HCG and elevated LH in Alzheimer patients

[Sergel]

While browsing alzheimmer info for my girl's aging mother, I came accross some studies that made me think my HCG use...

Elevated gonadotropin levels in patients with Alzheimer disease​

Elevated gonadotropin levels in patients with Alzheimer disease - PubMed

Gonadotropin levels are elevated in some patients with AD, ie, women not taking estrogen. Elevated gonadotropin levels may have a role in the production of amyloid-beta protein, which is related to formation of senile plaques. Therefore, elevated gonadotropin levels may be involved in the...

pubmed.ncbi.nlm.nih.gov

The Contribution of Luteinizing Hormone to Alzheimer Disease Pathogenesis​

The Contribution of Luteinizing Hormone to Alzheimer Disease Pathogenesis - PMC

Several hypotheses have been proposed that attempt to explain the pathogenesis of Alzheimer Disease (AD) including theories involving senile plaque and neurofibrillary tangle formation, increased oxidative stress, and cell cycle abnormalities, since ...

www.ncbi.nlm.nih.gov

Stuff like this made me pause:

There is growing evidence supporting a role for gonadotropins, particularly LH, in AD pathogenesis beginning with the finding of a two-fold increase in circulating gonadotropins in individuals with AD compared with age-matched controls.57,58 Since gonadotropin receptors in the brain are found within the hippocampus59 and gonadotropins are known to cross the blood brain barrier,60 we speculate that elevated gonadotropins, namely LH, may contribute to AD pathogenesis.57​

I never see this discussed on HCG threads... Some studies suggest that lowering LH in elderly could delay the onset of AD ... Naturally, all those studies done outside of the context of hormone replacement... and we all know one sure way to kill LH is exogenous testosterone... But what levels of HCG is safe? And is it the same as LH as it is LH like, but not LH...

Thoughts?

 

[Marcel]

This is very interesting, following

 

[Marcel]

Wait would that mean that clomid, enclomiphene and hcg are potentially bad for you??

 

[JmarkH]

Correlation doesn't equate to causation. That's why quality research is important. All those Alzheimers patients also had high exposures to dihydrogen monoxide.

 

[Cataceous]

Correlation doesn't equate to causation. That's why quality research is important. All those Alzheimers patients also had high exposures to dihydrogen monoxide.

However, the incidence of Alzheimer's disease doesn't correlate with the level of exposure to water, while it does correlate with the levels of gonadotropins. They used to think that reduced estrogen was the problem, but HRT studies have cast doubt on that hypothesis. Even if the link is causal it would be just one risk factor of many and probably not grounds for panic. It seems prudent to use the lowest effective dose of hCG. A concern is that its half-life when injected is orders of magnitude larger than natural LH, which significantly increases the total exposure. It's possible that using hCG makes a man's risk of having AD comparable to a woman's risk.

Edit: I think it may be the distribution half-life that differentiates between IM/SC injected hCG/LH and endogenous LH. Endogenous delivery is more directly into the bloodstream, allowing for pulses that are relatively high compared to average serum levels. With SC/IM injections the levels change more slowly, so you cannot emulate the endogenous behavior.

 

[Sergel]

However, the incidence of Alzheimer's disease doesn't correlate with the level of exposure to water, while it does correlate with the levels of gonadotropins. They used to think that reduced estrogen was the problem, but HRT studies have cast doubt on that hypothesis. Even if the link is causal it would be just one risk factor of many and probably not grounds for panic. It seems prudent to use the lowest effective dose of hCG. A concern is that its half-life when injected is orders of magnitude larger than natural LH, which significantly increases the total exposure. It's possible that using hCG makes a man's risk of having AD comparable to a woman's risk.

Thanks Cataceous, I thus wonder if the age related hypogonadism is primary in nature, that is gonads failing to produce Test thus pituitary signaling creating high level of LH would be a factor in Az ... Given this, more active men tend to keep better levels of T thus lower LH signaling... thus better cognitive outcomes...

The other consideration that is interesting is that exogenous T will drive you LH to basically 0 ... in theory should be protective against Az if the studies are right...

