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haidut

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I am posting about this study not because I am thrilled at the possibility of society now having oral (non-steroid) contraceptive methods for males, but rather because this study highlights that vitamin A is actually required for male fertility. Even minor interference with so-called retinoic acid receptor alpha (RAR-a) causes fertility problems and fully blocking that receptor invariably renders all subjects fully infertile. That receptor is activated by all-trans-retinoic acid - i.e. the "active" form of vitamin A synthesized from retinol and its various dietary/supplement precursors such as retinyl palmitate and retinyl acetate. The study managed to achieve full infertility in 99% of the study subjects (animals) by administering an RAR-a antagonist. The study also claims the effects were reversible after a few months of not using the RAR-a antagonist, but I have serious doubts about that claim. Why? Well, one reason is that vitamin A deficiency has been shown in many animal studies to often cause irreversible sterility if maintained for a sufficiently long period of time. The study itself readily acknowledges that fact while also explicitly stating that the RAR-a antagonist was initially abandoned by the pharma company that discovered it, since it was confirmed it acted as a "testicular toxin". Also, considering vitamin A is a required factor for steroidogenesis, and not just spermatogenesis, interfering with the RAR-a receptor may lead to hypogonadism severe enough to cause testicular atrophy, which is rarely reversible. Finally, since vitamin A and RAR-a activation are required for proper vision, this study may end up unleashing on the world a "solution" that causes terrible health problems in males on a global scale. Hhhm, if I was an evil person, dedicated to the cause of depopulation, I would probably think this drug is a "gift" from the gods. I wonder who funded those studies...Yes, that right, CONRAD - funded by Bill Gates and many other "elites" with an openly stated depopulation agenda. @Drareg

So, all in all, this study below should serve as a serious warning to the crowd out there arguing that supplementing with ANY amount of vitamin A is "toxic" and that apparently many health problems can be "cured" by simply restricting vitamin A in take to the point of deficiency.
Considering fertility is one of the primary biomarkers of good systemic health in males (and in females too), I fail to see how degrading it by reducing the activation of RAR-a (through vitamin A intake restriction) is in any way healthy. Perhaps the multitude of studies demonstrating virtually guaranteed cancer (usually hematological) development in organisms deficient in vitamin A would be even more convincing...if the vitamin A detractors can even be bothered reading them.

Oral Administration of a Retinoic Acid Receptor Antagonist Reversibly Inhibits Spermatogenesis in Mice
Could a birth control pill for men be on the horizon? Retinoic acid receptor antagonist interferes with sperm production

"...Scientists have known for almost 100 years that depriving an animal of dietary vitamin A causes male sterility. While investigating targeted loss of function of the gene encoding one of the RARs, RARalpha, which results in male infertility, senior author Debra J. Wolgemuth, Ph.D., ran across a paper by Bristol-Myers Squibb on a compound that was being tested for the treatment of skin and inflammatory diseases. The compound seemed to cause changes in the testis similar to the mutation that she and Dr. Chung were studying in Dr. Wolgemuth's lab. (Dr. Wolgemuth is professor of genetics and development and of obstetrics and gynecology; and Dr. Chung is an associate research scientist, both at Columbia University Medical Center). Bristol-Myers dropped its interest when it found that the compound also was ¬- in the company's words -- "a testicular toxin." The paper did not elaborate on how the drug caused infertility, so Dr. Wolgemuth and her team tested the drug in mice to find out; they noted that the changes it caused were similar to what one sees with vitamin A-deficiency and loss of function of RARalpha. "We were intrigued," said Dr. Wolgemuth. "One company's toxin may be another person's contraceptive." To investigate whether the compound prevented conception at even lower levels than those cited in the company's study, Dr. Wolgemuth and her team placed the treated male mice with females and found that reversible male sterility occurred with doses as low as 1.0mg/kg of body weight for a 4-week dosing period. One advantage of using a non-steroidal approach, the researchers say, is avoiding the side effects commonly associated with steroidal hormone-based methods."

