Is GnRH suppression hurting us?

Cataceous

Well-Known Member
Admittedly the last thing we need is some other nebulous danger to worry about that may not even exist. Read on at your peril.

TL;DR: Testosterone replacement therapy suppresses the production of GnRH. Receptors for GnRH are found in places besides the pituitary. One animal model suggests GnRH may have health benefits independent of its stimulation of LH and FSH production.

The background: Gonadotropin-releasing hormone, or GnRH, is the signal the hypothalamus uses to tell the pituitary gland to secrete luteinizing hormone and follicle stimulating hormone. Luteinizing hormone (LH) signals the gonads to make testosterone. In turn, testosterone and its metabolite estradiol tell the hypothalamus to reduce GnRH production. This is how testosterone is regulated in normal males, via the so-called HPT axis.

The problem: With testosterone replacement therapy we disrupt the normal regulation of the HPTA, suppressing GnRH, LH and FSH. Lack of FSH seems to affect mainly sperm production, and when needed FSH can be taken directly or in the form of HMG. When testosterone is delivered exogenously, the necessity of LH is debatable. There are numerous LH receptors in the body whose function and importance are not well understood. We simply don’t know if shutting down this signaling is a problem. Enter hCG. HCG is an LH analog, meaning it functions very similarly in the body, at least with regard to activating LH receptors. Many men use hCG along with TRT to reduce testicular atrophy. Some report subjective benefits, including better libido and mood. Others are unable to tolerate hCG at all.

The preceding is quite familiar to most TRT veterans. But GnRH is usually ignored in all this, perhaps due to an underlying assumption that it’s not used for anything beyond signaling the pituitary. But is this the case? Maybe not. “The detection of GnRH and its receptor in other tissues, including the breast, ovary, endometrium, placenta and prostate suggested that GnRH agonists and antagonists may also have direct actions at peripheral targets.”[1] Furthermore: “Multiple lines of evidence indicate that the expression of extrapituitary GnRH receptor is not limited to reproductive tissues. For instance, it has been demonstrated by RT-PCR and Southern blot hybridization that the receptor is also expressed in the liver, heart, skeletal muscle, kidney, and peripheral blood mononuclear cells.”[2]

What we see with GnRH is analogous to the situation with LH: receptors in many places and uncertainty as to their importance to our health.

If we look at some research on mice there are tantalizing links between GnRH and aging [3]:

GnRH treatment prevents aging-impaired neurogenesis
Based on the known role of GnRH in regulating sex hormones, GnRH changes in our mouse models might correlate with changes in sex hormones, and this prediction was proved ... However, a sex hormone may not be a primary mediator for aging phenotypes in our models, since hypothalamic IKKβ/NF-κB is important for aging in both sexes. This context provoked us to hypothesize that GnRH works as a primary mediator independently of a specific sex hormone. To explore if GnRH exerts intra-brain actions to affect aging, we delivered GnRH into hypothalamic third-ventricle of old mice, and examined aging-related changes in brain cell biology. A striking observation was that GnRH promoted adult neurogenesis despite aging. Using 7-day BrdU tracking to report neurogenesis12, we found that aging is characterized by diminished neurogenesis particularly in the hypothalamus and the hippocampus; however, this defect was substantially reversed by GnRH treatment. …
Then they see if they can get similar results with normal injections.

GnRH therapy decelerates aging development
Finally, to study if GnRH could affect aging, we subjected old MBH-IKKβ mice and MBH- Con described in Fig. 2 to daily GnRH therapy for a prolonged period, and then examined their aging physiology and histology. As we were also interested in testing if GnRH could act peripherally to affect aging, we treated mice with GnRH via peripheral injections. Excitingly, GnRH treatment reduced the magnitude of aging histology in control mice and abrogated the pro-aging phenotype in MBH-IKKβ mice (Fig. 6f–h). Interestingly, despite the peripheral administration, GnRH led to an amelioration of aging-related cognitive decline (Fig. 6i, suppl. Fig. 11). Thus, prolonged elevation of systemic GnRH can cumulatively yield actions on the brain; despite the mechanism remains to be studied, some GnRH-responsive brain regions outside of the blood-brain barrier, such as the median eminence, subfornical organ and area postrema, can have access to peripheral delivered GnRH. These effects of GnRH were not specific to a sex, as similar outcomes were shown in male (Fig. 6f–i, suppl. Fig. 11) and females (suppl. Fig. 12)
What does it mean? Well if you’re an old mouse then it looks like GnRH therapy could be worthwhile. What about humans? Particularly the ones who have artificially suppressed their GnRH production? I don’t have an answer to that. What might we do? If you don’t mind experimenting on yourself, then—under a doctor’s supervision—you might obtain some GnRH, readily available as gonadorelin, and inject yourself with 5-10 mcg one or more times a day. Is this advisable? I have no idea. This post is meant to stimulate discussion and further reviews of the literature, not to encourage self-treatment.
 
