Summary:

• The use of PSA as a screening tool for aggressive prostate cancer (PCa) is not supported by scientific studies of its effectiveness.
• Many men are subject to disabling, sometimes even fatal, interventions based on PSA tests when they would never have developed aggressive prostate cancer.
• The U.S. Preventive Services Task Force has prepared a draft recommendation to stop screening in those who have not been diagnosed with prostate cancer.
• There are many who, having benefited from PSA screening for PCa, feel strongly that this recommendation by the USPSTF is irresponsible.
• A broader understanding of the underlying causes of elevated PSA and PCa offers a ‘middle path’ of judicious PSA screening, with a meaningful action plan that doesn’t corner patients and doctors into risky invasive procedures or the anxiety of doing nothing. Factors such as insulin resistance and estrogen-testosterone balance are of vital importance for prostate and general health.

Anyone reading this is surely aware of the controversy swirling around the  draft recommendation statement of the U.S. Preventive Services Task Force (USPSTF) that…

“…recommends against prostate-specific antigen (PSA)-based screening for prostate cancer…This recommendation applies to men in the U.S. population that do not have symptoms that are highly suspicious for prostate cancer, regardless of age, race, or family history.”

The Task Force did not evaluate the use of the PSA test for men with highly suspicious symptoms or those with a diagnosis prostate cancer. This recommendation is based on a number of studies finding that PSA (including PSA velocity, the rate at which PSA goes up) is a poor predictor of prostate cancer in general and aggressive prostate cancer in particular, and the assertion that widespread screening has resulted in many unnecessarily invasive and debilitating procedures that themselves can be disabling and even fatal. Feelings are riding high as a large body of public health statistics is pitted against those who feel that a PSA test may have saved their life or the life of a patient. But practitioners and patients face more than a quandary—the debate as it’s currently framed is flawed by a glaring omission.

The PSA discussion is presently structured to assume that the response to a rising PSA can only be ignored (in favor of ‘watchful waiting’) or acted on with invasive biopsies that can seriously damage quality of life and aggressive therapies for what may in fact be indolent, slow growing tumors. That’s it, the clinical decision-making path would appear to fork into only those two roads. Here’s the problem: there is a surprising blind spot for the extensive body of science done on the underlying causes of prostate cancer that offer important opportunities to benefit.  Bear in mind that inflammation or enlargement of prostate tissue caused by various disrupting factors can elevate PSA. These can often be treated with lifestyle or wholesome, non-invasive measures that also reduce the risk of other conditions like diabetes and cardiovascular disease. You may wish to read earlier posts on this topic by typing ‘prostate’ in the search box above. For now consider a couple of the most glaring omissions:

To ignore the role of insulin resistance and metabolic syndrome in prostate disease is gigantic clinical error. Consider just one paper published recently in Nature Reviews Urology in which the authors state:

“The metabolic syndrome is common in countries with Western lifestyles. It comprises a number of disorders—including insulin resistance, hypertension and obesity—that all act as risk factors for cardiovascular diseases. Urological diseases have also been linked to the metabolic syndrome. Most established aspects of the metabolic syndrome are linked to benign prostatic hyperplasia (BPH) and prostate cancer. Fasting plasma insulin, in particular, has been linked to BPH and incident, aggressive and lethal prostate cancer.”

Moreover…

“Overall, the results of studies on urological aspects of the metabolic syndrome seem to indicate that BPH and prostate cancer could be regarded as two new aspects of the metabolic syndrome, and that an increased insulin level is a common underlying aberration that promotes both BPH and clinical prostate cancer.”