Now which brings me to my use of HCG... at 500iu twice a week, what equivalent LH level does that put me in...? I am thinking about cutting this in half and see if I still get the benefits...

I don't see this Az risk factored anywhere in the HCG discussions...

 

[Sergel]

Wait would that mean that clomid, enclomiphene and hcg are potentially bad for you??

Well, different modes of actions... Clomid will stimulate your own LH and FSH production, so they naturally have the normal half life... the half life of exogenous gonadotropin injected with HCG is 'LH Like' and has a way longer half life... it also I think crosses the blood brain barrier, exposing our brain to gonadotropins for longer... Thus my questioning...

But Clomid is definitely to be considered as well...

 

[ajax31]

While browsing alzheimmer info for my girl's aging mother, I came accross some studies that made me think my HCG use...

Elevated gonadotropin levels in patients with Alzheimer disease​

Elevated gonadotropin levels in patients with Alzheimer disease - PubMed

Gonadotropin levels are elevated in some patients with AD, ie, women not taking estrogen. Elevated gonadotropin levels may have a role in the production of amyloid-beta protein, which is related to formation of senile plaques. Therefore, elevated gonadotropin levels may be involved in the...

pubmed.ncbi.nlm.nih.gov

The Contribution of Luteinizing Hormone to Alzheimer Disease Pathogenesis​

The Contribution of Luteinizing Hormone to Alzheimer Disease Pathogenesis - PMC

Several hypotheses have been proposed that attempt to explain the pathogenesis of Alzheimer Disease (AD) including theories involving senile plaque and neurofibrillary tangle formation, increased oxidative stress, and cell cycle abnormalities, since ...

www.ncbi.nlm.nih.gov

Stuff like this made me pause:

There is growing evidence supporting a role for gonadotropins, particularly LH, in AD pathogenesis beginning with the finding of a two-fold increase in circulating gonadotropins in individuals with AD compared with age-matched controls.57,58 Since gonadotropin receptors in the brain are found within the hippocampus59 and gonadotropins are known to cross the blood brain barrier,60 we speculate that elevated gonadotropins, namely LH, may contribute to AD pathogenesis.57​

I never see this discussed on HCG threads... Some studies suggest that lowering LH in elderly could delay the onset of AD ... Naturally, all those studies done outside of the context of hormone replacement... and we all know one sure way to kill LH is exogenous testosterone... But what levels of HCG is safe? And is it the same as LH as it is LH like, but not LH...

Thoughts?

I don’t intend to make a flippant comment, but how about the increase in gonadotropins in menopausal women?

If elevated LH was causal instead of associated then every elderly woman should have Alzheimer’s Disease.

 

[Cataceous]

I don’t intend to make a flippant comment, but how about the increase in gonadotropins in menopausal women?

If elevated LH was causal instead of associated then every elderly woman should have Alzheimer’s Disease.

Women have higher rates of Alzheimer's disease, correlating with their higher levels of gonadotropins. This is one possible risk factor of many. Most smokers do not get lung cancer, after all.

 

[Cataceous]

Thanks Cataceous, I thus wonder if the age related hypogonadism is primary in nature, that is gonads failing to produce Test thus pituitary signaling creating high level of LH would be a factor in Az ... Given this, more active men tend to keep better levels of T thus lower LH signaling... thus better cognitive outcomes...

Yes, LH does tend to increase in males, presumably from reduced gonadal function:

As men age, there is a small and progressive (not precipitous, as in women) decline in several sex hormones, in particular testosterone and dehydroepiandrosterone, and related increases in luteinizing hormone, follicle-stimulating hormone, and sex hormone-binding globulin.[R]​

...
The other consideration that is interesting is that exogenous T will drive you LH to basically 0 ... in theory should be protective against Az if the studies are right...
...

Perhaps, but there are at least suggestions that concomitantly driving GnRH to zero could be bad for the brain.[R]

...
Now which brings me to my use of HCG... at 500iu twice a week, what equivalent LH level does that put me in...? I am thinking about cutting this in half and see if I still get the benefits...
...

