Low testosterone & high-risk prostate cancer

New study below.

"... mean free (6.2 vs. 5.2 ng/dL ...) and bioavailable (151 vs. 125 ng/dL ...) testosterone levels were found to be significantly different in men with low-intermediate and high-risk prostate cancer."

"Moreover, a significant correlation was found between free, and bioavailable testosterone levels and percentage of cores with cancer ... for bioavailable testosterone".

"This prospective clinical study demonstrates that reduced levels of calculated blood free and bioavailable testosterone levels are associated with an increased risk of high-grade prostate cancer. Based on these findings blood free and bioavailable testosterone levels may be be thought to be an adjunctive factor in the prediction of high-risk prostate cancer."

Note that free T is not bound to SHBG or albumin, & is usually 1-2% of total T. Bioavailable T is free T plus albumin-bound T, & can be near 50% of total T. Looks like the latter was estimated in this study.

The findings are consistent with other studies. The association does not necessarily imply that low T is a risk factor for aggressive disease, since PCa seems able to lower T levels.

I wonder if such men would benefit from T restoration?

-Patrick

ncbi.nlm.nih.gov/pubmed/288...

Turk J Urol. 2017 Sep;43(3):289-296. doi: 10.5152/tud.2017.35467. Epub 2017 Aug 1.

Low free and bioavailable testosterone levels may predict pathologically-proven high-risk prostate cancer: a prospective, clinical trial.

Bayar G1, Şirin H1, Aydın M2, Özağarı A3, Tanrıverdi O4, Kadıhasanoğlu M5, Kendirci M4.

Author information

Abstract

OBJECTIVE:

To determine the predictive value of free and bioavailable testosterone levels on the detection of high-grade prostate cancer proven by histopathological examination of transrectal prostate biopsy specimens.

MATERIAL AND METHODS:

A total of 405 patients who underwent transrectal prostate biopsy due to high prostatic specific antigen (PSA) (>2.5 ng/mL) and/or abnormal findings at digital rectal examination were included in this study. Blood free and bioavailable testosterone levels were calculated by the formula recommended by International Society for the Study of the Aging Male (ISSAM). The patients were stratified according to the D'Amico classification based on PSA levels and histological outcomes of prostate biopsies as benign, low, intermediate and high-risk prostate cancer. Patients were also divided into five groups according to the percentage of cancerous cores.

RESULTS:

Prostate cancer was detected in 160 of 405 (39.5%) patients. Total, free and bioavailable testosterone levels did not differ significantly between the patients with benign or malign histology. However, mean free (6.2 vs. 5.2 ng/dL, p=0.02) and bioavailable (151 vs. 125 ng/dL, p=0.001) testosterone levels were found to be significantly different in men with low-intermediate and high-risk prostate cancer. Moreover, a significant correlation was found between free, and bioavailable testosterone levels and percentage of cores with cancer (p=0.002 for free and p=0.016 for bioavailable testosterone, respectively).

CONCLUSION:

This prospective clinical study demonstrates that reduced levels of calculated blood free and bioavailable testosterone levels are associated with an increased risk of high-grade prostate cancer. Based on these findings blood free and bioavailable testosterone levels may be be thought to be an adjunctive factor in the prediction of high-risk prostate cancer.

KEYWORDS:

Prostate cancer; prostate-specific antigen; radical prostatectomy; testosterone; transrectal prostate biopsy

PMID: 28861300 PMCID: PMC5562247 DOI: 10.5152/tud.2017.35467

12 Replies

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  • Denmeade has said that in the general case, super-physiologic levels interfere with "licensing" - an aspect of cell division. (work of John Isaac.) Normal levels (ie testosterone supplementation) probably would not do that. I can look for a reference.

    My sense is that raising levels of T, in the context of increased AR, would not help.

    ncbi.nlm.nih.gov/pmc/articl...

  • I was thinking more of restoring protective balance.

    Epithelia prostate cells contain the beta estrogen receptor [ERbeta]. The natural ligand for ERbeta is, ironically, a metabolite of DHT: 3β-adiol.

    ncbi.nlm.nih.gov/pmc/articl...

