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Action Mechanism of Ginkgo biloba Leaf Extract Intervened by Exercise Therapy in Treatment of Benign Prostate Hyperplasia

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Benign prostatic hyperplasia (BPH), an imbalance between androgen/estrogen, overexpression of stromal, and epithelial growth factors associated with chronic inflammation, has become an atypical direct cause of mortality of aged male diseases. Ginkgo possesses anti-inflammatory, blood flow-enhancing, and free radical scavenging effects. Considering strenuous exercise can reduce BPH risks, we hypothesize Ginkgo + exercise (Ginkgo + Ex) could be beneficial to BPH. To verify this, rat BPH model was induced by s.c. 3.5 mg testosterone (T) and 0.1 mg estradiol (E2) per head per day successively for 8 weeks, using mineral oil as placebo. Cerenin® 8.33 μL/100 g was applied s.c. from the 10th to the 13th week, and simultaneously, Ex was applied (30 m/min, 3 times/week). In BPH, Ginkgo alone had no effect on T, 5α-reductase, and dihydrotestosterone (DHT), but suppressed androgen receptor (AR), aromatase, E2 and estrogen receptor (ER), and the proliferating cell nuclear antigen (PCNA); Ex alone significantly reduced T, aromatase, E2, ER, AR, and PCNA, but highly raised DHT. While Ginkgo + Ex androgenically downregulated T, aromatase, E2, and ER, but upregulated DHT, AR, and PCNA, implying Ginkgo + Ex tended to worsen BPH. Conclusively, Ginkgo or Ex alone may be more beneficial than Ginkgo + Ex for treatment of BPH.
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Evidence-Based Complementary and Alternative Medicine
Volume , Article ID ,  pages
http://dx.doi.org/.//
Research Article
Action Mechanism of Ginkgo biloba Leaf Extract Intervened by
Exercise Therapy in Treatment of Benign Prostate Hyperplasia
Chiung-Chi Peng,1Jia-Hong Liu,2,3 Chi-Huang Chang,2Jin-Yuan Chung,1,4 Kuan-Chou
Chen,4Kuang-Yu Chou,5and Robert Y. Peng2
1Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei 11031, Taiwan
2Research Institute of Biotechnology, Hungkuang University, 34 Chung-Chie Road, Shalu District, Taichung City 43302, Taiwan
3Department of Urology, Shuang Ho Hospital, Taipei Medical University, 291 Zhongzheng Road, Zhonghe, Taipei 23561, Taiwan
4Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei 11031, Taiwan
5Division of Urology, Department of Surgery, Shin Kong Wu Ho-Su Memorial Hospital, 95 Wen Chang Road, Taipei 111, Taiwan
Correspondence should be addressed to Kuan-Chou Chen; kc.chen@msa.hinet.net; Kuang-Yu Chou; ky chou@livemail.tw;
and Robert Y. Peng; ypeng@seed.net.tw
Received  December ; Revised  January ; Accepted  January 
Academic Editor: Gerhard Litscher
Copyright © 2013 Chiung-Chi Peng et al. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Benign prostatic hyperplasia (BPH), an imbalance between androgen/estrogen, overexpression of stromal, and epithelial growth
factors associated with chronic inammation, has become an atypical direct cause of mortality of aged male diseases. Ginkgo
possesses anti-inammatory, blood ow-enhancing, and free radical scavenging eects. Considering strenuous exercise can reduce
BPHrisks,wehypothesizeGinkgo +exercise(Ginkgo + Ex) could be benecial to BPH. To verify this, rat BPH model was
induced by s.c. . mg testosterone (T) and . mg estradiol (E) per head per day successively for  weeks, using mineral oil as
placebo. Cerenin. 𝜇L/ g was applied s.c. from the th to the th week, and simultaneously, Ex was applied ( m/min,
 times/week). In BPH, Ginkgo alone had no eect on T, 𝛼-reductase, and dihydrotestosterone (DHT), but suppressed androgen
receptor (AR), aromatase, E and estrogen receptor (ER), and the proliferating cell nuclear antigen (PCNA); Ex alone signicantly
reducedT,aromatase,E,ER,AR,andPCNA,buthighlyraisedDHT.WhileGinkgo + Ex androgenically downregulated T,
aromatase, E, and ER, but upregulated DHT, AR, and PCNA, implying Ginkgo +ExtendedtoworsenBPH.Conclusively,Ginkgo
or Ex alone may be more benecial than Ginkgo + Ex for treatment of BPH.
1. Introduction
Benign prostatic hyperplasia (BPH) and low urinary tract
symptoms (LUTS) are quite common male diseases. e
prevalence of BPH increases with aging []andhasnow
become an atypical direct cause of mortality []. Biochem-
ically, BPH is considered to be an imbalance between
androgen/estrogen [,], overexpression of stromal and
epithelial growth factors, cytokines, and steroid hormones
[,]. Pathologically, BPH is characterized by hyperplastic
epithelial and stromal growth that emerge into numerous
microscopic and macroscopic nodules in the prostate gland
[]. Tissue remodeling in the aging prostate [,], stem cell
defects [], hypoxia [], and chronic inammation []
or by many other factors is still obscure.
e clinical care for BPH usually involves 𝛼-blockers, 𝛼-
reductase inhibitors (e.g., nasteride), and surgery therapy,
or the combined treatment []. Currently, phytotherapeutic
agents are emerging and frequently used as the comple-
mentary alternative treatment of BPH []. Other nonmed-
ication agents include zinc, soy/tofu, selenium, vitamin E,
and amino acids []. e main constituents of Ginkgo
biloba leaf extract (for simplicity named “Ginkgo” herein)
comprise Ginkgo avone glycosides (biavonols, quercetin;
biavones, sciadopitysin; and proanthocyanidins, procyani-
din) and terpene lactone ginkgolides (ginkgolide A, B, C,
Evidence-Based Complementary and Alternative Medicine
and bilobalide) []. Ginkgo possesses antioxidant and anti-
inammatory activity []. Ginkgo biloba leaf extract
(Ginkgo) has been used for centuries in China for treating
asthma and bronchitis. Currently, Ginkgo has been widely
usedtotreatthecerebrovascularandtheperipheralvascular
insuciency, neurosensory problems, and disturbances in
vigilance, short-term memory, and other cognitive functions
that are associated with dementias, ageing, and senility [].
Many pharmacological and clinical studies have shown that
the extract of Gingko causes two main actions: increase of
blood ow in central and peripheral vessels and inhibition of
platelet aggregation and free radical scavenging. us Gingko
may be eective in cases of erectile dysfunction due to a
decreased blood ow [].
A review of Sea et al. () highly supports a clinically
signicant, independent, and strong inverse relationship
between exercise (Ex) and the development of BPH /LUTS
[]. Greater distances run per week may reduce BPH risk
independent of BMI,  km performance, and diet [].
e application of Ginkgo in treating BPH is still lacking.
In view of the above mentioned benecial biological activities
of Gingko and Ex, we hypothesize that Ginkgo +Extherapy
as well could be benecial to BPH. To verify this, we
conducted this experiment and the relevant biochemical,
immunological, and pathological parameters were examined
and compared.
2. Materials and Methods
2.1. Chemicals. Testosterone, dihydrotestosterone (DHT),
estradiol ELISA kits were provided by Cayman Chemical
Co. (Michigan, USA). Free PSA and Total PSA assay kits
were provided by Cusabio Biotech (Wuhan, China). Rat
IL- ELISA development kit is product of PeproTech Co.
(Rocky Hill, NJ, USA). Enhanced Chemiluminescence (ECL)
system was provided by Merk Millipore Co. (Billerica, MA,
USA). TEMED is a product of Bio-Rad Co. (Hercules,
CA, USA). Protein Extraction Solution was provided by
iNtRON Biotech. Co. (Kyungki-Do, Korea). e pharmaceu-
tical preparation of androgen, Sustanon,isaninjecttestos-
terone medication provided by Schering-Plough Company
(Kenilworth, NJ, USA), which in reality contains four testos-
terone esters. Each ampoule ( mL) contains testosterone pro-
pionate  mg, testosterone phenylpropionate  mg, testos-
teroneisocaproatemg,andtestosteronedecanoatemg.
e overall androgenic potency in per mL of Sustanon
is equivalent to  mg testosterone. e Ginkgo biloba
leaf extract, Cerenin, was purchased from Dr. Willmar
Schwabe Arzneimittel GmbH & Co. (Karlsruhe, Germany).