We can make some very crude estimates. If we use Dr. Saya's case study then the area under the curve from a 500 IU injection is about 174 mIU/mL-hours. Injecting twice a week gives you 348 mIU/mL-hours. Dividing by hours in a week gives you an average exposure of 2.1 mIU/mL. You might think this is low, but Marco Filicori cites a conversion rate of "1 IU hCG = 6-8 IU LH". In reality it's more complicated, with differing relative activities in different tissues. Nonetheless, the implication is that serum hCG of ~2 mIU/mL could be like having supraphysiological LH.

These estimates are too shaky for anyone to make significant protocol changes as a result. But if you can get the same results with lower doses then that's a reasonable thing to do.

 

[Fortunate]

Interesting discussion. Can I ask a related question (happy to move it to another thread so as not to hijack this one)?

I am currently in the process of evaluating life without hCG. I stopped about a week ago and have been running Natesto alone. I am looking for some information on hCG elimination based on half-life assumptions. It is essentially a basic pharmacokinetics question:

The half-life of Pregnyl is 23 hours. We'll call it one day to make things easy. Assuming Pregnyl follows first order kinetics, if it takes 4-5 half-lives to reach steady state, then is it safe to assume it takes 4-5 half-lives to almost completely eliminate the drug from steady state?

 

[Cataceous]

...
The half-life of Pregnyl is 23 hours. We'll call it one day to make things easy. Assuming Pregnyl follows first order kinetics, if it takes 4-5 half-lives to reach steady state, then is it safe to assume it takes 4-5 half-lives to almost completely eliminate the drug from steady state?

I'd say so. Some hCG studies have yielded a little longer half-life, so I'd give it a week before assuming the residual is negligible. Here's some representative data:

DEFINE_ME

 

[Fortunate]

I'd say so. Some hCG studies have yielded a little longer half-life, so I'd give it a week before assuming the residual is negligible. Here's some representative data:
View attachment 23319

DEFINE_ME

It’s interesting. 7-8 days corresponds very closely to a significant increase in tendinitis pain and severe fatigue. That said, I also stopped daily injections at the same time, but I think the hCG is playing a big role.

 

[Phil Goodman]

Interesting find and something that I’d like to see more studies on. The more we learn about human physiology the more interesting it gets. One thing that may make members of the forum feel a little better is this snippet:

“When we controlled for age, no differences in LH and FSH were observed in men with AD compared with normal controls.”


So it’s possible there are other mechanisms at play in the male body that can counter-act negative effects of LH(if there is a direct negative impact from LH with regards to Alzheimer’s). It’s also possible that there are factors which contribute to Alzheimer’s and also impact the body in a way that drives up LH in women. So the two could be results of a certain mechanism, yet they are looking at the two downstream effects and saying one is responsible for the other when in actuality there is a different factor responsible for both.


Again though I think this is a very interesting find and that the topic warrants more research.

 

[SMOS44]

Luteinizing Hormone: Evidence for direct action in the CNS - PMC

Hormonal dysfunction due to aging, especially during menopause, plays a substantial role in cognitive decline as well as the progression and development of neurodegenerative diseases. The hypothalamic-pituitary-gonadal (HPG) axis has long been ...

www.ncbi.nlm.nih.gov

In the paper linked they note that high levels of peripheral LH correlate negatively with brain LH (see below). I don't understand why that would be the case - can someone elucidate?

Also worth noting - this paper seems to indicate there are some direct effects here and that it's not all correlative.

 

[Cataceous]

...
In the paper linked they note that high levels of peripheral LH correlate negatively with brain LH (see below). I don't understand why that would be the case - can someone elucidate?
...

