Effects of hexanic extract of Serenoa repens (Permixon® 160 mg) on inflammation biomarkers in the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia

Abstract

Background: Chronic prostatic inflammation (CPI) could be a cause of symptomatic or complicated benign prostatic hyperplasia (BPH). In previous in vitro and in vivo studies, Hexanic Extract of Serenoa repens (HESr) namely Permixon(®) has demonstrated potent anti-inflammatory properties. With the aim to provide new insight onto HESr anti-inflammatory properties in human we explore its effect on CPI biomarkers in men with lower urinary tract symptoms (LUTS) related to BPH using a non-invasive method and investigate links between biomarkers and clinical symptoms.

Methods: An international, randomized, double-blind, parallel-group, tamsulosin-controlled study was carried out in 206 men with BPH-related LUTS. Patients received oral daily HESr 320mg or tamsulosin 0.4 mg during 3 months. The first urine stream after digital rectal examination (DRE) was collected at Day 1 and Day 90 and mRNA was extracted from prostatic epithelial cells desquaming in the lumen of the glands and seminal plasma fluid after DRE. mRNA quantification of the 29 most significant published inflammation markers in BPH and protein detection in urine was performed.

Results: At D90, a decrease in mean gene expression was observed for 65.4% of the markers detected in the HESr group versus 46.2% in the tamsulosin group. In the 15 most frequently expressed genes, this difference was higher (80% vs. 33% respectively). Three proteins (MCP-1/CCL2, IP-10/CXCL10, and MIF) were detected. At D90, a decrease in the number of patients who expressed MCP-1/CCL2 and IP-10/CXCL10 was observed only in the HESr group. Moreover, MIF expression was significantly reduced by HESr compared with tamsulosin (P = 0.007). Finally, in contrast to tamsulosin, the subgroup of patients treated by HESr and who over expressed MIF at baseline, had a higher response to the International Prostate Symptom Score (I-PSS) than those who did not over express this protein (mean I-PSS change: -6.4 vs. -4.5 respectively). As the study is exploratory, results should be confirmed in a powered clinical study.

Conclusions: These results showed for the first time at clinical level the anti-inflammatory properties of HESr, already indicated in BPH-related LUTS. Thus, HESr could be of interest to prevent unfavourable evolution in patients with CPI.

Keywords: benign prostatic hyperplasia; chronic prostatic inflammation; hexanic extract of serenoa repens; lower urinary tract symptoms; permixon®.

Figure 1

Patient flow chart.

Figure 2

Evolution of the 15 most frequently expressed inflammation genes (at least in 30 patients per group at baseline and D90). mRNA expression was quantified by qPCR. Percentage of patients for whom mRNA expression level was downregulated or upregulated between baseline and end of treament period (D90). Downregulation and upregulation were considered to occur when a change of at least twofold between baseline and D90 was observed (see Section 3.5: 'Statistical considerations'). Asterix * denoted nominally significant at P < 0.05.

Figure 3

Cumulative favourable effect by mRNA gene at the end of treatment (D90). For each mRNA gene, the global favourable effect corresponding to the sum of the delta of patients between treatment groups for downregulation and delta of patients for less upregulation was calculated. This was followed by a classification by group. Asterix * denoted nominally significant at P < 0.05.

Figure 4

Protein downregulation and upregulation at the end of treatment (D90). Downregulation and upregulation were considered to occur when a change of at least 25% was observed between D90 and baseline. Treatments were compared using a Cochran‐Mantel‐Haenszel test based on the rank score. Asterik * denoted P < 0.05.

Figure 5

I‐PSS overtime in both treatment groups. I‐PSS: International Prostate Symptom Score; D1: baseline, D30: follow‐up visit Day 30; D90: end of treatment visit Day 90.

Figure 6

I‐PSS adjusted* mean change from baseline to end of treatment (D90). In HESr group, response to I‐PSS at D90 was evaluated in patients who over expressed MIF protein at baseline (>3rd quartile) to those who did not over express this protein. * using Ancova model change=baseline+treatment. **>Q3 corresponds to the 25% of patients who expressed MIF at the highest level.