    "Indeed, 3β-adiol is considered as the physiological ligand for ERβ (27). This hypothesis is further supported by the fact that ERβ, activated by 3β-adiol, is involved in regulating the prostate AR content in wild-type mice, and in restraining epithelial growth (28). In addition, 3β-adiol is considered a powerful DHT metabolite since its intraprostatic protein level is 100-fold higher than that of estradiol (E2) (29). Notably, 3β-adiol has antiproliferative actions which are not reproduced by 17β-estradiol (30). Activation of ERβ by 3β-adiol induces apoptosis by upregulating the proapoptotic factor p53 and upregulating modulator of apoptosis (PUMA), an effect that implicates transcription factor FOXO3a (31)."

    At the least, 3β-adiol is protective against the growth stimulation of estradiol [E2], acting through ERalpha.

    Typically, when a man has low T, he also has elevated E2. With T supplementation, muscle:fat ratio should increase & E2 should fall.

    -Patrick

  • I realize that you were talking about restoring the protective balance, using the word protective to indicate the statistical level of T that on average conveyed a protective level in the studies you referred to, prior to the onset of cancer. My comment, right or wrong, was meant to say that a level that protects before the fact, may not protect after the fact, after the ARs have increasesed in number.

    I am aware that men have AR in both alpha and beta types, and ER again in two types. I can't intelligently comment on your speculation, since any comment is based only on my model of the disease, my preconceptions, and you are asking for somthing a little more tied to reality than that.

    The closest I can come is sayiing that Denmeade has said that at even higher levels, there does seem to be a protective effect, but at the levels that you are talking about, I can't recall.

    If you mean, pre-cancer, should men have supplementation, I actually agree, for whatever that is worth. I thnk it would be worthwhile, for a time at least, having Quest always do a Testosterone level when they do PSA. Get some data.

  • Hi Patrick,

    Could I get a citation for your statement that "Typically, when a man has low T, he also has elevated E2"?

    I note that you did not phrase that as a ratio (avoiding our annual debate on T:E ratios), otherwise you would have said "he also has [relatively] elevated E2." So I gather you mean that absolute low levels of T cause absolutely higher levels of E2. If you are right, where is the extra E2 coming from?

  • Hi Richard,

    {I actually tried not to provoke you by referring to the E2:T ratio. LOL}

    At or near the cut-off for hypogonadism (350 ng/dL), there is plenty of T to create E2, but where does the aromatase come from to produce elevated levels? Visceral fat.

    "The prevalence of obesity among US adults increased steadily since the 1990s and is now at epidemic proportions, with over two-thirds of US adults either overweight or obese". [1]

    Overweight men invariably have symptoms of the metabolic syndrome - particularly insulin resistance & elevated triglycerides. Excess triglycerides are stored as fat - particularly visceral fat. Visceral fat contains aromatase & secretes estradiol [E2]. At a certain level of E2, the body curtails T production. The ratio of fat:muscle decreases & E2 actually rises - not the intent. Breast tissue develops, etc. & there is no easy way out.

    The following study [2] reported only on obese men:

    "Serum estrone (E1) and 17beta-estradiol (E2) were noted to be 2-fold elevated in a group of morbidly obese men. Urinary E1 and E2 production rates were elevated in proportion to the degree of obesity, with values as high as 127 and 157 micrograms/day, respectively."

    "... serum testosterone (T) concentrations were reduced in obese men, averaging 348 +/- 35 vs. 519 +/- 42 ng/dl in lean controls"

    Similarly [3]:

    "In the obese subjects, IBW was inversely correlated (P < 0.001) with plasma concentrations of androstenedione (r = 0.81) and testosterone (r = 0.87), while the levels of estrone (r = 0.92) and estradiol (r = 0.95) increased with IBW (P < 0.001). Thus, when normal and obese subjects were compared as groups, plasma androstenedione decreased form 1.24 +/- 0.13 to 0.93 +/- 0.15 ng/ml (mean +/- SD) and plasma testosterone decreased from 5.89 +/- 0.82 to 3.29 +/- 0.92 ng/ml (P < 0.001), while estrone increased from 28.2 +/- 3.4 to 60.0 +/- 9.4 pg/ml, and estradiol increased from 21.7 +/- 3.5 to 43.9 +/- 5.3 pg/ml."

    "The testosterone to androstenedione and the estradiol to estrone ratios were not different in obesity, but changes in IBW were positively correlated (P < 0.001) with differences in the estrone to androstenedione (r = 0.93) and estradiol to testosterone ratios (r = 0.93), indicating that fat tissue may aromatize androgens ..."

