Progesterone Receptor.: ADTMan posted... - Advanced Prostate...

Advanced Prostate Cancer

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Progesterone Receptor.

pjoshea13 profile image
11 Replies

ADTMan posted "Progesteronr Bad" yesterday [1]

The article cited refers to a new study - see [2] for full text.

"Inhibiting 3βHSD1 to eliminate the oncogenic effects of progesterone in prostate cancer"

It might be helpful to glance at the steroidogenesis chart at this point [3].

Steroidogenesis begins with cholesterol & the two main early hormones produced are pregnenolone (the so-called 'grandmother' of all steroid hormones) & progesterone.

Abiraterone inhibits the enzyme that converts those hormones into downstream androgens such as DHEA, testosterone [T] & DHT. This presumable leads to higher than normal levels of pregnenolone & progesterone. Does that matter?

The new study claims that progesterone is indeed bad for PCa patients.

"To inhibit the conversion of pregnenolone to progesterone, steroidogenic enzyme 3βHSD1 is a promising target ... Currently, there is no 3βHSD1 inhibitor available in clinic." However, the natural isoflavone (a flavonoid) biochanin A turns out to be an inhibitor.

Biochanin A can be found in soy or red cover extracts, e.g. [4].

Statin drugs might lower pregnenolone & progesterone by reducing cholesterol.

***

I have a couple of progersterone threads going back 4 years, but this is a fresh start.

When I was diagnosed in 2004, there were men who were using 'natural' progesterone based on the writings of Dr. John Lee. Lee had died in 2003 but he remained influential, although I never succumbed. He still has a website. LOL

"Mifepristone is a steroidal antiprogestogen." "In the presence of progesterone, mifepristone acts as a competitive progesterone receptor antagonist" [5]

In a 2010 mouse study [6], there was some indication that a progesterone receptor antagonist might have a place in PCa therapy:

"There was a significant reduction of adverse events (i.e. a tumor >1 cm or bleeding from the penis) in those with prostate cancer treated with mifepristone."

A 2015 Norwegian paper [7] reported that "High progesterone receptor density in tumor cells of the prostate cancer tumor is an independent negative prognostic factor for clinical failure."

"The progesterone receptor (PGR) exists in two isoforms, PGR-A and PGR-B, and both are transcribed from the same gene. It belongs to the same receptor family as the androgen- and oestrogen receptors, which are expressed in both stromal and tumor cells of the PCa tissue. Currently, there is a general agreement of PGR presence in the stromal cells of PCa. Results regarding PGR’s presence in tumor cells, however, are conflicting. Thus, the importance of PGR in the human prostate and in prostate carcinogenesis has never been adequately explained. As a consequence we sought to evaluate the expression of PGR in both tumor cells derived from epithelia (TE) and tumor stromal cells (TS) in malignant prostatectomy specimens and found the PGR density level in both TE and TS to be associated with PCa progression."

Using radical prostatectomy tissue, it was "found that a high density level of PGR in TE is an independent prognostic factor for progression to CF in PCa. Further, high PGR density levels are significant for progression to CF in patients with Gleason score ≥ 7."

In 2018, Thea Grinstad followed up with [8]:

"Progesterone Receptors in Prostate Cancer: Progesterone receptor B is the isoform associated with disease progression"

***

The literature on PCa & progesterone is a bit muddy, but I'm inclined to follow Grinstad & be wary of the role of the progesterone receptor in PCa. I most certainly do not intend to purchase natural progesterone (sorry Dr, Lee.).

Is there a role for Mifepristone?

Abiraterone basically inhibits production of all of the major steroid hormones except pregnenolone & progesterone. Do we need to eradicate progesterone as well? Is that safe? How much biochanin A is required to make a difference. I doubt that this could be done with a Michael Milkin all-soy diet. Ugh!

-Patrick

[1] healthunlocked.com/advanced...

[2] cell.com/cell-reports-medic...

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

[4] amazon.com/Natures-Answer-C...

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

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

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

(full text) journals.plos.org/plosone/a...

[8] ncbi.nlm.nih.gov/labs/pmc/a...

