TRT Effect on 5 Alpha Reductase and Upstream Hormones- Cause of Low Mood and Anxiety?

[Gianluca]

In this video dr Mark Gordon, starting at 9min, explains how using good level of TRT can "burn" 5 alpha reductase enzyme, that beside being responsible for converting Test into DHT, it is also responsible for converting Progesterone into Allopregnanolone in the brain.

Throughout the years on TRT, and being around the forum, I have heard many people developing or worsening their anxiety and sleep on TRT, and I thought it would be related mostly to Pregnenolone levels declining. As Dr Gordon explains, many start to develop the issue 4 to 6 months into TRT, I can say that right about 6 months into my TRT, I started to have these issues as well.

Do we know if LH has anything to do with activating this enzyme that converts Progesterone into allopregnanolone? what else could we do to reactivate this enzymatic process?

 

[Fernando Almaguer]

Anybody have thoughts on this video?

 

[rayrock1]

thank you for posting this very interesting info.

 

[JA Battle]

I’d say the enzyme 5ar would not be down regulated. Dht further reinforces its own creation by upregulating 5ar to some extent. Also Does aromatase get burned? I’d say not. To me it seems that high levels of circulating androgens can and alter estrogens activity at the receptor or depending on the androgen actually lower aromatase. and in turn lower thyroid hormone output through several vectors. Thyroid hormone is responsible for stimulating the pregnenolone and subsequent steroid cascade. High or imbalanced levels of androgens can strongly oppose estrogens action and therefore cortisol to the point that thyroid hormone may not be cellularly viable. Cortisol is important for active thyroid to be a metabolically viable chemical. Try to recreate what nature intended. Not just speed our way to feeling better by taking large infrequent injections. If you need more testosterone than what you naturally created when you felt your best when you were in your prime, then there are other parts of your metabolism/hormonal cascade that need to be examined. Not adding more test.

 

[MarcoFL]

What a great video!!! well worth the time. Thank you Bonetti!

 

[rayrock1]

I was wondering if using HCG in combination with Test will fill back in this pathway. They did not discuss this in the interview. I know that Danny does not like/use HCG.

 

[Nelson Vergel]

Effect of TRT vs hCG/FSH on upstream hormone pathways.

The role of gonadotropins in testicular and adrenal androgen biosynthesis pathways -insights from males with congenital hypogonadotropic hypogonadism on hCG/rFSH and on testosterone replacement SUMMARY Objective: To delineate the role of gonadotropins in male androgen biosynthesis pathways...

www.excelmale.com

Question, backfilling the pathways?

What hormones are considered to be in the pathway? I see flow charts, but in the end there have to result in actual hormones. I know these hormones. Are there any I am missing that are important and part of the pathway? Are we assuming there are mystery hormones that are part of the pathway...

www.excelmale.com

 

[S1W]

One of the better TRT videos I've seen in a while. Thanks for sharing.

 

[Gianluca]

Effect of TRT vs hCG/FSH on upstream hormone pathways.

The role of gonadotropins in testicular and adrenal androgen biosynthesis pathways -insights from males with congenital hypogonadotropic hypogonadism on hCG/rFSH and on testosterone replacement SUMMARY Objective: To delineate the role of gonadotropins in male androgen biosynthesis pathways...

www.excelmale.com

Question, backfilling the pathways?

What hormones are considered to be in the pathway? I see flow charts, but in the end there have to result in actual hormones. I know these hormones. Are there any I am missing that are important and part of the pathway? Are we assuming there are mystery hormones that are part of the pathway...

www.excelmale.com

thanks for sharing this Nelson, I'm not fully understanding the data here, is LH needed to convert progesterone into allopregnanolone? as Mark Gordon says, 5AR is needed for this conversion. This is a huge point for those who started TRT and worsen anxiety and sleep.

after 6 months I had started my TRT, sleep and anxiety worsen, despite I was on 350IU HCG 3 x week

 

[rayrock1]

This is what I am trying to figure out as well. I though the hCG would give a feeling of well being and instead it gave anxiety. I have been experimenting with the hcg dosage amount,dosage frequency, next how diluted it is etc. Then trying to manage the high e2 from it, causing more emotional behavior, without having to take an ai. I also read that TRT and hcg can effect your cortisol levels.So it seems its all over the board with possible issues.

