Gabor Szendi:
Rethinking diseases of prostate

Prostate problem: an issue that will, at one point or another, impact most men over the course of their lives. Treating the condition once it took its toll is much harder and more dangerous than taking preventative measures.

Men suffering from the disease go through an experience akin to the person falling off of a 100 storey sky-scraper, noting midway through: 'so far so good!'

Sadly, once the pathology set in, modern medicine rarely takes the right measures to mitigate the problem.

A few thoughts on the paleo-disease theory

We happily accept the existence of myths and tales, and even derive some degree of pleasure out of them. This becomes a little more problematic when it comes to the area of medicine, since it typically costs hundreds of thousands of lives. The biggest fallacy of western medicinal schooling is that it blames factors on issues formed in the 19th and 20th century, that have existed all through human evolution. Such example would be deeming sunlight, animal fats and cholesterol, red meat or salt responsible for numerous modern diseases. In the case of prostate issues, blaming the pathologies on the presence of androgens is similarly faulty notion. Factors that remained unchanged throughout millions of years cannot be responsible for newly formed problems.

Prevalence of benign prostate hypertrophy (BPH) is one of the most common problems, and prostate cancer (PC) is one of the most common diseases responsible for male mortality. 40-50% of men face BPH by the age of 50, and 90% of them will do so by age 80¹. Similar trends pop up when looking at PC rates.

 

 

Prevalence of prostate cancer

Many of the initial encounters with PC came about during surgical interventions on prostate enlargement, where cancerous lesions were apparent in 25% of cases². The prevalence of PC began to grow rapidly, once the measurement of prostate specific Antigen (PSA) has gotten established.

A grand study had revealed that 15% of men indeed suffers from PC, despite PSA assessments showing normal values.

Thorough screening examinations and autopsies carried out on individuals passed away from different causes have concluded a 100% probability of PC assuming a 100 year life-span.³

A distinction has to be pointed out however between symptom-free and clinically diagnosable PC. Autopsies carried out on people passed away from other causes of mortality revealed a redundancy in discovering the cancer during their life-span, as it remained dormant until their death.

84% of cancer cases revealed by screening procedures are over diagnoses: the symptoms would not have showed up over the course of the patient's life-span, and the screenings are resulting in needless treatment-imposed risks.⁴

Comparing Hungarian and American data serves as a valuable illustration: While PC mortality rates are similar in both countries, (16-18 mortalities per 100,000 capita) there are large differences in the number of revealed PC cases: the US wins out with 180 cases as opposed to 34.⁵

Trends in the geographical distribution of PC mortalities reveal the significance of vitamin-D deficiency amongst several other risk factors: the fact that Norway has double the mortalities than countries such as Italy or Spain, serves as a prime example.⁶

Intense arguments are going on whether a relationship exists between BPH and PC, and if so, whether BPH precedes PC, or only acts as a risk factor.

Although it is hard to determine whether BPH is actually causing PC, many examinations have revealed that BPH is followed by PC.⁷

Medical reports to date deem BPH and PC to be a result of prostate cell proliferation and aggregation, which is stimulated by androgens. According to the theory, androgens (testosterone and dihydrotestosterone.) exert their impact over decades, which leads to clinically diagnosable enlargement and cell-proliferation. ⁸

Urologist Charles B. Huggins' dog experiments have revealed that BPH reverses upon castration. Later this method has been tested on humans, to discover that the administration of estrogen or the chemical termination of male sex hormone production (chemical castration) slows down the progression of BPH or PC.⁹

This theory has been supported by further empirical evidence. Examinations done on eunuchs showed that they had no tangible sized prostate.¹⁰ Further, men genetically lacking the enzyme 5-alpha reductase only develop the external parts of their reproductive organs only by late teenagehood.¹¹ This aided the discovery that conversion of testosterone into dihydrotestosterone, via 5-alpha reductase is largely responsible for the formation of internal and external reproductive organs, thereby also for prostate hypertrophy.

The development of 5-alpha reductase inhibitors (finasteride, dutasteride) upon this discovery effectively reduce prostate size. ¹²

Refuting the androgen-theory

From an evolutionary perspective it seems illogical that a condition such as BPH and PC would stand the test of millions of years. It serves as an illustration that mammals, with the exception of dogs growing up in urban households, do not develop BPH¹³ (this has made it challenging to establish an animal model to study the pathology). Similarly counter-intuitive is the phenomenon, that BPH and PC tends to develop mostly at ages when androgen levels naturally start to decline. ⁸

According to the theory we would expect to see a high prevalence of the pathology in youth, but that is not the case.

Observations in indigenous populations

Interesting lessons can be drawn from studies done on indigenous populations. Benjamin Trumble and colleagues have studied the Tsimane tribe in Bolivia, and have observed and contrasted their testosterone levels to men in Western societies.

