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

[mikeek1111]

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 Gonadorelin is allowed to be compounded. Does anyone have any input on this?

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Gonadorelin is a medication used in men for various purposes, including maintaining fertility and testicular function in those undergoing testosterone replacement therapy (TRT). It is a synthetic version of gonadotropin-releasing hormone (GnRH), which stimulates the pituitary gland to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH), thereby promoting the production of testosterone and sperm. Gonadorelin is often prescribed to prevent testicular shrinkage and maintain fertility in men on TRT, especially those who are concerned about their fertility or considering future parenthood[1]. The typical dosage for adults is 5 micrograms injected into a vein or under the skin every ninety minutes for twenty-one days[2]. Some healthcare providers also prescribe compounded gonadorelin along with testosterone and other medications as part of men's health regimens[3]. Studies have shown that gonadorelin is effective in maintaining testicular functioning and size for both fertility and TRT treatments[4]. In men, gonadorelin is used to stimulate spermatogenesis or sperm production and boost the production of testosterone by the testes[5].

Citations:
[1] Gonadorelin for Men on Testosterone Replacement Therapy (TRT) | Full Potential HRT Clinic
[2] Gonadorelin (Intravenous Route, Injection Route) Proper Use - Mayo Clinic
[3] Compounded Gonadorelin in Men’s Health | Empower Pharmacy
[4] https://www.novagenix.org/post/does-gonadorelin-work
[5] https://www.genemedics.com/gonadorelin

 

[swoops36]

I think Cataceous has been using that with some success. Maybe he’ll chime in. I’m interested in it too

 

[Cataceous]

Gonadorelin may work with TRT—producing endogenous LH and FSH—if you add a SERM. But it's not clear if even daily injections would be enough.

Kisspeptin is untested in this capacity, as far as I know. It's an interesting peptide, as its suppression in TRT could be detrimental to us, which may also be the case with gonadorelin/GnRH. For kisspeptin alone to stimulate production of gonadotropins it must first overcome negative feedback at the hypothalamus to produce endogenous GnRH. If this does happen then you still need a SERM to allow the endogenous GnRH to stimulate the pituitary. The hypothalamus has negative feedback from both androgens and estrogens. If we're lucky, all of this negative feedback is upstream of kisspeptin production, so that exogenous kisspeptin would lead to GnRH production. I'm not sure if infrequent injections of kisspeptin would be sufficient for this; it does have a short half-life.

Bottom line: I think you must use a SERM to get either of these possible hCG replacements to do something useful while on TRT. I've shown that gonadorelin is viable, though not necessarily practical. The situation with kisspeptin is less clear.

 

[mikeek1111]

Thank you for the explanation. you mention everyday injections, is that due to the minimal half life of each of these prodcuts? I was told that i would be looking at 2x per week but i have not received any kind of protocol yet.

 

[Cataceous]

To function normally the pituitary requires that GnRH be delivered in pulses. These are typically from one to three hours apart. The short half-life is actually a requirement. When exposed to GnRH continuously, the pituitary stops producing the gonadotropins, LH and FSH. There are long-lasting analogs of GnRH that are used to cause HPTA shutdown intentionally. These include triptorelin.

I'm less sure about what happens at the other extreme, with infrequent stimulation. Research has shown that after a period of normal stimulation, e.g. with a pulse every couple hours, the pituitary responds fairly normally to pulses that are eight hours apart. The study did not go on long enough to see if this would work indefinitely.

So there are at least two possible problems: there may be some limit to the relative infrequency of pituitary stimulation at which gonadotropin production drops. We know that after months of inactivity the pituitary usually does not initially respond to renewed GnRH pulses. Months are not a problem, but if it's only hours then it becomes impractical, requiring an infusion pump. The results to-date of the gonadorelin trial in the link above are ambiguous in this regard: there appear to be some subjective benefits in having even low levels of gonadotropins, around 1 mIU/mL. But this is with six injections a day; if there is not further improvement over time then things are much less promising for two injections a week.

That segues to the other question, which is whether single, infrequent pulses of the gonadotropins are sufficient to provide the desired benefits: prevention of testicular atrophy and other less tangible improvements, such as in libido, mood, etc.

