Cholesterol & High-Grade PCa.

[pjoshea13]

New study [1]. Somewhat perplexing.

It has been known for a century that solid tumors accumulate cholesterol. In PCa, cholesterol within cancer cells can be used to generate androgens. And, if cholesterol uptake is inhibited, the cells can manufacture cholesterol (unless prevented via a statin.)

"REDUCE was a four-year multi-center study testing the effect of daily Dutasteride {Avodart} on PC risk in men with a PSA of 2.5 to 10.0 ng/mL and a negative biopsy, with men undergoing study-mandated biopsies at 2- and 4-years." [2]

In Supplementary Table 3 of the new study, we find these odd associations with high-grade PCa:

- high LDL = 24% reduced risk

- high HDL = 64% increased risk

- high total cholesterol = 27% increased risk

The head of the new study was Steve Freedland, for whom I have a high regard.

It's a pity that they did not measure VLDL-C, i.e. very-low-density lipoprotein cholesterol. VLDL-C is supposedly readily taken up by PCa cells, whereas HDL-C is not. (Size matters.)

I don't believe that cholesterol is a risk factor for PCa. Seems to me that when PCa is of an aggressive type, an abundance of cholesterol is associated with its promotion. My first thought was that high cholesterol is related to the metabolic syndrome [MetS] - but MetS is also associated with lower HDL-C. Even so, the available data probably included triglycerides. The triglycerides:HDL-C ratio is a surrogate for insulin resistance. It would be interesting to see adjusted numbers, after controlling for insulin resistance.

Perhaps someone out there has a theory?

-Patrick

[1] nature.com/articles/s41391-...

Prostate Cancer and Prostatic Diseases

Article

Serum cholesterol and risk of high-grade prostate cancer: results from the REDUCE study

Juzar Jamnagerwalla, Lauren E. Howard, […]Stephen J. Freedland

Prostate Cancer and Prostatic Diseases (2017)

doi:10.1038/s41391-017-0030-9

Cancer epidemiologyCancer prevention

Received:

14 October 2017

Accepted:

13 November 2017

Published online:

27 December 2017

Abstract

Background

Epidemiologic evidence for a serum cholesterol-prostate cancer link is mixed. Prostate-specific antigen (PSA) is positively correlated with cholesterol, potentially increasing PSA-driven biopsy recommendations in men with high cholesterol, though biopsy compliance may be lower in men with comorbid conditions. These potential biases may affect PSA-driven biopsy rates and subsequent prostate cancer detection in men with high serum cholesterol. Our objective was to test the association between serum cholesterol and prostate cancer risk in men receiving PSA independent, study-mandated prostate biopsies.

Methods

We conducted a post hoc analysis of data from 4974 non-statin users in REDUCE, a randomized trial in men with elevated PSA and a negative baseline biopsy. Men underwent 2- and 4-year trial-mandated prostate biopsies. Associations between baseline serum levels of total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and prostate cancer risk, overall and by Gleason grade (<7 vs. ≥7), were examined using multivariable logistic regression.

Results

High total serum cholesterol was associated with an increased risk of high-grade prostate cancer diagnosis (OR per 10 mg/dL 1.05; 95% CI 1.00–1.09; p = 0.048), but cholesterol was unrelated to either overall or low-grade prostate cancer risk (p-values >0.185). There was no association between serum LDL and overall, low- or high-grade prostate cancer risk (p-values >0.137). In contrast, elevated serum HDL was associated with increased risk of both overall (OR per 10 mg/dL 1.08; 95% CI 1.01–1.16; p = 0.033) and high-grade prostate cancer (OR per 10 mg/dL 1.14; 95% CI 1.01–1.28; p = 0.034).

Conclusions

In REDUCE, where all men received PSA independent, trial-mandated biopsies thus ensuring complete prostate cancer ascertainment, high total serum cholesterol and high HDL were associated with increased risk of high-grade prostate cancer, supporting a cholesterol-prostate cancer link.

...

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

[Hidden]

Good post that proposes a question to ponder.

The role of testosterone in prostate cancer seems obscure to me, since testosterone is tightly connected to the AR to control gene expression of male pattern proteins. I do not understand its (proven) role in prostate cell division/multiplication.

And the testosterone axis has not as led to definitive treatment AsFarAsIKnow.

[pjoshea13 in reply to Hidden]

Martin,

From an androgen perspective, epithelial prostate growth is under intracrine control - & it works for most of our lives.