"...This study was supported in part by grants initially from CONRAD and subsequently from the NIH, NICHD."
 

youngsinatra

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I think that vitamin A deficiency is actually pretty hard to achieve. IIRC it took Grant Generoux almost 3-4 years to achieve near-deficient levels of serum vitamin A while eating almost no vitamin A at all.
 

Peatness

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This is a quote from Dr Peat about vitamin A in response to a question by Pulstar - "an overdose of vitamin A can create symptoms of a vitamin A deficiency"

Ray:
Since the symptoms can be produced by activation of the pro-inflammatory angiotension system, and an overdose of vitamin A can create symptoms of a vitamin A deficiency (vitamin A normally works with vitamin D to inhibit that system), I think it might help to supplement some vitamin D (about 5000 IU unless you get good sun exposure), vitamin A (about 10,000 IU), with some vitamin E (20 to 50 IU), thyroid hormone (according to temperature and pulse rate), and a good ratio of calcium to phosphate in the diet. An angiotensin blocker such as candesartan might help with joint pain and depression.


Are you able to elaborate on this @haidut please?
 
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Peatness

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That matches my experience after months of experimenting with liver and eggs.
Yet in that quote peat suggests more Vitamin A
 

Nebula

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That matches my experience after months of experimenting with liver and eggs.
Why does this happen? Does an overdose of preformed retinol damage some transport mechanism? What do those who thrive on high amounts of vitamin A have in common? My hunch is that the zinc deficient in particular don’t have enough retinol transport proteins to process any more then very small amounts of vitamin A, so it accumulates and oxidizes long before it can be utilized.
 

Zsazsa

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Why does this happen? Does an overdose of preformed retinol damage some transport mechanism?

Enzyme inhibition by its substrate in excess, substrate inhibition, is one of the common deviations from Michaelis–Menten kinetics
 

Zsazsa

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I thought RISUG was the latest news in male contraceptives

ETA
Sorry, I just found fresh news about actually marketing RAR-alpha blockers :oops:

 
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Zsazsa

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Contraceptives are designed for two main purposes: control of population growth and family planning. As of the writing of this editorial, there are nearly 7.8 billion people on our planet (see www.worldometers.info/world-population), with over one-third of the world’s population living in China (1.44 billion) or India (1.38 billion). This population expansion has had devastating effects on our environment—causing an increase in pollution, causing global warming, and eradicating species at a rate never before seen.
.....
We thank 1) the authors whose insightful articles are included in this special issue; 2) the gracious supporters of the 2019 NICHD Contraceptive Development meeting (Baylor College of Medicine, the Bill and Melinda Gates Foundation, the Burroughs Wellcome Fund, CMI Health, IMPT, Male Contraceptive Initiative, and the National Institutes of Health); and 3) the charitable funders of our research in the areas of contraception, drug discovery, and fertility (the Bill and Melinda Gates Foundation, Cancer Prevention Research Institute of Texas, Male Contraceptive Initiative, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the Welch Foundation).

© The Author(s) 2020. Published by Oxford University Press on behalf of Society for the Study of Reproduction.
...

Abstract
Retinoic acid receptor alpha (RARA), a nuclear receptor protein, has been validated as a target for male contraception by gene knockout studies and also pharmacologically using a pan-retinoic acid receptor antagonist. Retinoic acid receptor alpha activity is indispensable for the spermatogenic process, and therefore its antagonists have potential as male contraceptive agents. This review discusses the effects of systematic dosing regimen modifications of the orally bioavailable and reversible pan-antagonist BMS-189453 as well as studies with the alpha-selective antagonists BMS-189532 and BMS-189614 in a murine model. We also provide an overview of structure–activity studies of retinoic acid receptor alpha antagonists that provide insight for the design of novel alpha-selective ligands.
....