    "We suggest that enhanced aromatization of androstenedione due to an increased adipose tissue mass may account for the high plasma estrogen levels observed in obese men."

    [4]: "Obesity-associated reduction in testosterone is based on the effect of high estradiol from an increase in aromatase activity present in the abundant adipose tissue. The resulting hyperestrogenemia suppresses the hypothalamic-pituitary-gonadal unit resulting in low testosterone production."

    [5]: "a lower E2/T ratio was associated with a lower risk of incident MetS"

    -Patrick

    [1] cdc.gov/pcd/issues/2017/16_...

    [2] ncbi.nlm.nih.gov/pubmed/429...

    [3] ncbi.nlm.nih.gov/pubmed/741...

    [4] ncbi.nlm.nih.gov/pmc/articl...

    [5] ncbi.nlm.nih.gov/pubmed/256...

  • So, Patrick, is the following correct— yes/no?

    Instead of the statement that "Typically, when a man has low T, he also has elevated E2", it would be more accurate to say, based on the literature you cited, that, "In morbidly obese men it may in fact be possible to get an absolute rise in E2 even with low T."

    yes/no?

    If that rewording is correct, how is that "typically" the situation when estimates for obesity in the male USA population are in the range of only 1:4 men?

  • Richard,

    There is nothing magical about about a BMI of 30. One gains an ounce & suddenly one is no longer in the safety zone of "overweight"?

    2 of 3 American men are overweight (BMI=25-29.9) or obese (BMI=30 or greater).

    One of the studies stated that E2 increased with adiposity, so would be somewhat less in the overweight.

    OK, so overweight studies? The following study combined overweight with obese:

    [1] "In men, RMR {resting metabolic rate} positively correlated with cortisol ... and estradiol ... and RER {respiratory exchange ratio } positively correlated with insulin ..."

    [2] "Subjects with higher adiposity (BMI, waist circumference, skinfolds) had elevated E2 secretion throughout the day" "Given E2's role in male hypothalamic-pituitary-gonadal function and complex interfaces with the immune system, these results have important implications for models of male life history as rates of overweight and obesity rise in populations around the world."

    [3] "The men in the highest quintile of estrone and estradiol levels had significantly higher BMI than those in other quintiles."

    [4] "Effect of body weight on testosterone/estradiol ratio in oligozoospermic patients." Compared "underweight or normal weight patients (BMI = 25 kg/m2) vs. overweight or obese patients (BMI > 25 kg/m2)." "The testosterone/estradiol ratio was significantly reduced in the high BMI group as compared to the low BMI group ..."

    BMI is easy to measure, so it serves as a surrogate for visceral fat. But one need not have a high BMI to be carrying around a lot of fat (the LOFI phenomenon). A high-carb, high-fiber diet might do that.

    From a paper new to PubMed today:

    "... visceral white adipose tissue plays a more central role, as it is more bioenergetically active and is associated with a more procancer secretome than subcutaneous adipose tissue." [5]

    -Patrick

    [1] ncbi.nlm.nih.gov/pubmed/282...

    [2] ncbi.nlm.nih.gov/pubmed/245...

    [3] ncbi.nlm.nih.gov/pmc/articl...

    [4] ncbi.nlm.nih.gov/pubmed/164...

    [5] ncbi.nlm.nih.gov/pubmed/288...

  • Patrick,

    I don't know if this is worth a third and last try...but I don't see where any of those reference you list establish that it is TYPICAL for men who are low on T to have elevated E2. Obesity was not mentioned in your statement about typicality and that is what I asked about.

    Furthermore what I asked was not a percontation in the formal and classical meaning of that word. So why not reply "yes" or "no" to the original and straightforward yes or no question?

    Richard W.

  • It is obvious Wassersug, that if your T goes down, that you cannot assume your E2 also goes down. If it stays the same than your ratio of the E2 to T goes up in favor of E2. Another study which I posted about the hypothalamus---shows that this part of the brain monitors E2, and will itself produce and surge E2 when there is a signal sent from within the endocrine gland system, or the brain itself thru self monitoring will cause E2 to increase against T. And I presented a post from the work done in 1978 at Memorial Sloan---where the Cadavers of over two hundred men had their prostates removed and analyzed by High Pressure Liquid Chromatography in line with a Mass Spectrometer proved that there was an enormous amount of E2, present in the Prostate glands and very low Testosterone. The men all died of Prostate Cancer. One researcher stated, the molecular profile of the tissue was such that they thought they were looking at female tissue.

