Blair HA. Hexanic extract of Serenoa repens (Permixon®): a review in symptomatic benign prostatic hyperplasia. Drugs Aging. March 2022;39(3):235-243. doi: 10.1007/s40266-022-00924-3.
In men, benign prostatic hyperplasia (BPH), characterized by overproduction of epithelial and stromal cells in the prostate transition zone, enlarges the prostate and compresses the urethra. BPH causes lower urinary tract symptoms (LUTS) including voiding and storage problems that significantly reduce quality of life (QoL). The pathogenesis of BPH is uncertain, but persistent or chronic prostatic inflammation contributes to it and speeds disease progression. Reducing inflammation is a key goal of BPH treatment. Standard treatments include 5α-reductase inhibitors (5ARIs) and α1- adrenergic receptor antagonists (α-blockers; ABs), often associated with adverse effects (AEs) including sexual dysfunction. Evidence is limited for the efficacy of 5ARIs and ABs in reducing persistent prostatic inflammation. Phytotherapy is often used as an alternative and/or complementary treatment for LUTS and other health conditions in men.
Extracts of saw palmetto (SP; Serenoa repens, Arecaceae) are traditionally used for LUTS associated with BPH. Main types of SP extracts are hexanic, supercritical carbon dioxide, and ethanolic, with differing compositions. The SP hexanic extract Permixon® (Pierre Fabre Médicament; Paris, Île de France and Castres, Occitania, France), containing > 90% free fatty acids (lauric, oleic, myristic, and palmitic acids) and phytosterols, flavonoids, alcohols, and polyprenols, was approved for treatment of BPH in 1981. It demonstrated efficacy similar to that of the pharmacotherapy 5ARI finasteride. SP hexanic is the only SP extract approved under the European Medicines Agency's well-established use criteria. Other SP extracts have traditional use status.
Mechanisms proposed for SP hexanic's effects on prostatic tissue include anti-inflammatory, anti-proliferative, anti-androgenic, and anti-estrogenic activities. In preclinical and clinical studies, SP hexanic inhibited inflammatory cells, mediators, and proteins, and was associated with down-regulation of genes that encode inflammatory markers. In a randomized clinical trial, men who received 320 mg/d SP hexanic for six months had significantly lower inflammation and aggressiveness scores vs. baseline (P = 0.001 for both) and vs. controls who received no treatment (P < 0.009 for the main reduction in inflammation grading, aggressiveness grading, and total Irani's score). Antibodies specific to inflammatory cells were significantly reduced in the SP hexanic group (P < 0.001), with no significant reduction in the control group. In the exploratory multicenter Phase IV PERMIN study, SP hexanic reduced mean expression of more inflammatory markers more markedly than the pharmaceutical AB tamsulosin (TAM). Among SP hexanic's activities, summarized in Table 1, are inducing apoptosis and upregulating caspase-3, inhibiting type 1 and 2 isoforms of 5α-reductase without interfering with prostate-specific antigen (PSA) expression and, as seen in vivo, inhibiting nuclear estrogen receptors. Maximum plasma concentration (Cmax = 2.6 mg/L) SP hexanic was reached 1.5 hr post- one oral dose (320 mg) in healthy young men. Mean area under the concentration-time curve was 8.2 mg/L(hr) and elimination half-life was 1.9 hr. In healthy participants who took 160 mg SP hexanic with 5 mg radiolabeled FAs, Cmax was achieved at ~ 3 hr post-intake. SP has been shown to inhibit CYP2C9, CYP2D6, and CYP3A4 in vitro; yet no clinical relevance is known. In healthy participants, SP hexanic did not affect pharmacokinetics of substrates of these cytochromes.
The efficacy of SP hexanic was reported by the randomized, double-blinded, multicenter PERMAL and PERMIN clinical trials (RCTs) in comparison to TAM and in three open-label trials. One of the latter was a long-term (two year) trial. Patients in the PERMAL study had International Prostate Symptom Scores (I-PSS) ≥ 10, maximum urinary flow rate (Qmax) of 5-15 mL/s for a voided volume ≥ 150 mL and post-voiding volume < 150 mL, a prostate volume ≥ 25 cm3, and serum PSA < 5 ng/mL with a free total PSA ratio ≥ 15%. At 12 months, SP hexanic and TAM groups had similar reductions in I-PSS totals, and no significant between-group difference in reduction of irritative or obstructive symptoms. At 12 months, there was no significant difference in improved Qmax (50% improvement in 28% of the SP hexanic group vs. 31% in the TAM group). At 12 months, 34% in SP hexanic and 37% in TAM groups had improved Qmax ≥ 3 mL/s, respectively. Changes in sexual function score, prostate volume, and PSA level did not differ between groups.
In a PERMAL study subset of men with severe LUTS (I-PSS > 19), improvement from baseline in I-PSS total score with SP v approached statistical significance vs. TAM. Irritative symptoms improved significantly (P < 0.05) more with SP hexanic. PERMIN patients had a > 12-month history of BPH-related LUTS, I-PSS scores ≥ 12, prostate volume ≥ 30 cm3, Qmax 5-15 mL/s for voided volume ≥ 150-500 mL, and PSA < 4 ng/mL with free total PSA ≥ 25%. Primary endpoint was mRNA expression associated with genes encoding biomarkers of prostate inflammation after 90 days treatment with SP hexanic or TAM. Both treatments were associated with improved I-PSS, Qmax, sexual function score, and prostate volume. There was no relationship between changes in clinical symptoms and mRNA expression. Improvement in I-PSS scores with SP hexanic in patients who overexpressed macrophage migration inhibitory factor protein was greater than in patients who did not, a difference not seen with TAM treatment.
Observational studies also confirm the efficacy of SP hexanic for treatment of LUTS/BPH, including two prospective longitudinal studies conducted in real-life practice, QUALIPROST (participants = 1713) in Spain and PERSAT (759 evaluable) in France. In a QUALIPROST subset analysis, SP hexanic was similar to TAM in efficacy in men with moderate to severe LUTS/BPH. PERSAT followed patients treated with phytotherapy alone (mostly SP) or an AB, most commonly silodosin. At six months, both groups I-PSS scores had improved > 92%, with no significant difference. In an Italian study (n = 591), SP hexanic significantly improved I-PSS scores, bladder emptying, LUTS, and erectile function (P < 0.0055) over baseline. SP hexanic was well-tolerated, with fewer AEs and better patient acceptance than TAM, Abs, and 5ARIs in studies discussed.
The authors conclude SP hexanic is an effective and generally safe treatment option for management of BPH symptoms in men. The authors had no conflicts of interest.