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POIS Theory Master List

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Post theories/ideas regarding the Pathophysiology of POIS. This thread can function as a central hub. You may dump links to threads from other members in the comment section.

Rudimentary version

* Acute compression proprioceptive axonopathy in the muscle spindles.(1)
* Adrenal fatigue
* Atopy
* Autoimmunity: CD9+Prostasome SPAGs: GLIPR2/Annexin A1/PSCA, SOCS proteins, Extracellular Vesicles, Anti-neutrophil antibodies (reactive neutropenia), G-protein coupled receptor autoantibodies, adrenergic receptor autoantibodies, dopamine receptor autoantibodies, histamine receptor autoantibodies, flagellin antibodies, anticytokine autoantibodies (ACAAs, cytokine depletion), Mu-Opioid receptor autoantibodies, (risk of) Autoimmunity is associated with Th1 polarization and low Vit D status
* Autoinflammation (activation of NLRP3 inflammasome, Exosome-mediated inflammation)
* Impaired Barrier function: VEGF, tight junction proteins: (zonulin, occludins, claudins, JAMs), leaky gut, IL-33-ST2-ILC2 axis, leukocyte infiltration, collagen defects, protease-activated receptor-mediated epithelial barrier dysfunction, disrupted neurovascular unit
* Brain region contenders: Periaqueductal gray, Brainstem (CFS/POIS combo patients, Allergic reactivity modulator), Trigeminal nerve, Frontal Lobe, Pons (+rhythmic breathing automaticity issues), (1), VTA, Medulla Oblongata
* Brain signal misinterpretation/misfiring, brain activity (Electric), brain waves
* Cellular senescence
* Central and/or peripheral sensitization syndrome/sensory amplification disorder (1), (hypersensitivities, lowered trigger thresholds, high reactive neural networks, QST, altered nociception, Low signal-to-noise ratio=low NE/SP ratio), dorsal horn circuitry
* Cerebral blood flow, Frontal Lobe, abnormal orgasm induced cerebral perfusion (vagus driven), altered blood flow to nerves, capillary stalling/hypoxic pockets, POIS relief by niacin flush
* Channelopathy: PIEZO2, NaV1.5
* Chronic Fatigue-like illness, (1)
* Cytokines: Imbalance between pro- and anti-inflammatory cytokines, abnormal response, reactive cytokine depression/depletion, Pyrogens (reactive fever), Synergetic cascade (Example: IFN-g, IL-12,15,18), interferon signaling (flu inducers)
* Damage-associated molecular pattern (AKA danger signals, alarmin): (IL-33-ST2-ILC2 axis, Stress proteins)
* Dysbiosis (Commensal): Seminal proteome/microbiome, Gut microbiome/SIBO/SIFO, gut virome, loss of butyrate producing strains, Gut/Brain axis
* Dopaminergic hypofunction: low level, slow return to baseline, DA/DBH/NE metabolism, loss of dopaminergic neurons, too many dopamine transporters, Flibanserin increases NE and DA.
* Dysautonomia, (1): Autonomic hyperreflexia, Sympathetic hyperactivity, norepinephrine (transporter) deficiency
* Eicosanoid inflammatory mediator cascade
* Endocrine: Hypogonadism, Progesterone (1, 2) ,RAA system(dehydration)
* Endogenous opioid system disorder (Mu-opioid withdrawal, endorphin signaling), Hippocampus
* Endothelial Dysfunction, (Regional) Vasomotor Dysfunction, decreased vascular resistance
* Eosinophil activation (Allergic inflammation: Eosinophil cationic protein)
* Epididymitis, (2)
* Excitotoxin Syndrome
* Enzymes: COX, PLA2, PLC, Adenylyl cyclase (1, 2, 3), impaired 17-20 lyase activity and 17-a-hydroxylase activity, PDE5, 21-hydroxylase (elevated Progesterone in some patients), MAO/Co-enzyme FAD (alcohol trigger), Cytochrome c oxidase
* Glial activation (cascade? Glial activation markers?)
* HLA DNA-profile
* Histadelia/High brain histamine
* Hypersensitivity Type I, III, IV: IVa (Th1/Monocyte directed), IVb (Th2/Eosinophil directed), IVc (CD8+/Fas/perforin/Granzyme B directed), IVd (IL-8/GM-CSF/Neutrophil directed), Type VI. (A48)
* Infection: Neurotropic Virus Reactivation (1), Post-Viral Syndrome, viral products/DNA in seminal fluid, UTI, bacterial infection, fungal/C.Albicans infection (reactive drop of fungal defense IL-17 post O in susceptible patients?), VDR blockade through pathogen infection, hCG, Seminal vesicles
* Intracellular calcium: Decreased post O in lymphocytes (cytokine depression)
* Lectin signaling
* Limbic dysregulation
* Malabsorption
* Malnourishment
* Mast Cell Activation Syndrome (MCAS), 1, 2, See video section, Omalizumab Impaired Glia/Mast cell communication, mast cell derived exosomes, Genetic disposition, MC subtype genes, CD117 in GI tract, MC infiltrates in genitourinary tract, activation of brain MCs, Hormonal triggers
* (PI3K-Akt-)mTOR activation
* Mechanical: radiculopathy of the sacral spinal nerve roots (SSNR), pinched vagus nerve, (cranio) cervical instability, Atlas Subluxation, nerve root irritation, brainstem compression, Ossification of spinal ligaments
* Metabolism: Catecholamines, Histamine (HNMT, DAO), NO/NOS/Arganine, Tryptophan, Hyperammonia, wrong transsulfuration pathway.
* Methylation related problem, lack of methyl donors, SAM-e defficiency, MTHFR mutation
* Molecular mimicry
* Mucosal Immunity (sIgA/IgG)
* Myofascial Pain Syndrome
* NAD+ or NAD+/NADH ratio: Low--> CD38/NAD+ axis signaling, IDO/TDO induced depletion of Tryptophan.
* Natural killer cell response
* Nerve conduction (thermal hypersensitivity)
* Neuroendocrine response: Abnormal HPA response, Uncoupling between the vagal tone and HPA axis.
* Neuroinflammatory disease (stress mediated + increased stress susceptibility)
* Neurotransmitter profile (unique to POIS, Glutamate/GABA etc.), Low Serotonin (premature ejaculation)
* Polyamines: Spermidine and Spermine depletion (SAM acts as the precursor in the biosynthesis)
* Receptor over/under expression/activation: 6-ND, CD38 (CD4+ freq.), CD20, CRH-R1/2 (Mast Cell), alpha1AR/betaAR, H1-4, mu-opioid (PAG neurons), DAR (Immune cells?, D2 autoreceptor, D3), androgen receptor, NMDAR, FC receptors, PAR-2, estrogen receptors, GPR109A (Niacin), ST2, Sigma receptors, VDR, 5-HT2C/Melanocortin (underweight), 5-HT2A. CGRP. Involvement of relatively high density and widespread receptors like ACE2 or GPCR
* Refractory period (sluggish, stuck)
* Ripoptosome activation
* ROS/antioxidant capacity ratio is off--->oxidative state, ROS cascade
* Semen regeneration
* Seminal exosomes: Dysregulated function, Altered content
* Small fiber neuropathy/dysfunction
* Spinal Cord Injury
* Synaptic Fatigue
* Th1/Th2 imbalance (Dynamic changes by sexual activity)
* T memory cells (proliferation+survival leading to increased sensitization)
* Transcription Factors: Upregulated NF-kB
* Transiently Induced Immune Deficiency
* Tregs (self tolerance): Abnormal count, FOXP3+ expression or impaired IL-2/IL-10/TGF-b signaling.
* Tyrosine kinase; abnormal signal transduction
* Low Tryptophan and 5-HT. High IDO1 activity, Kynurenic acid and Quinolinic acid.
* Vagus nerve dysfunction/infection, Body inflammatory regulator, POIS female, withdrawal of vagal tone, Post-exertional malaise (vagus nerve driven peristalsis), Brain/vagus nerve/mast cell axis, (acetyl)choline deficiency
* Varicocele, p53–Bax-Bcl2-Caspase3 apoptic signaling cascade, HSPs
* Vitamin D deficiency-associated disorder, Polymorphisms Vit D gene, (acquired) Vitamin D resistance (1) (M.D. had a POIS patient with vit D status close to 0 and wasn't able to increase it by supplementation), Chapter 13 inflammationOr a combination of more than one of the above.

