DHEA was first discovered as a urine metabolite in 1934 by Adolf Buteiiandt and Hans Dannenbaum from Germany. It was reaffirmed as a urinary metabolite in 1943 and isolated from serum in 1954. Basically, the actions of DHEA oppose those of cortisol, but in addition it is used as raw material for production of a long list of “neurosteroid” hormones.
Figure 1, Synthesis and metabolism of DHEA
DHEA, a lipophilic prohormone, is pluripotent.
In Humans, it is manufactured in the adrenal glands and the brain (the brain is the sole source of DHEA in lower animals) and to a lesser extent by the testes, ovaries and skin. (1)
The adrenal supply is delivered to the serum in its hydrophilic, sulfated form, “DHEAS”, which is not bound by SHBG. It is utilised internally by all cells of the body, after removal of the Sulfur moiety, to produce that mix of “downstream” hormones which is necessary for each particular cell.
Human DHEA output by the adrenals begins to fall, 1%-2% per annum, by age 26 (humans original life expectancy) and production reaches zero by age 80, at which point the brain is the only source of the prohormone (figure 1).
As the level drops to less than 6 µmol/Litre, we begin to see progressive deterioration of functions dependent on DHEA. (2, 2a).
Figure 2: This graphic explains the Human Lifetime cancer risk of 38.4% and compares it with the cancer risk of most long-lived mammals (= 4%,)….. For detail, regarding human cancer statistics, click here.
CAVEATS, re. Figure 2:
(1) Figure 2 implies a normal serum DHEAS maximum of 9.2 µmol/L in men and 2000 ng/mL (5.428 µmol/L) in women (9). This is different from my experience, in that the CML healthcare, the Laboratory I used in Toronto, quotes DHEAS in micromoles/L, with a maximum of 14.14 in males at age 40 and 11.04 in females at age 30.
(2) An excellent study, “Low Levels of Dehydroepiandrosterone Sulfate in Younger Burnout Patients”by Anna-Karin Lennartsson et al, showed that in chronically stressed individuals, there is a 25% reduction in serum DHEAS in the 3rd decade of life. (3)
(3) My experience is that most disease presents to the family doctor when the serum DHEAS falls below 6.0 µmol/L (2a). Therefore
(4) Dr. Nyce’s upper limits of normal seem low, although that fact does not affect the importance, nor the veracity, of his excellent graphic.
(5) The “endmemo” unit conversion website (9) provides a Ng/mL-to-NanoMole/L table, from which I have calculated as follows:
|DHEAS, nanograms/mL||DHEAS, nanomoles/L||DHEAS, micromoles/L|
|Conversion: multiply Ng/mL by 0.02714|
(6) Long-term-stressed individuals in the 3rd decade of life constitute a particular, important group, because a 25% lower serum DHEAS (10) translates into an enhanced liability to neoplastic disease, in contrast to the nonstressed population.
In these individuals, circulating DHEAS (blue and grey lines in figure 2), necessary for targeting G6PD, may never reach optimal levels.
Especially in the presence of overt or unrecognized childhood PTSD, the at-risk age may lie within the 2nd decade. However that situation may be masked, because such children tend to maintain their DHEA levels as a hedge against depression. (11)
When serum DHEAS attains optimal levels, maximum production is maintained only until age 25 years (the original life expectancy of humans). From age 25, production falls by 1% – 2%, each year in all humans, except in some females with polycystic ovaries (the Stein- Leventhal syndrome), many of whom overproduce it.
As human DHEA production progressively falls, there is an exponential rise in cancer risk with increasing age (Figure 2, red line).
However in species such as the elephant, moose and naked mole rat, which use tumor suppression systems that do not decline with age, (4) there is little or no increased risk of cancer with age (Figure 2, green line). (4)
(1) Extremely low levels of DHEA, permissive of organ malfunction, are pervasive in severe, critical illness. (5)
(2), As suggested with regard to long-term-stressed individuals(above), the age group 0–24 years has experienced the greatest increase in cancer risk since 1990.
(3) It would be interesting to find out whether DHEA levels in the 0–24 year group have been maintained, or fallen, since 1990,
I am indebted to Dr. Nyce for his superlative (2018) explanation of the anticancer effects of DHEA (6), which inspired me to write this paper and to Ozaki and Nakagawara, whose excellent (2011) article on p53 (7) was cited in Dr. Nyce’s paper.
