2022-02-05

INTRACELLULAR (FUNCTIONAL) HYPOTHYROIDISM

Cardiomyocyte-specific inactivation of thyroid hormone in pathologic ventricular hypertrophy, by Christine J. Pol,Alice Muller, and Warner S. Simonides, was published in Nov. 2008.

It proves Deiodinase-3 activity in ventricular hypertrophy, causing heart failure, associated with severe impairment of cardiac T3 signaling.

If you have an interest in heart failure, especially cardiomyopathy, have a look at this paper (the abstract is not a difficult read and the article as a whole isn’t bad from the point of view of readability).

DHEA prevents cancer.

TP53 and DHEA

This note was inspired by a very well-written, easy-to-read, but very long and complicated dissertation on how DHEA prevents cancer, entitled “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”, by 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/   

DNA DAMAGE AND MALIGNANT TRANSFORMATION

Our cells are constantly exposed to a variety of cellular stressors and are prone to DNA damage, which can lead to mutation, formation of abnormal genes and eventually, cancer.
Therefore, to protect cells from malignant transformation, the cells’ nuclei carry a special gene called TP53.

TP53 activates other genes, “KILLER GENES”, which can arrest cell metabolism and kill the cell.
This is a natural process called apoptosis, which is good because cells with cancerous potential are destroyed.
However the cells only carry tiny quantities of TP53 and it exists in a dormant, inactive form.

When DNA is damaged, TP53 is induced to accumulate in the cell nucleus and is converted into an active form, which triggers the killer genes to induce cell cycle arrest and/or apoptosis, depending on how much DNA damage has occurred.

If the damage is mild, cell metabolic slowdown permits DNA repair, but if the situation is bad enough, TP53 triggers the killer genes to destroy the cell.
In this way dangerously damaged cells are prevented from cloning themselves and producing daughter cells with damaged DNA and cancer potential.
This idea is supported by the fact that TP53-deficient mice develop spontaneous cancers.

ssociated increase in human cancer risk to that of most other species (dashed red line).

MUTATON OF THE TP53 GENE, ITSELF.

The background point is that TP53 blockade by mutant TP53 depends on an enzyme, glucose-6-phosphate dehydrogenase (G6PD):
G6PD facilitates production of NADP and
NADP inactivates any normal TP53, keeping the abnormal cell alive.

HOW DOES DHEA PREVENT CANCER?

(1) Many years ago (BACK IN THE ’80S), DHEA, the “mother hormone” made by our adrenal glands and our brains, was observed to inhibit spontaneous breast cancer and chemically induced tumors of the lung and colon, in mice.
In mice, it also stopped tumour formation by a carcinogen named DMBA and another called TPA. In fact it was proved to be effective in stopping cancer formation generally, excepting that it promoted liver cancer in rats.
This action of DHEA remained a mystery for decades, but in 2018, Jonathan W Nyce reported a breakthrough: now we know that DHEA potently blocks G6PD, stopping NADP formation. Without NADP, TP53 is activated, and triggers the killer genes.

(2) 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 if a mutation produces “wild” cells, the TP53 gene shuts off G6PD and the developing cancer cell is killed by increasing reactive oxygen species.
However some cancer mutations prevent activation of the TP53 gene, so G6PD keeps the oxygen species low in the cancer cell, allowing it to grow and multiply.
DHEA prevents cancer by shutting off G6PD, thus allowing a lethal rise of oxygen species inside the cell which kills the cancer cell.
But our production of DHEA is reduced by 1% every year from the age of 26 and due to this, our protection from cancer-producing mutations gets lower as we get older!

(3) So supplementing DHEA prevents cancer, in most cases.

(4) DHEA may not be effective against all cancers and so what we are talking about here is using it to prevent cancer, not about a guaranteed cure for an existing tumour.

(5) Many of us fail to produce normal amounts of DHEA from the beginning, perhaps because of PTSD in childhood, so when DHEA production starts going down at age 26, high producers start from normal and low producers, from whatever they had in their teens. So by age 80, the highest DHEA producers are down to 10-20% of their original level and poor producers are down to zero.

