"The roles of estrogen and progesterone in human prostate carcinogenesis have been only recently recognized."
Not true. Some recognized it at least 15 years ago, but it is not close to being accepted in the US, so far as I can tell.
It has long been know, however, that ERbeta is down-regulated in PCa cells. Goodbye to protection from estradiol.
"The expressions of ER-β and PR were significantly higher in the epithelium in benign cases as compared with malignant cases. Ki-67 expression was significantly higher in the malignant group as compared with the benign group."
Ki-67 has long been used as a measure of proliferation, although I don't recall anyone on a PCa group saying that they had been tested.
"Antigen KI-67 is a nuclear protein that is associated with and may be necessary for cellular proliferation." [2]
"Ki-67 is an excellent marker to determine the growth fraction of a given cell population. The fraction of Ki-67-positive tumor cells (the Ki-67 labeling index) is often correlated with the clinical course of cancer. The best-studied examples in this context are prostate, brain and breast carcinomas, as well as nephroblastoma and neuroendocrine tumors." [2]
Immunoexpression of Estrogen Receptor-β and Progesterone Receptor in Prostate Adenocarcinoma, Does It Inhibit Neoplastic Proliferation and Invasion?
Kinjal N Bera 1 , Shakti K Yadav 1 , Om Prakash 2 , Sompal Singh 1 , Namrata Sarin 1
Affiliations collapse
Affiliations
1 Department of Pathology, North Delhi Municipal Corporation Medical College and Hindu Rao Hospital, Delhi, India.
2 Department of Urology, North Delhi Municipal Corporation Medical College and Hindu Rao Hospital, Delhi, India.
PMID: 32108623 DOI: 10.4103/IJPM.IJPM_467_18
Abstract
Context: The roles of estrogen and progesterone in human prostate carcinogenesis have been only recently recognized.
Aims: This study was conducted to evaluate the expressions of esterone receptor-beta (ER-β), progesterone receptor (PR), and Ki-67 in benign and malignant lesions of the prostate.
Settings and design: The study was conducted at a tertiary care hospital. It was an analytical cross-sectional study.
Materials and methods: We selected a total of 39 cases including 26 cases of benign prostatic hyperplasia and 13 cases of adenocarcinoma prostate. The proportion of cases showing expression for ER-β, PR, and Ki-67 was noted for both groups. A difference in immunoexpression between benign and malignant cases was evaluated. Association between receptor expression and Gleason grade was evaluated for malignant cases.
Statistical analysis used: To compare the difference in expressions of ER-β, PR, and Ki-67 Mann-Whitney U test was used. Association between ER-β, PR, and Ki-67 expression and Gleason grade was analyzed using the Chi-square test.
Results: ER-β expression was seen in all benign and malignant cases, whereas the majority of the malignant cases (61.54%) were negative for progesterone expression. Epithelial expressions of ER-β and PR were significantly higher in benign as compared with malignant lesions. Malignant cases showed a significantly higher expression of Ki-67. However, we did not find any association between the expressions of these markers with Gleason grade.
Conclusions: The expressions of ER-β and PR were significantly higher in the epithelium in benign cases as compared with malignant cases. Ki-67 expression was significantly higher in the malignant group as compared with the benign group.
Would not the lower expression of ER-B receptor in malignant PC be at least partially compensated for by higher levels of estradiol such as from patch treatment?
The loss of ERbeta & the ascendancy or ERalpha in malignant cells is not a concern when on ADT. With classic ADT, testosterone [T] & estradiol [E2] are both very low. With the high-dose E2 patch, T is very low. E2 cannot drive growth when T is absent.
During active surveillance [AS], E2 can stimulate growth when T is low. When T is high-normal, it will resist growth. Some men with very low T (castrate-lite) are somewhat protected.
I doubt that many men test or correct for estrogen dominance while on AS (or an IADT holiday).
Decreasing prolactin levels I have read may be beneficial, but I do not understand if increasing progesterone can be beneficial or harmful with low T (zytiga) . Vitex agnus can lower prolactine levels but can increase progesterone 🤔🙄
Abiraterone [Zytiga] blocks the conversion of progesterone to DHEA and androstenedione, precursors of testosterone. So progesterone might not be a problem.
I expect that progesterone increases in those on Abi.
My serum Progesterone is quite low 0.42 ng/ml (normal range 2.5-17) possibly because I take Avodart and Saw Palmetto for DHT.
Googling Progesterone, I landed on this, not strictly a medical article, that I would like your comments on, particularly regarding the validity of the claim of Progesterone bearing an Estrogen counter-balancing role.