DNA DAMAGE AND MALIGNANT TRANSFORMATION
Our cells are constantly exposed to a variety of cellular stressors and are prone to DNA damage, leading to mutation, with production of abnormal genes and eventually, cancer.
Therefore, to protect our cells from malignant transformation, the cells’ nuclei carry tiny quantities of a special gene, TP53, which exists in a dormant, inactive form.
When DNA is damaged or mutated, one, of three, scenarios may obtain:
(1) If the damage is mild and the TP53 gene is intact, the cell repairs itself.
(2) If the damage is severe enough, TP53 is “promoted”. It accumulates in the cell nucleus and converts to an active form. Active TP53 triggers rapid production of “ROS” (reactive oxygen species), which kill the cell.
This natural process, called apoptosis, ensures that cells with cancerous potential are destroyed before they can clone themselves and produce a cancer.
(3) If the mutation includes an abnormality of the TP53 gene itself, no ROS is produced, because mutant TP53 malfunction supports an enzyme, glucose-6-phosphate dehydrogenase (G6PD), which neutralises ROS and facilitates production of NADP.
NADP inactivates any existing normal TP53, allowing the abnormal cell to grow, clone itself and start a cancer. (7)
This idea has beenconfirmed by studying TP53-deficient mice, who develop spontaneous cancers.
HOW DOES DHEA PREVENT CANCER?
Many years ago, DHEA was observed to inhibit both spontaneous breast cancer and chemically induced tumors of the lung and colon, in mice.
It also stopped tumour formation when mice were given a cancer-promoting drug called DMBA, or one called TPA.
DHEA was generally effective in stopping cancer formation except in rats, in whom it promoted liver cancer (we don’t know why).
This anti-cancer action of DHEA remained a mystery for decades, but Dr. Nyce’s (2018) breakthrough proved that DHEA works by blocking glucose-6-phosphate dehydrogenase (G6PD), allowing a rapid rise in ROS and by stopping NADP formation.
To put it another way, under normal circumstances G6PD keeps reactive oxygen species low within normal cells: without G6PD, reactive oxygen species would kill them.
So when a cell goes “wild”, normal TP53 shuts off G6PD, ROS accumulates and the cell dies.
But when a mutation includes damage to the TP53 gene, G6PD function continues, keeping the ROS low and allowing the abnormal cell to grow, multiply and produce a cancer.
That’s where DHEA comes in: DHEA shuts off G6PD, allowing a lethal rise of reactive oxygen species inside the cell, which kills it.
THE HUMAN PROBLEM
Our DHEA production falls by 1% every year* from age 26. So as we age, there is less and less DHEA to prevent cancer.
Consequently, our protection from cancer-producing mutations falls as we age.
Therefore I, Dr. Nyce and other MDs of like mind surmise that supplementing DHEA should prevent cancer (review Fig 2, see Fig 4),
Figure 4, “the potential for pharmacologic extension of the DHEA kill switch”, is also from Dr. Nyce’s paper.
It shows that normally, Humans are protected by their adrenal DHEA-mediated “kill switch” up to age 30.
However I observed, in my 15-year experience of treating DHEA deficiency syndromes,
high-stress individuals are protected only as long as their circulating DHEAS exceeds 5.0 – 6.0 µmol/L, which is slightly less than 2000 ng/mL. (2a).
What Figure 2 does not show, is that some individuals’ serum concentration of DHEA is reduced to less than 6 µmol/L before age 25. (3)
In these people, who become DHEA-deficient earlier in life, the exponential increase in cancer risk depicted in figures 2 and 4 begins earlier and progresses more rapidly.
The bottom line is that we can elevate serum DHEAS Immediately upon diagnosis and we can maintain it at normal levels into old age (Figure 4: dashed blue and grey lines).
Doing so will, hopefully, reduce the age-adjusted cancer risk, hopefully holding it to 4%.
How much DHEA should one take, and when should one start taking it?
The dose of DHEA needs to be tailored to the individual. For females, 25 to 50 mg per day is sufficient to achieve a high-normal testosterone level while avoiding testosterone side effects such as facial hair, oily skin and acne.
