Kisspeptin-10 as a replacement for compounded HCG?

[30005Gator]

My Dr told me that their pharmacy can no longer compound HCG, but that he is going to start using Kisspeptin-10 as the alternative without increasing my monthly fee.

He told me that Kisspeptin acts like GnRH and stimulates the Pituitary to release both LH and FSH. I've done some reading online and it seems like a pretty legit alternative (and possibly better, as I would be getting FSH as well, which is why I take HMG once a month).

Has anyone tried Kisspeptin along with TRT? If so, what did you find...did it work well, sides, etc?
Does it even work if you have Secondary HypoG (meaning, with the pituitary gland process it correctly)? I would imagine it wouldn't work if the problem is GnRH reception on the PG.

 

[Cataceous]

The explanation of its function doesn't match what Wiki says:

Kisspeptin's ability to stimulate the release of GnRH and gonadotropins is the result of its effect on GnRH release at the hypothalamus.​

​

What I was wondering is whether or not you need pulsatile delivery of kisspeptin to get normal pulsatile release of GnRH. This research says it's not necessary.

The ability of continuous kisspeptin infusion to induce pulsatile gonadotropin secretion further indicates that GnRH neurons are able to set up pulsatile secretion in the absence of pulsatile exogenous kisspeptin.​

Because most men with non-primary hypogonadism respond to clomiphene to some degree it seems as though pituitary reception is not the issue and kisspeptin is an interesting avenue of treatment. However, there is definitely negative feedback from estrogens at the pituitary, and possibly also some from androgens, so the use of kisspeptin with TRT is problematic, and may at a minimum require the use of a SERM.

Another potential issue is half-life. Assuming oral delivery isn't possible, the iv infusion half-life is four minutes, so even if the half-life for subcutaneous administration is ten times as long then you are still looking at a pretty short duration of action. Is the doctor proposing an infusion pump or multiple daily injections?

 

[30005Gator]

The explanation of its function doesn't match what Wiki says:

Kisspeptin's ability to stimulate the release of GnRH and gonadotropins is the result of its effect on GnRH release at the hypothalamus.​

​

What I was wondering is whether or not you need pulsatile delivery of kisspeptin to get normal pulsatile release of GnRH. This research says it's not necessary.

The ability of continuous kisspeptin infusion to induce pulsatile gonadotropin secretion further indicates that GnRH neurons are able to set up pulsatile secretion in the absence of pulsatile exogenous kisspeptin.​

Because most men with non-primary hypogonadism respond to clomiphene to some degree it seems as though pituitary reception is not the issue and kisspeptin is an interesting avenue of treatment. However, there is definitely negative feedback from estrogens at the pituitary, and possibly also some from androgens, so the use of kisspeptin with TRT is problematic, and may at a minimum require the use of a SERM.

Another potential issue is half-life. Assuming oral delivery isn't possible, the iv infusion half-life is four minutes, so even if the half-life for subcutaneous administration is ten times as long then you are still looking at a pretty short duration of action. Is the doctor proposing an infusion pump or multiple daily injections?

I have no idea...it was a very cursory conversation. They haven't finalized the treatment plan yet.

 

[Cataceous]

I have no idea...it was a very cursory conversation. They haven't finalized the treatment plan yet.

I'd be very interested in seeing what you learn about it, if you're willing to share. I see that Tailor Made Pharmacy offers kisspeptin-10. They are suggesting 100 mcg daily. One article I came across suggested that natural men can get a boost in LH for many hours after an injection. Assuming it even works with TRT, I'd want to know what dosing schedule would be needed for various benefits, such as preventing testicular atrophy and improving libido.

