Why DHEA Must Be Taken In Small Doses Only

[Rand56]

I work with doctor on a daily basis too. What experiments with estrogen are they performing that come back so positive? Evidence, please! Are you familiar with the meaning of that word??

C'mon, you mean you're not familiar with the youtube channel "TOT Revolution" ? I know this channel has been brought up on other threads when the topic of estrogen is discussed. I know the guy who runs the channel, Jay Campbell, can act like a buffoon at times, but I'm more interested in what their roundtable of TRT doctors talk about. They ALL are NOT fans of using AI's. Check it out sometime if you aren't familiar with that channel. If you think I'm just being a lying troll, then go listen to them yourself. Its rare they don't talk about AI's on the videos.

 

[haidut]

C'mon, you mean you're not familiar with the youtube channel "TOT Revolution" ? I know this channel has been brought up on other threads when the topic of estrogen is discussed. I know the guy who runs the channel, Jay Campbell, can act like a buffoon at times, but I'm more interested in what their roundtable of TRT doctors talk about. They ALL are NOT fans of using AI's. Check it out sometime if you aren't familiar with that channel. If you think I'm just being a lying troll, then go listen to them yourself. Its rare they don't talk about AI's on the videos.

I am not exactly in love with AI. But in specific cases they can be lifesaving. Why do you think first-line therapy for women with breast cancer is an AI? Because they have the highest benefit/hazard ratio for the so-called "chemotherapy-naive" patients. As I mentioned on several other threads, the *zoles (letrozole, fardozole, anastrozole) are pretty harsh drugs and I don't think their use is justified. But things like formestane or exemestane, in lower than clinically-prescribed doses, have pretty good track record. Btw, formestane quickly metabolizes into 4-OH-testosterone.
Formestane - Wikipedia
"...Formestane is often used to suppress the production of estrogens from anabolic steroids or prohormones. It also acts as a prohormone to 4-hydroxytestosterone, an active steroid which displays weak androgenic activity in addition to acting as a weak aromatase inhibitor."
4-Hydroxytestosterone - Wikipedia

The only difference between regular T and 4-OH-T is that the latter cannot be aromatized. So, you are basically getting TRT without many/most of the risks since even mainstream medicine claims that most side effects of TRT are due to aromatization. Are you against safe(er) TRT for the cases where it is needed?
Similar for exemestane. It is just a pro-drug for 6-methylene-boldenone. The only difference between boldenone and 6-Met-boldenone is that the latter cannot be aromatized. Boldenone is used clinically too when T is not available.
Methylene boldenone | 122370-91-6

Now, because the steroidal AI likely trigger negative feedback in higher doses since they metabolize into potent androgens, I suggested that lower than clinical doses should be discussed with the doctor especially considering that for all of the steroidal AI the IC50 are achievable with fractions of the clinically used doses. So, if you can get the benefits of lower estrogen, no/little suppresison, and the benefits of TRT all in one package, don't you think this is a net positive? And just to keep the estrogen pathway supplied in case there is true deficiency somewhere, adding a little pregnenolone/DHEA should be enough to compensate. But the vast majority of people have excess and nor deficiency of estrogen. Every extra gram of fat tissue shifts the balance away from progesterone/DHEA/T towards estrogen. And for most people, fat tissue does not diminish with age, right?

Do I think AI should be popped like candy? Absolutely not. I have only discussed AI for people with excess estrogen and even Peat said several times that if the side effects of AI can be controlled he would not be against them. If a person is skinny, prolactin is low, and thyroid function is good and they have few moles/spots on their skin then there is no reason to consider AI. But if the person is an aging male or menopausal woman (both usually overweight hence with a lot of aromatase), male has gyno, both have sarcopenia, prolactin is close to upper limit or above it, DHEA is low, plenty of moles/spots, etc (all of these are signs of elevated estrogen) then I think low dose steroidal AI is something that can be discussed with the doctor as a preferable alternative to all other interventions. Ideally, the person reacts well to progesterone and their estrogen is reigned in as progesterone is likely safer than the AIs. But if that does not happen, then low dose AI is one of the few acceptable risk options for people with estrogenic overload that cannot be controlled through other means.

Since you mentioned that channel, please post some of the links I posted here on the channel or email them to the Jay. I am genuinely interested in how those doctors or he would justify the use of estrogen, especially in light of the WHI study which basically said no menopausal woman should be prescribed HRT (estrogen) unless it is an emergency. And I don't even know what emergency would justify using estrogen in a post-menopausal woman but maybe those doctors on the channel could explain more. Again, I am genuinely curious what the response would be. The doctors I have talked to all defer to FDA and say HRT is FDA-approved therapy. But they all ask their patients to sign a disclaimer that HRT does cause cancer and that it is not the doctor's fault no matter what happens. So, aside from claiming that their patients "just feel better" on HRT I would love to see what objective improvements those doctors saw in their patients. Lower CVD, dementia, osteoporosis, cancer, etc risk? Anything that goes beyond "just feels better" would be greatly appreciated.

