DHEA As A Cure For Cancer

[Wagner83]

I'm curious to hear @aguilaroja 's thoughts on dhea-s being a mere form of storage for dhea.

This was several years ago. Now he routinely recommends DHEA, but cautions it has to be in lower doses to prevent estrogen elevation. For many people even massive pregnenolone doses do not raise DHEA because of "naturally" elevated cortisol/estrogen with age, both of which block 17,20-lyase - the crucial enzyme for DHEA synthesis.
The comment on DHEA and Alzheimer needs to be followed up with him IMO. Many subsequent studies found lower DHEA levels in Alzheimer patients and animal models show protective effect.
Neuroprotective effects of dehydroepiandrosterone (DHEA) in rat model of Alzheimer's disease. - PubMed - NCBI
A Potential Blood Test for Alzheimer’s Disease
Testosterone and DHEA are Directly Involved in Alzheimer’s Disease | Journal of Alzheimer's Disease

Direct intervention trials found mild benefit, but definitely no deterioration as a result of DHEA.
DHEA for Alzheimer’s disease

Thanks for the links. Btw one of the side-links was made for you: Windows into estradiol effects in Alzheimer's disease therapy. - PubMed - NCBI

 

[haidut]

I'm curious to hear @aguilaroja 's thoughts on dhea-s being a mere form of storage for dhea.

Thanks for the links. Btw one of the side-links was made for you: Windows into estradiol effects in Alzheimer's disease therapy. - PubMed - NCBI

On an interesting side note, even Wikipedia now states that DHEA-S synthesis in young people is 10mg-15mg daily. So, the medical recommendations of 25mg-50mg DHEA being physiological are bunk.
Dehydroepiandrosterone sulfate - Wikipedia
"...DHEA and DHEA-S are produced in the zona reticularis of the adrenal cortex under the control of adrenocorticotropic hormone (ACTH).[1] DHEA is synthesized from cholesterol via the enzymescholesterol side-chain cleavage enzyme (CYP11A1; P450scc) and 17α-hydroxylase/17,20-lyase (CYP17A1), with pregnenolone and 17α-hydroxypregnenolone as intermediates.[13] Then, DHEA-S is formed by sulfation of DHEA at the C3β position via the sulfotransferase enzymes SULT2A1 and to a lesser extent SULT1E1.[13][14][15] Whereas DHEA is derived mostly from the adrenal cortex but is also secreted to a lesser extent by the gonads (10%),[16] DHEA-S is almost exclusively produced and secreted by the adrenal cortex, with 95 to 100% originating from the adrenal cortex in women.[1][17][18] Approximately 10 to 15 mg of DHEA-S is secreted by the adrenal cortex per day in young adults."

Steroid Hormones and the T-Cell Cytokine Profile

Btw, a small clarification. DHEA-S does have its own roles as a neurosteroid, mostly through the GABA receptor and some opioid receptors, as well as possibly ER-beta. But as far as its relationship with DHEA goes, I do think it is mainly the long term storage form.

 

[Mito]

The authors describe the almost perfectly negative correlation between DHEA levels and increase in cancer incidence in both humans and animals.

How do saliva (DHEA) and dried urine (DHEA-S) levels differ from blood (DHEA-S) levels? I’ve tested all three and the saliva and urine tests are consistently in the low end of the reference range, but blood levels are “normal” in the middle of the reference range (71.6-375.4 ug/dL). Have you measured your DHEA-S levels, and if so do you like to see them in the upper quarter of the reference range for yourself?

 

[lollipop]

How do saliva (DHEA) and dried urine (DHEA-S) levels differ from blood (DHEA-S) levels? I’ve tested all three and the saliva and urine tests are consistently in the low end of the reference range, but blood levels are “normal” in the middle of the reference range (71.6-375.4 ug/dL). Have you measured your DHEA-S levels, and if so do you like to see them in the upper quarter of the reference range for yourself?

Good question @Mito , I am curious as well @haidut about these measuring differences.

 

[haidut]

How do saliva (DHEA) and dried urine (DHEA-S) levels differ from blood (DHEA-S) levels? I’ve tested all three and the saliva and urine tests are consistently in the low end of the reference range, but blood levels are “normal” in the middle of the reference range (71.6-375.4 ug/dL). Have you measured your DHEA-S levels, and if so do you like to see them in the upper quarter of the reference range for yourself?

