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

[Fortunate]

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

The only way to prove this is to have a bunch of us take pregnenolone and/or progesterone (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 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 sleep and a good life (no stress).

I think BP is ok. To be fair, I have had chronic headaches my whole life and am treated for them. The game I play is reducing any and all things to contribute to headaches.

Bummer you are not feeling great. Did your mood improve on cream initially? I felt great for a few weeks only to crash after 3-4 weeks.

 

[Nelson Vergel]

@madman @Cataceous @Gianluca @readalot

I would love to hear your opinions

 

[Nelson Vergel]

Did your mood improve on cream initially? I felt great for a few weeks only to crash after 3-4 weeks.

The hydrogel testosterone cream from Empower works well and keeps my T and free T levels were 100 mg per week of testosterone enanthate got me to. I am still using it (2 clicks on scrotum and 2 clicks on shoulders, once per day). I had an initial boost in libido that went back to baseline after 4 weeks. I like it but, like everything we do (specially long term and older TRT users), nothing is the magic bullet by itself. I need to bring back hCG (forgot to get a refill three weeks ago), but want to test upstream hormones with pregnenolone supplementation (plus TRT) first.

 

[Fortunate]

I have found that maybe I feel worse on DHEA in terms of mood. Could that be contributing to your mood?

 

[Nelson Vergel]

I have found that maybe I feel worse on DHEA in terms of mood. Could that be contributing to your mood?

I am not taking it. Tried it several times years ago and did not feel well on it (bloating and acne). My DHEA-S on TRT is within range.

 

[Cataceous]

@madman @Cataceous @Gianluca @readalot

I would love to hear your opinions

Near the end Dr. Gordon does seem to say that levels of 5ar are lower when testosterone is high, and they're doing a study on how to restore them. It would be interesting to know the mechanism. Otherwise it's easy to imagine a situation with competitive inhibition, where there's so much testosterone relative to progesterone that less progesterone can be converted to allopregnanolone via 5a-dihydroprogesterone.

It's gratifying to see that Dr. Gordon shares some of the ideas that have been promoted here: the disruption of the hormonal milieu caused by TRT—he mentions 35 hormones being affected; in replacement, aiming for median hormone levels rather than significantly higher—though my version uses median levels for healthy young men; avoiding the use of higher and higher levels of testosterone to solve problems—he said it's like trying to pump up only one flat tire on your car when all of them are flat—it means there's "no balance".

 

[Fortunate]

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.

@Nelson Vergel, at the risk of sounding kooky, I'll throw this out there: have you ever tried meditation? I did mindfulness meditation for several years with varying results. Last year, I became curious about transcendental meditation. I was fairly skeptical about the organization as a whole, but decided to go through the training. I now practice the technique on a semi regular basis.

By no means has it cured physical ailments for me and I do not levitate! But, I would say, overall, it has elevated my baseline level of "life satisfaction" and mood. It's a bit of an interesting organization. Some would even have stronger words to describe it. That said, I think there is benefit in the technique.

Just a thought. Obviously, mood and energy are driven by a myriad of biological processes, including hormones. But, it can be useful to attack problems from more than one angle.

 

[Charliebizz]

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

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.

I should be getting results from a full work up this week and can share my results also. On test e only. My ferritin has dropped from 157 natural to 50. Will see if it has dropped further. I also experience headaches and low mood on trt.

 

[Nelson Vergel]

@Nelson Vergel, at the risk of sounding kooky, I'll throw this out there: have you ever tried meditation? I did mindfulness meditation for several years with varying results. Last year, I became curious about transcendental meditation. I was fairly skeptical about the organization as a whole, but decided to go through the training. I now practice the technique on a semi regular basis.

@Fortunate
It is so interesting that you mention this. I called one of the institutes in Houston that train people for Transcendental Meditation last week. I also considering yoga as some friends swear by it, not only for stress but also for flexibility and to strengthen your core.
I will let you know what my experience is. I have done a lot of mindfulness meditation (had a coach in the past), but I feel like I need to explore transcendental also. Anything that helps! Hormones are only part of the equation!

I wonder how many men in their 60's go through another version of mid-life (two-third life LOL) crisis when you start wondering what you will do with the rest of your life.

 

[Gianluca]

@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

I believe supplementing downstream hormones is a better strategy than HCG, I know it looks great on paper reactivating "naturally" that pathway. HCG did not help my anxiety/worsening of adrenal function while on TRT, Pregnenolone/DHEA/Progesterone did. The only thing that I may be afraid of, is that LH may be needed for some enzymatic process that we don't know yet.

