Progesterone Receptors in Prostate Cancer.

[pjoshea13]

New study below [1].

The trouble with Charles Huggins castration therapy of 1941, which looks as though it will be around in 2041, is that not only is it not a cure, but it has led to an obsession with the androgen receptor [AR]. Most of the alterations that occur in the AR are not due to the natural progression of the cancer, but rather as responses to treatment. The AR is often quite normal at diagnosis.

What isn't normal at diagnosis is estrogen receptor [ER] balance.

In a young healthy prostate we expect to find ERalpha in stroma cells & ERbeta in epithelial cells. ERalpha is pro-growth, whereas ERbeta is growth-resistant. By the time that PCa is emerging in the epithelium, ERbeta is being replaced by ERalpha. And yet there is very little interest in this fact.

Or in the fact that our estradiol:testosterone ratio [E2:T] is much higher than it was decades earlier.

If there is little interest in E2, there is virtually no interest in progesterone.

The presence of the progesterone receptor [PR] in stromal cells has been known for several decades.

From 2001, Bonkoff (Germany):

"The recent discovery of the classical estrogen receptor alpha (ERalpha) in metastatic and recurrent prostatic adenocarcinoma suggests that estrogens are implicated in prostate cancer progression."

"To get more insight into estrogen signaling in prostate cancer tissue, the current study has examined the immunoprofile of the estrogen-inducible progesterone receptor (PR), and evaluated its relation to ERalpha gene expression."

"In primary tumors, the PR was detectable in 36% of primary Gleason grade 3 (5 of 14 cases), 33% of primary Gleason grade 4 (5 of 15 cases), and in 58% of primary Gleason grade 5 tumors (7 of 12 cases). None of the 41 primary tumors investigated revealed significant PR expression in more than 50% of tumor cells. Conversely, moderate to strong receptor expression was observed in 60% of metastatic lesions (9 of 15 cases), and in 54% of androgen-insensitive tumors (38 of 71 cases). Irrespective of grades and stages, the presence of the PR was invariably associated with high steady state levels of ERalpha mRNA ..."

"The progressive emergence of the PR during tumor progression obviously reflects the ability of metastatic and androgen-insensitive tumors to use estrogens through a ERalpha-mediated pathway. The present data provide a theoretical background for studying the efficiency of antiestrogens and antigestagens in the medical treatment of advanced prostate cancer."

...

Mifepristone is a steroidal antiprogestogen that acts as a competitive progesterone receptor antagonist. [3]

Check (2010) had the crazy idea to try it out on male mice with male cancers [4]:

"Eight-week-old mice with a strong predisposition to testicular or prostate cancer were gavaged with mifepristone. Olive oil was used in place of mifepristone in order to provide a control. Survival rates and body conditioning scores were compared after one year of treatment."

"... data support the hypothesis that various cancers may utilize a mechanism that is present in normal pregnancy that involves secretion of a progesterone-induced protein that blocks natural killer cell activity. The hypothesis that the cancer cells have the capacity to direct local progesterone production is supported by demonstrating the benefit of a progesterone receptor antagonist in tumors restricted to males."

...

Grindstat (2015), Norway, reported [5]:

"In univariate analyses, high tumor cell density ... and high tumor stromal cell density level ... of progesterone receptor were both significantly associated with tumor progression and clinical failure. In multivariate analysis, progesterone receptor expression in tumor cells was an independent negative prognostic factor for clinical failure (HR: 2.5 ...)."

The new study is a follow-up:

"The role of steroid hormones in carcinogenesis of the prostate is to some extent unraveled thorough the effect of androgen deprivation therapy on prostate cancer (PCa) progression. Other members of the steroid hormone family, such as progesterone, are also implicated in PCa, but progesterone's role remains undefined. This study aimed to examine the distribution of progesterone receptor isoforms (PGRA, PGRB) in PCa tissue and their association with clinical endpoints. This was conducted retrospectively by collecting radical prostatectomy specimens from 535 patients. Tissue was analyzed using tissue microarray, where representative tumor areas were carefully selected. ... Herein, we discovered a solely stromal PGRA- and a stromal and epithelial PGRB expression. Further, a high PGRB expression in tumor tissue was associated with an unfavorable prognosis in both univariate and multivariate analyses: Biochemical failure (HR: 2.0 ...) and clinical failure (HR: 2.5 ...)"