Blood levels are most reliable, as they show adrenal health and are inversely proportional to cortisol levels (except in possibly Cushing disease, which is rare). I try to keep mine in the top 25% range. Blood/urine mostly shows tissue utilization and turnover effectiveness.
@lisaferraro

 

[sladerunner69]

A fascinating study, which highlights once again not only the role of one of the "youth" steroids in human health but also demonstrates that the protective/therapeutic mechanisms of DHEA against cancer are due to increase in metabolism and ROS generation. The primary restrictive mechanism on ROS generation in humans is the enzyme glucose-6-phosphatase dehydrogenase.
Glucose-6-phosphate dehydrogenase - Wikipedia

Excess activity of this enzyme strongly dampens ROS levels, while excessive inhibition may lead to hemolytic anemia. Androgens are well-known inhibitors of the enzyme, and in higher doses are known to lead to hemolytic anemia. Other inhibitors include progesterone, long chain saturated fatty acids (SFA) and a redox state in favor of oxidation. Activators of G6PD include estrogen, hypoxia (HIF-1) and redox state in favor of reduction. It just so happens that DHEA is one of the most potent inhibitors and perhaps the primary endogenous inhibitor after puberty.
The authors describe the almost perfectly negative correlation between DHEA levels and increase in cancer incidence in both humans and animals. They also openly state that the current direction of efforts for cancer cure are likely dead-wrong, that cancer has little to do with mutations, and that DHEA may just be the simple, master "kill switch" for most cancers that keeps young/healthy people so resilient to this disease. A progesterone/DHEA or pregnenolone/DHEA combination likely potentiates the anti-cancer effects, considering the role of pregnenolone, progesterone and other androgens as G6PD inhibitors.


Detection of a novel, primate-specific ‘kill switch’ tumor suppression mechanism that may fundamentally control cancer risk in humans: an unexpected twist in the basic biology of TP53 : Endocrine-Related Cancer

"...The activation of TP53 is well known to exert tumor suppressive effects. We have detected a primate-specific adrenal androgen-mediated tumor suppression system in which circulating DHEAS is converted to DHEA specifically in cells in which TP53 has been inactivated. DHEA is an uncompetitive inhibitor of glucose-6-phosphate dehydrogenase (G6PD), an enzyme indispensable for maintaining reactive oxygen species within limits survivable by the cell. Uncompetitive inhibition is otherwise unknown in natural systems because it becomes irreversible in the presence of high concentrations of substrate and inhibitor. In addition to primate-specific circulating DHEAS, a unique, primate-specific sequence motif that disables an activating regulatory site in the glucose-6-phosphatase (G6PC) promoter was also required to enable function of this previously unrecognized tumor suppression system. In human somatic cells, loss of TP53 thus triggers activation of DHEAS transport proteins and steroid sulfatase, which converts circulating DHEAS into intracellular DHEA, and hexokinase which increases glucose-6-phosphate substrate concentration. The triggering of these enzymes in the TP53-affected cell combines with the primate-specific G6PC promoter sequence motif that enables G6P substrate accumulation, driving uncompetitive inhibition of G6PD to irreversibility and ROS-mediated cell death. By this catastrophic ‘kill switch’ mechanism, TP53 mutations are effectively prevented from initiating tumorigenesis in the somatic cells of humans, the primate with the highest peak levels of circulating DHEAS. TP53 mutations in human tumors therefore represent fossils of kill switch failure resulting from an age-related decline in circulating DHEAS, a potentially reversible artifact of hominid evolution."