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Scout4answers profile image
Scout4answers

Patrick

Interested to see your reference to Michael Milkin all-soy diet.

Being involved in the markets and knowing of his 20 battle with PCa he was one of the first sources I looked to for an answer to the PCa dilemma.

I ordered his out of print books trying to read the chicken scratches as to what he had done to survive. The books ( they are mostly cook books) offer no details of what therapies he had done. His Foundation does not mention his books or his diet and there is no info about him personally.

My investigation into Soy left me with mixed opinions as to whether it is good or bad for PCa.

Your thought on Milkin and or Soy?

pjoshea13 profile image
pjoshea13 in reply to Scout4answers

In the days leading up to surgery, my poor wife was already working through the first cookbook. The 'Junk Bond King' loves junk food, so he hired a chef who could replicate his favorites with soy.

It was a relief to both of us when I asked her to stop. But top marks to the chef, the results were better than could be hoped.

I was impressed that Milken was alive at the time - 18 years ago. And he is still alive - & pardoned by Trump in 2020. No longer an ex-felon? I wonder what that cost?

Milken was sentenced to ten years. He was fined $600,000,000. His sentence was reduced to two years, due to 'cooperation'. That was in 1993. He was immediately diagnosed with advanced PCa. He was 47.

Doubtless he would have died in prison. By the time I was diagnosed, he had survived 11 years. So I was extremely interested in his soy diet.

Also doubtless, he left prison with personal wealth more than all of us put together. That & his aggressive approach to problems probably saved his life. He involved himself in research & became a powerful figure in the PCa world. At 76, Milken has survived 29 years!

When I came out of hospital after my RP, I remember wondering if it was better to use a high dose soy extract. The product was Life Extensions 'Ultra Soy'. Today it is $57 for 150 caps (5 a day). Back then, one was supposed to take 5 four times a day. Today that would be $228 / month. In the end, I ditched the diet & went with the caps.

A while later, I became aware of papers that claimed that genistein was biphasic - growth-promoting at physiologal levels (from diet) & anti-proliferating at pharmaceutical levels. This was reported for breast cancer and PCa.

Actually, the first, below [1] is from 1997, but I wasn't into BCa studies initially:

"Phytoestrogen concentration determines effects on DNA synthesis in human breast cancer cells"

"At 0.1-10 microM, coumestrol, genistein, biochanin A, apigenin, luteolin, kaempferol, and enterolactone induced DNA synthesis 150-235% and, at 20-90 microM, inhibited DNA synthesis by 50%."

The second [2] is from 1999:

"The two phyto-oestrogens genistein and quercetin exert different effects on oestrogen receptor function"

"Genistein exerted a biphasic effect on growth of MCF-7 cells, stimulating at low and inhibiting at high concentrations, whereas quercetin was only growth inhibitory."

[2004] [3]:

"Phyto-oestrogens, their mechanism of action: current evidence for a role in breast and prostate cancer"

"In vitro studies have shown that genistein exerts biphasic effects on cancer cell growth, stimulating growth at low concentrations (<10 microm) and inhibiting growth at high concentrations (>10 microm), which suggests that low phyto-oestrogen levels may stimulate cancer growth in vivo. Plasma phyto-oestrogen concentrations of >10 microm cannot be achieved by dietary intake and therefore the timing of exposure to phyto-oestrogens may be of the utmost importance in determining their chemopreventive effects. The present paper reviews the effects of phyto-oestrogens on breast and prostate cancer in vivo and in vitro and discusses possible mechanisms of action via which these compounds may exert their effects."

[2006] [4]:

"Genistein modulates prostate epithelial cell proliferation via estrogen- and extracellular signal-regulated kinase-dependent pathways"

"Low concentrations of genistein (0-12.5 micromol/L) significantly increased cell proliferation and ERK1/2 activity (P<.01) in RWPE-1 cells, while higher concentrations (50 and 100 micromol/L) of genistein significantly inhibited cell proliferation and ERK1/2 activity (P<.001). A similar biphasic effect of genistein on MEK1 activity, an ERK1/2 kinase, was also observed."