For males, 50 to 75 mg per day is enough to improve self-confidence and muscle (including heart muscle) maintenance.
Some males do quite well with 100 – 150 mg of DHEA per day, but many develop gynecomastia when taking 100 mg or more:
Therefore, The recommended dosage is 50 mg, taken at 8 AM
DHEA CURES PROSTATE CANCER: ONE CASE
A small, quiet and unassuming, but intelligent gentleman with a good family history, born in 1947, was admitted to our clinic in January 2006, after his family doctor retired.
He attended fairly regularly, usually accompanied by his adult son, who translated to and from his native language.
He was semiretired, a drug-free non-smoker and an occasional user of alcohol.
He had a prior history of hypercholesterolemia and hypertension, for which he had been prescribed 40 mg of Simvastatin, Coversyl 2 mg and HCTZ, 25 mg daily: he took his medications faithfully and both conditions were in satisfactory control.
He had no other medical conditions and when first seen, had no symptoms.
His family history was excellent.
Routine investigation was entirely normal excepting for a blood sugar of 6.3, but his HbA1C was consistently normal and a glucose tolerance test done in November 2009, was normal.
PSA and hormone balance tests were not done in 2006.
- In November 2009, when he was 62 years old, a routine PSA was 3.56 (almost 4.0, the upper limit of normal).
His DHEA was 5.0, which was “Normal for age 65”, but low as compared with the normal serum level at age 25:
I considered it suspicious.
- He then complained of “LUTS” (Lower Urinary Tract Symptoms) and an ultrasound in January 2010 showed benign prostate enlargement, with incomplete emptying of the bladder and also, a 1 cm nodule in the right side of the prostate.
He was referred to an urologist, who diagnosed BPH, with a benign nodule, recommended against a needle biopsy and prescribed Flomax and Dutasteride.
- Despite Dutasteride, his PSA rose to 4.57 in January 2010 and 5.09 in August, 2011.
Because of this, the prostate ultrasound was repeated and a second nodule was found. He was referred for a biopsy.
- A transrectal prostate biopsy, done in December, 2011, produced eight specimens, of which one showed a small, but unequivocal, Gleason 6 Carcinoma of the Prostate.
Discussion with the patient.
I showed the biopsy report to this cooperative patient and his son.
I explained the demographic evidence for “watchful waiting” and the possibility that DHEA would either advance or retard the progress of his prostate cancer (we had previously discussed Neurosteroids, Steroidopenia and the role of DHEA in cancer prevention).
The patient and his son expressed an interest in a trial of treatment with DHEA and Pregnenolone, providing that it would be discontinued if there was a rapid rise in his PSA.
He stopped taking Flomax and Dutasteride and began DHEA, 150 mg and Pregnenolone, 50 mg on 19 January, 2012.
Figure 5. Case report: summary of observations, November 2009, to November 2022.
“PSA” = prostate specific antigen.
PSAr = free PSA/PSA ratio (normal = >0.25).
|Nov ’09||3.56||5.0||Ultrasound: BPH, 1 nodule|
|14 Jan ‘10||Flomax, Dutasteride||3.42||Urologist reported BPH, benign nodule|
|3 Mar ‘11||4.57||US: 1 nodule on the right|
|16 Mar ‘11||4.57|
|23 Jun ‘11||5.09|
|1 Sep ‘11||3.84||0.27||US: 2 nodules found|
|4 Dec ‘11||DHEA 150mg, preg. 50 mg||4.1||US with biopsy: Gleason 6 Ca|
|3 Feb ‘12||4.66||25.5|
|17 Feb ‘12||4.03||0.2|
|16 Mar ‘12||4.04||21.7|
|10 Apr ‘12||4.47||27.1|
|8 Jun ‘12||3.98||23.6|
|5 Jul ‘12||3.96|
|7 Aug ‘12||4.0|
|4 Dec ‘12||4.1||US: no nodule. No biopsy.|
|12 Dec ‘12||Urologist stopped DHEA|
|23 Dec ‘13||3.73|
|3 Jul ‘14||DHEA 100 mg, preg 50 mg||4.24||0.3||Biopsy: high-grade PIN|
|3 Jul ‘14||Plan: continue DHEA|
|12 Nov ‘14||DHEA,7KDHEA, Preg,50mg||3.73|
|4 Jan ‘15||5.25||17.2|
|3 Mar ‘15||4.86||0.2||DRE: 30 g BPH, no nodule|
|26 May ‘15||4.29||4.2|
|3 Jul ‘15||3.86|
|15 Sep ‘15||4.26||4.2|
|18 Dec ‘15||4.76||4.2|
|31 Oct ‘16||5.1|
|3 Jan ‘17||4.87|
|15 May ‘18||4.77|
|Aug ‘22||Prostate resection: no cancer.|
|Sept ‘22||Repeat resection: no cancer.|
In summary, this patient presented with a suspicious PSA result in 2009 and was proven to have a Gleason 6 cancer of the prostate. In November 2011.