 

[Nelson Vergel]

Gonadorelin is nothing like hCG. Gonadorelin half like is extremely short and you would have to inject several times per day instead of two to three times per week as is the case with hCG. If your clinic does not want to ship hCG to you since they have no relationship with Empower Pharmacy, demand to have their doctor call in a prescription to your local pharmacy for brand name hCG. Here are prices are places to buy it.

https://m.goodrx.com/hcg

You will see a lot of desperate men make false claims about various peptides like kisspeptin and gonadorelin as a replacement for HCG.

Unfortunately, neither of these are replacements for any gonadotropin. Both work via the gonadotropin releasing hormone receptor but this does not mean it stimulates LH.

The opposite usually happens, suppression of LH. This is one reason gonadorelin never took off as an effective releasing hormone when it was a commercial drug. They especially will not work if the patient is on TRT since neither can override negative feedback from T like HCG does (HCG works directly on the testicles).

Basically, for any gonadotropin releasing agonist to work, the injections have to be timed perfectly multiple times per day (in pulse) with zero exposure to exogenous T for it to possibly raise LH. Most of the time these conditions are impossible to meet therefore the patients LH (and therefore T) actually decreases.

Kisspeptin is also not available in the US and is not on the approved bulk substance list of approved compounds, so no one can compound it legally anyway.

 

[Cataceous]

It's true that for most men on TRT these hormones are not practical replacements for hCG; without proper dosing and co-administration of a SERM it's unlikely the negative feedback of TRT will be overcome. However, the point about LH suppression needs to be clarified. TRT itself is what suppresses LH. The goal with these esoteric treatments, gonadorelin or kisspeptin, is to reverse this. Even when LH is present, gonadorelin does not suppress it unless the gonadorelin is delivered continuously. Similarly, kisspeptin stimulates rather than suppresses production of LH in normal men:

Kisspeptin-10 Is a Potent Stimulator of LH and Increases Pulse Frequency in Men - PMC

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. We investigated our hypothesis that kisspeptin-10 increases GnRH and ...

www.ncbi.nlm.nih.gov

 

[persevera]

Some compounding pharmacies looked at Gonadorelin as a replacement for HCG in 2008 when they thought compounded HCG was going away due to FDA essential guidance enforcement, thankfully that never happened. Gonadorelin is not a good choice for either testicular volumizing on TRT or as a monotherapy to increase T. It will not stimulate LH unless its timed in specific intervals throughout the day, if this timing is off it will create a paradoxical effect where the LH actually suppresses, therefore, lower T. This is why gonadorelin is never used in urology or male infertility due to its unpredictable results and poor efficacy for this purpose. The same applies to Kisspeptin.

Even if Kisspeptin was efficacious, its not listed on the FDA's approved bulks list. This is the list of chemicals US compounders are allowed to compound with. Unfortunately, there are several compounding pharmacies who do not follow the regs and compound unregistered peptides. This fathers everyone's confusion

 

[Cataceous]

We looked into gonadorelin as a replacement for HCG back in 2008 when we thought compounded HCG was going away due to FDA essential guidance enforcement, thankfully that never happened. Gonadorelin is not a good choice for either testicular volumizing on TRT or as a monotherapy to increase T. It will not stimulate LH unless its timed in specific intervals throughout the day, if this timing is off it will create a paradoxical effect where the LH actually suppresses, therefore, lower T. This is why gonadorelin is never used in urology or male infertility due to its unpredictable results and poor efficacy for this purpose. The same applies to Kisspeptin.
...

There are numerous studies on using gonadorelin to successfully treat hypogonadotropic hypogonadism. I see no mention that the inter-dose interval is so critical. Probably every one to three hours is viable. In the trial I describe, 6 doses a day at roughly 3-hour intervals are producing some LH and a significant increase in testicular volume compared to hCG alone—while TRT is continued. Gonadorelin isn't commonly used because you need an infusion pump to do it right. Technological advances in insulin pumps may make this form of treatment more practical.

The dose required to achieve an LH level equivalent to normal men were not different for 2 or 4-hour IPIs [interpulse intervals] and the dose required at the 1-hour IPI was greater than that required at the 4- or 8-hour IPI.​

(PDF) Interplay between Dose and Frequency of GnRH Administration in Determining Pituitary Gonadotropin Responsiveness

PDF | The dose, frequency and contour of GnRH stimulation of the pituitary gonadotrope have been shown to be independent variables influencing pituitary... | Find, read and cite all the research you need on ResearchGate

www.researchgate.net

See also:

Optimal treatment for spermatogenesis in male patients with ... : Medicine

ogenesis. Methods: In total, 220 idiopathic/isolated HH patients were divided into the GnRH pulse therapy and HCG/HMG combined treatment groups (n = 103 and n = 117, respectively). The luteinizing hormone and follicle-stimulating hormone levels were monitored in the groups for the 1st week and...

journals.lww.com

 

[DorianGray]

You will see a lot of desperate men make false claims about various peptides like kisspeptin and gonadorelin as a replacement for HCG.