[2009] [5]:

"Identification of a biphasic role for genistein in the regulation of prostate cancer growth and metastasis"

"Our results suggest the presence of a biphasic regulation of CaP growth and metastasis by genistein, warranting careful examination of the effects of genistein on hormone-dependent cancers in a chemotherapeutic setting."

[2019] [6]:

"Achieving the balance: Biphasic effects of genistein on PC-3 cells"

"This study examined the response of PC-3 cells to physiological (0.5, 2.5, 5, 10 μM) and pharmacological (50 μM) concentrations of genistein which is a main bioactive compound in soy. Following 48 hr genistein treatment, cell-based assays and genome-wide microarray were performed. It was evidenced that maximal physiologically achievable concentrations of genistein (0.5-10 μM) lead to significant increase in cell viability (p < 0.05) and decrease in migration at 0.5 μM (p = 0.000) and 10 μM (p = 0.001). The highest percentage of apoptotic cells was obtained at 50 μM. Microarray analysis gave the most critical pathways such as cell cycle regulation and proliferation, tumorigenesis, DNA damage and repair, stress response, and apoptosis. Physiological concentrations (≤10 μM) induced activation of CDKs, MAPKs, and RPSKs, while high concentrations of genistein (>10 μM) appeared to have a novel mechanism of action, specifically down-regulating TGF-β by decreasing specifically SMAD 2/3,4 which are in the downstream TGF-β signaling cascade. PRACTICAL APPLICATIONS: This study highlights for the first time that maximal physiologically achievable concentrations of genistein (0.5-10 μM) have proliferative effects evidenced by alterations in global gene expression patterns of PC-3 cells. Our results particularly represent a closer examination of dietary genistein consumption for the prevention and/or treatment of cancer that maximal physiologically achievable concentrations of genistein could have detrimental effects on individuals with prostate cancer. Further studies as in vivo would be necessary to remove shadows on the effect of genistein on prostate cancer progression."

***

I could never manage to take 4x5 UltraSoy caps, but did take 5/day for years. LEF eventually decided that 5/ day was enough. It is clearly a product aimed at cancer - who but a cancer patient would consider a pharma dose of genistein to be a good idea?

***

After diagnosis, the beta estrogen receptor [ERbeta] will be at the highest level in our PCa cells that we will ever see. As PCa progresses, the cancer downregulates ERbeta & upregulates ERalpha.

Genistein preferentially binds to ERbeta. Without ERbeta, we cannot counteract the growth-promoter ERalpha.

I don't know if I would benefit from genistein at this point.

Incidentally, there are a number of studies that show that genistein radiosensitizes PCa cells. I used high-dose UltraSoy throughout my two series of spinal radiation.

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/934...

[2] pubmed.ncbi.nlm.nih.gov/103...

[3] pubmed.ncbi.nlm.nih.gov/150...

[4] pubmed.ncbi.nlm.nih.gov/161...

[5] pubmed.ncbi.nlm.nih.gov/193...

[6] pubmed.ncbi.nlm.nih.gov/313...

Scout4answers profile image
Scout4answers in reply to pjoshea13

Thanks for a thoughtful and well researched reply - as always!

you said:

Incidentally, there are a number of studies that show that genistein radiosensitizes PCa cells

Does that mean genistein may be helpful before and during radiation?

pjoshea13 profile image
pjoshea13 in reply to Scout4answers

PCa begins to resist radiation treatment beginning with the first session. The knee-jerk survival resposes include activation of NF-kB & HIP-1alpha.

I began using genistein days before starting radiation and daily until some time after the final session (at least a month.)

Important to use a pharma dose.

[1] "Genistein potentiates the radiation effect on prostate carcinoma cells"

[2] "Enhancing effect of isoflavonoid genistein on radiosensitivity of DU145 prostate cancer cells"

[3] "Genistein potentiates inhibition of tumor growth by radiation in a prostate cancer orthotopic model"

[4] "Combination of genistein with ionizing radiation on androgen-independent prostate cancer cells"

[5] "Genistein inhibits radiation-induced activation of NF-kappaB in prostate cancer cells promoting apoptosis and G2/M cell cycle arrest"

[6] "Soy isoflavones enhance radiotherapy in a metastatic prostate cancer model"

[7] "Radiation-induced HIF-1alpha cell survival pathway is inhibited by soy isoflavones in prostate cancer cells"

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/112...

