GnRH

tl;dr GnRH is a natural peptide used to “jumpstart” sex hormone production. You will not make testosterone without it’s pulse release in your brain. These effects are well-researched. Some new research is exploring what else it can do for brain aging and disease. GnRH can also be used to as PCT to reboot a broken HPTA.

Names: GnRH, GNRH, GnRF, Gonadorelin

Introduction

GnRH is Gonadotropin-Releasing Hormone. Depending on what you’re reading it’s also called FSH-RH, LHRH, or GnRF. While it is often categorized in the GHRP/GHRH series it really belongs in it’s class. The somewhat similar name doesn’t mean it does the same things.

Pulsatile action similar to hGH

GHRP/GHRH cause the release of hGH with a pulse release. GnRH works to release different hormones though. But GnRF does work in a pulse manner similar to these peptides.

Controls testosterone, sperm, and egg production

GnRH is a naturally occurring peptide. It is the prime mover to start many sexual functions. It binds to it’s own receptor (the gonadotropin-releasing hormone receptor) on the pituitary to start the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This in turn makes testosterone.

In this way it also acts a fertility hormone. Males and females with a GnRH problem are not going to be able to make sperm or eggs. And male testosterone generation is first controlled by GnRH secretion. Each gender’s release of GnRH is on different cycles as well.

Effective for PCT after steroid use

GnRH can be very useful to reboot a damaged HPTA axis or for PCT. Some anabolics will stop natural LH, FSH, and T production. GnRH can reboot this. You can read more about this in the PCT section.

“ GnRH production/release is one of the few confirmed examples of behavior influencing hormones, rather than the other way around.[citation needed] “” wikipedia, easy link

GnRH Medical Studies

Decades of medical research

GnRH is heavily research with studies dating back to the 1960’s detailing it’s effects on FSH, LH, and testosterone. The benefits of natural testosterone production, or replacement therapy TRT, for male performance are too obvious to mention here. And you can’t discuss women’s fertility without knowing GnRH’s role in production of FSH and LH.

So lets not re-explore 40 years worth of data about the relationship of GnRH to downstream hormones. It’s signaling effects can certainly be recreated by replacement. Instead are there effects that GnRH itself provides independent of other hormones?

What can GnRH do beside hormone signaling

Lets see how it does in keeping our goals in mind:

PTSD

Evidence:

Effect:

There are no studies testing GnRH as a PTSD cure/treatment. There are however several links between a two way relationship between stress and GnRH problems in humans and animals.

Stress situations and actual endocrine stress ¹ both “negatively regulates GnRH neurons” ² and directly “modulates GnRH secretion.” ³

In an animal model, social interactions and other stressful situations also had an inhibitory effect on GnRH production.⁴ The same applies to humans. When tested by blocking GnRH activity people reported having more mental distress.⁵

And as emotionally stressful situations also downregulate GnRH, there is a cyclical effect at play. The more stressed you get the worse your GnRH pathway functions. The worse your GnRH pathways function, the worse you feel.

Low theoretical effectiveness for PTSD

In a chronic PTSD situation with impaired GnRH production, GnRH injections or stimulation might offer an effective brake against endocrine issues. While not curing PTSD directly this might offer the person a chance at having a more normal endocrine system to bounce back from daily stress and begin tackling the root cause head on.

TBI

Evidence:

There is no link between GnRH assisting recovery or life quality in TBI cases. TBI in children might require GnRH and hGH supplementation if there is local damage to the pituitary. ⁶

But in general, there is no studied effect of anything unique to GnRH for TBI recovery.

Alzheimer’s/Brain Aging

Evidence:

Effect:

Links to brain aging but not in a curative manner

GnRH activity and Alzheimer’s have some interplay. The exact mechanism is still a matter of debate.

Using GnRHr agonists

Optional Biochemistry Nerd Information: The way to test it is this: use a synthetic GnRH agonist (but NOT actual GnRH peptides.) This will cause a brief, but massive, LH/FSH spike. This is called a flare protocol. ⁷⁸⁹ Because it is so effective, the pituitary gland quickly downregulates GnRH receptors. After the flare’s effects wear off the receptors remain downregulated. The body is now affected much less by GnRH and it stays in a low LH/FSH/T state.

The biggest clue is the rise in LH seen at the start of Alzheimer’s and old age.¹⁰¹¹ Since GnRH causes the release of LH, is there a broken feedback system at work? Could inhibiting GnRH - or normalizing it throughout old age - prevent this disease?