 

[Nelson Vergel]

Gonadorelin alternative to hCG - Kisspeptin a peptide that is not approved for compounding

After doing some digging since a clinic i know is no longer using hCG, a called a few pharmacies and found out they are going to be offering Gonadorelin and NOT Kisspeptin. Kisspeptin is a peptide and it is NOT approved to be compounded and states like California will not approve it, while...

www.excelmale.com

 

[Nelson Vergel]

Effects of the Hormone Kisspeptin on Reproductive Hormone Release in Humans

The kisspeptins are a family of neuropeptides which act as upstream stimulators of gonadotrophin releasing hormone (GnRH) neurons. Kisspeptin signalling is prerequisite to establishing the normal human reproductive phenotype; loss of function mutations in the <i>KISS1</i> or <i>KISS1R</i> gene...

www.hindawi.com

 

[Nelson Vergel]

Evaluation of serum kisspeptin in infertile men with severe oligospermia

Menoufia Medical Journal, 2019, Vol.32(3), p.1009-1012

Objective
The aim of this study was to determine whether an abnormality in the serum levels of kisspeptin is associated with oligospermia and male infertility.

Background The study of kisspeptin has yielded a new concept on the physiology of the hypothalamic–pituitary–testicular axis and thus the sexual and reproductive functions of men. Patients and methods Our case–control study included 44 male participants aged 20–45 years divided into two groups: a case group composed of 22 infertile men with severe oligospermia and with normal serum levels of testosterone, luteinizing hormone, follicle-stimulating hormone, and prolactin and an age-matched control group composed of 22 fertile men. Serum kisspeptin levels were evaluated by an enzyme-linked immunosorbent assay in both groups.

Results The results of our study showed that the serum levels of kisspeptin in the infertile oligospermic group were significantly lower than those of the fertile group. Conclusion Deficiency of serum kisspeptin might be associated with oligospermia and fertility problems.

 

[Nelson Vergel]

Age‐dependent changes in the reproductive axis responsiveness to kisspeptin‐10 administration in healthy men

Andrologia, May 2019, Vol.51(4), pp.n/a-n/a

The present study was designed to assess the responsiveness of hypothalamic–pituitary–gonadal axis to kisspeptin administration with increasing age in men. Human kisspeptin‐10 was administered in single iv bolus dose (1 µg/kg BW) to healthy adult, middle and advanced age men. Serial blood samples were collected for 30 min pre‐ and 120 min post‐kisspeptin injection periods at 30‐min interval. Analysis of plasma LH by ELISA showed a significant ( < 0.05) increase after kisspeptin‐10 administration in all groups, whereas plasma testosterone concentration was significantly elevated ( < 0.05) after kisspeptin‐10 injection only in the adult men group. Present results suggest that in men, central hypothalamic–pituitary axis remains active and shows responsiveness to kisspeptin stimulation across life. However, Leydig cell responsiveness to kisspeptin‐induced LH decreases with age in men.

 

[Nelson Vergel]

Kisspeptin Resets the Hypothalamic GnRH Clock in Men

The Journal of Clinical Endocrinology & Metabolism, June 2011, Vol.96(6), pp.E908-E915


Administration of kisspeptin to healthy men reveals that a single iv dose of kisspeptin induces prolonged GnRH secretion and also resets the GnRH pulse generator.

Context: Reproduction in all mammals is controlled by a hypothalamic clock that produces periodic secretory pulses of GnRH, but how the timing of these pulses is determined is poorly understood. The neuropeptide kisspeptin potently and selectively stimulates the secretion of GnRH. Although this property of kisspeptin is well described, the effects of kisspeptin on endogenous GnRH pulse generation remain largely unexplored.

Objective: The objective of the study was to detail the effects of kisspeptin on GnRH secretion, as reflected by LH secretion, in men.

Participants: Thirteen healthy adult men participated in the study.

Intervention: The intervention was the administration of a single iv bolus of the C-terminal decapeptide of kisspeptin (amino acids 112–121 of the parent protein).

Results: Kisspeptin induced an immediate LH pulse, regardless of the timing of the previous endogenous pulse. The kisspeptin-induced pulses were on average larger than endogenous pulses (amplitude 5.0 ± 1.0 vs. 2.1 ± 0.3 mIU/ml, P = 0.02). Comparison of the morphology of kisspeptin-induced LH pulses in healthy men with that of GnRH-induced LH pulses in men with isolated GnRH deficiency suggests that a single iv bolus of kisspeptin triggered sustained GnRH release lasting approximately 17 min. Furthermore, kisspeptin reset the GnRH pulse generator, as it not only induced an immediate LH pulse but also delayed the next endogenous pulse by an interval approximating the normal interpulse interval.

