Saw palmetto (Serenoa repens) is a dwarf palm tree in the family Arecaceae, which is native to the southeast region of the U.S. Atlantic coast. It grows up to six feet with 18"–30" wide leaves divided into 6–20 fan-shaped gray to bluish-green lobes. Its tiny, fragrant, cream-colored flowers are hidden among the leaves in the summer followed by egg-shaped purple-black berries. The berries of this impressive palm are gathered from September until January.¹

History of Herbal Use in Medicine

The earliest documented use of various plant extracts was reported as early as fifteenth century B.C. in Egypt to treat urethral obstruction.² Some plant extracts are still used in medical treatment of benign prostatic hyperplasia (BPH) such as Africanum plum (Pygeum africanum), aspen (Populus tremula), pumpkin seeds (Cucurbita pepo), South African star grass (Hipoxis rooperi) and saw palmetto (Serenoa repens).³ In Germany, the vast majority of patients with BPH are treated with a phytopharmaceutical agent. Urologists in other countries, e.g., Italy and France, also prefer to use some form of phytopharmaceutical agent, especially saw palmetto extract, as an alternative to drug therapy.

John Lloyd, a nineteenth century medical botanist, observed that saw palmetto berries have an appetite-stimulating effect and the animals that ate these berries grew healthy and fat. Early settlers searching for fodder for their livestock made similar observations. In the early 1870s it was demonstrated that the berries had beneficial effects on body weight, general health and disposition, tranquilization, appetite stimulation and reproductive health.³

Florida is the largest producer of saw palmetto berries, with the remaining supply coming from South Carolina and other southeastern states. Until recently, interest in this remedy in the U.S. was low, and most of the crop was exported to Europe.

The herb was included in the National Formulary (NF) and U.S. Pharmacopoeia (USP) but was deleted in 1950 and 1916, respectively, because an active ingredient could not be found to account for its observed effects.⁴ European herbal use and research continued throughout the ’50s and ’60s but the medical community in the U.S. largely discounted herbal remedies whose "active ingredient" was unknown. Eventually saw palmetto regained recognition in Europe in the mid ’80s as a result of large-scale clinical studies proving the efficacy of Serenoa extract.³

Chemical Composition

Analysis of the 95% ethanol extract of the berries for the known lipid content showed fatty acids, fatty acid esters, and phytosterols.⁵

Fatty Acids: Free fatty acid composition is rich in shorter chain length fatty acids such as capric, caprylic, lauric and myristic acid. Additionally, the extract contains palmitic, stearic, oleic, linoleic and linolenic acid. A small portion of the fatty acids are found in the ester form, mainly in ethyl-ester.

Phytosterols: The following sterols have been identified in the alcoholic extract: campesterol, stigmasterol, ß-sitosterol and cycloartenol.

Other chemical constituents identified in the berries include aliphatic alcohols (C26-30), polyprenic compounds, flavonoids, glucose, galactose, arabinose, uronic acid and other polysaccharides. The actual active ingredient in the berries, however, remains undetermined.

Medicinal Uses

Saw palmetto has been used as a mild diuretic and urinary antiseptic. It gained a clinical reputation in the early part of this century as an expectorant and for the treatment of chronic cystitis.⁶ Recent interest in saw palmetto has been linked with the finding that sitosterols may act on steroid receptors. Remedies made from the berries gained a reputation for treating symptoms related to BPH. A lipido/sterolic extract (Permixon), using n-hexane to extract Serenoa repens, has long been available in Europe and used in in vitro and in vivo studies in humans and animals.

The prostate gland—the solid, chestnut-shaped organ that forms part of the male reproductive system—surrounds the first part of the urethra and is situated immediately under the bladder and in front of the rectum. It produces secretions that form part of the seminal fluid secreted into the urethra when sperm move through, i.e., during sexual climax. Prostate enlargement/maturation is initiated by androgen hormones at puberty and stops at about age 20. The enlargement continues later in a man’s life but rarely causes a problem before age 40. At age 60, about 50% of males experience some symptoms of BPH. Over 90% of males in their 70s experience symptoms. The following symptoms suggest a prostate problem: more frequent urination, especially during the night; a hesitant, interrupted, weak urine stream; urgency; and leaking or dribbling. Additional symptoms include lower back pain, diminished libido and discomfort during intercourse.⁷

Surgery represents a final solution for BPH patients. In the U.S., 350,000 surgical procedures are performed annually while an additional 1.6 million patients undergo pharmacological treatment.⁸ The phytopharmaceutical therapy of BPH includes different plant extract capsules of seeds, roots, leaves and berries that are currently available in the U.S. and are widely used in Europe for symptomatic relief. The most popular among these herbal remedies is saw palmetto.