Oh, and I will tag @RisingSun and @Rhino who are doctors and hopefully they can chime in on whether what I said above is complete lunacy or at least backed by evidence and/or in line with their opinion/practice.

 

[Rand56]

I am not exactly in love with AI. But in specific cases they can be lifesaving. Why do you think first-line therapy for women with breast cancer is an AI? Because they have the highest benefit/hazard ratio for the so-called "chemotherapy-naive" patients. As I mentioned on several other threads, the *zoles (letrozole, fardozole, anastrozole) are pretty harsh drugs and I don't think their use is justified. But things like formestane or exemestane, in lower than clinically-prescribed doses, have pretty good track record. Btw, formestane quickly metabolizes into 4-OH-testosterone.
Formestane - Wikipedia
"...Formestane is often used to suppress the production of estrogens from anabolic steroids or prohormones. It also acts as a prohormone to 4-hydroxytestosterone, an active steroid which displays weak androgenic activity in addition to acting as a weak aromatase inhibitor."
4-Hydroxytestosterone - Wikipedia

The only difference between regular T and 4-OH-T is that the latter cannot be aromatized. So, you are basically getting TRT without many/most of the risks since even mainstream medicine claims that most side effects of TRT are due to aromatization. Are you against safe(er) TRT for the cases where it is needed?
Similar for exemestane. It is just a pro-drug for 6-methylene-boldenone. The only difference between boldenone and 6-Met-boldenone is that the latter cannot be aromatized. Boldenone is used clinically too when T is not available.
Methylene boldenone | 122370-91-6

Now, because the steroidal AI likely trigger negative feedback in higher doses since they metabolize into potent androgens, I suggested that lower than clinical doses should be discussed with the doctor especially considering that for all of the steroidal AI the IC50 are achievable with fractions of the clinically used doses. So, if you can get the benefits of lower estrogen, no/little suppresison, and the benefits of TRT all in one package, don't you think this is a net positive? And just to keep the estrogen pathway supplied in case there is true deficiency somewhere, adding a little pregnenolone/DHEA should be enough to compensate. But the vast majority of people have excess and nor deficiency of estrogen. Every extra gram of fat tissue shifts the balance away from progesterone/DHEA/T towards estrogen. And for most people, fat tissue does not diminish with age, right?

Do I think AI should be popped like candy? Absolutely not. I have only discussed AI for people with excess estrogen and even Peat said several times that if the side effects of AI can be controlled he would not be against them. If a person is skinny, prolactin is low, and thyroid function is good and they have few moles/spots on their skin then there is no reason to consider AI. But if the person is an aging male or menopausal woman (both usually overweight hence with a lot of aromatase), male has gyno, both have sarcopenia, prolactin is close to upper limit or above it, DHEA is low, plenty of moles/spots, etc (all of these are signs of elevated estrogen) then I think low dose steroidal AI is something that can be discussed with the doctor as a preferable alternative to all other interventions. Ideally, the person reacts well to progesterone and their estrogen is reigned in as progesterone is likely safer than the AIs. But if that does not happen, then low dose AI is one of the few acceptable risk options for people with estrogenic overload that cannot be controlled through other means.

Since you mentioned that channel, please post some of the links I posted here on the channel or email them to the Jay. I am genuinely interested in how those doctors or he would justify the use of estrogen, especially in light of the WHI study which basically said no menopausal woman should be prescribed HRT (estrogen) unless it is an emergency. And I don't even know what emergency would justify using estrogen in a post-menopausal woman but maybe those doctors on the channel could explain more. Again, I am genuinely curious what the response would be. The doctors I have talked to all defer to FDA and say HRT is FDA-approved therapy. But they all ask their patients to sign a disclaimer that HRT does cause cancer and that it is not the doctor's fault no matter what happens. So, aside from claiming that their patients "just feel better" on HRT I would love to see what objective improvements those doctors saw in their patients. Lower CVD, dementia, osteoporosis, cancer, etc risk? Anything that goes beyond "just feels better" would be greatly appreciated.

Oh, and I will tag @RisingSun and @Rhino who are doctors and hopefully they can chime in on whether what I said above is complete lunacy or at least backed by evidence and/or in line with their opinion/practice.

What I think would be better, see if you can get on one of their vids as a guest. Have a good debate. I'd want to watch it, as I'm sure many others would want to also.

 

[haidut]

What I think would be better, see if you can get on one of their vids as a guest. Have a good debate. I'd want to watch it, as I'm sure many others would want to also.

OK, I am emailing Jay as we speak. Let's hope he sees my email among the several hundred/thousand he probably receives every day.

 

[Cgj1]

I'm familiar with the TOT Revolution videos by Jay Campbell. They advocate DHEA/pregnenolone, as a standard protocol, especially for young people who want to avoid the TRT route to maintain fertility.