Ginkgo consisted of % of Ginkgo avone glycosides, mainly
kaempferol and quercetin glucorhamnoside esters, and %
of the characteristic terpene lactones, the bilobalide, and
ginkgolides, namely, A, B, C, and very small quantities of
ginkgolide. e inject solution contained in per mL . mg
Ginkgo ( mg/g avonoids and  mg/g terpenoids),  mg
of  mL/L ethanol,  mg sorbitol, and . mol/L NaOH.
All other chemicals, not cited but used in this experiment,
were of reagent grade provided by Wako Pure Chemical Co.
(Osaka,Japan).esourcesoftheantibodiesusedinthis
experiment were 𝛼-reductase and androgen receptor (Santa
Cruz Biotech Inc., Santa Cruz, CA, USA), estrogen receptor 𝛼
(ER𝛼) (Merk Millipore, Billerica, MA, USA), aromatase and
proliferating cell nuclear antigen (PCNA) (Epitomics Inc.,
Burlingame, CA, USA), and 𝛽-actin from Novus Biologicals
(Littleton, CO, USA).
2.2. Animal Grouping. is experiment was proved by the
Institutional Animal Care and Ethic Committee of China
Medical University (Taichung, Taiwan). Ninety-six Sprague-
Dawley (SD) rats weighing approximately g were pur-
chased from BioLasco Animal Centre, Taiwan. e rats were
housed in a controlled environment,  in each cage, with
 h/ h light/dark cycle, at 28 ± 1C and under relative
humidity –%. ese rats were acclimated in such an
environment for the rst week. en rats were divided into
eight groups. e ve controls involved Group , the normal
control; Group , the BPH control; Group , the Ginkgo-only
treatedcontrol;Group,theEx-onlycontrol;andGroup,
the Ginkgo + Ex.emedicationtreatedgroupswereGroup
, BPH treated with Ginkgo; Group , BPH treated with Ex;
and Group , BPH treated with Ginkgo +Ex,eachhaving
rats. e exercise groups were subjected to treadmill exercise
protocol.etreatmentstartedfromweektoweek.
2.3. BPH Induction: e Hormone-Induced Rat BPH Model.
e protocol to induce BPH was conducted according to
Suzuki et al. () with slight modication []. Briey, in
the beginning of week , all healthy controls (groups , , ,
and ) were s.c. administered  𝜇L mineral oil/head/day as
placebo. e BPH groups (groups , , , and ) were s.c.
administered a combined testosterone (Sustanon) . mg
with estradiol . mg per head per day successively from week
 to week , that is, a total induction period of  weeks.
2.4. Ginkgo biloba Extract Administration Protocol. e dose
of Cereninwas calculated from the recommended dose for
clinical human use, that is,  mg ( mL injection solution)
i.v. for  kg adults. us in the beginning of week 
immediately prior to the treatment experiment, a dose of
Cerenin. 𝜇L/ g was recommended daily for each
Ginkgo medicated group. e whole treatment course sus-
tained for  weeks (i.e., from week  to week ).
2.5. Treadmill Exercise Training Protocol. For treadmill exer-
cise training, the groups , , , and  were rst acclimated
from week  to , starting with min,  min,  min, and
then  min per time per day. e formal exercise therapy was
then started from week  until week , three times per week,
 min per time at a speed of  m/min on a motorized rodent
treadmill (Fortelice International Co., Ltd., Taipei, Taiwan).
2.6. Blood and Tissue Collection. At the end of week , blood
samples were withdrawn from the abdominal aorta under
ether anesthesia. e blood was collected and centrifuged at
 ×g for  minutes to separate the serum. e prostates
Evidence-Based Complementary and Alternative Medicine
were excised, immediately frozen with liquid nitrogen and
stored in C or xed by immersion with % formalin in
PBS (pH .).
2.7. Hematoxylin-Eosin (HE) and Sirius Red Staining. e
prostateswerexedbyimmersionin%formalin-PBS(pH
.  ) a t C for  h and processed for paran embedding.
Paran sections were dewaxed in xylene and rehydrated in a
series of ethanol washes. e nuclei of these specimens were
subjected to hematoxylin-eosin stain. Otherwise, the collagen
content was stained with Sirius Red (Sigma-Aldrich Co., MO,
USA) [].
2.8. Enzyme-Linked Immunosorbent Assay (ELISA). Serum
levels of testosterone, estradiol, dihydrotestosterone (DHT),
prostate-specic antigen (PSA), and IL- were measured by
the ELISA kits. All protocols were performed by following
themanufacturersinstruction.eEZReadMicroplate
ReaderusedwasaproductofBiochromCo.(Cambridge,
UK) [].
2.9. Immunohistochemical (IHC) Staining. e protein
expression of androgen receptor and proliferating cell nuclear
antigen were analyzed by IHC according to previous protocol
cited []. Quantitative analysis was performed using an
Image-Pro Plus (Meyer Instruments, USA) analysis system.
e integrated optical density (IOD) was measured. e sum
of the IOD was obtained with the mean value calculated.
2.10. Western Blotting. Levels of 𝛼-reductase, estrogen
receptor 𝛼, and aromatase were analyzed. Briey, frozen
prostate tissue samples (approximately  mg) were
homogenized with the homogenizer (T basic, e IKA
Company, Germany) in  mL of Pro-PREP lysis buer
(pH .). e homogenate was centrifuged at  ×gfor
 min at C, and the supernatant was collected as tissue
sample lysate. e sample lysates were heated at Cfor
 min before loading and separated on precasted .%
SDS-PAGE. e proteins were electrotransferred onto the
PVDF membrane in transfer buer for  h.
e nonspecic binding to the membrane was blocked
for  h at room temperature with % nonfat milk in TBS
buer. e membranes were then incubated for  h at C
with various primary antibodies. Aer extensive washing
in TBS buer, the membranes were then incubated with
secondaryantibodyinblockingbuercontaining%nonfat
milk for  h at room temperature. Membranes were then
washed with TBS buer and the signals were quantied using
the Luminescent Image Analyzer LAS- (Fujilm, Tokyo,
Japan). 𝛽-actin was used as the reference protein [].
2.11. Statistical Analysis. Data obtained in the same group
were treated with ANOVA and Duncan’s multiple range tests
with computer statistical soware SAS . (SAS Institute
Inc., Cary, NC, USA). Dierent letters indicate signicant
dierences at 𝑃 < 0.05.
3. Results
3.1. BPH Reduced the Body Weight but Raised the Ratio of
Prostate Weight to Body Weight. Starting from the original
body weight ( to  g), the body weight of all groups was
seen increasing steadily from week  to week  (week  for
acclimation) (Figure (a)). When induced with BPH at week
 and with induct ion maintained daily until week , all control
groups showed substantive increase of body weight to range
within . ±. . ±.gatweek.Ascontrast,
in all BPH groups no apparent body weight increase was
found; all remained in range . ±.. ±. g/rat
until week  (Figure (a)). e ratio prostate to body weight
remained within . . in all normal groups but were
raised to . . in all BPH rats (Figure (b)).
3.2. Microscopic Pathological Examination. Microscopically,
in the normal prostates the acini were lined by columnar
epithelial cells and the lumens were lled with eosinophilic
secretion. Regular acini and alignment were apparently per-
ceivable (Figure (a), upper panel). In the BPH prostates,
mild epithelial hyperplasia and irregular acinar shape with
villous projections were clearly perceived. e epithelial
hyperplasia budding out with intraepithelial vacuoles was
very apparent, and in this region some epithelial cells indi-
cated loss of polarity (Figure (a) lower panel). Statistically,
the pathological incidence rate (rat number per group) of
prostate hyperplasia was ., ., ., and . for the four
groups without exercise, that is, the normal control, BPH con-
trol, Ginkgo control, and BPH + Ginkgo, respectively. When
treated with exercise, the incidence rates were apparently
shied to ., ., ., and ., respectively, for Ex con-
trol, BPH + Ex, Ginkgo +Ex,andBPH+Ginkgo +Ex.Usually
BPH is accompanied with inammation. e incidence rate
of inammation was ., ., ., and ., for the normal
control, BPH control, Ginkgo control, and BPH + Ginkgo,
respectively. Aer exercise training, the incidence rate of
inammation was improved to give ., ., ., and .,
respectively, for Ex control, BPH + Ex, Ginkgo +Ex,andBPH
+Ginkgo +Ex(Drs.ChenT.-Y.andLeeK.-H.,Diagnos-
tic Laboratory of Laboratory Rodents, National Laboratory
Animal Center (NLAC), Taipei, Taiwan), implying the fact
that Ginkgo was benecial to curing BPH, and also eective
to suppress the inammation status. e Sirius Red stain
revealed huge amount of collagen deposition occurring in
BPH group (Figures (b) and (c)), apparently loca lized in the
interstitial tissues and intracellular cytoplasm. Ginkgo alone
seemed to have alleviated the majority of these pathologically
adverse eects. Exercise alone improved it to some extent
only comparable to the eect with Ginkgo + Ex (Figures (b)
and (c)). Amazingly, the normal Ex groups also revealed
some collagen deposition (Figures (b) and (c)).
