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.
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 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 (3 separate experiments, n=3 for each group)