Kisspeptin suppression under TRT: Can it affect mood and libido?

[Cataceous]

TD;LR: Kisspeptin may affect how we act and feel. It seems plausible that a TRT-induced reduction in this hormone is a problem for some men.

I’d previously asked if suppression of GnRH by TRT is a problem. The literature at least hints that it is possible. The situation with kisspeptin may be similar. The kisspeptin hormone sits near the top of the male sex hormone cascade. It helps stimulate GnRH production, which in turn leads to LH and FSH, which leads to testosterone and then estradiol. Testosterone and estradiol then provide negative feedback for kisspeptin production in the hypothalamus. Testosterone replacement therapy tends to swamp this feedback mechanism, leading to a presumed suppression of hypothalamic kisspeptin and the other intermediate hormones. However, there are other sources of kisspeptin, albeit maybe smaller ones. These include the hippocampus and the adrenal gland. This leaves uncertainly about the importance of the likely reduction in kisspeptin caused by TRT. Nonetheless, it may be that due to inter-individual variably some men tolerate the reduction, while others have issues.

What issues? This review article lays out some possibilities. After explaining kisspeptin’s role in GnRH production, the authors say “… kisspeptin signaling is not limited to the hypothalamus but also occurs in other extrahypothalamic brain regions. It is these locations for kisspeptin signaling that gave the first clues to kisspeptin’s role in sexual and emotional processing.” In particular, in various species there’s “a role for kisspeptin in behavioral networks related to reproduction including olfaction, audition, fear, anxiety, mood, and sexual arousal.”

Of particular interest are the references to anxiety, mood and libido. These are common problem areas. It is encouraging that experiments on men yielded some positive results:

“… peripheral kisspeptin administration to healthy men reduces negative mood…”​

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“These data from rodent, zebrafish, and human studies therefore implicate kisspeptin signaling in the modulation of mood and anxiety with antidepressant-like effects which may have clinical implications.”​

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“This suggests that kisspeptin signaling could enhance reward-system activity during sexual arousal (particularly in those generally less responsive to reward), thereby triggering a desire for sexual activity and possibly subsequent reproduction.”​

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“It is therefore possible, that other factors are also important in modulating libido that may include upstream kisspeptin signaling. Certainly, the expression pattern of kisspeptin and its cognate receptor in limbic and paralimbic structures would point towards this as well as the more recent studies identifying a role in sexual brain processing and erection generation. Further studies are required to determine if kisspeptin signaling could be exploited in future therapies for patients with sexual and emotional disorders.”​

So we have some hints of the potential importance of kisspeptin. While speculative, it seems possible that kisspeptin suppression via TRT can have detrimental effects. If so then the next question is, can these problems be resolved by supplementation? Further research is needed to give us some answers.

 

[sh1973]

So do you think this could be a contributing factor to some men losing libido on trt?

 

[DorianGray]

It's an incredibly complex system with wide individual differences, it would be hard to know for sure, I'd think. I would love to try kisspeptin in conjunction with PT-141 to test the effects on libido.

 

[Nelson Vergel]

The same can be said of the suppression of LH and FSH. That is why some men feel so much better on hCG plus TRT.

 

[Cataceous]

So do you think this could be a contributing factor to some men losing libido on trt?

I think it's possible, and referring to reduced kisspeptin and GnRH collectively, I think it's even probable.

 

[Joe Sixpack]

IDK about reduced libido. TRT has made me WAY more randy than I was in my 20's. Of course, I get it that your mileage may vary.

BTW, I find it hilarious that this hormone is called kisspeptin.

 

[Cataceous]

IDK about reduced libido. TRT has made me WAY more randy than I was in my 20's. Of course, I get it that your mileage may vary.

BTW, I find it hilarious that this hormone is called kisspeptin.

The idea is that kisspeptin is but one of many possible contributors to libido. The same goes for GnRH. It's possible that different men react differently to reductions in these hormones, just as we seem to see happening with LH, where some men need to replace it with hCG to get decent results on TRT. For now though the concept remains a hypothesis that needs to be tested.

Regarding how kisspeptin got its name:

In 1996, Dr. Danny Welch's lab in Hershey, Pennsylvania isolated a cDNA from a cancer cell that was not able to undergo metastasis after the human chromosome 6 was added to the cell. This gene was named KISS1 because of the location of where it was discovered (Hershey, Pennsylvania, home of Hershey's Kisses).​

Ref.