3.3. Serum Total Prostate-Specic Antigen (𝑡-PSA) in BPH Was
Upregulated by Ginkgo, but Suppressed by Exercise Training.
e normal total PSA level of the control and the BPH
groups were ranging within 44 ± 8ng/mL and 55 ± 5pg/mL
(Figure (a)). Ginkgo elevated the levels in both the Ginkgo
Evidence-Based Complementary and Alternative Medicine
800
700
600
500
400
300
200
02468101214
Body weight (g)
Week
Control
BPH
BPH +
Ex
BPH + Ex
𝐺𝑖𝑛𝑘𝑔𝑜𝐺𝑖𝑛𝑘𝑔𝑜 BPH + 𝐺𝑖𝑛𝑘𝑔𝑜 + Ex
𝐺𝑖𝑛𝑘𝑔𝑜 + Ex
(a)
0.020
0.015
0.010
0.005
0.000
Control Ex
Group
Normal
BPH
Ratio of prostate to body weight
bb
b
b
a
aa
a
𝐺𝑖𝑛𝑘𝑔𝑜 𝐺𝑖𝑛𝑘𝑔𝑜 + Ex
(b)
F : Duration-dependent variation of body weight (a) and the ratio prostate to body weight among all groups (b). Week -week :
acclimation. Week –week : BPH induction period. Week : exercise pretraining. Week –week : receiving treatment. e grouping of
rats was described in the text. ( rats in each group, 𝑃 < 0.05) BPH: benign prostate hyperplasia. Ex: exercise.
and the BPH + Ginkgo groups signicantly to 57 ± 6pg/mL
and 68 ± 9 pg/mL. As contrast, exercise signicantly reduced
thetotalPSAlevelsinboththeExandBPH+Exgroups.
Conversely, in the Ginkgo +Exgroup,bothlevelsremained
unchangedwhencomparedwiththenormalandBPHcontrol
groups (Figure (a)).
3.4. Free PSA/Total PSA Ratio Was Suppressed by Ginkgo,
Exercise, and the Combined erapy. e free PSA to total
PSA ratio (𝑓-PSA/𝑡-PSA) in normal controls ranged within
1.03 ± 0.12%,andthatofBPHwithin0.86 ± 0.10%. Ginkgo,
exercise, and Ginkgo + Ex all signicantly reduced the levels
to ranges within .. pg/mL (Figure (b)). No appar-
ent dierence was found for any treated group, indicating
the eect of Ginkgo to be comparable to exercise alone.
However in the combined therapy of Ginkgo + Ex, no better
eect was further found (Figure (b)); suggestively, the action
mechanism of Ginkgo and exercise probably via the same
pathway.
3.5. e Serum Level of Testosterone Was Not Aected by
Ginkgo Alone, but Improved Slightly by Exercise and the
Combined erapy. e serum level of testosterone in the
normal control maintained at a level of 806.8 ± 175.6 pg/mL.
While in the BPH control, it was apparently raised to 1494.1±
202.1pg/mL. Exercise alone and Ginkgo +Exseemedtohave
only slightly yet signicantly suppressed these testosterone
levels (Figure (a)).
3.6. Ginkgo Alone Did Not Aected DHT, However Exercise
and the Combined erapy Signicantly Raised DHT Level in
BPH Groups. Ginkgo alone did not aect the prostatic DHT
levels in both the normal and BPH groups. Alternatively,
exercise and the combined therapy signicantly elevated the
prostatic DHT levels to reach 1420.4 ± 58.8 and . ±
.pg/mL in BPH groups, respectively (Figure (b)). e
DHT levels in the normal Ginkgo + Ex group also increased
(844.64 ± 39.1pg/mL) compared with normal control
(530.8 ± 68.3 pg/mL) (Figure (b)).
As contrast, Western blotting revealed 𝛼-reductase to
be totally unaected by any of these specic therapies (Fig-
ure (c)).
3.7. AR Highly Upregulated by BPH Was Separately Downreg-
ulated by Ginkgo and Ex Alone, yet Further Upregulated by
Ginkgo + Ex erapy. Immunohistochemical stain showed
prostatic androgen receptors were highly upregulated in BPH
group (IOD 3.15 ± 0.32%) (Figures (a) and (b)). Ginkgo
or exercise was shown able to suppress most parts of the
upregulated AR (IOD 2.52 ± 0.04%, 1.74 ± 0.23%). However
strangely, Ginkgo + Ex further upregulated the level of AR in
BPH group (IOD 3.97 ± 0.48%) (Figures (a) and (b)).
3.8. BPH Highly Upregulated Serum Estradiol Which Was
Suppressed by Ginkgo, Ex, and Ginkgo + Ex. Alternatively,
theestradiollevelofthenormalcontrolrangedwithin37.5±
5.6pg/mL, and that of BPH control within 60.2 ± 4.0pg/mL.
All three treatments were shown to improve to 23.1 ± 3.1,
31.6 ± 2.0,and43.4 ± 8.6 pg/mL, respectively, by Ginkgo,Ex,
and Ginkgo +Ex(Figure(a)).
3.9. e Expression of Estrogen Receptor Was Upregulated by
BPH Control, Completely Ameliorated by Ginkgo, and Partially
Evidence-Based Complementary and Alternative Medicine
ExNormal
BPH BPH + BPH + Ex BPH +
Ex
𝐺𝑖𝑛𝑘𝑔𝑜
𝐺𝑖𝑛𝑘𝑔𝑜
𝐺𝑖𝑛𝑘𝑔𝑜 + Ex
𝐺𝑖𝑛𝑘𝑔𝑜 +
(a)
ExNormal
BPH BPH + BPH + Ex BPH +
Ex
𝐺𝑖𝑛𝑘𝑔𝑜 +
𝐺𝑖𝑛𝑘𝑔𝑜
𝐺𝑖𝑛𝑘𝑔𝑜
𝐺𝑖𝑛𝑘𝑔𝑜
+ Ex
(b)
Control Ex
Group
Normal
BPH
10
8
6
4
2
0
Collagen stain (%)
e
a
e
cd bd
bc
ed
b
𝐺𝑖𝑛𝑘𝑔𝑜 𝐺𝑖𝑛𝑘𝑔𝑜 + Ex
(c)
F : Hematoxylin-eosin stain (a) and Sirius Red stain of collagen deposition (b) of prostatic tissues of the normal controls (upper
panel), and the BPH groups (lower panel) (×); and the quantication of collagen deposition (c). (Upper panels: normal, Gingko control,
Ex control, and Gingko + Ex control; lower panels: BPH control, BPH + Gingko, BPH + Ex, and BPH + Gingko + Ex.) Data were collected and
statistically treated with ANOVA and Duncan’s multiple range tests (𝑛=3). Dierent letters indicate signicant dierence between groups
(𝑃 < 0.05). BPH: benign prostate hyperplasia. Gingko:theGingko biloba leaf extract. Ex: exercise.
100
80
60
40
20
0
Total PSA (ng/mL)
cbc b
a
eebc b
Control Ex
Group
Normal
BPH
𝐺𝑖𝑛𝑘𝑔𝑜 𝐺𝑖𝑛𝑘𝑔𝑜 + Ex
(a)
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Free PSA/total PSA (%)
Control Ex
Group
Normal
BPH
a
ab
cccccc
𝐺𝑖𝑛𝑘𝑔𝑜 𝐺𝑖𝑛𝑘𝑔𝑜 + Ex
(b)
F : Serum level of total-PSA (a) and the percent ratio free-to-total PSA (b), of the normal controls and the BPH groups when treated
with Gingko,Ex,andGinkgo + Ex. Data were collected and statistically treated with ANOVA and Duncan’s multiple range tests (𝑛=3).
Dierent letters indicate signicant dierence between groups (𝑃 < 0.05). PSA: prostate-specic antigen. BPH: benign prostate hyperplasia.
Ex: exercise.