What else?


Premature Ejaculation:

Increased APP, AB42 in seminal plasma. Abnormal PSSR (lifelong PE)
Low Serotonin
Low serotonin + High Interferon gamma
Low serum BDNF
High Leptin/5-HT ratio
Low seminal plasma magnesium
Low NO
Imbalance between excitatory and inhibitory signals in the brain
Altered serotonin receptor activity
Hyperexcitability of penile sensory receptors
Changes in the neural processing of sensory signals
ANS dysfunction (lifelong PE)
TRP ion channels
weakened connectivity between the inner brain regions in the dopamine system and strengthened connectivity between the dopamine system and other brain areas
Decreased TPH2 expression in brain.
Altered ALFF of frontal, parietal cortex, and putamen
Caudate nucleus volume
Dopamine autoreceptors
DAT1 polymorphism
Increased Norepinephrine firing? Low Norepinephrine?
Medial preoptic area in the rostral hypothalamus and nucleus paragigantocellularis in the ventral medulla
Increased nerve fibers (NGF?)
Dynamic changes of brain activity (Lifelong PE)

Hormonal Risk factors: High Testosterone, High Estradiol, Low Prolactin, High oxytocin, High FT3, High FT4, High Leptin.

Exercise intolerance

Histamine depletion
Histamine response
Natural Killer cell response
Post-exertional Malaise
PSN/SNS tone
Gut and plasma microbiome
S100B compromised
Testosterone and Heat shock protein response
Impaired microcirculation/deficient action of NO
Defective Growth Hormone response
Elevated Cytokines
Decreased rate of ammonia clearance: Amino acids: Aspartic acid deficiency
Dysfunctional increase in WASF3 protein

Headache inducers


Non-IgE mediated food hypersensitivity

The cholinergic tone as a modulator of Food Allergy
Central sensitization
Eosinophil/ECP (ECP is a better marker for allergic activation than IgE, need source)
Type IV hypersensitivity
MRGPRX2 mediated pseudo-allergy
Intestinal B cell activating factor
Intestinal epithelial barrier disruption


Muscle hypoperfusion
INSL3/RXFP2 signaling

Ocular itch

Gastrin-releasing peptide receptors in trigeminal sensory system



(Sudden) Muscle wasting/weight loss not reversed by nutrition

Reminder: Some ideas might be left inside other threads like POIS paper treatment summary etc.

Reserved 2

Reserved final

POIS Patients are rarely tested for DAMPs:


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