My research began with the thought that PSSD was due to permanently desensitized 5-HT1A auto-receptors, which would explain the sexual and emotional changes induced by SSRI antidepressants. This was very interesting, but it had some flaws. Namely, what was causing this persistent desensitization? I eventually tracked back the likely culprit: SERT/ 5-HTT, the serotonin transporter. Levels had been shown to be decreased in SSRI treatment, and at the same time that the 5-HT1A auto-receptor desensitized. It made sense then that chronic SERT decreases would lead to chronically high 5-HT levels, and therefore chronic 5-HT1A desensitization. I then ran into another problem. What was causing this chronic decrease in SERT? Looking through lab results of many PSSD patients, we noticed that Progesterone levels were high in most of them. This was a breakthrough for me becuase I realized that chronically altered Progesterone levels could affect SERT density in the brain. Of special interest were the enzymes that catalyzed the conversions of these steroid hormones.
Another breakthrough was learning that researchers had noted that Estrogen treatment was known to reverse PSSD-like symptoms in mice that were treated with antidepressants early in development. I looked into this literature, and found it to be the case. In fact, the PSSD-like state was totally reversed in mice treated with Estrogen and DHT.
I wrote more in depth about this theory (and how it’s evolved) on the ray peat forum on 8/30/17. You can find the original text here.
…additionally… I’ve quoted it below…
My research began with the thought that PSSD was due to permanently desensitized 5-HT1A autoreceptors, which would explain the sexual and emotional changes induced by SSRI antidepressants. Around this time, I wrote the following article about how these changes could lead to PSSD symptoms:
(https://pssdlab.files.wordpress.com/2017/02/ghost-2016a.pdf)
This was very interesting, but it had some flaws. Namely, what was causing this persistent desensitization? I eventually tracked back the likely culprit: SERT/ 5-HTT, the serotonin transporter. Levels had been shown to be decreased in SSRI treatment, and at the same time that the 5-HT1A auto-receptor desensitized both functionally and on the g-protein level. It made sense then that chronic SERT decreases would lead to chronically high 5-HT levels, and therefore chronic 5-HT1A desensitization. I then ran into another problem. What was causing this chronic decrease in SERT? Looking through lab results of many PSSD patients, we noticed that progesterone levels were high in most of them. This was a breakthrough becuase we realized that chronically altered progesterone levels could possibly affect SERT density and 5HT1A autoreceptor sensitivity in in the brain (although at this point we weren’t sure as to how).
Another enormous breakthrough for me was talking to a researcher last fall. He noted that estradiol treatment was known to reverse PSSD-like symptoms in mice that were treated with antidepressants early in development. I looked into this literature, and found it to be the case. In fact, the PSSD-like state was totally reversed in mice treated with estradiol and DHT. Studies from transgender sex reassignments showed that estradiol (and testosterone through being aromatized to estradiol) was protective of SERT levels. When a user on the forum tried estradiol, his symptoms temporarily went into remission. I was curious as to how progesterone was involved in this, so I keep digging deeper and collecting more progesterone levels from users.
I have collected 11 hormone results from PSSD sufferers, and have noticed a shocking trend. 8 of the 12 have high progesterone levels, and 2 more have levels that are right on the border of being high. There are only 2 of the 12 PSSD patients with progesterone levels in the middle of the range.
During a brief literature search, I have found that progesterone can decrease male sexuality without influencing testosterone levels, and that this is partially mediated by estradiol uptake in the preoptic area. Because estradiol is important for maintaining SERT density (and therefore normal 5HT1A activity), I believe that high progesterone levels could be causing the sexual dysfunction that is seen in hundreds of users (majority are young men) on my forum.”
So…
I know that SERT and 5-HT are impacted in SSRI treatment. That has been shown over and over again in the literature. I don’t know about in PSSD for certain, but that would be my guess for many reasons (no one has studied it yet). So much of PSSD symptoms point back to Dopamine being inhibited, and I really believe that serotonin is playing a role in this. Moving further, it makes sense that SERT is impacted. Not only has SERT been shown to be decreased with SSRIs, but lowering SERT would give a mechanism for 5-HT1A to remain desensitized indefinitely because it would let 5-HT run free. I’ve looked for a SERT/5-HT link for PFS, but only briefly. I don’t know if that has even been looked at to be honest. I know that depression has been noted in PFS, and that is tied closely to 5-HT, so maybe that’s where it would be seen in literature. Anyways, it seems that if estrogen receptor binding was decreased in the POA that this could be the cause of SERT decreases seen in SSRI treatment (Look at the studies with transgender reassignments below). I could tie that (lowered estrogen and decreased SERT) to progesterone. It’s tricky because no study has ever talked about increased progesterone in SSRI treatment (but one has shown changed levels with some up and some down), yet so many with PSSD show elevated levels. It would seen that elevated Prog would be sufficient (in theory) to desensitize the 5-HT1A autoreceptor. You may think that this is a stretch, but this has been found (desensitized 5HT1A AR) in pregnant females when Prog levels rise. I haven’t seen a researcher tie this all together yet, but the pieces start to fall into place. Take into account also that Prog can inhibit LH release, which has been shown to be inhibited significantly in humans on SSRIs (and even lower in patients on SSRIs with sexual dysfunction).
