complementary medications in the treatment of luts/bph · • in the western world, bph is a very...

DONGGUK UNIVERSITY INTERNATIONAL HOSPITAL

Complementary medicationsComplementary medicationsin the treatment of LUTS/BPHin the treatment of LUTS/BPH

Lee Hae WonDept. of Urology, College of Medicine

Dong-Guk University International Hospital, Korea


Introduction• Becoming more popular in the treatment of

benign prostatic hyperplasia(BPH).• Commonly prescribed in Europe in the

treatment of lower urinary tract symptoms (LUTS)/BPH.

• Self prescribed by patients in the United States without a prescription.

• Thirty to ninety percent of patients seen by urologists for BPH/LUTS may be taking these agents.


• Numerous plants extracts are derived from roots, seeds, fruits, or barks.

• Derived from one plants or a combination of more than one plant

• Contain numerous components including phytosterols, plants oils, fatty acids, and phytoestrogens.

• Variable d/t the variability in extraction procedures and natural variability in plants.

• zinc, soy/tofu, selenium, vitamin E, and amino acids.


Table 1. ORIGIN OF PLANT EXTRACTS

Species Common Name

Serenoa repens, Sabal serrulataSaw palmetto berry/American dwarf palm

Hypoxis rooperi South African star grass

Pygeum africanum African plum tree

Urtica dioica Stinging nettle

Secale cereale Rye pollen

Cucurbita pepo Pumpkin seed

Opuntia Cactus flower

Pinus Pine flower

Picea Spruce


Table 2. COMPONENTS OF PLANT EXTRACTS

Phytosterols Phytoestrogens Terpenoids

β-Sitosterol Coumestrol Lectins

Δ-5-Sterol Genistein(isoflavone) Polysaccharides

Δ-7-Sterol Flavonoids Aliphatic alcohols

Stigmasterol Fatty acids Plant oils

Campesterol Free

Esterified


Mechanism of action• Generally unknown• Numerous proposed mechanisms• Supraphysiologic doses• Typically examined in tissue culture, not

in-vivo effect• Three mechanisms; anti-inflammatory

effects, 5 alpha reductase inhibition, and growth factor alteration


Table 3. SUGGESTED MECHANISM OF ACTION OF

PLANT EXTRACTSInhibition of 5 α-reductase

Anti-inflammatory

Interference with growth factors

Antiandrogenic

Estrogenic

Inhibition of aromatase

Decrease sex hormone-binding globulin

Alteration of cholesterol metabolism

Action on α-adrenergic receptors

Free radical scavenger

Alteration of lipid peroxidation

Modulation of prolactin-induced prostatic growth

Protection of bladder and detrusor function

Placebo effect


1. Anti-inflammatory effects• modulated by effects on prostaglandin

synthesis • Flavonoids ; inhibitors of both

cyclooxygenase and lipooxygenase enzymes• Serenoa repens(Permixon)-inhibit phospholipase A2 activity -decreasing arachidonic acid metabolites and

PGE2 synthesis- Inhibition of the production of lipooxygenase

metabolites and leukotrienes


Ragab A et al. Acta Medica 1987Paubert-Braquet M et al. Leuko Prost Ess Fat Acids 1998Data on file

1 5 10 50 100

100

50

% in

hibi

tion

Saw palmetto (μg/ml)

IC50 = 5.4 μg/ml

PHOSPHOLIPASE A2PHOSPHOLIPASE A2

Free arachidonic Acid

% in

hibi

tion

CYCLOCYCLO--OXYGENASEOXYGENASE

Prostaglandin E2

1 5 10 50 100

100

50

Saw palmetto(μg/ml)

IC50 = 6 μg/ml

1

100

50

% in

hibi

tion

Saw palmetto (μg/ml)

IC50 = 12 μg/ml

55--LIPOXYGENASELIPOXYGENASE

Leukotriene LTB4

3 10 30 100

Anti-inflammatory effects


2. 5 alpha reductase inhibitor- S. repens in experimental model - Using foreskin fibroblast, transfected Sf9

insect cells, DU145 cancer cell line, primary culture of human BPH cells

- Conflicting results(ex-vivo experiments)- In-vivo experiment demonstrated a reduction

of serum DHT levels with finasteride but not with S.repens.


