Testosterone may be beneficial for metabolic syndrome-associated prostate inflammation

The Correlation Between Metabolic Syndrome and Prostatic Diseases. De Nunzio C, Aronson W, Freedland SJ, Giovannucci E. Eur Urology 2012;61:560-570.

Testosterone protects from metabolic syndrome-associated prostate inflammation: an experimental study in rabbit. Vignozzi L, Morelli A, Sarchielli S, et al. J Endocrinology 2012;212:71-84.

A recent non-systematic literature review evaluated studies providing evidence of the role of metabolic syndrome in the development and progression of benign prostatic hyperplasia (BPH) and prostate cancer (PCa). In this evaluation the authors considered relevant articles (in both humans and animals) published between 1995 and September 2011 that were identified using PubMed. The review highlighted several observational studies which showed that metabolic syndrome is associated with an increased risk of lower urinary tract symptoms (LUTS) and BPH. Although the molecular pathways of metabolic syndrome as related to the prostate remain incompletely characterized, the cumulative evidence suggests an association between metabolic syndrome and its mediators and the development of BPH and PCa. An understanding of the metabolic syndrome pathway may identify new therapeutic targets and expose novel strategies to reduce the risk of benign and malignant prostate tumors.

A separate interventional study of an animal model of prostate inflammation was reported. A rabbit model of high-fat diet (HFD)-induced metabolic syndrome was used to study prostate inflammation and investigate the effect of dosing testosterone or INT-747 (a farnesoid X receptor [FXR] agonist), both agents having previously shown amelioration/treatment of several features of metabolic syndrome. In prior animal studies, testosterone supplementation (but not INT-747) was shown to revert metabolic syndrome-associated hypogonadism.

Key Points

  • A growing body of evidence has documented a strong and independent association between obesity/metabolic syndrome and BPH/LUTS
  • The prevalence of metabolic syndrome is increasing in developing countries reflecting the worldwide transition from a traditional to a Western-like lifestyle. Currently, the prevalence of metabolic syndrome rises from the age of 20 years until 50 years, when it levels and affects >40% of the population in the USA and nearly 30% in Europe1,2
  • Management of metabolic syndrome is considered a major challenge to global public health. Arguably, the most effective way to deal with it and its related consequences is through primary prevention

    • The ATP-III panel recommend that obesity should be the primary target of intervention for metabolic syndrome. Weight loss (of 7%–10% during the first year of treatment) together with more regular or moderate physical activity (30 min/d) lowers triglycerides and raises HDL cholesterol, lowers blood pressure, and reduces insulin resistance3,4
    • Although data on the effect of diet and lifestyle intervention on the natural histories of BPH and PCa require confirmation, it is reasonable to suggest that patients who exercise regularly, eat a balanced diet, and maintain a healthy weight can prevent or reverse metabolic syndrome. This advice can improve cardiac health and reduce the risk of cardiovascular disease, the most common cause of male mortality. In due course, these interventions (as well as identification of new therapeutic targets and development of associated therapies) may also be shown to influence the development and progression of BPH and PCa and maintain prostate health
  • In a rabbit model of metabolic syndrome, overt hypogonadism was induced by a high fat diet (HFD) and characterized by low testosterone (75% reduction in blood levels) along with prostate, seminal vesicle, and testis hypotrophy (56%, 38%, and 19% reduction in weight, respectively when compared with controls). In addition, HFD significantly (p<0.05) upregulated prostatic mRNA levels of inflammatory markers including TLR2, TLR4, CD4, CD8, LACTF, STAMP 2, RAGE, IL-8, IL-1β, TNF-α and IL-6. HFD also significantly (p<0.05) upregulated the expression of fibrosis (Figure 1) and myofibroblast activation markers, including TGFβ1, αSMA, RhoA, ROCK1 and ROCK2
  • Testosterone treatment prevented (and did not induce) prostatic diseases and normalized markers of metabolic syndrome in HFD-treated rabbits