Interestingly, while young Tsimane men appeared to have lower testosterone levels^14-16, their initial levels of testosterone seemed to remain relatively stable across their lifespan, as opposed to men in western societies, who's initially higher testosterone levels began to plummet with aging.¹⁷

Other, native populations show similarly lower, more consistent levels of testosterone over the course of their lives, therefore it's feasible that the observations on Tsimanes also apply to other, similar indigenous communities. Prostate size of Tsimanes enlarges at a much slower pace than that of men in western societies; Only 31,7% men between the ages of 60-80 have a larger prostate size of 20 cm3, (the upper, determined limit of normal prostate size) as opposed to 76% in men from the US. Tsimane men only reach 40 cm3 by 0,56%, as opposed to 20% in Americans. ¹⁸

Another interesting finding of the above investigations is that the occurrence of BPH is almost double for people with high readings of HbA1c (marker for average blood sugar levels).

A 1% increase in HbA1c contributes to 20 years worth of prostate hypertrophy.

This study by itself helps to conclude that an evolutionarily founded lifestyle can help us to be protected against - amongst other diseases- prostate related pathologies, as PC and BPH belong among the diseases of civilization. Several epidemiological observations support the notion that the above pathologies are a life-style related diseases.

In China for instance, 1900 autopsies revealed a 6,6% occurrence rate of BPH IN 1936.¹⁹ This number had risen to 30,5% by 1993²⁰. In South Korea, BPH rates are considerably lower in rural areas than that in major cities^21,22. The phenomenon that the countrysides present lower occurrence rates of BPH is a common observation, which serves to point out the role of lifestyle differences in the development of pathologies²³.

The same pattern seems to appear with regards to PC, especially prior to the implementation PSA screenings²⁴.

A 2012 systematic review of 16 studies, measuring the incidence rates of PC in rural and urban areas concluded that the disease is indeed more common in cities²⁵.

Though not subject to current analysis, the difference in disease development between rural and urban areas correlates well with the trends to consume larger quantities of whole, natural foods as opposed to processed ones in one area compared to the other. As well, the classic analysis of the Garland brothers in 1980 has indicated already that the risk of colon cancer in those living in cities are double of those in the countryside due to their lowered vitamin-D level. ⁸⁵

All of this seems to indicate that BPH and PC are diseases of western lifestyle, much more so than the cumulative effect of androgens over the decades. This is supported by data derived from migrating populations, whose PC risk get elevated upon moving from low to high risk areas. ²⁶

It is clear to see that creators of the androgen-hypothesis within the medical community try to ignore facts attempting to question androgen theory in order to maintain the status of their theory.

Rebuttal of the androgen-hypothesis for BPH and PC - the role of testosterone

As discussed, the enzyme 5-alfa reductase converts testosterone into it's more potent form, dihydrotestosterone, which is - contrary to common belief - a requirement for proper functioning and development of the prostate. Within dividing tissues, cell growth and death is continuous, which is a necessity for normal prostate functioning. ^27,28 As it turns out, blood serum testosterone levels are not a predictor of dihydrotestosterone levels measured in the prostate²⁹, nor that of BPH and PC risk.,

Castration and chemical castration applied in cases of advanced state BPH and prostate cancer tends to only slow down the progression of the disease initially, whereupon castration-resistant PC develops: thus the termination of testosterone and dihydrotestosterone is futile, the development of BPH and PC continues.³⁰

A 20 year long longitudinal study has found that higher levels of testosterone on average are associated with a 56% reduction of urinary complaints.³¹ Similar conclusions were drawn from another, 10 year study, that found high testosterone levels to be protective against BPH. ³²

Abraham Morgentaler in 2007 has accounted for 16 longitudinal studies, in which testosterone replacement therapy in aging men did not increase the risk of PC development or advancement. ³³ Morgentaler quoted several studies, which, - contrary to the androgen-based theory - demonstrate the increase in PC risk with low, as opposed to high testosterone levels. This has since been confirmed by follow up studies as well. ^{34, 35} As he puts it, if scientists from a different planet were to visit earth, they would immediately start examining the relationship between low testosterone and PC, as the disease - just like BPH - begins to spread amongst men after the lowering of their testosterone level.

The testosterone-hypothesis of PC appears to be yet another myth within the medical community, which took its routes with the publication of B. Huggings.