Some research seems to implicate GnRH is the worsening of Alzheimer’s.¹² By blocking and limiting the effects of naturally occurring GnRH with an analog, parts (but not all) of the brain were somewhat less affected. But this was in a rat model and only offered partial protection.

Humans have a somewhat similar mechanism.¹³ At least in prostate cancer patients, this GnRH protocol caused less Alzheimer’s deaths. It also helps some post menopausal women from worsening with the disease as well.¹⁴

GnRH itself seems secondary to any brain aging

GnRH itself seems to be implicated in the progression of the disease. Halting or slowing down the natural effects of GnRH seems to the be way to go. While GnRH itself does not cause anything bad, it’s actions in the pituitary to cause LH/FSH release might be to blame. Based on that, low level GnRH use would be perhaps the worst possible thing for a dementia/Alzheimer patient to do.

Neuroprotective Effects

Evidence:

Effect:

Theoretical use of GnRH inside the brain

The evidence is that there are some GnRH receptors deep in the brain and on some motor neurons. There would be no reason for these receptors to have evolved there if GnRH was not providing some effect there.

Nerve Regrowth

Evidence:

Effect:

Several studies point to GnRH as having positive effects for spinal cord injury recovery.

In the most promising study a GnRH agonist was shown to improve functions after spinal cord compression injury in rats after 5 weeks. They recovered much better compared to the control group without GnRH activation. ¹⁶

The effects are measurable and real. The rats with damaged spinal cords had a better gait and nerve regrowth after treatment. ¹⁷

A similar study shows how the GnRH receptor in spinal cord neurons play a role in neuronal plasticity.¹⁸ This would also mean that GnRH could help heal spinal cord injuries by stimulating growth.

GnRH could heal nerve damage…

A big question from these studies is if natural GnRH ever makes it to the injury in the first place. Perhaps the forced over-activation on GnRHR triggers a central nervous system repair? If this is true, using GnRH for non-severing spinal injuries could help recover lost functions in human.

This works with a pet theory I have: that the spinal cord is capable of magnified healing. For whatever reason though, perhaps distance from the brain, nerve regrowth factors simply don’t reach it. This causes reduced healing. This (along with many other reasons) also makes it impossible for autophagy or Schwann cell recruitment to take place.

…but synthetic analogs would be better suited

Many studies use synthetic GnRH analogs (ex: leuprolide acetate) that are super potent and long lasting. Compare this to the natural fragile peptide with a 5 minute half-life that must somehow travel across the spine. Perhaps future trials of GnRH analogs could finally allow for completely severed spinal cord recovery.

Outside of the central nervous system though, GnRH does not appear to be used for any peripheral nerve growth, repair, or regeneration. A very similar peptide GnRH II is used in the peripheral nervous system though.¹⁹

Muscle Growth

Evidence:

GnRH as a TRT Replacement

Can GnRH be used a replacement for TRT for secondary hypogonadism? Instead of using just T which can halt LH/FSH production and cause infertility, perhaps GnRH could be used instead to naturally elevate levels of all 3.

Needs very long term studies

It will be 40 years before guys in their 30s on TRT now start starting entering older age. Would pulsatile GnRH have been better because there is a certain something in it that just testosterone + hCG can’t provide?

Unfortunately the use of GnRH past 1-2 years is not in any medical studies. And having a pump deliver GnRH every 90 minutes for life is more trouble than an E3D/E7D shot.

GnRH is Stress Sensitive

GnRH levels are related to external and internal stress

GnRH production is sensitive to stress. Both in the bio-chemical sense and the psychological sense.

Environment stress situations are shown to reduce GnRH release. Much of the research is done on animal breeding. For example in birds and rodents specifically it is believed GnRH inhibitory hormones “may serve as a transducer of environmental information and social interactions.”²¹ Similar effects are seen in fish breeding with social stress causing endocrine stress via cortisol.²²

Many different stressors can reduce GnRH

Humans are also affected because we can release a hormone designed just to inhibit GnRH as well. This hormone is called gonadotropin-inhibitory hormone (GnIH) and functions as a brake on, ultimately, Testosterone production. It can be so strong that it can cause infertility.²³

As in other animals this could be due to a sensitive social feedback loop, or the stress/inflammatory pathways in the body. Specifically IKK-β and NF-κB seem to implicated in inhibition of GnRH.

It seems the easiest way to naturally boost GnRH levels and keep it effective is to be less stressed. This avoids the negative feedback loops.

GnRH for PCT

Evidence:

Effect:

Useful, but timing is important

Natural GnRH and GnRH drug analogs can get the same effect but behave very differently. Natural GnRH is released in pulses approximately every 90 minutes and has a very short half-life - just a few minutes.²⁴ At natural doses there is no downregulation.