Unfortunately, neither of these are replacements for any gonadotropin. Both work via the gonadotropin releasing hormone receptor but this does not mean it stimulates LH.

The opposite usually happens, suppression of LH. This is one reason gonadorelin never took off as an effective releasing hormone when it was a commercial drug. They especially will not work if the patient is on TRT since neither can override negative feedback from T like HCG does (HCG works directly on the testicles).

Basically, for any gonadotropin releasing agonist to work, the injections have to be timed perfectly multiple times per day (in pulse) with zero exposure to exogenous T for it to possibly raise LH. Most of the time these conditions are impossible to meet therefore the patients LH (and therefore T) actually decreases.

Kisspeptin is also not available in the US and is not on the approved bulk substance list of approved compounds, so no one can compound it legally anyway.

Kisspeptin is available from TailorMade Compounding if you have a physician that will prescribe it.

 

[mikeek1111]

Kisspeptin is available from TailorMade Compounding if you have a physician that will prescribe it.

Amazing considering it is not fda approved for compounding and they just had major issue.

 

[persevera]

Patients will not be compliant with multiple timed daily injections of a product that does not work with the same efficacy as its downstream cousin- HCG. These studies prove the point.

Studies can be quite different than real practice. If you speak directly to the urologists/andrologists who manage infertility in men, you wont see any of them utilizing gonadorelin, although they are all familiar with it. Compounded gonadorelin has been marketed for a while and it never picked up steam because it simply does not work to adequately stimulate LH in men not receiving exogenous T.

TailorMade is in trouble for compounding chemicals that are not on the FDAs approved bulks list (ie unregistered drugs). This includes kisspeptin. No one can compound with kisspeptin and still remain within the US compounding regulations.

 

[Cataceous]

Patients will not be compliant with multiple timed daily injections of a product that does not work with the same efficacy as its downstream cousin- HCG. These studies prove the point.

Studies can be quite different than real practice. If you speak directly to the urologists/andrologists who manage infertility in men, you wont see any of them utilizing gonadorelin, although they are all familiar with it.
...

Nobody has seriously proposed multiple, manual GnRH injections every day as a standard treatment. But with an infusion pump the treatment is better than gonadotropin injections in various ways, as per the study I referenced. Newer pump technology has small, wireless, stick-on pods that last for days and communicate with your phone. This would the way of the future for GnRH therapy.

Most of these urologists/andrologists you speak of probably prescribe one injection of testosterone cypionate every two weeks for hypogonadism. For infertility it's probably 50-100 mg of Clomid a day. I'm not too concerned about what these doctors think the standard of treatment should be when they're running 20 years behind the times.

...
Compounded gonadorelin has been marketed for a while and it never picked up steam because it simply does not work to adequately stimulate LH in men not receiving exogenous T.
...

What is your evidence to support this statement? I believe gonadorelin hasn't caught on simply because it's a major hassle compared to other treatments, not because it's ineffective.

I increasingly believe that GnRH suppression may be harming men on TRT. It's nothing dramatic, but if you look at some of the anecdotal reports of men who never do that well on TRT, and then consider the possible mechanisms for harm, the idea cannot be immediately dismissed.

Recognize also that hCG is not LH, and using it as a substitute has potential risks, which we touched on again here:

Question for some of the knowledgeable guys on the board about HCG

Thinking of guys like you @Cataceous ! I've heard it argued recently that HCG is not similar enough to LH to have the same exact effect. The beta subunit is very different than LH. Essentially they're saying just because it triggers the LH receptor, doesn't mean it's actually having the same...

www.excelmale.com

 

[Eklutna]

Kisspeptin is available from TailorMade Compounding if you have a physician that will prescribe it.

It’s available while they still have inventory. Once depleted then no more. Better hurry.