The issue is that Huggings had drawn his conclusions from a single case study.³⁶

One placebo-controlled study, on the other hand, confirmed, that testosterone-replacement-therapy produced significant improvements in various BPH related symptoms, such as urinary difficulties. ³⁷

Testosterone-replacement becomes increasingly important with aging due to its ability to prevent age related sarcopenia (muscle loss), body fat gain and osteoporosis. ³⁸

The role of dihydrotestosterone

We see a different picture with dihydrotestosterone, the levels of which in the prostate do not decrease with aging. ³⁹ Surprising is the finding that it is still present in the prostate - although to a lesser extent - post castration.⁴⁰

Nevertheless, dihydrotestosterone by itself is only a pre-requisite, not a direct cause of BPH. (41) The lack of quantifiable differences between symptom-free individuals and those afflicted by BPH demonstrate this notion. ^42,43

The factors playing the primary role in BPH are those upsetting the balance between cell death and growth, thus increasing the rate of cell growth. ⁴⁴

Enzyme-inhibiting medication such as finasteride and dutasteride have been shown to drastically decrease the size even of already hypertrophied prostate, ⁴⁵ thereby PC progression could be inhibited as well. ⁴⁶ Still, since dihydrotestosterone is not the real culprit behind prostate issues, this methodology can be viewed as a cop out of sorts.

A question of high interest for instance is the reason behind considerably higher risk of PC within black compared to white populations, ^{47, 48} despite having no differences in testosterone and dihydrotestosterone levels. ⁴⁹ The answer lies in vitamin-D levels. African Americans tend to get afflicted more commonly by other types of cancers too. ⁵⁰

Civilization based reasons behind pathological changes in prostate

People in western societies differ from those living in indigenous cultures in various aspects of lifestyle: the consumption of refined carbohydrates, vitamin-D deficiency, the suboptimal ratio of omega-6 to omega-3, the lack of activity and the avoidance of sunlight are primary examples. The consequences of these poor lifestyle habits are weight gain, high blood sugar, insulin and IGF-1 levels as well as elevated degrees of systemic inflammation (besides greater overall risk of metabolic syndrome). (The role of androgen disruptors and other such adverse chemical impacts will not be discussed in this article, as they generally don't appear to be the major contributors.)

Metabolic syndrome

Aleksandra Ryl and colleagues have demonstrated that metabolic syndrome is a doubled risk factor for BPH. ⁵¹

Jan Hammarsten and colleagues have reported all components of metabolic syndrome to be correlating with an increase in prostate hypertrophy. In case of diabetes the rate of growth was shown to be double that of non-diabetic patients. ⁵² The conclusion of the study established a strong relationship between BPH and metabolic syndrome.

Weight gain and obesity

BPH is primarily brought about by central obesity. Waist girth measurements over 90 centimeters correlate with a 3,4, and combined with a BMI over 25, a 5 fold increase in BPH risk. ⁵³

Men with above 100 centimeters of waist measurement show a 40% increase in prostate size, a 2 fold increase in PSA-value, and experience prostate issues (such as urinary complaints) 68% more compared to those with waist-girths under 90 centimeters. ⁵⁴

An increase in waist-to hip ratio presents itself with a threefold increase in PSA value, which is an indicator of enlarged and/or cancerous inflicted prostate. ⁵⁵ Although initial studies had not found an increased risk of PC as a result of weight gain⁵⁶, when local cancerous lesions were distinguished from more severe or metastatic cancer types, it became clear that obesity poses a serious risk to the latter. ⁵⁷ One study showed an 1,4, and 3,5 fold increase in overweight (25 < BMI < 30) and obese (BMI > 35) populations respectively. ⁵⁸ PC related mortality is 30-40% more common in overweight populations⁵⁹, and a 10% reduction in bodyweight could already produce significant reductions in prostate related complaints. ⁶⁰

Glucose metabolism

The other important component of metabolic syndrome is impaired glucose metabolism.

Fasting blood glucose levels above 6,2 mmol/l (111.6 mg/dl) correlates with a 2,25 elevation in BPH risk. ⁶¹ High insulin levels is also an independent risk factor of BPH. ⁶² Type 2 diabetes (high blood glucose and insulin levels), according to one review, increases the risk of BPH development by 1,5-3 fold. ⁶³ People suffering from BPH have double the insulin levels, besides having a doubling in prostate size as well. ⁶⁴

High insulin levels are accompanied by high levels of IGF-1: both are growth factors. People with the highest levels of IGF-1 have a 2,6 fold increase in PC. ⁶⁵ Men under the age of 60 have an even higher, 4 fold increase in PC risk. ⁶⁶

The role of estrogen

As discussed previously, high testosterone is not a risk factor, but is rather protective against prostate related pathologies. Fat cells convert testosterone into oestradiol, (the primary female sex hormone) which means a linear relationship between circulating oestradiol levels and increases in body-fat levels. ⁶⁷ High levels in oestradiol are an independent risk factor for BPH. ⁶⁸

Oestradiol possesses alpha and beta receptors, and binding through its alpha receptors stimulates BPH hypertrophy as well as its cancerous differentiation. ⁶⁹ Inhibiting receptor activity has been shown to prevent PC formation, and delay its progression.

