Pregnenolone Joint Pain

[DixieWrecked]

I was thinking about the suppression of the hormones upstream from testosterone due to TRT. I noticed my body is a little achy on trt and have wondered if the suppression of pregnenolone and it's downstream hormones may be causing this. Anyone else experience these side effects? Delt with them in any way?

 

[hunterdon goose]

I was thinking about the suppression of the hormones upstream from testosterone due to TRT. I noticed my body is a little achy on trt and have wondered if the suppression of pregnenolone and it's downstream hormones may be causing this. Anyone else experience these side effects? Delt with them in any way?

How is your sleep ? If the pregnenolone and or DHEA are low it will be affected negatively. The only way to know for sure if pregnenolone makes sense for you is a blood test or see if supplements help.

 

[DixieWrecked]

Sleep is not great. But I'm really more curious if there is a connection between low pregnenolone and body/joint aches.

 

[hunterdon goose]

Sleep is not great. But I'm really more curious if there is a connection between low pregnenolone and body/joint aches.

Estrogen might be too low . Are you using an AI ? I have low pregnenolone and I have aches myself

 

[FunkOdyssey]

Estrogen might be too low . Are you using an AI ? I have low pregnenolone and I have aches myself

I would guess low pregnenolone is not a cause of joint pain, because nearly everyone on TRT has very low pregnenolone, and TRT is not typically associated with joint pain.

 

[DixieWrecked]

How could one have low pregnenolone, but not low glucocortisoids? Hormones like cortisol are our anti-inflammatories and it seems like if we had low pregnenolone we would naturally have low cortisol.

 

[Gman86]

How could one have low pregnenolone, but not low glucocortisoids? Hormones like cortisol are our anti-inflammatories and it seems like if we had low pregnenolone we would naturally have low cortisol.

Could it be the same type of thing as ferritin and TRT? Doesn’t ferritin decrease while on TRT due to the increased iron utilization? I could be wrong about that, but I think that’s how it works. So is there any way that preg lowers on TRT because more of its being used? Otherwise I’m just as confused as u. Ive wonder the same thing many times. How could downstream hormones even be made if there’s extremely little preg to create them? Ive had preg tested and mine usually comes back basically zero, a lot of the time. Not sure if a serum preg level is accurate or not

 

[ajax31]

There are luteinizing hormone (LH) receptors in the adrenals, which work through the STAR pathway to convert cholesterol to progesterone, pregnenolone, etc.
@Nelson made a YouTube video about hCG and its pathways. I believe this is the one:

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Role of the steroidogenic acute regulatory protein in health and disease

Steroid hormones are an important class of regulatory molecules that are synthesized in steroidogenic cells of the adrenal, ovary, testis, placenta, brain and skin, and influence a spectrum of developmental and physiological processes. The steroidogenic ...

www.ncbi.nlm.nih.gov

Cortisol production is under the control of pituitary ACTH (and hypothalamic CRH upstream), which isn't inhibited by TRT. Although, now that I've said that, and knowing this in the Internet, I expect someone to chime in that testosterone replacement does suppress adrenal function. Not likely - with millions of men on TRT we would have seen that if it were a real problem. If your adrenals are really suppressed, you would be hard pressed to get out of bed let alone go to the gym.

 

[FunkOdyssey]

Adrenal hormones are synthesized directly from cholesterol which enters the adrenal glands, in response to various signals like ACTH. The adrenal hormone production does not depend on any precursor hormones that you would measure in serum, like pregnenolone.

Serum pregnenolone seems to be primarily "spillover" from the testes because it drops precipitously when men start TRT. Whether the low serum pregnenolone is just a biomarker for someone that has shut down their HPT axis or whether it has important hormonal effects is open for debate.

Personally, I lean toward it just being a sign that someone has shut down their HPT axis. IMO, too many men are thriving without supplementing pregnenolone for it to actually be important as a hormone.

 

[DixieWrecked]

Estrogen might be too low . Are you using an AI ? I have low pregnenolone and I have aches myself

I don't take any AI and my estrogen is fine. I don't have any kind of dysfunction with my aromatase of anything. Have you ever tried pregnenolone?

 

[FunkOdyssey]

More on adrenal hormones, their regulation and synthesis:

 

[hunterdon goose]

Adrenal hormones are synthesized directly from cholesterol which enters the adrenal glands, in response to various signals like ACTH. The adrenal hormone production does not depend on any precursor hormones that you would measure in serum, like pregnenolone.

Serum pregnenolone seems to be primarily "spillover" from the testes because it drops precipitously when men start TRT. Whether the low serum pregnenolone is just a biomarker for someone that has shut down their HPT axis or whether it has important hormonal effects is open for debate.

Personally, I lean toward it just being a sign that someone has shut down their HPT axis. IMO, too many men are thriving without supplementing pregnenolone for it to actually be important as a hormone.

If he is having trouble sleeping he should give DHEA and Pregnenolone in case TRT gives insomnia. It helped me . Also keep in mind DHEA and Pregnenolone decline with age and you do see older adults have insomnia issues

 

[hunterdon goose]

I don't take any AI and my estrogen is fine. I don't have any kind of dysfunction with my aromatase of anything. Have you ever tried pregnenolone?

