Author: ghostpssd

Intro to inflammatory cytokines

Date: [July 29, 2018]

Yesterday I wrote about H. Pylori and discussed inflammatory cytokines mentioned in Nasrat et al.’s 2016 paper. But what exactly are they? How could they be important to PSSD?

First, we need to understand how cells signal to themselves and to other cells. We can break this down into three categories:

  • Autocrine Signaling
  • Paracrine Signaling
  • Endocrine Signaling

Autocrine signaling occurs when a cell secretes a hormone or chemical messenger that binds to receptors on that same cell, leading to changes in the cell releasing the chemical or hormone.

Paracrine signaling also involves a cell releasing a chemical or hormone, but the agent is intended for receptors on a nearby cell.

Endocrine signaling often uses the bloodstream to disperse chemicals released from a cell to receptors on a far away cell.

 

Signaling in the bodySignaling

Cytokines use all three types of signaling in the body, making them important on a system-wide scale on physiology.

Cytokines are produced by various types of cells (immune cells like macrophages, B lymphocytes, T lymphocytes and mast cells, as well as endothelial cells). Different cell types may in some cases produce the same cytokines.

You might have picked up on the strong connection to the immune system, as cytokines are very important in the immune response. In our case, we’re concerned with their role in inflammation.

Inflammatory cytokines are, as the name suggests, cytokines that promote inflammation. They include interleukin-1 (IL-1), IL-12, and IL-18, tumor necrosis factor (TNF), interferon gamma (IFN-gamma), and granulocyte-macrophage colony stimulating factor. Balancing pro vs anti inflammatory cytokines is important, as dysfunction of these systems is strongly correlated with depression and other mental illnesses.

For today, I’ll focus on the pro-inflammatory cytokines mentioned in the other paper cited in yesterday’s log as being relevant to H. Pylori.

H. pylori infection is associated with the up-regulation of toll-like receptors and cytokine overproduction, especially tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, and IL-8

Budzyński and Kłopocka (2014)

IL-1

The Interleukin-1 (IL-1) family is a group of 11  pro-inflammatory (mostly) cytokines. IL-1 is produced widely in tissue macrophages, monocytes, fibroblasts, and dendritic cells, but is also expressed by B lymphocytes, NK cells, microglia, and epithelial cells. IL-1 cytokines are very important in the infection response. They affect the activity of the hypothalamus, the thermoregulatory center, leading to a rise in body temperature (fever). However, IL-1 has several other roles – causing hyperalgesia (increased pain sensitivity), vasodilation and hypotension.

 

IL-6

Interleukin-6 (IL-6) acts as a pro-inflammatory cytokine and is also involved in temperature control (among other things throughout the body). It’s interesting to note that cortisol spikes can increase the release of IL-6.

 

IL-8

IL-8 induces a series of physiological responses required for migration and phagocytosis in target cells, such as increases in intracellular Ca2+, exocytosis (e.g. histamine release), and the respiratory burst. (Again, I’m really simplifying here. These cytokines have MANY roles in the body and there actions are still not fully understood).

 

TNF-Alpha

The primary role of TNF is in the regulation of immune cells. It is able to produce apoptotic cell death, cachexia, and inflammation. TNF dysfunction is implicated in a myriad of disorders including Alzheimer’s disease, cancer, depression, and inflammatory bowel disease.

 

With a basic introduction to inflammatory cytokines under our belt, we can dig deeper into their connection to sexual, mental, and emotional health in later logs. Of special interest to me is how they may influence penile health and function. I’m curious about their role in H. Pylori and what the existing literature has to offer.

 

Ghost

 

 

 

 

 

 

 

 

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RE: Brain-gut axis in the pathogenesis of Helicobacter pylori infection

Date: [July 28, 2018]
Article Location: [NCBI]
Article Name: [Brain-gut axis in the pathogenesis of H. pylori]

I became interested in H. Pylori after reading about a patient whose PSSD resolved after he was treated for his H. Pylori infection. H. Pylori is a very common infection, with some experts suggesting that over half of the world (most in developing nations) might have this pesky bacteria. Most people will never exhibit any signs of infection, but H. Pylori can wreck havoc in the background. For example, H. Pylori is suspected to be a contributing factor to many GI tract cancers. In addition, around 10-15% of people with H. Pylori will develop ulcers.

Why am I interested for PSSD?

There are a few reasons. First of all, Helicobacter pylori is associated with lower androgen activity among men. More importantly, the connection between sexual dysfunction and H. Pylori is documented in the literature. A 2016 study from Nasrat et al. shows that the infection increased mucosal production of inflammatory cytokines which could play an integral role in the pathogenesis of ED. In their study, 17 of young participants with erectile Dysfunction (ED) and H. Pylori infection were treated with antibiotics. After H. Pylori was resolved, 90% of them returned to their normal erectile functioning. Finally, there have been online reports of deadened libido during H. Pylori infection that alleviate after treatment.