A 12 month treatment reduces tumor size by 48%. ⁷⁰ High levels of oestradiol measured in the blood are associated with a 4 times higher chance of developing severe PC. ⁷¹ It is bizarre in light of all this that estrogen is commonly applied as a complementary treatment, which we know recognize as a particularly carcinogenic substance. ⁷²

Paras Singh and colleagues have brought attention to an important association: one study examining the 5-alpha reductase inhibitor finasteride found a reduced risk and lessened severity for BPH, but a 10% relative increase in severe metastatic PC rates.

The reason for this could be the increased production of oestradiol as a result of higher testosterone levels, ⁷³ which had increased PC risk. In conclusion, it might not be enough to reduce dihydrotestosterone levels, but it may be necessary to inhibit the conversion of testosterone into oestradiol. (see at www.lef.org)

The role of inflammation

Inflammation is yet another important risk factor for prostate pathologies. Prostate inflammation approximately doubles PC risk, and 57% of BPH patients have or have had prostate inflammation.⁷⁴

We now recognize omega-6 to be proinflammatory, and omega 3 to be anti-inflammatory agents. Having the largest ratios of omega-6 to omega-3 is associated with a 3,5 fold increase compared to having the smallest ratios⁷⁵. High fish and omega-3 consuming populations have a low risk of prostate cancer.⁷⁶

Plant derived omega-3 fatty sources (alpha-linoleic acid) convert poorly to omega-3, and plays a controversial role in PC formation: several studies have shown it to pose serious risk.⁷⁷

Vitamin-D

The anti-cancer properties of vitamin-D come from the cell-division regulating properties of this hormone. The advancement of BPH is inversely proportional to vitamin-D levels.⁷⁸ Like many other forms of cancer, prostate cancer shows a close relationship with vitamin-D deficiency.⁷⁹

Prostate cancer shows up at an increasing rate, as we look at Northern areas⁸⁰. Cancer patients diagnosed with PSA-test had a 2,33 fold increased risk of metastatic cancer in case of vitamin-D deficiency (vitamin D levels< 12 ng/ml) compared to those with normal vitamin-D levels. (vitamin-D levels > 30 ng/ml). ⁸¹ The optimal level is between 60 and 80 ng/ml.

Dairy and calcium

It needs to be mentioned that increased calcium intake, as related to dairy consumption showed an increased PC risk. ⁸² One longitudinal study showed a 2,7 times higher chance of PC related mortality in people with the highest levels of calcium levels. ⁸³

The PC-risk inducing effects of calcium have been confirmed by several studies.⁸⁴

Conclusions

Within the new paradigm of BPH and PC, testosterone is a protective agent, not a risk factor; testosterone replacement therapy reduces the probability of disease development. In a 2016 study applying high dose testosterone cycling on castration resistant PC patients was able to significantly reduce PSA levels, with an occasional reduction in tumor size, and complete reversal of the disease in one instance. ⁸⁶ While dihydrotestosterone is not the main cause of BPH, in interaction with western lifestyle becomes causative factor, so reduction of dihydrotestosterone level by natural or pharmaceutical agents can effectively prevent and treat BPH. It is important however to reduce estrogen exposure through aromatase-enzyme inhibition, as estrogen levels increase both with age and increased body-fat levels.

The real purpose of a review like this is providing guidance with both prevention and treatment. It is important to emphasize however that these theoretical recommendations do not replace medical examination and supervision.

The importance of omega-3 and vitamin-D have been long emphasized within the paleo framework, and their potential to prevent BPH and PC have been proven.

The levels of DHT can be reduced through various natural products (pumpkin seeds, saw palmetto, nettle root, Pygeum Africanum bark, etc.) as well as the prescription medications finasteride and dutasteride. Over the ages of 50-60 it is advisable to increase testosterone levels pharmaceutically or naturally: numerous food supplements are available for such purposes.

This however is only advisable in conjunction with the inhibition of the aromatase-enzyme, thereby the reduction of estrogen levels. If the conversion of testosterone into estrogen is inhibited pharmaceutically (through the prescription medication arimidex, for example) through natural agents or lifestyle improvements such as weight loss, testosterone levels will inevitably be elevated.

Since estrogen plays an important role in males as well, the goal is not to completely diminish it, but rather to keep it at an optimal level, at around the range of 20-30 pg/mL.⁸⁷ It is important to reduce estrogen exposure through other measures too. One natural way to achieve this is through supplementation with broccoli-extract, which contains compounds blocking the alpha-receptors of estrogen, and exerts its impacts directly in prostate tissues.

I think it's time to reconsider the prevention and treatment of prostate diseases from the evolutionary point of view.

 

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