    The Point Patrick was making by obvious intuitiveness is that however the E2 gets to a higher than optimal ratio against T, as T goes down---you are looking at high probability for men obtaining aggressive PC. Suggest you monitor your E2 as well as your T, as some us here do.

    Nalakrats

  • Hi there,

    I've inserted a few quick replies statin with dashes.

    It is obvious Wassersug, that if your T goes down, that you cannot assume your E2 also goes down. If it stays the same than your ratio of the E2 to T goes up in favor of E2.

    --But Patrick was talking about absolute values, not a ratio.

    Another study which I posted about the hypothalamus---shows that this part of the brain monitors E2, and will itself produce and surge E2 when there is a signal sent from within the endocrine gland system, or the brain itself thru self monitoring will cause E2 to increase against T.

    --And were does that #2 come from except as an aromatized product of T?

    And I presented a post from the work done in 1978 at Memorial Sloan---where the Cadavers of over two hundred men had their prostates removed and analyzed by High Pressure Liquid Chromatography in line with a Mass Spectrometer proved that there was an enormous amount of E2, present in the Prostate glands and very low Testosterone. The men all died of Prostate Cancer.

    --And how do we know that they wouldn't have died sooner if there wasn't E2 in the gland to "protect" it? To be clear, I don't actually believe that, but I raise it just to point out that a correlation of the sort you have flagged here should be treated with caution. Correlation does not equal causation.

    One researcher stated, the molecular profile of the tissue was such that they thought they were looking at female tissue.

    The Point Patrick was making by obvious intuitiveness is that however the E2 gets to a higher than optimal ratio against T, as T goes down---you are looking at high probability for men obtaining aggressive PC.

    --So how do you explain the positive results of the PATCH study that have been published so far in the UK? [Note: I'm biased here having published with the PATCH team earlier this year,]

    Suggest you monitor your E2 as well as your T, as some us here do.

    --I have been monitoring my E2 levels for well over a decade and a half. I am happy to keep my estrogen beta receptor density high since there is evidence that that can help keep PCa in check. Note: Patrick and I don't agree on the best drug strategy for managing PCa. But for the moment we are both alive, and there need not be only one strategy that works. [My PSA by the way, is below the detectable limit.]

    Nalakrats

  • Thanks--Patrick and I will follow about the same path.

    Nalakrats

  • Patrick, this may be a New Study, but we have books written, By Dr. Liebowitz, back in the early 2000's from research conducted in the 1990's Also you may find a mention in Walsh's book, and from someone from Compassionate Oncology, where they do a lot of BAT.

    Using Leibowitz, to keep this short--he determined that any middle aged man or men in their sixties, should have a Testosterone Test every year. He considered the T test to be more important than the routine PSA test. So over the course of many hundreds of men he found that men with Low T--I believe he used 300 ng/dl, as the breaking point--he then performed a PSA---and in almost every case with no DRE predictors---he found that [most] of the men with low T, had normal PSA's---many with numbers from 2-3. He then encouraged all of these low T men over a period of ten years to be subjected to a Biopsy, of the Prostate, with low PSA's. 20% of the men with a perfect DRE, and a very acceptable PSA, had prostate cancer, and all was aggressive.

    My barber is a perfect example with a very smart Doctor. He was 57 when he went to his Urologist for his yearly routine PSA. This time the Dr. wanted to do a T test. His T came in at 270, and his PSA was 2.1. He was encouraged to do a Biopsy. Biopsy showed agressive cancer, a Gleason 7[4+3]. He had sparring Robotic Surgery his T is being regulated up with supplementation, and his PSA is Undetectable---3 years later.

    When doing research, I always go back to work that has never gone main stream, and I have found nuggets--in many endeavors. My first Publication in 1967 regarding the Polyphenols, of both Green and Black Tea, could never have been published from my research, without the discovery of a paper from the Germans in 1937, having to do with carbohydrates. Sometimes we already have certain info. My College Professor[ Mentor], while working on my Masters in Organic Synthesis Chemistry left a huge mark on me. Alone he told me, '-----, when you graduate you will have forgotten 90% of what you learned. And you will have to look up somewhere, what was learned, but forgotten, and what was not taught. So true!

    Nalakrats

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