In Vitro Studies: Recent research has focused on comparing the inhibitory effect of Permixon on 5-a-reductase enzyme, which converts testosterone to dihydrotestosterone (DHT), to 5-a-reductase inhibitors such as finasteride and 4-MA (17-(N,N-diethyl)carbamoyl-4-methyl-4-aza-5-androstan-3-one).^9,10 Finasteride and other highly specific 5-a-reductase inhibitors have been developed on the premise that the blockage of DHT synthesis leads to a reduction of prostate growth.¹¹ Two isoenzymes of 5-a-reductase, types I and II, have been detected in cultured human prostate cells. While there is some controversy over which type is dominant, it is generally agreed that type II predominates and that finasteride selectively inhibits 5-a-reductase II.¹² In vitro studies using the eukaryotic expression system demonstrated that the lipido/sterolic extract of saw palmetto inhibits both isoenzymes.

Other studies have shown that Serenoa extract inhibits androgenic activity by competing with DHT for the androgen receptor, thereby affecting testosterone metabolism.¹³ The binding of two synthetic androgens, mibolerone and methyltrienolone, that are specific for androgen receptors at low concentrations (5nM), were inhibited by Serenoa extract (Permixon) in a competitive manner. Various plant steroids were tested for competitive binding to androgen receptors and found to be inactive.^13,14 The inhibitory effect of Serenoa extract on DHT and testosterone binding was tested in tissue from 11 BPH patients. An average of 40%-42% reduction in receptor binding was observed for both hormones.¹⁵

Prostatic cell lines, LNCaP and PC3, responsive and unresponsive to androgen stimulation respectively, have been treated with Permixon.¹⁶ In LNCaP cell lines, Permixon-induced proliferation and differentiation that was not observed in PC3 cells. In PC3 cells cotransfected with wild-type androgen receptor and chloramphenicol transferase CAT reporter genes under the control of androgen responsive element, inhibited the androgen-induced CAT transcription. The authors concluded that the Permixon effect is mediated through androgen receptors.

Serenoa repens extract was shown to inhibit estradiol/testosterone-induced prostate enlargement in rats.¹⁷ A 60- to 90-day treatment resulted in lower weight for the dorsal and lateral regions of the prostate compared to the control groups. The weight of the ventral region of the prostate was significantly lowered after 30 and 60 days of treatment. This experiment showed that the saw palmetto treatment has region specificity, which arouses speculation as to the varying roles of the different parts of the prostate.

In Vivo Studies: A large-scale, 6-month, double-blind study of 1,098 patients was conducted to compare phytotherapy (Permixon 320 mg) with finasteride 5 mg.¹¹ Patients with moderate BPH were selected and the International Prostate Symptoms Scores (IPSS) were used as the primary end-points. The IPSS is a 7-item questionnaire rating urinary symptoms such as urgency, hesitancy, and frequency on a scale of 0 to 5. Both Permixon and finasteride decreased IPSS (–37% and –39%, respectively) and improved urinary flow rate and overall quality of life in similar manners. There was no statistical difference in the percentage of patients responding to either treatment. While finasteride decreased the prostate volume and the prostate specific antigen (PSA) level, Permixon had little effect on the volume and no significant change in the PSA level. However, Permixon elicited fewer sexual function complaints from subjects than did finasteride. A one-week, open, randomized, placebo-controlled trial comparing finasteride (5 mg/day) with Permixon (80 mg BID) included 32 healthy young males (age range 20–30 years).¹⁰ Serum testosterone and dihydrotestosterone levels were determined on Day 1 as baseline, followed by randomization of subjects for treatment. Finasteride decreased the DHT level significantly after 24 hours, while levels in the placebo and Permixon group did not differ significantly from baseline. Another group of investigators using the same number of patients for a week confirmed these data, which do not support the hypothesis that Permixon exerts its effect by inhibiting 5-a-reductase activity.¹⁸