 

[Gianluca]

This is what I am trying to figure out as well. I though the hCG would give a feeling of well being and instead it gave anxiety. I have been experimenting with the hcg dosage amount,dosage frequency, next how diluted it is etc. Then trying to manage the high e2 from it, causing more emotional behavior, without having to take an ai. I also read that TRT and hcg can effect your cortisol levels.So it seems its all over the board with possible issues.

try stopping HCG, and focus to supplement with Pregnenolone first then DHEA, there is no need for HCG to increase Pregnenolone levels. To my understanding ACTH also activate some enzymatic process that converts Pregnenolone into downstream metabolites, but it is possible that LH is needed also, peraphs ACTH activates some, and LH activates some other,

maybe someone who has a better understanding of this can explain, but if Mark Gordon doesn't know yet how to reactivate fully 5AR1, I doubt there is a easy answer to it

 

[Willyt]

thanks for sharing this Nelson, I'm not fully understanding the data here, is LH needed to convert progesterone into allopregnanolone? as Mark Gordon says, 5AR is needed for this conversion. This is a huge point for those who started TRT and worsen anxiety and sleep.

after 6 months I had started my TRT, sleep and anxiety worsen, despite I was on 350IU HCG 3 x week

Did your TRT anxiety start before or after introducing HCG? I ask because my anxiety ramps up quickly on HCG even with low doses. Many have had similar experience on this forum.

 

[JoeMatts]

Considering levels of DHT remain normal the entire time a man is on trt, I find it far more likely that the development of anxiety Gordon discusses is due to a deficiency of substrate for 5ar, rather than an issue with the enzyme itself. Progesterone -> 5a-dihydroprogesterone via 5ar precedes 5a-dihydroprogesterone -> allopregnanolone via 3a-HSD, with allopreg being an extremely potent agonist at the GABA-A receptor, and thus a strong anxiolytic. Given trt is known to decrease pregnenolone, the precursor to progesterone, it is unsurprising that prolonged trt without the use of pregnenolone, and maybe hcg, can lead to anxiety; but this has nothing to do with 5ar being 'burnt out'.

 

[rayrock1]

Did your TRT anxiety start before or after introducing HCG? I ask because my anxiety ramps up quickly on HCG even with low doses. Many have had similar experience on this forum.

For me it was anxiety centered around hcg use. I added it because of the achy balls issue and that my test injection protocol of e3.5d was leaving me with a down feeling one day before injection day and on my injection day, in effect to smooth things out. Bonetti thank you for the advice, I will update after I speak to my dr next week.

 

[Gianluca]

Did your TRT anxiety start before or after introducing HCG? I ask because my anxiety ramps up quickly on HCG even with low doses. Many have had similar experience on this forum.

I started TRT in 2015, I was started on Test + 350IU HCG 3 x week to preserve fertility, I had some anxiety prior TRT already. My first 6 months were life changing, anxiety, depression and more all gone, then things started to worsen with anxiety and sleep, even more than prior TRT, Pregnenolone/DHEA helped me allot

 

[Willyt]

I started TRT in 2015, I was started on Test + 350IU HCG 3 x week to preserve fertility, I had some anxiety prior TRT already. My first 6 months were life changing, anxiety, depression and more all gone, then things started to worsen with anxiety and sleep, even more than prior TRT, Pregnenolone/DHEA helped me allot

What is your DHEA/Preg dose & schedule? Sounds like it has helped, but not eliminated the anxiety?

I didn’t realize the anxiety at 6 month mark was common problem. I always figured it was the opposite. My first TRT attempt was without HCG and I had the opposite problem at 6 months - emotionally flat, zero sentimentality. Felt like a very efficient robot.

 

[Gianluca]

What is your DHEA/Preg dose & schedule? Sounds like it has helped, but not eliminated the anxiety?

I didn’t realize the anxiety at 6 month mark was common problem. I always figured it was the opposite. My first TRT attempt was without HCG and I had the opposite problem at 6 months - emotionally flat, zero sentimentality. Felt like a very efficient robot.

correct, helped but not fully eliminated my anxiety, I need to experiment more with Pregnenolone/DHEA. I use 100mg Pregn 10mg DHEA in the am with breakfast. To complicate things, I feel the type pregnenolone ingested matter, I use a micronized RX, but when in the past I was using an OTC micronized and in a lipid matrix, I thought it helped more with anxiety and feeling calm,

 

[Nelson Vergel]

thanks for sharing this Nelson, I'm not fully understanding the data here, is LH needed to convert progesterone into allopregnanolone? as Mark Gordon says, 5AR is needed for this conversion. This is a huge point for those who started TRT and worsen anxiety and sleep.

after 6 months I had started my TRT, sleep and anxiety worsen, despite I was on 350IU HCG 3 x week

I am sorry that it took me a long time to jump in. I have been busy with work.

I think there is something to this.

Some guys may be more susceptible to the decrease in neuro-steroids (pregnenolone, progesterone) that is caused by TRT due to its shut down effect on LH.