[2] pubmed.ncbi.nlm.nih.gov/151...

[3] pubmed.ncbi.nlm.nih.gov/154...

[4] pubmed.ncbi.nlm.nih.gov/155...

[5] pubmed.ncbi.nlm.nih.gov/166...

[6] pubmed.ncbi.nlm.nih.gov/173...

[7] pubmed.ncbi.nlm.nih.gov/191...

Scout4answers profile image
Scout4answers in reply to pjoshea13

Interestingly, treatment with soy isoflavones did not increase metastasis to para-aortic lymph nodes in contrast to the consistent increase caused by pure genistein. Histologically prostate tumors, treated with soy isoflavones and radiation, showed tumor destruction and in situ tissue alterations, comparable with genistein and radiation effects. However, genistein, but not soy isoflavones, caused induction of HIF1-alpha in prostate tumors, suggesting that induction of hypoxia by pure genistein could contribute to increased metastasis. Our studies demonstrate the safety and potential role of soy isoflavones for enhancing the therapeutic effect of radiotherapy in prostate cancer.

Looks like Soy isoflaones but Genistein are helpful during radiation, anything else that you can suggest during radiation? I already have Melatonin on my list from our previous discussions.

Kuanyin profile image
Kuanyin

Hi Patrick,Don't know whether you remember or not, but many years ago there was a guy who popularized the benefits of Red Clover tea. One of his suggestions was to prepare a large glass (that was emphasized) bottle of Red Clover tea in the morning which one drank throughout the day. Naturally the tea was a "cure all" for all kinds of maladies. I'm not quite sure if I drank the stuff (at this age memory and imagination often blend together), but since I like to drink tea I may purchase some on Amazon tomorrow when my Citibank reward points will be available.

--K

pjoshea13 profile image
pjoshea13 in reply to Kuanyin

The only thing that has stayed in my head over the years regarding red clover, is that it can make ewes infertile come tupping time, if it is growing where they graze.

Best, -Patrick

Perhaps that is one of the reasons that soy appears to be somewhat preventative for occurrence and, for most phenotypes, progression?

I found a small RCT that showed an increase in progesterone after 9 weeks of therapy:

A Study to Determine Safety and Tolerability of Enzalutamide (MDV3100) in Combination With Abiraterone Acetate in Bone Metastatic Castration-Resistant Prostate Cancer Patients - Study Results - ClinicalTrials.gov

clinicaltrials.gov/ct2/show...

I don't see the baseline but the change might be significant (1.4 nmol/L when normal men's levels are around 2 nmol/L).

This small RCT concluded that mifepristone (blocks progesterone) was not effective for the CRPC subjects:

A phase II study of mifepristone (RU-486) in castration-resistant prostate cancer, with a correlative assessment of androgen-related hormones – PubMed pubmed.ncbi.nlm.nih.gov/183...

Some researchers think that we just don't know enough about progesterone and PCa. It probably plays a role but how and when on what stage?

Would mifepristone show more efficacy in larger trials or with hormone-sensitive men?

pjoshea13 profile image
pjoshea13 in reply to

Perhaps if one could identify the men with high levels of progesterone receptors in their tumors, mifepristone would show efficacy. It is an effective drug for females, so has proven bioavailability.

Thanks for your research.

The key papers in my post were from Norway. No interest in the U.S. regarding PCa & estrogens, let alone progesterone.

-Patrick

in reply to pjoshea13

I'm going to put this in my "test this to see if it helps" list. I can test once to see if it affects PSA or PSA fall-time during an HSPC, high testosterone BAT phase, once during a low phase, and repeat for when/if I become CRPC.

j-o-h-n profile image
j-o-h-n

Ironic: MICHAEL MILK in all-soy diet....

Good Luck, Good Health and Good Humor.

j-o-h-n Friday 03/18/2022 11:03 PM DST

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