Beta-Sitosterol and theAging Prostate Gland

by Stephen B. Strum, MD, FACP, and William Faloon

Prostate disorders wreak havoc on the majority of agingmen. Scientists have identified nutrients and drugs that

alleviate symptoms of benign enlargement and reduceprostate cancer risk.

A plant extract called beta-sitosterol may be ofparticular benefit. Published studies indicate that

beta-sitosterol consistently improves urinary symptomsrelated to prostate enlargement.

The good news is that beta-sitosterol costs so little that men canincrease their consumption without spending extra dollars. > > >

For the past several decades,European doctors have routinelyprescribed a variety of plant-baseddrugs to treat benign prostateenlargement and lower urinary tractsymptoms. Saw palmetto, pygeum,and nettle root extracts are commonplant-based drugs prescribed to mil-lions of men in Europe.

Consumers in the U.S. have openaccess to these same nutrients that areapproved as drugs in Europe to com-hat urinary symptoms of benignprostate enlargement.

Beta-sitosterol is a plant fat con-tained in several European prostatedrugs, though it is not routinely usedin the United States. Multiple ran-domized studies have confirmed theefficacy of beta-sitosterol in alleviatingthe types of prostate discomfort thataging men so frequently encounter.

Measuring Symptoms ofProstate Enlargement

In order for scientists around theworld to evaluate the efficacy of aparticular therapy, certain testingstandards have been established.

One of the most common standardsis the International Prostate Symp-tom Score (IPSS). The score is statedas a number that can range from 0to 35, depending on the severity oflower urinary tract symptoms. TheInternational Prostate SymptomScore also includes a scoring ofquality of life as it relates to urinarysymptoms.

A measurement to assess thestrength of the urinary stream is calledthe maximum urinary flow rate(Qmax). The maximum urinary flowis commonly decreased with benignprostate disease such as BPH (benignprostatic hyperplasia).

The third test is the amount ofresiduai urine that remains in thebladder after voiding, or post-voidresidual urine (PVR). This is mosteasily assessed with pre- and post-void ultrasounds of the hiadder.

Remarkable Effects ofBeta-Sitosterol

In a randomized, double-blind,placebo-controlled, multicenter studyof 200 men with benign prostateenlargement, half the group received180 mg of beta-sitosterol daily whilethe other half received placebo.After six months, the beta-sitosterolgroup saw improvement in theInternational Prostate SymptomScore, the measurement of urineflow (Qmax), and the amount ofresidual urine remaining in the blad-der (PVR).'

The beta-sitosterol group showeda 7.4-point decrease in the Inter-national Prostate Symptom Score,compared to a decrease of only 2.1points in the placebo group. This wasa significant 3.5-foId improvementin the men taking beta-sitosterol(Figure 1).'

The measurement of urinary flowincreased to an average of 15.2milliliters (ml) per second from 9.9ml/second in the men receiving beta-sitosterol. The placebo group onlyincreased to 11.4 ml/second from10.2 ml/second at baseline. Urinaryflow thus improved almost 35%in the group taking beta-sitosterol,compared to only 11% in the placebogroup.'

Most remarkably, residual urine inthe bladder decreased to 30.4 ml from65.8 ml in the men using beta-sitos-terol ... a reduction of almost 54%! Inthe placebo group, residual bladderurine declined from 64.8 ml to 54.3 ml... a reduction of only around 16%.'

In a follow-up study that evaluateddurability of response to beta-sitos-terol, the beneficial effects for beta-sitosterol were found to bemaintained during an additional 18months of observation.^

Figure 1 ou tliis page shows thesignificant difference in the Intematio-nai Prostate Symptom Score in menreceiving beta-sitosterol compared toplacebo.

