I have heard of men on androgen ablation as primary therapy using estrogen patches to alleviate symptoms of androgen ablation, but not as a concurrent therapy with a therapeutic dose. I have heard of men using patches (or DES) as their primary therapy, but not in conjunction with androgen ablation.
Has anyone heard of concurrent use?
It makes sense in that combining other therapies seems to provide an enhanced effect. I would be surprised if this hasn't been tried before?
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Geoff-H
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Dr. G. Larry Goldenberg, MD at the Vancouver General Hospital is the Principle Investigator of a Prostate Cancer Canada funded clinical trial on using transdermal estradiol along with LHRH drugs for ADT. The combination should provide good testosterone suppression without the hot flashes and osteoporosis. It may also reduce the risk of cognitive impairment. Furthermore a recent paper in BJUi by Gilbert et al. suggests that it should help to some extent preserve sexual interest.
Is the transdermal estradiol dosing at the estrogen ablation level used in, say, the PATCHES trial in the UK, or is it a lower dose mainly to alleviate ADT symptons? I can't seem to find information on this.
The target levels for the estradiol (E2) in the Vancouver study (which as far as I know has yet to accrue) is lower than the dose my colleagues aim for in the PATCH study. Are you interested in getting into either study or simply talking your MD into letting you go on E2?.
I am in theory involved a bit in both studies and would be happy to talk to you about the pros and cons of E2 for Pca patients. Just email me off line and let me know what times and numbers work of you, if you would like to talk.
The term “ablation” refers to a removal or taking away. Estrogens have been used in PCa treatment as a means of androgen ablation, but this involves introducing estrogen levels that are abnormally high for a male, bringing them up to around what are normal levels for females. This is not “estrogen ablation”, which is what your cited PubMed article is talking about - the authors are proposing ablation of both estrogens and androgens. This has not been commonly done.
You can find articles about the PATCH research on PubMed:
I think what the authors are proposing is ablation of PCa cells by both ADT and DES (or E2) therapy concurrently, as they believe there are 2 different types of PCa cells (light and dark basal cells). So as well as continuing Lupron to ablate light basal PCa cells they want to also use DES (or E2) to ablate dark basal PCa cells, thus not allowing either population of PCa cells to proliferate and for the PCa to progress.
Now there are several problems with this paper. It was published in a low ranking journal, using decades old histology. Also it refers to use of DES, which hasn't been used in most countries for decades. Also the idea of sorting prostate tissue by light versus dark basal cells is very unusual, indeed unheard of.
But... What if there is something to it, not for the reasons they propose, but for other unidentified reasons (eg: genetic variations in PCa cells)?
Geoff: They are NOT proposing ADT and DES (or other estrogen) therapy concurrenty. DES therapy would raise estrogen levels, but the authors are proposing estrogen repression. Though the conclusion of the abstract does not state by what means estrogens would be “ablated”, it does state very plainly that they are proposing estrogen ablation:
“PCa has at least two populations of cells: androgen-dependent light basal and estrogen-dependent dark basal cells. ADT did not destroy estrogen-dependent cells which may have given rise to CRPC tumors. Therefore, ADT is an incomplete treatment. For a more complete treatment of PCa, we recommend concurrent androgen and estrogen ablation, together with the inhibition of selected steroid biosynthetic enzymes.”
Yes, it is an interesting paper - interesting to me that as of now, there are no other PubMed hits for <prostate "estrogen-dependent" basal>. How is it that these "estrogen-dependent dark basal cells" have never been spotted in CRPC?
Many men with PCa have estradiol [E2] > 30 pg/mL at diagnosis - but that changes dramatically while on ADT. Male E2 derives largely from aromatization of testosterone [T]. With castrate T, E2 can sink below the ~12 pg/mL needed for bone health. The authors seem to think that this is high enough to promote growth of the estrogen-dependent dark basal cells.