Evidence-Based Complementary and Alternative Medicine
2500
2000
1500
500
0
d
a
d
a
e
b
e
c
Testosterone (pg/mL)
1000
Control Ex
Group
Normal
BPH
𝐺𝑖𝑛𝑘𝑔𝑜 𝐺𝑖𝑛𝑘𝑔𝑜 + Ex
(a)
2000
1500
1000
500
0
DHT (pg/mL)
e
c
e
c
e
a
d
b
Control Ex
Group
Normal
BPH
𝐺𝑖𝑛𝑘𝑔𝑜 𝐺𝑖𝑛𝑘𝑔𝑜 + Ex
(b)
3.0
2.5
2.0
1.5
1.0
0.5
0.0
aaa
a
a
a
aa
Control Ex
Group
Normal
BPH
+
+
+
+
+
+
+
+
+
+
+
+
BPH
Ex
Actin
5𝛼-reductase
5𝛼-reductase/actin
𝐺𝑖𝑛𝑘𝑔𝑜
𝐺𝑖𝑛𝑘𝑔𝑜
𝐺𝑖𝑛𝑘𝑔𝑜 + Ex
(c)
F : Serum levels of Testosterone (a), DHT (b), and the Western blotting of 𝛼-reductase (c) in prostates of the normal controls and the
BPH groups. 𝛽-actin was used as the reference constitutive protein. Data were collected and statistically treated with ANOVA and Duncan’s
multiple range tests (𝑛=3). Dierent letters indicate signicant dierence between groups (𝑃 < 0.05). DHT: dihydrotestosterone. BPH:
benign prostate hyperplasia. Ex: exercise.
Evidence-Based Complementary and Alternative Medicine
ExNormal
BPH BPH + BPH + Ex BPH +
Ex
𝐺𝑖𝑛𝑘𝑔𝑜 +
𝐺𝑖𝑛𝑘𝑔𝑜
𝐺𝑖𝑛𝑘𝑔𝑜
𝐺𝑖𝑛𝑘𝑔𝑜
+ Ex
(a)
Control Ex
Group
Normal
BPH
8
6
4
2
0
AR stain (IOD%)
d
b
dcdd
de
a
𝐺𝑖𝑛𝑘𝑔𝑜 𝐺𝑖𝑛𝑘𝑔𝑜 + Ex
(b)
F : Immunohistochemical stain of AR (a), and its quantication (b) in the prostate tissues of the normal controls and the BPH groups.
(Upper panels: normal, Gingko control, Ex control, and Gingko + Ex control; lower panels: BPH control, BPH + Gingko, BPH + Ex, and BPH
+Gingko + Ex.) Data were collected and statistically treated with ANOVA and Duncan’s multiple range tests (𝑛=3). Dierent letters indicate
signicant dierence between groups (𝑃 < 0.05). AR: androgen receptor. BPH: benign prostate hyperplasia. Ex: exercise.
Alleviated by Ex Alone and Ginkgo + Ex. e levels of estro-
gen receptor in all normal groups were not aected by any of
the three treatments. Conversely, the ER highly upregulated
in the BPH group was signicantly downregulated by all the
three therapies. Ginkgo in this case completely alleviated the
upregulated level of ER (Figure (b)). Alternatively, exercise
and the combined therapy seemed to be less eective than
Ginkgo alone (Figure (b)).
3.10. Ginkgo Suppressed the Aromatase Level of BPH to Better
an Either Ex or the Combined erapy. Similarly, BPH
upregulated prostatic aromatase, Ginkgo completely allevi-
ated, and exercise alone and Ginkgo +Exwereshownableto
partially ameliorate the upregulation of prostatic aromatase.
Interestingly, the levels of aromatase in all normal groups
were unchanged (Figure (c)).
3.11. Prostate IL-1, Highly Upregulated in BPH, Was Amelio-
rated by Any of the erapies. In prostate of BPH, the level
of IL- was signicantly raised to 5.3 ± 1.2ng/mL, which was
completely ameliorated by all therapies (Figure ), implying
Ginkgo,exercise,andthecombinedtherapytoactaseective
anti-inammatory agents.
3.12. PCNA Raised in BPH Was Ameliorated by Ginkgo, Exer-
cise, and the Combined Treatments. Either Ginkgo or exercise
was found to have eectively suppressed the upregulated
PCNA in BPH group (Figure ), apparently showing their
promising antiproliferative eect. Astonishingly, the PCNA
was insuppressible by the combined therapy (Figure ).
Data were slightly inconsistent with the pathological ndings
(NLAC).
4. Discussions
e normal and all controls showed normal growth increas-
ing rate, conversely the growth rates of all BPH victims were
severely retarded (Figure (a)). In reality, the body weight and
prostate weight can be greatly aected by hormonal status
[]. e castrated male Wistar rats, the castrated + T, and the
castrated + T + E showed body weight at age  weeks 419.6±
26.2,438.0± 27.3,and379.6± 26.4g, respectively, comparing
to the normal control body weight 478.6 ± 59.9g[]. e
body weight retardation in the BPH groups was apparently
perceivable. All experimental BPH SD rats retained their
body weight within . ±. . ±. g at week 
(Figure (b)), evidencing the main antigrowth eect exerted
by the combined treatment of T + E.
e eect of Ginkgo alone or any of the combined therapy
was more or less eective, but limited to some aspects regard-
ing the amelioration of pathological damages in prostates, like
the lining up acini by columnar epithelial cells, eosinophilic
secretion, epithelial hyperplasia, and deformed acinar shape
(Figure (a), lower panel). Much of the literatures have
indicated many benets of Ginkgo; however most of which
were limited only to its antioxidant and anti-inammatory
eects [,]. To our belief, we are the rst who report
Ginkgo to be benecial to BPH. Ginkgo was shown to be the
most eective with respect to suppressing the intracellular
cytoplasmic collagen deposition in the interstitial tissues
(Figures (b) and (c)). Tissue from men with lower urinary
tract symptoms was signicantly stier (𝑃 = 0.00160)with
signicantly higher collagen content (𝑃 = 0.0038)andlower
granularity than that from men without lower urinary tract
symptoms (American Urological Association symptom index
orgreaterversusorless)[]. us, brosis can be a factor
contributing to lower urinary tract symptom etiology.
Evidence-Based Complementary and Alternative Medicine
𝐺𝑖𝑛𝑘𝑔𝑜 𝐺𝑖𝑛𝑘𝑔𝑜 + Ex
100
80
60
40
20
0
Estradiol (pg/mL)
b
a
b
cd
b
c
bb
Control Ex
Group
Normal
BPH
(a)
ER/actin
6
5
4
3
2
1
0
cd
a
dcc
b
d
b
Control
Group
Normal
BPH
+
+
+
+
+
+
+
+
+
+
+
+
BPH
Ex
Actin
ER
Ex Ex
𝐺𝑖𝑛𝑘𝑔𝑜 𝐺𝑖𝑛𝑘𝑔𝑜 +
𝐺𝑖𝑛𝑘𝑔𝑜
(b)
6
5
4
3
2
1
0
Aromatase/actin
c
a
ccc
b
c
b
Control Ex
Group
Normal
BPH
+
+
+
+
+
+
+
+
+
+
+
+
BPH
Ex
Actin
Aromatase
𝐺𝑖𝑛𝑘𝑔𝑜
𝐺𝑖𝑛𝑘𝑔𝑜
𝐺𝑖𝑛𝑘𝑔𝑜 + Ex
(c)
F : Serum levels of Estradiol (a), the Western blotting of ER ((b) upper) and its quantication ((b) lower), and the Western blotting of
aromatase ((c) upper) and its quantication ((c) lower) in the prostates of dierent groups. 𝛽-actin was used as the reference constitutive
protein. Data were collected and statistically treated with ANOVA and Duncan’s multiple range tests (𝑛=3). Dierent letters indicate
signicant dierence between groups (𝑃 < 0.05)(𝑛=3). ER: estrogen receptor. Ex: exercise.
Evidence-Based Complementary and Alternative Medicine
Control Ex
Group
Normal
BPH
10
8
6
4
2
0
c
a
c
b
c
b
c
b
IL-1 (ng/mL)
𝐺𝑖𝑛𝑘𝑔𝑜 𝐺𝑖𝑛𝑘𝑔𝑜 + Ex
F : Levels of prostatic tissue interleukin- (IL-) aected by
dierent therapies. Data were collected and statistically treated with
ANOVA and Duncan’s multiple range tests (𝑛=3). Dierent letters
indicate signicant dierence between groups (𝑃 < 0.05).
Diagnostically, prostate-specic antigen (PSA) and the
ratio of free-to-total PSA are widely used as the tumor mark-
ers, but the eect of exercise on these parameters is unclear.