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sh1973

Active Member
Most of this makes sense and this could also be one of the pieces of the puzzle regarding elusive libido as well as the blunted emotions in some men. Something changes on trt that hcg and testosterone don’t solve. I’ve finally got myself in a decent spot with trt but have spent a great deal of time struggling. At this point with trt, I don’t think we truly understand what all truly gets disrupted. You might very well be into something here.
 

xqfq

Active Member
As a point of skepticism, it’s not surprising the hypothalamus would see some neurogenesis when exposed to GnRH. That’s where the GnRH is being produced, after all. Like maybe these hypothalamus cells multiply when exposed to GnRH in anticipation of having to produce more GnRH in the future. I’m not sure how this works really, but just putting that out there.

It would be more surprising if different regions of the brain were shown to undergo neurogenesis with GnRH exposure.

The in vivo mouse study is more interesting but maybe the effects are just due to the more youthful hormones being produced?
 

xqfq

Active Member
I have heard reports of GnRH analogs such as Triptorelin being used for either “one shot” HPTA restarts or potentially even moderately curing cases of anabolic steroid induced hypogonadism. There is so little data in this area. But maybe the GnRH analog could cause this neurogenesis- creating more GnRH producing cells - and then “kick start” the HPTA that way. Meaning the hypothalamus would then produce more GnRH than it would naturally.
 

antelopers

Active Member
I have heard reports of GnRH analogs such as Triptorelin being used for either “one shot” HPTA restarts or potentially even moderately curing cases of anabolic steroid induced hypogonadism. There is so little data in this area. But maybe the GnRH analog could cause this neurogenesis- creating more GnRH producing cells - and then “kick start” the HPTA that way. Meaning the hypothalamus would then produce more GnRH than it would naturally.
I tried this twice. No luck.
 

Cataceous

Well-Known Member
As a point of skepticism, it’s not surprising the hypothalamus would see some neurogenesis when exposed to GnRH. That’s where the GnRH is being produced, after all. Like maybe these hypothalamus cells multiply when exposed to GnRH in anticipation of having to produce more GnRH in the future. I’m not sure how this works really, but just putting that out there.

It would be more surprising if different regions of the brain were shown to undergo neurogenesis with GnRH exposure.
...
Seems to be more general neurogenesis: "... we discovered that GnRH induces adult neurogenesis broadly in the brain, and GnRH therapy can greatly amend aging disorders. Thus, while inhibition of GnRH by NF-κB may lead to the end of reproductive length – which seems necessary for species’ quality, it initiates systemic aging at the same time."
 

xqfq

Active Member
Seems to be more general neurogenesis: "... we discovered that GnRH induces adult neurogenesis broadly in the brain, and GnRH therapy can greatly amend aging disorders. Thus, while inhibition of GnRH by NF-κB may lead to the end of reproductive length – which seems necessary for species’ quality, it initiates systemic aging at the same time."

Unless I'm missing something, they only measured neurogenesis in vitro in the hypothalamus. The other results are in vivo in the rats given GnRH, so could be related to a general rise in hormones. Lots of studies show that estrogen increases neurogenesis, for instance.
 

Cataceous

Well-Known Member
Unless I'm missing something, they only measured neurogenesis in vitro in the hypothalamus. The other results are in vivo in the rats given GnRH, so could be related to a general rise in hormones. Lots of studies show that estrogen increases neurogenesis, for instance.
In a related article the results are characterized this way: "Therapeutically, GnRH treatment significantly although partially reversed aging-impaired neurogenesis in the hypothalamus, hippocampus and other brain regions. GnRH therapy also led to amelioration of various aging effects, including skin atrophy, muscle weakness, and bone loss. Therefore, in addition to the reproductive role, GnRH works in the brain and the periphery to regulate systemic aging."

