Summary: in this study prostate size correlated with fasting blood sugar. Elevated fasting glucose is a risk factor for prostate disease.

A study recently published in the Journal of Korean Medical Science offers further evidence for the association between blood glucose regulation and prostate disease. The authors state:

“We evaluated the correlations between BMI, fasting glucose, insulin, testosterone level, insulin resistance, and prostate size in non-diabetic benign prostatic hyperplasia (BPH) patients with normal testosterone levels.”

They examined ata from 212 non-diabetic BPH patients with normal testosterone levels, excluding those with diabetes or serum testosterone levels less than 3.50 ng/mL. Their data showed that…

“Prostate size correlated positively with age, PSA , and fasting glucose level, but not with BMI, testosterone, insulin level, or HOMA-IR.Testosterone level inversely correlated with BMI, insulin level, and HOMA-IR [insulin resistance], but not with age, prostate size, PSA, or fasting glucose. HOMA-IR significantly correlated with BMI, fasting glucose, and insulin level, but not with age, PSA, or prostate size.”

There seems to be a disconnect here regarding the association of prostate size with fasting glucose but not the calculated insulin resistance that requires further investigation. The authors, however, are clear in their conclusion regarding blood sugar and prostate hypertrophy:

“In non-DM BPH patients with normal testosterone levels, fasting glucose level is an independent risk factor for prostate hyperplasia.”

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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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While hormone balance, autonomic nervous system function, anatomic and other factors are necessary aspects of case management for erectile dysfunction, the capacity of the local vascular system to regulate blood delivery to the tissues of interest is as important for sexual as it is for cardiac function. No wonder a paper just published in the Archives of Internal Medicine provides evidence that lifestyle modification of cardiovascular function improves erectile dysfunction. The authors state:

“Erectile dysfunction (ED) shares similar modifiable risks factors with coronary artery disease (CAD). Lifestyle modification that targets CAD risk factors may also lead to improvement in ED. We conducted a systematic review and meta-analysis of randomized controlled trials evaluating the effect of lifestyle interventions and pharmacotherapy for cardiovascular (CV) risk factors on the severity of ED.”

They examined multiple electronic databases from randomized controlled clinical trials with follow-up of at least 6 weeks of lifestyle modification intervention or pharmacotherapy for cardiovascular risk factor reduction. Their main outcome measure was differences in the International Index of Erectile Dysfunction (IIEF-5) score. Their data demonstrated significant effectiveness:

“A total of 740 participants from 6 clinical trials in 4 countries were identified. Lifestyle modifications and pharmacotherapy for CV risk factors were associated with statistically significant improvement in sexual function (IIEF-5 score): weighted mean difference, 2.66. If the trials with statin intervention (n = 143) are excluded, the remaining 4 trials of lifestyle modification interventions (n = 597) demonstrate statistically significant improvement in sexual function: weighted mean difference, 2.40.”

Readers may wish to search this site for several reports on the cautions and limitations associated with statin use. There are, however, no risks associated with skillful lifestyle modification of CV risk factors. The authors conclude:

“The results of our study further strengthen the evidence that lifestyle modification and pharmacotherapy for CV risk factors are effective in improving sexual function in men with ED.”

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A study just published in The Journal of Sexual Medicine documents the persistent sexual side effects of finasteride (Propecia, Proscar), a medication commonly used for both male pattern baldness and prostate hyperplasia, that too often are not discussed when prescribed. The authors observe:

“Finasteride has been associated with reversible adverse sexual side effects in multiple randomized, controlled trials for the treatment of male pattern hair loss (MPHL). The Medicines and Healthcare Products Regulatory Agency of the United Kingdom and the Swedish Medical Products Agency have both updated their patient information leaflets to include a statement that “persistence of erectile dysfunction after discontinuation of treatment with Propecia has been reported in post-marketing use.””

They set out to…

“…characterize the types and duration of persistent sexual side effects in otherwise healthy men who took finasteride for MPHL,”…

…by investigating the new onset of sexual side effects lasting for at least 3 months despite discontinuing finasteride. What did their data show?

“Subjects reported new-onset persistent sexual dysfunction associated with the use of finasteride: 94% developed low libido, 92% developed erectile dysfunction, 92% developed decreased arousal, and 69% developed problems with orgasm…The mean duration of finasteride use was 28 months and the mean duration of persistent sexual side effects was 40 months from the time of finasteride cessation to the interview date.”

The authors admonished practitioners in their conclusion to offer patients the courtesy of full disclosure:

“Physicians treating MPHL should discuss the potential risk of persistent sexual side effects associated with finasteride.”