Ratio of free-to-total PSA was equally improved by Ginkgo,
exercise, and Ginkgo +Ex(Figure(b)). Literature indicated
that the free-to-total PSA ratio was signicantly lower statis-
tically in master athletes compared with recreational athletes,
but is not clinically signicant []. Nonetheless, the free-to-
total PSA ratio can be aected by long-term athletic training,
which could be rather important when evaluating athletes
with prostate-related disorders [].
e testosterone levels in groups BPH + Ex and BPH +
Ginkgo + Ex were seen signicantly lower than those in the
BPH control. Speculatively, the highly upregulated DHT in
these two groups implied BPH possibly incurable by these
treatments. AR was seen more highly expressed in BPH +
Ginkgo + Ex group (Figure ), while the 𝛼-reductase in
all groups remaining at comparable levels, a fact evidently
suggesting that exercise and Ginkgo +Exprobablywereonly
capable of enhancing the activity but incapable of aecting
the quantity of 𝛼-reductase (Figure (c)). Suzuki et al.
demonstrated that the values of both the 𝑉max and the 𝐾𝑚
for nuclear 𝛼-reductase in the rat dorsal lateral prostate were
enhanced by treatment with T + E []. us our ndings
were rather consistent with Suzuki et al. () [].
Testosterone is biotransformed into estradiol-𝛽by
action of aromatase. e prostate is an estrogen target
tissue and estrogens directly and indirectly aect growth and
dierentiation of prostate []. BPH highly elevated the levels
of aromatase, estradiol, and ER (Figure ). Estrogens and
selectiveestrogenreceptormodulatorshavebeenshownto
promote or inhibit prostate proliferation, signifying poten-
tial role of BPH and LUTS []. Aromatase, estradiol, and
ER upregulated in BPH were suppressed by all the three
treatments, while Ginkgo showed the most promising eect
(Figure ).
Ginkgo has been shown to exhibit estrogenic and antie-
strogenic activities depending on the E and Ginkgo con-
centration, via ER-dependent and ER-independent pathways
[]. Ginkgo reduced the E levels by stimulating the E
metabolism and inhibiting E synthesis []. As BPH usually
is accompanied with inammation [,], results apparently
pointed to the rescuing eect of these three therapies.
Clinical studies have revealed a close relationship
between inammation and prostate disease [,].
Much of literatures showed more than % incidences of
inammatory lesions in prostate tissue in BPH [,]. IL- is
a paracrine inducer of FGF, a key epithelial growth factor in
BPH []. In BPH, IL- can be upregulated to induce FGF,
which in turn leads to further epithelial growth and increases
IL- secretion, establishing the so-called “Double Paracrine
Loop” []. Ginkgo,Ex,andGinkgo +Exalleectively
alleviated the elevation of IL- (Figure ). As well known,
such anti-inammatory eect has been well cited [,].
Level of PCNA was lowered in Ginkgo andExgroups
comparing to the BPH control. Conversely, the PCNA level
in Ginkgo + Ex remained unaected at a level as high as the
BPH control (Figure (b)).
Literature indicated that the pathogenesis of BPH could
be caused by high proliferating rate and low apoptosis rate
of hyperplasia epithelium []. Recent studies by Alonso-
Magdalena et al. demonstrated BPH is not a disease of
prostatic stroma proliferation but rather of accumulation of
mesenchymal-like cells derived from the prostatic epithelium
and the endothelium []. No evidence of proliferation was
found in the stroma but in the epithelium of some ducts; .%
ofthebasaland.%oftheluminalcellswerepositiveforthe
nuclear antigen Ki and the PCNA [].
In summary, BPH tended to retard growth and increase
organ weights of prostate. Although Ginkgo,exercise,and
Ginkgo + Ex were all eective in alleviating collagen depo-
sition, the combined Ginkgo +Exwasthemostineective.
Testosterone was unaected by Ginkgo but signicantly
suppressed by Ex and Ginkgo + Ex. e levels of 𝛼-reductase
were totally unaected by all three treatments. Ginkgo alone
did not aect DHT level, but Ex and Ginkgo +Exhighly
stimulated DHT. Ginkgo and Ex downregulated AR, but
Ginkgo +Exhighlyupregulatedtheleveltohigherthan
the BPH control. e upregulated E was suppressed by all
three therapies. e highly upregulated PCNA in BPH was
signicantly and separately suppressed by Ginkgo and Ex,
but unalleviated by Ginkgo + Ex. Results that underlie both
Ginkgo andexercisewereeective,butthecombinedtherapy
was ineective for BPH treatment. e action mechanisms
of Ginkgo andexerciseintreatingBPHaresummarizedin
Figure .
5. Conclusion
In BPH, Ginkgo acts as an antiandrogenic (regarding the
DHT level), an anti-AR, an aromatase inhibitor, and a potent
anti-ER and a strong antiestrogenic (regarding the estradiol
 Evidence-Based Complementary and Alternative Medicine
Normal
BPH BPH + BPH +
BPH +
Ex Ex
Ex
Ex
𝐺𝑖𝑛𝑘𝑔𝑜
+
𝐺𝑖𝑛𝑘𝑔𝑜 +
𝐺𝑖𝑛𝑘𝑔𝑜
𝐺𝑖𝑛𝑘𝑔𝑜
(a)
100
80
60
40
20
0
PCNA
d
a
d
b
d
b
cd
a
Control
Group
Normal
BPH
ExEx
𝐺𝑖𝑛𝑘𝑔𝑜 𝐺𝑖𝑛𝑘𝑔𝑜 +
(b)
F : Immunohistochemical stain of the PCNA (a) (×) and its quantication (b). Data were collected and statistically treated with
ANOVA and Duncan’s multiple range tests (𝑛=3). Dierent letters indicate signicant dierence between groups (𝑃 < 0.05). PCNA: mouse
proliferating cell nuclear antigen.
Exercise
Exercise
Exercise
Exercise
Exercise
NE
NE
NE
5𝛼-reductase
DHT
AR
AR DHT
Aromatase
NE
NE
exercise exercise
𝑡-PSA
𝑓-PSA/𝑡-PSA
Estradiol
ER
ER
PCNA
IL-1
Collagen
deposition
Survival? Proliferation? BPH rescued
NE: no eect
Test o s t e r one Estradiol
𝐺𝑖𝑛𝑘𝑔𝑜
𝐺𝑖𝑛𝑘𝑔𝑜
𝐺𝑖𝑛𝑘𝑔𝑜
𝐺𝑖𝑛𝑘𝑔𝑜
𝐺𝑖𝑛𝑘𝑔𝑜
𝐺𝑖𝑛𝑘𝑔𝑜
+
𝐺𝑖𝑛𝑘𝑔𝑜 +
𝐺𝑖𝑛𝑘𝑔𝑜 + exercise
𝐺𝑖𝑛𝑘𝑔𝑜 + exercise
F : Summary of the therapeutic eects assessed from dierent treatments: Gingko,Ex,andthecombinedGingko +ExontheBPH.
AR: androgen receptor, ER: estrogen receptor, 𝑓-PSA: free PSA, 𝑡-PSA: total PSA, PCNA: proliferating cell nuclear antigen.
Evidence-Based Complementary and Alternative Medicine 
level). Exercise acts as an androgenic (regarding the DHT
level),ananti-AR,amoderateanti-ER,amoderatearomatase
inhibitor, and an estrogenic (regarding the estradiol level).
e combined therapy behaves as an androgenic (regarding
the DHT level), an AR-upregulator, a moderate anti-ER, a
moderate aromatase inhibitor, and an antiestrogenic (regard-
ing the estradiol level). us, the therapeutic outcomes could
be very complicated and dierent from each other. Overall,
pathologically Ginkgo alone and exercise alone may be more
benecial than the combined therapy.
Conflict of Interests
e authors report no conict of interests.
Acknowledgments
e authors want to show their gratitude to the nancial
supports issued by Grant no. NSC –-B---MY
and NSC --B-- from the National Science
CouncilandbyGrantno.SKH-TMU--fromShinKong
Wu Ho - Su Memorial Hospital.
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... In rats, a daily injection of a commercial G. biloba leaf extract Cerenin for 4 weeks at a dose of 3.5 mg/mL (240 mg/g flavonoids and 60 mg/g terpenoids) in a solution containing ethanol, sorbitol, and NaOH have been able to suppress inflammation [68]. The therapeutic potential of G. biloba in the management of benign prostatic hyperplasia is believed to be mediated mainly by the reduction of proliferating cell nuclear antigen thereby lowering the risk of the disease. ...
... The therapeutic potential of G. biloba in the management of benign prostatic hyperplasia is believed to be mediated mainly by the reduction of proliferating cell nuclear antigen thereby lowering the risk of the disease. It also ameliorates the upregulation of prostatic aromatase enzyme indicating its effectiveness in curing benign prostatic hyperplasia [68]. ...