"...The p53 gene was discovered almost 40 years ago (Kress et al. 1979, Lane & Crawford 1979, Linzer & Levine 1979), and its role as a major tumor suppressor was identified a decade later (Baker et al. 1989, Takahashi et al. 1989). The p53-knockout mouse model of human cancer has been a staple of cancer research for some 26 years (Donehower et al. 1992). The depth of infiltration of this model into the fabric of human cancer research is demonstrated by the fact that it has been accepted by the FDA as a preclinical model for human drug development for more than 20 years (FDA 1997). The use of this model system over this long period of time has created a paradigm in which mutations in p53 are considered to be linear initiators of carcinogenesis with virtually universal application independent of species, such that results in one species, e.g., the mouse, are thought to accurately translate to another, e.g., the human. Yet, new research in non-murine species (dog, elephant, naked mole rat, etc.) suggests that while p53 may be a universal sensor of mutagenic insult, many animals, including humans, adopt species-specific solutions to such insult and those species-specific solutions triggered by p53 inactivation appear frequently to converge mechanistically upon lethal inhibition of G6PD. These observations suggest that the focus of nature’s anti-cancer effort is the singularity. In this way, nature suppresses cancer at its most vulnerable point, at the level of the initial, potentially transformed cell, before it has initiated the explosion of diversification that has made clinical cancer incurable up to now. This appears to be how the elephant suppresses cancer throughout its long life, with its species-specific method to enhance its p53-mediated kill switch system. It also appears to be how chimpanzees and other great apes suppress cancer (McClure 1973, Hill et al. 2001, Brown et al. 2009), capitalizing upon primate-specific circulating DHEAS and G6PC promoter motifs, as well as the uncompetitive G6PD inhibition kinetics of DHEA. We believe that the species-specific DHEAS-mediated kill switch is fundamental to cancer suppression in humans."

"...Such data do not encourage a ‘stay the course’ approach to cancer research, but rather suggest that something is fundamentally wrong with the paradigms that have been guiding this endeavor for at least three decades. The unanticipated existence of an essentially human-specific adrenal androgen-mediated kill switch tumor suppression mechanism clearly undermines much of the research that has been performed ex vivo, in vivo and in vitro over this long period of time:"

"...The slow, very meager progress in prolonging cancer survival, the fact that such survival appears to be at an asymptotic boundary beyond which any further progress may be impossible, and the extreme, accelerating and clearly unsustainable costs of new cancer drugs that only minimally extend life (Sidduqui & Rajkumar 2012, Cohen 2017, Davis et al. 2017, Jackson & Nahata 2017, Prasad & Mailankody 2017, Carrera et al. 2018, Dranitsaris et al. 2018), all indicate the necessity for reappraisal of the current paradigm in which developed tumors are the target for virtually all of our anti-cancer research efforts. It may be time to redirect our labors and research expenditures toward understanding the singularity, the apparent focus of nature’s major effort at tumor suppression. If tumor complexity has been the Gordian knot of the cancer problem, preventing real progress in cancer treatment, then reactivating a kill switch made latent by an age-related decline in DHEAS may represent Alexander’s blade. The adrenal androgen-mediated kill switch tumor suppression system has the singularity as its target, and its evolutionary programming for a prehistoric, not a modern life span, may be responsible for the anomaly of an exponentially increasing rate of cancer with increasing age in our species. Singularities occurring in aging modern humans experience a diminishing capacity to undergo irreversible G6PD inhibition because of the dramatically declining levels of circulating DHEAS and consequent inability to trigger the kill switch mechanism. While this was not problematic for our ancestors who rarely reached the age of 30 years, it is problematic for modern humans who regularly live into and beyond their ninth decade. The life-long low, flat cancer risk observed in other long-lived animals that employ parallel, but life-long species-specific tumor suppression strategies, suggests that a similarly life-long low, flat cancer risk may be achievable in humans; that is, there appears to be no a priori reason, such as accumulated genomic damage, that makes an age-related increase in human cancer unavoidable. Rather, an approximately 4% lifetime cancer risk may be the norm for all species, including Homo sapiens. The lesson from other long-lived species appears to be that kill switch mechanisms that function throughout life extinguish almost all potentially tumorigenic damage at the level of the singularity. If pharmacological maintenance of DHEAS at peak levels establishes life-long functionality of the adrenal androgen-mediated kill switch, humans might join the majority of the animal kingdom in which death from cancer is a rare event and has little to do with advancing age. Determining what the true background risk of cancer is in the presence of such a fully functional, life-long adrenal androgen-mediated kill switch tumor suppression system should therefore be a primary goal of our species."