Reference: Anabolic steroids and TRT decrease SHBG, DHEA, pregnenolone and progesterone in men.

I explain how LH may be involved in the synthesis of pregnenolone and progesterone from cholesterol in this video (and the effect of hCG as a LH analog). TRT shuts down LH, and thus it decreases pregenenolone and its downstream hormones. The adrenals can still make some pregnenolone, but in men with some adrenal insufficiency, that may be extremely limited and not enough to compensate for the effect of shutting down LH.

As we know, progesterone is a "calming" hormone.

We need pregnenolone to make progesterone and we need progesterone to make allopregnanolone, a hormone that has been tied to mood. Any effect on 5 alpha reductase (enzyme also responsible for converting testosterone to DHT), can affect allopregnanolone. Allopregnanolone has been linked to mood disorders.

Allopregnanolone in mood disorders

ABSTRACT The neuroactive steroid allopregnanolone (ALLO) is an endogenous positive allosteric modulator of GABA type A receptor (GABAAR), and the down-regulation of its biosynthesis has been attributed to the development of mood disorders, such as depression, anxiety, and post-traumatic stress...

www.excelmale.com

I felt really tired and had low mood when taking a DHT analog like oxandrolone (with TRT) that may affect the action of 5 alpha reductase. This enzyme is not only key to converting testosterone to DHT but also progesterone to allopregnanolone.

Some men on 5 alpha reductase inhibitors like finasteride have experienced more depression (due to the lack or low allopregnanolone?). Increased self-harm, depression risks associated with 5-alpha-reductase inhibitors

Why do some men feel great on TRT (and/or hCG) and others don't? That is the question that I have seen no data on. My hypothesis is that there are genetic or adrenal factors that may make some men more susceptible to lowering upstream neuro-steroids. Some of us supplement pregnenolone and/or progesterone to compensate, but I have honestly not seen enough evidence to see if this improves mood and quality of life. I started pregnenolone 100 mg every night 3 weeks ago and I think I am sleeping better and may have some improvements in the low mood I have had lately. I will test my preg, prog, and other levels next week using this panel:

Hormone Panel for Men on TRT- Comprehensive

This hormone panel for men on testosterone replacement therapy (TRT) contains upstream and downstream hormones to testosterone. TRT has been shown to decrease upstream hormones like pregnenolone and progesterone, and slightly decrease DHEA. Downstream ho

www.discountedlabs.com

I think we have no good data on testosterone-induced anxiety. Some studies (not done in men on TRT) have hinted to the fact that high testosterone can increase the odds of anxiety. But most men I know feel better, not worse, on TRT.

High Levels of Androgens in Men Associated With Increased Risk for Anxiety Disorders - Psychiatry Advisor

Higher serum total testosterone in men and androstenedione in young men may increase the risk for anxiety disorders.

www.psychiatryadvisor.com

 

[Fortunate]

I am sorry that it took me a long time to jump in. I have been busy with work.

I think there is something to this.

Some guys may be more susceptible to the decrease in neuro-steroids (pregnenolone, progesterone) that is caused by TRT due to its shut down effect on LH.

Reference: Anabolic steroids and TRT decrease SHBG, DHEA, pregnenolone and progesterone in men.

View attachment 15097
I explain how LH may be involved in the synthesis of pregnenolone and progesterone from cholesterol in this video (and the effect of hCG as a LH analog). TRT shuts down LH, and thus it decreases pregenenolone and its downstream hormones. The adrenals can still make some pregnenolone, but in men with some adrenal insufficiency, that may be extremely limited and not enough to compensate for the effect of shutting down LH.

As we know, progesterone is a "calming" hormone.

We need pregnenolone to make progesterone and we need progesterone to make allopregnanolone, a hormone that has been tied to mood.

View attachment 15096


Why do some men feel great on TRT (and/or hCG) and others don't? That is the question that I have seen no data on. My hypothesis is that there are genetic or adrenal factors that may make some men more susceptible to lowering upstream neuro-steroids. Some of us supplement pregnenolone and/or progesterone to compensate, but I have honestly not seen enough evidence to see if this improves mood and quality of life. I started pregnenolone 100 mg every night 3 weeks ago and I think I am sleeping better and may have some improvements in the low mood I have had lately. I will test my preg, prog, and other levels next week using this panel:

Hormone Panel for Men on TRT- Comprehensive

This hormone panel for men on testosterone replacement therapy (TRT) contains upstream and downstream hormones to testosterone. TRT has been shown to decrease upstream hormones like pregnenolone and progesterone, and slightly decrease DHEA. Downstream ho

www.discountedlabs.com

I felt really tired and had low mood when taking a DHT analog like oxandrolone 9with TRT) that may affect the action of 5 alpha reductase. This enzyme is not only key to converting testosterone to DHT but also progesterone to allopregnanolone.

