Neuropathy and genital fibrosis, hypothesis and speculation on PSSD

[anacleta]

Patients with PSSD show on average high rates of genital fibrosis, or scar tissue, which can cause or worsen symptoms of erectile dysfunction and genital numbness.

Clinical studies on patients with PSSD about it:

- Waldinger MD, van Coevorden RS, Schweitzer DH, Georgiadis J. Penile anesthesia in Post SSRI Sexual Dysfunction (PSSD) responds to low-power laser irradiation: a case study and hypothesis about the role of transient receptor potential (TRP) ion channels. Eur J Pharmacol. 2015 Apr 15;753:263-8. https://doi.org/10.1016/j.ejphar.2014.11.031. Epub 2014 Dec 4. PMID: 25483212.

It is hypothesized that SSRI treatment induces disturbances of transient receptor potential (TRP) ion channels of mechano-, thermo- and chemosensitive nerve endings and receptors resulting in the penile anesthesia in PSSD. It is further hypothesized that there are two types of PSSD, one of which occurs soon after the start of SSRI treatment.

- A. Waraich, J. Yih, S. Goldstein, I. Goldstein, 076 Post-SSRI Sexual Dysfunction (PSSD): Ten Year Retrospective Chart Review, The Journal of Sexual Medicine, Volume 18, Issue Supplement_1, March 2021, Page S41, https://doi.org/10.1016/j.jsxm.2021.01.046

New information includes the facts that 1) ED is most often severe, 2) erectile tissue inhomogeneity is common, consistent with erectile tissue fibrosis/decreased erectile tissue expandability as an underlying vascular ED.

- NM094 | POST-RETINOID, POST-FINASTERIDE AND POST-SSRI SYNDROMES: PATIENT EVALUATION AND INITIAL TREATMENT, Kenneth M. Peters, Jackson A. Stachelek, Bernadette M.M. Zwaans (blog page https://disfunzionisessualipostssri.blo ... tudio.html )

Von Frey filament testing showed reduced penile sensation, FirmTech® device measured on average 2-3 weak nocturnal erections, and CCM testing indicated variable neuro-inflammation. All patients who used the Biowave® reported improved penile sensation and tumescence. Erection quality improved after shockwave therapy. All patients continue with anhedonia and feeling of disconnect between the penis and the brain. 

Other studies potentially involved:

- Frohlich PF, Meston CM. Evidence that serotonin affects female sexual functioning via peripheral mechanisms. Physiol Behav. 2000 Nov 1-15;71(3-4):383-93. https://doi.org/10.1016/s0031-9384(00)00344-9. PMID: 11150571.

- AbdelRazek MA, Chwalisz B, Oaklander AL, Venna N. Evidence of small-fiber neuropathy (SFN) in two patients with unexplained genital sensory loss and sensory urinary cystopathy. J Neurol Sci. 2017 Sep 15;380:82-84. https://doi.org/10.1016%2Fj.jns.2017.07.016. Epub 2017 Jul 9. PMID: 28870595; PMCID: PMC5999027.

- David Healy, Joshua LaPalme, and Michael Levin. Post-SSRI Sexual Dysfunction: A Bioelectric Mechanism? Bioelectricity. Mar 2020. 7-13. http://doi.org/10.1089/bioe.2019.0010

- Rahardjo HE, Märker V, Tsikas D, Kuczyk MA, Ückert S, Bannowsky A. Fibrotic Diseases of the Human Urinary and Genital Tract: Current Understanding and Potential Strategies for Treatment. J Clin Med. 2023 Jul 19;12(14):4770. https://doi.org/10.3390%2Fjcm12144770. PMID: 37510885; PMCID: PMC10381287.

- Mann DA, Oakley F. Serotonin paracrine signaling in tissue fibrosis. Biochim Biophys Acta. 2013 Jul;1832(7):905-10. https://doi.org/10.1016%2Fj.bbadis.2012.09.009. Epub 2012 Sep 29. PMID: 23032152; PMCID: PMC3793867.