However Jay Campbell advocates metformin and fasting and lots of cardio which goes against the orthodox view on this forum. Still theirs alot of valuable information.

As for being against AI's (especially Dr Robert Kominiarek, who is pretty smart), they don't seem to distinguish between the zole drugs and aromasin etc. Haidut has mentioned different AI's, are not same, and act on different metabolic/hormonal pathways.



Personally I use 6mg of Aromasin EOD and I find it androgenic with no side effects.

 

[Rand56]

OK, I am emailing Jay as we speak. Let's hope he sees my email among the several hundred/thousand he probably receives every day.

Awesome. I can also make a comment on an upcoming vid to see if that would also help. What email address did you use to email him? I can reference it in my comment.

 

[haidut]

Awesome. I can also make a comment on an upcoming vid to see if that would also help. What email address did you use to email him? I can reference it in my comment.

I sent an email through this link.
Contact - TOT Revolution

 

[Rand56]

I sent an email through this link.
Contact - TOT Revolution

Ok thanks. I also sent a message thru that link. The more the merrier. Hope it can happen.

 

[TheBeard]

C'mon, you mean you're not familiar with the youtube channel "TOT Revolution" ? I know this channel has been brought up on other threads when the topic of estrogen is discussed. I know the guy who runs the channel, Jay Campbell, can act like a buffoon at times, but I'm more interested in what their roundtable of TRT doctors talk about. They ALL are NOT fans of using AI's. Check it out sometime if you aren't familiar with that channel. If you think I'm just being a lying troll, then go listen to them yourself. Its rare they don't talk about AI's on the videos.

We are all familiar with the TOT and the lifting dermatologist on here, at least those who are serious about understanding endocrinology.

It is still you hearing about doctor’s experience vs Georgi reading studies, you don’t have more first-hand knowledge than him, you just heard doctors who supposedly have first hand knowledge, like we all did.

They report having patients « feeling better ». Let’s stop for a second and ponder how vast the array of physiological phenomenons leading to that « feeling better » is.

Let alone knowing whether that « feeling better » leads to a healthier present state, not even mentioning a healthier future state.

All we have is 4 doctors telling you that their patients applying T to their scrotum and dropping the AI « feel better ».

I don’t know about you, but I can’t conclude anything about estrogen’s malignancy based on that

 

[RisingSun]

I am not exactly in love with AI. But in specific cases they can be lifesaving. Why do you think first-line therapy for women with breast cancer is an AI? Because they have the highest benefit/hazard ratio for the so-called "chemotherapy-naive" patients. As I mentioned on several other threads, the *zoles (letrozole, fardozole, anastrozole) are pretty harsh drugs and I don't think their use is justified. But things like formestane or exemestane, in lower than clinically-prescribed doses, have pretty good track record. Btw, formestane quickly metabolizes into 4-OH-testosterone.
Formestane - Wikipedia
"...Formestane is often used to suppress the production of estrogens from anabolic steroids or prohormones. It also acts as a prohormone to 4-hydroxytestosterone, an active steroid which displays weak androgenic activity in addition to acting as a weak aromatase inhibitor."
4-Hydroxytestosterone - Wikipedia

The only difference between regular T and 4-OH-T is that the latter cannot be aromatized. So, you are basically getting TRT without many/most of the risks since even mainstream medicine claims that most side effects of TRT are due to aromatization. Are you against safe(er) TRT for the cases where it is needed?
Similar for exemestane. It is just a pro-drug for 6-methylene-boldenone. The only difference between boldenone and 6-Met-boldenone is that the latter cannot be aromatized. Boldenone is used clinically too when T is not available.
Methylene boldenone | 122370-91-6

Now, because the steroidal AI likely trigger negative feedback in higher doses since they metabolize into potent androgens, I suggested that lower than clinical doses should be discussed with the doctor especially considering that for all of the steroidal AI the IC50 are achievable with fractions of the clinically used doses. So, if you can get the benefits of lower estrogen, no/little suppresison, and the benefits of TRT all in one package, don't you think this is a net positive? And just to keep the estrogen pathway supplied in case there is true deficiency somewhere, adding a little pregnenolone/DHEA should be enough to compensate. But the vast majority of people have excess and nor deficiency of estrogen. Every extra gram of fat tissue shifts the balance away from progesterone/DHEA/T towards estrogen. And for most people, fat tissue does not diminish with age, right?

Do I think AI should be popped like candy? Absolutely not. I have only discussed AI for people with excess estrogen and even Peat said several times that if the side effects of AI can be controlled he would not be against them. If a person is skinny, prolactin is low, and thyroid function is good and they have few moles/spots on their skin then there is no reason to consider AI. But if the person is an aging male or menopausal woman (both usually overweight hence with a lot of aromatase), male has gyno, both have sarcopenia, prolactin is close to upper limit or above it, DHEA is low, plenty of moles/spots, etc (all of these are signs of elevated estrogen) then I think low dose steroidal AI is something that can be discussed with the doctor as a preferable alternative to all other interventions. Ideally, the person reacts well to progesterone and their estrogen is reigned in as progesterone is likely safer than the AIs. But if that does not happen, then low dose AI is one of the few acceptable risk options for people with estrogenic overload that cannot be controlled through other means.