He was treated with DHEA 50 mg and pregnenolone 50 mg until December, 2012, at which point his urologist discontinued DHEA on the grounds that it would accelerate the progress of his prostate cancer.
Despite discontinuation of DHEA, serial tests showed no further increase of his PSA, apart from slight increase to 5.25 and 5.47 in January 2015 and October 2016: both of these elevations were most likely due to prostatitis.
He was unable to urinate in July,2022 and prostate resection in August showed no evidence of prostate cancer.
Complications of the surgery led to repeat resection of the prostate, In September 2022 and again, no cancer was found in the prostate tissue which was removed.
I conclude: this man’s prostate cancer was cured by a one year course of DHEA.
(1) Sexual Hormones in Human Skin, Zouboulis CC et al. Horm Metab Res 2007; 39: 85–95 Horm Metab Res 2007; DOI 10.1055/s-2007-961807 https://d-nb.info/1179576837/34
(2) Review of Age-Related Dehydroepiandrosterone Decline and Its Association with Well-Known Geriatric Syndromes: Is Treatment Beneficial?, Nikolaos Samaras,1,2 Dimitrios Samaras,2,3 Emilia Frangos,4 Alexandre Forster,1 and Jacques Philippe5 Rejuvenation Res. 2013 Aug; (4) Role of p53 in Cell Death and Human Cancers: Toshinori Ozaki1 and Akira Nakagawara , Cancers (Basel). 2011 Mar; 3(1): 994–1013.Published online 2011 Mar 3. doi: 10.3390/cancers3010994, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756401/
(2a) Personal series of 600+ individuals: to be reported.
(3) Low Levels of Dehydroepiandrosterone Sulfate in Younger Burnout Patients
Anna-Karin Lennartsson, 1 , 2 ,* Töres Theorell, 3 Mark M. Kushnir, 4 and Ingibjörg H. Jonsdottir, Onno C Meijer, Editor PLoS One. 2015; 10(10): e0140054. Published online 2015 Oct 6. doi: 10.1371/journal.pone.0140054 PMCID: PMC4595129, PMID: 26441131
(4) Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans, Lisa M Abegglen 1 , Aleah F Caulin 2 , Ashley Chan 1 , Kristy Lee 1 , Rosann Robinson 1 , Michael S Campbell 3 , Wendy K Kiso 4 , Dennis L Schmitt 4 , Peter J Waddell 5 , Srividya Bhaskara 6 , Shane T Jensen 7 , Carlo C Maley 8 , Joshua D Schiffman JAMA 2015 Nov 3;314(17):1850-60, doi: 10.1001/jama.2015.13134. https://pubmed.ncbi.nlm.nih.gov/26447779/
(5) Decreased levels of dehydroepiandrosterone sulphate in severe critical illness: a sign of exhausted adrenal reserve? Albertus Beishuizen,1 Lambertus G Thijs,2 and István Vermes3 Crit Care. 2002; 6(5): 434–438.
Published online 2002 Jul 9. doi: 10.1186/cc1530 , PMCID: PMC130144, PMID: 12398784, Crit Care. 2002; 6(5): 434–438.