    • Testosterone (30 mg/kg i.m. weekly over 12 weeks) not only restored prostate and seminal vesicle weight, but also normalized metabolic markers including fasting glucose (66% inhibition, p<0.05), glucose tolerance (35% inhibition, p<0.01), and dramatically decreased visceral fat (>400% inhibition, p<0.001) in HFD-treated rabbits. Oral treatment with INT-747 (10mg/kg daily for 5 days, over 12 weeks) also significantly normalized fasting glucose (96% inhibition, p<0.01) glucose tolerance (39% inhibition, p<0.05) and decreased visceral fat (>250% inhibition, p<0.001) in HFD-treated rabbits
    • Testosterone treatment reduced prostate fibrosis (Figure 1) and normalized levels of HFD-upregulated mRNA of all the prostatic inflammatory markers plus expression of fibrotic and myofibroblast activation markers (p<0.05 vs HFD for all). However, INT-747 treatment had no effect on these parameters
    • The differential effects of testosterone and INT-747 in this model suggest that the positive effect of testosterone is not via a component of metabolic syndrome. It was proposed that this activity on the prostate gland by testosterone is mediated by a reduction in mean arterial pressure
  • Testosterone protects rabbit prostate from metabolic syndrome-induced prostatic hypoxia, fibrosis and inflammation which can all play a role toward the development and/or progression of BPH/LUTS. These findings clarify pathogenic links between metabolic syndrome and prostate inflammation and provide new perspectives for prevention and intervention in BPH/LUTS

What is known

Men with LUTS and BPH often present with relatively low androgen and high estrogen levels. This condition, also observed in men with metabolic syndrome, may play a role in BPH pathogenesis.5,6

In epidemiological studies, LUTS was associated with several features of metabolic syndrome, including obesity,7-9 hypertension, type 2 diabetes mellitus,10-12 hyperglycemia and low high density lipoprotein (HDL) cholesterol,13 and high polyunsaturated fat energy intake.14

Metabolic syndrome appears to be related to the development of LUTS. Potential common etiological factors include hyperglycemia, insulin resistance, low-grade chronic inflammation15 and also hypogonadism.16 Recent data have suggested that low testosterone in males might be considered an additional metabolic syndrome component.17-21 Although testosterone supplementation in metabolic syndrome significantly improves metabolic parameters (fasting glucose, glucose tolerance, waist circumference, triglycerides, and HDL cholesterol),18 concerns of potential prostatic side effects have limited clinical use. Such concerns are based on the concept that androgens are essential for prostate growth, which potentially can worsen LUTS. On the contrary, data from prospective22,23 and cross-sectional studies24-28 have demonstrated an inverse association between serum testosterone levels and LUTS or BPH. Consistent with these observations, testosterone replacement therapy has been reported to relieve LUTS in hypogonadal men with both BPH29-35 and metabolic syndrome.36

What these studies add

Metabolic syndrome is a complex and common condition in patients with BPH and PCa. Although there is growing evidence of the association of metabolic syndrome with the initiation and clinical progression of BPH and PCA, molecular mechanisms and effects on treatment efficacy remain unclear.

Nevertheless, the non-systematic review highlighted that one of the most effective ways to deal with metabolic syndrome and its related consequences is prevention and that obesity should be the primary target of intervention for this condition.

Increased levels of physical activity have been associated with a decreased risk of BPH and LUTS in several large studies. However, despite this evidence no randomized clinical trials have been conducted to explore whether lifestyle interventions can influence the natural history of these conditions.

The study by Vignozzi et al. showed that testosterone supplementation normalized prostatic alterations, including inflammation, hypoxia and fibrosis in the HFD-induced rabbit model of metabolic syndrome. The mechanism for this activity has yet to be clarified, but it is unlikely to be due to an effect on a component of metabolic syndrome as INT-747 (an FXR agonist), in common with testosterone, abrogates several features of metabolic syndrome, but had no effect on prostate inflammation, fibrosis and hypoxia. The authors propose that the positive results of testosterone on the prostate gland in this model may be via a reduction in mean arterial pressure.

These results generated with testosterone in the rabbit model offer new insights and perspectives for prevention and intervention in BPH/LUTS.

Figure 1: Testosterone treatment inhibits fibrosis in HFD rabbit prostate tissue as measured by histology

References


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