Since you mentioned that channel, please post some of the links I posted here on the channel or email them to the Jay. I am genuinely interested in how those doctors or he would justify the use of estrogen, especially in light of the WHI study which basically said no menopausal woman should be prescribed HRT (estrogen) unless it is an emergency. And I don't even know what emergency would justify using estrogen in a post-menopausal woman but maybe those doctors on the channel could explain more. Again, I am genuinely curious what the response would be. The doctors I have talked to all defer to FDA and say HRT is FDA-approved therapy. But they all ask their patients to sign a disclaimer that HRT does cause cancer and that it is not the doctor's fault no matter what happens. So, aside from claiming that their patients "just feel better" on HRT I would love to see what objective improvements those doctors saw in their patients. Lower CVD, dementia, osteoporosis, cancer, etc risk? Anything that goes beyond "just feels better" would be greatly appreciated.

Oh, and I will tag @RisingSun and @Rhino who are doctors and hopefully they can chime in on whether what I said above is complete lunacy or at least backed by evidence and/or in line with their opinion/practice.

There are a few indications where the use of an AI is warranted.

Some endos swear by using a prophylactic dose of AI when starting a man on TRT.
I’m not one of those.
I like to start with as few compounds as necessary, namely just testosterone, and go from there judging by lab work and how the patient fares.

A distinction needs to be made based on the modus operandi of the AI. Steroidal AI have a much safer profile than the first gen ones, and I tend to only prescribe exemestane when an AI is needed for that reason.

They certainly have proved useful in the halting of breast cancers.

In the management of andropause where high estrogen is the culprit too.


As far as causing a negative feedback loop when too high a dose is used because of the androgenic metabolites, studies point towards an upregulation of endogenous androgens after 10 days on 25mg exemestane.
Not sure what qualifies as high dose in this case @haidut

 

[Rand56]

However Jay Campbell advocates metformin and fasting and lots of cardio which goes against the orthodox view on this forum. Still theirs alot of valuable information.

Yeah he is probably nuts for taking the amount of Metformin he does. but what do I know. He said he takes 1000 mg's twice a day, and said he has been taking this much for many years. I was actually about to pull the trigger to order some, but wanted to read thru the opinions on it here, and also watched a vid with Dr. Chandler Marrs saying it blocks thiamine from getting in the cell. That's not a good thing, so I decided to not order it.

 

[haidut]

There are a few indications where the use of an AI is warranted.

Some endos swear by using a prophylactic dose of AI when starting a man on TRT.
I’m not one of those.
I like to start with as few compounds as necessary, namely just testosterone, and go from there judging by lab work and how the patient fares.

A distinction needs to be made based on the modus operandi of the AI. Steroidal AI have a much safer profile than the first gen ones, and I tend to only prescribe exemestane when an AI is needed for that reason.

They certainly have proved useful in the halting of breast cancers.

In the management of andropause where high estrogen is the culprit too.


As far as causing a negative feedback loop when too high a dose is used because of the androgenic metabolites, studies point towards an upregulation of endogenous androgens after 10 days on 25mg exemestane.
Not sure what qualifies as high dose in this case @haidut

Thanks for chiming in. By high dose, I meant the clinically used exemestane doses - usually 25mg daily. This is the dose that most people seem to experience first hand simply because as far as I am aware exemestane is not typically available in smaller doses unless the doctor works with a compounding pharmacy and requests smaller pills/doses. Yes, it has a long enough half life to be used EOD or even every 3rd day but I am not aware of such schedules used clinically. Multiple studies looked at the dose-response relationship for exemestane and its effects on estrogen and the results seem to show that anything over 10mg does not suppress E1 or E2 further in a clinically relevant manner. Here is one.
Endocrine and clinical effects of exemestane (PNU 155971), a novel steroidal aromatase inhibitor, in postmenopausal breast cancer patients: a phase... - PubMed - NCBI
"...Exemestane (10 mg o.d.) caused maximal suppression of plasma estradiol (E2) and estrone (E1) to a mean of 14.6 and 5.8% of pretreatment levels, respectively, whereas 25 mg of exemestane o.d. suppressed estrone sulfate (E1S) to 8.9% of pretreatment levels. No fall in adrenal steroid levels was recorded. Exemestane (5 mg o.d.) suppressed urinary E2 and E1 to a mean of 11.9 and 12.2% of pretreatment levels, respectively. Administering exemestane at doses of 50-200 mg o.d. caused no further suppression of urinary E1, whereas urinary E2 fell to 6-7% of pretreatment levels. Median time to progression was 63 weeks. We conclude that exemestane is a well-tolerated aromatase inhibitor that effectively suppresses plasma and urinary estrogens in postmenopausal patients with breast cancer."