Benefits of Beta-SitosterolConfirmed

To confirm these remarkable effectsof beta-sitosterol. another study wasperformed and the results were pub-lished in the British Journal of Urology.The study involved 177 patients withbenign prostate enlargement. Patientsreceived 130 mg of beta-sitosteroleach day and were monitored for morethan six months. Measurements of theInternational Prostate SymptomScore, urinary flow, and residual urinein the bladder after voiding wererecorded.^

• placebobeta-sitosterol

Months

Figure 1: International Prostate Symptom Scores (IPSS): Beta-Sitosterolvs. Placebo. Data comparing men treated with beta-sitosterol to those receivingplacebo indicate a significant decrease in symptom scores in the beta-sitosterol

group after three and six months of treatment.^ In a follow-up study, theseimprovements were maintained for an additional 18 months of observation."

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Agent Number of Patients Daily Dose IPSS Qmax (ml/sec) PVR (ml) Reference

Beta-sitosterol

Beta-sitosterol

Beta-sitosterol

177

200

519

130mg

60 mg

not stated

-5.4

-5 .3

-4.9

+ 4.5

+ 5.3

+ 3.91

-33.5

-35.4

- 28.62

KlippeUtaL'

Berges,etal.*

Witt,etal/

Table 1: Summary of Key Randomized Studies of Beta-Sitosterol in BPH Patients. Effects of beta-sitosterol on theInternational Prostate Symptom Score (IPSS), maximum urinary flow rate (Qmax), and post-void residual volume (PVR) are

remarkably consistent. The study by Wilt and colleagues' examined four different randomized studies.

On average, urinary flow valuesincreased by 4.5 ml/second whileresidual urine volumes decreasedby a substantial 33.5 ml. TheInternational Prostate SymptomScores showed a statistically signifi-cant improvement. These results withbeta-sitosterol are comparable tothose seen with the commonly pre-scribed drug Proscar", used to treatbenign prostate enlargement.'

Two years later, a review of ail exist-ing studies of beta-sitosterol in thetreatment of benign prostate enlarge-ment was conducted. The researchersidentified randomized, piaceho-con-trolled, double-blind trials involving atotal of 519 men. In three of the trials,beta-sitosterol was used, and in onetrial, a glucoside of beta-sitosterol wasused. In these studies, beta-sitosterolimproved urinary symptom scores andurinary flow rates, and significantlyreduced the volume of residual urine inthe bladder." Table 1 summarizessome of the randomized studies ofbeta-sitosterol in the treatment of BPH.

The magnitude of reduction inprostate symptoms and improvementin urinary tlow rates is a strong incen-tive for the use of beta-sitosterol,either alone or in combination withstandard pharmacologic interventionssuch as alpha-adrenergic blockers(Cardura ; Hytrin", UroxatraJ*, Floma^)or 5-alpha reductase inhibitors(Proscar**, Avodart*).

Beta-Sitosterol andProstate Cancer

A study using the prostate cancercell line LNCaP (an androgen depend-ent tumor) showed that beta-sitos-terol decreased cancer cell growth by24% and induced apoptosis (pro-grammed cell death) four-fold. Thesefindings were correlated with a 50%increase in ceramide production."Research suggests that ceramide, animportant component of the cellmembrane, induces apopotosis.'

Growth of the human prostate can-cer PC-3 cell line (androgen inde-pendent) implanted in mice wascompared in two groups receivingeither a 2% phytosterol mixture or acholesterol mixture. In the in vitro

studies, both beta-sitosterol andcampesterol inhibited the growthof PC-3 cells by 70% and 14%, respec-tively. Cholesterol supplementation,by contrast, increased the growth by18% when compared with controls."

Phytosterols inhibited the invasionof PC-3 celis into Matrigel-coatedmembranes by 78% (a measure ofcancer invasiveness), while choles-terol increased it by 43% compared tothe cells in the control media."

Migration of tumor celis through8-micron pore membranes (a meas-ure of tumor motility) was reducedby 60-93% when the PC-3 cells werein phytosterol media, compared toa 67% increase after cholesterolsupplementation.^

Phytosterol vs. Cholesterol Effects on PC-3 Cells

100-

50—

-50-

-100-

Cholesterol i

Phytosterol

18

GROWTH MIGRATION

Figure 2. Effects of Phytosterol (Beta-Sitosterol + Campesterol) Mixture onPC-3 Cancer Cell Behavior. The phytosterol mixture significantly reduced PC-3

cell growth, invasiveness, migration, and binding, compared to cholesterol.'"