 

[Cataceous]

A tip of the hat to "ghce" over at PeakT for the link to this article:

JCI Insight - Kisspeptin enhances brain responses to olfactory and visual cues of attraction in men

insight.jci.org

It is recent and goes into detail on possible links between kisspeptin and libido. If TRT does disrupt natural kisspeptin production then we may be looking at one of the mechanisms by which TRT harms libido.

We observed that kisspeptin significantly enhanced brain activity compared with placebo in key limbic areas related to olfaction and sexual processing...​

...​

Moreover, kisspeptin’s enhancement of thalamus and insula activity corresponded to these established areas of activation during physiological sexual arousal (35). Collectively, these data indicate that kisspeptin augments olfactory as well as sexual and emotional processing in response to pleasurable olfactory stimuli in men.​

...​

Here, kisspeptin significantly enhanced brain activity in both the olfactory and sexual arousal systems but not in the control motor system, which highlights the specificity of kisspeptin’s effects (Figure 2C).​

...​

Kisspeptin enhanced brain activity in areas governing the evaluation of beauty, on viewing female faces. ... Together, these findings demonstrate that kisspeptin augments the processing of facial beauty across a spectrum of facial attractiveness, therefore serving as an amplifier within the human neural aesthetic circuitry involved in the assessment of facial beauty.​

 

[sh1973]

I really think you’re onto something cataceous because there are so many men that develop libido issues including myself and nothing seems to help

 

[Pursuit_Sanus]

"A decade of study has conclusively shown that the reproductive hormone kisspeptin is a critical regulator of the HPG axis acting in the hypothalamus to control GnRH secretion. More recently, the role of kisspeptin outside the HPG axis has received increasing attention with the emergence of associations between kisspeptin, brain processing and behaviour. In this talk, I will provide evidence from studies in rodents to humans, that collectively demonstrate that kisspeptin can integrate reproductive and emotional behaviour with the control of the HPG axis. These findings have important clinical implications for the treatment of patients with related conditions. "

 

[HarryCat2]

"A decade of study has conclusively shown that the reproductive hormone kisspeptin is a critical regulator of the HPG axis acting in the hypothalamus to control GnRH secretion. More recently, the role of kisspeptin outside the HPG axis has received increasing attention with the emergence of associations between kisspeptin, brain processing and behaviour. In this talk, I will provide evidence from studies in rodents to humans, that collectively demonstrate that kisspeptin can integrate reproductive and emotional behaviour with the control of the HPG axis. These findings have important clinical implications for the treatment of patients with related conditions. "

Thanks for that link. At 1:36 he shows this chart and mentions that testosterone replacement does not restore psychosexual function to the same level as age-matched controls.

 

[Nelson Vergel]

Hormone Infusion Shows Promise for Low Sexual Desire

Pair of trials demonstrated efficacy in hypoactive sexual desire disorder

www.medpagetoday.com

 

[SkiDaddy]

Nelson: Does Kisspeptin affect Blood Pressure?
I have tried PT-141 and my BP goes up 30 points for 3-4 hours.

 

[Nelson Vergel]

Nelson: Does Kisspeptin affect Blood Pressure?
I have tried PT-141 and my BP goes up 30 points for 3-4 hours.

I really don’t know. It’s one of the few things I have not tried.

Some compounding pharmacies are making it, so I may give it a try.

 

[madman]

Hormone Infusion Shows Promise for Low Sexual Desire

Pair of trials demonstrated efficacy in hypoactive sexual desire disorder

www.medpagetoday.com

Bet those run-of-the-mill clinics will go ape shit pushing injectable KP-10 as the next best thing!

Everyone needs to keep this in mind!


*KP-10, KP-54, and kisspeptin receptor agonists such as TAK-683 [11] and MVT-602 (formerly known as TAK448) [12] are the kisspeptin peptides that have been studied in humans to date. KP-10 is potent against KISS1R in vitro but is not believed to cross the blood-brain barrier and has a shorter half-life than KP-54 (t1/2 3 vs. 28 min) due to significant enzymatic degradation, making it less suitable for bolus administration [2]. Native KP-54 has a longer half-life and induces greater LH rises in vivo after bolus administration but is more expensive to manufacture than KP-10 due to its longer peptide length [13]. KISS1R-analogs, such as TAK-683 and MVT-602, which have been recently developed by modification of KP-10, possess increased stability and potency, hence enabling more cost-effective peptide manufacture [11,12].