Conclusions: As the first known agent capable of resetting the hypothalamic GnRH pulse generator, kisspeptin can be used as a physiological tool for studying GnRH pulse generation and opens a door to understanding the mechanisms of biological clocks in general.

 

[Nelson Vergel]

Intratesticular action of kisspeptin in rhesus monkey (Macaca mulatta)
Irfan, S ; Ehmcke, J ; Wahab, F ; Shahab, M ; Schlatt, S
Andrologia (Online), Aug 2014, Vol.46(6), pp.610-617

Kisspeptin-Kiss1R signalling in mammals has been implicated as an integral part of the reproductive cascade. Kisspeptinergic neurons upstream of GnRH neurons are involved in the activation of the hypothalamic GnRH pulse gener- ator during pubertal onset. Thus, the major research focus has been on the central effects of kisspeptin. The demonstration of the presence of KissR expression in human testes suggests additional unknown actions of kisspeptin- KISS1R signalling at the distal component of the male reproductive axis. Here we explored the impact of kisspeptin at the testis in the adult male rhesus monkey. We employed the clamped monkey model to assess the intratesticular actions of kisspeptin. Plasma testosterone and LH levels were monitored in four adult male monkeys. The peripheral administration of human kisspeptin- 10 (50 lg, iv bolus) caused a single LH pulse, which was followed by a robust increase in plasma testosterone levels sustained for at least 180 min. This response was abolished when kisspeptin was administered to GnRH receptor antagonist (acyline) pre-treated animals. However, kisspeptin administration significantly (P < 0.005) elevated hCG-stimulated testosterone levels in acyline pre-treated monkeys when compared with saline+ hCG treatment. These results revealed a novel peripheral facet of kisspeptin signalling.

 

[Nelson Vergel]

Pituitary restart while on TRT: promising initial results with GnRH plus enclomiphene

TL;DR: Over a period of seven weeks, treatment with GnRH and enclomiphene raised LH and FSH from around 0.1 mIU/mL to about 1.0 mIU/mL, even though TRT and hCG dosing were continued. Subjective results have been encouraging. I had written previously on the subject of GnRH suppression on TRT...

www.excelmale.com

 

[cmatt15]

Nelson i am very interested in your take on these studies I found , indicating that Kisspeptin -10 is a significant vaso constrictor on endothelial tissues/ arteries, and show an increased inflammation response and plaque build up .

https://www.ahajournals.org/doi/10.1161/JAHA.117.005790

The effects of kisspeptin-10 on serum metabolism and myocardium in rats - PMC

Kisspeptin is a peptide encoded by the Kiss 1 gene and is also called metastin. Previous studies have generally focused on several functions of this peptide, including metastasis, puberty, vasoconstriction and reproduction. However, few studies have ...

www.ncbi.nlm.nih.gov

A POTENT VASOCONSTRICTOR KISSPEPTIN-10 ACCELERATES ATHEROSCLEROTIC PLAQUE PROGRESSION AND INSTABILITY | JACC: Journal of the American College of Cardiology

 

[Cataceous]

As with most things, too much or too little and you have problems. In the rat experiment each animal received about 52 mcg per day. The equivalent human dose is nearly 3 mg, which is 30 times the suggested dose of 100 mcg that's been floating around. And even 100 mcg is probably supraphysiological

 

[cmatt15]

As with most things, too much or too little and you have problems. In the rat experiment each animal received about 52 mcg per day. The equivalent human dose is nearly 3 mg, which is 30 times the suggested dose of 100 mcg that's been floating around. And even 100 mcg is probably supraphysiological

Thank you sir ! I was unable to do the conversion correctly . Much appreciated.

