Saw Palmetto

"Saw palmetto" refers to the berries from the dwarf palm tree known as American Serenoa repens which have traditionally been used for male fertility and libido and claimed to increase breast size in women.^[1]

The ground fruits of saw palmetto, referenced as SRM 3250,^[2] have the following composition:

• Two of the main bioactive fatty acids (see the rest of the Full Summary for details): (Z)-9-octadecenoic acid (C18:1 n-9) (oleic acid) at 3.24±0.15% dry mass as triglycerides and 33.7±1.9mg/g dry mass as free fatty acids, and dodecanoic acid (C12:0) (lauric acid) 2.962±0.062% dry mass as triglycerides and 7.21±0.036mg/g dry mass as free fatty acids^[3]
• Octanoic acid (C8:0) (caprylic acid): 0.1072±0.0027% dry mass as trigycerides and 0.781±0.036mg/g dry mass as free fatty acids^[3]
• Decanoic acid (C10:0) (capric acid): 0.1175±0.0055% dry mass as triglycerides^[3]
• Tridecanoic acid (C13:0): 0.0076±0.0014% dry mass as trglycerides and 0.0165±0.0011mg/g dry mass as free fatty acids^[3]
• Tetradecanoic acid (C14:0) (myristic acid): 1.103±0.007% dry mass as tryglycerides and 5.96±0.21mg/g dry mass as free fatty acids^[3]
• Pentadecanoic acid (C15:0): 0.0047±0.0006% dry mass as triglycerides and 0.0121±0.0009mg/g dry weight as free fatty acids^[3]
• Hexadecanoic acid (C16:0) (palmitic acid): 0.869±0.027% dry mass as triglycerides and 8.72±0.45mg/g dry mass as free fatty acids^[3]
• (Z)-9-Hexadecenoic acid (C16:1 n-7) (palmitoleic acid): 0.0158±0.0010% dry mass as triglycerides and 0.216±0.014mg/g dry weight as free fatty acids^[3]
• Heptadecanoic acid (C17:0): 0.0061±0.0007% dry mass as triglycerides and 0.0926±0.0060mg/g as free fatty acids^[3]
• Octadecanoic acid (C18:0) (stearic acid): 0.1791±0.0054% dry mass as triglycerides and 2.023±0.094mg/g as free fatty acids^[3]
• (Z)-11-Octadecenoic acid (C18:1 n-7) (vaccenic acid): 0.0547±0.0030% dry mass as triglycerides and 0.789±0.053mg/g dry mass as free fatty acids^[3]
• (Z,Z)-9,12-Octadecadienoic acid (C18:2 n-6) (linoleic acid): 0.824±0.055% dry mass as tryglycerides and 5.70±0.48mg/g dry weight as free fatty acids^[3]
• (Z,Z,Z)-9,12,15-Octadecatrienoic acid (C18:3 n-3) (linolenic acid): 0.194±0.025% dry mass as tryglycerides and 1.351±0.050mg/g as free fatty acids^[3] -Eicosanoic acid (C20:0) (arachidic acid): 0.0097±0.0002% dry mass as triglycerides and 0.1455±0.0076mg/mg dry mass as free fatty acids^[3] -(Z)-11-Eicosenoic acid (C20:1 n-9) (gondoic acid): 0.0173±0.0006% dry mass as triglycerides^[3] -Docosanoic acid (C22:0) (behenic acid): 0.0066±0.0002% dry mass as triglycerides and 0.0564±0.0050mg/g dry mass as free fatty acids^[3] -Tetracosanoic acid (C24:0) (lignoceric acid) 0.0107±0.0003% dry mass as triglycerides and 0.0960±0.0033mg/g as free fatty acids^[3]
• Campesterol (a phytosterol) at 0.1175±0.0025mg/g dry mass^[3]
• β-Sitosterol (a phytosterol) at 0.454±0.018mg/g dry mass^[3]
• Stigmasterol (a phytosterol) at 0.0477±0.0020mg/g dry mass^[3]

In general, most of the fatty acids in saw palmetto exist in triglyceride form over the free fatty acid form.^[3]

Saw palmetto contains numerous fatty acids, mostly in triglyceride form, and phytosterols.

The mechanism of action that saw palmetto is most known for is inhibition of the enzyme 5α-reductase, which is responsible for converting testosterone into its more androgenic form, dihydrotestosterone (DHT). Anti-5α-reductase activity is found in the lipid soluble extracts of the fruits,^[4] with more potency in the saponifiable subfraction.^[4]

Saw palmetto bioactivity tends to be concentrated in the fat-soluble components of the berry.

