Kisspeptin - perhaps a new 'reset' after several cycles to avoid TRT

[Lemonada8]

"Kisspeptin Resets the Hypothalamic GnRH Clock in Men"
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 kisspeptininduced
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.

http://jcem.endojournals.org/content/96/6/E908.short

Seems very promising in the sense of people who do several cycles seem to end up on TRT, Kisspeptin reset the 'clock' regulating the pulses of GnRH and the following pulses were also amped up, compared to the pulses before the addition of it. So in a sense it put the pit back in the puberty state with higher pulses which result in higher natural production of gonadotropins.
I dont know how well this would work in a PCT setting after a cycle, since it was only one administeration, and who knows after multiple suppressions then stimulations if it would work as well or what.

much more promising than the GnRHa (triptorelin) administeration IMO because to much of that can result in medical castration and kisspeptin seems to be the step before a GnRHa (since it releases the GnRH) instead of having a agonist of GnRH

[Lemonada8]

bump i guess a mod plz move this to TRT section or something to get some responses :-S

[Times Roman]

thought you were goofing me, so I checked, and you are not....

http://en.wikipedia.org/wiki/Kisspeptin

[Swifto]

Moved.

Good post.

I will look into this.

[bass]

it all sounded Greek to me! GDevine can you please explain in plain English? i guess what i understood is Kisspeptin sets the clock back in men! how does this work with testosterone deficient men exactly?

[Lemonada8]

^^ lol well ok heres the basic priniciple..

the hypothalamus is the 'control' center of the brain, it regulates basically everything in the body. So when puberty hits, *this is still being discovered* it releases a kisspeptin which stimulates the production and release of GnRH (gonadotropin releasing hormone) which then goes to the pituitary gland which then releases LH and FSH (gonadotropins). These hormones then go to the testes and there produce testosterone , and stimulate spermatogensis (making viable sperm to have kids.. which its all about back to the basic principle of life)

what the study is saying is that when this kisspeptin is given to a patient, it stimulated the very first step of making testosterone in the hypothalamus (aka control center) and it produces the LH release from the pit, which then goes to the testes and makes test. there are many clocks regulating the body in the hypothalamus (think of circadian rhythm, why do you sleep and wake at the same time regularaly.. .stuff like that) This kisspeptin reset the clock for the production of GnRH which it then showed the peak of LH (pre-test necessity) then the following LH spikes were also larger than before and were at a certain time apart.

it gets pretty heavy into physiology the deeper you go... but the basic sense is that it made your brain think you are starting puberty again, so in theory you reset the biological clock of aging in regard to test production. and with repeated suppressions of this system (AAS cycle) and how it seems many AAS users end up on TRT.. .this may help them avoid that fate of biweekly shots for the rest of your life...

some things you have have heard of:
HCG is basically the same as LH
Triptorelin is a GnRHa (gonadotropin releasing hormone agonist)

[GotNoBlueMilk]

Any GxRH will have an effect on subsequent pulses. So it is no surprise that this compound increases the amplutude of subsequent pulses. CJC-1293 and GHRH do the same thing on GH release. Even after you stop using them, you see the benefit for a couple weeks.

This study is actually more informative: George JT, Veldhuis JD, Roseweir AK, et al. Kisspeptin-10 Is a Potent Stimulator of LH and Increases Pulse Frequency in Men. Journal of Clinical Endocrinology & Metabolism

Objective: We investigated our hypothesis that kisspeptin-10 increases GnRH and thus LH pulse frequency.

Design and Participants: The dose response of kisspeptin-10 was investigated by administering iv bolus doses (0.01–3.0 μg/kg) and vehicle to healthy men. Effects on LH pulse frequency and size were determined by deconvolution analysis during infusion of kisspeptin-10 for up to 22.5 h.

