Very promising theory on PSSD being caused by changes in Kisspeptin expression

This is for hypothesis and even educated speculation.
Brain food
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Very promising theory on PSSD being caused by changes in Kisspeptin expression

Unread post by Brain food »

I was researching Kisspeptins after Dr. Healy put up his new RxISK Research Forum for Enduring Sexual Dysfunction. I think that these peptides could explain PSSD. See literature review below. I have also copied and pasted the passages that I found most relevant.

Mills, Edouard G., et al. "Current Perspectives on Kisspeptins Role in Behaviour." Frontiers in Endocrinology (2022): 1165.

https://www.frontiersin.org/articles/10 ... 28143/full

Humans with inactivating mutations of KISS1 or KISS1R display a phenotype of hypogonadotropic hypogonadism (6, 7), whereas activating mutations of KISS1 or KISS1R causes central precocious puberty (13).

Peripheral Kisspeptin Expression
Moreover, abundant Kiss1 and Kiss1r expression is detected in peripheral reproductive organs in rodents, including ovary (35), uterus (37) and testes (38). Regarding humans, KISS1 mRNA expression is principally found in the placenta and testis, as well as moderate expression levels in the liver, pancreas, small intestine (9, 11).

Sexual Partner Preference and Sexual Motivation

In a landmark study in 2007 which triggered much of the recent interest in kisspeptin and behaviour, whereas wildtype male mice spend >70% of their investigatory time with female stimulus animals, gonad intact Kiss1r knockout (KO) male mice exhibit no preference for either sex and spend an equivalent investigatory time with male and female conspecifics, despite normosmia (56). Of note, testosterone replacement in these mutant mice fails to restore normal partner preference (56), highlighting a key role for the kisspeptin receptor specifically in controlling sexual partner preference. Similarly, using the chemogenetic DREADDs (Designer Receptor Exclusively Activated by Designer Drugs) approach to selectively stimulate kisspeptin neurons in the posterodorsal subnucleus of the MeA (MePD), doubles the time male mice spend investigating an oestrous female over another gonadally-intact male (57).

Moreover, a very recent study examined the effects of kisspeptin on sexual motivation and its dependence on testosterone levels in male rodents (58). In this study, behavioural effects with an oestrous female were evaluated following intranasal administration of a GnRH analogue (buserelin), intraperitoneal kisspeptin or intranasal kisspeptin. Intranasal buserelin increased circulating testosterone levels but did not affect behavioural measures of sexual incentive motivation, whereas intraperitoneal kisspeptin increased both circulating testosterone and sexual motivation. Notably, intranasal kisspeptin also increased sexual motivation, despite not affecting circulating testosterone levels (58). Taken together, these data provide interesting insight for GnRH/testosterone-independent kisspeptin-effects to stimulate sexual motivation in male rodents.

A similar critical role for kisspeptin-signalling in regulating sexual partner preference in female rodents has been observed in a key elegant study. Ovariectomised and hormone-primed Kiss1 KO mice fail to display normal male-directed preference, whereas a single peripheral injection of kisspeptin resolves this deficit (59). Interestingly, selective viral ablation of AVPV kisspeptin neurons also results in female mice failing to display any male-direct preference, which again resolves following a single peripheral injection of kisspeptin (59), indicating site-specificity of the AVPV for kisspeptins control of mate preference in female mice. Furthermore, exploiting a transgenic GnRH deficient mouse model (which progressively loses GnRH expression during adulthood) results in female mice displaying female rather than male-directed preference, which normalises following a single peripheral injection of GnRH (but not kisspeptin) (59). This indicates that kisspeptin signals through GnRH neurons to specifically mediate sexual partner preference.

