Dihydrotestosterone [DHT] & PCa castration resistance [CRPC].

[pjoshea13]

New study below.

A dozen years ago, with PSA continuing to rise, & no good conventional options at the time. IMO, I decided to try testosterone supplementation.

My understanding of DHT at the time was this:

- the appearance of DHT in a prostatic cell caused the generation of an enzyme to clear it. This is a common intracrine control mechanism for a hormone created within a cell for activity within the cell. DHT thus has a limited window for proliferation in normal cells.

- a metabolite of DHT is actually an estrogen - 3beta-adiol. It is the natural ligand for the protective beta estrogen receptor [ERbeta]. So DHT is important in controling growth.

- DHT would be basically harmless provided the enzyme & ERbeta continued as normal. I knew that ERbeta expression tends to be inhibited at an early stage, but I thought maybe a strong testosterone: estradiol ratio [T:E2] might help keep ERbeta in play.

For each of 6 months my T remained static - until I injected vitamin B12 for 4 months. Even so, my PSA doubling time [PSADT] resumed at >24 months.

I remained on continuous T for a number of years, but PSADT eventually dropped back to 3 months, & I moved to 3 months castrate / 3 months high T cycles.

The new study adds to the above. Castration therapy causes the cancer cells to suppress induction of the DHT clearance enzyme. This allows DHT proliferation to be sustained.

Following CRPC, T replacement is beneficial for some men, but not for others. The loss of the enzyme might have something to do with that.

-Patrick

jbc.org/content/293/46/1782...

Loss of dihydrotestosterone-inactivation activity promotes prostate cancer castration resistance detectable by functional imaging

Ziqi Zhu‡, Yoon-Mi Chung‡, Olga Sergeeva§, Vladimir Kepe¶, Michael Berk‡, Jianneng Li‡, Hyun-Kyung Ko‡, Zhenfei Li‡, Marianne Petro‡, Frank P. DiFilippo¶, Zhenghong Lee§,‖ and Nima Sharifi‡,**,‡‡1

- Author Affiliations

From the ‡Genitourinary Malignancies Research Center, Department of Cancer Biology, Lerner Research Institute,

the ¶Department of Nuclear Medicine, Imaging Institute,

the **Department of Urology, Glickman Urological and Kidney Institute,

the ‡‡Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195, and

the Departments of §Radiology and

‖Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44124

↵1 To whom correspondence should be addressed. Tel.: [phone]; Fax: [phone]; E-mail: [e-mail].

Edited by Xiao-Fan Wang

Abstract

Androgens such as testosterone and dihydrotestosterone are a critical driver of prostate cancer progression. Cancer resistance to androgen deprivation therapies ensues when tumors engage metabolic processes that produce sustained androgen levels in the tissue. However, the molecular mechanisms involved in this resistance process are unclear, and functional imaging modalities that predict impending resistance are lacking. Here, using the human LNCaP and C4-2 cell line models of prostate cancer, we show that castration treatment–sensitive prostate cancer cells that normally have an intact glucuronidation pathway that rapidly conjugates and inactivates dihydrotestosterone and thereby limits androgen signaling, become glucuronidation deficient and resistant to androgen deprivation. Mechanistically, using CRISPR/Cas9-mediated gene ablation, we found that loss of UDP glucuronosyltransferase family 2 member B15 (UGT2B15) and UGT2B17 is sufficient to restore free dihydrotestosterone, sustained androgen signaling, and development of castration resistance. Furthermore, loss of glucuronidation enzymatic activity was also detectable with a nonsteroid glucuronidation substrate. Of note, glucuronidation-incompetent cells and the resultant loss of intracellular conjugated dihydrotestosterone were detectable in vivo by 18F-dihydrotestosterone PET. Together, these findings couple a mechanism with a functional imaging modality to identify impending castration resistance in prostate cancers.

steroid steroid hormone receptor steroidogenesis metabolism metabolic regulation androgen uridine 5'-diphospho-glucuronosyltransferase (UDP-glucuronosyltransferase) castration-resistant prostate cancer nuclear medicine PET prostate cancer

Footnotes

This work was supported by a Howard Hughes Medical Institute Physician-Scientist Early Career Award and a Prostate Cancer Foundation Challenge Award (to N. S.), National Institutes of Health NCI Grants R01CA168899, R01CA172382, and R01CA190289 (to N. S.), NCI Grant 5R01CA204373 (to Z. L.), and Congressionally Directed Medical Research Programs, Prostate Cancer Research Program Award PC141550 (to Z. Z.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

This article contains Figs. S1–S3.

Received July 11, 2018.

Revision received September 17, 2018.

© 2018 Zhu et al.

Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.

[snoraste]

Patrick- Can you expand on the results please. My understanding was that DHT can be metabolized by PCa cells and therefore it should be inhibited thru avodart or similar. This piece seems to be arguing FOR it.