Natural GnRH supplementation is very effective:

• Pulsatile GnRH treatment fixes HPTA axis problems and restarts T production. ²⁵

• Pulsatile GnRH at 90 minute intervals restored fertility, ovulation, and allowed for pregnancy in women who did not respond to Clomid.²⁶

• The same pulses of 5-20 micrograms of GnRH every 89 minutes made men fertile enough to father children again.²⁷

GnRH peptides vs synthetic analogs like Triptorelin for PCT

Drug analogs can have much longer half-lifes, often lasting hours.²⁸ They also can bind for much longer and overwhelm GnRH receptors because their binding capacity can be more than 100x that of GnRH itself.²⁹ This could cause all kinds of sensitivity issues that can take weeks to recover from if not monitored. Not a fun thing to have on top of an already possibly out of sync HPTA axis.

(You can read more about synthetic GnRH analog use in the optional Biochemistry Nerd section of GnRH for Alzheimer’s disease treatment above)

There is an exciting report of how Italian doctors successfully restarted the HPTA axis of a patient.³⁰ His LF/FSH/T levels rebounded after 13 years of steroid use. All it took was one injection of the GnRH agonist Triptorelin at 100mcg to get his pituitary working again. T levels went back to normal then.

Single shot for PCT…

This study has been the rationale behind claiming GnRH/Triptorelin is a “one and done” fix for bodybuilding PCT.

The studies show that for someone who is in HPTA shutdown GnRH or triptorelin acetate could result in recovery. It was just an N=1 report though. For bodybuilding it seems people report it working about 50% of the time. Unfortunately this research is suffering for lack of access to pure Triptorelin.

…but it often isn’t that easy

In many cases the use of GnRH is confused with an analog. Or the triptorelin’s source is questionable, or the PCT is run on top of Clomid/hCG. Or, even worse, people think that Triptorelin is GnRH itself. Since the two have dosing differences of 10-20x this is dangerous.

Triptorelin would best be prescribed by a doctor to ensure getting an accurate product. If after 1 or 2 100mcg doses the blood work doesn’t come back normal though, there is something else going on preventing T production.

Using just GnRH peptide itself like your body does

Pure GnRH peptides should also restart sex hormone production. The downside is mimicking the 90 minute pulse effects and getting the dose right: natural GnRH works at the 5-10mcg level for restoring testical functions.³¹

Instead of multiple injections throughout the day of GnRH peptides, modifying a diabetes pump would be more effective. It will automatically release the correct amounts on schedule.

Overdoing it can cause severe problems

But the effectiveness of GnRH therapy can come at a cost. Is it possible to overdo it though? Yes.

The fact is any GnRH analog like Triptorelin gives a nice, healthy jumpstart to sex hormone production.

Continuous use though will cause suppression of the same hormones. Overloading your GnRH system is, for all intents, chemical castration - German sex offenders are being chemically castrated using GnRH agonists.³². Triptorelin is used to PREVENT puberty from starting.³³ Long term GnRH analogs also had a 94% success rate in chemical castration.³⁴

This is the complete opposite of PCT.

Patents

Patents for GnRH are mostly focused on the downregulation/de-sensitization aspects. Blocking GnRH functions leads to a massive drop in sex-hormone levels. Certain cancers like breast or prostate cancer are sensitive to these. By dropping sex-hormone levels these cancers can be treated easier.

Patent US20150231053A1: Treatment of skin, including aging skin, to improve appearance uses, among other hormones, GnRH for better skin tone.

Dosing

• 5-10mcg every ~90 minutes mimics natural human production. The constant pulse release of GnRH is needed for it’s effects.
• A single 100mcg injection of GnRH analog Triptorelin for PCT
• 10 mcg/kg has been tested in rats

Pricing

GnRH as a reference chemical is sold either as analogs (ex: Triptorelin) or as the pharmaceutical name Gonadorelin. Peptide sites often sell Triptorelin and GnRH interchangeable. Their mass spectrometry results should show that Triptorelin is C64H82N18O13, GnRH is C55H75N17O13 if they aren’t showing a difference.

Peptide site pricing:

• GnRH: $25-$42 for 2000mcg/2mg
• Triptorelin: $30-$36 for 100mcg

Chemical vendor pricing:

• Gonadorelin: $54-138 for 5mg, $310 for 250mg
• Triptorelin: $210 for 100mg

References

Last updated: Feb 27, 2017