 

[Cataceous]

Also see what the first citation says about the concentrations in general:

The physiological relevance of the KP‐10 concentrations used in our in vitro and in vivo experiments warrants further discussion. First, the concentrations of KP‐10 needed to influence multiple HUVEC, HMDM, and HASMC responses were considerably high (maximum ≈7400‐fold) compared with average plasma concentration of KP‐10 (1.35 nmol/L [1.05 ng/mL]) in 28 healthy volunteers (Figure S2B). In the vascular wall, ECs and macrophages generate large amounts of KP‐10 in an autocrine/paracrine manner. Plasma KP‐54 concentration increases by 1000‐ to 10 000‐fold during pregnancy.41Consequently, it is not surprising that local levels of KP‐10 were increased in a similar degree. Second, the concentration of KP‐10 in serum obtained from a healthy human volunteer was 0.32 nmol/L (0.41 ng/mL) in our study. Therefore, the 10% concentration added to culture medium for HMDMs (32 pmol/L) was negligible compared with the concentrations of KP‐10 added. Third, the concentrations of KP‐10 differed in terms of the inflammation responses that they provoked in HUVECs, as well as their influence on monocyte‐HUVEC adhesion, macrophage foam cell formation and effector expression, HASMC migration and proliferation, and ECM production. This likely reflects the different cell types used and their intracellular signals. Fourth, the dose of KP‐10 (12.5 μg/kg per hour) infusion into mice is 9.6‐fold higher compared with its dose (1.3 μg/kg per hour [1.0 nmol/kg per hour]) used in humans.42 It is generally accepted to examine the effect of drugs at such a high dose in animal experiments. Fifth, plasma KP‐10 concentration in ApoE−/− mice infused with KP‐10 was significantly higher by 3‐ to 4‐fold (Table 1), which were not as high as we anticipated. KP‐10 might therefore be metabolized, to some degree, in circulating blood.43 Last, plasma KP‐10 concentration in ApoE−/− mice infused with KP‐10+P234 was higher compared with KP‐10 alone (Table 2). Given that the amino‐acid sequence of KP‐10 is 70% identical to that of P234 (inactive form), the ELISA kit may detect P234 as KP‐10 (possible cross‐reaction).​

 

[Chopsuey]

Kisspeptin Resets the Hypothalamic GnRH Clock in Men

The Journal of Clinical Endocrinology & Metabolism, June 2011, Vol.96(6), pp.E908-E915


Administration of kisspeptin to healthy men reveals that a single iv dose of kisspeptin induces prolonged GnRH secretion and also resets the GnRH pulse generator.

Context: Reproduction in all mammals is controlled by a hypothalamic clock that produces periodic secretory pulses of GnRH, but how the timing of these pulses is determined is poorly understood. The neuropeptide kisspeptin potently and selectively stimulates the secretion of GnRH. Although this property of kisspeptin is well described, the effects of kisspeptin on endogenous GnRH pulse generation remain largely unexplored.

Objective: The objective of the study was to detail the effects of kisspeptin on GnRH secretion, as reflected by LH secretion, in men.

Participants: Thirteen healthy adult men participated in the study.

Intervention: The intervention was the administration of a single iv bolus of the C-terminal decapeptide of kisspeptin (amino acids 112–121 of the parent protein).

Results: Kisspeptin induced an immediate LH pulse, regardless of the timing of the previous endogenous pulse. The kisspeptin-induced pulses were on average larger than endogenous pulses (amplitude 5.0 ± 1.0 vs. 2.1 ± 0.3 mIU/ml, P = 0.02). Comparison of the morphology of kisspeptin-induced LH pulses in healthy men with that of GnRH-induced LH pulses in men with isolated GnRH deficiency suggests that a single iv bolus of kisspeptin triggered sustained GnRH release lasting approximately 17 min. Furthermore, kisspeptin reset the GnRH pulse generator, as it not only induced an immediate LH pulse but also delayed the next endogenous pulse by an interval approximating the normal interpulse interval.

Conclusions: As the first known agent capable of resetting the hypothalamic GnRH pulse generator, kisspeptin can be used as a physiological tool for studying GnRH pulse generation and opens a door to understanding the mechanisms of biological clocks in general.