Chapter
Among Asian populations, including that of the Indian subcontinent, herbal remedies have been practiced since ancient times for the management of many complex diseases, including andrological problems. The efficacy of herbal medicines has largely been attributed to the synergistic interactions of the individual components because they are used mostly as whole extracts. In recent times, investigative studies have been taken up to validate the clinical efficacy and safety of individual herbal extracts, discrete chemical ingredients as well as their active principles apart from elucidating their mechanism of action in the management of such disorders. In this chapter, we discuss various pharmacological effects of three such herbs Ginkgo biloba, Curcuma longa, and Camellia sinensis that may be useful in the management of a wide array of andrological disorders such as male infertility, hypogonadism, erectile dysfunction, testicular cancer, prostate cancer, and benign prostatic hyperplasia. We have also attempted to provide their potential molecular mechanisms of action, to have a better understanding of how these herbal medicines exert their effects. Supplementation of G. biloba, C. longa, and C. sinensis has the potential to reduce oxidative stress levels and may uplift the health of reproductively compromised men posing as low-cost alternatives. By combining these herbs with lifestyle modification and standard medical treatment, the clinician may be able to maximize the chances of restoring normal reproductive functioning in such men. We have summarized the outcomes of already published reports on G. biloba, C. longa, and C. sinensis; however, not carried out any dose-response relationship or toxicological study. As such, more clinical intervention trials are needed to elucidate the exact mechanism of action of these herbs in humans. Carefully designed dose-response human studies may be able to incorporate G. biloba, C. longa, and C. sinensis as potential alternatives in the clinical management of andrological problems.
... In rats, a daily injection of a commercial G. biloba leaf extract Cerenin for 4 weeks at a dose of 3.5 mg/mL (240 mg/g flavonoids and 60 mg/g terpenoids) in a solution containing ethanol, sorbitol, and NaOH have been able to suppress inflammation [68]. The therapeutic potential of G. biloba in the management of benign prostatic hyperplasia is believed to be mediated mainly by the reduction of proliferating cell nuclear antigen thereby lowering the risk of the disease. ...
... The therapeutic potential of G. biloba in the management of benign prostatic hyperplasia is believed to be mediated mainly by the reduction of proliferating cell nuclear antigen thereby lowering the risk of the disease. It also ameliorates the upregulation of prostatic aromatase enzyme indicating its effectiveness in curing benign prostatic hyperplasia [68]. ...
... Previous studies indicated that testosterone level was not shown to have similar patterns with DHT level. 33,34 Testosterone plays an important role in the development of the male reproductive system. Testosterone level was measured to observe the changes in serum and prostate tissue after TP injection. ...
Article
Cranberry powder (CR) is reported to be effective against lower urinary tract symptoms (LUTS) and recurrent urinary tract infections. Benign prostatic hyperplasia (BPH) in men older than 50 years is a common cause of LUTS. Here, we attempted to evaluate if CR is also effective for treating BPH using a BPH-induced rat model, which was orally administered CR. Male Sprague-Dawley rats weighing 200-250 g were randomly divided into the following six groups (n = 9): noncastration group; castration group; BPH group; BPH and cranberry for 8-week (CR8W) group; BPH and cranberry for 4-week (CR4W) group; and BPH and saw palmetto group (saw palmetto). Compared with the BPH group, the CR8W group showed a significant decrease in prostate weight (by 33%), dihydrotestosterone (DHT) levels (by 18% in serum and 28% in prostate), 5-alpha reductase levels (18% reduction of type 1 and 35% of type 2), and histological changes. These results indicate that CR could attenuate BPH by inhibiting 5-alpha reductase and by reducing other biomarkers such as prostate weight and DHT levels. Thus, CR may be an effective candidate for the development of a functional food for BPH treatment. IACUC (USW-IACUC-R-2015-004).
... However, the increased apoptosis induced by high-dose BPA treatment might attenuate the trend of hyperplasia 28 . Prostate is a hormone-sensitive organ, and the interaction between estrogen and androgen is essential to maintain its normal development 29,30 . As a non-steroidal estrogen, BPA can disturb the expression of hormone receptors in some target tissues and affecte the endogenous hormone activity. ...
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Full-text available
This study aimed to identify prostaglandin synthases (PGS) that mediate bisphenol A (BPA)-induced prostatic hyperplasia and explore their underlying mechanisms. In an in vivo study, male adult Sprague–Dawley rats were treated with different concentrations of BPA (10, 30, 90, or 270 μg/kg, i.g., daily), or with vehicle for 4 weeks. Results revealed that low-dose BPA induced prostatic hyperplasia with increased PCNA/TUNEL ratio. It significantly upregulated the expression of cyclooxygenase-2 (COX-2) and NF-κB in the dorsolateral prostate (P < 0.05) and the expression of lipocalin-type prostaglandin D synthase (L-PGDS) in ventral prostate (P < 0.05). The level of estradiol (E2)/testosterone (T) and expression of androgen receptor (AR) and estrogen receptor α (ERα) were also altered. In vitro studies showed that low-dose BPA (0.1–10 nM) promoted the proliferation of human prostate fibroblasts and epithelial cells, and significantly upregulated the expression of COX-2 and L-PGDS in the cells. The two types of cell proliferation induced by BPA were inhibited by COX-2 inhibitor (NS398) and L-PGDS inhibitor (AT56), with increased apoptosis level. These findings suggested that COX-2 and L-PGDS could mediate low-dose BPA-induced prostatic hyperplasia through pathways involved in cell proliferation and apoptosis, which might be related to the functions of ERα and AR. The role of COX-2/NF-κB pathway in dorsolateral prostate requires further research.
... Immediately, the blood samples were collected from the abdominal aorta and centrifuged at 3000×g for 15 minutes, in order to obtain the serum. Serum levels of TE and prostate-specific antigen (PSA) were measured by the enzyme-linked immunosorbent assay (ELISA) kits, following the manufacturer's instructions [30,31]. ...
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Full-text available
Benign prostatic hyperplasia (BPH) is a common aging disease in men. Garlic is known to have anti-proliferative effects. Therefore, this study was designed to investigate the curative and preventive effects of garlic on BPH in rats. Rats were divided into five groups: control group, orchiectomized group (where rats were subjected to bilateral orchiectomies operation), BPH group [BPH was induced by intramuscular injection of testosterone (TE) enanthate once weekly for five weeks after orchiectomy], curative group (where rats were injected with TE for five weeks followed by daily administration of garlic powder for other five weeks), and preventive group (where rats were given garlic powder simultaneously with TE injections for five weeks). Serum levels of TE and prostate-specific antigen (PSA) were measured, and prostate weighed and processed for light microscopic, immunohistochemical and transmission electron microscopy (TEM) examination. Serum levels of TE and PSA, and prostate weight (PW) were significantly increased in BPH group and significantly decreased in curative and preventive ones. Histologically and morphometrically, BPH group showed epithelial hyperplasia, stromal expansion and reduced acinar lumens that were significantly improved in both curative and preventive groups. Proliferating cell nuclear antigen (PCNA) expression was increased while caspase-3 expression was decreased in BPH group. These results were reversed in both curative and preventive groups. TEM showed nuclear irregularities, dilated endoplasmic reticulum (ER) cisterns, and lost cell boundaries, secretory vesicles and apical microvilli. Most of the previous changes were minimized in preventive group more than in curative one.
Article
Purpose Prostate problems, such as prostate cancer, and benign prostate hyperplasia have been recognized as problems largely related to androgens and genetic factors. They affect a large fraction of the elderly population, contributing significantly to morbidity and mortality. Therefore, the purpose of this review paper was to investigate a therapeutic strategies for prostate cancer and benign prostate hyperplasia. Methods In order to determine the therapeutic exercise strategies for prostate cancer and benign prostate hyperplasia, previous literature was reviewed with MEDLINE, PubMed, and Scopus databases. Results Prostate cancer and its associated treatments can cause significant and lasting morbidities, such as cardiovascular and sexual dysfunctions. Various interventions have attempted to prevent or mitigate these dysfunctions. This review summarizes the available evidence concerning the effects of exercise training on male sexual health in the cancer prevalent population. Smoking cessation, regular exercise, and maintaining healthy weight are important public health targets for intervention. Importantly, several lifestyle modifications may lower the risk of developing more aggressive cancer or offer survival benefits to prostate cancer patients. Conclusions In this review article, physical exercise training can increase apoptosis markers in the prostate, suggesting exercise training as a potential novel therapeutic strategies for treating prostate cancer and benign prostate hyperplasia. Future studies in more advanced and varied prostate cancer populations are required to ascertain the duration, intensity and frequency of exercise that optimizes the effects of exercise training on prostate cancer and benign prostate hyperplasia.