*different kisspeptin peptide forms (KP-54, KP-10, KP-analogue), durations, frequencies (bolus or continuous infusion), and administration routes (central, subcutaneous, intranasal, or intravenous)

Novel therapeutic avenues for kisspeptin

Novel therapeutic avenues for kisspeptin (2022) Jovanna Tsoutsoukia, Ali Abbarab, and Waljit Dhillo Abstract Kisspeptin is a hypothalamic neuropeptide that acts via the hypothalamus to stimulate hypothalamic gonadotrophin-releasing hormone secretion and downstream gonadotrophin release. In...

www.excelmale.com

Background

The kisspeptins are a family of peptides encoded by the KISS1 gene in humans (KISS1 in non-human primates and Kiss1 in other mammals) [1]. The prepropeptide consists of 145 amino acids that are subsequently proteolyzed into shorter peptides of lengths denoted by their suffixes, such as kisspeptin-54 (KP-54), -14, -13, and -10 (KP-10) [2]. All forms share a common C-terminal decapeptide sequence, equivalent to KP-10, which is important for their binding to the G-protein-coupled kisspeptin receptor, KISS1R (formerly known as the orphan receptor GRP54) [2]. Kisspeptin primarily stimulates the hypothalamus to regulate the hypothalamic-pituitary-gonadal axis [3]. Indeed, the decreased KISS1R signaling in humans results in absent puberty and hypogonadotropic hypogonadism [4,5], whereas increased KISS1R signaling results in precocious puberty [6]

Outside the human hypothalamus [7], kisspeptin and its receptor are expressed in the brain in key limbic and paralimbic regions [7], and in peripheral tissues such as the gonads, placenta, liver, adipose tissue, and bone [7]. Consequently, beyond its central role in stimulating hypothalamic gonadotrophin-releasing hormone (GnRH) secretion, kisspeptin has been studied in sexual and emotional brain processing [7], bone turnover [8], metabolism [9], and as a biomarker of pregnancy complications [10]. Herein, we summarise data on the pharmacological use of kisspeptin in reproductive disorders and fertility treatment, as well as its putative utility in hypoactive sexual desire disorder (HSDD), osteoporosis, and non-alcoholic fatty liver disease, now known as metabolic dysfunction-associated fatty liver disease (MAFLD) (Figure 1).




Kisspeptin trials in healthy men and women

KP-10, KP-54, and kisspeptin receptor agonists such as TAK-683 [11] and MVT-602 (formerly known as TAK448) [12] are the kisspeptin peptides that have been studied in humans to date. KP-10 is potent against KISS1R in vitro but is not believed to cross the blood-brain barrier and has a shorter half-life than KP-54 (t1/2 3 vs. 28 min) due to significant enzymatic degradation, making it less suitable for bolus administration [2]. Native KP-54 has a longer half-life and induces greater LH rises in vivo after bolus administration but is more expensive to manufacture than KP-10 due to its longer peptide length [13]. KISS1R-analogs, such as TAK-683 and MVT-602, which have been recently developed by modification of KP-10, possess increased stability and potency, hence enabling more cost-effective peptide manufacture [11,12].

Exogenous kisspeptin has been reported to potently stimulate GnRH and in turn luteinizing hormone (LH), in healthy men and women, and in patients with the reproductive disease, using different kisspeptin peptide forms (KP-54, KP-10, KP-analogue), durations, frequencies (bolus or continuous infusion) and administration routes (central, subcutaneous, intranasal or intravenous) [2,14-19]. Subcutaneous KP-54 stimulated gonadotrophin secretion in healthy females throughout all phases of their menstrual cycle [18,20,21], but with the greatest LH rises during the preovulatory phase [18,22e24]. Intravenous KP-10 was the least effective during the follicular phase of the menstrual cycle and evoked no gonadotrophin response when administered subcutaneously [25,26].

In healthy men, both an intravenous bolus and a continuous infusion of KP-10 produced significant LH responses with the latter maintaining LH secretion for at least 22.5 h [17,25]. Acute and chronic administration of intravenous KP-10-induced LH increases in obese hypogonadal diabetic men [27] and healthy older men [28], thereby highlighting promising therapeutic avenues for the use of kisspeptin in male functional hypogonadism related to diabetes, obesity, or age.

Recently, kisspeptin receptor agonists, including MVT-602 and TAK-683, were shown to potently increase LH secretion in men and women [12,29-31]. MVT-602 administered during the follicular phase of the menstrual cycle of healthy women triggered a similar LH amplitude to KP-54 yet produced a more sustained LH rise, with a correspondingly increased area under the curve of LH rise [12]. However, pharmacokinetic properties were similar between MVT-602 and KP-54, suggesting that the longer duration of effect was centered on differential activation of the kisspeptin receptor [12]. When studied in vitro on mouse GnRH neurons, MVT-602 was more potent and induced a more sustained duration of GnRH-neuronal firing than KP-54 (115 vs. 55 min) [12]. Importantly, kisspeptins have been administered to a few hundred patients by different research groups and to different populations but have not been associated with any adverse effects [11,15-17,32-34]. Indeed, kisspeptin levels increase dramatically during pregnancy from non-pregnant levels (8 pmol/L) to 1230 pmol/L during the first trimester and 9590 pmol/L during the third trimester [35e37], consistent with the reported wide therapeutic safety window [10].

