Not BAT, but ...

[pjoshea13]

New Chinese study below [1].

"While early studies indicated that high physiological doses of androgens might suppress rather than promote PCa cell growth in some selective CRPC patients ..."

This might be a reference to Huggins. No mention of Denmeade in the Abstract.

The "high-dose-androgen" used in the study was dihydrotestosterone, DHT.

"Together, these in vitro and in vivo data provide new insights for understanding the mechanisms underlying high-dose-DHT suppression of the EnzR {Enzalutamide-resistant} CRPC cell growth, supporting a potential therapy using high-dose-androgens to suppress CRPC progression in the future."

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/353...

Cell Death Discov

. 2022 Mar 22;8(1):128. doi: 10.1038/s41420-022-00898-6.

High-dose-androgen-induced autophagic cell death to suppress the Enzalutamide-resistant prostate cancer growth via altering the circRNA-BCL2/miRNA-198/AMBRA1 signaling

Lei Chen # 1 2 , Yin Sun # 2 , Min Tang # 2 3 , Denglong Wu # 4 , Zhendong Xiang 4 , Chi-Ping Huang 5 , Bosen You 2 , Dongdong Xie 1 , Qinglin Ye 1 , Dexin Yu 6 , Chawnshang Chang 7 8

Affiliations collapse

Affiliations

1 Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230000, China.

2 George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA.

3 Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

4 Department of Urology, Tongji Hospital, School of Medicine, Tongji Universiry, Shanghai, 200092, China.

5 Sex Hormone Research Center, Department of Urology, China Medical University/Hospital, Taichung, 404, Taiwan, ROC.

6 Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230000, China. [e-mail].

7 George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA. [e-mail].

8 Sex Hormone Research Center, Department of Urology, China Medical University/Hospital, Taichung, 404, Taiwan, ROC. [e-mail].

# Contributed equally.

PMID: 35318303 DOI: 10.1038/s41420-022-00898-6

Abstract

Androgen deprivation therapy (ADT) is a gold standard treatment for advanced PCa. However, most patients eventually develop the castration-resistant prostate cancer (CRPC) that progresses rapidly despite ongoing systemic androgen deprivation. While early studies indicated that high physiological doses of androgens might suppress rather than promote PCa cell growth in some selective CRPC patients, the exact mechanism of this opposite effect remains unclear. Here we found that Enzalutamide-resistant (EnzR) CRPC cells can be suppressed by the high-dose-androgen (dihydrotestosterone, DHT). Mechanism dissection suggested that a high-dose-DHT can suppress the circular RNA-BCL2 (circRNA-BCL2) expression via transcriptional regulation of its host gene BCL2. The suppressed circRNA-BCL2 can then alter the expression of miRNA-198 to modulate the AMBRA1 expression via direct binding to the 3'UTR of AMBRA1 mRNA. The consequences of high-dose-DHT suppressed circRNA-BCL2/miRNA-198/AMBRA1 signaling likely result in induction of the autophagic cell death to suppress the EnzR CRPC cell growth. Preclinical studies using in vivo xenograft mouse models also demonstrated that AMBRA1-shRNA to suppress the autophagic cell death can weaken the effect of high-dose-DHT on EnzR CRPC tumors. Together, these in vitro and in vivo data provide new insights for understanding the mechanisms underlying high-dose-DHT suppression of the EnzR CRPC cell growth, supporting a potential therapy using high-dose-androgens to suppress CRPC progression in the future.

© 2022. The Author(s).

[Scout4answers]

Nice find Patrick

So how do we take or use dihydrotestosterone?

[Hidden in reply to Scout4answers]

T converts to DHT via 5AR. (5-10%)So, for BAT do T and don't use a 5ARI (I don't because I think we might want DHT to be high on the high phase).

[noahware in reply to Hidden]

If you were trying to cycle your 5ARI, then I think finasteride would be the only option. Dutasteride stays active in the body WAY longer (w/ a half-life of 5 weeks vs about 5 hours).