Results: Intravenous bolus kisspeptin-10 resulted in a rapid and dose-dependent rise in serum LH concentration, with maximal stimulation at 1 μg/kg (4.1 ± 0.4 to 12.4 ± 1.7 IU/liter at 30 min, P < 0.001, n = 6). Administration of 3 μg/kg elicited a reduced response vs. 1 μg/kg (P < 0.05). Infusion of kisspeptin-10 at 4 μg/kg • h for 22.5 h elicited an increase in LH from a mean of 5.4 ± 0.7 to 20.8 ± 4.9 IU/liter (n = 4; P < 0.05) and serum testosterone increased from 16.6 ± 2.4 to 24.0 ± 2.5 nmol/liter (P < 0.001). LH pulses were obscured at this high rate of secretion, but a lower dose infusion of kisspeptin-10 (1.5 μg/kg • h) increased mean LH from 5.2 ± 0.8 to 14.1 ± 1.7 IU/liter (n = 4; P < 0.01) and increased LH pulse frequency from 0.7 ± 0.1 to 1.0 ± 0.2 pulses/h (P < 0.05) and secretory burst mass from 3.9 ± 0.4 to 12.8 ± 2.6 IU/liter (P < 0.05).

-------------------------------
So 1 mcg / kg of body weight (90 mcg for a 200 lb man) was the maximum response. The response fell off at higher doses.

The stuff is a little expensive at the moment, roughly $25 a dose from a quality peptide synthesis company. The chinese stuff is a lot less

[bass]

^^ lol well ok heres the basic priniciple..

the hypothalamus is the 'control' center of the brain, it regulates basically everything in the body. So when puberty hits, *this is still being discovered* it releases a kisspeptin which stimulates the production and release of GnRH (gonadotropin releasing hormone) which then goes to the pituitary gland which then releases LH and FSH (gonadotropins). These hormones then go to the testes and there produce testosterone , and stimulate spermatogensis (making viable sperm to have kids.. which its all about back to the basic principle of life)

what the study is saying is that when this kisspeptin is given to a patient, it stimulated the very first step of making testosterone in the hypothalamus (aka control center) and it produces the LH release from the pit, which then goes to the testes and makes test. there are many clocks regulating the body in the hypothalamus (think of circadian rhythm, why do you sleep and wake at the same time regularaly.. .stuff like that) This kisspeptin reset the clock for the production of GnRH which it then showed the peak of LH (pre-test necessity) then the following LH spikes were also larger than before and were at a certain time apart.

it gets pretty heavy into physiology the deeper you go... but the basic sense is that it made your brain think you are starting puberty again, so in theory you reset the biological clock of aging in regard to test production. and with repeated suppressions of this system (AAS cycle) and how it seems many AAS users end up on TRT.. .this may help them avoid that fate of biweekly shots for the rest of your life...

some things you have have heard of:
HCG is basically the same as LH
Triptorelin is a GnRHa (gonadotropin releasing hormone agonist)

thanks! i think i understand. so will this have any effect on growth, will it add few inches to your height?!

[GotNoBlueMilk]

thanks! i think i understand. so will this have any effect on growth, will it add few inches to your height?!

Higher LH means higher natural Test production by the body. Growth, in terms of height, is a GH thing and only before your last growth spurt ends. So once you stop growing taller, no amount of GH will make you grow again. As a long standing member of this forum bass, and the fact that this forum is for HRT, I'm pretty sure your teenage years are long behind you.

[spywizard]

So, now all we need them to do is a study on older men.. 40+.. I'm assuming that the results would be the same, or would it be a restart to the expected production of an aged man..??

or

would one assume that with a reset, it would restore production for the aged man to that of when he was younger??

[kelkel]

Just want to say the amount of knowledge passed around this forum is phenominal! Great post Lemon! Great reponse GNBM! Always something new to learn. I find myself constantly reading the stickies and interesting posts so the knowledge sinks in and then going over it in my mind again and again to be sure. It's especially nice to be able to talk to your doctor on the same level (or better) when it comes to trt. When your doc knows that your on top of things, they seem to be much better prepared for your visit.

just my .02

sorry for the short rant!

Thanks!

