DHEA As A Cure For Cancer

[haidut]

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.

Thanks. I think there is a reluctance of large institutions to study DHEA both due to its lack of profitability as well as avoiding indirectly creating bad publicity for the synthetic glucocorticoids. After all, if DHEA opposes cortisol and high corticol begins to be seen as bad by the general public a lot of patients will refuse therapy with presnisone, dexamethasone, etc. Allopregnanolone was also largely avoided in research circles until synthetic derivatives like Ganaxolone came around and now it is all the rage for depression. Maybe we have to wait for a synthetic/patented DHEA analog to appear and then we may see a boom in DHEA research.

 

[managing]

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."

The symptoms of hemolytic anemia are essentially what many report from supplemnenting DHEA, ie, shortness of breath. You state "Androgens are well-known inhibitors of the enzyme, and in higher doses are known to lead to hemolytic anemia. "

Although many get these symptoms from even small doses (1-2 mg of DHEA), could this be what is going on? Perhaps "low" doses are sufficient when the body is adapted to "low" levels to begin with? But then, might you expect, over time, for G6PD to recover from the downregulation? What other factors might help resist this downregulation (from going too far)? I think it is not as bad with Magnesium supplementation, for example. What else might help?

 

[haidut]

The symptoms of hemolytic anemia are essentially what many report from supplemnenting DHEA, ie, shortness of breath. You state "Androgens are well-known inhibitors of the enzyme, and in higher doses are known to lead to hemolytic anemia. "

Although many get these symptoms from even small doses (1-2 mg of DHEA), could this be what is going on? Perhaps "low" doses are sufficient when the body is adapted to "low" levels to begin with? But then, might you expect, over time, for G6PD to recover from the downregulation? What other factors might help resist this downregulation (from going too far)? I think it is not as bad with Magnesium supplementation, for example. What else might help?

Estrogen is well-known to suppress hemoglobin levels, and DHEA may raise estrogen even more in hypo people. So, in a situation of low hemoglobin increasing RBC hemolysis could exacerbate the hypoxia. I don't know if it happens at low DHEA doses though. Also, progesterone protects from the hemolysis, which is another reason to combine DHEA with either progesterone or pregnenolone. Funny enough, the study below found that DHEA itself protects against hemolysis but this did not take into account the metabolism of DHEA into downstream androgens that increase hemolysis.
https://www.journal-of-hepatology.eu/article/S0168-8278(14)00008-7/pdf

 

[Lucas]

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.

I am a proof of it. My Dhea is above range and Dhea-S low, don’t know if my cortisol is high or normal. I have hypothyroidism and thyroid medication don’t work for me. Maybe my problem is stress, not the thyroid. When I take a 5 mg oral Dhea I fell relaxed and sleepy.

Serum 8 am cortisol: 20,8 ug/dl Ref: 5,3 – 22,5

DHEA-S sérum: 186,4 ug/dl Ref: 34,5 – 568,9

DHEA: 14,5 ng/ml Ref: 3 - 11

 

[haidut]

I am a proof of it. My Dhea is above range and Dhea-S low, don’t know if my cortisol is high or normal. I have hypothyroidism and thyroid medication don’t work for me. Maybe my problem is stress, not the thyroid. When I take a 5 mg oral Dhea I fell relaxed and sleepy.

Serum 8 am cortisol: 20,8 ug/dl Ref: 5,3 – 22,5

DHEA-S sérum: 186,4 ug/dl Ref: 34,5 – 568,9

DHEA: 14,5 ng/ml Ref: 3 - 11

I would ask the doctor to test PM cortisol. I would not be surprised if yours is high in the afternoon as the normal range for PM cortisol is different (lower) and if you cortisol stays at these levels throughout the day it will probably be above range in the PM. That would explain the relaxation from DHEA.
Stress is always the cardinal problem, hypothyroidism is usually just a sign/symptom of it. That's what Selye spent his entire career trying to convince the world of but most people either laughed or told him "stop with your nonsense or you'll get all of us fired. medicine is not about truth but money/employment".

 

[Lucas]

Thanks’ Haidut!

I will test the 4 pm cortisol and update the result. My TSH is around 5, but I don’t have Hashimoto and my ultrasound is fine, my Thyroid is perfect. I don’t have the thyroid phenotype, I am a lean male, less than 31 inches waist whit 5’9’’ height but had a fat face whit sagging jowls, nasolabial folds and dark circles under eyes. It looks like a cortisol dysregulation. I wake up tired, have joint pain but always feels better after 6 pm.

If tests confirm that I had high cortisol, I will take dhea whit pregnenolone and stop thyroid medication.