Supercritical CO2 extracts of saw palmetto, also known under the brand name Sabalselect®, tend to have a high percentage of unsaturated fatty acids (84%) with lower amounts of fatty acid esters (10%) and less than 2% of other chemical components (phytosterols, aliphatic alcohols, and polypyrenic compounds).^[5] Sabalselect® is similar to the National Institute of Standards and Technology's reference material SRM 3251, which is extracted using a similar procedure.^[2]

This extraction increases process the amount of fatty acids as triglycerides relative to the ground fruit (by 6-25 times^[2]) and is composed predominately of the unsaturated fatty acids lauric (aka. dodecanoic) and oleic acid with some myristic acid and palmitic acid as the next major components.^[5][6][2]

This particular extraction, in contrast to the raw berries, has certified concentrations of phytosterols (campesterol, β-sitosterol and stigmasterol), carotenoids (46.8μg/g as β-carotene), and vitamers of Vitamin E (gamma and delta tocopherol at 280μg/g and 35.3μg/g).^[2]

Supercritical CO₂ extracts are one of the basic forms of saw palmetto extracts.

There is another extract known as Permixon® which is an n-hexane extract lipodo/sterolic extract of the fruits.^[7]

The extraction known as IDS 89 (Strogen®) is able to inhibit 5α-reductase in vitro with an IC₅₀ of 2,200µg/mL when tested in whole prostate homogenates, while having some efficacy at 500µg/mL in both epithelial and stromal prostate cells.^[4] This extract was found to be a noncompetitive inhibitor.^[4]

Oleic acid and lauric acid obtained from saw palmetto, as well as reference standards of these two fatty acids, appear reduce binding of prazosin to α1-adrenergic receptors.^[5] The IC₅₀ for preventing prazosin binding was 41.8-46.3µg/mL and 84-92.1µg/mL for oleic acid and lauric acid respectively.^[5] A later study found that oils from saw palmetto (composition not specified) inhibited binding of both prazosin and tamsulosin to α1-adrenergic receptors.^[8]

This reduction of ligand binding is not thought to occur through a competitive mechanism, as saw palmetto appeared to reduce the total number of binding sites on α1-adrenergic receptors and (when tested in isolation) signaling through the receptor.^[8]

In vitro studies have shown that components of saw palmetto impair the ability of ligands to bind to the α1-adrenergic receptor, inhibiting downstream signaling.

Oral ingestion of saw palmetto supercritical CO₂ extract at 6-60mg/kg in rats over the course of four weeks has been found to increase the B_max (total binding capacity) of prazosin to α1-adrenergic receptors expressed in the prostate,^[9] suggesting a chronic adaptation in opposition to the acute effects.

Oleic acid and lauric acid obtained from saw palmetto, as well as reference standards of these two fatty acids, appear to have affinity for muscarinic receptors with IC₅₀ values (for reducing binding of N-methylscopolamine (NMS) in brain tissue) of 70.6-91.3µg/mL and 157-163µg/mL respectively.^[5]

Chronic ingestion of 0.6-60mg/kg of a supercritical CO₂ extract of saw palmetto has been found to decrease the B_max (total binding affinity) of NMS in the bladder at all tested doses.^[9]

Both oleic acid and lauric acid have once been noted to reduce binding of isradipine to 1,4-DHP (dihydropyridine) receptors,^[5] which are calcium channel antagonistic receptors.^[10] The IC₅₀ of oleic acid in preventing isradipine binding was 33.3-50.6µg/mL whereas the IC₅₀ for lauric acid was 65.7-79.5µg/mL.^[5]

A supercritical CO₂ extract used in trials (Sabalselect^[11]) has been tested for its actions on rat 5α-reductase where it was found that two constituent fatty acids, oleic acid and lauric acid, inhibited the activity of this enzyme with IC₅₀ values of 54.3-54.5µg/mL and 66.2-67.6µg/mL respectively.^[5] This inhibitory action was of similar potency to the fatty acids obtained from other sources when compared to those obtained via saw palmetto.^[5]

One human study attempting to assess 5α-reductase activity in response to 160mg of a lipidosterolic extract found that after one week of supplementation that both serum testosterone and DHT were unaffected compared to baseline.^[12]

Saw palmetto has been noted to have an inhibitory effect on CYP2C8 activity, with an IC₅₀ value of 15.4+/-1.7μg/mL which in theory could be physiologically relevant.^[13]