[GotNoBlueMilk]

So, now all we need them to do is a study on older men.. 40+.. I'm assuming that the results would be the same, or would it be a restart to the expected production of an aged man..??

This is not exactly a given. There are a couple factors with aging men. First, decreased testosterone levels can be from leydig cells failing to respond to LH. So in this case, Kisspeptin will not benefit testosterone levels at all.

Another consideration is that we can't assume the pituitary in an aged man will produce LH in the same capacity as a younger man. Kisspeptin is a releasing hormone, so the LH has to already be in the pituitary waiting for a signal to be released. If the pituitary is not producing and storing LH as it should, the release hormone will have little benefit.

Many studies show that the pituitary in an aged man still has the same capacity to produce GH, but does not release the GH like a younger man. Unfortunately, this is not necessarily the case with LH.

All is not lost though. It would benefit many aged men, just not all aged men.

[Lemonada8]

CJC1293 and GHRH work in 2 different ways though, the cjc makes the pulses larger by continous stimulation of production of GH and the GHRH will release the stored GH but yea in the same sense, very similar

I wonder how long the effects last for the kisspeptin, how long the following LH pulses were larger before going back to pre-administeration pulses...

Another thing with aging, is the responsiveness of the testes to LH. Sure the pit will produce more but it all depends also at the testes which make the testosterone .

Very promising for the future though

[GotNoBlueMilk]

That is the million dollar question. Do you have to dose this stuff daily, weekly, etc. And of course, there really seems to be no longterm studies on the peptide. So we know nothing about longterm use and sides. Hopefully these studies will surface soon.

[Lemonada8]

found these:
hronic subcutaneous administration of kisspeptin-54 causes testicular degeneration in adult male rats
http://ajpendo.physiology.org/content/291/5/E1074.short
Histological examination showed degeneration of the seminiferous tubules associated with a significant decrease in the circulating levels of the testes-derived hormone, inhibin B. Plasma free and total testosterone were also lower, although these changes did not reach statistical significance. Further studies examined the effects of shorter periods of continuous kisspeptin administration. Subcutaneous administration of 50 nmol kisspeptin-54 for 1 day increased plasma LH and testosterone. This effect was lost after 2 days of administration, suggesting a downregulation of the HPG axis response to kisspeptin following continuous administration however with only one administeration of this kisspeptin, the effects are long lasting (saw that in the google search preview of this article... maybe too much = overwhelming?

Effects of Single or Repeated Intravenous Administration of Kisspeptin upon Dynamic LH Secretion in Conscious Male Rats
http://endo.endojournals.org/content/147/6/2696.short
. The ability of kisspeptin-10 to stimulate LH release was fully preserved, and even doubled in terms of relative increases, after short-term fasting despite suppression of prevailing LH levels. Repeated injections of kisspeptin-10 (four boluses, at 75-min intervals) evoked associated LH secretory pulses, the magnitude of which remained constant along the study period. Moreover, in this setting, in vivo LH responses to a terminal injection of GnRH were preserved,

Seems with continued administeration of this kisspeptin, it basically overwhelms the testes which results in lower production of test. I bet there is another control mechanism that is testes based on how long fertility lasts in males also.
That is interesting about the inhibitin B though... * had to read up in some books on this real quick.
"serum inhibitin B, a marker of sertoli cell function and spermatogensis, was shown to be rewlatively well maintained in healthy elderly men, ableit at the cost of clearly increased FSH stimulation that compensates for an age-related regression of sertoli cell mass and funciton" - From the book "testosterone: action, deficiency, substituition" by Eberhard Nieschlag and Hermann M Behre
I wonder, since LH is only higher than FSH during reproductive times that the kisspeptin stimulates the production and initial start of LH release which then begins the onset of puberty. And since spermatogensis can be maintained with people on TRT with HCG (LH stimulation) for an amount of time but the quality and function of sperm decline with time in a FSH deficiency setting. There is a delicate balance between FSH and LH, both endocrine and local factors in spermatogensis which is still foggy on what is actually going on. It is clear however that LH can maintain spermatogensis in the absence of FSH, but the absence of LH and with FSH spermatogensis is severely impacted/or nearly gone.