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Phytosterol supplementationreduced the binding of PC-3 cellsto laminin by 15-38% and tofibronectin by 23%, whiie cholesterolincreased binding to type IV collagen(a measure of adhesiveness and abilityto form tumor clumps) by 36%."The results are presented in Figure 2on the previous page.

The researchers concluded thatphytosterol indirectly [in vivo as adietary supplement) and directly (intissue culture media) inhibited thegrowth and metastasis of PC-3 cells.Beta-sitosterol was more effectivethan campestero! in offering this pro-tection in most of the parametersstudied." Results of this study andother cell line trials involving phytos-terols in cancer are shown in Table 2shown on this page.

Combining Beta-Sitosteroland Resveratrol

Dr. Atif B. Awad and his team at theState University of NewYork at Buffalohave found that beta-sitosterolinhibits prostate and breast cancercell growth, and induces cell cyclearrest. Yet, since their studies werepublished in 2000-2001, little researchhas been done to determine themechanisms by which this occurs."'^

In the March 2005 issue of the jour-nal Prostaglandins, Leukotrlenes and

Essential Fatty Acids, Awad and histeam published cutting-edge findingsof the possible mechanisms by whichresveratrol and beta-sitosterol inhib-it the growth of human prostate can-cer cells."

After researchers supplementedprostate cancer cells with resveratrolandbeta-sitosterol, they reported thatlong-term supplementation witheither beta-sitosterol or resveratrolelevated basal prostaglandin release,but that beta-sitosterol was morepotent in this regard. Of the two phy-tochemicals, beta-sitosterol was alsomore effective in inducing apoptosisand inhibiting the growth at concen-trations tested. The scientists con-cluded that these phytochemicalsmay induce the inhibition of tumorgrowth by stimulating apoptosis andarresting cells at different locations inthe cell cycle, and that the mechanismmay involve alterations in reactiveoxygen species and prostaglandinproduction.'^

Conclusion

As men grow older, cells in theirprostate glands often overgrow, caus-ing a swelling that obstructs the blad-der opening, resulting in slowness inurination and bladder emptying. Thisnon-malignant enlargement of theprostate gland causes pressure on the

urethra, acting like a clamp. The resultis a weak urinary stream, hesitancy,and other uncomfortable urinarysymptoms such as increased night-time frequency and urgency. SeeFigure 3 next page.

While a man aged 31 to 40 has onlyan 8% chance of having benignprostate enlargement, the risk increas-es to 40-50% in men aged 51 to 60 andto over 80% in men older than 80."

For millions of men in America,benign prostate enlargement willseverely downgrade their quality oflife. Yet across the ocean are drugs thathave been shown in carefully con-trolled studies to alleviate much of thediscomfort associated with prostategland overgrowth.

Europeans use beta-sitosterol byitself or in combination with saw pal-metto to alleviate urinary symptomsof benign prostate enlargement.

As the word gets out about the doc-umented benefits of beta-sitosterol,American consumers can expect to seemore prostate support products thatcontain this low-cost plant sterol. •

References

1, Berges RR, Kassen A, Senge T. Treatment ofs^inptomatic benign prostatic hyperplasia

Cell Line Phytosterol Product Cell Growth Apoptosis Tumor Size Other Findings Reference

MDA-MB-231 humanbreast cancer

MDA-MB-231 humanbreast cancer

PC-3humanprostate cancer

LNCaPhumanprostate cancer

HT-29humancolon cancer

beta-sitostero!and campesteroi

beta-sitosterol

2% phytosterolmixture

beta sitosterol

beta-sitosterol

80% 6-fold 33%

Metastases to lungsand nodes 4-20%

70%

70% 40-43%

4-fold

•G2M phase cellcycle arrest

• Inhibition of basementmembrane invasion

Metastases tolungs and

nodes 4.-50%

^Ceramideproduction 50%

FCeramide production

^•membranecholesterol 26%

12,13

14

10

16,17

Table 2: Tumor Cell Lines and Effects of Phytosterols. Breast, prostate, and colon cancer cell lines showed significant decreasesin cancer cell growth and tumor size after phytosterol administration. Metastases to lymph nodes and lungs were also decreased.