This is so important yet has been so ignored. Here it is again:

“Key points

• The metabolic syndrome is a cluster of disorders, including type 2 diabetes, atherosclerotic disease manifestations, hypertension, obesity and dyslipidemia, and is prevalent in countries with Western lifestyles
• The most important common underlying endocrine aberration of these disorders is an increased insulin level, which is also linked to benign prostatic hyperplasia (BPH) and prostate cancer
• Most aspects of the metabolic syndrome are risk factors for BPH and prostate cancer, which seems to suggest that these tumors are themselves aspects of the metabolic syndrome”

Insulin at high levels due to receptor resistance damages sensitive tissues and can act as a tumor promoter. The authors conclude:

“Urologists need to be aware of the effect that the metabolic syndrome has on urological disorders and should transfer this knowledge to their patients.”

Another of the most egregious omissions in prostate cancer management and prevention is attendance to the role played by estrogens in PCa development and progression. Consider a paper published in 2007 in the Journal of Cellular Biochemistry in which the authors observe:

“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.”

Furthermore…

“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. 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…In animal model systems estrogens, combined with androgens, appear to be required for the malignant transformation of prostate epithelial cells.”

After reviewing other aspects estrogen stimulation of prostate tissue including the opposing role of ERα and ERβ receptors, the authors conclude:

“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.”

The authors of a review published subsequently in European Urology recognized the dual role of estrogen receptors in prostate cancer when they set out to…

“…examine mechanisms of how oestrogens may affect prostate carcinogenesis and tumour progression.”

They report evidence for the effects of estrogenic stimulation of prostate tissue:

“The human prostate is equipped with a dual system of oestrogen receptors (oestrogen receptor alpha [ERα], oestrogen receptor beta [ERβ]) that undergoes profound remodelling during PCa development and tumour progression. In high-grade prostatic intraepithelial neoplasia (HGPIN), the ERα is upregulated and most likely mediates carcinogenic effects of estradiol as demonstrated in animal models…The partial loss of the ERβ in HGPIN indicates that the ERβ acts as a tumour suppressor…The progressive emergence of the ERα and the oestrogen-regulated progesterone receptor (PR) during PCa progression and hormone-refractory disease suggests that these tumours can use oestrogens and progestins for their growth.”

Moreover…

“The TMPRSS2-ERG gene fusion recently reported as a potentially aggressive molecular subtype of PCa is regulated by ER-dependent signalling.”

The authors also conclude:

“Oestrogens and their receptors are implicated in PCa development and tumour progression. There is significant potential for the use of ERα antagonists and ERβ agonists to prevent PCa and delay disease progression.”

A paper just published in the journal Endocrinology and Metabolism Clinics of North America echoes the theme:

“The mainstay targets for hormonal prostate cancer (PCa) therapies are based on negating androgen action. Recent epidemiologic and experimental data have pinpointed the key roles of estrogens in PCa development and progression. Racial and geographic differences, as well as age-associated changes, in estrogen synthesis and metabolism contribute significantly to the etiology.”

The authors go on to report on how estrogens and estrogen mimics contribute to development of PCa, and the roles of the different estrogen mediators in the process.

As is often the case, the principle of balance comes into play as examined in a fine paper published in The Journal of Steroid Biochemistry & Molecular Biology on the estrogen:androgen ratio in the prostate gland. The authors state:

“Although androgens and estrogens both play significant roles in the prostate, it is their combined action – and specifically their balance – that is critically important in maintaining prostate health and tissue homeostasis in adulthood. In men, serum testosterone levels drop by about 35% between the ages of 21 and 85 while estradiol levels remain constant or increase. This changing androgen:estrogen (T:E) ratio has been implicated in the development of benign and malignant prostate disease.”

They review the role of the aromatase enzyme in the production of estrogens from androgens, and the fact that its aberrant expression plays a critical role in the development of malignancy in a number of tissues. In the case of PCa, it leads to an altered T:E ratio that is associated with the development of disease. And since we do have for treatment purposes wholesome modulators of estrogen receptor function as well as aromatase enzyme inhibitors…

“The role of estrogen and the T:E balance in the prostate is further complicated by the differential actions of both estrogen receptors, α and β. Stimulation of ERα leads to aberrant proliferation, inflammation and pre-malignant pathology; whereas activation of ERβ appears to have beneficial effects regarding cellular proliferation and a putative protective role against carcinogenesis.”