(6) 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 TP 53, Jonathan W Nyce, In: Endocr Relat Cancer. 2018 Nov; 25(11): R497–R517., Published online 2018 Jun 25. Doi: 10.1530/ERC-18-0241, PMCID: PMC6106910, PMID: 29941676 , at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106910/,
(7) Role of p53 in Cell Death and Human Cancers: Toshinori Ozaki1 and Akira Nakagawara , Cancers (Basel). 2011 Mar; 3(1): 994–1013. Published online 2011 Mar 3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756401/
(8) Dehydroepiandrosterone sulfate (DHEA-S) ng/mL ↔ nmol/L Conversion Table
(9) Clinical correlates of DHEA associated with post-traumatic stress disorder, R Yehuda 1 , S R Brand, J A Golier, R-K Yang, Acta Psych. Scand, 2006 Sep;114(3):187-93. doi: 10.1111/j.1600-0447.2006.00801. PMID: 16889589, DOI: 10.1111/j.1600-0447.2006.00801.x https://pubmed.ncbi.nlm.nih.gov/16889589/
(10) Cortisol and DHEA in development and psychopathology, Hayley S.Kamin, Darlene A.Kertes, Hormones and Behavior, Vol 89, Mar2017, P69-85, https://doi.org/10.1016/j.yhbeh.2016.11.018, https://www.sciencedirect.com/science/article/abs/pii/S0018506X1630215X
(11) Influence of DHEA administration on 24-hour cortisol concentrations , by Patricia D Kroboth, Janet A Amico, Roslyn A Stone, Maggie Folan, Reginald F Frye, Frank J Kroboth, Kristin L Bigos, Tanya J Fabian, Ana M Linares, Bruce G Pollock, Charles Hakala, J.Clin.Psychopharmacol,2003Feb;23(1):96-9,PMID:12544381,DOI:10.1097/00004714-200302000-00014
(12) Double-blind treatment of major depression with dehydroepiandrosterone, by Wolkowitz OM, Reus VI, Keebler A, Nelson N, Friedland M, Brizendine L, Roberts E, in Am J Psychiatry. 1999;156:646-9. https://pubmed.ncbi.nlm.nih.gov/10200751/
(13) Testosterone therapy in men with prostate cancer, Alan L Kaplan 1 , Jim C Hu 2 , Abraham Morgentaler 3 , :John P Mulhall 4 , Claude C Schulman 5 , Francesco Montorsi, Eur Urol. 2016 May; 69 (5): 894–903. DOI: 10. 1016/J.eururo.2015. Epub 2015 Dec 21. PM ID: 26719015, PMC ID PMC 5000551 . DOI: 10. 1016/J.eururo. 2015. 12. 005.
(14) Species-specific mechanisms of tumor suppression are fundamental drivers of vertebrate speciation: critical implications for the ‘war on cancer’.
Nyce JW. Endocr Relat Cancer. 2019 Feb;26(2):C1-C5. doi: 10.1530/ERC-18-0468. PMID: 30400061 Free PMC article.
(15) A lex naturalis delineates components of a human-specific, adrenal androgen-dependent, p53-mediated ‘kill switch’ tumor suppression mechanism.
Nyce JW. Endocr Relat Cancer. 2020 Feb;27(2):R51-R65. doi: 10.1530/ERC-19-0382. PMID: 31815681 Free PMC article.
(16) In Vivo and In Vitro Evidences of Dehydroepiandrosterone Protective Role on the Cardiovascular System, Int J Endocrinol Metab. 2015 Apr; 13(2): e24660, by Tiphaine Mannic,1,2,* Joanna Viguie,3 and Michel Florian Rossier1,4, Published online 2015 Apr 30. doi: 10.5812/ijem.24660, PMCID: PMC4389253, PMID: 25926854, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389253/
(17) Dehydroepiandrosterone sulfate (DHEAS) secretion in early and advanced solid neoplasms: selective deficiency in metastatic disease, by P Lissoni 1 , F Rovelli, L Giani, M Mandala, S Meregalli, S Barni, G Confalonieri, A Bonfanti, in Int J Biol Markers, . Jul-Sep 1998;13(3):154-7, PMID: 10079390, https://pubmed.ncbi.nlm.nih.gov/10079390/
(18) Cancer prevention with DHEA: has the day arrived ? https://cbhrt.ca/2022/01/24/dhea-and-cancer-prevention/