

rsID: not applicable

Zygosity: indeterminate (structural)

Ref Allele: not applicable

Alt Allele: amplification

Freq: not displayed

CADD: not available

REVEL: not applicable

NOTES/OTHER: chr1:32,292,083–32,333,635. Aliases: GON-10, HD1, KDAC1, RPD3L1. MANE transcript: ENST00000373548.8. 0 point variants identified. Classified under "High or moderate impact" as transcript amplification. Class I histone deacetylase — epigenetic regulator. Finasteride and other endocrine disruptors are known to alter histone acetylation patterns; HDAC1 amplification could potentiate persistent epigenetic repression in the PFS context.

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IGV View — CYP2D6

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Gene: CYP2D6

Variant: IGV visual inspection

Protein: not applicable (coverage inspection)

rsID: not applicable

Zygosity: indeterminate

Ref Allele: not applicable

Alt Allele: not applicable

Freq: not applicable

CADD: not applicable

REVEL: not applicable

NOTES/OTHER: IGV capture of the chr22:42,124,499–42,132,810 region (GRCh38). BAM file (sample.bam) loaded with coverage and aligned reads. Coverage appears variable with some reduced-depth regions. Some colored reads (red, green, purple) suggesting soft-clips or mismatches — to be evaluated for potential structural rearrangements (CYP2D6 is known for duplications/deletions/CYP2D6-CYP2D7 hybrids). The Powers subreddit CNV script had already flagged CYP2D6 as potentially abnormal.

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- HGVSc: ENST00000338206.6:c.779G>A

- rsID: rs371697004

- Zygosity: Het

- Ref Allele: C

- Alt Allele: T

- gnomAD genomes v4: 0.0000526 AF · 0.0000735 max ancestry · 8 alt / 152 046 total · 0 hom

- REVEL: 0.307

- Quality: Sufficient depth and allele counts

- Conservation: Marginally conserved (0.443)

- Reads: 49

With the announcement of Claude Science, I would assume that this would be a major aid in the development of Dr Powers’ PFS theory. It would be ideal if we could all essentially chip in with a tool like this and generate some really good credible additions or acknowledgments of the current theory using this. Hopefully this could potentially advance a cure at some point? Curious to know you guys’ thoughts.