Low Testosterone Levels Tied To Worse Prognosis For Prostate Cancer

[haidut]

I think every urologist should read this study before they put their patients on anti-androgenic drugs to treat BPH and early stage prostate cancer.

Low free testosterone levels predict disease reclassification in men with prostate cancer undergoing active surveillance - San Francisco - 2014 - BJU International - Wiley Online Library
https://www.sciencedaily.com/releases/2014/05/140505094213.htm

"...These results suggest low levels of testosterone are associated with more aggressive prostate cancer. This contradicts long-held beliefs that high testosterone is risky for prostate cancer, and low testosterone is protective," said Dr. San Francisco. The results of this study provide valuable information to clinicians and their patients concerning risk factors for prostate cancer progression in men undergoing active surveillance. "In borderline cases, the presence of low values of free testosterone may help determine whether it is more prudent to initiate treatment rather than continue observation," said Dr. San Francisco."

 

[Koveras]

Can you clarify some thoughts of yours on the biological activity of free versus bound testosterone?

I understand Ray has said with thyroid that the bound hormones have activity (perhaps even more than 'free' thyroid hormones) - but I wonder if the case is different for sex hormones. For example SHBG preferentially binds testosterone relative to estrogen - so in cases of elevated SHBG, men can sometimes suffer symptoms of excess estrogen (as in gynecomastia with hyperthyroidism).

 

[haidut]

Can you clarify some thoughts of yours on the biological activity of free versus bound testosterone?

I understand Ray has said with thyroid that the bound hormones have activity (perhaps even more than 'free' thyroid hormones) - but I wonder if the case is different for sex hormones. For example SHBG preferentially binds testosterone relative to estrogen - so in cases of elevated SHBG, men can sometimes suffer symptoms of excess estrogen (as in gynecomastia with hyperthyroidism).

I think the hormones that have an effect are the ones bound to albumin and other proteins like SHBG that can carry them inside the cell. The so-called free testosterone can't do much while in the blood stream. Here is an article from Peat where he talks about progesterone and thyroid, and "free" vs. bound hormones. The discussion applies just as well to testosterone. Bottom line is that while blood tests are unreliable, you probably want as high total testosterone and as low free testosterone as possible.
Thyroid: Therapies, Confusion, and Fraud
"...The idea that the "free hormone" is the active form has been tested in a few situations, and in the case of the thyroid hormone, it is clearly not true for the brain, and some other organs. The protein-bound hormone is, in these cases, the active form; the associations between the "free hormone" and the biological processes and diseases will be completely false, if they are ignoring the active forms of the hormone in favor of the less active forms. The conclusions will be false, as they are when T4 is measured, and T3 ignored. Thyroid-dependent processes will appear to be independent of the level of thyroid hormone; hypothyroidism could be caller hyperthyroidism.

Although progesterone is more fat soluble than cortisol and the thyroid hormones, the behavior of progesterone in the blood illustrates some of the problems that have to be considered for interpreting thyroid physiology. When red cells are broken up, they are found to contain progesterone at about twice the concentration of the serum. In the serum, 40 to 80% of the progesterone is probably carried on albumin. (Albumin easily delivers its progesterone load into tissues.) Progesterone, like cholesterol, can be carried on/in the lipoproteins, in moderate quantities. This leaves a very small fraction to be bound to the "steroid binding globulin." Anyone who has tried to dissolve progesterone in various solvents and mixtures knows that it takes just a tiny amount of water in a solvent to make progesterone precipitate from solution as crystals; its solubility in water is essentially zero. "Free" progesterone would seem to mean progesterone not attached to proteins or dissolved in red blood cells or lipoproteins, and this would be zero. The tests that purport to measure free progesterone are measuring something, but not the progesterone in the watery fraction of the serum.

The thyroid hormones associate with three types of simple proteins in the serum: Transthyretin (prealbumin), thyroid binding globulin, and albumin. A very significant amount is also associated with various serum lipoproteins, including HDL, LDL, and VLDL (very low density lipoproteins). A very large portion of the thyroid in the blood is associated with the red blood cells. When red cells were incubated in a medium containing serum albumin, with the cells at roughly the concentration found in the blood, they retained T3 at a concentration 13.5 times higher than that of the medium. In a larger amount of medium, their concentration of T3 was 50 times higher than the medium's. When laboratories measure the hormones in the serum only, they have already thrown out about 95% of the thyroid hormone that the blood contained.

The T3 was found to be strongly associated with the cells' cytoplasmic proteins, but to move rapidly between the proteins inside the cells and other proteins outside the cells.

When people speak of hormones travelling "on" the red blood cells, rather than "in" them, it is a concession to the doctrine of the impenetrable membrane barrier.

Much more T3 bound to albumin is taken up by the liver than the small amount identified in vitro as free T3 (Terasaki, et al., 1987). The specific binding of T3 to albumin alters the protein's electrical properties, changing the way the albumin interacts with cells and other proteins. (Albumin becomes electrically more positive when it binds the hormone; this would make the albumin enter cells more easily. Giving up its T3 to the cell, it would become more negative, making it tend to leave the cell.) This active role of albumin in helping cells take up T3 might account for its increased uptake by the red cells when there were fewer cells in proportion to the albumin medium. This could also account for the favorable prognosis associated with higher levels of serum albumin in various sicknesses.

When T3 is attached chemically (covalently, permanently) to the outside of red blood cells, apparently preventing its entry into other cells, the presence of these red cells produces reactions in other cells that are the same as some of those produced by the supposedly "free hormone." If T3 attached to whole cells can exert its hormonal action, why should we think of the hormone bound to proteins as being unable to affect cells? The idea of measuring the "free hormone" is that it supposedly represents the biologically active hormone, but in fact it is easier to measure the biological effects than it is to measure this hypothetical entity. Who cares how many angels might be dancing on the head of a pin, if the pin is effective in keeping your shirt closed? "

 

[Drareg]

Has anyone any idea on how to specifically increase transthyretin ?
Would mitolipin work?

I'm not sure what this study implies,is there a pattern?


Cholesterol and anionic phospholipids increase the binding of amyloidogenic transthyretin to lipid membranes
Abstract
Deposition of transthyretin (TTR) amyloid is a pathological hallmark of familial amyloidotic polyneuropathy (FAP). Recently we showed that TTR binds to membrane lipids via electrostatic interactions and that membrane binding is correlated with the cytotoxicity induced by amyloidogenic TTR. In the present study, we examined the role of lipid composition in membrane binding of TTR by a surface plasmon resonance (SPR) approach. TTR bound to lipid bilayers through both high- and low-affinity interactions. Increasing the mole fraction of cholesterol in the bilayer led to an increase in the amount of high-affinity binding of an amyloidogenic mutant (L55P) TTR. In addition, a greater amount of L55P TTR bound with high affinity to membranes made from anionic phospholipids, phosphatidylglycerol (PG) and phosphatidylserine (PS), than to membranes made from zwitterionic phospholipid phosphatidylcholine (PC). The anionic phospholipids (PS and PG) promoted the aggregation of L55P TTR by accelerating the nucleation phase of aggregation, whereas the zwitterionic phospholipid PC had little effect. These results suggest that cholesterol and anionic phospholipids may be important for TTR aggregation and TTR-induced cytotoxicity.

 

[ddjd]

Bottom line is that while blood tests are unreliable, you probably want as high total testosterone and as low free testosterone as possible.

and should SHBG ideally be high then?