 

[Nelson Vergel]

HCG did not help my anxiety/worsening of adrenal function while on TRT, Pregnenolone/DHEA/Progesterone did.

Did you measure each pre and after supplementing for a while? Just curious.

 

[Gianluca]

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

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.

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 15115
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.

View attachment 15117

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

@Nelson Vergel I agree with you to the fact that having some adrenal dysfunction, perhaps even before starting TRT, will negatively impact the outcome of the TRT treatment. I believe most men on TRT develop anxiety and other adrenal like symptoms, for the reduction of Pregnenolone/Progesterone. Perhaps not even a reduction in these hormones, but if we optimize Testosterone we need to bring up other hormones at an optimal level as well, we know all hormones work together. Years ago I was complaining of E2 symptoms, then I started Pregnenolone capsule which increased my Progesterone, and no more of what I thought were "E2" symptoms.

Progesterone blood test, should be included in pre and post treatment.

I remember Dr Crisler often talking about post Finasteride syndrome, and I'm convinced that is related to the loss of allopregnenolone.

There is a video I just saw on Pregnenolone, I think it is a great presentation, especially about the low Pregnenolone symptoms people may experience on TRT, I hope it is ok to share this here again. If you have some time watch it all, but you can skip to 5:00 on the Pregnenoone symptoms. He explains how some people cannot tolerate optimal levels of Testosterone, due to the lack of Pregnenolone. Again, I learned this my self the hard way

 

[Gianluca]

Did you measure each pre and after supplementing for a while? Just curious.

I did not the pre on Pregnenolone when I started 100mg RX capsule the first time, I did the after for both Pregnenolone and Progesterone though. If I change anything with Pregnenolone/Progesterone supplementation, I always make sure to test Progesterone, I check less often Pregnenolone due to the cost of the test.

I also saw an increase in Pregnenolone when I started to use more Saturated Fat into my diet, same dose Pregnenolone but more SFA into my diet brought my Pregnenolone LC/MS from 61 to 100! no HCG use

 

[Nelson Vergel]

I also saw an increase in Pregnenolone when I started to use more Saturated Fat into my diet, same dose Pregnenolone but more SFA into my diet brought my Pregnenolone LC/MS from 61 to 100! no HCG use

It makes sense since pregnenolone comes from cholesterol. Thanks for sharing.

 

[Nelson Vergel]

If I change anything with Pregnenolone/Progesterone supplementation, I always make sure to test Progesterone, I check less often Pregnenolone due to the cost of the test.

What products and dosages are you using now for each?

I added both pregnenolone and progesterone tests measured by liquid chromatography/mass spectrometry on DiscountedLabs.com. LC/MS is even more important at low levels of hormones and may make it easier to obtain accurate levels when supplementing.

Pregnenolone Lab Test at Discounted Labs

Pregnenolone test

www.discountedlabs.com

Progesterone test (LC/MS)

Progesterone blood test for men and women

www.discountedlabs.com

 

[Gianluca]

What products and dosages are you using now for each?

I added both pregnenolone and progesterone tests measured by liquid chromatography/mass spectrometry on DiscountedLabs.com. LC/MS is even more important at low levels of hormones and may make it easier to obtain accurate levels when supplementing.

Pregnenolone Lab Test at Discounted Labs

Pregnenolone test

www.discountedlabs.com

Progesterone test (LC/MS)

Progesterone blood test for men and women

www.discountedlabs.com

for Pregnenolone I use 50mg cap plus 50mg cream (empower) I have tried the cream at night for the past two days, it worked great for sleep. Progesterone 5mg cap generally once per day at night or as needed

 

[Nelson Vergel]

Thanks. I found the three Empower products:

Pregnenolone Capsules | Empower Pharmacy | Compounding Pharmacy (50mg capsule)

Pregnenolone Cream | Empower Pharmacy | Compounding Pharmacy (50mg cream)

Progesterone Capsules | Empower Pharmacy | Compounding Pharmacy (you take 5mg capsule? Do they have it?)

I may try your protocol (without hCG) after I get my lab test results. Thank you for sharing.

Have you noticed any testicular volume improvement or reversal of atrophy?