This report follows a study published earlier this year on persistent sexual side effects from finasteride and another 5α-reductase inhibitor (5α-RI), dutasteride, when used to treat urinary tract symptoms caused by prostate enlargement. They also stated:

“Prolonged adverse effects on sexual function such as erectile dysfunction and diminished libido are reported by a subset of men, raising the possibility of a causal relationship…We suggest discussion with patients on the potential sexual side effects of 5α-RIs before commencing therapy. Alternative therapies may be considered in the discussion, especially when treating androgenetic alopecia.”

Clinicians reading this will know that 5α-reductase inhibitors block the conversion of testosterone to dihydrotestosterone (DHT). DHT is 10 times stronger in conferring androgen stimulation on tissues—the loss of male hormone effects is more precipitous with smaller reductions of DHT. It is important to note that the hormone measurements were not done for these patients. Other factors, and other hormones, including estrogen and insulin, also affect the prostate. In the functional approach to MPHL and prostate hyperplasia the bioactive free fractions of testosterone, DHT and estrogen, along with other analytes are always measured to determine (1) if DHT is actually too high (not always the case), and (2) if a natural or synthetic 5α-reductase inhibitor is used, to make sure that DHT is not reduced too much (by follow-up tests). Excessive reduction of testosterone receptor stimulation is a risk not only for sexual side effects but also depression, cardiovascular disease, sarcopenia (loss of muscle mass), osteoporosis and other ailments.

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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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A recent FDA MedWatch announcement alerts doctors to the increased risk of diabetes, heart attacks and strokes for patients with prostate cancer undergoing hormone blockade therapy, specifically treatment with Gonadotropin-Releasing Hormone (GnRH) agonists such as Lupron.

“Gonadotropin-Releasing Hormone (GnRH) agonists will have new safety information added to the Warnings and Precautions section of the drug labels. This new information warns about increased risk of diabetes and certain cardiovascular diseases (heart attack, sudden cardiac death, stroke) in men receiving these medications for the treatment of prostate cancer.”

The normal action of gonadotropin-releasing hormone is to stimulate the secretion of the gonadotropins LH (luteinizing hormone) and FSH (follicle stimulating hormone) from the pituitary. These hormones in turn stimulate the production of testosterone and sperm by the testes. The GnRH agonists flood the pituitary receptors causing an inhibition of gonadotropin secretion in the same way that over-stimulation of any hormone receptor suppresses the system (as occurs with topical hormone replacement, insulin resistance, etc.)

Incidentally the FDA also notes:

“The benefits of GnRH agonist use for earlier stages of prostate cancer that have not spread (non-metastatic prostate cancer) have not been established.“

I have personally seen how GnRH agonists exacerbate tendencies for metabolic syndrome and cardiovascular disease and appreciate the seriousness of their advice to practitioners:

“Healthcare professionals should evaluate patients for risk factors for these diseases and carefully weigh the benefits and risks of using GnRH agonists before determining appropriate treatment for prostate cancer. Patients who are receiving treatment with GnRH agonists should undergo periodic monitoring of blood glucose and/or glycosylated hemoglobin (HbA1c). Healthcare professionals should also monitor patients for signs and symptoms suggestive of development of cardiovascular disease and manage according to current clinical practice.”

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More evidence of the importance of testosterone in preventing heart disease for men is offered in a study just published in the journal Heart in which the authors set out to…

“…examine the effect of serum testosterone levels on survival in a consecutive series of men with confirmed coronary disease and calculate the prevalence of testosterone deficiency.”

They followed 930 men with coronary disease for an average of seven years and correlating all-cause mortality and vascular mortality with testosterone deficiency. What did the data show?

“The overall prevalence of biochemical testosterone deficiency in the coronary disease cohort using bio-available testosterone (bio-T) was 20.9%, using total testosterone was 16.9% and using either was 24%. Excess mortality was noted in the androgen-deficient group compared with normal (41 (21%) vs 88 (12%). The only parameters found to influence time to all-cause and vascular mortality in multivariate analyses were the presence of left ventricular dysfunction, aspirin therapy, β-blocker therapy and low serum bio-T.”

Notice that the bio-available testosterone (free fraction or unbound testosterone, the small percentage that is actually ‘working’) was more revealing than the total testosterone. This is most conveniently measured in a saliva specimen. Clinicians and patients should bear in mind the authors’ conclusion:

“In patients with coronary disease testosterone deficiency is common and impacts significantly negatively on survival.“

Important: testosterone replacement by gel, cream or patch (transdermal) can easily accumulate to abnormally high (supraphysiologic) levels which ‘back-fires’ by causing testosterone receptor desensitization and pituitary suppression. This may be missed if the correct testosterone test (the bio-active, free fraction portion) is not done.