Why Progesterone for men? Progesterone is commonly thought of as a ‘female’ sex hormone. This is misleading as it is vital to sustain not just health but life itself in all mammals of both sexes.
As a man gets older Testosterone is converted into di-hydroTestosterone (DHT), which some believe is the cause of benign prostatic hyperplasia (BPH) and cancer, but some do not.
Estrogen levels also increase as a man gets older. Estrogen is known to stimulate cell growth. Reading between the lines, because as yet, there is no definitive study done on this, it appears to be the increased Estrogen level which is the problem and not the two Testosterones. As Progesterone is a powerful counter-balance for estrogen, Progesterone for men is essential.
If in fact Testosterone were the culprit, then men aged 22 would have the highest incidence of BPH and cancer, as Testosterone levels are at their highest point in the early 20’s, but of course they don’t. From the early twenty’s to the late twenty’s – Testosterone makes its greatest drop, thereafter it continues to decline, but at a slower rate.
BPH starts affecting a man in his fifties and interestingly Estradiol (E2) levels start climbing from the age of fifty and are at their highest point in men in their late 60’s, but during the same period Progesterone levels are declining. Progesterone for men becomes that much more important with age.
5-alpha reductase inhibitors such as Finasteride are usually given to prevent the conversion of Testosterone to DHT, but research has found that Progesterone is a natural inhibitor of 5-alpha reductase.
Progesterone also down regulates the action of Estrogen if used in a sufficiently high dose. The endogenous Estrogen made by humans is now being supplemented by synthetic Estrogens found in the environment. They are now found in food, air, water, plastics, skin care products, no one can avoid them. Some authorities speculate this is the cause of the increase in problems such as hyperplasia or cancers of any hormonally sensitive tissues, such as the prostate, endometrium, cervix and breasts. So, despite often being, erroneously, thought of as a ‘female’ hormone Progesterone for men is essential to preserve masculinity!
It’s safety for men is without question. It’s now given via IV transfusions for Traumatic Brain Injury, over 70% of TBI victims are men."
"... the expression level of PR {Progesterone Receptor} in cancer cells increased with Gleason score, tumor progression, and clinical failure. Interestingly, PR expression was increased after androgen-deprivation therapy, suggesting a negative regulation of PR expression by AR. These results suggest that PR in cancer cells and the associated stromal cells distinctly regulate prostate cancer pathogenesis."
This is exactly the point that made me asking for your comment.
Every paper that I read was mentioning Progesterone related to cancer cells.
BUT, we measure Progesterone into the blood.
Two opposing mechanisms can produce a low Progesterone blood count:
1) Progesterone from the cancerous cells, in a PSA fashion, gets into the blood and if so, a low count is a good indication of little proliferation.
2) Progesterone produced by other organs is circulated by blood, gets strained/bonded by the cancerous cells and if so, a low count is not a good indication.
Which one of the two, or possibly a third mechanism, do you think more applicable?
Progesterone is somewhat complicated in that it is produced high up in the steroidogenesis cascade, so who knows what it will be used for in the aging male body with/without PCa:
"The metabolism of progesterone is rapid and extensive and occurs mainly in the liver, though enzymes that metabolize progesterone are also expressed widely in the brain, skin, and various other extrahepatic tissues. Progesterone has an elimination half-life of only approximately 5 minutes in circulation."
I rely on a statin drug. I do not worry about cholesterol in my diet, that is,. I do not aim for zero dietary cholesterol. The liver is the main source of cholesterol.
The issue of which category of statin drug has often been discussed here. A recent paper articulates my reason for choosing a lipophilic drug [Simvastatin]:
"... it appears that the antitumor potential depends on the physicochemical properties of the statins, more precisely their lipophilicity. The chemical structure of the molecule dictates the solubility of the statin, which in turn will affect the pharmacokinetic profile. The lipophilicity promotes access to different tissues, including cancer cells. Statins are taken up into cells by the organic anion-transporting polypeptide OATP1B1 mainly expressed by hepatocytes and for lipophilic statins also by passive diffusion through the membrane. As a result, hydrophilic statins show an increased affinity for hepatic tissue, but not for other tissues. However, lipophilic statins achieve higher levels in extrahepatic tissues where they interfere with the synthesis of cholesterol"
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Inhibition of estrogen signaling through depletion of estrogen receptor alpha by ursolic acid and betulinic acid from Prunella vulgaris var.
Estrogen receptor β regulates AKT activity through up-regulation of INPP4B and inhibits migration of prostate cancer cell line PC-3
