I have fallen into the hormone-hole of trying to figure out the why, where and how of this disease... AND of its treatment. It has recently occurred to me that many (most?) of the problems that men experience on ADT are not actually directly from low-T, but they are from low-E (and that is a direct result of low-T, since estrogen in men is derived from testosterone).
When we make T the target of our therapy, we also kill E, to our possible detriment. But do we need to do that? Okay, maybe E, and not T, is the real target. We don't know. All we know for sure is that AR (androgen receptor) and ER (estrogen receptor, both alpha and beta), and related cellular signalling, play some role in PC progression and remission. What we DO know for sure is that many of the negative outcomes of ADT (especially loss of bone density) can be attributed to lower estrogen levels that directly result from lower T levels. That can be addressed with transdermal estrogen. Have your docs told you this? Not mine!
But even if we know that most aging men show changing serum levels of both sex hormones (among other hormonal/physiological changes), independent of any clinically significant PC, how do we know what is really going on inside the prostate or inside prostate cells (normal or cancerous)? Do serum levels alone tell us the whole story?
Nalakrats in a prior post noted that the prostates of men who had died of PC showed very high amounts of E. This would seem to be independent of serum levels, if even measured. Well, where did this E come from? It came from T, of course! Where else? So we want to know, why did so much T turn into so much E, within the prostate, and what does that mean in terms of causes and "cures" for PC?
Let's assume that, within the prostate, high levels of T get aromatized (via high expression of aromatase WITHIN THE PROSTATE) into high levels of E. How does that give us any solid evidence of how to proceed so far as BLOOD LEVELS of either T or E are concerned, or whether aromatase inhibitors or other interventional meds/supplements are helpful or harmful? Do blood level measurements necessarily reflect what happens within the prostate or within PC cells?
Gat/Goren (2009) supposed that intra-prostatic T-levels of some men may be very high, relative to serum levels, as a result of, well... of varicocele or other "plumbing" issues with veins and drainage "down there." (As men and their systems age, just as other fluid-flow systems age, potential issues with plumbing increase.) This paper supposed that serum levels of T or E could NOT tell you what was going on WITHIN the prostate. This observation, to me, seems to reveal a crucial flaw in current approaches to any mainstream analysis of PC that is done by looking only at serum levels of hormones and other markers, rather than also exploring intra-prostatic levels and how they might relate to potential PC progression/regression.
Which men have the most complete explorations of what has actually happened in their bones and in their prostates and other organs? Dead men, of course. They are easy to cut up and investigate. And dead men, contrary to the saying, DO tell tales. In the 1970s, they started telling the tale that PC was intrinsically metastatic. But what is the tale of high levels of estrogen, within the dead man's prostate, really trying to tell us? We hear the tale, but cannot be sure we know what it means.
If aromatase expression is high within the prostate, then super-high T levels there will mean super-high E levels. We see it in a dead man's prostate. Can we see this in serum levels? Even if we do, who exactly is the culprit here, and how do we recognize and catch him (T) or her (E) or it (aromatase)? Do various drugs and supplements impact the prostate and PC cells directly, or can they serve as "false flags" by differentially impacting serum biomarkers, like PSA and T and E levels, leading us to pay too much attention to proxies for cancer (and the prostate) rather than to the cancer (and the prostate) itself?
We already see assertions that men on Proscar have what are considered "artificially" low PSA levels, and that their "real levels" are about double what blood tests reveal. Sometimes it seems like the goal of therapy is to reduce PSA as tested, since PSA progression is a proxy for cancer progression. But a low PSA does NOT always mean a declining tumor burden! In fact, a focus that is ONLY on low PSA can ignore the very real potential for progression of hormone-sensitive PC to hormone-insensitive PC.
The geeky questions of this post are probably mostly directed to Nalakrats and Patrick (who seem to fall into more of a "pro-T, anti-E" paradigm), but for everybody else: why is the mainstream ADT standard of care totally unconcerned with your very low estrogen levels (as a result of low T from ADT) and the resulting negative consequences, and why are you putting up with it? It seems to me that a certain amount of suffering from the current standard of care remains unaddressed, and may be unwarranted. It CAN be addressed, with (horrors!) estrogen.
Perhaps more importantly to me: do I have any idea whatsoever of what I am talking about? (Thanks, no need to answer that one.) Just hoping to see if anyone has a better clue than I do!
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noahware
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Good questions/discussion noahware. I wish we knew the answers because it would certainly inform treatment choices.... but there are a lot of ambiguous and contradictory positions on the T, E2, DHT, etc... by oncologists and academics. I believe a big part of the solution to our predicaments is to control the hormones.... but how?
I discussed with an MO, who prescribes Avodart to control DHT, but is not concerned about E2. My E2 is in the low 30s, which he says is within range for a man with total T > 800 and perfectly healthy. I avoid phytoestrogens (soy) and take some supplements (DIM, mushrooms) that may have some inhibitory effect on the aromatase (less E2 from T), but otherwise try not to worry about E2 too much.