Nice reference. It would be interesting to look into what they've done since then. The possible inverse correlation between peripheral and brain LH is discussed in this paragraph below. They don't know the mechanism, but it's plausible that some form of negative feedback exists:

Along with the direct and peripheral effects of hCG, we have recently discovered that LH is produced in the brain (Figure 1). It is expressed in cognition modulating areas such as the hippocampus, the cingulate cortex and midbrain structures such as the thalamus and superior colliculi (Figure 1A), and it co-localizes with neuronal markers such as NeuN in pyramidal neurons (Figure 1B). Electron microscopy shows that LH appears to be encapsulated in vesicles (Figure 1C). Importantly, we have shown that LH mRNA levels are reduced in hippocampi of AD patients compared to controls, and in ovariectomized 3xTg AD mice LH immunoreactivity in the superior colliculus is decreased (Palm et al., 2014). Downregulation of peripheral LH using leuprolide acetate normalizes brain LH to levels observed in SHAM operated mice (Palm et al., 2014). Therefore, there seems to be an inverse relationship of LH expression between the brain and bloodstream. How the underlying mechanisms are associated with this inverse relationship are unknown, but we identified that LH levels in the superior colliculus were positively correlated with cognitive function (Palm et al., 2014). This suggests that levels of brain LH may, at least partially, regulate cognitive function (Figure 2). Importantly, this could explain why ovariectomy, especially in the absence of estrogen effectiveness, or states that involve high peripheral LH, such as polycystic ovarian syndrome lead to cognitive deficits (Barnard et al., 2007).​

 

[SMOS44]

This makes me think Natesto/Troches are an interesting methodology as it may provide symptom relief and delay cognitive function degradation via peripheral LH downregulation.

As to what they’ve done recently:

Luteinizing hormone and the aging brain

Fluctuations in luteinizing hormone (LH) release contribute to the development and maintenance of the reproductive system and become dysregulated duri…

www.sciencedirect.com

 

[Cataceous]

...
As to what they’ve done recently:

Luteinizing hormone and the aging brain

Fluctuations in luteinizing hormone (LH) release contribute to the development and maintenance of the reproductive system and become dysregulated duri…

www.sciencedirect.com

Interesting. They hypothesize that excess hCG/LH downregulates the LH receptors in the brain, leading to the cognitive issues. After seeing all this I would more than ever steer guys away from hCG monotherapy and encourage use of the lowest effective dose with TRT. There could also be ramifications for guys using SERMs—perhaps they should ensure LH remains physiological.

... To this end, it well understood that that LHCGR is quickly internalized and downregulated in the presence of high levels of its ligand (Peegel et al., 1994). Thus, under the hypothesis that LH crosses the blood brain barrier to bind LHCGR, high levels of LH within the brain could downregulate LHCGR expression and lead to cognitive deficits. Reducing circulating LH with GnRHR antagonists could in turn allow LHCGR levels to normalize and resume its normal function. Alternatively, one could also speculate that supra-physiological levels of LH or hCG delivered directly into the brain or delivered to gonadectomized animals (already with high levels of circulating LH) could have similar downregulating effects onto LHCGR expression, which could also impact signaling and function negatively. This would explain why studies using high doses of hCG (Barron et al., 2010; Lukacs et al., 1995) would have detrimental effects on function but studies using lower doses (Blair et al., 2019; Movsas et al., 2017) would have beneficial effects. Thus, precisely characterizing central LHCGR dynamics under different treatment conditions seems to be imperative to understand the nature of the effects of this hormone and its receptor's potential as a therapeutic target for age-related neurodegenerative disease such as AD.​

 

[Sergel]

I have stopped HCG completely... Although I see some slight mood benefits, I don't think it's worth the risk long term with TRT... I sure would like my balls back though... but hey, I would rather be a small balled 80 year old than a big balled 80 year old nut... lol

Hopefully we will learn more in time... but since TRT obliterates LH, one could hypothesize that it has a neurodegenerative protective effect.... no?

 

[Cataceous]

...
Hopefully we will learn more in time... but since TRT obliterates LH, one could hypothesize that it has a neurodegenerative protective effect.... no?

What's typical of hormones is that either high or low levels cause problems. Therefore I'm not ready to say that leaving LH obliterated by TRT is necessarily preferable to adding some appropriate amount of hCG to the protocol. As you suggest, more research is needed. Personally I wouldn't be too worried about cumulative hCG dosing of up to 500 IU per week. I base this in part on anecdotal reports about side effects—their increasing likelihood could be a proxy for excessive levels.