Also with Suppression, LH is what goes down the quickest compared to FSH so in regard to someone who does multiple cycles of AAS equaling in temporary suppression of gonadotropins the kisspeptin seems very promising for re-initiating LH production, as long as there is a functional FSH production/usage in the body. - Another good reason to have time off between cycles, to let those hormones get as close back to normal as possible.

[Sicko]

Impressive knowledge fellas, I am interested to see if this study continues to progress to more practical uses in human evolution/preservation.
Not that we really need a bunch of old men making babies though, but it would make for a great sex life I would think...I remember what I was like as I came into puberty...eheheheh...

[GotNoBlueMilk]

found these:
hronic subcutaneous administration of kisspeptin-54 causes testicular degeneration in adult male rats
http://ajpendo.physiology.org/content/291/5/E1074.short
Histological examination showed degeneration of the seminiferous tubules associated with a significant decrease in the circulating levels of the testes-derived hormone, inhibin B. Plasma free and total testosterone were also lower, although these changes did not reach statistical significance. Further studies examined the effects of shorter periods of continuous kisspeptin administration. Subcutaneous administration of 50 nmol kisspeptin-54 for 1 day increased plasma LH and testosterone. This effect was lost after 2 days of administration, suggesting a downregulation of the HPG axis response to kisspeptin following continuous administration

Effects of Single or Repeated Intravenous Administration of Kisspeptin upon Dynamic LH Secretion in Conscious Male Rats
http://endo.endojournals.org/content/147/6/2696.short
. The ability of kisspeptin-10 to stimulate LH release was fully preserved, and even doubled in terms of relative increases, after short-term fasting despite suppression of prevailing LH levels. Repeated injections of kisspeptin-10 (four boluses, at 75-min intervals) evoked associated LH secretory pulses, the magnitude of which remained constant along the study period. Moreover, in this setting, in vivo LH responses to a terminal injection of GnRH were preserved,

Seems with continued administeration of this kisspeptin, it basically overwhelms the testes which results in lower production of test. I bet there is another control mechanism that is testes based on how long fertility lasts in males also.
That is interesting about the inhibitin B though...

The kisspeptide-54 study is irrelevant. That is the full 54-peptide chain kisspeptide and has much different results than using just the last 10 amino acids (kisspeptide-10) in the peptide chain. It is only the kisspeptide-10 studies that are of relevance to us.

[Lemonada8]

^^ re read my post, i edited it :-) and didnt feel like spamming it lolz

Ill check into the differences with the 54 chain vs 10 chain... I imagine it to be similar to the GH peptides.. where else have you seen info on the differences?


A kisspeptin-10 analog with greater in vivo bioactivity than kisspeptin-10
http://ajpendo.physiology.org/content/298/2/E296.short

The kisspeptins are neuropeptides that stimulate the hypothalamo-pituitary-gonadal (HPG) axis. The smallest endogenous kisspeptin, kisspeptin-10 (KP-10), binds to the receptor KISS1R with a similar affinity to the full-length peptide, kisspeptin-54 (KP-54), but is less effective in vivo, possibly because of increased enzymatic breakdown or clearance. The kisspeptin system may have therapeutic potential in the treatment of reproductive disorders and endocrine cancers. We have rationally modified the structure of KP-10 and tested the binding affinity of these analogs for the KISS1R. Those analogs that bound with relatively high affinity to KISS1R were tested for ability to stimulate ERK1/2 phosphorylation in vitro and for their ability to stimulate the HPG axis in vivo. One analog, [dY]1KP-10, bound to KISS1R with lower affinity to KP-10 and exhibited similar bioactivity in vitro. However, in vivo peripheral administration of [dY]1KP-10 increased plasma LH and testosterone more potently than KP-10 itself at 20 min postinjection in mice. In addition, 60 min postinjection, 0.15 nmol [dY]1KP-10 significantly increased total testosterone levels in mice whereas the same dose of KP-10 had no significant effect. Should manipulation of the kisspeptin/KISS1R signaling system prove therapeutically useful, long-lasting analogs such as [dY]1KP-10 may have greater therapeutic potential than endogenous forms of kisspeptin.