One study in rats found that giving 60mg/kg of the supercritical CO₂ extract orally for four weeks increased the binding of prazosin to the α1-adrenergic receptor in cardiac tissue by 30.5%, an effect not noticeable at doses of 6mg/kg or lower; no dose in the 0.6-60mg/kg range influenced muscarinic receptor B_max (maximal binding capacities of a ligand).^[9]

In keratinocytes trreated with an inflammatory stressor (LPS), a mixture of saw palmetto with L-carnitine and Alpha-lipoic acid at 0.1% of the medium (ratios unspecified) had antiinflammatory actions as assessed by changes in some biomarkers (CCL17, CXCL6, and Leukotriene B4).^[14] Because the effects of saw palmetto in isolation were not examined in this particular study, it is not clear what individual component(s) of this mixture were responsible for the antiinflammatory activity.

An anti-inflammatory effect has been noted with Permixon®, a hexanic lipidosterolic extract of saw palmetto, in human prostate cells (BPH-1, WPMY-1, and PC3) at concentrations of 10-56µg/mL by reducing the expression and content of chemokine receptor (MCP-1/CCL2) and adhesion factors (VCAM-1).^[15] This effect has been replicated in another study using a benign prostatic hyperplasia cell line, where several genes involved in inflammation were downregulated leading to the inflammatory effect of a few cytokines (IL-6, IL-15, and IL-17) being suppressed.^[16]

A supercritical CO₂ extract used in trials (Sabalselect®^[11]) has been tested for its actions on rat 5α-reductase where it was found that two constituent fatty acids, oleic acid and lauric acid, inhibited the activity of this enzyme with IC₅₀ values of 54.3-54.5µg/mL and 66.2-67.6µg/mL respectively^[5] (lauric acid has been noted to reach peak efficacy at 200µM^[4]). This inhibitory action was of similar potency to the fatty acids obtained from other sources when compared to those obtained via saw palmetto.^[5] Elsewhere fatty acids tested at even higher concentrations (2mM) found efficacy with myristic acid^[4] known to also be present in saw palmetto.^[5]

Other studies assessing saw palmetto noted that an n-hexane extract of a saw palmetto extract (Permixon®) in insect cells expressing the DNA for 5α-reductase inhibitied the type I 5α-reductase isomer with an IC₅₀ of 4µg/mL while also inhibiting the type II isomer at 7µg/mL;^[17] this potency was hypothesized, but not confirmed, to be due to aliphatic fatty acids which are known to interact with this enzyme.^[18] Other studies using this extract have found efficacy at a concentration of 10µg/mL (which is the calculated plasma concentration at a therapeutic oral dose),^[19][7] inhibiting up to 72-76% of both isoforms. This efficacy is comparable to finasteride (83%) at its own therapeutic concentration of 5nM.^[7]

This inhibitory effect has been shown to reduce DHT synthesis from testosterone in prostatic epithelial cells, where most local DHT synthesis takes place, and in prostatic fibroblasts; the Permixon® extract had an IC₅₀ of less than 10µg/mL in fibroblasts and of 70µg/mL in epithelial cells.^[20]

Saw palmetto, specifically the n-hexane extract, seems to inhibit both isomers of the 5α-reductase enzyme at concentrations which approximate plasma concentrations reached via oral ingestion of the supplement. These inhibitory effects have been shown to reduce DHT formation in vitro, and while less potent it is seems to be comparable in efficacy to finasteride. It is not certain what molecule(s) mediate this effect, as the potency seen in some extracts is far greater than the dietary fatty acids present in saw palmetto.

It has been noted in prostate cancer cells (LNCaP) that, while finasteride suppresses the activity of the type II isomer of 5α-reductase alongside other effects (suppression of PSA secretion and downregulation of prostatic androgen receptors), saw palmetto failed to downregulate the androgen receptor or influence PSA secretion rates.^[7]

This extract of saw palmetto also failed to influence androgen receptor binding to its promoter in LNCaP cells.^[7] Another study using fibroblasts from human foreskin noted inhibitory effects on DHT binding to both cytosolic and nuclear receptors (the latter thought to be the androgen receptor).^[21]

There is mixed evidence as to the effects of saw palmetto on the androgen receptor.