Very interesting study indeed. One major concern I would have in using DHEA to treat cancer would be t's tendency for estrogen conversion, that seems to happen to some people even on relatively tiny doses.

 

[lollipop]

Blood levels are most reliable, as they show adrenal health and are inversely proportional to cortisol levels (except in possibly Cushing disease, which is rare). I try to keep mine in the top 25% range. Blood/urine mostly shows tissue utilization and turnover effectiveness.
@lisaferraro

Thank you! Good to know. That way I won’t spend the $$ for dried urine...

 

[lollipop]

Very interesting study indeed. One major concern I would have in using DHEA to treat cancer would be t's tendency for estrogen conversion, that seems to happen to some people even on relatively tiny doses.

I read that this happens more in men than women. For pre menopausal, menopausal, and post menopausal women it supposedly tends towards the testosterone pathway.

 

[Sourdoughbanana]

It looks like DHT at low doses, a non suppressive mild aromatase inhibitor and opposing estrogen at the cellular level, could be a very good addition to DHEA. In males of course

 

[haidut]

It looks like DHT at low doses, a non suppressive mild aromatase inhibitor and opposing estrogen at the cellular level, could be a very good addition to DHEA. In males of course

Yes, and DHT/androsterone have a known synergy with DHEA, especially on immune system health which is key for cancer protection/treatment. The immune boost is probably due to estrogen opposition from the strong androgens.
Androsterone - Liquid Androsterone For Lab/R&D
Immune Decline (Not Genetics) Causes Cancer And It Can Be Easily Fixed
Reducing Estrogen Synthesis Regenerates Thymus Destroyed By Aging

 

[Mito]

Blood/urine mostly shows tissue utilization and turnover effectiveness.

Any idea what might influence tissue utilization and turnover (high or low) rates of DHEA? Would a high tissue utilization/turnover of DHEA correlate to lower blood levels DHEA-S?

 

[haidut]

Any idea what might influence tissue utilization and turnover (high or low) rates of DHEA? Would a high tissue utilization/turnover of DHEA correlate to lower blood levels DHEA-S?

Chronically low DHEA-S is usually a sign of high cortisol. Many things influence DHEA turnover especially infections, insulin sensitivity, trauma, age, metabolic rate, CVD, etc. There is no one single reason that would increase DHEA utilization. Ideally, you want DHEA-S to be in the upper 75% and DHEA to be in the bottom 25%. High DHEA and low-normal or low DHEA-S is usually a sign of excessive glucocorticoid signalling, and low both DHEA/DHEA-S is usually a sign of impending adrenal failure, very old age or clinical chronic disease.

 

[LeeLemonoil]

High Cortisol = low DHEA-S, that much is certain. So to achieve the anti-cancer activity in a fictive scenario applying the study discussed here, lowering cortisol/stress got to be a simultaneous strategy to supplementing DHEA.

Reading the paper all over again I notice that his theorem has not been replicated under lab conditions. Should be easy to take some early or pre-cancerous cells in vitro and check the proposed mechanism. I doubt someone will do it though, it threatens too many cancer research careers.

 

[LeeLemonoil]

Of note: the Author sells supps for dog cancer treatment that got him FDA attention and a lot of criticism. Maybe he’s just a quack, maybe he is onto something

 

[Wagner83]

On an interesting side note, even Wikipedia now states that DHEA-S synthesis in young people is 10mg-15mg daily. So, the medical recommendations of 25mg-50mg DHEA being physiological are bunk.
Dehydroepiandrosterone sulfate - Wikipedia
"...DHEA and DHEA-S are produced in the zona reticularis of the adrenal cortex under the control of adrenocorticotropic hormone (ACTH).[1] DHEA is synthesized from cholesterol via the enzymescholesterol side-chain cleavage enzyme (CYP11A1; P450scc) and 17α-hydroxylase/17,20-lyase (CYP17A1), with pregnenolone and 17α-hydroxypregnenolone as intermediates.[13] Then, DHEA-S is formed by sulfation of DHEA at the C3β position via the sulfotransferase enzymes SULT2A1 and to a lesser extent SULT1E1.[13][14][15] Whereas DHEA is derived mostly from the adrenal cortex but is also secreted to a lesser extent by the gonads (10%),[16] DHEA-S is almost exclusively produced and secreted by the adrenal cortex, with 95 to 100% originating from the adrenal cortex in women.[1][17][18] Approximately 10 to 15 mg of DHEA-S is secreted by the adrenal cortex per day in young adults."

