I'm always interested in studies related to the emergence of the pro-growth alpha estrogen receptor, & the aromatase enzyme (which converts testosterone to estradiol.)
Androgenic to estrogenic switch in human adult prostate gland is regulated by epigenetic silencing of steroid 5α-reductase 2.
Wang Z1, Hu L1,2, Salari K1, Bechis S1, Ge R3, Wu S1,4, Rassoulian C1, Pham J1, Wu CL1,4, Tabatabaei S1, Douglas SW5, Olumi AF1.
Author information
1
Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
2
Department of Urology, Yan'an Affiliated hospital of Kunming Medical University, Yunnan, China.
3
Department of Pathology, University of Massachusetts Medical Center, Worcester, MA, USA.
4
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
5
Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA.
Abstract
Benign prostatic hyperplasia (BPH) is the most common proliferative abnormality of the prostate. While all men experience some prostate growth as they age, the rate of growth varies among individuals. Steroid 5α-reductase 2 (SRD5A2) is a critical enzyme for prostatic development and growth. Previous work indicates that one-third of adult prostate samples do not express SRD5A2, secondary to epigenetic modifications. Here we show that estradiol is dramatically elevated, concomitant with significantly upregulated estrogen response genes, in prostate samples that are methylated at the SRD5A2 promoter. The phosphorylation of estrogen receptor α (ERα) in prostate stroma is upregulated when SRD5A2 expression is absent. We show that TNF-α suppresses SRD5A2 mRNA and protein expression, and simultaneously promotes expression of aromatase, the enzyme responsible for conversion of testosterone to estradiol. Concomitant suppression of SRD5A2 and treatment with TNF-α synergistically up-regulate the aromatase levels. The data suggest that in the absence of prostatic SRD5A2 there is an androgenic to estrogenic switch. These findings have broad implications for choosing appropriate classes of medications for management of benign and malignant prostatic diseases.
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Can you translate, how this would affect someone with metastatic prostate cancer. I am not sure what I would ask my oncologist? Are there specific tests which could be used? How would results change the treatment that I am currently on which is Chemo and ADT? Sorry for all the questions but your interesting finding is hard for me to make use as I am not familiar with the issues raised in it.
When I was diagnosed 13+ years ago, there was a general view that testosterone [T] was dangerous ("fuel" for PCa). Doctors were afraid to treat hypogonadal men, for fear that T restoration therapy [TRT] might increase the risk for PCa, or unmask latent PCa.
Thanks to Dr. Morgentaler, mostly, we know that TRT does not affect PCa risk. Morgentaler has even prescribed T for men with PCa. In his saturation model, PCa has all the T it can use at fairly low levels. However, he seems to have no interest in the effect of estrogen when T is normal-low.
Dr. Myers has said the estadiol [E2] is irrelevant.
& yet, studies show that at quite early stages, growth-promoting ERalpha emerges & protective ERbeta disappears in PCa cells. Further, men with low T at diagnosis (& therefore an unfavorable E2: T ratio) have a poorer prognosis.
No-one seems to be paying attention to the studies that implicate E2 in PCa.
The topic is important for men on active surveillance, men with PCa who are being treated, but not via a castration therapy, & men without PCa who have low T.
For men on ADT, E2 is not an issue, since our E2 comes from the aromatization of T. And, in any case, E2 cannot promote growth in the absence of T.
If anything, E2 might be too low while on ADT. E2 < 12 pg/mL might lead to osteoporosis, & a low-dose E2 patch (e.g. Vivelle-Dot) might be useful. (A better solution than a bisphosphonate.)
IMO, estradiol [E2] is a threat when there is sufficient testosterone [T] to be growth-permissive - say >250 ng/dL - but where the E2:T ratio is unfavorable (estrogen dominance).
With high-dose E2 for ADT, T becomes too low to facilitate growth, & E2 can't stimulate growth without T participation.
Basically, the issue affects men with the metabolic syndrome, where visceral fat is secreting E2. The body responds by cutting back on T. So we get a T value of below or near 350 ng/dL & E2 of >30 pg/mL.
Many thanks Patrick, you've put my mind at ease wrt Estrodial.
Peter
The authors mention BPH (enlarged prostate). That's about the only medical term I recognized or understood in this paper. I had BPH 10 years prior to my PC diagnosis. I wonder how many of us here with PC had BPH too?
Most of the old papers, as I recall, deny that BPH is a precursor of PCa. But BPH is an inflammarory condition (as is PCa) & one might expect it to be a risk factor.
However, while PCa is without symptoms until it is relatively advanced, BPH is not. Any treatment for BPH that targets inflammation might actually lower PCa risk. (Not having had BPH (my case) might increase PCa risk, since subclinical inflammation would not then be not addressed. LOL)
From a recent paper on the subject [1]:
("Inflammation in Prostatic Hyperplasia and Carcinoma ...")
"Benign prostatic hyperplasia is caused by changes in hormone balance and consequently in cell growth, but molecular pathways leading to this condition are still largely unknown. Inflammatory component is believed to have an important role while presence and degree of inflammation corresponds to prostate volume and weight".
"Chronic inflammatory microenvironment is considered to have a contribution in the development of prostate cancer."
But BPH cells are not pre-cancerous in the sense that PIN cells are.
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Genistein for PCa hormonal control.