A study using saw palmetto paired with Haematococcus pluvialis as a source of astaxanthin at 800-1,200mg a day (specific doses of the constituents and type of extractions not specified) found an increase in testosterone in the 1,200mg group of 38.04% relative to placebo when used over the course of 14 days that failed to reach statistical significance; a reduction in DHT of unspecified magnitude appeared to reach significance.^[22] Other studies assessing saw palmetto on testosterone are similarly confounded with other nutrients^{[23][24][25][26]} with one study using saw palmetto (lipidosterolic extract) in isolation at 160mg over one week failing to influence serum testosterone or DHT concentrations relative to baseline (while finasteride was effective at reducing DHT).^[12]

Studies assessing saw palmetto on testosterone are currently highly confounded with other nutrients or have potential conflicts of interest. One lone study lasting only a week using saw palmetto in isolation failed to find any influence on testosterone or DHT concentrations.

The mechanisms of saw palmetto that are thought to be relevant for its actions in the lower urinary tract include its suppression of α1-adrenergic signalling, muscarinic receptors, and 1,4-dihydropyridine receptors.^[11][9]

A study in rats using saw palmetto extract (supercritical CO₂) at 0.6mg/kg, 6mg/kg, or 60mg/kg daily over four weeks has been noted to increase the B_max values (maximum number of binding sites) for prazosin in the prostate at the two higher doses by 23.6-36.7%, whereas only the higher dose affected the spleen (26.1%) and heart (30.5%).^[9] The opposite effect was noted with muscarinic receptors where B_max decreased in the bladder at the two higher doses (31.8-41.2%) with a decrease in the submaxillary gland at 60mg/kg (17.9%) and slight increase at 0.6mg/kg (13.8%).^[9]

6-60mg/kg of the supercritical CO₂ extract of saw palmetto, when given to rats orally over four weeks, increases the B_max of prazosin in the prostate by 23.6-36.7%; 0.6mg/kg was ineffective.^[9]

A retrospective study on 320mg Peroxim in men with benign prostatic hyperplasia with PSA less than 10ng/mL found that circulating PSA concentrations appeared to decrease from 5.39ng/mL down to 4.38ng/mL (19%) over the course of the six month study.^[27]

One study in glioma cells (U87 and U251) using saw palmetto at 1μg/mL found that incubation was able to reduce the protein content of PI3K (which is involved in a signalling pathway known to have a role in promoting invasion of these cell lines^[28][29]) and the prosurvival protein Bcl-xL in both cell lines while p53 showed differential effects depending on the cell line.^[30]

LNCaP and PC3 cancer cells treated with saw palmetto lipido-sterolic extract (44 or 88μg/mL) found both concentrations were able to decrease cell count at three tested time points (24, 48, and 72 hours)^[31] while CD45^-/CK5-CK8⁺ cells excised from prostate adenocarcinoma patients appeared to also have their growth reduced from 44μg/mL of this extract, which induced apoptosis and interfered with NF-kB activation.^[31]

One trial (open label and uncontrolled) using a formulaton of saw palmetto with seven other herbs (based off of the commercial formulation known as PC-SPES^[32]) found an improvement in PSA levels in the 10 subjects enrolled with hormone refractory prostate cancer after 24 weeks of treatment.^[33] Withdrawal of the herb led to PSA levels returning to baseline.^[33]

Male pattern baldness, also known as androgenic alopecia, is an androgen-dependent hair loss disorder heavily dependent on dihydrotestosterone (DHT) which is produced by the 5α-reductase enzyme.^[34] There are two isomers of this enzyme, with 5α-reductase type II being more heavily implicated in hair loss leading to the selective 5α-reductase type II inhibitor, finasteride, being investigated with success in preventing baldness associated with androgens (regardless of biological sex^[35][36]). Despite the abundance of type II isoforms in hair follicles, inhibiting both type I and type II may be more effective at preventing hair loss, since dutasteride (an inhibitor of both) outperforms finasteride.^[37][38] Saw palmetto has been studied in male pattern baldness due to having inhibitory actions against both isoforms of the enzyme.^[5]

The liposterolic extract of saw palmetto (200mg of 85-95% liposterolic content) paired with 50mg β-sitosterol and some B-vitamins (biotin at 100mcg and niacin at 15mg) in 10 otherwise healthy men with androgenic alopecia over the course of 18-24.7 weeks found that 60% of the subjects had their hair improved (blinded investigator-assessed) compared to one subject in placebo although no objective measurements were taken.^[39] A later study assessing usage of 320mg saw palmetto over the course of two years in otherwise healthy men with male pattern baldness noted that 38% of subjects treated with saw palmetto reported an increase in hair growth which performed less effectively than 1mg finasteride (66%); saw palmetto appeared to work primarily at the crown of the head whereas finasteride was effective at the crown and frontal regions.^[40]

Dihydrotestoterone (DHT), produce by two isozymes of 5α-reductase, is known to play a role in male pattern baldness. Since saw palmetto inhibits both isozymes, it has been studied in humans and seems to be somewhat effective based on limited evidence, but not as effective as finasteride.