Steroid Hormones and the T-Cell Cytokine Profile

Btw, a small clarification. DHEA-S does have its own roles as a neurosteroid, mostly through the GABA receptor and some opioid receptors, as well as possibly ER-beta. But as far as its relationship with DHEA goes, I do think it is mainly the long term storage form.

High Cortisol = low DHEA-S, that much is certain. So to achieve the anti-cancer activity in a fictive scenario applying the study discussed here, lowering cortisol/stress got to be a simultaneous strategy to supplementing DHEA.

Reading the paper all over again I notice that his theorem has not been replicated under lab conditions. Should be easy to take some early or pre-cancerous cells in vitro and check the proposed mechanism. I doubt someone will do it though, it threatens too many cancer research careers.

This reminded me of the following
exchange, this post and the following ones: Even Minor Stress Substantially Decreases DHEA-S Levels

 

[CLASH]

@haidut

In one of the linked threads you postulated that estrogen and testosterone via conversion to estrogen destroys the thymus while strong androgens are somewhat protective. If this study hasnt already been brought up I think it partly vindicates what your saying.

Effects of various steroids on the thymus, spleen, ventral prostate and seminal vesicles in old orchidectomized rats. - PubMed - NCBI

“After orchidectomy only, a multilobular thymus was present, and histologically the tissue appeared healthy. In testosterone- and oestradiol-treated rats, thymus weight was reduced to about 50% of that in untreated animals. Histologically, much of the thymus taken at autopsy was fat and what remained was poorly organized and contained a much lower density of thymocytes. The total white cell count was significantly reduced in these animals, the effect appearing to be predominantly on lymphocytes. Although treatment with DHT also resulted in a lower mean thymus weight than that of orchidectomized animals, histologically the tissue appeared similar to that of the untreated castrated animals. In rats treated with DHT, the total white cell count was significantly higher than in testosterone-implanted rats. Both progesterone and corticosterone implants resulted in significantly smaller mean thymus weights, although these steroids were not as potent as testosterone or oestradiol.”

 

[haidut]

@haidut

In one of the linked threads you postulated that estrogen and testosterone via conversion to estrogen destroys the thymus while strong androgens are somewhat protective. If this study hasnt already been brought up I think it partly vindicates what your saying.

Effects of various steroids on the thymus, spleen, ventral prostate and seminal vesicles in old orchidectomized rats. - PubMed - NCBI

“After orchidectomy only, a multilobular thymus was present, and histologically the tissue appeared healthy. In testosterone- and oestradiol-treated rats, thymus weight was reduced to about 50% of that in untreated animals. Histologically, much of the thymus taken at autopsy was fat and what remained was poorly organized and contained a much lower density of thymocytes. The total white cell count was significantly reduced in these animals, the effect appearing to be predominantly on lymphocytes. Although treatment with DHT also resulted in a lower mean thymus weight than that of orchidectomized animals, histologically the tissue appeared similar to that of the untreated castrated animals. In rats treated with DHT, the total white cell count was significantly higher than in testosterone-implanted rats. Both progesterone and corticosterone implants resulted in significantly smaller mean thymus weights, although these steroids were not as potent as testosterone or oestradiol.”

Amazing, thank you! I think this warrants a separate thread with this study and you can reference these threads below if you feel they are relevant.
Reducing Estrogen Synthesis Regenerates Thymus Destroyed By Aging
Immune Decline (Not Genetics) Causes Cancer And It Can Be Easily Fixed

 

[alywest]

Thanks Haidut for your explainations here.
I‘ve seen serum-measurements from people with either mental or other inflammatory diseases. DHEA-S was always lower than in controls while DHEA was higher than in healthy controls.
Could it be that the diseased organisms desulfatizate their DHEA-S reserves so that DHEA can perform its protective functions?
Theoretically, once the pathology subsides, DHEA would then be restored as its sulfate, that’s where supplementation of DHEA would come in helpful.
Still, I don’t think it can be excluded that DHEA-S on its own has important physiological functions in that it might interact differently with receptors/proteins/cells and membranes due to its different lipophilicity and charge than DHEA