So, the "low dose" discussed here is in the 5mg-10mg daily range, even though some studies shave shown as little as 2.5mg daily having potent estrogen-suppressive effects.
Endocrinological and clinical evaluation of exemestane, a new steroidal aromatase inhibitor. - PubMed - NCBI

So, overall, considering the propensity for side effects with increasing dose for all drugs, including steroidal AI, on the forum we typically discuss using the lowest effective exemestane dose as a potentially lower risk approach than TRT. Now, you mentioned that you prefer to try low dose TRT first. May I ask what is considered low dose TRT and what is the methods of administration (injection, transdermal, oral, etc)? Related to this, you also mentioned a case where AI-only therapy may be warranted - i.e. secondary hypogonadism due to excess estrogen. Multiple publications have came out arguing that in most cases for aging males the issue is secondary hypogonadism.
Alternatives to testosterone replacement: testosterone restoration McCullough A - Asian J Androl
"...The European Male Aging Study has demonstrated that the hypogonadism of male aging is predominantly secondary. Theoretically with appropriate stimulation from the pituitary, the aging testis should be able to produce eugonadal levels of testosterone. The strategies for the treatment of late onset hypogonadism (LOH) have focused on replacement with exogenous testosterone versus restoration of endogenous production. The purpose of this article is to review existing peer-reviewed literature supporting the concept of restoration of endogenous testosterone in the treatment of LOH."

Does the above study match your experience - i.e. that most hypogonadism cases are secondary? If yes, is secondary hypogonadism related to excess estrogen diagnosed officially only by doing blood tests for E2? I am asking because there is evidence that blood levels of E2 may be quite unreliable in estimating total body estrogen stores and more reliable biomakers such as prolactin and estrone sulfate (E1S) are rarely used clinically, to the best of my knowledge.
Test For Estrogenic Activity And Prostate Cancer
Prolactin Is A Good Biomarker For Serotonin / Estrogen Activity

So, it seems quite possible (and dare I say maybe even common) to have a male with low T but normal E2, in which case an AI-only therapy will likely not be considered since the E2 is in range. Anything you can share on differential diagnosis and how you decide on AI-only vs. low-dose TRT would be appreciated.

I guess the question really comes down to this. For males with secondary hypogonadism what has higher benefit/risk ratio - low dose TRT (with the risk of aromatization increasing with advanced age due to greater fat accumulation and the high aromatase expression in fat) or low dose steroidal AI with the clarification that the steroidal AI like formestane and exemestane are actually prodrugs for steroids very similar to T? My point is that those lower-dose steroidal AI-only regimens seem to provide the benefits of TRT without many of the risks. I think endocrinology has long ago recognized the potential benefit of non-aromatizable androgens for both treating cancer (e.g. Drostanolone) and hypogonadism treatment. It just so happens that there is no approved non-aromatizable steroid for treating male hypogonadism, so TRT is used instead. To me, the evidence seems to point to low-dose steroidal AI like formestane and exemestane being pro-hormones for exactly such male hypogonadism treatment with non-aromatizable androgens, and as such probably a good first-line therapy as the link above on European Male Aging Study argues. Even calls for using DHT for TRT have been made but I don't think this will go anywhere given the bad reputation DHT has currently.
Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent. - PubMed - NCBI
Should the Nonaromatizable Androgen Dihydrotestosterone Be Considered as an Alternative to Testosterone in the Treatment of the Andropause?

Which bring us back to the low-dose steroidal AI as possibly the best compromise (in my layman opinion) among the available therapies for secondary hypogonadism. The reason I am saying this is that apparently most cases of secondary hypogonadism respond robustly to SERMs. If that is the case then does that not imply that increased estrogen signalling (whether reflected by blood tests or not) is the cause behind most cases of secondary hypogonadism? And perhaps more importantly, if SERMs work for most cases of secondary hypogonadism then what do SERMs have to offer in terms of safety and effectiveness that a low-dose steroidal AI cannot?
https://www.endocrinologyadvisor.co...-hypogonadism-causes-and-potential-treatment/
"...Most cases of secondary hypogonadism appear to respond to selective estrogen receptor modulator (SERM) therapy. However, intolerance to SERMs is common or they may cause unwanted side effects, according to Paul Turek, MD, director of the Turek Clinic in Beverly Hills and San Francisco, California. “I would say there is sea of change in the way we treat hypogonadotropic hypogonadism (HH) lately,” Dr Turek told Endocrinology Advisor. “This is because reproductive urologists have become more comfortable using SERMs off-label for men, and endocrinologists are now learning how effective SERMs can be to help men wean off anabolic steroids. This class of agents is truly ‘bioidentical’ for testosterone replacement, as they augment native or endogenous testosterone levels rather than replacing them with exogenous testosterone.”