Studies focusing on urine flow rate and post void residual (PVR) showed promising results. In a double-blind trial of 22 patients (Permixon 320 mg/day) for two months, a significant increase in the flow rate and a decrease in PVR were noted.¹⁹ Similar results were seen after one month of treatment with Permixon (320 mg/day), showing an increase in flow rate, while the PVR dropped to half of the initial volume.²⁰ In contrast, a double-blind study evaluating 70 patients’ data showed no statistical difference between the placebo and Permixon (320 mg/day) groups.²¹ Smith and co-workers concluded that flow rate increased and symptomatic improvement was seen in both groups, but the difference between the placebo and the treated group was not statistically significant.²¹ Other uncontrolled studies with numbers of patients ranging from 20–1,334 treated for six months with 160 mg/day of Serenoa extract showed improvements in most urinary parameters tested.^22,23

A double-blind, placebo-controlled study was performed on 35 BPH patients randomized into two groups and treated with Serenoa extract (160 mg/day) or placebo for 3 months. At the end of the treatment all patients underwent transvesical prostatectomy. Prostatic tissues were used for binding studies, and steroid receptors were evaluated in the nuclear and cytosolic fractions using Scatchard analysis for androgen (AR), and estrogen (ER) receptors or enzyme immunoassay for ER and progesterone receptors (PgR).²⁴ Two classes of binding sites, one with high-affinity low-capacity and the other with low-affinity high-capacity, were identified. In the untreated group, ER was higher in the nuclear fraction than in the cytosol. ER nuclear fractions were positive in the immunoassay in 14 cases and ER cytosolic fraction in 12 out of 17 cases. In the BPH group treated with Serenoa extract, ER nuclear fractions were negative for both binding in 17 cases, while the cytosolic fractions were negative in 6 of 18 cases. Similar results were obtained for PgR, with the treated group being significantly lower than that of the untreated group. The results of these experiments showed Serenoa treatment significantly lowered nuclear estrogen and androgen receptors in the prostate, indicating that saw palmetto’s effect might be mediated through receptor down-regulation, therefore minimizing estrogen and androgen action.²⁴

A possible anti-inflammatory effect of Serenoa extract has also been suggested. Previous studies show that repeated inflammation of the prostate leads to BPH and that prostaglandins are involved in the evolution of the clinical symptoms. Phospholipase A2, which is responsible for the initial step in eicosanoid synthesis, releases arachidonic acid from membrane phospholipids. It has been suggested that inhibition of this enzyme might enable improvement of functional disturbance of BPH.²⁵ Indeed, sitosterol was found to reduce prostaglandin content of pathological glands following in vivo administration.²⁶

Safety and Tolerability

Overall, few patients have withdrawn from Serenoa trials because of reported adverse effects. In general, Serenoa repens is well tolerated in trials lasting 3 months.²⁷ The most common adverse effects are gastrointestinal, e.g., nausea and abdominal pain. A few incidents of hypertension, headache, urinary retention and back pain have also occurred. Clinically significant changes in laboratory parameters did not occur in clinical trials at dosages of 160–320 mg/day.

Recommended dosage of Serenoa repens for men is 160 mg twice daily with the morning and evening meal to minimize gastrointestinal disturbances.

Conclusion

Studies aimed at pinpointing the mechanism of action are inconclusive. However, the overall clinical efficacy of Serenoa extract shows promise despite some concerns published recently regarding length of therapy (usually no more than 3 months), and problems with the inclusion/exclusion criteria and lack of uniform symptom score analysis.^27,28

In vitro studies showed inhibition of 5-a-reductase for both isoenzymes; however, these results have not been substantiated in vivo. The inhibition of the binding of testosterone and DHT is more likely since there are supportive data obtained under different experimental conditions. Similarly, the Serenoa extract might also affect nuclear steroid receptor regulation. Other mechanisms possibly involved, such as attenuation of inflammatory processes (inhibiting production of 5-lipoxygenase metabolites and derivatives), inhibitory effect on reactive oxygen species produced by neutrophils, and reduction in the levels of epidermal growth factors, require further study.

The International Consultation of Benign Prostatic Hyperplasia concluded that phytotherapeutic agents should be considered as a symptomatic treatment and the choice of therapy should be a decision between the physician and the patient.

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