The PSSD research effort is rarely fruitful. Because we are working with barely any budget and only a few hundred active members, it’s hard to get new ideas. Because of this, tracking down those that are plausible is a good use of time. At this point, it’s impossible to say if H. Pylori has any connection to PSSD at all, but it is possible. At the very least this work will acquaint us with the world of inflammatory cytokines and their possible role in PSSD pathology.

As such, onwards to today’s paper!

The researchers are interested in the connection between the Central Nervous System (The brain and spinal cord), and the Enteric Nervous System (which consists of some 500 million neurons – note that this is A LOT of neurons for a region that we rarely think of as neurological. It’s 1/200 as many as your brain and 5 times the number of neurons in your spinal cord!). This “little brain” communicates with your brain via endocrine, immunological and neuronal messages. The researchers claim that this communication is bidirectional.

“Little Brain (ENS)” <<< >>> “Brain (CNS)”

They note that stress and mental disorders have a harmful effect on digestive tract function and intestinal bacterial flora, and that patients with digestive tract disorders have a high prevalence of co-morbid mental disorders (depression/anxiety/OCD). It seems as if H. Pylori could impact these communications between neural areas. Their arguments and cited sources are below (take special note of #4):

(1) the overlapping of upper and lower digestive tract functional symptoms in H. pylori infected patients[18,41–43] and the effect of H. pylori infection on IBS symptoms[43] (but see Breckan et al[44]) and pancreatic juice secretion[45]

(2) the protection against IBD appearance by H. pylori infection[17,46] resulting from changes induced in brain-gut axis function (neuroendocrine-immune crosstalk)[6,15,21,22,26,47,48]

(3) the association of H. pylori infection with ANS-related extra-digestive diseases, such as atherosclerosis or cardiac arrhythmia[3,35]

(4) the improved physical and psychological health-related quality of life and sexual relationships after digestive tract symptom alleviation and H. pylori eradication[49,50]

(5) the proposed association between H. pylori infection and the development of axonal type Guillain-Barré neuropathy, multiple sclerosis and epilepsy[51–53], and case reports of gastric MALT lymphoma followed by primary CNS lymphoma[54]; and

(6) the modulation of ANS (Autonomic Nervous System) balance by H. pylori infection[35].

…

[H. Pylori influence] the release of various neurotransmitters, including acetylocholine (vagal nerve, parasympathetic part), noradrenaline, adrenaline and sympathetic dopamine, as well as the neuropeptides leptin, ghrelin, calcitonin gene-related peptide (CGRP), nitric oxide, neuropeptide Y, substance P (SP), somatostatin (STS) and cholecystokinin (CCK).

Moreover, H. pylori infection is associated with the up-regulation of toll-like receptors and cytokine overproduction, especially tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, and IL-8[57–59], thereby indirectly influencing the brain-gut axis. These immune-mediators may stimulate mast cells (MC) in the gastric mucosa, as well as the hypothalamus and brain stem (via neuroendocrine-immuno crosstalk)[6,22], thereby activating the sympathetic ANS and pituitary-suprarenal axis, resulting in increased cortisol and adrenalin secretion[6,21,22,60,61].

Budzyński and Kłopocka (2014)

What could this mean for sufferers of H. Pylori?

(1) axon injury or stimulation (neuroinflammation) by bacterial cytotoxins (VacA)[60,72,78], neutrophil-attractant chemokine IL-8[79], and/or neutrophil-activating protein (H. pylori-NAP)[75,79]

(2) axon damage or stimulation by autoimmunological reactions due to mimicry of VacA, bacterial aquaporin (AQP), H. pylori-NAP and human antigens[51,53,79,80]

(3) H. pylori-induced production of free radicals[80–82], cytotoxins and cytokines[57–61,78], which may also result in blood-brain barrier disruption

(4) changes in neurotransmitter secretion in gastric mucosa and spinal cord[56,72,75,81,83–85]

(5) neuron injury resulting from gastric mucosa atrophy and a decrease in vitamin B12 absorption[86]

(6) changes in stomach and intestinal microbiota[6,87–89].