60 To order call toll-free 1-800-544-4440

6.

Figure 3. Increasing Prevalence of Lower Urinary Tract Symptoms (LUTS) with Advancing Age.As men age, the prevalence of LUTS increases as a reflection of prostate enlargement.'

with beta-sitosterol: an 18-month follow-up.BJUInt. 2000May;85(7):842-6.

2. Berges RR, Windeler I, Trampisch HI, SengeT. Randomised, placebo-controlled, dou-ble-blind clinical trial of beta-silosleroi inpatients with benign prostatic hyperplasia.Beta-sitosterol Study Group, lancet. 1995|unl7;345(8964):1529-32.

3. Klippel KF, Hiltl DM, Schipp B. Aniulticentric, placebo-controlled, double-blind clinical trial of heta-sitosterol (phy-tosterol) for the treatment of benignprostatic hyperplasia. German BPH-PhytoStudy group. Brj Urol. 1997 Sep;80(3);427-32.

4. Wilt TI, MacDonald R, Ishani A. beta-sitos-terol for the treatment of benign prostatichyperplasia: a systematic review. B}U Int.1999jun;83(9):976-83.

5. Wilt T, Ishani A, MacDonald R, Stark G,MulrowC, Lau I. Beta-sitosterols for benignprostatic hyperplasia. Cochrane DatabaseSysi Rev. 2000;(2):CD001043.

von Holtz RL, Fink CS, Awad AB. Beta-Sitosterol activates the sphingnmyelin cycleand induces apoptosis in LNGaP humanprostate cancer cells. Nutr Cancer.1998;32(1):8-12.

1. Duan RD. Anticancer compounds andsphingolipid metabolism in the colon. InVivo. 2005 Ian-Feb;19(l):293-300.

a. Awad AB, Fink GS, Williams H, Kim U. invitro and in vivo [SGID mice) effects of phy-tosterols on the growth and disseminationof human prostate cancer PG-3 cells. Eur /Cancer Prev. 2001 Dec;10(6):507-13.

9. Awad AB, Gan Y, Fink GS. Effect of beta-sitosterol, a plant sterol, on growth, protein

phosphatase 2A, and phospholipase D inLNGaP cells. Nutr Cancer. 2000;3(S( i );74-8.

10. Awad AB, Downie A, FinkGS, Kim U. Dietaryphytosterol inhibits the growth and metas-tasis of MI)A-MB-2:-)l human breast cancercells grown in SGID mice. Anticancer Res.2()00Mar;20(2A):82]-4.

11. Awad AB, Downie AG, Fink CS. Inhibition ofgrowth and stimulation of apoptosis bybeta-sitosterol treatment of MDA-MB-231human breast cancer cells in culture. !nt JMo/Merf. 2000 May:5(5):541-5.

12. AwadAB, WilliamsH, FinkGS. Phytosterols

reduce in vitro metastatic ability of MDA-MB-231 human breast cancer cells. NutrCflHCt-r. 2001;40(2):157-64.

13. AwadAB, Burr AT, FinkGS. Effect of resver-atrol and beta-sitosterol in combination onreactive oxygen species and prostaglandinrelease by PC-:-) cells. Prosiaglandins LeukotEssent Fatty Acids. 2005 Mar;72(3);219-2e.

14. Glynn RI, Gampion EW, Bouchard GR,Silbert JE. The development of benign pro-static hyperplasia among volunteers in theNormative Aging Study. Am J Epidemiol.1985Ian:121(l):78-90.

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