(6) FAQ:
Do we get cancers because we don’t make enough DHEA?
If I take DHEA as a supplement, will it prevent cancer?
If I have a cancer, will DHEA stop it?
Why don’t all doctors know about this ?
Why is DHEA on the “dangerous drugs list” in Canada?

DHEA: NATURAL production levels in humans, vs. animals.
This graphic representation of DHEA levels in animals and humans was taken from the above referenced paper, by J.W. Nyce, at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106910/    – see the notes below.

The decline of DHEA production,Leading to an increase in cancer risk
Object name is erc-25-R497-g004.jpg

Figure 4, explanation (quotation from text by Dr. J. W. Nyce):
Species-specific kill switch tumor suppression systems targeting G6PD.

In humans, circulating DHEAS (blue and grey lines), and therefore, kill switch function is maintained at optimal levels only up until about age 25 years – the life expectancy for humans for most of our existence as a species. The adrenal androgen-mediated kill switch evolved to provide protection for such short human life spans (blue rectangular prism), and declines sharply thereafter.
Because modern humans live for much longer periods of time, the phenomenon of exponentially increasing cancer risk with increasing age is observed (red line). Species such as the elephant, moose and naked mole rat, which use tumor suppression systems that do not decline with age, experience little or no increased risk of cancer as they age (green line).
(http://www.cancerresearchuk.org/health-professional/cancer-statistics/incidence/age).
Human Lifetime cancer risk of 38.4% (https://www.cancer.gov/about-cancer/understanding/statistics).
Cancer risk of most long-lived mammals = 4%, from Abegglen et al. (2015). Circulating DHEAS levels redrawn after (dePeretti & Forest 1976, Parker & Odell 1980, Vermuelen 1980, Orentreich et al. 1984, Labrie et al. 1997).


Effect of DHEA supplementation, on liability to cancer: taken from Dr. Nyce’s paper, at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106910/   

Reducing cancer risk by maintaining DHEA levels.
Object name is erc-25-R497-g005.jpg

Figure 5
Potential for pharmacologic extension of adrenal androgen-mediated kill switch. Humans are protected by their natural adrenal androgen-mediated kill switch only until about age 30 (blue rectangular prism). Circulating DHEAS levels decline dramatically thereafter in both men and women (solid blue and grey lines, respectively), resulting in a species-specific exponential increase in cancer risk with increasing age (solid red line).
However, optimum DHEAS levels can be pharmacologically maintained (dashed blue and grey lines) throughout life into old age (green rectangular prism).
If the analogy holds with other long-lived species such as chimpanzees and elephants, in which kill switch mechanisms targeting G6PD are maintained throughout life, pharmacological maintenance of peak DHEAS levels throughout the modern human life span may normalize the age-adjusted cancer risk.

REFERENCES

(1) 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/

(2) 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, Jonathan W Nyce,
2018 Nov;25(11):R497-R517., oi: 10.1530/ERC-18-0241. Epub 2018 Jun 25.
PMID: 29941676, PMCID: PMC6106910, DOI: 10.1530/ERC-18-0241, https://pubmed.ncbi.nlm.nih.gov/29941676/

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Request for donations

Hi All,

I just found an Article in JAMA (the Journal of the American Medical Association), dated June 21, 2021, by WK Silverstein and D. Grady, entitled “Overuse of Levothyroxine in Patients With Subclinical Hypothyroidism: Time to “Leve”-Out-Thyroxine“.
The abstract (the summary) of this article reads as follows:
“Recent clinical trials and a meta-analysis demonstrate no symptomatic benefit from treatment with levothyroxine among nonpregnant adults with subclinical hypothyroidism ……. Contemporary evidence-based clinical practice guidelines strongly advise against levothyroxine (ELTROXIN or SYTHROID) supplementation for subclinical hypothyroidism …. (and) …. older guidelines from professional societies generally do not recommend treatment for subclinical hypothyroidism.”

This sort of information is very important to many of you, especially the people who are unhappy about being treated with Eltroxin or Synthroid and I would love to write a post about it.