[Hidden in reply to noahware]

Fina is the only realistic option that I know of. I used to do duta but had to let it wash for months prior to ending SPT.

[cigafred]

Grateful for the information. Do you expect this will affect your own regimen?

[Hidden in reply to cigafred]

No changes for mine. An excellent confirmation though!

[pjoshea13 in reply to cigafred]

Well, as Dr. Myers has said, the point of ADT is to control DHT - not T. So it makes perfect sense that the study used DHT.

When I began my BAT experiment I wondered if I should stop Avodart. It has a very long half-life, so you can't quickly stop using it:

"The terminal elimination half-life of dutasteride is approximately 5 weeks at steady state. The average steady-state serum dutasteride concentration was 40 ng/mL following 0.5 mg/day for 1 year."

Not sure why I decided to continue, but BAT was working well with Avodart. And Denmeade aims for a T of ~2,000 ng/dL for his DNA double-strand breaks. He doesn't mention a DHT target - LOL.

But maybe BAT would work better without Avodart. As RSH1 noted, Denmeade excludes men who are current 5ARI users. I assumed that was for his own convenience - one less variable to control for.

I think maybe I will stop taking Avodart, and keep an eye on my BAT numbers as the 5ARI slowly clears from my body,

-Patrick

[Hidden]

Thanks. I've read some studies that indicate that DHT works, possibly via the same and/or different mechanisms than T. Note that Danmeade doesn't use 5ARIs in his program. I haven't been using 5ARIs outside of finasteride during the low T phase.

[Hidden]

Another possible DHT benefit: jme.bioscientifica.com/down...

[pjoshea13 in reply to Hidden]

I absolutely did not want to inhibit DHT in my early years, since a metabolite of DHT is 3beta-adiol, which is the natural ligand for ER beta.

As I have mentioned before, DHT is your friend until DHT is no longer your friend. That is the sign that ERbeta has exited the scene. That's when I started using Avodart.

-Patrick

[Hidden in reply to pjoshea13]

How do you tell when DHT is no longer your best buddy?

[pjoshea13 in reply to Hidden]

I was using continuous T for a few years & PSADT was around 24 months. When PSADT got below 9 months, I moved to Plan B - 3 months T / 3 months ADT. That was good for many years.

But for most men at diagnosis, the AR is 'wild type' & ERbeta is still a presence. If T is low, DHT might still be protective.

Too much of a paradox for many, I suppose.

-Patrick

[Hidden in reply to pjoshea13]

Thanks. I track PSADT and PSA and set decision points to exit therapies. I was on continuous T for 2 years and my trip was reached. So now a modified BAT. PSA based. Been at it 7 months. So far it is going well and I predicted 6 months so exceeded it. I thought my PSA nadir would be around 0.2 at this time, it's zero.

when trip is triggered I might add the 5ARIs to see if that pushes it on for a bit. Fasting, Keto, high E burst, next perhaps Xtandi and then modified BAT repeats with Xtandi, then perhaps RT. Hopefully, there won't be anything needed after that.

[Hidden in reply to pjoshea13]

Some of the research is around DHT causing DSBs even more than T does. I guess maybe a trial of 5ARIs when PSA doesn't react well to BAT?

[Justfor_ in reply to Hidden]

We need to know the efficacy of either because the suppression of DHT increases tT. I was 800+ tT and it climbed to 1100+ after starting Avodart. Now, after starting low dose Bicalutamide it climbed to 2000 or thereabout. One lab reports up to 2500 the other 1800+. The only explanation I can think of regarding this discrepancy is that high values like these may fall outside the calibrated range for either or both labs. And on top of this, my DHT is low in percentage but over normal range in absolute terms.

[Hidden in reply to Justfor_]

DHT is supposedly 5x as androgenic as T. Bicalutamide blocks approx 80% of T->AR activity. When I did Bicalutamide my T went above 2000. Shouldn't have gone quite that high but it did and I had multiple blood tests.

My current lab reports up to 7500 (finally I can see what my T value is - I thought).