Article
PURPOSE: Benign prostatic hypertrophy (BPH) is a common finding in older men and a frequent cause of lower urinary tract symptoms. The efficacy of exercise in the management of BPH-related inflammation is not fully understood. Thus, we investigated the effects of exercise on inflammatory markers in a mouse model of BPH.METHODS: A total of 36 male C57BL/6 mice were divided into three groups; CON (sham control, n=12), BPH-CON (received testosterone propionate [TP] control, n=12), and BPH-EXE (TP+aerobic exercise group, n=12). For BPH induction, mice were castrated and testosterone propionate (3 mg/kg/day) was administered by subcutaneous injection. The exercise group was forced to run on a treadmill for 30 minutes 3 times per week for 12 weeks.RESULTS: The BPH-CON group showed significantly increased blood pro-inflammatory cytokines such as interleukin-6, -1β, and TNF-α compared with CON (p<.05). Furthermore, NF-kb and COX-2 mRNA expression were significantly increased in prostate tissue (p<.05). In contrast, the BPH-EXE group exhibited a significant decrease in IL-1β and TNF-α cytokines and NF-kb and COX-2 mRNA, but a significant increase in SOD activity when compared to the BPH-CON group (p<.05).CONCLUSIONS: These results suggest that inflammation may be an important factor for the prevention and management of BPH, and that exercise may contribute to the alleviation of inflammation in the blood and prostate tissues of men with BPH.
Article
This study investigated the changes in the prostate of high-fat diet (HFD)-fed mice with insulin resistance (IR) and explored the possible mechanisms of the effects of 8-week treadmill aerobic exercise on prostatic hyperplasia in insulin-resistant mice through the IGF-1/IGF-1R/ERK/AKT signalling pathway. Results showed IR in mice caused an increase in prostate-related indicators, such as prostate weight (PW) and prostate volume (PV), resulting in prostatic hyperplasia. The area of the glandular lumen and the height of the glandular epithelium in mice with IR were increased, which indicating that it caused prostatic hyperplasia through epithelial cell proliferation. In addition, the level of IGF-1 in serum and the expression of IGF-1R, ERK and AKT in prostate tissue of high-fat diet induced IR mice increased significantly, which might be related to the proliferation of prostate cells. However, aerobic exercise lowered the blood sugar, serum insulin and IGF-1; inhibited the combination of IGF-1 and IGF-1R on the prostate; down-regulated the expression of IGF-1R, ERK and AKT proteins; and then suppressed the expression of downstream proliferation genes, thereby achieving the purpose of inhibiting the proliferation of prostate epithelial cells. In conclusion. Eight weeks of aerobic exercise might improve the prostate hyperplasia in mice via down-regulating the serum insulin and IGF-1, thus enhancing the insulin sensitivity of insulin-resistant mice and regulating the IGF-1/IGF-1R/ERK/AKT signalling pathway by inhibiting the expression of IGF-1R, ERK and AKT in the prostate tissue. However, this exercise had no significant effect on PV, PW and prostate index (PI).
Chapter
Several medicinal plants are traditionally used in different regions of Africa for the treatment of male infertility, sexual asthenia, erectile dysfunction, and impotency or used as an aphrodisiac. Scientific studies, mostly conducted in vitro or in animals, have proven the acclaimed traditional use of these plants to enhance sexual activities or sperm concentration, motility, and viability. Some of the mechanisms of actions associated with these plants include increased level of testosterone and the relaxation of the smooth cavernosal muscles. However, some plants were also shown to have detrimental effects on the male reproductive system. This may be due to the varying modes of plant extraction, duration of treatment, experimental design, dosage used, quality of the plant, or toxic effects. There is a need to standardize the protocols as well as to better understand the mechanism of actions of the respective plants. Further studies should be conducted using human subjects.
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Benign prostate hyperplasia (BPH) is a common disease in elderly men. It has been found that the occurrence of BPH was closely related to dysregulated steroid hormones. Here, a rapid, sensitive, accurate and specific method for the quantitative profiling of five androgens in man serum was developed and validated by the use of liquid chromatography–tandem mass spectrometry (LC‐MS/MS). Using this method, dehydroepiandrosterone (DHEA), androstenedione (A4), testosterone (T), androsterone (A), dihydrotestosterone (DHT), oestrone (E1) and oestradiol (E2) were quantified in serum from man with and without BPH. BPH patients were characterised by the decreases in DHEA, A4 and T as well as increases in DHT, E2 and E1 in serum. Meanwhile, DHEA and DHT in serum were screened as sensitive biomarkers of BPH patients. This study will provide a new perspective of dysregulated steroid hormones for the diagnosis and prevention of BPH.
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Estrogen, which acts through estrogen receptors (ERs) and , has been implicated in the pathogenesis of benign and ma- lignant human prostatic tumors, i.e. benign prostatic hyper- plasia and prostate cancer, thought to originate from differ- ent zones of the prostate (the transition zone (TZ) and peripheral zone (PZ), respectively). Here, we examined the cellular distribution of ER and ER in human normal and hyperplastic prostate tissues, using in situ hybridization and immunohistochemistry. ER expression was restricted to stromal cells of PZ. In contrast, ER was expressed in the stromal cells of PZ as well as TZ. ER-positive epithelial cells were evenly distributed in PZ and TZ of the prostate. Our results suggest that estrogen may play a crucial role in the pathogenesis of benign prostatic hyperplasia through ER. (J Clin Endocrinol Metab 88: 1333-1340, 2003)
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Background: Evidence is lacking for multi-ingredient herbal supplements claiming therapeutic effect in sexual dysfunction in men. We examined the safety and efficacy of VigRX Plus (VXP) - a proprietary polyherbal preparation for improving male sexual function, in a double blind, randomized placebo-controlled, parallel groups, multi-centre study. Methods: 78 men aged 25-50 years of age; suffering from mild to moderate erectile dysfunction (ED), participated in this study. Subjects were randomized to receive VXP or placebo at a dose of two capsules twice daily for 12 weeks. The international index of erectile function (IIEF) was the primary outcome measure of efficacy. Other efficacy measures were: Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS), Serum testosterone, Semen analysis, Investigator's Global assessment and Subjects' opinion. Results: In subjects receiving VXP, the IIEF-Erectile Function (EF) scores improved significantly as compared to placebo. After 12 weeks of treatment, the mean (sd) IIEF-EF score at baseline increased from 16.08 (2.87) to 25.08 (4.56) in the VXP group versus 15.86 (3.24) to 16.47 (4.25) in the placebo group (P < 0.0001). Similar results were observed in each of the remaining four domains of the IIEF (orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction).There was a significant difference for VXP versus placebo comparison of mean (sd) EDITS scores of patients: 82.31(20.23) vs 36.78(22.53) and partners :(82.75(9.8) vs 18.50(9.44);P < 0.001. Thirty-five out of 39 (90%) subjects from the VXP group and one (3%) from the placebo group wished to continue with the treatment they received. Investigator's global assessment rated VXP therapy as very good to excellent in more than 50% patients and placebo therapy as fair to good in about 25% of patients. Incidence of side effects and subject's rating for tolerability of treatment was similar in both groups. Conclusions: VigRX Plus was well tolerated and more effective than placebo in improving sexual function in men. Trial registration: Clinical Trial Registry India, CTRI/2009/091/000099, 31-03-2009.
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Chronic elevation of glucose level activates vascular inflammation and increases endothelial adhesiveness to monocytes, an early sign of atherogenesis. This study aimed to elucidate the detailed mechanisms of high-glucose-induced endothelial inflammation, and to investigate the potential effects of Ginkgo biloba extract (GBE), an antioxidant herbal medicine, on such inflammation. Human aortic endothelial cells were cultured in high glucose or mannitol as osmotic control for 4 days. The expression of cytokines and adhesion molecules and the adhesiveness of endothelial cells to monocytes were examined. The effects of pretreatment of GBE or N-acetylcysteine, an antioxidant, were also investigated. Either high glucose or mannitol significantly increased reactive oxygen species (ROS) production, interleukin-6 secretion, intercellular adhesion molecule-1 (ICAM-1) expression, as well as endothelial adhesiveness to monocytes. The high-glucose-induced endothelial adhesiveness was significantly reduced either by an anti-ICAM-1 antibody or by an interleukin-6 neutralizing antibody. Interleukin-6 (5 ng/ml) significantly increased endothelial ICAM-1 expression. Piceatannol, a signal transducer and activator of transcription (STAT) 1/3 inhibitor, but not fludarabine, a STAT1 inhibitor, suppressed high-glucose-induced ICAM-1 expression. Pretreatment with GBE or N-acetylcysteine inhibited high-glucose-induced ROS, interleukin-6 production, STAT1/3 activation, ICAM-1 expression, and endothelial adhesiveness to monocytes. Long-term presence of high glucose induced STAT3 mediated ICAM-1 dependent endothelial adhesiveness to monocytes via the osmotic-related redox-dependent interleukin-6 pathways. GBE reduced high-glucose-induced endothelial inflammation mainly by inhibiting interleukin-6 activation. Future study is indicated to validate the antioxidant/anti-inflammatory strategy targeting on interleukin-6 for endothelial protection in in vivo and clinical hyperglycemia.