Literature:
Estradiol-17 beta increases serotonin transporter (SERT) mRNA levels and the density of SERT-binding sites in female rat brain. Estradiol-17 beta increases serotonin transporter (SERT) mRNA levels and the density of SERT-binding sites in female rat brain. – PubMed – NCBI
SSRIs act as selective brain steroidogenic stimulants (SBSSs) at low doses that are inactive on 5-HT reuptake. SSRIs act as selective brain steroidogenic stimulants (SBSSs) at low doses that are inactive on 5-HT reuptake. – PubMed – NCBI
Serotonin Clearance In Vivo Is Altered to a Greater Extent by Antidepressant-Induced Downregulation of the Serotonin Transporter than by Acute Blockade of this Transporter
http://www.jneurosci.org/content/22/15/6766.fullEvaluation of Endocrine Profile and Hypothalamic-Pituitary-Testis Axis in Selective Serotonin Reuptake Inhibitor-Induced Male Sexual Dysfunction. Evaluation of Endocrine Profile and… : Journal of Clinical Psychopharmacology
Antidepressant-induced internalization of the serotonin transporter in serotonergic neurons
Sign In5-HT1A Receptor Function in Major Depressive Disorder
5-HT1A Receptor Function in Major Depressive DisorderEffects of Chronic Antidepressant Treatments on Serotonin Transporter Function, Density, and mRNA Level
http://www.jneurosci.org/content/19/23/10494.full.pdfHigh-Dose Testosterone Treatment Increases Serotonin Transporter Binding in Transgender People.
http://www.ncbi.nlm.nih.gov/pubmed/25497691Serotonin transporter SERT mRNA and binding site densities in male rat brain affected by sex steroids. http://www.sciencedirect.com/science/ar … 8X98002812
Effects of progesterone on the sexual behavior of castrated, testosterone-treated male cynomolgus monkeys (Macaca fascicularis).
https://www.ncbi.nlm.nih.gov/pubmed/9226343Progesterone decreases mating and estradiol uptake in preoptic areas of male monkeys.
https://www.ncbi.nlm.nih.gov/pubmed/11790421Enhanced Sexual Behaviors and Androgen Receptor Immunoreactivity in the Male Progesterone Receptor Knockout Mouse
https://academic.oup.com/endo/article-l … .2005-0490
…
Further research on the hormone theory of PSSD is being planned at multiple institutions. Stay tuned for updates.
A few (of many) sources:
Estradiol-17 beta increases serotonin transporter (SERT) mRNA levels and the density of SERT-binding sites in female rat brain.
McQueen JK, Wilson H, Fink G.
PMID: 9105666
https://www.ncbi.nlm.nih.gov/pubmed/9105666
Serotonin transporter SERT mRNA and binding site densities in male rat brain affected by sex steroids
Judith K. McQueen, Helen Wilson, Barbara E.H. Sumner, George Fink
http://www.sciencedirect.com/science/ar … 8X98002812
Hormone replacement with 17β-estradiol plus dihydrotestosterone restores male sexual behavior in rats treated neonatally with clomipramine.
Limón-Morales O, Soria-Fregozo C, Arteaga-Silva M, González MH, Vázquez-Palacios G5, Bonilla-Jaime H.
PMID: 25449595
https://www.ncbi.nlm.nih.gov/pubmed/25449595
SSRIs act as selective brain steroidogenic stimulants (SBSSs) at low doses that are inactive on 5-HT reuptake.
Pinna G, Costa E, Guidotti A.
PMCID: PMC2670606
https://www.ncbi.nlm.nih.gov/pubmed/19157982
Additional Literature:
Vasiliki Michopoulos, BA, Sarah L. Berga, MD, and Mark E. Wilson, PhDPMCID: PMC3253022
NIHMSID: NIHMS344504
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253022/
ANCA POP, DIANA IOANA LUPU, JULIEN CHERFAN, BELA KISS, and FELICIA LOGHINPMCID: PMC4632899
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632899/
Doodipala Samba ReddyPMCID: PMC3139029
NIHMSID: NIHMS306855
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139029/
Pinna G, Costa E, Guidotti A.PMCID: PMC2670606
https://www.ncbi.nlm.nih.gov/pubmed/19157982
Activation of the Liver X Receptor Increases Neuroactive Steroid Levels and Protects from Diabetes-Induced Peripheral Neuropathy
Gaia Cermenati, Silvia Giatti, Guido Cavaletti, Roberto Bianchi, Omar Maschi, Marzia Pesaresi, Federico Abbiati, Alessandro Volonterio, Enrique Saez, Donatella Caruso, Roberto Cosimo Melcangi and Nico Mitro
“LXR ligand treatment of streptozotocin-treated rats increases expression in the sciatic nerve of steroidogenic acute regulatory protein (a molecule involved in the transfer of cholesterol into mitochondria), of the enzyme P450scc (responsible for conversion of cholesterol into pregnenolone), of 5α-reductase (an enzyme involved in the generation of neuroactive steroids)”
Schüle C, Romeo E, Uzunov DP, Eser D, di Michele F, Baghai TC, Pasini A, Schwarz M, Kempter H, Rupprecht R.PMID: 16344854
https://www.ncbi.nlm.nih.gov/pubmed/16344854