Yes when it works it really helped my sleep. beward of lots of supplement companies counterfeiting it

 

[Charliebizz]

Adrenal hormones are synthesized directly from cholesterol which enters the adrenal glands, in response to various signals like ACTH. The adrenal hormone production does not depend on any precursor hormones that you would measure in serum, like pregnenolone.

Serum pregnenolone seems to be primarily "spillover" from the testes because it drops precipitously when men start TRT. Whether the low serum pregnenolone is just a biomarker for someone that has shut down their HPT axis or whether it has important hormonal effects is open for debate.

Personally, I lean toward it just being a sign that someone has shut down their HPT axis. IMO, too many men are thriving without supplementing pregnenolone for it to actually be important as a hormone.

I really wonder why back a few years ago. Test cyp “seemed“ to lower my cortisol as far as blood and Saliva tests were concerned. And man did I feel it. Once I got off my cortisol levels went back up. enanthate and cream have no effects on my cortisol levels.

 

[electrify]

I would guess low pregnenolone is not a cause of joint pain, because nearly everyone on TRT has very low pregnenolone, and TRT is not typically associated with joint pain.

Over time on TRT which I began around 2016 in my experience pregnenolone did come back up. In the beginning I did notice a drop way back but somehow it just normalized. I did use HCG+Preg but later even without those it stayed up.

At least until my current issues last year triggered by the covid/alc hangover incident (while still on TRT). After that actually my pregnenolone sharply declined. So it seems like it’s really more physiological stress related. preg has partly recovered to around 80 but not completely back to what it was before which was like 130.

DHEAS interestingly for me was always fine though or even high.

But yea im not sure why it dropped in beginning then eventually just came up again. I ascribe it to the body just getting used to TRT.

So the people who you say are thriving on TRT, well their pregnenolone levels might well be fine. Mine were fine again after about 6 months on TRT.

And imo it is a very important hormone. Pregnenolone is used to make allopreg which is GABAergic, and the big medication Zuranolone that will come out this month targets allopreg. Im actually curious whether Zuranolone could help restore someone’s HPA axis even without resorting to TRT (or in conjunction).

 

[FunkOdyssey]

Over time on TRT which I began around 2016 in my experience pregnenolone did come back up. In the beginning I did notice a drop way back but somehow it just normalized. I did use HCG+Preg but later even without those it stayed up.

At least until my current issues last year triggered by the covid/alc hangover incident (while still on TRT). After that actually my pregnenolone sharply declined. So it seems like it’s really more physiological stress related. preg has partly recovered to around 80 but not completely back to what it was before which was like 130.

DHEAS interestingly for me was always fine though or even high.

But yea im not sure why it dropped in beginning then eventually just came up again. I ascribe it to the body just getting used to TRT.

So the people who you say are thriving on TRT, well their pregnenolone levels might well be fine. Mine were fine again after about 6 months on TRT.

And imo it is a very important hormone. Pregnenolone is used to make allopreg which is GABAergic, and the big medication Zuranolone that will come out this month targets allopreg. Im actually curious whether Zuranolone could help restore someone’s HPA axis even without resorting to TRT (or in conjunction).

It would definitely be interesting to take a bunch of people that report they are "dialed in" and check their pregnenolone levels. I do think for the majority of people on TRT their pregnenolone drops significantly and stays lower than before they started. It would take more data to prove that though.

I found an interesting rat study where they chopped their nuts off and measured levels of neurosteroids in different regions of the brain. They found levels of pregnenolone, progesterone, tetrahydroprogesterone (allopregnanolone) were sometimes reduced, sometimes maintained, and sometimes increased depending on the region. In some cases, levels were reduced short-term, but then recovered long-term as the rat adapted, not unlike your anecdote with serum pregnenolone.

Sci-Hub | Effect of Short-and Long-Term Gonadectomy on Neuroactive Steroid Levels in the Central and Peripheral Nervous System of Male and Female Rats | 10.1111/j.1365-2826.2010.02064.x

I haven't really seen too many people doing well with years of pregnenolone supplementation under their belt. Typically people try it for a little while, can't find a dose that consistently delivers net benefits, and give up. I can probably count the exceptions on one hand.

So, I favor keeping it simple, taking TRT alone and letting your body and brain adapt over time to the HPTA shutdown, like one of the study rats.

 

[FunkOdyssey]

Pregnenolone is used to make allopreg which is GABAergic, and the big medication Zuranolone that will come out this month targets allopreg. Im actually curious whether Zuranolone could help restore someone’s HPA axis even without resorting to TRT (or in conjunction).

It doesn't look like zuranolone is going to be a blockbuster. The FDA denied their application for approval for major depressive disorder, saying they hadn't provided enough evidence of efficacy. Apparently the effect size was too small in the two successful clinical trials and there was a third clinical trial that failed.