Some men on 5 alpha reductase inhibitors like finasteride have experienced more depression (due to the lack or low allopregnanolone?). Increased self-harm, depression risks associated with 5-alpha-reductase inhibitors


I think we have no good data on testosterone-induced anxiety. Some studies (not done in men on TRT) have hinted to the fact that high testosterone can increase the odds of anxiety. But most men I know feel better, not worse, on TRT.

High Levels of Androgens in Men Associated With Increased Risk for Anxiety Disorders - Psychiatry Advisor

Higher serum total testosterone in men and androstenedione in young men may increase the risk for anxiety disorders.

www.psychiatryadvisor.com

@Nelson Vergel, that was a great summary of steroidogenesis and why we should all consider hCG. I personally have used it for years, while jumping around on various forms of TRT. I have (non-scientifically) started to suspect hCG may be contributing to developing headaches, so I have gone off for periods of time. Anecdotally, I do think headache frequency has dropped while off it.

Another issue I have noticed is what is described above as the six-month problems. In my case, after starting Xyosted, I felt really good for several months and then started to feel like crap. I got labs and T levels were a bit high (not crazy) and E2 was higher than usual. I blamed the crappy feeling on E2, started a tiny dose of anastrazole and struggled to find the "zone" again. Since then, have been trying different protocols.

I would love to have a "culprit" for both my headaches and the six-month crash and it would be great if I could just blame hCG. Maybe TRT alone without hCG is my answer. I may be exploring that, but based on what we know (as demonstrated by your excellent summary), hCG actually does more than just stimulate Leydig cells.

I watched portions of Dr. Gordon's presentation, but still need to watch the whole thing. It seemed to me that he is a proponent of supplementing with some of the upstream end-products (pregnenelone). It seems that the "natural" way to get upstream hormone production would be to use an LH analogue (hCG). But, if anxiety (and in my case, headaches) are an issue you are trying to resolve, and if one concludes hCG somehow contributes to these issue, I wonder if simply supplementing with pregnenolone and/or DHEA will get us in the same place (provide us with needed upstream hormones)?

Most of this is just my thinking out loud, but if I had a direct question it would be: for those who suspect they don't tolerate hCG, would supplement with pregnenlone and/or DHEA suffice as a way to maintain healthy levels of those hormones?

I have used DHEA in the past, but I noticed that it makes me really sleepy, so I tend to use it before bed. I have never used pregnenolone and might be interested in trying it to see how it affects mood.

Would love to anyone's thoughts on my ramble

 

[Nelson Vergel]

I would love to have a "culprit" for both my headaches and the six-month crash and it would be great if I could just blame hCG. Maybe TRT alone without hCG is my answer. I may be exploring that, but based on what we know (as demonstrated by your excellent summary), hCG actually does more than just stimulate Leydig cells.

Did you check your blood pressure and hematocrit while having those headaches?

I am following data on ferritin drops in men on TRT (even without blood donations). It may be a reason why some may feel fatigued after a few months

Testosterone Replacement Therapy (TRT) Decreases Ferritin

Testosterone replacement can cause a decrease in ferritin in men even without the presence or use of blood donations or therapeutic phlebotomies. A study gave men testosterone enanthate at a dose of 125 mg per week (it also used T enanthate with or without finasteride to see the effect of...

www.excelmale.com

Most of this is just my thinking out loud, but if I had a direct question it would be: for those who suspect they don't tolerate hCG, would supplement with pregnenlone and/or DHEA suffice as a way to maintain healthy levels of those hormones?

The only way to prove this is to have a bunch of us take pregnenolone and/or progesterone and run upstream hormone tests using LC/MS. I don't supplement DHEA since the reduction on DHEA caused by TRT is small since this hormone has a strong adrenal- non LH origin. I started taking pregnenolone a few weeks ago (100 mg per night) and will check my upstream and downstream hormones on Monday using this panel I created for that purpose.

Hormone Panel for Men on TRT- Comprehensive

This hormone panel for men on testosterone replacement therapy (TRT) contains upstream and downstream hormones to testosterone. TRT has been shown to decrease upstream hormones like pregnenolone and progesterone, and slightly decrease DHEA. Downstream ho

www.discountedlabs.com

I am also taking lactoferrin, Vitamin C and low dose iron to improve my low ferritin (it was sitting at 30 a month ago- I have not had a therapeutic phlebotomy in years). I have had low mood and fatigue for two months even with good T, free T, thyroid hormone levels, good sleep and a no stress that may deplete my adrenals.