- 5alpha reductase must be produced to convert testosterone [T] to dihydrotestosterone [DHT]

- the presence of DHT is sufficient to cause production of the enzymes that will break it down. i.e. there is a narrow window for DHT to do its pro-growth thing

- one of the enzymes leads to 3beta adiol, which is the natural ligand for the beta estrogen receptor. ERbeta resists growth.

The whole thing is controlled within the cell.

There are also AR coactivators & corepressors.

ERalpha in stromal cells have a paracrine influence on the epithelium.

& somehow, there is control at the organ level, since cell death & cell division must be in balance in the adult organ.

youtube.com/watch?v=bA89enH...(Not working as expected?)

-Patrick

[Hidden in reply to Hidden]

Cholesterol was the topic and it can be used to make testosterone.

The role of testosterone and the AR I do understand is part of gene expression. I do hear that the steroidal hormones do have an effect in the cells unrelated to gene expression, but it is not generally understood what those effects are. They say they know that there are some "nongenommic actions" because the effects are immediate, which would not be true for the gene expression mechanism.

footnote: Human Physiology, 14th edition, Chapter 11, page 324

paragraph "Mechanism of steroid hormone action"

You do say "epithelial prostate growth is under intracrine control - & it works for most of our lives" but I don't understand the mechanism of prostate growth as relates to T; ie, the regulation of cell division as relates to steroid hormones.

[Sisira]

I agree with your thinking that cholesterol is not a risk factor for PCa. But in the aggressive type an abundance of cholesterol can be associated with its promotion.

Thank you for your post.

Sisira

[vandy69]

Good Morning pjoshea13,

Dr. Charles "Snuffy" Myers always hinted at a connection between cholesterol and aggressive PCa and used statins with many of his patients, including me.

He used Livalo, which most docs have never heard of. I still take it, but since I have had so many drugs over the past 5 1/2 years, it is not possible to ever isolate impact, but I am still here!

Best wishes. Never Give In.

Mark, Atlanta

[Break60 in reply to vandy69]

Mark

I’ve been on statins for many years due I was told to the fact that I was genetically predisposed to produce excessive cholesterol. When I was dx with PCa I was encouraged to stay on crestor as it was considered an inhibitor of PCa by Snuffy.

Bob

[pjoshea13 in reply to Break60]

Bob,

I believe that the prevention of cholesterol generation in PCa cells is more effective if the statin is lipophilic - more readily taken up by the cells.

"In terms of lipophilic nature, lovastatin and simvastatin are the most lipophilic, followed by atorvastatin, fluvastatin, and pravastatin. Rosuvastatin {Crestor} ... can be placed between fluvastatin and pravastatin."

pharmacytimes.com/publicati...

-Patrick

[dave2 in reply to pjoshea13]

Patrick,

That 2005 article was written before Livalo (pitavastatin) received FDA approval in 2009. Here's a table that quantifies lipophilcity for most statins ncbi.nlm.nih.gov/pmc/articl...

[Break60 in reply to dave2]

So I should change to simvastatin?

Bob

[Roland632017 in reply to Break60]

Hi Bob

I know it winter up your end so when the last game of golf?

On 27 December 17 I have my weekly veterans golf day.

The Wednesday before I wasn't able to play as I admitted my self to hospital for a condition left hydroureter and hydrophenosis. I then have my 2nd Cystoscopy and a left ureteric stent.

On 25 December 17 after chatting with Dan59 I decided to escalate my treatment by increasing dosage but not using doxycycline/vitamin c.

So on 27 December 17 during golf I started feeling weak. I took 2x500 mg paracetamol

[Roland632017 in reply to Roland632017]

Sorry...... I was able to watch my buddies play their rounds and have a good time but I had to stop my golf to not strain myself.

The cancer in me has created all this weakness/discomfort and also aches/pain in my other cancerous region namely bladder and bone spine.

Normally when these symptoms overwhelms you, you are in deep shit.

But I was aggressive killing the cancer cells so I anticipated them.

To up the ante I had sex on the early morning of 28 December 17. I have to withdraw when ejaculating. I noticed clear fluid from my discharge and they wee pinkish. I then went to the golf course to walk with a friend (still too weak for golf) When I got home 2 hours later I found blood in my urine. Fearing I could die not from cancer but from my medication I ask my wife to be ready to call for an ambulance in things turn south.

By googling I found out that a stroke is potentially likely from bleeding in the brain (13 % of stroke haemorrhagesis)

I was lucky my bleeding stopped and tragedy averted.

Now after 2 days my weakness/ flu symptoms disappeared. Them from last night the bone spine pain is also slowly dessipating. I am very bewildered by all these events.