Future directions
The orally bioavailable pan-antagonist 1 (BMS-189453) has provided proof of principle that inhibition of RAR leads to infertility in male mice and that this is a reversible process and well tolerated. Genetic studies underscore the critical role of RARA in particular in spermatogenesis and hence male fertility; however, an effective RARA-specific antagonist that is orally bioavailable has yet to be identified. Therefore, future studies should focus on discovering and evaluating orally active RARA-selective antagonists.
Grant Support: This work was supported by National Institute of Child Health and Human Development Grants U01-HD060479 and U54-HD093540/P50-HD093540, project 1 (to D.J.W. and S.S.W.C.) and HHSN275201300017C (to G.I.G) and U54-HD093540/P50-HD093540 (to G.I.G.).

ETA
And they are already marketing it because all of a sudden it will become completely safe...
 
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James b

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This is a quote from Dr Peat about vitamin A in response to a question by Pulstar - "an overdose of vitamin A can create symptoms of a vitamin A deficiency"

Ray:
Since the symptoms can be produced by activation of the pro-inflammatory angiotension system, and an overdose of vitamin A can create symptoms of a vitamin A deficiency (vitamin A normally works with vitamin D to inhibit that system), I think it might help to supplement some vitamin D (about 5000 IU unless you get good sun exposure), vitamin A (about 10,000 IU), with some vitamin E (20 to 50 IU), thyroid hormone (according to temperature and pulse rate), and a good ratio of calcium to phosphate in the diet. An angiotensin blocker such as candesartan might help with joint pain and depression.


Are you able to elaborate on this @haidut please?
Out of curiosity, does anyone know why Ray might have stipulated candesartan here over any of the other Sartans?
 

Peatness

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Out of curiosity, does anyone know why Ray might have stipulated candesartan here over any of the other Sartans?
No but the sartans all have difference properties, see attached paper. Candesartan was shown to reduce urinary albumin/creatinine ratio and it is claimed it reduces the risk of dementia.

There is ongoing clinical trial on it's use for biopolar depression

 

Attachments

  • The Different Therapeutic Choices with ARBs Which One to Give When Why.pdf
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aliml

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Out of curiosity, does anyone know why Ray might have stipulated candesartan here over any of the other Sartans?
Candesartan has a very low maintenance dose. The metabolism for the drug is unique as it is a cascading pro-drug. Candesartan has good bioavailibility and is more potent among the AT-1 receptor antagonists.

Candesartan is marketed as the cyclohexyl 1-hydroxyethyl carbonate (cilexetil) ester, known candesartan cilexetil. Candesartan cilexetil is metabolised completely by esterases in the intestinal wall during absorption to the active candesartan moiety. The first step that occurs in the cascading pro-drug mechanism of Candesartan is that the carbonate gets hydrolyzed. The carbonate gets hydrolyzed and releases carbon dioxide.
 

tastyfood

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Well, one reason is that vitamin A deficiency has been shown in many animal studies to often cause irreversible sterility if maintained for a sufficiently long period of time.

Do you think a blood test for Vitamin A is useful to identify a possible deficiency?

Labcorp has a mass spectrometry option to test Vitamin A: 017509: Vitamin A | Labcorp
 
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Thanks Haidut. I almost entertained the vitamin A avoidance stuff.

Interesting how our ancestors ate way more vitamin A than we do, and in the last 50 years hypothyroidism skyrockets, so some people call vitamin A toxic because they can reverse some symptoms lowering it... failing to see it’s the same logic as keto or vegan.
 

Peatness

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Most toxicity comes from the use of supplemental synthetic vitamin A not dietary sources.
 

GreekDemiGod

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Thanks Haidut. I almost entertained the vitamin A avoidance stuff.

Interesting how our ancestors ate way more vitamin A than we do, and in the last 50 years hypothyroidism skyrockets, so some people call vitamin A toxic because they can reverse some symptoms lowering it... failing to see it’s the same logic as keto or vegan.
I think it would be interesting to try to find explanations for why they see massive improvements in their health from restricting Vit. A.
 

TheCalciumCad

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Most toxicity comes from the use of supplemental synthetic vitamin A not dietary sources.
Thats was my assumption years ago when I realised the supplements were a disaster for me. I began removing high vit A foods recently and am more androgenic now than at any point Peating. I also stopped vit D/K supps and started reducing coffee in that time, all are supposedly androgenic, hmmm.
 

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