So here’s the problem: JAMA, like many journals, especially those which belong to big online “libraries”, charges fees to allow access to articles. If I were working at a teaching hospital or a university, my institution would pay these fees, but I am not.

As a “standalone” researcher I could buy the article for US$40, or I could join an outfit called “DeepDyve” for US$499 per year.
That doesn’t sound like such a lot, but here, I am talking about one single article! If I am going to do that sort of thing, I would need to join four or five other libraries so as to access articles which I should read so as to give you the cogent information which I would like to provide.
Frankly, such sums are not available to me.

MESSAGE:
Funds donated to this website will be applied to cover the costs involved in acquisition of information you need.
So …… ?
With my thanks, in advance, and with my best wishes, for 2022 !
Gervais A. Harry.

LONG COVID DERMATITIS AND THE PRIMROSE

Here is one more anecdotal story.

In February of 2020, my wife went to London for a conference, returning on the 5th of March.
On the return trip she had a mild sore throat, which she reported to the border officer at the airport: she was advised that since she was feeling fine, there was no need for a covid-19 test.

On the news two days later we heard that Sophie Trudeau had returned from London with a covid-19 infection, the night before my wife’s flight.

We did not develop any respiratory symptoms and we decided not to worry about it, but five days later I developed classical “Covid toes”, involving my right foot and the inflammation, with swelling, burning, pain and tenderness, lasted about five days.

In June of 2020, I began to experience extraordinarily itchy, little spots, of different sizes, symmetrically positioned on my legs (right and left), then my back (at the tip of each scapula), then my arms (usually at the elbows, or over the triceps muscles).

I unsuccessfully searched the web for causes of dermatitis in an 80-year old and consulted with a family physician friend, then with a dermatologist, online: the consensus was that I had nummular neurodermatitis. 

Treatment with “Liderm”, a corticosteroid cream, stopped the itching about 20 minutes after application, but next day I would have another crop of itchy spots, always symmetrically placed, right and left.

The problem continued, getting very slowly better until it stopped in October of 2021.

I had my first Covid vaccinations (Pfizer) on 13th March, and my second in July, of 2021.
My booster was scheduled for 11th January 2022.

On the 7th of January 2022, I had a sniffly nose. The dermatitis began again and on 9th January my Covid toes recurred, milder this time. 
Neither the itch nor the inflammation of the toes is as severe as it was in March of 2020.
I have not redone the home Covid test because it is currently not easily available.

On the 11th of January, I went for the booster shot anyway.

I began applying Liderm to the itchy spots, but this time it did not work well, so my wife suggested taking primrose oil capsules, by mouth: I am taking one, twice per day.
The primrose oil stopped the itching in two days and I have no “spots”.

DISCUSSION: 

  • It is uncertain as to whether or not I had Covid in March 2020, and it is even less certain that I have got it again now, but the circumstantial evidence suggests that I did.
  • Although I am 82 years old, my hormone balance and vitamin levels are those of a 30 or 35 year-old and I take 5,000 iu of Vitamin D daily, which might explain the fact that I did not develop a severe covid infection in March, 2021, or Jan, 2922. 
  • Regardless of the answers to these questions, it is fair to say that primrose oil has relieved my itch within two days.

Primrose oil contains GLA (Linoleic Acid), an omega-6 essential fatty acid that has anti-inflammatory effects in the body, so it is not surprising that it has helped my dermatitis.

According to the “WEB MD” site, it is used for the nerve damage of Diabetes and for Osteoporosis.


NOW, IT’S YOUR BALL

So, come to your own conclusions, but I think that if you have dermatitis from long Covid, you should give primrose oil a try!

If you have further information, comments or objections to this post, please do send me a note.