At the moment I am at home watching TV with my wife. I am feeling good and able to eat and jump about. It is quite hot outside now and when it's a little cooler I will move my lawn.

Have a Happy New Year.

Roland

[Break60 in reply to Roland632017]

I live in Hilton Head Island SC where golf is usually playable year round. But there’s a cold spell coming which will preclude golf for the next seven days at least. Right now I’m in CA where the temp has been in the 80’s so I played three times! Awesome! 🤗

I must say that I’ve lost distance and endurance while on ADT3 with T at 3.0. Also brain fog has caused lack of focus at times. Sucks but at least I’m still playing!

Bob

[Roland632017 in reply to Break60]

Hi Bob

Just woke and routinely checking my Urine and Saliva PH as I am still aggressive treating my prostate cancer.

The progress of my prognosis is good.

I am getting fitter from my couple of days weakness from my treatment.

Yesterday I was able to mow my lawn and use the edger(weeper sniper) but an hour later my calf aches from lactic build up.

This morning I feel great and pain free.

Should be able to resume golf.

Today is 31.12.17 so I will relax and do a Lui chipping in my backyard.

I might go out to the Opera House to watch the 9 pm New Year Fireworks. The main event is at Midnight her in Sydney.

A very Happy New Year to you and your family.

Roland

[Break60 in reply to Roland632017]

Roland

Didn’t realize you’re down under. I was in Melbourne frequently in late 70’s . Love ❤️ Australia! Happy and healthy New Year!

Bob

[dave2 in reply to Break60]

Bob,

You asked if there's enough evidence to justify a switch from rosuvastatin (Crestor) to simvastatin (Zocor). Both are lipophilic, but Zocor much more so. Then there's the study Patrick just posted ncbi.nlm.nih.gov/pmc/articl... As Patrick pointed out, that study used a 5X higher dose of Crestor compared to the Zocor dose to get what appears to be comparable reduction in the ability of PC-3 cells to grow in bone marrow stroma. There are two aspects of this study that I find troubling as the basis for a medication switch: it is an in vitro study, and the statin concentrations used were more than 100X the peak serum concentration normally achievable at the maximum recommended human Zocor dose (and about 700X the peak concentration normally achievable at the max recommended Crestor dose). The study does appear to support use of lipophilic statins for those with PCa.

Do we have scientific evidence to guide the selection of one statin vs others to reduce the risk of PCa progression/mortality? The evidence looks weak to me, but there do appear to be some emerging indications of differences. My main concern is whether the researchers are correctly modeling their in vitro experiments to reveal relevant differences that would also show up in an in vivo trial.

Statins are an interesting drug category--many researchers are seeing possible benefits beyond lower cardiovascular risk: cancer benefits, fatty liver disease benefits, inflammation benefits, etc. But we appear to be at an early stage in understanding the mechanisms in play and how well each statin performs in helping to achieve these desired benefits.

[pjoshea13 in reply to dave2]

Dave,

Thanks for the link - very useful!

-Patrick

[Hidden in reply to pjoshea13]

Statins prevent synthesis of cholesterol in the liver, dont they? I have heard that prostate cells can synthesize androgens, out of cholesterol, but not that they can synthesize cholesterol itself. Synthesize from what?

[snoraste in reply to pjoshea13]

Patrick,

Has there been any study on which statins are least damaging to the liver? Or if any of them that may have adverse drug interaction with Zytega/Lupron/prednisone ( basically the new standard of care)?

Shayan

[pjoshea13 in reply to snoraste]

Shayan,

I'm not aware of liver studies. Dr Myers, in the video I posted claims that liver problems are rare.

I favor Simvastatin, which is used by an astonishing 8% of American adults. (Obviously, a much higher percentage for my age group.) With that many prescriptions being filled, it must have a good safety record.

See my response to Nameless regarding statins with Zytiga.

-Patrick

[vandy69 in reply to Break60]

Hi Bob,

Snuffy had me on Crestor but then switched to Livalo. Believe it had to do with fewer potential drug interactions at the time.

Mark

[pjoshea13 in reply to vandy69]

Mark,

Livalo does not raise blood sugar.

Also raises adiponectin. Good for PCa.

See: askdrmyers.wordpress.com/20...

I tried it, but it messed up my liver. I went back to Simvastatin.

{I waited months for insurance to approve Livalo. & even then it cost a small fortune.}

-Patrick

[vandy69 in reply to pjoshea13]

I viewed the link and realize how much I miss him. He treated the whole patient and his detailed knowledge of drugs was immense.

Mark