I have been doing Nandrolone and a standard T test can't distinguish between Nandrolone and T. I had my T measured yesterday and it T is >7500 (my doctor called in a panic). I don't know exactly what happened because my Nandrolone should be about 1000 and my T should be 1800. Obviously, something else is going on. Or maybe my calculations are way off (last 3 years usually get them within 5% though - took a few months to figure out my own "bio-absorption factor".

The LC-MS T test should distinguish between the two though and I'm going to have that done tomorrow. If it's still off I'm going to drop Nandrolone and after it clears have my T tested again.

If your DHT is low-normal with 2000+ T floating around, perhaps your 5AR conversion doesn't convert that much. Some sups and even foods supposedly interfere with it. Finasteride and/or dutasteride are going to really hammer it. Duta more than Fina. Duta has a super long half life though.

I think we're all guessing when it comes to DHT, T, Nandrolone metabolites etc. There isn't a great consensus on any of it.

Tell me what you want to prove and I'll prove it... Kind of reminds me of my engineering days. When I was in my 20s they loved me because I'd show the managers whatever they wanted. I got older and ethics took over. I was no longer the fair-haired boy. I morphed into a thorny old man and they were relieved when I left.

[Justfor_ in reply to Hidden]

This may explain the discrepancy. Some supplement adds to the tT as measured by lab A but not by lab B. Since Nov. last, when started taking Bicalutamide, I have 3+3 measurements:

Lab A: 2255, 3090, 2525 ng/dl

Lab B: 981, 1650, 1700 ng/dl

Latest DHT: 0.92 ng/ml (0.03-0.50 normal range) -> 5.4% of tT

[Hidden in reply to Justfor_]

So, a standard test vs. a mass spectrometry test? The MS test is the best.

T-> DHT average conversion is about 10% but Casodex might mess up the conversion ratio. So, assuming your non-Caso T is about 1000 you're converting about 9%. Normal.

[Magnus1964]

Great find, I will bring this up to my research doc. Thanks.

[George71]

I have been supplementing super T for about 2 years and taking Avadart.

For the 4 years prior to that I was only taking Avadart .5 mg daily.

When I started Avadart (5 years ago) my PSA doubling time went from 7 months to over 2 years. Currently PSA is 1.7 ---- it was 0.7 when I started Avadart in late 2016 based on Snuffy Meyers recommendation and clinical trial results.

[George71 in reply to George71]

Patrick --- I just saw that you had already posted this or I would not have post on the same findings. Sorry

[George71]

Patrick,

You said you are doing 3 months on T injections and then 3 months off of T while on ADT. Why not just stop T injections every 3 months and then your T will drop to zero for 3 months without needing to take ADT and ADT's other negative side effects.

It seems 3 months T with Avadart (to block the DHT making ability) and then 3 months with nothing but Avadart would accomplish the same thing?

Apparently many people get off ADT (for a vacation) and go 5 or 6 months before they begin making any Tat all (naturally). In their case I think they might do better by taking T immediately when starting an ADT vacation... that way the cancer would not try to mutate around the no T problem (allowing for more years of BAT).

[George71]

As you know, Snuffy Meyers and LE cited a trial that covered over 30,000 non cancer males and lasted 17 years and concluded that merely taking Finasteride (which lowers DHT making ability) reduced the incidence of PCa by 25%.

I wouldn't think taking DHT would ever be a good thing until CRPC and only for a brief shock purpose. Probably super T cpr would be as good or better like Denmeade.

[nuc1111]

I’m Brac2 Gleason 9 whose psa was 200 at dx and bumping from 14-22 after 7 months zytiga and orgovix- MO advises prostate bed radiation

Do you think Bat or variation of it would be helpful

For me at some point?

Pelvic lymph nodes and some bladder involvement-no bone Mets

Thanks so much

Ed

[pjoshea13 in reply to nuc1111]

I view BAT as being a way of extending the duration of ADT - i.e. delaying CRPC.

My version of BAT though, is to apply a jolt of testosterone every two months.

IMO this is best started along with ADT.

-Patrick

[nuc1111 in reply to pjoshea13]

Thanks Patrick----