Saw palmetto may affect benign prostatic hyperplasia (BPH) inhibits 5α-reductase^[5] and binds to α1-adrenergic receptors,^[5] both of which are molecular targets for BPH (assuming inhibition of α1-adrenergic receptors).^[41]

In regard to prostate specific antigen (PSA), a biomarker of prostate cancer, treatment of cells with the Permixon® mixture of saw palmetto has been noted to inhibit 5α-reductase enzymes at 10µg/mL (up to 72-76% with similar potency between isoforms) without influencing secretion of PSA^[19][7] even when the culture is stimulated with testosterone or DHT;^[19][7] this effect differs from finasteride which, at its therapeutic concentration, suppresses DHT-induced increases of PSA.^[7] This discrepancy is thought to be due to how PSA is regulated by androgens^[42] since saw palmetto does not interfere with androgen signalling in the prostate cell.^[7]

Saw palmetto inhibits 5α-reductase in prostate cancer cells in vitro, but does not affect PSA levels. This may be because saw palmetto does not interfere with androgen signalling in prostate cells, and PSA is regulated by androgens.

Saw palmetto has undergone numerous trials and meta-analyses for BPH, with mixed results.

One early trial found that saw palmetto increases urine flow and decreases nocturia in patients with BPH.^[43]

Another early double-blind, placebo-controlled study of 320mg Permixon® daily found significant improvement in many symptoms of BPH over placebo.^[44] A later retrospective study in men with urinary symptoms caused by BPH (no prostatic cancer and PSA less than 10ng/mL) given 320mg saw palmetto (Permixon®) for six months confirmed this.^[27] It found an improvement in urinary symptoms when saw palmetto was used alone as well as when used alongside an alpha-blocker, although saw palmetto alone showed better responses on mean void volume and intermittence in urinary flow while combination therapy had a more rapid improvement in maximum flow.^[27]

Another study using saw palmetto alongside tamsulosin (α1-adrenergic receptor antagonist) over 6-12 months in men with BPH found combination therapy more effective than tamsulosin alone^[45] while combination therapy with selenium (50mcg) and lycopene (5mg) alongside the supercritical extract of saw palmetto (320mg) appeared to perform equally to 400mcg tamsulosin after a year in improving urinary and erectile symptoms;^[46] adding tamsulosin to this combination therapy further increased benefits.^[46]

Despite these individual positive findings, a later Cochrane review has concluded that saw palmetto is no better than placebo for many aspects of BPH.^[47] This is in contrast to an earlier Cochrane review, which concluded saw palmetto to be effective.^[48] The reason given for the reversal of their conclusion was due to the fact that most of the studies in the earlier review were short-termed and under-powered, and also used unvalidated measures of outcomes. The later review included two trials^[49][50] which used the well-validated International Prostate Symptom Score. The former showed a small, barely significant improvement in this score, and the latter did not. When taking these studies into account in addition to other newer studies, the authors of the review concluded that there was no substantial benefit over placebo but state that the evidence is somewhat mixed.^[47] The most recent review from the Cochrane group, which included two new studies, found statistically significant effects for nocturia and patient-reported symptoms, but no statistically significant effects for American Urological Association score, peak urine flow, physician-assessed improvement of symptoms, or prostate size in studies compared to placebo.^[51]

The evidence of saw palmetto's effects on BPH appears to be mixed. Several small studies have found some benefit, but larger, more well-conducted studies tend to find no or weak benefits, with a newer systematic review finding little substantial benefit over placebo.

Saw palmetto contains tannic acids, which bind to iron and reduce bioavailability.^[52] Minor sexual dysfunction has also been reported, possibly through pro-estrogenic effects. Beyond that, side-effects are not discernable from placebo.^[53]

Two case-reports have repoted pancreatitis from saw palmetto.^[54][55] In one case liver damage was reported.^[56]

There is one case study of a young girl (11 years of age) given saw palmetto for treatment of telogen effluvium (a type of hair loss) who experienced hot flashes that ceased when the supplement was no longer taken; it was seen as probable that this side-effect was due to the supplement used.^[57] A second case study in a 10-year old girl also described hot flashes when taking a supplement containing saw palmetto for hirsutism.^[58] The hot flashes reappeared after a rechallenge, and menstruation began 4 months after taking the supplement.^[58]