Prior to their "Conclusion", the authors describe those cells as being androgen-independent. This term is now generally avoided. That's because it was realized some years ago that the androgen receptor [AR] continues to have a role when Lupron, say, fails. CRPC often means that androgen deprivation isn't complete. Zytiga & Xtandi were developed to address that.
The success of Zytiga & Xtandi in CRPC, however brief, indicates that the cancer remains driven by the AR - not the estrogen receptor [ER].
Failure of Zytiga & Xtandi is often due to AR splice variants. With AR-V7, for example, androgen is no longer required, but AR remains so.
The following is implied in the paper:
"ER was usually localized in dark cells. The number of dark cells progressively increased in DES-treated patients indicating their androgen-independence", ergo, the cells are "estrogen-dependent". But they don't demonstrate that in the Abstract.
Another interesting thing about the study is that the men on ADT were using DES, rather than Lupron, say. According to Wikipedia: "The last remaining U.S. manufacturer of DES, Eli Lilly, stopped making and marketing it in 1997." Strange study.
“ …interesting to me that as of now, there are no other PubMed hits for <prostate "estrogen-dependent" basal>. How is it that these "estrogen-dependent dark basal cells" have never been spotted in CRPC?”
There are some highly technical abstracts on PubMed that discuss estrogens potentially being “bi-phasic” in promoting or inhibiting growth of prostate cancer cells, but these are way beyond my capacity to comprehend. Here is a snippet from one of them, which I found with search terms <estrogen dependent "prostate cancer”>:
“Locally produced or metabolically transformed estrogens may differently affect proliferative activity of prostate cancer cells. In our studies, estrogen may either stimulate or decrease prostate cancer cell growth, also depending on the receptor status. In particular, an imbalance of ERalpha and ERbeta expression may be critical to determine the ultimate estrogen effects on prostate cancer cell growth.”
There are many papers thant acknowledge that estradiol can promote growth, but androgen is always involved. Typically, low levels of testosterone [T] (estrogen dominance) puts T in a growth-permissive role, whereas high-normal T is protective .
I have never heard of cells being estrogen-dependent, in the sense of no androgen required, as suggested by the paper that started this thread.
The role of estradiol [E2] is usually ignored. Myers denies E2 is invoved in PCa. Morgentaler has no place for E2 in his saturation model.
The fact is that the appearance of ERalpha in PCa cells is an early event, as is the disappearance of ERbeta. It is generally accepted that ERbeta oppose the growth tendencies of ERalpha. In addition, ERalpha can be upregulated as PCa progresses, as well as production of aromatase, which converts T to E2.
In contrast, the androgen receptor [AR] is usually quite normal at diagnosis. Most of the changes than can occur are due to ADT.
The following quotes are from a U.K. paper published in June [1].
"Mutations of the androgen receptor are uncommon in the early stages of prostate cancer but are much more frequent in late-stage disease. In one study, out of 99 patients diagnosed with early-stage prostate cancer, none were found to have mutations in the androgen receptor. On the contrary, 8 tumours out of 38 patients with advanced prostate cancer were found to harbour androgen receptor mutations (Marcelli et al. 2000, Brooke & Bevan 2009). There is, however, mounting evidence that oestrogens may be involved in the initiation and progression of prostate cancer ..."
"Males are exposed to a high oestrogen/androgen (E/T) ratio twice in their lifetime. The first is as a foetus, during the third trimester when the maternal E2 levels increase and foetal androgen levels decrease. Raised E2 levels stimulate the developing epithelial cells of the prostate to proliferate and also cause morphological changes. ..........."