The molecule serotonin (5-hydroxytryptamine or 5-HT) is involved in numerous biological processes both inside and outside of the central nervous system. 5-HT signals through 5-HT receptors and it is the diversity of these receptors and their subtypes that give rise to the varied physiological responses. It is clear that platelet derived serotonin is critical for normal wound healing in multiple organs including, liver, lung heart and skin. 5-HT stimulates both vasoconstriction and vasodilation, influences inflammatory responses and promotes formation of a temporary scar which acts as a scaffold for normal tissue to be restored. However, in situations of chronic injury or damage 5-HT signaling can have deleterious effects and promote aberrant wound healing resulting in tissue fibrosis and impaired organ regeneration. This review highlights the diverse actions of serotonin signaling in the pathogenesis of fibrotic disease and explores how modulating the activity of specific 5-HT receptors, in particular the 5-HT2 subclass could have the potential to limit fibrosis and restore tissue regeneration.

Some questions, assumptions and speculations by a non-scientist.

Is fibrotic tissue created in response to damage or inflammation of nerve endings/small fibres or also for other reasons?

SSRIs are also used to relieve neuropathic pain and premature ejaculation (i.e., cause hypoesthesia).

SSRIs could cause genital hypoesthesia via central/cerebral effects or also via peripheral effects (ion channels in small nerve fibres in the skin).

Can SSRIs CAUSE neuropathy? Through serotonergic action or through indirect effects (action on neurosteroids or other)?

SSRIs can cause reduced genital sensation to touch, pain, pleasure, and sexual dysfunction. During a neuropathy/inflammation caused by other factors (viral influences, traumatic injury...?), taking SSRIs could act as an anesthetic and cause one not to feel pain or burning.

SSRIs could cause abnormalities in fibrotic tissue formation via serotonergic action.

If there was genital inflammation and one did not notice it through sensation, and even pleasurable sensations were reduced, more insistent and aggressive stimulation/masturbation could worsen the inflammation and create micro lesions resulting in fibrotic formation that is abnormal because of the SSRI itself. This hypothesis would obviously not explain many things and all cases at all.

There are cases of PSSD as an adverse reaction to a few doses, and based on the description of the symptoms of sexual dysfunction, their onset and evolution, it would be important to know: can fibrosis form even in a short time or does it take a longer time? Perhaps fibrosis can make symptoms first caused by neuropathy chronic.

PSSD with marked symptoms seems to affect an extreme minority of SSRI users and that PSSD actually presents varied cases with different symptoms. For example, those who have strong emotional numbess and anhedonia (and perhaps a functioning erection but without pleasure) claim that PSSD starts with that, while those who only have sexual dysfunction claim that there can be PSSD even without those symptoms.

Sometimes I wonder if the PSSD community is all in all a small group of exceptional cases among which some have the same kind of problem and some others, and this related not only to whether it is a central or peripheral problem, but also which nervous or epigenome or microbiota districts etc. are involved and in what way and in what mix.

From the community we know that antipsychotics can also cause persistent symptoms apparently very similar to those caused by SSRI/SNRIs. Finasteride and isotretinoin can do this as well but still in a large minority of cases.

Some people remained affected by PSSD only after years of various treatments with SSRIs, which suggests that at the time PSSD is triggered there may be a momentary vulnerability of the system, on whom some effect of the drug has raged toxicly with chronic consequences, rather than some unfortunate genetics in relation to SSRI.

Those who suffer from symptoms that seem cerebral might have had in the course of taking SSRIs a vulnerable condition such as a particular inflammation, viral or bacterial, or something else without realizing it, with which the SSRI interacted with catastrophic consequences? For example anesthetizing sensation while increasing inflammation, while wearing out receptors or altering neurosteroids and enzymes, or what is needed for the body to heal itself, triggering epigenetic changes as a form of extreme defense, or whatever is causing the chronicity of the disorder.