 

[BadassBlues]

Bet those run-of-the-mill clinics will go ape shit pushing injectable KP-10 as the next best thing!

Everyone needs to keep this in mind!


*KP-10, KP-54, and kisspeptin receptor agonists such as TAK-683 [11] and MVT-602 (formerly known as TAK448) [12] are the kisspeptin peptides that have been studied in humans to date. KP-10 is potent against KISS1R in vitro but is not believed to cross the blood-brain barrier and has a shorter half-life than KP-54 (t1/2 3 vs. 28 min) due to significant enzymatic degradation, making it less suitable for bolus administration [2]. Native KP-54 has a longer half-life and induces greater LH rises in vivo after bolus administration but is more expensive to manufacture than KP-10 due to its longer peptide length [13]. KISS1R-analogs, such as TAK-683 and MVT-602, which have been recently developed by modification of KP-10, possess increased stability and potency, hence enabling more cost-effective peptide manufacture [11,12].


*different kisspeptin peptide forms (KP-54, KP-10, KP-analogue), durations, frequencies (bolus or continuous infusion), and administration routes (central, subcutaneous, intranasal, or intravenous)

Novel therapeutic avenues for kisspeptin

Novel therapeutic avenues for kisspeptin (2022) Jovanna Tsoutsoukia, Ali Abbarab, and Waljit Dhillo Abstract Kisspeptin is a hypothalamic neuropeptide that acts via the hypothalamus to stimulate hypothalamic gonadotrophin-releasing hormone secretion and downstream gonadotrophin release. In...

www.excelmale.com

Background

The kisspeptins are a family of peptides encoded by the KISS1 gene in humans (KISS1 in non-human primates and Kiss1 in other mammals) [1]. The prepropeptide consists of 145 amino acids that are subsequently proteolyzed into shorter peptides of lengths denoted by their suffixes, such as kisspeptin-54 (KP-54), -14, -13, and -10 (KP-10) [2]. All forms share a common C-terminal decapeptide sequence, equivalent to KP-10, which is important for their binding to the G-protein-coupled kisspeptin receptor, KISS1R (formerly known as the orphan receptor GRP54) [2]. Kisspeptin primarily stimulates the hypothalamus to regulate the hypothalamic-pituitary-gonadal axis [3]. Indeed, the decreased KISS1R signaling in humans results in absent puberty and hypogonadotropic hypogonadism [4,5], whereas increased KISS1R signaling results in precocious puberty [6]

Outside the human hypothalamus [7], kisspeptin and its receptor are expressed in the brain in key limbic and paralimbic regions [7], and in peripheral tissues such as the gonads, placenta, liver, adipose tissue, and bone [7]. Consequently, beyond its central role in stimulating hypothalamic gonadotrophin-releasing hormone (GnRH) secretion, kisspeptin has been studied in sexual and emotional brain processing [7], bone turnover [8], metabolism [9], and as a biomarker of pregnancy complications [10]. Herein, we summarise data on the pharmacological use of kisspeptin in reproductive disorders and fertility treatment, as well as its putative utility in hypoactive sexual desire disorder (HSDD), osteoporosis, and non-alcoholic fatty liver disease, now known as metabolic dysfunction-associated fatty liver disease (MAFLD) (Figure 1).




Kisspeptin trials in healthy men and women

KP-10, KP-54, and kisspeptin receptor agonists such as TAK-683 [11] and MVT-602 (formerly known as TAK448) [12] are the kisspeptin peptides that have been studied in humans to date. KP-10 is potent against KISS1R in vitro but is not believed to cross the blood-brain barrier and has a shorter half-life than KP-54 (t1/2 3 vs. 28 min) due to significant enzymatic degradation, making it less suitable for bolus administration [2]. Native KP-54 has a longer half-life and induces greater LH rises in vivo after bolus administration but is more expensive to manufacture than KP-10 due to its longer peptide length [13]. KISS1R-analogs, such as TAK-683 and MVT-602, which have been recently developed by modification of KP-10, possess increased stability and potency, hence enabling more cost-effective peptide manufacture [11,12].