Zuranolone approved for postpartum depression but misses out on bigger MDD indication

Zurzuvae represents a major breakthrough for postpartum depression (PDD), an indication with a high unmet need for relevant therapies.

www.clinicaltrialsarena.com

Although the approval for PPD is significant, the FDA rejected Zurzuvae for the treatment of major depressive disorder (MDD), issuing a complete response letter (CRL). This is very disappointing for Sage Therapeutics and Biogen, given the large patient population with MDD versus PPD and thus significant missed commercial potential. Although Zurzuvae met its primary endpoints in two Phase III trials—SHORELINE (NCT03864614) and WATERFALL (NCT04442490)—the size of the effect was small. This, combined with a previous Phase III failure (MOUNTAIN; NCT03672175), has meant that the FDA requires an additional clinical trial to confirm the efficacy of Zurzuvae for MDD. Sage Therapeutics and Biogen have yet to confirm whether this is the next step they will take, having previously terminated two additional planned Phase III trials—REDWOOD (NCT04007367) and RAINFOREST (NCT03771664)—believing them not to be necessary for a new drug application.

 

[Charliebizz]

It would definitely be interesting to take a bunch of people that report they are "dialed in" and check their pregnenolone levels. I do think for the majority of people on TRT their pregnenolone drops significantly and stays lower than before they started. It would take more data to prove that though.

I found an interesting rat study where they chopped their nuts off and measured levels of neurosteroids in different regions of the brain. They found levels of pregnenolone, progesterone, tetrahydroprogesterone (allopregnanolone) were sometimes reduced, sometimes maintained, and sometimes increased depending on the region. In some cases, levels were reduced short-term, but then recovered long-term as the rat adapted, not unlike your anecdote with serum pregnenolone.

Sci-Hub | Effect of Short-and Long-Term Gonadectomy on Neuroactive Steroid Levels in the Central and Peripheral Nervous System of Male and Female Rats | 10.1111/j.1365-2826.2010.02064.x

I haven't really seen too many people doing well with years of pregnenolone supplementation under their belt. Typically people try it for a little while, can't find a dose that consistently delivers net benefits, and give up. I can probably count the exceptions on one hand.

So, I favor keeping it simple, taking TRT alone and letting your body and brain adapt over time to the HPTA shutdown, like one of the study rats.

Great work man !! Makes me feel so much better about my low preg levels. Ive noticed mine keep getting lower as time goes on. And seems they really tanked on cream.

every time I try preg I get Side effects. Even as low as 5mg per day

 

[FunkOdyssey]

Great work man !! Makes me feel so much better about my low preg levels. Ive noticed mine keep getting lower as time goes on. And seems they really tanked on cream.

every time I try preg I get Side effects. Even as low as 5mg per day

My friend is on an EOD protocol of testosterone cypionate, 140 mg weekly, and just gave up on pregnenolone also. He thought it improved his sleep at first and was all excited about it, but that quickly turned into "feeling like a zombie", even at just 5 mg.

 

[electrify]

It doesn't look like zuranolone is going to be a blockbuster. The FDA denied their application for approval for major depressive disorder, saying they hadn't provided enough evidence of efficacy. Apparently the effect size was too small in the two successful clinical trials and there was a third clinical trial that failed.

Zuranolone approved for postpartum depression but misses out on bigger MDD indication

Zurzuvae represents a major breakthrough for postpartum depression (PDD), an indication with a high unmet need for relevant therapies.

www.clinicaltrialsarena.com

I don't trust these typical FDA RCTs for depression anymore. It could be that Zuranolone is good for certain subtypes of depressions. The problem is MDD as a diagnosis is too heterogenous. What would be nice is if we start having proper stratified trials and then see. May be that people who respond to Benzos could do well with Zuranolone. I'll find out myself soon lol, I do get a subtle positive effect from Etifoxine though which ups AlloP. Allopreg is also anti-inflammatory in the gut as well and I know I have issues going on there.

A few years ago NSI-189 failed trials because it didn't improve depression scores on a scale. However it did improve cognition which is a huge issue in bad enough depression, and there are anecdotes on forums about people having more emotions/hedonic tone. But cognition/emotionality are extremely poorly assessed with all the standard scales yet are-at least to me and many others- the most important things along with sexual symptoms. If your cognition, hedonic tone, and libido is fine that's already such a big thing even if you may still have low mood.

At least in my case the shit that works is basically nothing standard but all non-standard. Serotonin or NE stuff is horrible for me. I can't understand why drugs like SSRIs are antidepressants when they can create PSSD emotional blunting/anhedonia. Drugs like MAOIs were demonized unnecessarily but don't have PSSD problems and have helped so many resistant cases.

For me benzos have always helped with pretty much any symptom. Armodafinil, not normally an anxiety med, also helps anxiety for me and I think its via dopamine and it does not affect NE. Meanwhile Ritalin is also very blunting, although in a different way to SSRI.

I've always suspected the true 'happy chemicals' if we wanna oversimplify to be GABA+Dopamine+Endorphins.

Even TRT is GABA (via DHT)/dopaminergic, and E2 also has AD effects and one of the effects of E2 is actually increasing SERT expression (aka the opposite direction of what an SSRI does) and inhibiting MAO.