Twice-Weekly Administration of Kisspeptin-54 for 8 Weeks Stimulates Release of Reproductive Hormones in Women With Hypothalamic Amenorrhea
http://www.nature.com/clpt/journal/v...t2010204a.html

Kisspeptin is a novel therapeutic target for infertility. A single kisspeptin-54 (KP-54) injection acutely stimulates the release of reproductive hormones in women with hypothalamic amenorrhea (HA), a commonly occurring condition characterized by absence of menstruation; however, twice-daily administration of KP-54 results in tachyphylaxis. We determined the time course of desensitization to twice-daily KP-54 injections, compared the effects of twice-daily and twice-weekly administration regimens of KP-54, and studied the effects of long-term twice-weekly administration of KP-54 on the release of reproductive hormones in women with HA. When KP-54 was administered twice daily, responsiveness to luteinizing hormone (LH) diminished gradually, whereas responsiveness to follicle-stimulating hormone (FSH) was nearly abolished by day 2. Twice-weekly KP-54 administration resulted in only partial desensitization, in contrast to the complete tolerance achieved with twice-daily administration. Women with HA who were treated with twice-weekly KP-54 injections had significantly elevated levels of reproductive hormones after 8 weeks as compared with treatment with saline. No adverse effects were observed. This study provides novel pharmacological data on the effects of KP-54 on the release of reproductive hormones in women with HA.

Kisspeptin-10 Is a Potent Stimulator of LH and Increases Pulse Frequency in Men
http://jcem.endojournals.org/content...-0089.abstract

Context: Kisspeptins stimulate GnRH and thus gonadotropin secretion. Kisspeptin-10 is the minimal kisspeptin sequence with full intrinsic bioactivity, but it has not been studied in man.

Objective: We investigated our hypothesis that kisspeptin-10 increases GnRH and thus LH pulse frequency.

Design and Participants: The dose response of kisspeptin-10 was investigated by administering iv bolus doses (0.01–3.0 μg/kg) and vehicle to healthy men. Effects on LH pulse frequency and size were determined by deconvolution analysis during infusion of kisspeptin-10 for up to 22.5 h.

Results: Intravenous bolus kisspeptin-10 resulted in a rapid and dose-dependent rise in serum LH concentration, with maximal stimulation at 1 μg/kg (4.1 ± 0.4 to 12.4 ± 1.7 IU/liter at 30 min, P < 0.001, n = 6). Administration of 3 μg/kg elicited a reduced response vs. 1 μg/kg (P < 0.05). Infusion of kisspeptin-10 at 4 μg/kg · h for 22.5 h elicited an increase in LH from a mean of 5.4 ± 0.7 to 20.8 ± 4.9 IU/liter (n = 4; P < 0.05) and serum testosterone increased from 16.6 ± 2.4 to 24.0 ± 2.5 nmol/liter (P < 0.001). LH pulses were obscured at this high rate of secretion, but a lower dose infusion of kisspeptin-10 (1.5 μg/kg · h) increased mean LH from 5.2 ± 0.8 to 14.1 ± 1.7 IU/liter (n = 4; P < 0.01) and increased LH pulse frequency from 0.7 ± 0.1 to 1.0 ± 0.2 pulses/h (P < 0.05) and secretory burst mass from 3.9 ± 0.4 to 12.8 ± 2.6 IU/liter (P < 0.05).

Conclusions: Kisspeptin-10 boluses potently evoke LH secretion in men, and continuous infusion increases testosterone, LH pulse frequency, and pulse size. Kisspeptin analogues have therapeutic potential as regulators of LH and thus testosterone secretion.