 

[Nelson Vergel]

You have to inject Gonadorelin several times per day (over 5 times!). Who is willing to do that? It is also not FDA approved for any compounding pharmacy to make. In my opinion, its a complete waste of money and time. hCG is still available via brand name products

https://www.goodrx.com/hcg

Don't fall for the hype. The reason online TRT clinics do not want to call in a prescription of brand name hCG to a regular pharmacy is because it will cut into their profits. Resist!
The clinics that actually start calling in scripts into a Walgreens, CVS. etc would also have to have a doctor with a medical license in that state, which is something that many clinics do not have. The clinics that adapt will succeed and get patients from other clinics to transfer to them. Easy business tactic that will soon be picked up by the clinics that have doctors licensed in most states.

 

[mikeek1111]

You have to inject Gonadorelin several times per day (over 5 times!). Who is willing to do that? It is also not FDA approved for any compounding pharmacy to make. In my opinion, its a complete waste of money and time. hCG is still available via brand name products

https://www.goodrx.com/hcg

Don't fall for the hype. The reason online TRT clinics do not want to call in a prescription of brand name hCG to a regular pharmacy is because it will cut into their profits. Resist!
The clinics that actually start calling in scripts into a Walgreens, CVS. etc would also have to have a doctor with a medical license in that state, which is something that many clinics do not have. The clinics that adapt will succeed and get patients from other clinics to transfer to them. Easy business tactic that will soon be picked up by the clinics that have doctors licensed in most states.

Just FYI, gonadorelin is FDA approved. Kisspeptin is the one that is not.

Drugs@FDA: FDA-Approved Drugs

 

[Nelson Vergel]

Just FYI, gonadorelin is FDA approved. Kisspeptin is the one that is not.

Drugs@FDA: FDA-Approved Drugs

This is what I said:

It is also not FDA approved for any compounding pharmacy to make. Compounding pharmacies are not allowed to make it unless they apply for a BLA, just like hCG.

Where is everyone getting their gonadorelin? I bet it is not from a pharmaceutical company but from compounding pharmacies.

Ganirelix prices:

6 syringes with 250 micrograms each: https://www.goodrx.com/ganirelix?do...m=syringe&label_override=Ganirelix&quantity=6

So, total cost per day is about $300 for the brand name product.

 

[Cataceous]

...
It is also not FDA approved for any compounding pharmacy to make. Compounding pharmacies are not allowed to make it unless they apply for a BLA, just like hCG.

Where is everyone getting their gonadorelin? I bet it is not from a pharmaceutical company but from compounding pharmacies.
...

Gonadorelin is available from Hallandale Pharmacy, and they do compound it. It is not considered to be a biological product. Hallandale maintains that the necessary FDA approvals exist for them to sell it.

 

[Nelson Vergel]

Hollandale is lying. Gonadorelin isn't an FDA approved product for compounding, so it violates the 503A Bulks List, the same way Kisspeptin does. They will eventually be stopped.

We should be advocating for access to low cost hCG, a product that can be used 2-3 times per week instead of a product that needs to be injected several times a day with high cost.

 

[Cataceous]

Hollandale is lying. Gonadorelin isn't an FDA approved product for compounding, so it violates the 503A Bulks List, the same way Kisspeptin does. They will eventually be stopped.

We should be advocating for access to low cost hCG, a product that can be used 2-3 times per week instead of a product that needs to be injected several times a day with high cost.

I would like to understand how Hallandale is lying. According to FDA:

State-licensed physicians and pharmacists that compound under section 503A of the Federal Food, Drug, and Cosmetic Act (FD&C Act) may only compound drug products using bulk drug substances that:

1. comply with an applicable United States Pharmacopeia (USP) or National Formulary (NF) monograph if one exists, and the USP chapter on pharmacy compounding;
2. are components of FDA-approved drug products if an applicable USP or NF monograph does not exist; or
3. appear on FDA’s list of bulk drug substances that can be used in compounding (the 503A bulks list) if such a monograph does not exist and the substance is not a component of an FDA-approved drug product.

In addition, bulk drug substances must be accompanied by a valid certificate of analysis and must have been manufactured by an establishment registered with FDA under section 510 of the FD&C Act. The agency urges compounders to know your bulks supplier.

I would interpret this as not requiring that a bulk drug substance be on the FDA's list of bulk drug substances for compounding if there is an applicable USP-NF monograph or if the substance is a component of an FDA-approved drug product. It appears that both of these conditions are met with gonadorelin.

I don't disagree that the TRT community at large should have a stronger focus on access to hCG. But I think it's beneficial to have gonadorelin as an option for those who want or need it.