Copulatory Behaviour and Arousal
Preclinical Animal Studies
The MeA is a key brain region involved in sexual behaviour. Lesioning of the MeA in rats suppresses male copulatory behaviours such as erections and intromissions (72, 73). Although androgen receptors are present in the MeA (74), direct administration of androgens does not cause spontaneous erections (75), suggesting that additional factors are required to stimulate this physiological pathway. In keeping with this, microinjections of kisspeptin directly into the MeA of male rats dose-dependently stimulates ex-copula erections, an effect blocked by pre-treatment with a kisspeptin receptor antagonist (76). Furthermore, when kisspeptin is infused into the intracerebroventricular space, no erections are observed (despite comparable rises in circulating LH), demonstrating site-specificity of the MeA for kisspeptin’s effects on rodent erections and crucially suggests its role in this aspect of sexual behaviour is independent of downstream GnRH, LH or testosterone (76).
Human Studies
In healthy heterosexual men, peripheral administration of kisspeptin enhances limbic brain activity (as determined by fMRI) in response to visual sexual stimuli, including the anterior and posterior cingulate and amygdala (78). Given that desire for sexual stimulation is an important component of the human sexual response (79), it is intriguing that in this study the greater kisspeptin enhanced limbic brain activity (including in the putamen) to sexual images, the less aversion to sex healthy men displayed (determined using behavioural tests). Moreover, in response to sexual images, kisspeptin was observed to activate limbic structures (including the hippocampus) more in men with lower baseline reward behavioural scores, which is highly relevant given that human sexual behaviour is closely associated with pleasure and reward.

Mood and Emotions

Kisspeptins antidepressant-like effects have been identified in male mice using a modified forced swimming paradigm (90). During this test, rodents are placed into a container filled with water and assessed for active (swimming and climbing) and passive (immobility) behaviours, suggestive of anti-depressant and depressant effects, respectively (91). This study revealed that intracerebroventricular delivery of kisspeptin increased antidepressant-like behaviours (climbing and swimming times), whilst reducing the duration of immobility (90). Regarding interplay with downstream systems, pre-treatment with a nonselective α-adrenergic, α2-adrenergic or nonselective 5-HT2 serotonergic receptor blocker abolished kisspeptins anti-depressive actions, whereas pre-treatment with a cholinergic, dopaminergic or GABAergic receptor blocker had no effect on kisspeptins actions. Therefore, the results from these receptor blockade experiments indicate that kisspeptin can interplay with downstream adrenergic and serotonergic systems to bring about antidepressant-like effects (90).

Given the interaction between kisspeptin and the serotonergic system, it is interesting to consider the brain regions involved in eliciting the antidepressant-like effects. In a recent study, adult male rats received four weeks of intraperitoneal escitalopram (92), a widely prescribed selective serotonin reuptake inhibitor for mood disorders, which increases serotonin activity in the brain by limiting its reabsorption. This experimental paradigm significantly upregulated Kiss1 mRNA expression in the amygdala (272% increase compared to saline treated rats). Furthermore, Kiss1r mRNA was highly increased in the hypothalamus, hippocampus and cerebellum by 170%, 177% and 131%, respectively (92). Indeed, these findings are congruent with a previous study demonstrating that intra-cerebroventricular injections of serotonin hydrochloride to male rats significantly enhances hypothalamic kisspeptin expression and resultant circulating LH concentrations (93). Collectively, these data garner further evidence for the interplay between kisspeptin and the serotonergic system in eliciting antidepressant actions, as well as evidence for the putative brain regions involved.
Brain food
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Re: Very promising theory on PSSD being caused by changes in Kisspeptin expression

Unread post by Brain food »

So I have done some more research and have further refined my theory. I think that it's likely that if Kisspeptin causes PSSD, it does so by causing damage to the testicles (in men at least, in women it would be another part of the body). This study from Imperial College London shows that Kisspeptin at high doses causes testicular degeneration in rats. It showed that the rats treated with Kisspeptin experienced damage to their seminiferous tubules. There are several studies in rats that show that SSRIs and Finasteride damage the seminiferous tubules. In review that I mentioned above, the study #92 shows that escitalopram greatly increases kisspeptin levels in certain areas of the brain in rats. This could be causing damage to their testicles and might be the biological mechanism behind PSSD and PFS.