5α-r

educ

tase

act

ivity

(% c

ontro

l)

0

20

101 100 1,000 10,000

40

60

80

100

120

140

0

20

101 100 1,000 10,000

finasteride (nM)

40

60

80

100

120

140

Saw palmetto (μg/ml)Epithelium

Fibroblasts

Délos S et al. Journal of Steroid Biochemistry and Molecular Biology, 1995

5 alpha reductase inhibition


3. Growth factor alteration• In-vitro studies with P.africanum

demonstrated an inhibitory effect on both bFGF and EGF induced human and rat prostate fibroblast proliferation.

• S.repens have also shown inhibition of bFGF- and EGF- induced proliferation of human BPH prostate cells from biopsy specimens.


Growth factor alteration• Antiproliferative – inhibition of intraprostatic EGF

Untreated(n = 15)

Saw palmetto 320mg/day(n = 10)

0

4

8

12

ng/m

g D

NA

16

p < 0.01

Di Silverio F et al. The Prostate, 1998


• Although experimental data have suggested numerous possible mechanisms of action for the phytotherapeutic agents, it is uncertain which, if any, of these proposed mechanisms is responsible for the clinical response.


Serenoa repens(Saw Palmetto Berry Extract)

• Most popular phytotherapeutic agent.• Numerous mechanisms of action including

anti-androgenic effects, inhibition of type 1 and type 2 isoenzymes of 5 alpha reductase, inhibition of growth factors, and an anti-inflammatory effect.

• Supraphysiologic dosages.


• Never been conclusively proven in double blind-randomized placebo controlled trials.

• Wilt et.al.-18 randomized clinical trials involving more than

2900 men with symptomatic BPH.-Mild to moderate improvement in symptom score

and urinary flow.


• Meta-analysis completed by Lowe et.al.- The 7 studies utilizing Permixon brand SPB

analyzed were all were of short duration (<3 months)

- Nocturia decreased by 0.5 times per night.- The increase in peak urine flow was 1.5ml/sec.


• A comparison to finasteride, the 5-alpha reductase inhibitor.

- A six month, randomized, double blind study consisting of 1098 patients.

- Lack of a placebo group- Symptom scores were improved to an equal

extent in both groups (37% with Permixon vs. 39% with finasteride) and MFR were improved to a similar extent(2.7ml/sec with Permixon vs. 3.2ml/sec with finasteride).


• In summary, the current evidence suggests a possible benefit of SPB in the treatment of LUTS,

however, it has not been proven conclusively.

• The mechanism of action is not known.


Pygeum africanum (African Plum)

• Pygeum africanum is commonly used in France under the trade name Tadenan.

• Bark of the African plum tree.

• It is frequently sold in combination with SPB and other agents as part of “men’s health” pills.


• Shown in-vitro to have several effects.- Include inhibition of fibroblast growth factors,

anti-estrogenic effects, inhibition of chemotacticleukotrienes and other 5-lipooxygenase metabolites

- A protective effect on the bladder.

; In rabbits subjected to partial bladder outlet obstruction, Tadenan had a protective affect on bladder mass, compliance, and contractility.


• No recent placebo-controlled clinical studies using Tadenan.

• Breza et.al.- A two-month, open-label trial utilizing 100 mg

daily dosage of Pygeum africanum.- IPSS scores were 16.17 at baseline and 9.71 at

the end of treatment.(40% reduction in symptom score)

- Mean peak urinary flow rates were 10.97ml/sec at baseline and 13.07ml/sec at the end of therapy.

- No side effects.


HypoxisHypoxis rooperirooperi(South African Star Grass)(South African Star Grass)

• The extract from the South African star grass contains mainly beta-sitosterol with lesser amounts of other sterols.

• Beta-sitosterol marketed as Harzol.

• Marketed as Azuprostat.


• In vitro studies Harzol enhances the production and secretion of plasminogenactivators in isolated epithelial cells.

• Found to have increased levels of TGF-beta 1. - TGF-beta-1 is a differentiation factor and

induces apoptosis. - Have not been shown to occur in vivo.

• In a double-blind, placebo-controlled study.- Placebo three times per week or a preparation

of a phytosterol for six months.


- Difference was greater for those treated with the phytosterol.

- IPSS improvement ; 5.1 units- 4.1 ml/sec greater improvement in peak flow

rate in those treated with Harzol compared with placebo.

- A significant decrease in the PVR . - At 18 month follow-up, the placebo group was

subsequently treated with Harzol and demonstrated improvements in symptoms and flow rates comparable with the group initially treated with Harzol.


• Azuprostat significantly greater effect than placebo with regards to IPSS, quality of life, peak flow rate, and decrease in residual urine.

• 2.8 units for placebo vs. 8.2 units for beta-sitosterol.