 

[jitsmonkey]

That's what Selye spent his entire career trying to convince the world of but most people either laughed or told him "stop with your nonsense or you'll get all of us fired. medicine is not about truth but money/employment".

Every person who visits this forum should be required to read this.
So many things become confusing, contradictory, etc when you fail to see and ask through this lens.
Hans = Triple OG

 

[CLASH]

@haidut
What exactly was Hans trying to get everyone to see (I ask not to challenge, I ask because I want to know)?

 

[jitsmonkey]

@haidut
What exactly was Hans trying to get everyone to see (I ask not to challenge, I ask because I want to know)?

free download from THE man himself
Stress in Health and Disease | Hans Selye (Auth.) | download

 

[jitsmonkey]

free bonus without purchase
Hormones and Resistance: Part 1 and Part 2 | Professor Hans Selye C. C., M. D., Ph. D., D.Sc., D. Sc(hon.), M.D.(hon.), F.R.S.(C), F.I.C.S.(hon.) (auth.) | download

 

[lollipop]

Thank you dearly @jitsmonkey for these links. Crazy cool.

 

[aguilaroja]

...Stress is always the cardinal problem, hypothyroidism is usually just a sign/symptom of it. That's what Selye spent his entire career trying to convince the world of but most people either laughed or told him "stop with your nonsense...

free download from THE man himself
Stress in Health and Disease | ...

Selye is largely remembered through his popular books "Stress of Life" and "Stress without Distress". Rapidly his general ideas about biological stress morphed into psychological memes about stress only as worry and high pressure in daily events.

In first studying Dr. Peat's ideas about biological stress and metabolism, I looked through many journal articles by Selye. The richness of Selye's ideas came through in his journal articles, more than his popular books, and also his technical books. Due to limited digital resources then, I do not have a summary. I don't know science historians who have extensively reviewed the Selye work. Maybe it's out there.

 

[jitsmonkey]

Selye is largely remembered through his popular books "Stress of Life" and "Stress without Distress". Rapidly his general ideas about biological stress morphed into psychological memes about stress only as worry and high pressure in daily events.

In first studying Dr. Peat's ideas about biological stress and metabolism, I looked through many journal articles by Selye. The richness of Selye's ideas came through in his journal articles, more than his popular books, and also his technical books. Due to limited digital resources then, I do not have a summary. I don't know science historians who have extensively reviewed the Selye work. Maybe it's out there.

I agree 100% that's why I posted these two technical texts instead of his paperbacks sold on amazon or other typical booksellers.
for contrast "Stress in Health & Disease" is a collegiate text that sells DIGITALLY on amazon for 70 bucks (the hardcover is 200). Compared to his mass market paperbacks at 12.

 

[Andman]

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

this is kinda off topic, but i found the link you posted interesting:

A recent Harvard study

examined the relationship between social rejection, biological vulnerability, and creativity.:
Historical and empirical data have linked artistic creativity to depression and other affective disorders. This study examined how vulnerability to experiencing negative affect, measured with biological products, and intense negative emotions influenced artistic creativity. The authors assessed participants' baseline levels of an adrenal steroid (dehydroepiandrosterone-sulfate, or DHEAS), previously linked to depression, as a measure of affective vulnerability. They then manipulated emotional responses by randomly assigning participants to receive social rejection or social approval or to a nonsocial situation. Participants then completed artistic collages, which were later evaluated by artists. Results confirmed a person-by-situation interaction. Social rejection was associated with greater artistic creativity; however, the interaction between affective vulnerability (lower baseline DHEAS) and condition was significant, suggesting that situational triggers of negative affect were especially influential among those lower in DHEAS, which resulted in the most creative products. These data provide evidence of possible biological and social pathways to artistic creativity.

The implication of DHEAS as an insulating factor against social rejection is remarkably consistent with the pheromone effects which have been reported by early testers

this is pretty cool, although the quality of art is highly subjective of course, i myself have noticed a big difference in music, film, literature taste since peating.

 

[CLASH]

Very much appreciated @jitsmonkey
Like free gold...

 

[haidut]

@haidut
What exactly was Hans trying to get everyone to see (I ask not to challenge, I ask because I want to know)?