Kisspeptin-54 at high doses acutely induces testicular degeneration in adult male rats via central mechanisms

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2697701/

https://bpspubs.onlinelibrary.wiley.com ... 08.00061.x
HzeTmy
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Re: Very promising theory on PSSD being caused by changes in Kisspeptin expression

Unread post by HzeTmy »

This theory sounds good bro thx for share.
anonym123
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Re: Very promising theory on PSSD being caused by changes in Kisspeptin expression

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This is not your theory. You could have at least credited the person who came up with this idea instead of appropriating it. A guy named Johann, on the rxisk blog, presented this idea in the comments section on August 12, 2022: https://rxisk.org/our-love-life-needs-y ... /#comments. His comment evokes everything you mention. Stealing someone else's idea is intellectually dishonest to say the least...
Brain food
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Re: Very promising theory on PSSD being caused by changes in Kisspeptin expression

Unread post by Brain food »

anonym123 wrote: Sat Aug 27, 2022 6:49 pm This is not your theory. You could have at least credited the person who came up with this idea instead of appropriating it. A guy named Johann, on the rxisk blog, presented this idea in the comments section on August 12, 2022: https://rxisk.org/our-love-life-needs-y ... /#comments. His comment evokes everything you mention. Stealing someone else's idea is intellectually dishonest to say the least...
To be honest, I didn’t steal his theory but I also admit that I wasn’t the one who gave David Healy the idea to put Kisspeptin on his new RxISK Research Forum. I didn’t even see Johann’s comment until you posted the link. And I strongly disagree that his comment evokes everything that I mentioned. However, I admit that I did more research into Kisspeptin after I saw Dr. Healy posted it as one of the things to look into on his RxISK research forum. I had previously come across Kisspeptin earlier this summer when I was looking into the research of Victor M. Navarro’s lab at Harvard. However, at the time, I didn’t think that it was a promising enough candidate to post about on here or email David Healy about. So I guess that I do owe Johann credit because he is the one who gave David Healy the idea to include Kisspeptin as a tab on the RxISK research forum and this is what made me do more research into it. I didn’t know where David Healy got the idea to include Kisspeptin from, but now I know. However, I wasn’t trying pretend that I came up with Kisspeptin idea all on my own. The first sentence of my post reads “I was researching Kisspeptins after Dr. Healy put up his new RxISK Research Forum for Enduring Sexual Dysfunction.”
Brain food
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Re: Very promising theory on PSSD being caused by changes in Kisspeptin expression

Unread post by Brain food »

anonym123 wrote: Sat Aug 27, 2022 6:49 pm This is not your theory. You could have at least credited the person who came up with this idea instead of appropriating it. A guy named Johann, on the rxisk blog, presented this idea in the comments section on August 12, 2022: https://rxisk.org/our-love-life-needs-you-to-be-wiked/#comments. His comment evokes everything you mention. Stealing someone else's idea is intellectually dishonest to say the least...
Also, there are previous mentions of Kisspeptin on this forum that were made long before Johann’s comment. GIXXER made a post titled “ kisspeptin Mental Viagra” on January 28, 2017. Let’s just try to be collaborative and add relevant articles to the new RxISK Research Forum.
Brain food
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Re: Very promising theory on PSSD being caused by changes in Kisspeptin expression

Unread post by Brain food »

There is currently an ongoing Phase 2 trial at Massachusetts General Hospital called “ Prolonged Pulsatile Kisspeptin Administration in Hypogonadotropic Hypogonadism”. Stephanie B. Seminara, MD is the sponsor. This probably isn’t the most relevant study for PSSD/PFS sufferers because Hypogonadotropic (secondary) Hypogonadism is due to problems with either the hypothalamus or pituitary gland. From all of the evidence it seems much more likely that PSSD is caused by problems with the testicles in men and another organ in women, so studies of treatments for Hypergonadotropic (primary) hypogonadism would be more relevant. Also, we won’t have results for a few more years. See schedule below:

Actual Study Start Date :
January 20, 2021
Estimated Primary Completion Date :
November 30, 2024
Estimated Study Completion Date :
February 28, 2025


https://clinicaltrials.gov/ct2/show/NCT ... w=6&rank=1
anonym123
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Re: Very promising theory on PSSD being caused by changes in Kisspeptin expression

Unread post by anonym123 »