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An important study just published in the Annals of Oncology adds more evidence of the exceptional importance of  metabolic syndrome for prostate cancer. The authors state:

“Metabolic syndrome (MS) is a set of risk factors that includes obesity and insulin resistance and has been implicated in the development of prostate cancer.”

They proceeded to examine the impact of metabolic syndrome on prostate cancer patients treated with androgen deprivation therapy (ADT, blocking the production or signaling of male hormones). Comparing the data between patients with and without metabolic syndrome for the average time to PSA progression and overall survival (OS) yielded a stark contrast:

“Median time to PSA progression for patients with MS was 16 versus 36 months without MS. The median OS for patients with MS was 36.5 months after commencing ADT compared with 46.7 months for those patients without MS.”

The authors sum up their evidence in the usual understated fashion:

“This preliminary data suggest that MS is a risk factor for earlier development of castration-resistant prostate cancer and support the need for a prospective evaluation of this finding.”

It’s troubling to see how often clinicians fail to emphasize the great importance of blood sugar and insulin control when managing prostate cancer. Patients need to be aware that the lifestyle factors that address this are among the most important things they can do.

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An important paper was just published in the journal Cancer Epidemiology that provides further evidence of insulin as a tumor promoter in prostate cancer. The authors state:

“A higher insulin level has been linked to the risk of prostate cancer promotion…the insulin hypothesis was tested once more prospectively in men with a benign prostatic disorder.”

They proceeded by following 389 patients who had lower urinary tract symptoms without prostate cancer over 8-12 years. There were notable differences between the 44 who developed prostate cancer and the rest who didn’t:

“”Men with prostate cancer diagnosis had a higher systolic and diastolic blood pressure, were more obese as measured by BMI, waist and hip measurements than men who did not have prostate cancer diagnosis at follow-up. These men also had a higher uric acid level, and a higher fasting serum insulin level than men who did not have prostate cancer diagnosis at follow-up.”

All of these accessory factors—blood pressure, BMI, waist and hip circumference, uric acid—are directly related to elevated insulin. Considering the prevalence of both prostate cancer and metabolic syndrome (high insulin), it’s important for clinicians and the public alike to bear in mind the authors’ conclusion:

“Our data support the hypothesis that a higher insulin level is a promoter of prostate cancer. Moreover, our data suggest that the insulin level could be used as a marker of the risk of developing prostate cancer. The present findings also seem to confirm that prostate cancer is a component of the metabolic syndrome. Finally, our data generate the hypothesis that the metabolic syndrome conceals early prostate cancer.“

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There are fascinating and profound biological differences between men and women, so it’s not surprising that a study just published in Nutrition, Metabolism and Cardiovascular Diseases proves that there is a gender difference in the blood ‘anti-stickiness’ benefit from omega-3 fatty acids. The authors begin by stating:

“Increased platelet aggregation is a major risk factor for heart attacks, stroke and thrombosis. Long chain omega-3 polyunsaturated fatty acids (LCn-3PUFA; eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA) reduce platelet aggregation…Recent in vitro studies have demonstrated that inhibition of platelet aggregation by LCn-3PUFA is gender specific. We examined the acute effects of dietary supplementation with EPA or DHA rich oils on platelet aggregation in healthy male and females.“

Platelet aggregation is the ‘sticking together’ or clotting of the sub-cellular blood platelets. Blood that is too ‘sticky’ or clots too easily is a risk factor for heart attacks and strokes and a hindrance to the blood perfusion of tissues. The authors dosed males and females with EPA or DHA rich oil and measured the post-supplementation platelet aggregation. What did the data show?

“EPA was significantly the most effective in reducing platelet aggregation in males…whereas DHA was not effective relative to placebo. In contrast, in females, DHA significantly reduced platelet aggregation at 24 h (while EPA was not effective. An inverse relationship between testosterone levels and platelet aggregation following EPA supplementation was observed.”

This paper follows another recent study reporting that cholesterol levels vary with the menstrual cycle. Practitioners must bear in mind these and other gender differences. The authors conclude:

“Interactions between sex hormones and omega-3 fatty acids exist to differentially reduce platelet aggregation. For healthy individuals, males may benefit more from EPA supplementation while females are more responsive to DHA.“

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