REFERENCES

(1) Web MD:

https://www.webmd.com/vitamins/ai/ingredientmono-1006/evening-primrose-oil

(2) Evening primrose oil: Bryan Bayles 1 Richard Usatine: Am Fam Physician, 2009 Dec 15;80(12):1405-8. https://pubmed.ncbi.nlm.nih.gov/20000302/

(3) Review Article karger.com/Article/Fulltext/512932#

FUNCTIONAL MEDICINE

As I understand it, “functional medicine” includes:
1] EDUCATED PATIENTS: The high school curriculum includes hormonal, metabolic and microbiome health as a formal subject, so that all understand health maintainance.
2] HEALTH CARE PRACTITIONER: The healthcare professional is an MD, trained in the application of the principles of standard medicine and in the art of metabolic and hormonal maintenance. *

3] FIRST ASSESSMENT: Preferably, the first assessment should be at age 15; it can be done earlier if puberty begins before age 11 or if the child is obese, anorexic, depressed or subject to PTSD for any reason.
The patient’s physical, psychological, metabolic and hormonal status is assessed by history, physical examination and standard “checkup” tests, plus testing for neurosteroid hormone balance, microbiome status, adrenal function, vitamin D level, toxic load, thyroid function (including T3 and rT3, so as to exclude functional hypothyroidism) and other investigations as may seem necessary. **
4] INITIAL CARE: Investigation results are compared with those expected of a healthy, functionally euthyroid 15-25 year old of the same gender and the physician endeavours to correct such metabolic, or hormonal, deviations as may be discovered so as to maintain metabolic and hormonal health at youthful (age 15-25 years) levels ***.
5] HEALTH SURVEILLANCE: If all parameters are within normal limits, or when aberrations have been corrected, the assessment is repeated every five years.
Routine immunisations and “preventions” such as PAP smears, mammography, colon cancer tests, PSA etc. are provided according to accepted routine.
6] ONGOING CARE: Following each 5-yearly reassessment, deviation from normal hormonal, microbiome and metabolic balance is regarded as prodromal to illness and is managed proactively by supplementation of hormones, minerals, vitamins, antioxidants, probiotics etc, ad hoc.
7] INCIDENTAL ILLNESS: Illness presenting in spite of functional maintenance is investigated and treated as it currently is, without discontinuing supplementation.
8] ELDERCARE: At menopause or symptomatic andropause, hormone restoration tailored to the individual is provided as it is currently, utilising bioidentical preparations.

* Currently, functional, antiaging and hormone restoration medicine associations, mostly in the USA, offer training courses which culminate in formal examinations and granting of certificates of competence.
These organisations do accept non-medical candidates.
My certification acronym is ABAARM, from the American Academy for Aging and Metabolic Medicine, which is owned and operated by the TARSUS group.

** “Hormone balance tests”, done on both men and women, include DHEA, Testosterone, IGF-1 ****, Oestradiol, Progesterone, Thyroid function (TSH, T4, T3 and reverse T3), Cortisol and Allopregnanolone (when it becomes available).

*** 1] Normal hormone production rates are not a given: children subject to PTSD, severe illness, trauma or major surgery often fail to achieve normal rates in early adulthood and for example, 60-y-o DHEA levels can be found in many “20-somethings”.
2] At age 26 we all, both men and women, begin to reduce our neurosteroid hormone production, from whatever level we acheive at 25, by 1-2% per annum. Thyroid hormone, Growth hormone, Melatonin etc also decline.
3] Because of this “slide”, we should reassess all our “normal” test ranges, accepting only healthy, functionally euthyroid individuals between the ages of 20 and 25 years.
4] “Age-adjusted normal” is a misnomer: a better term would be “Age-related deficiency”.
**** 5] IGF-1 is a marker for human growth hormone (HGH), which promotes growth and maturation in youth and functions as an “anabolic” (muscle and organ maintenance) hormone throughout life.
As with most of the other hormones, HGH production falls as we age and HGH deficiency is one of the factors which lead to loss of muscle mass and progressive frailty as we age.
Please see my blog regarding HGH.

MESSAGE:
Keeping the internal millieu of the human body at youthful levels assists maintenance and repair processes, including apoptosis of new cancer cells, repair of brain tissue, optimisation of glucose and cholesterol management, fat control, (heart and skeletal) muscle maintenance, cognition and just about everything else.
Therefore hormone balance should be maintained via supplementation of deficient hormones or hormone precursors, along with vitamin and mineral balance, whether the individual remains healthy or develops some pathology, so as to ensure that the body’s repair tools are always available.






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