"Estrogen and Prostate Cancer: An Eclipsed Truth in an Androgen-Dominated Scenario"
"Prostate cancer is the commonest non-skin cancer in men. Incidence and mortality rates of this tumor vary strikingly throughout the world. Although several factors have been implicated to explain this remarkable variation, lifestyle and dietary factors may play a dominant role, with sex hormones behaving as intermediaries between exogenous factors and molecular targets in development and progression of prostate cancer. Human prostate cancer is generally considered a paradigm of androgen-dependent tumor; however, estrogen role in both normal and malignant prostate appears to be equally important. The association between plasma androgens and prostate cancer remains contradictory and mostly not compatible with the androgen hypothesis. Similar evidence apply to estrogens, although the ratio of androgen to estrogen in plasma declines with age. Apart from methodological problems, a major issue is to what extent circulating hormones can be considered representative of their intraprostatic levels. Both nontumoral and malignant human prostate tissues and cells are endowed with key enzymes of steroid metabolism, including 17betahydroxysteroid dehydrogenase (17betaHSD), 5beta-reductase, 3alpha/3betaHSD, and aromatase. A divergent expression and/or activity of these enzymes may eventually lead to a differential prostate accumulation of steroid derivatives having distinct biological activities, as it occurs for hydroxylated estrogens in the human breast. Locally produced or metabolically transformed estrogens may differently affect proliferative activity of prostate cancer cells. Aberrant aromatase expression and activity has been reported in prostate tumor tissues and cells, implying that androgen aromatization to estrogens may play a role in prostate carcinogenesis or tumor progression. Interestingly, many genes encoding for steroid enzymes are polymorphic, although only a few studies have supported their relation with risk of prostate cancer. In animal model systems estrogens, combined with androgens, appear to be required for the malignant transformation of prostate epithelial cells. Although the mechanisms underlying the hormonal induction of prostate cancer in experimental animals remain uncertain, there is however evidence to support the assumption that long term administration of androgens and estrogens results in an estrogenic milieu in rat prostates and in the ensuing development of dysplasia and cancer. Both androgen and estrogen have been reported to stimulate proliferation of cultured prostate cancer cells, primarily through receptor-mediated effects. As for estrogens, the two major receptor types, ERalpha and ERbeta, are expressed in both normal and diseased human prostate, though with a different cellular localization. Since these two receptors are different in terms of ligand binding, heterodimerization, transactivation, and estrogen response element activity, it is likely that an imbalance of their expression may be critical to determine the ultimate estrogen effects on prostate cancer cells. In prostate cancer, ERbeta activation appears to limit cell proliferation directly or through ERalpha inhibition, and loss of ERbeta has been consistently associated with tumor progression. Several splicing variants of both ERalpha and ERbeta exist. Little is known about their expression and function in the human prostate, although reciprocal regulation and interaction with gene promoter both warrant further investigation. In summary, although multiple consistent evidence suggests that estrogens are critical players in human prostate cancer, their role has been only recently reconsidered, being eclipsed for years by an androgen-dominated interest."
Yes, current SOC seems to have lots of problems, with plenty of questions unanswered and, perhaps worse, with plenty of questions UNASKED by those who promote and provide mainstream SOC.
But quickly, regarding an E2 blood number and how to know what minimal number on E2 will be "OK " for any given man... to know the actual biological effects of serum E2 in that man, wouldn't we also need to know all the interactions of inhibitors, coinhibitors, ligands at hormone receptors?
I don't think the numbers always tell the whole story (although the number "zero" can often convey pretty reliable information).
But again, how does a generalized model account for potential variations from man to man in how multiple individual factors (like mutations, gene expression, inhibitors, coinhibitors, ligands, etc.) are all actually interacting and being expressed at the cellular level?
If things were always as simple as expressed in a theoretical model, then clinical application of its principles would approach 100% success in nearly 100% of patients!
We know some men get PC and some don't, and in men that do, some PC is aggressive and some is not, and some of that PC responds to some treatments and some does not.
The Leibowitz protocol throws so many things at the PC, all at once, that we really can't say which factor or combination of factors is doing what. We also don't have a really good indication of how and when that protocol might fail, because any patient failures of Dr. Bob are not likely to show up in his lectures. Even if he has a great hitting streak, I doubt he could be batting a thousand, whether using the Friedman model or not.
Friedman even admits that when to use aromatase inhibition and for how long is essentially a guess. This does not mean the basis for the model is not sound, but just that it is likely incomplete. That it is logically consistent does not make it a homerun in clinical application.
I would love to see my doubts proven wrong, and to see his model proven accurate and complete on the basis of repeated clinical successes!
For me to get completely behind a model, I'd like to see more. For example, Bob Gattenby's model for "adaptive therapy" in PC is based in mathematical equations derived from studies in population ecology, and the model has shown to hold across populations within a variety of ecosystems.
Let me put it another way, by quoting one paper that explored the issue; "Circulating concentrations of sex steroid hormones are poor surrogate measures of the intraprostatic hormonal milieu."
So those dead men whose frozen prostates were found to contain high levels of E2: what were the serum levels of E2 of those men? We don't know, but we shouldn't presume that serum levels tell us exactly what is happening within cells (prostate or other) or at all receptor sites... for better or for worse.
Perhaps Friedman answered this and I missed it, but would taking an aromatase inhibitor always ensure us that excessive aromatization or problematic receptor activity could not still occur within the prostate? And if he did answer, is his answer based on a theoretical model or on clinical observation?
My situation is a little different from yours, but I would love to hear your opinion here. Namely, how hormonal processes can change after breast augmentation in women. What can happen and whether it can negatively affect my body.
My situation is a little different from yours, but I would love to hear your opinion here. Namely, how hormonal processes can change after breast augmentation in women. What can happen and whether it can negatively affect my body. I decided to undergo breast augmentation surgery, but my husband constantly discourages me, as he believes that surgical intervention in the body has negative consequences. My doctor advised me to try an alternative solution to this problem. He told me about the existence of cream for breast enlargement. The doctor recommended that we order the cream at curvesfw.com/ and test its effect on my body, I hope that everything will work out.
Not sure I can give any useful opinion on that, myself. The other poster on this thread, Patrick (pjoshea13), is far more likely to be helpful than I. You might try asking him, or find a forum that directly relates to your situation. Best of luck.
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Estrogen therapy prior to cancer?
How did you have access to estrogen patches if outside trial?
How fast should T drop when Re-starting ADT?