Finally, it is my suggestion that adding pregnenolone (P5) would make this approach even more effective, by backfilling any pathways the steroidal AI may be inhibiting, and P5 may also mitigate some of the commonly reported side effects such joint pain (which I think is due to AI interfering with progesterone synthesis). One major benefit of P5 is that it does not seem to trigger negative feedback mechanisms in humans even in high doses on the order of 500mg daily. Check table 6 of this study for hormonal status before/after 8 weeks of 500mg daily P5. Btw, there are at least 4 more human studies with 500mg P5 daily that did not find any change in the steroid balance suggesting negative feedback/suppression kicking in due to P5.
Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia

I don't think 500mg P5 doses are needed, those were given as a reliable way to raise allopregnanolone. For gonadal steroidogenesis much lower doses are sufficient. Physiological doses of 30mg-50mg daily should be plenty and it should help achieve a more robust gonadal T synthesis with a smaller elevation in LH/FSH. I believe the latter is considered a desirable effect in endocrinology as it implies higher sensitivity of Leydig cells to pituitary signalling, right?

Anyways, that's just my layman opinion, so feel free to criticize it Thank again for any feedback.

 

[haidut]

Yeah he is probably nuts for taking the amount of Metformin he does. but what do I know. He said he takes 1000 mg's twice a day, and said he has been taking this much for many years. I was actually about to pull the trigger to order some, but wanted to read thru the opinions on it here, and also watched a vid with Dr. Chandler Marrs saying it blocks thiamine from getting in the cell. That's not a good thing, so I decided to not order it.

We have been talking about metformin on the forum and Peat also spoke against it. The main issue with is is that it seems to inhibit ETC, elevate lactate and as such promote systemic acidosis. That lactate promoting effect has even been used by scientists to initiate cancer.
https://raypeatforum.com/community/threads/metformin-is-a-mitochondrial-toxin-and-raises-lactate.3896/
https://raypeatforum.com/community/threads/baking-soda-may-treat-cancer-metformin-may-cause-it.29266/

 

[Hans]

If hypogonadism is secondary, then the elevated estrogen or increased aromatase is not completely the cause of low T. Endotoxins, elevated PUFAs, oxidative stress & inflammation, low thyroid, insulin resistance, etc., are also all major causes of low T. Using an aromatase inhibitor can help greatly lower E and increase T, but it would not be very good on its own at fixing the other conditions and can make them dependent on those substances. Just an additional thought to those that want to use only an AI + a few other prohormones.

 

[Rand56]

studies point towards an upregulation of endogenous androgens after 10 days on 25mg exemestane.

So this is just exemestane taken solo? If so, if I tried that high dose, I'm thnking every bone in my body would be sore.

 

[RisingSun]

Thanks for chiming in. By high dose, I meant the clinically used exemestane doses - usually 25mg daily. This is the dose that most people seem to experience first hand simply because as far as I am aware exemestane is not typically available in smaller doses unless the doctor works with a compounding pharmacy and requests smaller pills/doses. Yes, it has a long enough half life to be used EOD or even every 3rd day but I am not aware of such schedules used clinically. Multiple studies looked at the dose-response relationship for exemestane and its effects on estrogen and the results seem to show that anything over 10mg does not suppress E1 or E2 further in a clinically relevant manner. Here is one.
Endocrine and clinical effects of exemestane (PNU 155971), a novel steroidal aromatase inhibitor, in postmenopausal breast cancer patients: a phase... - PubMed - NCBI
"...Exemestane (10 mg o.d.) caused maximal suppression of plasma estradiol (E2) and estrone (E1) to a mean of 14.6 and 5.8% of pretreatment levels, respectively, whereas 25 mg of exemestane o.d. suppressed estrone sulfate (E1S) to 8.9% of pretreatment levels. No fall in adrenal steroid levels was recorded. Exemestane (5 mg o.d.) suppressed urinary E2 and E1 to a mean of 11.9 and 12.2% of pretreatment levels, respectively. Administering exemestane at doses of 50-200 mg o.d. caused no further suppression of urinary E1, whereas urinary E2 fell to 6-7% of pretreatment levels. Median time to progression was 63 weeks. We conclude that exemestane is a well-tolerated aromatase inhibitor that effectively suppresses plasma and urinary estrogens in postmenopausal patients with breast cancer."

