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Serenoa Repens for benign prostatic hypertrophy

Benign prostatic hyperplasia (BPH) is a noncancerous growth of the prostate. Most of the BPH evidences occurs in men over 80. Human prostate grows with age. This continued growth (hyperplasia) can enlarge the prostate to the extent that it compresses the urethra and limits the flow of urine, causing urinary symptoms (4). The most common manifestation of BPH is lower urinary tract symptoms (LUTS), a group of clinical symptoms comprising obstructive symptoms including hesitancy, poor stream, incomplete voiding, urinary retention, and overflow incontinence as well as irritative symptoms including frequent urination, urgent urination, nocturia, and urge incontinence (Roehrborn, 2005). The reasons causing the prostate to enlarge are still poorly understood. In general, dihydrotestosterone (DHT), a metabolite of testosterone, is thought to be a critical mediator of prostatic growth (7). DHT is derived from testosterone in specific tissues including the prostate gland via the action of 5α-reductase. DHT binds to nuclear androgen receptors and activates the transcription of androgen-regulated genes that are mitogenic to both epithelial and stromal cells (8).

Treatment options are medication and surgery. Many clinical trials have validated the efficacy of two 5α-reductase inhibitor (5-ARI), finasteride and dutasteride and 5α-blockers (terazosin, doxazosin, tamsulosin, alfuzosin, and silodosin), which were subsequently approved by the US Food and Drug Administration for the treatment of BPH (3). Another medication treatment come from phytotheraphy. There are about 30 phytotherapeutic compounds available for the treatment of BPH, and the most widely used of the plant pharmaceuticals is an extract from the berry of the American saw palmetto or dwarf palm plant, Serenoa repens (also known by its botanical name of Sabal serrulatum). While the mechanism of Serenoa repens is unknown, some of those proposed are: alteration in cholesterol metabolism; antiestrogenic and antiandrogenic effects, with Serenoa repens (Permixon®) acting as a weak surrogate 5-ARI, inhibiting the conversion of testosterone to dihydrotestosterone (DHT); anti-inflammatory effects; a decrease in available sex hormone-binding globulin; pro-apoptotic properties and inhibition of cellular proliferation; the dependent inhibition of 5-ARI in the stroma and epithelium of the prostate; and the relaxation of smooth muscles via α1-adrenergic receptors (9).

The dried ripe fruit of S. repens contains primary and secondary metabolites:

  1. Carbohydrates: Polysaccharides with an acid character: galactose (38.4%), arabinose (18.7%), uronic acid (14%), invert sugar (28.2%) and mannitol
  2. Sterols: Beta-sitosterol, beta-sitosterol-3-O-beta-D-glycoside, beta-sitosterol-3-O-beta-D-diglycoside and several esters of beta-sitosterol with saturated fatty acids; campestrol and stigmasterol
  3. Flavonoids: Isoquercitrin, rutin, kaempferol-3-O-beta-D-glucoside and rhoifolin
  4. Triglycerides and fatty acids: Capric acid, caproic acid, caprylic acid, lauric acid, myristic acid, oleic acid(s) (oleic acid and myristoleic acid) and palmitic acid: free form, ethylic esters or in triglycerides
  5. Other substances: Volatile oil, anthranilic acid, carotene, resin, tannin.

There may be a variation in qualitative and quantitative composition. Habib & Willie 2004 reported a free acid content variation from 41 to 81% of the total lipid content, while glycerides are reported to vary between 7 and 52% of the total lipid content. Some marketed products contain olive oil, which can lead to confusion with regard to the lipid composition (1).

The most common pharmaceutical form of S. repens is taking one capsule daily, after meals with plenty amount of water.

Herbal preparations of Serenoa repens are widely used for treatment of lower urinary tract symptoms related to BPH. One hexane extract and several ethanolic extracts have been marketed for at least 30 years in the EU. Although BPH symptoms may vary and there is tendency to see converging of these symptoms in verum as well as in placebo groups, positive therapeutic outcomes have been reported for hexane extracts of Serenoa repens in several clinical studies with placebo. Furthermore the therapeutic outcomes with hexane extracts of Serenoa repens were comparable with tamsulosin and finasteride. Both substances tamsulosin and finasteride are considered as having a proven benefit for patients with BPH. Positive outcomes on BPH symptoms could be seen after 4 weeks to 12 months. Despite the frequent use throughout the EU, relatively few undesirable effects were reported. Liver damage and pancreatitis have been reported very rarely in relation to the use of Serenoa repens. In general Serenoa repens preparations are well tolerated. Several experimental findings support the use of Serenoa repens in BPH. From in vitro experiments the following properties were identified: inhibition of 5-alpha-reductase; influence on androgenreceptor binding; inhibition of alpha-receptor binding; inhibition of eicosanoid synthesis; spasmolytic effects and anti-inflammatory effects. The activity can differ from one extract to another, probably dependent upon the content of fatty acids. Anti-androgenic and anti-inflammatory effects were confirmed in in vivo experiments. These findings have a qualitative or semi-quantitative character, due to the sometimes high concentrations and high doses needed. Toxicity of the hexane extract appears low. There are no data on genotoxicity, carcinogenicity or fertility. Most minor side effects are related to the gastro-intestinal system, especially when taken on an empty stomach. There is plausibility for gynecomastia. Cases of allergy have been reported. Increases in blood pressure and ocular effects have been reported according in some SmPCs of marketed products. These minor effects are reported as side effects and kept in drug information databases. Mostly no scientific evidence is given (1).