The Effects of Kisspeptin-10 on Reproductive Hormone Release Show Sexual Dimorphism in Humans
http://jcem.endojournals.org/content...-1408.abstract

Background: Kisspeptin peptides are critical in human reproductive physiology and are potential therapies for infertility. Kisspeptin-10 stimulates gonadotropin release in both male and female rodents. However, few studies have investigated the effects of kisspeptin-10 on gonadotropin release in humans, and none have investigated the effect in women. If kisspeptin is to be useful for treating reproductive disease, its effects in both men and women must be established.

Aim: To compare the effects of kisspeptin-10 administration on reproductive hormone release in healthy men and women.

Methods: Intravenous bolus kisspeptin-10 was administered to men and women (n = 4–5 per group). Subcutaneous bolus and iv infusion of kisspeptin-10 was also administered to female women (n = 4–5 per group). Circulating reproductive hormones were measured.

Results: In healthy men, serum LH and FSH were elevated after iv bolus kisspeptin-10, at doses as low as 0.3 and 1.0 nmol/kg, respectively. In healthy women during the follicular phase of the menstrual cycle, no alterations in serum gonadotropins were observed after iv bolus, sc bolus, or iv infusion of kisspeptin-10 at maximal doses of 10 nmol/kg, 32 nmol/kg, and 720pmol/kg/min, respectively. In women during the preovulatory phase, serum LH and FSH were elevated after iv bolus kisspeptin-10 (10 nmol/kg).

Conclusion: Kisspeptin-10 stimulates gonadotropin release in men as well as women during the preovulatory phase of menstrual cycle but fails to stimulate gonadotropin release in women during the follicular phase. The sexual dimorphism of the responsiveness of healthy men and women to kisspeptin-10 administration has important clinical implications for the potential of kisspeptin-10 to treat disorders of reproduction.

^^ Hmmm....

[spywizard]

thanks guys..

So, synthetic GH in the aged man is still the recommended coarse for "young man" levels of GH

and possible the kisspeptin-10 analog would reset the testosterone levels of production in the BB that has a system that has been repressed due to steroid use .. but is questionable for the aged male.?

What about the man that has been successfully treated for prostrate cancer.... ?? restart since his system is so shut down from the treatment??

[Lemonada8]

thanks guys..

So, synthetic GH in the aged man is still the recommended coarse for "young man" levels of GH I would think that the peptides would also be beneficial, esp for the cost difference. Using the CJC1293 or modgrf in combo with a GHRP. That maximizes natural GH release and usage.

and possible the kisspeptin-10 analog would reset the testosterone levels of production in the BB that has a system that has been repressed due to steroid use .. but is questionable for the aged male.? I think the big key is how the other parts of the system are working. The thing with the BBer is that he is still in a 'reproductive' period in his life. As for a normal aged male w/ no AAS cycles i would think that it would be of some help if his LH was low, but that also will depend on how well his testes function also. With increased age, there is a decreased response to LH, and an increase in SHBG. But SHBG is increased with elevated estrogen, so if you could control those while initiating and then are able to reach a steady balance i would think that it would work to help restart LH production and increase test levels. I would also think it would increase fertility also as long as everything is working decently

What about the man that has been successfully treated for prostrate cancer.... ?? restart since his system is so shut down from the treatment?? Good question! I would also think this would work, however constant montioring of the prostate would have to be done and maybe add a DHT inhibitor to prevent any flareups with the prostate (mainly due to DHT... but T and E also play a part) It wouldnt be good for the man who is treated for prostate issues to have them return, and it may depend on the cause of the prostate issue and how it started. if there were some genetic part in play that had a large issue in the proliferation of the cancer, it may not be good to have him restart his natural test b/c it may restart the prostate issues.

Good points, i think there are many applications in the future with kisspeptin due to it works at the hypothalamic level and not at any other level. Kinda like starting at the top of the mountain to let the 'snow pebble' begin to roll and have it gain its 'size' naturally vs having a larger 'snow pebble, more like a snow basketball" somewhere downhill from there.