[cesanon in reply to snoraste]

Yes, Patrick would you please expand on it.

Especially with respect to the use of Avodart.

[pjoshea13 in reply to snoraste]

There are 2 parts to this post.

[1] DHT is no longer protective when ERbeta disappears. (Not dealt with in the study. Simply background.)

[2] When CRPC occurs, DHT is not cleared. This makes DHT more dangerous than at the start of ADT.

We know that castrate T doesn't necessarily mean castrate DHT. (Thanks Dr Myers for pointing out that this "naturally" occurs in some men.) My concern (& others too) is that the escape from ADT can include backdoor production of DHT. Avodart can stop that. This kind of DHT production can't be detected via a blood test.

The message from the study is that with CRPC, when DHT is present, it may not get cleared as it does in normal cells. If DHT can be created & its effects sustained, we have even more reason to consider Avodart.

& as Dr Myers has said a few times - the problem isn't testosterone - it is DHT.

-Patrick

[EdBar in reply to pjoshea13]

After reading Myers book and later becoming a patient of his I’ve been taking Avodart since my dx 4+ years ago. If memory serves me, Myers said that PCa that is deprived of T will turn to other sources like LDL cholesterol which it will convert to DHT in order to survive. Avodart will block this work around by PCa. My current PCa onc, Dr. Sartor has no problem with it. Current PSA is undetectable.

One thing that did catch my eye is the mention of B12 injections in your post - Sartor said to stay away from B12 and folic acid, PCa loves it.

Ed

[pjoshea13 in reply to EdBar]

Hi Ed,

Very interested to read of Sartor's view on B12 & folic acid. What PCa actually loves is the methyl component of folic acid (or folate). And for men who do not produce sufficient intrinsic factor in the stomach (needed for B12 uptake), there may be insufficient B12 in the body to allow access to methyl from donors such as folic acid. (One of the few good things about aging.)

But one must be careful to avoid serious B12 deficiency. By the time that symptoms appear, they cannot be reversed.

Dr. Myers once posted to his vlog the issue with LDL cholesterol [LDL-C]. Apparently, HDL is too big for HDL-C to pass into the cell. The smaller the protein the greater the chance of it being taken up. Unfortunately, ADT causes a shift in lipoprotein size to very low-density [VLDL] & VLDL-C can get anywhere (including into arterial walls.)

All solid cancers have a greater uptake of cholesterol & there is a case for using a statin to lower the supply & inhibiting production by the cancer. But cholesterol is a double threat in PCa, since cholesterol is the starting point for steroid hormone production. Seems prudent to prevent possible DHT production with Avodart. (Perhaps not necessary if on Zytiga.)

-Patrick

[jdm3 in reply to pjoshea13]

Yeah. I've been told no need for Avodart until I stop the Zytiga + Pred + Lupron. My T < 3 so according to the doc, "castrate T = castrate DHT". Never measured DHT so not sure that is correct and I understand in some men DHT is still an issue when on ADT.

[pjoshea13 in reply to jdm3]

For Dr. Myers himself, DHT was an issue. He was an overproducer.

So he was sensitive to the problem & found it hard to believe that most doctors who measured T ignored DHT.

While basic ADT (castration) deals with gonadal T, Myers said that DHT was the true target, so why not measure it? Only a small percentage of men produce significant DHT while castrate, & some of those need only one Avodart cap / week, but it can be a cause of treatment failure for those men.

I would add that on the way to CRPC, PCa might find how to produce DHT (from a path that does not involve T), & a blood test will probably not detect it because its creation & use is entirely within the cell. It's prudent to block that possibility, even if the probabilty is low.

Zytiga inhibits steroidogenesis (downstream of pregnenolone and progesterone) throughout the body, including within PCa cells. Although not at 100%, enough not to worry about DHT while on it, perhaps. If Zytiga fails, it will likely be due to reasons other than DHT. If on ADT without Zytiga, there is no protection from backdoor DHT unless on a 5ARi, preferrably Avodart.

-Patrick

[EdBar in reply to pjoshea13]

Snuffy actually recommended that I take B12 during our last consult, if I recall it was to help with some of the ADT cognitive issues I experience. When Sartor did a review of my supplements he told me to stop taking it “PCa loves it”, said the same about folic acid.

As for statins, I’ve used a statin for years but actually had to reduce the dose after being on a Mediterranean diet per Snuffy for a couple years. He said if LDL goes too low it can cause issues with brain function. So went from 20mg to 5mg of Crestor, Lipid panel still looks great.

Ed

[pjoshea13 in reply to EdBar]

B12 is complicated & I guess that Dr. Myers was being cautious. Deficiency can contribute to Alzheimer's. But I doubt that B12 would compensate for ADT-related cognitive issues - i.e. where onset was clearly related to ADT. Some here will know a lot more on the subject.

-Patrick