A chinese double blind, placebo-controlled study of 354 patients with LUTS/BPH from 19 institutions have shown that S. repens extract was effective, safe and well tolerated, and clinically and statistically superior to placebo in the target LUTS/BPH population (10). The study of Champault et al obtained, with about 100 patients, positive urinary parameters improved significantly with Serenoa repens as compared with placebo. Another study was conducted in 98 urology centers in Europe: The authors conclude that their study demonstrated the clinical equivalence of Serenoa repens with tamsulosin in the treatment of lower urinary tract symptoms due to BPH. Both treatments provide similar improvements in symptoms and urinary flow rate, with a similar tolerability profile, except for a higher incidence of retrograde ejaculation reported in the tamsulosin group (2).

On the other side, there are many reviews that report the efficacy of Serenoa repens in doubt. James Tacklind et al., have published a systematic review, including 18 trials, of which only 6 randomized 100 subjects or more. The other 12 trials ranged from 22 to 80 subjects, concluding there is an exaggerated use of Serenoa repens from millions of mens with little or no evidence of its efficacy or safety (Tacklind J. et al., 2012). The latest evidence, based largely on the Cochrane review, suggests that S. repens is not superior to placebo in treating LUTS/BPH as a monotherapy, even at double and triple doses (5).

Despite the disagreement between the present scientific literature, the treatment of benign prostatic hyperplasia with herbal medicines based on Serenoa repens can be considered safe, although some studies have observed a similar effect to placebo.

 

Bibliography

  1. Assessment report on Serenoa repens (W. Bartram) Small, fructus EMA/HMPC/137250/2013
  2. Debruyne F, Boyle P, Calais da Silva F, Gillenwater JG, Hamdy FC, Perrin P, Teillac P, Vela-Navarrete R, Raynaud JP, Schulman C. Evaluation du bénéfice clinique de Permixon et de la tamsulosine dans le traitement de l’hypertrophie bénigne de la prostate (HBP) sévère: analyse d’un sous-groupe de l’étude PERMAL [Evaluation of the clinical benefit of Permixon and tamsulosin in severe BPH patients–PERMAL study subset analysis]. Prog Urol. 2004 Jun;14(3):326-31. French. PMID: 15373174.
  3. Lepor H. Medical treatment of benign prostatic hyperplasia. Rev Urol. 2011;13(1):20-33. PMID: 21826125; PMCID: PMC3151584.
  4. Lepor H. Pathophysiology of benign prostatic hyperplasia in the aging male population. Rev Urol. 2005;7 Suppl 4(Suppl 4):S3-S12. PMID: 16986052; PMCID: PMC1477609.
  5. Ooi SL, Pak SC. Serenoa repens for Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia: Current Evidence and Its Clinical Implications in Naturopathic Medicine. J Altern Complement Med. 2017 Aug;23(8):599-606. doi: 10.1089/acm.2016.0302. Epub 2017 Apr 24. PMID: 28436684.
  6. Rhodes L, Primka RL, Berman C, Vergult G, Gabriel M, Pierre-Malice M, Gibelin B. Comparison of finasteride (Proscar), a 5 alpha reductase inhibitor, and various commercial plant extracts in in vitro and in vivo 5 alpha reductase inhibition. Prostate. 1993;22(1):43-51. doi: 10.1002/pros.2990220107. PMID: 8381228.
  7. Roehrborn CG. Benign prostatic hyperplasia: an overview. Rev Urol. 2005;7 Suppl 9(Suppl 9):S3-S14. PMID: 16985902; PMCID: PMC1477638.
  8. Saad F, Yassin AA, Haider A, Gooren L. Effects of testosterone on the lower urinary tract go beyond the prostate: New insights, new treatment options. Arab J Urol. 2011 Jun;9(2):147-52. doi: 10.1016/j.aju.2011.06.003. Epub 2011 Sep 9. PMID: 26579287; PMCID: PMC4150581.
  9. Tacklind J, MacDonald R, Rutks I, Wilt TJ. Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD001423. doi: 10.1002/14651858.CD001423.pub2. Update in: Cochrane Database Syst Rev. 2012;12:CD001423. PMID: 19370565; PMCID: PMC3090655.
  10. Ye Z, Huang J, Zhou L, Chen S, Wang Z, Ma L, Wang D, Wang G, Wang S, Liang C, Qiu S, Gu X, Liu J, Weng Z, Wu C, Wei Q, Xie L, Wu W, Cheng Y, Hu J, Wang Z, Zeng X. Efficacy and Safety of Serenoa repens Extract Among Patients with Benign Prostatic Hyperplasia in China: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial. Urology. 2019 Jul;129:172-179. doi: 10.1016/j.urology.2019.02.030. Epub 2019 Mar 14. PMID: 30880074.