So, the "low dose" discussed here is in the 5mg-10mg daily range, even though some studies shave shown as little as 2.5mg daily having potent estrogen-suppressive effects.
Endocrinological and clinical evaluation of exemestane, a new steroidal aromatase inhibitor. - PubMed - NCBI

So, overall, considering the propensity for side effects with increasing dose for all drugs, including steroidal AI, on the forum we typically discuss using the lowest effective exemestane dose as a potentially lower risk approach than TRT. Now, you mentioned that you prefer to try low dose TRT first. May I ask what is considered low dose TRT and what is the methods of administration (injection, transdermal, oral, etc)? Related to this, you also mentioned a case where AI-only therapy may be warranted - i.e. secondary hypogonadism due to excess estrogen. Multiple publications have came out arguing that in most cases for aging males the issue is secondary hypogonadism.
Alternatives to testosterone replacement: testosterone restoration McCullough A - Asian J Androl
"...The European Male Aging Study has demonstrated that the hypogonadism of male aging is predominantly secondary. Theoretically with appropriate stimulation from the pituitary, the aging testis should be able to produce eugonadal levels of testosterone. The strategies for the treatment of late onset hypogonadism (LOH) have focused on replacement with exogenous testosterone versus restoration of endogenous production. The purpose of this article is to review existing peer-reviewed literature supporting the concept of restoration of endogenous testosterone in the treatment of LOH."

Does the above study match your experience - i.e. that most hypogonadism cases are secondary? If yes, is secondary hypogonadism related to excess estrogen diagnosed officially only by doing blood tests for E2? I am asking because there is evidence that blood levels of E2 may be quite unreliable in estimating total body estrogen stores and more reliable biomakers such as prolactin and estrone sulfate (E1S) are rarely used clinically, to the best of my knowledge.
Test For Estrogenic Activity And Prostate Cancer
Prolactin Is A Good Biomarker For Serotonin / Estrogen Activity

So, it seems quite possible (and dare I say maybe even common) to have a male with low T but normal E2, in which case an AI-only therapy will likely not be considered since the E2 is in range. Anything you can share on differential diagnosis and how you decide on AI-only vs. low-dose TRT would be appreciated.

I guess the question really comes down to this. For males with secondary hypogonadism what has higher benefit/risk ratio - low dose TRT (with the risk of aromatization increasing with advanced age due to greater fat accumulation and the high aromatase expression in fat) or low dose steroidal AI with the clarification that the steroidal AI like formestane and exemestane are actually prodrugs for steroids very similar to T? My point is that those lower-dose steroidal AI-only regimens seem to provide the benefits of TRT without many of the risks. I think endocrinology has long ago recognized the potential benefit of non-aromatizable androgens for both treating cancer (e.g. Drostanolone) and hypogonadism treatment. It just so happens that there is no approved non-aromatizable steroid for treating male hypogonadism, so TRT is used instead. To me, the evidence seems to point to low-dose steroidal AI like formestane and exemestane being pro-hormones for exactly such male hypogonadism treatment with non-aromatizable androgens, and as such probably a good first-line therapy as the link above on European Male Aging Study argues. Even calls for using DHT for TRT have been made but I don't think this will go anywhere given the bad reputation DHT has currently.
Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent. - PubMed - NCBI
Should the Nonaromatizable Androgen Dihydrotestosterone Be Considered as an Alternative to Testosterone in the Treatment of the Andropause?

Which bring us back to the low-dose steroidal AI as possibly the best compromise (in my layman opinion) among the available therapies for secondary hypogonadism. The reason I am saying this is that apparently most cases of secondary hypogonadism respond robustly to SERMs. If that is the case then does that not imply that increased estrogen signalling (whether reflected by blood tests or not) is the cause behind most cases of secondary hypogonadism? And perhaps more importantly, if SERMs work for most cases of secondary hypogonadism then what do SERMs have to offer in terms of safety and effectiveness that a low-dose steroidal AI cannot?
https://www.endocrinologyadvisor.co...-hypogonadism-causes-and-potential-treatment/
"...Most cases of secondary hypogonadism appear to respond to selective estrogen receptor modulator (SERM) therapy. However, intolerance to SERMs is common or they may cause unwanted side effects, according to Paul Turek, MD, director of the Turek Clinic in Beverly Hills and San Francisco, California. “I would say there is sea of change in the way we treat hypogonadotropic hypogonadism (HH) lately,” Dr Turek told Endocrinology Advisor. “This is because reproductive urologists have become more comfortable using SERMs off-label for men, and endocrinologists are now learning how effective SERMs can be to help men wean off anabolic steroids. This class of agents is truly ‘bioidentical’ for testosterone replacement, as they augment native or endogenous testosterone levels rather than replacing them with exogenous testosterone.”

Finally, it is my suggestion that adding pregnenolone (P5) would make this approach even more effective, by backfilling any pathways the steroidal AI may be inhibiting, and P5 may also mitigate some of the commonly reported side effects such joint pain (which I think is due to AI interfering with progesterone synthesis). One major benefit of P5 is that it does not seem to trigger negative feedback mechanisms in humans even in high doses on the order of 500mg daily. Check table 6 of this study for hormonal status before/after 8 weeks of 500mg daily P5. Btw, there are at least 4 more human studies with 500mg P5 daily that did not find any change in the steroid balance suggesting negative feedback/suppression kicking in due to P5.
Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia

I don't think 500mg P5 doses are needed, those were given as a reliable way to raise allopregnanolone. For gonadal steroidogenesis much lower doses are sufficient. Physiological doses of 30mg-50mg daily should be plenty and it should help achieve a more robust gonadal T synthesis with a smaller elevation in LH/FSH. I believe the latter is considered a desirable effect in endocrinology as it implies higher sensitivity of Leydig cells to pituitary signalling, right?