"The second time men are exposed to a high E/T ratio is during old age when serum testosterone decreases, partly due to a dampened HPG axis and partly due to reduced Leydig cell function in the testes. In addition to this, sex hormone-binding globulin (SHBG), which has a higher affinity to testosterone than E2 (Knochenhauer et al. 1998), also increases with age which further decreases free serum testosterone relative to free serum E2 (Samaras et al. 2012). Furthermore, there is evidence that E1 and E2 not only remain at the same level, but in fact increase with age even when accounted for BMI and other metabolic diseases (Jasuja et al. 2013). While the evidence for an association between serum oestrogen concentration and risk of prostate cancer is unclear and inconsistent, increased serum oestrogen concentrations may stimulate the prostate stroma and epithelia to proliferate and subsequently become neoplastic. Indeed, a higher oestrogen:androgen ratio stimulates proliferation of normal prostate stromal (PrSC) and normal epithelial (PrEC) cell lines in vitro (King et al. 2006)."
"While in pre-menopausal females the primary source of oestrogens is the ovaries, in males, there is no central organ which produces substantial quantities of E2. Instead, peripheral conversion of oestrogen precursors is the main source of oestrogen in men. Local synthesis of E1 and E2 is regulated by a plethora of enzymes. DHEA secreted from the zona reticularis of the adrenal glands, and stored in the blood as a reservoir as DHEAS, is the ultimate precursor. Adipose tissue is another notable source of oestrogen synthesis (Cui et al. 2013). White adipose tissues (the predominant type in obesity) express significant quantities of cytochrome P450 aromatase enzyme (CYP19A1) in the abdominal adipose fat of male human samples, which is the final catalyst in the conversion of androgens to oestrogens (Wang et al. 2013, Polari et al. 2015). There is also a positive correlation between the amount of visceral adipose tissue and serum E2 levels as shown in a study of 229 men with a mean age of 53.6 years, where visceral fat was measured using magnetic resonance imaging (Gautier et al. 2013)."
"As mentioned previously, aromatase is a key enzyme required for oestrogen synthesis from androgen precursors. Aromatase converts androstenedione and testosterone to E1 and E2, respectively (White et al. 2013). The local synthesis of E2 within the prostate has previously been debated as not all experiments have identified aromatase expression in normal prostate tissue (Ellem et al. 2004). However, it has been demonstrated in human samples by substrate conversion assays and mass spectrometry that E2 synthesis does occur in prostate cancer cells (and benign prostatic hyperplasia) via aromatisation (Härkönen & Mäkelä 2004, Ellem & Risbridger 2009)."
"In normal prostate, aromatase is expressed by the stromal tissue but not the epithelial cells; however, once malignant, epithelial cells also express aromatase (Ellem & Risbridger 2007)."
Very important IMO. PCa is invariably an epithelial cancer. Stromal cells are involved, however, owing to crosstalk with the epithelium. ERalpha is normally found in the stroma, but appears in cancerous epithelial cells - along with the enzyme to create E2 from T.
"the expression of aromatase is up to 30-fold greater in metastatic prostate cancer compared with primary tumours (Miftakhova et al. 2016)"
"overexpression of aromatase increased the progression of bony metastasis in xenograft experiments where nude mice were injected with PC3 cell lines transfected to overexpress aromatase (Miftakhova et al. 2016)."
"In non-cancerous prostate, ERα is predominantly expressed in the stromal compartment and ERβ is predominantly expressed in basal-epithelial cells. However, in prostate cancer, ERα expression is downregulated in stromal cells and upregulated in the cancerous epithelial cells. ERβ expression is downregulated in epithelial cells as seen by immunostaining in human prostate tissue (Yeh et al. 2014). Indeed, there is evidence that downregulation of ERβ promotes activation of NF-κB mediated by hypoxia-inducible factor 1 (HIF-1). In immortalised normal prostate epithelial cell line PNT1a, loss of ERβ using shRNA showed an increase in NF-κB mRNA expression and activity. This mirrors what is seen in high-grade, late-stage prostate cancer (Mak et al. 2015). Consequently, it appears that an increase in ERα expression and decrease in ERβ expression is what shifts the balance between protective effects of oestrogens and proliferative effects of oestrogens as has been suggested in other cancers (Barzi et al. 2013, Burns & Korach 2012)."
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