Interesting website; pheromone sprays that use DHEA-S (and other hormones)
DHEAS - Pheromone & Social Influence Research Forum

 

[haidut]

I‘ve seen serum-measurements from people with either mental or other inflammatory diseases. DHEA-S was always lower than in controls while DHEA was higher than in healthy controls.
Could it be that the diseased organisms desulfatizate their DHEA-S reserves so that DHEA can perform its protective functions?

Yes, a few studies discussed that and I have seen it in practice - doctors testing DHEA (which is very short-lived) and finding it is normal or even above normal and telling the person they are perfectly fine. Then later they test DHEA-S and find it is very low. The good news is that since DHEA is the "active" form, as long as the DHEA is in the normal range then the person should still be protected. But when the layer of adrenals producing DHEA gets completely atrophied from cortisol and both DHEA and DHEA-S tank, the situation is pretty bad.
DHEA-S has its own role as a neurosteroid as I mentioned to @Wagner83 in an earlier post. But as far as DHEA is concerned, it is mostly a long-term storage. Same applies to estrone sulfate (ES), which is the estrogen reservoir (that almost nobody emasures) while estrone, estradiol and estriol are the "active" molecules synthesized from ES as needed. Pregnenolone and PS have the same relationship.

 

[aguilaroja]

...Dehydroepiandrosterone sulfate - Wikipedia
"... Whereas DHEA is derived mostly from the adrenal cortex but is also secreted to a lesser extent by the gonads (10%),[16] DHEA-S is almost exclusively produced and secreted by the adrenal cortex, with 95 to 100% originating from the adrenal cortex in women.[1][17][18]...
...DHEA-S does have its own roles as a neurosteroid, mostly through the GABA receptor and some opioid receptors, as well as possibly ER-beta.

For decades, "steroid" investigation has been dominated by glucocorticoid/cortisol considerations. This mirrors the commercial use of pharma glucocorticoids. Since cortisol and DHEAS are produced in the adrenal cortex, speculative ideas about DHEAS remain mixed in.

Prognostic Value of Dehydroepiandrosterone Sulfate for Patients With Cardiovascular Disease: A Systematic Review and Meta‐Analysis
"As both cortisol and DHEAS are synthesized within the adrenal cortex, and it is conceivable that their respective relative contributions to adrenal steroid output might define observed biological action. Furthermore, the cortisol to DHEAS ratio has been found to predict health outcomes better than the level of either hormone alone and in aging, Alzheimer's disease, metabolic syndrome, and all‐cause mortality (ACM). By far, the strongest associations with the metabolic syndrome were observed in the cortisol/DHEAS ratio by Phillips et al. As DHEAS and cortisol have opposing effects on the innate immune system, while DHEAS enhances, cortisol suppresses, and the molar ratio of cortisol to DHEAS also increases with age, so it may be an important marker of glucocorticoid function."

"Several studies have documented that DHEA and DHEAS might be implicated in a broad range of biological abnormalities including obesity, diabetes mellitus, osteoporosis, sexual dysfunction, cancer, and mental disorders, leading to speculation that a relative DHEAS deficiency may contribute to the development of common age‐related diseases or diminished longevity...."

"The mechanisms of the effect of DHEA and DHEAS on health outcomes remain unclear. Although DHEAS does not directly interact with the glucocorticoid receptor, research suggests that it may act as a functional antagonist to the effects of glucocorticoids....This counterbalancing action might explain the relationship between DHEAS level and health outcomes known to be affected by chronically elevated cortisol levels, such as heart disease, diabetes mellitus, and cognitive impairment... A direct role for DHEA in opposing atherosclerosis is suggested by its ability to facilitate fibrinolysis,...inhibit platelet aggregation, and retard cell proliferation.... Previous pathological research elucidated that the zona reticularis, which is responsible for DHEA production, is highly susceptibility to vascular damage....Given these findings, DHEAS might reflect underlying vascular disease manifesting as endocrine dysfunction.