Anyways, that's just my layman opinion, so feel free to criticize it Thank again for any feedback.

Indeed the vast majority of patients come in with secondary hypogonadism rather than primary.

In the case where this secondary hypogonadism exhibits estrogen levels at least within two upward standard deviations from the mean range, it is of value to try an Exemestane-only treatment to see whether estrogen normalization induces T normalization.

But in most of my cases E2 comes back very close to mid range, with T below mid-range.
And in those cases, when Exemestane-only treatment is tried, there are complaints of low E2 symptoms (or what are believed to be commonly accepted as low E2 symptoms, I’ve read that Ray Peat thinks they are a direct consequence of the AI).

That’s why in most cases, a prophylactic dose of 100mg/week Test E is given as first line treatment.
I give the choice to my patients to switch to a compounded cream depending on how they feel and respond to that treatment.

60% end up staying on the injection, with a final dose of 200mg/week.
The rest goes for the cream applied twice daily.

I see higher test values with the injections, but the overall well being improvement is equivalent in both groups.

Given the cost of E1S blood work I usually go by sensitive E2 only, which seems to be accurate enough, at least judging by patients’ responses when we adjust treatment based on that value only.

Sorry I can’t give you more info on that E2 vs E1S diagnosis, you may know more than I do already :)

 

[Rand56]

Just from a comparitive perspective, these roundtable TRT docs aren't concerned about "staying in a range" on a blood test, they treat by resolution of symptoms, and if I recall correctly, I believe it was Dr. Keith Nichols who said he doesn't even flinch an eye if E2 gets up in the 50 to 70 range, along with the rise in T.

 

[haidut]

If hypogonadism is secondary, then the elevated estrogen or increased aromatase is not completely the cause of low T. Endotoxins, elevated PUFAs, oxidative stress & inflammation, low thyroid, insulin resistance, etc., are also all major causes of low T. Using an aromatase inhibitor can help greatly lower E and increase T, but it would not be very good on its own at fixing the other conditions and can make them dependent on those substances. Just an additional thought to those that want to use only an AI + a few other prohormones.

Agreed, but then why would most cases of secondary hypogonadism respond to SERM then? Doesn't that suggest (relative) excess estrogen signalling is still the main cause?

 

[haidut]

Indeed the vast majority of patients come in with secondary hypogonadism rather than primary.

In the case where this secondary hypogonadism exhibits estrogen levels at least within two upward standard deviations from the mean range, it is of value to try an Exemestane-only treatment to see whether estrogen normalization induces T normalization.

But in most of my cases E2 comes back very close to mid range, with T below mid-range.
And in those cases, when Exemestane-only treatment is tried, there are complaints of low E2 symptoms (or what are believed to be commonly accepted as low E2 symptoms, I’ve read that Ray Peat thinks they are a direct consequence of the AI).

That’s why in most cases, a prophylactic dose of 100mg/week Test E is given as first line treatment.
I give the choice to my patients to switch to a compounded cream depending on how they feel and respond to that treatment.

60% end up staying on the injection, with a final dose of 200mg/week.
The rest goes for the cream applied twice daily.

I see higher test values with the injections, but the overall well being improvement is equivalent in both groups.

Given the cost of E1S blood work I usually go by sensitive E2 only, which seems to be accurate enough, at least judging by patients’ responses when we adjust treatment based on that value only.

Sorry I can’t give you more info on that E2 vs E1S diagnosis, you may know more than I do already :)

Thanks. All good points, and I certainly see the benefit of TRT, especially low dose like that.

 

[Hans]

Agreed, but then why would most cases of secondary hypogonadism respond to SERM then? Doesn't that suggest (relative) excess estrogen signalling is still the main cause?

Indeed, estrogen is a major cause of suppression, probably one of the biggest. Like you mentioned, aromatase, because of excess fat tissue, is a much greater cause of elevated estrogen and suppressed T than endotoxins.

https://www.physiology.org/doi/full/10.1152/ajpendo.00279.2017
"We recognize that the impact of chronic-low level inflammation on testosterone levels seen in our observational study was relatively minor, thereby suggesting that other mechanisms such the conversion of testosterone to estrogen by adipose tissue aromatase probably play a more dominant role in obesity related hypogonadism (9)."

I was just adding that endotoxins and PUFAs and other inflammatory promoting substances/compounds also increase the aromatase and promote estrogen and they also inhibit normal testicular function. But the increased estrogen is the greatest cause yes. Aspirin is a great example of something that inhibits the aromatase and lowers inflammation and can significantly increase T.