@Nelson Vergel

Hi Nelson, in the conclusion it says "Furthermore, kisspeptin reset the GnRH pulse generator, as it not only induced an immediate LH pulse but also delayed the next endogenous pulse by an interval approximating the normal interpulse interval."

Am I understanding this correctly that kisspeptin could be used to try and reboot the HPTA system after coming off trt and trying to get natural production back online?

For example using kisspeptin for a short stint to reset the system and hoping everything starts working again?

Thank you

 

[Cataceous]

... in the conclusion it says "Furthermore, kisspeptin reset the GnRH pulse generator, as it not only induced an immediate LH pulse but also delayed the next endogenous pulse by an interval approximating the normal interpulse interval."

Am I understanding this correctly that kisspeptin could be used to try and reboot the HPTA system after coming off trt and trying to get natural production back online?

For example using kisspeptin for a short stint to reset the system and hoping everything starts working again?
...

My two cents: That conclusion applies to an HPTA that is functional. You're not going to see immediate results if you've been shut down for some time.

On the other hand, what if you started kisspeptin well before coming off of TRT? Perhaps if it were combined with enclomiphene you'd be able to get most of the HPTA functioning before stopping the exogenous testosterone. In theory, after some time the hypothalamus would start producing GnRH. Then after some additional time the pituitary would start making LH. And finally after some more time the testicles would start making testosterone.

If you were after the fastest possible results then you could tackle all three at once, taking kisspeptin for the hypothalamus, GnRH for the pituitary, and hCG for the testicles. Then each is being stimulated concurrently, instead of consecutively as with kisspeptin alone.

The fly in the ointment is that GnRH, and possibly kisspeptin as well, must be taken multiple times daily to attain reasonable results. Perhaps some would find this doable if they knew it was temporary.

 

[Vvs1]

I have read that Kisspeptin activates parts of the brain for libido. Hence the reason its prefixed “kiss.” Can anyone confirms it increases libido?

 

[Chopsuey]

I have read that Kisspeptin activates parts of the brain for libido. Hence the reason its prefixed “kiss.” Can anyone confirms it increases libido?

That's not why its called kisspeptin, the scientist that found it lived near a hershey factory and named it after hersheys kisses...they didn't understand how significant it was going to be at the time so was a bit of a joke....

But anyways it is suppose to increase libido from research I've seen.

 

[Chopsuey]

My two cents: That conclusion applies to an HPTA that is functional. You're not going to see immediate results if you've been shut down for some time.

On the other hand, what if you started kisspeptin well before coming off of TRT? Perhaps if it were combined with enclomiphene you'd be able to get most of the HPTA functioning before stopping the exogenous testosterone. In theory, after some time the hypothalamus would start producing GnRH. Then after some additional time the pituitary would start making LH. And finally after some more time the testicles would start making testosterone.

If you were after the fastest possible results then you could tackle all three at once, taking kisspeptin for the hypothalamus, GnRH for the pituitary, and hCG for the testicles. Then each is being stimulated concurrently, instead of consecutively as with kisspeptin alone.

The fly in the ointment is that GnRH, and possibly kisspeptin as well, must be taken multiple times daily to attain reasonable results. Perhaps some would find this doable if they knew it was temporary.

Interesting, thank you for the reply.

My only concern wouldn't taking kisspeptin and GnRH at the same time possibly stimulate too much gonadrotropins and thus possibly act as the opposite? From my understand GnRH at high dose can be used as chemical castration.

I guess the dose is the thing that's going to decide.

I've seen PCT protocol's that use 100mcg of GnRH for 10 days, do you think 100mcg of GnRH + 100mcg of Kisspeptin for 10 days would be safe/good protocol to try?

Its really hard to find dosing info for kisspeptin, I've been researching like crazy for the past few days.

I've already come off trt, feel like death but want to see if I can recover because I could never fix the libido issue on trt plus I want kids so figured I'd give it one last shot to see if I can recover.