• Peak flow rates improved by 4.4 ml/sec for placebo and 8.8 ml/sec for treated patients.


• In summary, the above studies with Beta-sitosterol products are very promising.

• If these results can be duplicated, beta-sitosterols may have a role in the medical management of BPH/LUTS.


Urtica dioica(Stinging Nettle)• In Germany , widely utilized.• At least 16 different preparations.• Water-soluble compounds including lectins, phenols,

sterols, and lignans.• Iimited clinical data • no benefit as they had low patient numbers and were less

than 3 months in duration.• German study using a liquid preparation of stinging needle

showed significant improvement compared with placebo in terms of IPSS.

; Small numbers(41 patients) and short duration(3 months).• Taken off the market because of poor taste.


Secale Cerale (Rye Pollen) • Cernilton is a pollen extract prepared from

several plants that grow in Southern Sweden.• Many European countries, Argentina, Japan,

and Korea.• The extract consists of a water soluble fraction

and a fat soluble fraction.• Improvement in detrusor activity, reduction in

prostatic urethral resistance, inhibition of 5-alpha reductase activity, and an influence of androgen metabolism in the prostate.


- In 1996 this 4 month trial, the effect of Cerniltonwas compared with Tadenan.

• Lacked a placebo arm.• A better response with regards to symptom

scores, peak flow, and residual volumes.- In summary, the exact mechanism of Cernilton

remains to be elucidated.- In addition, long-term, double-blind, placebo-

controlled studies need to be performed to determine the efficacy of Cernilton.


Combinations of Phytotherapeutic Agents.

• Sold as combination pills with more than one agent.• no data to support increased efficacy or synergy with

plant extracts.• Prostagutt forte is a combination of Serenoa repens and

urtica dioica.- A two week placebo 6 months of double blind treatment.- 6 months of open-label treatment.- Improvement in IPSS score and peak flow improved

significantly greater with Prostagutt forte than with placebo.

- Symptom scores improved by 7.5 units in the treated group and by 1.4 units in the placebo group.


• Peak flow improved by 2.3ml/sec in the treated group open label extenstion by 1.15ml/sec.

• the need for long term studies (at least one year)

• Prostagutt forte was compared to finasteride in a 48 week trial consisting of 489 randomized patients.

- No placebo arm.- There was improvement in IPSS scores and peak urinary

flow in both groups.- However, the differences between the groups were not

statistically significant.


Soy• The rationale comes from epidemiological data.• In the Western world, BPH is a very common

disorder as well as clinical prostate cancer.• Probably not genetic as the incidence of these

entities increase in Orientals that migrate to the United States.

• Environmental factors such as diet may play a role in the etiology of BPH and prostate cancer.


• High intake of soybean products.• Genistein is made from soybean and is a

major ingredient of tofu.- is an isoflavonoid that is found in

significant levels in the blood of Orientals.- is an active estrogen with high affinity for

the estrogen receptor.- a dose dependent decrease in the growth

of human BPH tissue in histoculture.


• A soy cookie.• In summary, the epidemiologic and laboratory

data support a possible role of soy in the management and/or prevention of BPH/LUTS.

• Further studies elucidate the clinical efficacy of soy products will be necessary.


Zinc• Very little data on the use of zinc • May be important in prostatic health, because of its

high concentration in the prostate.• Zinc levels in human BPH tissue have been found to be

elevated, equal, or decreased • thought to be a factor/component of prostatic anti-

bacterial factor which inhibits infection.• Oral ingestion has never been shown to increase zinc

levels in the prostate or prostatic secretions.• Although there is no evidence at this time to support

the efficacy of zinc in the management of BPH/LUTS, it is still widely taken by the public.


Selenium• Selenium is another agent promoted for it’s

positive effects on the prostate gland.• In one study, selenium prevented the growth

stimulatory effects of cadmium on the prostate gland.

• Selenium may play a role in the prevention of prostate cancer.

• However, there is little evidence to support its use in the management of BPH/LUTS.


Clinical manaegement of phytotherapeutic agents

• There is no standard care with regards to management of patients who are taking phytotherapeutic agents for LUTS/BPH.

• Patients should be counseled that the efficacy, mechanism of action, and long term side effects of these agents are unknown.


• For patients who develop urinary retention, UTI, bladder calculi, or deterioration of renal function phytotherapeutic agents should be discouraged from use; more aggressive medical and surgical management should be undertaken.


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complementary medications in the treatment of luts/bph · • in the western world, bph is a very...

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