Clinicians who manage, support patients with, or endeavor to prevent prostate cancer must bear their conclusion in mind:

“Overall, these data reveal that homeostasis in the normal prostate involves a finely tuned balance between androgens and estrogens. This has identified estrogen, in addition to androgens, as integral to maintaining normal prostate health, but also as an important mediator of prostate disease.”

A more comprehensive perspective on the use of PSA

There far more evidence for the application of these and other factors in prostate cancer development and expression that are equally important for conditions ranging from cardiovascular disease and diabetes to dementia than can be presented in this post. It is clear, however, that we must go beyond the fascination with the false promise of ‘silver bullet’ medications and lure of lucrative procedures to properly examine and treat the more complex web of underlying factors that support prostate cancer. In the judicious hands of a skilled clinician who has the knowledge and experience to evaluate the risk of prostate cancer in the context of the total health of their patient, observing an elevation of PSA offers more than a specter of indecision over the stark choices of invasive procedures or doing nothing. It is an opportunity to intervene in positive and wholesome ways that advance the overall, not just prostate, health of the patient in their care.

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Many practitioners have used PSA velocity (the rate at which prostate-specific antigen values increase) as an important indicator to gauge the risk of aggressive prostate cancer and weigh the decision to proceed to biopsy. A study just published in the Journal of the National Cancer Institute reveals that PSA velocity is not a reliable indicator and can lead to many needless interventions. The authors state their intention to examine pre-existing assumptions about the significance of the rate of PSA change:

“The National Comprehensive Cancer Network and American Urological Association guidelines on early detection of prostate cancer recommend biopsy on the basis of high prostate-specific antigen (PSA) velocity, even in the absence of other indications such as an elevated PSA or a positive digital rectal exam (DRE)…To evaluate the current guideline, we compared the area under the curve of a multivariable model for prostate cancer including age, PSA, DRE, family history, and prior biopsy, with and without PSA velocity, in 5519 men undergoing biopsy, regardless of clinical indication, in the control arm of the Prostate Cancer Prevention Trial. We also evaluated the clinical implications of using PSA velocity cut points to determine biopsy in men with low PSA and negative DRE in terms of additional cancers found and unnecessary biopsies conducted. All statistical tests were two-sided.”

The current guideline based on an unproven assumption was clearly contradicted by their data:

“Incorporation of PSA velocity led to a very small increase in area under the curve from 0.702 to 0.709. Improvements in predictive accuracy were smaller for the endpoints of high-grade cancer (Gleason score of 7 or greater) and clinically significant cancer (Epstein criteria). Biopsying men with high PSA velocity but no other indication would lead to a large number of additional biopsies, with close to one in seven men being biopsied.”

The implication of these findings is starkly articulated in their conclusion:

“We found no evidence to support the recommendation that men with high PSA velocity should be biopsied in the absence of other indications; this measure should not be included in practice guidelines.“

The authors of an accompanying editorial thoughtfully state:

“The results…suggest that using PSA velocity may not provide more information to either physician or patient as we try to come to a decision about interpreting the results of any screening…The studies by Zeliadt et al. and Vickers et al. help us refine and focus our clinical approach, but they also remind us that the use of PSA as a screening tool still leaves much to be desired. Indeed, after more than 20 years of PSA screening, it has been estimated that approximately 1 million men may have been unnecessarily treated for clinically insignificant prostate cancer.”

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This paper in the journal Clinical Cancer Research reports that pomegranate juice slows rising PSA (prostate-specific antigen) after surgery or radiation for prostate cancer: “The statistically significant prolongation of PSA doubling time, coupled with corresponding laboratory effects on prostate cancer in vitro cell proliferation and apoptosis as well as oxidative stress, warrant further testing in a placebo-controlled study.”

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