A combination of these effects could cause problems for PSSD sufferers, especially anything that increased inflammatory cytokine formation or increased sympathetic nervous system activity or neurotransmitter function. The researchers go on (Note number 2)…

Intermediate effects of chronic H. pylori infection on brain-gut axis function have been clinically observed as:

(1) the alteration of feeding patterns[15,19]

(2) cognitive and memory dysfunction[18,19,27,82,93], increased vulnerability to stress[15,19,27] and anxiety- and depressive-like behaviors[19]

(3) alterations in endocrine functions of the stomach, including the production of SP, VIP, CCK, STS, gastrin and ghrelin[81,94]

(4) changes in visceral ANS balance and the action of vagal visceral reflexes[95]

(5) alterations in gastrointestinal motility[21]

(6) increased visceral perception (chemo- and mechano-hypersensitivity)[67,96]

(7) changes in gastrointestinal secretion[21,45]

(8) increased intestinal permeability[23,61]

(9) intestinal microbiota[87–89], with indirect effects on the brain-gut axis[27,28,97–99]

(10) alterations in immunological reactivity, resulting in decreased prevalence of food allergies and inflammatory bowel diseases[46,100]

(11) the overlapping of gastrointestinal disorders from upper and lower parts of the digestive tract[43].

 

Moreover, H. pylori eradication has also been shown to normalize some of these alterations[55,95,100–103].

…

A proportion of H. pylori effects on the brain-gut axis may be secondary to central and peripheral nerve demyelination and blood-brain barrier disruption[79]. The cross-mimicry between VacA and H. pylori-NAP is recognized as the most important immunological reaction[79], which induces auto-reactive T cells and initiates or worsens gastric autoimmunity leading to atrophic gastritis and gastric cancer[91,92].

As noted above, H. Pylori is implicated in memory functioning:

In a large, cross-sectional study of United States adults by Beydoun et al[115], H. pylori-seropositivity was associated with poor cognition based on declining verbal memory test performance. H. pylori, as with other urease-positive bacteria that produce ammonia, is also recognized as a cause of liver-like encephalopathy[116]. In a study by Roubaud Baudron et al[117] who followed-up individuals aged 65 years or older for 20 years, H. pylori infection was recognized as a significant risk factor for the development of dementia as a result of enhanced neurodegenerative processes, a hypothesis that has been suggested by Deretzi et al[80].

What might these findings mean?

First of all, we have no idea if anyone with PSSD has H. Pylori infection. That’s step one. I’ve ordered my tests, and will be completing them soon.

Is there an high chance that H. Pylori contributes to the PSSD symptoms of most sufferers?

I would say no, but with a lack of existing therapies and because of the possible sexual, mental, and emotional side effects of H. Pylori, more research and testing is necessary. In the end, there is only one way to know: test.

 

Ghost

 

 

RE: My Solution For Post Finasteride Syndrome (Ray Peat Forum)

This is the first blog post of my “Logging” series, where I will comment on findings from articles and threads that I have read and create short summaries of them and add my response. (There is no real structure to these, simply loggings).

Date: [July 27, 2018]

Article Location: [Ray Peat Forum]

Article Name: "My Solution For Post Finasteride Syndrom[e]"

Ray Peat Forum (RPF) member Baltazar posted on April 22nd of this year that he was rid of his Post-Finasteride Syndrome (PFS). His regimen? Weird and potentially dangerous…

I’m especially worried about looking at the sun directly – NEVER a good idea.

While Balatzar’s story is interesting, there are some comments that intrigued me even more.

 

The member, brix, posted:

I took a low dose anti-progestin (a medication called Ella) for 5 days. This brought back libido and erections 75%. Then focused on digestion and eating healthy which got me back to baseline.

I would say my libido and sexual function is the best it’s been in my entire life now.

…

I split the pill into 6ths. Very low dose. Haidut has posted studies about males using mifepristone successfully. Mifepristone is similar to ella in that it blocks progesterone receptors, which resensitizes the receptor. Many others have been “cured” or [have] made progress [for their] pfs [using it].

 

Member “Haidut” chimes in:

The only commercially available anti-progestins I know of are RU486 and Ulipristal, but those are anti-glucocorticoid more than anything else so it is hard to separate their cortisol blocking effects from their anti-progestin ones. Be that as it may, both RU486 and ulipristal are used by males or things like Cushing syndrome and muscle wasting due to HIV/cancer/etc.