Exogenous kisspeptin has been reported to potently stimulate GnRH and in turn luteinizing hormone (LH), in healthy men and women, and in patients with the reproductive disease, using different kisspeptin peptide forms (KP-54, KP-10, KP-analogue), durations, frequencies (bolus or continuous infusion) and administration routes (central, subcutaneous, intranasal or intravenous) [2,14-19]. Subcutaneous KP-54 stimulated gonadotrophin secretion in healthy females throughout all phases of their menstrual cycle [18,20,21], but with the greatest LH rises during the preovulatory phase [18,22e24]. Intravenous KP-10 was the least effective during the follicular phase of the menstrual cycle and evoked no gonadotrophin response when administered subcutaneously [25,26].

In healthy men, both an intravenous bolus and a continuous infusion of KP-10 produced significant LH responses with the latter maintaining LH secretion for at least 22.5 h [17,25]. Acute and chronic administration of intravenous KP-10-induced LH increases in obese hypogonadal diabetic men [27] and healthy older men [28], thereby highlighting promising therapeutic avenues for the use of kisspeptin in male functional hypogonadism related to diabetes, obesity, or age.

Recently, kisspeptin receptor agonists, including MVT-602 and TAK-683, were shown to potently increase LH secretion in men and women [12,29-31]. MVT-602 administered during the follicular phase of the menstrual cycle of healthy women triggered a similar LH amplitude to KP-54 yet produced a more sustained LH rise, with a correspondingly increased area under the curve of LH rise [12]. However, pharmacokinetic properties were similar between MVT-602 and KP-54, suggesting that the longer duration of effect was centered on differential activation of the kisspeptin receptor [12]. When studied in vitro on mouse GnRH neurons, MVT-602 was more potent and induced a more sustained duration of GnRH-neuronal firing than KP-54 (115 vs. 55 min) [12]. Importantly, kisspeptins have been administered to a few hundred patients by different research groups and to different populations but have not been associated with any adverse effects [11,15-17,32-34]. Indeed, kisspeptin levels increase dramatically during pregnancy from non-pregnant levels (8 pmol/L) to 1230 pmol/L during the first trimester and 9590 pmol/L during the third trimester [35e37], consistent with the reported wide therapeutic safety window [10].

This appears to state that K10 is potentially ineffective due to a short half life and a molecular size that may not cross the BBB. Then this statement:

In healthy men, both an intravenous bolus and a continuous infusion of KP-10 produced significant LH responses with the latter maintaining LH secretion for at least 22.5 h [17,25]. Acute and chronic administration of intravenous KP-10-induced LH increases in obese hypogonadal diabetic men [27] and healthy older men [28], thereby highlighting promising therapeutic avenues for the use of kisspeptin in male functional hypogonadism related to diabetes, obesity, or age.

They reference only IV administration however.

There are some interesting animal studies, which I won't post here, that have the same mixed reviews. Good results were seen with constant IV administration.

Out of curiosity and a glimmer of hope, I ordered some and will post my personal findings.

 

[BadassBlues]

Received 5mg lyphilized KP10 from PS. I am researching dosing protocols. I’m considering 250 mcg EOD. Getting labs next week to get a baseline.

 

[Aging Disgracefully]

Received 5mg lyphilized KP10 from PS. I am researching dosing protocols. I’m considering 250 mcg EOD. Getting labs next week to get a baseline.

Any follow up on this? Very interested as this may be helpful to my situation.

 

[BadassBlues]

Any follow up on this? Very interested as this may be helpful to my situation.

Due to other factors, I did not have the opportunity to have labs done. I still plan to do so at some point, but there are too many other variables at this time for me to focus on this one.

I did receive the product and have several weeks of use. I can give you my personal observations if that helps.

I have been injecting 10 units sub q EOD for 2 weeks. I am on TRT and also HCG, so keep that in mind.

I notice a subtle elevation in mood and wellbeing after injection. Different than HCG, but similar. I never viewed this as any kind of replacement for HCG, my thoughts were that it would be interesting to see if it did indeed cause an elevation in LH, rather than acting as an analog. This can't be proven without labs, but the elevation in mood and an overall feeling of wellbeing indicates it is doing something.

I do notice a nice libido increase, but it's likely due to the elevation of mood. Its similar to oxytocin if you have ever tried that.

Overall, I like it and will continue using it. Once I have the other variables cleared, I'll get labs done.

Hope that helps...

 

[M.J]

So do you think this could be a contributing factor to some men losing libido on trt?

More like most men