Brain food wrote: Sat Aug 27, 2022 9:24 pm
anonym123 wrote: Sat Aug 27, 2022 6:49 pm This is not your theory. You could have at least credited the person who came up with this idea instead of appropriating it. A guy named Johann, on the rxisk blog, presented this idea in the comments section on August 12, 2022: https://rxisk.org/our-love-life-needs-y ... /#comments. His comment evokes everything you mention. Stealing someone else's idea is intellectually dishonest to say the least...
To be honest, I didn’t steal his theory but I also admit that I wasn’t the one who gave David Healy the idea to put Kisspeptin on his new RxISK Research Forum. I didn’t even see Johann’s comment until you posted the link. And I strongly disagree that his comment evokes everything that I mentioned. However, I admit that I did more research into Kisspeptin after I saw Dr. Healy posted it as one of the things to look into on his RxISK research forum. I had previously come across Kisspeptin earlier this summer when I was looking into the research of Victor M. Navarro’s lab at Harvard. However, at the time, I didn’t think that it was a promising enough candidate to post about on here or email David Healy about. So I guess that I do owe Johann credit because he is the one who gave David Healy the idea to include Kisspeptin as a tab on the RxISK research forum and this is what made me do more research into it. I didn’t know where David Healy got the idea to include Kisspeptin from, but now I know. However, I wasn’t trying pretend that I came up with Kisspeptin idea all on my own. The first sentence of my post reads “I was researching Kisspeptins after Dr. Healy put up his new RxISK Research Forum for Enduring Sexual Dysfunction.”
Ok fair enough. Interesting thoughts by the way.
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anacleta
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Re: Very promising theory on PSSD being caused by changes in Kisspeptin expression

Unread post by anacleta »

Brain food wrote: Sat Aug 27, 2022 4:37 pm So I have done some more research and have further refined my theory. I think that it's likely that if Kisspeptin causes PSSD, it does so by causing damage to the testicles (in men at least, in women it would be another part of the body). This study from Imperial College London shows that Kisspeptin at high doses causes testicular degeneration in rats. It showed that the rats treated with Kisspeptin experienced damage to their seminiferous tubules. There are several studies in rats that show that SSRIs and Finasteride damage the seminiferous tubules. In review that I mentioned above, the study #92 shows that escitalopram greatly increases kisspeptin levels in certain areas of the brain in rats. This could be causing damage to their testicles and might be the biological mechanism behind PSSD and PFS.

Kisspeptin-54 at high doses acutely induces testicular degeneration in adult male rats via central mechanisms

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2697701/

https://bpspubs.onlinelibrary.wiley.com ... 08.00061.x

thanks for the research. i haven't read in detail (i don't have the head to do that right now) but i read about possible "testicular degeneration" so i wonder if it results in reduced male fertility, if so would it be interesting to do a semen analysis? maybe a study comparing sperm quality between men with pssd and without pssd (I think it would also be pretty easy and cheap!)
Brain food
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Re: Very promising theory on PSSD being caused by changes in Kisspeptin expression

Unread post by Brain food »

anacleta wrote: Mon Aug 29, 2022 10:17 am
Brain food wrote: Sat Aug 27, 2022 4:37 pm So I have done some more research and have further refined my theory. I think that it's likely that if Kisspeptin causes PSSD, it does so by causing damage to the testicles (in men at least, in women it would be another part of the body). This study from Imperial College London shows that Kisspeptin at high doses causes testicular degeneration in rats. It showed that the rats treated with Kisspeptin experienced damage to their seminiferous tubules. There are several studies in rats that show that SSRIs and Finasteride damage the seminiferous tubules. In review that I mentioned above, the study #92 shows that escitalopram greatly increases kisspeptin levels in certain areas of the brain in rats. This could be causing damage to their testicles and might be the biological mechanism behind PSSD and PFS.

Kisspeptin-54 at high doses acutely induces testicular degeneration in adult male rats via central mechanisms

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2697701/

https://bpspubs.onlinelibrary.wiley.com ... 08.00061.x

thanks for the research. i haven't read in detail (i don't have the head to do that right now) but i read about possible "testicular degeneration" so i wonder if it results in reduced male fertility, if so would it be interesting to do a semen analysis? maybe a study comparing sperm quality between men with pssd and without pssd (I think it would also be pretty easy and cheap!)
I’m definitely infertile and I’m almost sure that it’s because of PSSD. However, my doctor doesn’t think that antidepressants caused this because he has never read a study that says antidepressants can make people infertile. I have actually read studies that say antidepressants reduce semen quality in mice, but usually they’re done by Universities in poor countries. I think the problem is political. The large research Universities in the US and the top medical journals don’t want to publish research that can be used against the pharmaceutical companies in lawsuits.
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