…

Glucocorticoid antagonists usually do not change cortisol levels, except in high doses where they may raise cortisol levels due to the feedback mechanism. Drugs like RU486 simply block the effects of cortisol, and blocking cortisol effects has been shown to be powerfully antidepressant and neurotrophic, and to restore proper steroidogenesis. Ulipristal is also a glucocorticoid antagonist, it is almost the same molecule as RU486. Both were developed as glucocorticoid antagonists and only subsequently marketed as progesterone antagonists as the market for the latter is much bigger and more profitable. Here is at least one link showing ulipristal acting as glucocorticoid antagonist and having comparable effects to RU486. Ulipirstal is about 60% weaker than RU486 as GR antagonist but still very potent.
https://www.tga.gov.au/sites/default/files/auspar-ulipristal-acetate-150904.docx
“…The pituitary, liver and adrenal gland also showed notable changes with treatment. Pituitary gland hyperplasia was observed in rats at all doses in the 6 month study, and bodyweight relative pituitary weight was significantly increased in rats with treatment at ≥5 mg/kg/day for 6 months and at ≥20 mg/kg/day for 2 weeks. These effects were not observed in monkeys. Hepatocellular hypertrophy was observed in rats treated at the high dose levels in the 2 week and 6 month studies, together with increased bodyweight relative liver weight. Bodyweight relative liver weight was also increased at the high dose level in the 2 week monkey study, but there were no effects on liver weight or histology in the 6 and 9 month monkey studies (≤25 mg/kg/day). Adrenal cortical hypertrophy was commonly observed in high dose animals in the 2 week and 6 month rat studies and in the 6 month monkey study. Increased bodyweight relative adrenal weight was seen at the high dose levels in the 6 month rat study and the 2 week and 6 month monkey studies. Serum cortisol was found to be increased in monkeys at the high dose level in the 2 week study, at all doses in the 6 month study and at the high dose level in the 9 month study. The effects observed with ulipristal acetate are similar to those seen previously with mifepristone, and are consistent with the drug’s anti progesterone and anti glucocorticoid activities. No overt toxicity was seen in any of the repeat dose toxicity studies.”

Given the side effects mentioned above, especially the increase in pituitary, liver and adrenal weight (which also occur with RU486) I would be highly reluctant to use this chemical, especially long term. Again, safer ways of opposing cortisol and restoring androgen and neurosteroid synthesis are available. I don’t want to get into another forum cross-argument, so this is the last thing I will post on this topic.
Finally, if all those people on hackstasis truly cured their issues why are they still there and keep posting???

…

Receptor antagonists do NOT lower levels of the steroid they antagonize but rather increase it. Look at the quote for Ulipristal – it raised cortisol. RU486 does the same – it raises cortisol and progesterone while it is being taken because it is an antagonist at both GR and PR. The abortion effects occur since RU486 blocks PR, so it is preventing progesterone from doing its job. Taking an antagonist is a signal to the organism that you have LOW levels of a specific hormone so it increases endogenous production. So, while RU486 is taken levels of cortisol and progesterone will increase. After you stop it, due to increased receptor expression for GR and PR as a result of taking an antagonist like RU486, those cortisol and progesterone levels will drop to levels probably lower than before taking RU486. Increased receptor expression after you stop taking the antagonist signal the organism that you don’t need as much of the cortisol/progesterone so it lowers endogenous synthesis. That’s how RU486 treats diabetes II – it increases GR receptor expression and that causes cortisol synthesis levels to drop unless you have Cushign disease in which case cortisol levels will stay elevated. So, people with Cushing have to take RU486 basically for life.

 

User “Dahir” disagreed a bit with Haidut on the effectiveness of these drugs:

Granted, the most frequent posters who were there from the beginning is a relatively small sample size, but they seem to all have significant improvements in their baseline. So if they were at say 30% before Ella or Ru486, taking those drugs could get them to 70 or 80% as a baseline, and the people who respond very well seem to maintain the benefits for a long period of time, maybe permanently. It is too early to tell. Most guys who have logged their progress with these drugs have had very good experiences with them.

…

There are a handful of recoveries from people who have really worked hard at this over the past few months. You should read them and look for trends if you’re interested.

 

This conversation is one that interests me. Recall that in 2017 there was a big interest in Ella on the PSSD Forum. It was around this time that conterversal Hackstasis member “Gboldouv” (aka “Gbold”) was banned from RPF and moved his writings elsewhere.

Reading this thread today has allowed me to reflect on Progesterone and anti-progestins, which have long been a part of my Neurohormone Theory.

I’ve also been reviewing videos that I made last summer. Because new ideas are always thrown around on the PSSD Forum, I think that it’s important to review older theories for anything that might have been missed the first time around.

 

Cheers,

Ghost

 

 

 

 

 

PSSD Wikipedia

Today was a busy day for me. I spent a lot of time adding content to this site and responding to emails and messages that had been backing up.

 

However, the biggest accomplishment was getting the PSSD Wikipedia page back online.

This is huge in getting PSSD the attention that it deserves.

Check it out here!

*edit: Since this writing the PSSD Wikipedia has been removed once more. I am working to revise the article and re-submit it to Wikipedia.

*edit 2.0: Article is undergoing revision and is back online.

A Call for Help

The growth of this site has been hindered by my (quickly approaching) finals for this term at my university.

Although I am dedicated to continuing to build this platform to share PSSD research with the scientific community at large, I don’t have the resources to write the content that I wish that it had in a timely fashion.

Any and all help contributing to this project would be greatly appreciated. If you believe that a resource or page isn’t available/ finished, I would love opinions/help on how to fill these gaps.

I can be contacted at:

ghostpssd@gmail.com