...

Abiraterone acetate (Zytiga) inhibits CYP17A1 & thus prevents the conversion of pregnenolone and progesterone to downstream steroid hormones. Presumably, this leaves one with a surfeit of pregnenolone and progesterone. Might not be relevant, but it's worth noting.

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/300...

[2] ncbi.nlm.nih.gov/pubmed/115...

[3] en.wikipedia.org/wiki/Mifep...

[4] ncbi.nlm.nih.gov/pubmed/211...

[5] ncbi.nlm.nih.gov/pubmed/257...

[cesanon]

Patrick, can you translate this into a what might be an actionable treatment strategy for today or for the future?

[pjoshea13 in reply to cesanon]

If progesterone has a significant role in advanced PCa, it can be blocked with Mifepristone.

In the absence of clinical trials, there is not much chance of getting it prescribed.

But if all else has failed, one may somehow be able to get hold of Mifepristone - after all, it is used for abortions.

I doubt that many PCa docs are aware of the progesterone receptor research. & that is unlikely to change soon.

-Patrick

[cesanon in reply to pjoshea13]

"I doubt that many PCa docs are aware of the progesterone receptor research. & that is unlikely to change soon."

Where is Dr. Myers when we need him.

Is anyone aware of any oncologist who may be stepping up to match his willingness to invest the time and energy to keep up with, and implement, new advances into cutting edge treatment protocols.

Is there any Doc out there doing this now?

[curt504a in reply to cesanon]

I would suggest, 2nd or 3rd opinions by an integrative oncologist. There are many but here is one I met at a conference. She has many youtubes up. Search Youtube for here name:

Dawn Lamanne, youtube.com/results?search_...

and her home page: oregonio.com/news/

From the books we've read, conferences we've gone to: cancer is very smart, use the same protocol too long and it morphs into one that that protocol no longer works on. The latest ideas have to do with pulsing and rotating the agents being used, protocols.

In parallel use the starve the CTCs and tumor tactic: careoncology.com

[curt504a]

Hi Patrick,

Getting my path out of the way first, I had a 3T MRI at this place, $2.5k cash out of pocket and was glad I did. No side effects prone needles with their in-accuracies etc.

sperlingprostatecenter.com/

We went to Ancestral Health Symposium 2018, google AHS18. Home page: ancestralhealth.org/confere...

Listened to Oncologist Dawn Lamanne, youtube.com/results?search_..., and her home page: oregonio.com/news/

Dr Lamanne's presentation ended on a path of PCA using the current popular castration protocol. Her talk followed:

Androgen sensitive PCA --> castration + chemo --> antrogen insensitive metastatic cancer and now highly aggressive.

==== Earlier in this year we went to the medical cannibus conference: Patients out of time, a very high quality top TOP presenters. Over and over the story was that metastatic cancer is worse then the original tumor. Non-standard of care protocols (last 24 mo) are now focusing on CTC's (circulating Tumor Cells) knocking them out to stop the metastasis.

An org we met at the Orlando conference: careoncology.com

CARE is mentioned in this increadible book by a patent: Starving Cancer

amazon.com/gp/product/09519...

Nasha Winters, Metabolic approach to cancer is also tops, per our recent cancer seminars and followup book reading;

amazon.com/gp/product/B071Z...

I realize I should be posting this on its own thread, but ... was saving this up and your mention of progesterone. Your comment:

>> is that not only is it not a cure, but it has led to an obsession with the androgen receptor [AR].

Triggered my interest to re tell what I heard from Dr Dawn Lemanne, at the AHS18 conference.

Best of luck to all!!!

[Hidden in reply to curt504a]

Interesting stuff on Dawn's website on how to evaluate an oncologist -- competent (most are) vs engaged -- willing to go beyond standard-of-care.

[cesanon in reply to curt504a]

"medical cannibus conference" I would be cautious about the cannabis.

Dr. Myers seemed to observe some association between self-medication with cannabis and aggressive prostate cancer growth in his clinical practice. And prostate cancer cells do have more cannabinoid receptors.

When you go to hospice, the cannabis may be good for the pain, but until then what it might be doing is improving the health of your tumors.

[George71]

Patrick,

I have the same question as cesanon,

Can you translate this into a what might be an actionable treatment strategy?

[pjoshea13 in reply to George71]

George, see my response to him. -Patrick