 

[Nelson Vergel]

Pharmacology of pregnenolone and progesterone:

"Oral administration of 50 or 100 mg pregnenolone has been found to have minimal or negligible effect on urinary levels of testosterone and testosterone metabolites, including of androsterone, etiocholanolone, 5-androstanediol, androstadienol, and androstenol (and/or their conjugates), and this suggests that only a small amount of pregnenolone is converted into testosterone.[17][18] This is in accordance with findings on the conversion of DHEA into testosterone, in which only 1.5% of an oral dose of DHEA was found to be converted into testosterone.[17] In contrast to the androstanes, 50 or 100 mg oral pregnenolone has been found to significantly and in fact "strongly" increase urinary levels of the progesterone metabolites pregnanediol and pregnanolone (and/or their conjugates), whereas pregnanetriol was unaffected.[17][18] Unlike the case of oral administration, transdermal administration of 30 mg/day pregnenolone cream has not been found to affect urinary levels of metabolites of any other steroids, including of progesterone.[18]"

Pregnenolone - Wikipedia

************

"Pregnenolone can be administered orally, subcutaneously, intravenously, intranasally, and topically/transdermally. Oral pregnenolone has high metabolism and low bioavailability.28 It is lipophilic and readily crosses the blood brain barrier.

There is very limited data on the pharmacokinetics of exogenous pregnenolone. Oral pregnenolone is metabolized in preference to allopregnanolone, rather than other hormones biosynthesized from pregnenolone substrate, such as cortisol or DHEA. One study observed that three hours after oral consumption of a single dose of 400mg of pregnenolone, pregnenolone serum levels increased by approximately 60%. Two hours after this dose, allopregnanolone serum levels tripled. An earlier study shows that a single oral dose of 175mg of pregnenolone approximately doubled pregnenolone serum levels over the course of four to eight hours.

One study observed the effects of exogenous pregnenolone on patients diagnosed with schizophrenia or schizoaffective disorder. Participants were given eight weeks of oral pregnenolone--with an escalating fixed-dose approach, where patients took 500mg per day for the last four weeks. Serum levels of pregnenolone and certain downstream metabolites were measured. Treatment with oral pregnenolone elevated pregnenolone serum levels fourfold, pregnenolone sulfate serum levels tripled, and allopregnanolone serum levels increased fivefold. Furthermore, treatment with oral pregnenolone elevated progesterone serum levels more than fourfold and DHEAS levels by approximately 16%. In this study, exogenous pregnenolone did not increase serum levels of testosterone, free testosterone, cortisol, DHEA, estradiol, or androstenedione levels."

Marx CE, Keefe RSE, et al. Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia. Neuropsychopharmacology. 2009 Jul; 34(8): 1885–1903.

Pregnenolone and Progesterone for Men: Pharmacokinetics and Studies

"Pregnenolone can be administered orally, subcutaneously, intravenously, intranasally, and topically/transdermally. Oral pregnenolone has high metabolism and low bioavailability.28 It is lipophilic and readily crosses the blood brain barrier. There is very limited data on the pharmacokinetics...

www.excelmale.com

 

[Gianluca]

Thanks. I found the three Empower products:

Pregnenolone Capsules | Empower Pharmacy | Compounding Pharmacy (50mg capsule)

Pregnenolone Cream | Empower Pharmacy | Compounding Pharmacy (50mg cream)

Progesterone Capsules | Empower Pharmacy | Compounding Pharmacy (you take 5mg capsule? Do they have it?)

I may try your protocol (without hCG) after I get my lab test results. Thank you for sharing.

Have you noticed any testicular volume improvement or reversal of atrophy?

Excellent! I’m deciding to stick with the cream in the am since it helps me with energy prior my work out better than the capsule, and I will take the 50mg capsule at night since it quickly converts into Progesterone, I think it makes more sense this way. I really love the cream, I hope it works well for you as well.

Empower had to make a special order for my 5mg Progesterone, because in fact they don’t carry this strength

I didn’t notice any testicular volume improvement.

You certainly know and thought all of us how to use and manage hormones for health, but I still feel obligated to say this: if you change to cream/cap protocol, I would wait a week or two before introducing/trying Progesterone cap

 

[Nelson Vergel]

You certainly know and thought all of us how to use and manage hormones for health, but I still feel obligated to say this: if you change to cream/cap protocol, I would wait a week or two before introducing/trying Progesterone cap

Thank you.

I have been reluctant to supplement upstream hormones since I have been using hCG plus TRT for years. But I am now in the mood to actually experiment to see if taking pregnenolone plus or minus progesterone can improve mood and sleep without any adverse effects. You have been leading the way on this subject, so I am learning from your experiences.

I have a strong feeling that the TRT field has become complacent (researchers, physicians, etc) with men that do not respond well to TRT (those with increased anxiety on TRT in particular). It would be nice to see if we can collectively do our own open label pilot on these upstream neuro-steroids that are dramatically decreased by TRT and anabolic steroids, specially as hCG access becomes more problematic with FDA restrictions on compounding pharmacies.