That the organism cannot be separated from its environment, that biological stress is the primary cause of negative health effect, that named diseases are usually simply manifestations of the failure of the organism to adapt to stressful conditions due to low production of energy (aka "the adaptation syndrome"), that questions of health are inevitably always questions about environmental quality and the various stressors it contains, and so on and so on. He was not the first one, as systematic studies of this go back to at least the 1800s, and individually it has been recognized by various people across the ages but has deliberately been put down as it can undermine the powers that be.
Cholesterol, longevity, intelligence, and health.
"...But those harmful factors all had their defenders: Who defends socioeconomic stress? All of the social institutions that fail to alleviate it. In 1847, Rudolph Virchow was sent to Poland to study the health situation there, and when he returned, the highly regarded anatomist, physiologist and pathologist announced that the Poles wouldn't have a health problem if the government would stop oppressing them, and institute economic reforms to alleviate their poverty. The reforms weren't made, and Virchow lost his job. Other harmful factors, such as seed oils, degraded foods, and radiation, have specific, very well organized and powerful lobbies to defend them. "

 

[managing]

Estrogen is well-known to suppress hemoglobin levels, and DHEA may raise estrogen even more in hypo people. So, in a situation of low hemoglobin increasing RBC hemolysis could exacerbate the hypoxia. I don't know if it happens at low DHEA doses though. Also, progesterone protects from the hemolysis, which is another reason to combine DHEA with either progesterone or pregnenolone. Funny enough, the study below found that DHEA itself protects against hemolysis but this did not take into account the metabolism of DHEA into downstream androgens that increase hemolysis.
https://www.journal-of-hepatology.eu/article/S0168-8278(14)00008-7/pdf

What would you consider low hemoglobin?

As you may recall, I experience this with DHEA supplementation . Oral or transdermal. Whenever I donate blood, my hemoglobin is usually on the low end of what they will take. 12.5 to 13.5 always. I also get this if I supplement DHEA and pregnenolone together. Have never tried it w/ progesterone. Also always constipates me, and makes my liver glycogen deplete faster. Otherwise, constipation is never a problem, and liver glycogen, while not ideal, is adequate to go 6 hours between meals.

Are there proactive ways to raise hemoglobin proactively for some time before taking dhea?

 

[alywest]

What would you consider low hemoglobin?

As you may recall, I experience this with DHEA supplementation . Oral or transdermal. Whenever I donate blood, my hemoglobin is usually on the low end of what they will take. 12.5 to 13.5 always. I also get this if I supplement DHEA and pregnenolone together. Have never tried it w/ progesterone. Also always constipates me, and makes my liver glycogen deplete faster. Otherwise, constipation is never a problem, and liver glycogen, while not ideal, is adequate to go 6 hours between meals.

Are there proactive ways to raise hemoglobin proactively for some time before taking dhea?

You could try 7-keto dhea which doesn't increase testosterone or estrogen levels. Actually in a study with males using 25 mg topically, testosterone and estrogen went down over time but there is no evidence that it happens when you take it orally.
Edit:
This study shows some of the results of oral supplementation:
https://www.sciencedirect.com/science/article/pii/S0011393X00800260
Of the 30 subjects who entered the study, 23 completed the 8-week protocol. Seven subjects dropped out for personal reasons unrelated to the study. Group 1 lost a significant amount of body weight compared with Group 2 (−2.88 kg vs −0.97 kg; P = 0.01) over the 8 weeks. Group 1 also achieved a significant reduction in body fat compared with Group 2 (−1.8% vs −0.57%; P = 0.02). The rate of change in body fat per 4-week interval in Group 1 was 3.1 times that in Group 2 (−0.88% vs −0.28%; P < 0.01). Group 1 also experienced a significant increase in triiodothyronine (T3) levels compared with Group 2 over the 8-week study period (+17.88 ng/dL vs 2.75 ng/dL; P = 0.04). There were no significant changes in levels of thyroid-stimulating hormone (TSH) or thyroxine (T4) in either group. In addition, no significant changes were observed in vital signs, blood sugar, testosterone and estradiol levels, liver and renal function, or overall caloric intake during the study. No subjective adverse effects were reported throughout the study.

Conclusions
The results of the study suggest that 7-oxo-DHEA combined with moderate exercise and a reduced-calorie diet significantly reduces body weight and body fat compared with exercise and a reduced-calorie diet alone. In addition, 7-oxo-DHEA significantly elevated T3 levels but did not affect TSH or T4 levels, indicating that it does not adversely affect thyroid function in the short term.

 

[alywest]

this is kinda off topic, but i found the link you posted interesting:

Haha, yes, it is a bit off topic, however some others were discussing the unavailability of DHEA in its sulfated form, and this seems to be the only way to obtain it (in pheromone sprays lol)

this is pretty cool, although the quality of art is highly subjective of course, i myself have noticed a big difference in music, film, literature taste since peating.

This is fascinating. So low DHEA-S results in higher levels of artistic creativity, but mainly because one is less insulated against social rejection when low in DHEA-S? Interesting...

 

[Motorneuron]

If a person is deficient in G6PD what is the recommended action?