Edit: Although there's no attempt to control for sex hormone levels, the authors of the first paper seem to think the effect is independent, as stated in the section GnRH treatment prevents aging-impaired neurogenesis quoted above...
 
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Cataceous

Well-Known Member
Most of this makes sense and this could also be one of the pieces of the puzzle regarding elusive libido as well as the blunted emotions in some men. Something changes on trt that hcg and testosterone don’t solve. I’ve finally got myself in a decent spot with trt but have spent a great deal of time struggling. At this point with trt, I don’t think we truly understand what all truly gets disrupted. You might very well be into something here.
It would certainly be good to know if lack of GnRH is contributing to some of the problems guys have with TRT. If so it's at least something that can be addressed. Hopefully we will have an answer about this in time.
 

sh1973

Active Member
As you’ve probably experienced at some point, there’s definitely something that causes blunted emotions, especially with higher doses. It’s almost like things that should make a person sad simply don’t have an effect. I think it could possibly factor into libido as well because there’s such a vast amount of chemicals and neurotransmitters that play a part in arousal. Perhaps this missing piece could actually play a bigger role in libido than testosterone, estrogen or dopamine.
 

Cataceous

Well-Known Member
As you’ve probably experienced at some point, there’s definitely something that causes blunted emotions, especially with higher doses. It’s almost like things that should make a person sad simply don’t have an effect. I think it could possibly factor into libido as well because there’s such a vast amount of chemicals and neurotransmitters that play a part in arousal. Perhaps this missing piece could actually play a bigger role in libido than testosterone, estrogen or dopamine.
I've felt a blunting of emotions during two conditions: with a combination of high testosterone and high estradiol; and with very low estradiol. With normal testosterone and high estradiol I felt an amplification of emotions.

It would be great if GnRH were this "missing piece" for libido, but when is anything TRT-related ever that simple?
 

sh1973

Active Member
Makes me wonder if something like enclomiphene would be a better long term to keep all the bodies systems active. I’d like to hear from men that have used this after a while.
 

Cataceous

Well-Known Member
I did just ask Dr. Saya to give us a report on enclomiphene after he's accumulated some experience with it; Defy recently started offering this drug.

What troubles me is that the clinical trial results apparently were lackluster, which is why the FDA didn't grant approval yet.
 

Cataceous

Well-Known Member
I have heard reports of GnRH analogs such as triptorelin being used for either “one shot” HPTA restarts or potentially even moderately curing cases of anabolic steroid induced hypogonadism. ...
I tried this twice. No luck.
Same here
Presumably we've all seen that one case study floating around where ostensibly a single 100-mcg dose of triptorelin restarted a guy. But triptorelin has a relatively long half-life, making its pharmacokinetics unnatural, and is why it's used more often to intentionally shut down the HPTA. In hindsight, even for a restart, if I were going that route I would bite the bullet and just inject a few micrograms of gonadorelin as frequently as I could stand to, but always at least a couple hours apart.

I say "in hindsight" because I did try a short course of triptorelin (10 mcg/d) last summer during a period of low estradiol. In theory this should have been the best time to achieve some pituitary activation, as I believe estradiol is the main suppressing agent there. And I did manage to double my LH. But that's not saying much considering the starting point was only 0.1 mIU/mL. Now I'm wondering what the results would have been with gonadorelin.
 

antelopers

Active Member
Presumably we've all seen that one case study floating around where ostensibly a single 100-mcg dose of triptorelin restarted a guy. But triptorelin has a relatively long half-life, making its pharmacokinetics unnatural, and is why it's used more often to intentionally shut down the HPTA. In hindsight, even for a restart, if I were going that route I would bite the bullet and just inject a few micrograms of gonadorelin as frequently as I could stand to, but always at least a couple hours apart.

I say "in hindsight" because I did try a short course of triptorelin (10 mcg/d) last summer during a period of low estradiol. In theory this should have been the best time to achieve some pituitary activation, as I believe estradiol is the main suppressing agent there. And I did manage to double my LH. But that's not saying much considering the starting point was only 0.1 mIU/mL. Now I'm wondering what the results would have been with gonadorelin.
Correct, I tried the 100mcg shot based on that very unconvincing case study from Italy I believe that floats around the internet.
 

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