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Recently published data suggest that clinical benign prostatic hyperplasia (BPH), which is hallmarked by the occurrence of moderate-to-severe lower urinary tract symptoms (LUTS), occurs in about one quarter of men in their 50s, one third of men in their 60s, and about half of all men 80 years or older. Although effective treatments for LUTS/BPH are available, this condition often occurs in the context of common, age-related comorbidities such as cardiovascular disease, hypertension, and erectile dysfunction. Alpha(1)-selective adrenergic receptor (alpha(1)-AR) antagonists (eg, alfuzosin, doxazosin, tamsulosin, terazosin) remain the cornerstone of therapy for LUTS/BPH. In addition, 5-alpha-reductase inhibitors (ie, dutasteride, finasteride) have been associated with improvements in LUTS/BPH in men with larger prostates, especially when used in combination with alpha(1)-AR antagonists. Although all these drugs have been shown to be beneficial for the treatment of BPH, there are differences in side-effect profiles. When selecting an appropriate course of therapy, these side effects and any impact they may have on existing comorbid conditions must be considered.
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Background: Chronic kidney disease (CKD) is usually associated with cardiac apoptosis and/or cardiac hypertrophy. We hypothesized that exercise can reduce the CKD-induced cardiac damage. Methods and results: The doxorubicin-induced CKD (DRCKD) model was used in rats to compare two exercise models: 60-min running and 60-min swimming. Results indicated that in healthy normal groups, the signals cardiotrophin-1 (CT-1), interleukin 6 (IL-6), leukaemia inhibitory factor receptor (LIFR), and gp130 were upregulated and janus kinase (JAK) and signal transducer and activation of transcription (STAT) were downregulated by both exercises. In contrast, all signals were highly upregulated in CKD. After exercise training, all signals (CT-1, IL-6, LIFR, gp130, and STAT) were downregulated, with JAK being only slightly upregulated in the running group but not in the swimming group. The myocyte death pathway (CT-1/IL-6 → LIFR/gp130 → PI3K → Akt → Bad) was excluded due to no change found for Bad. Nitric oxide (NO; normal, 15.63 ± 0.86 µmol/l) was significantly suppressed in CKD rats (2.95 ± 0.32 µmol/l), and both running and swimming training highly upregulated the NO level to 30.33 ± 1.03 µmol/l and 27.82 ± 2.47 µmol/l in normal subjects and 24.0 ± 3.2 µmol/l and 22.69 ± 3.79 µmol/l in the DRCKD rats, respectively. The endothelial progenic cells CD34 were significantly suppressed in DRCKD rats, which were not rescued significantly by exercise. In contrast, the CD 34 cells were only slightly suppressed in the healthy subjects by exercise. Conclusion: Both exercise regimens were beneficial by rescuing cardiac function in CKD victims. Its action mechanism was by way of inhibiting myocyte death and rescuing cardiac hypertrophy.
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Current therapies for male lower urinary tract symptoms secondary to prostate enlargement prevent hormonal effects on prostate growth and inhibit smooth muscle contraction to ease bladder neck and urethral pressure. However, lower urinary tract symptoms can be refractory to these therapies, suggesting that additional biological processes not addressed by them may also contribute to lower urinary tract symptoms. Aging associated fibrotic changes in tissue architecture contribute to dysfunction in multiple organ systems. Thus, we tested whether such changes potentially have a role in impaired urethral function and perhaps in male lower urinary tract symptoms. Periurethral tissues were obtained from a whole prostate ex vivo and from 28 consecutive men treated with radical prostatectomy. Lower urinary tract symptoms were assessed using the American Urological Association symptom index. Prostate tissues were subjected to mechanical testing to assess rigidity and stiffness. Fixed sections of these tissues were evaluated for collagen and elastin content, and glandularity to assess fibrosis. Statistical analysis included the Student t test and calculation of Pearson correlation coefficients to compare groups. Periurethral prostate tissues demonstrated nonlinear viscoelastic mechanical behavior. Tissue from men with lower urinary tract symptoms was significantly stiffer (p = 0.0016) with significantly higher collagen content (p = 0.0038) and lower glandularity than that from men without lower urinary tract symptoms (American Urological Association symptom index 8 or greater vs 7 or less). Findings show that extracellular matrix deposition and fibrosis characterize the periurethral prostate tissue of some men with lower urinary tract symptoms. They point to fibrosis as a factor contributing to lower urinary tract symptom etiology.
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Ginkgo biloba extract (EGb), a potent antioxidant and monoamine oxidase B (MAO-B) inhibitor, was evaluated for its anti-parkinsonian effects in a 6-hydroxydopamine (6-OHDA) rat model of the disease. Rats were treated with 50, 100, and 150 mg/kg EGb for 3 weeks. On day 21, 2 µL 6-OHDA (10 µg in 0.1% ascorbic acid saline) was injected into the right striatum, while the sham-operated group received 2 µL of vehicle. Three weeks after 6-OHDA injection, rats were tested for rotational behaviour, locomotor activity, and muscular coordination. After 6 weeks, they were killed to estimate the generation of thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH) content, to measure activities of glutathione-S-transferase (GST), glutathione reductase (GR), glutathione peroxidase (GPx), catalase, and superoxide dismutase (SOD), and to quantify catecholamines, dopamine (DA) D2 receptor binding, and tyrosine hydroxylase-immunoreactive (TH-IR) fibre density. The increase in drug-induced rotations and deficits in locomotor activity and muscular coordination due to 6-OHDA injections were significantly and dose-dependently restored by EGb. The lesion was followed by an increased generation of TBARS and significant depletion of GSH content in substantia nigra, which was gradually restored with EGb treatment. EGb also dose-dependently restored the activities of glutathione-dependent enzymes, catalase, and SOD in striatum, which had reduced significantly by lesioning. A significant decrease in the level of DA and its metabolites and an increase in the number of dopaminergic D2 receptors in striatum were observed after 6-OHDA injection, both of which were significantly recovered following EGb treatment. Finally, all of these results were exhibited by an increase in the density of TH-IR fibers in the ipsilateral substantia nigra of the lesioned group following treatment with EGb; the lesioning had induced almost a complete loss of TH-IR fibers. Considering our behavioural studies, biochemical analysis, and immunohistochemical observation, we conclude that EGb can be used as a therapeutic approach to check the neuronal loss following parkinsonism.
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Ginkgo biloba has been existing on earth since 200 million years and is considered as a "living fossil". It is among the most sold medicinal plants in the world. A number of secondary metabolites representing terpenoids, polyphenols, allyl phenols, organic acids, carbohydrates, fatty acids and lipids, inorganic salts and amino acids have been isolated from the plant. However, the main bioactive constituents are terpene trilactones and flavonoid glycosides which are considered responsible for the pharmacological activities of its standardized leaf extract. Scattered information is available on the extraction and analysis of these pharmacologically important constituents which have been compiled in the present review.
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Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are common clinical problems in urology. While the precise molecular etiology remains unclear, sex steroids have been implicated in the development and maintenance of BPH. Sufficient data exists linking androgens and androgen receptor pathways to BPH and use of androgen reducing compounds, such as 5α-reductase inhibitors which block the conversion of testosterone into dihydrotestosterone, are a component of the standard of care for men with LUTS attributed to an enlarged prostate. However, BPH is a multifactorial disease and not all men respond well to currently available treatments, suggesting factors other than androgens are involved. Testosterone, the primary circulating androgen in men, can also be metabolized via CYP19/aromatase into the potent estrogen, estradiol-17β. The prostate is an estrogen target tissue and estrogens directly and indirectly affect growth and differentiation of prostate. The precise role of endogenous and exogenous estrogens in directly affecting prostate growth and differentiation in the context of BPH is an understudied area. Estrogens and selective estrogen receptor modulators (SERMs) have been shown to promote or inhibit prostate proliferation signifying potential roles in BPH. Recent research has demonstrated that estrogen receptor signaling pathways may be important in the development and maintenance of BPH and LUTS; however, new models are needed to genetically dissect estrogen regulated molecular mechanisms involved in BPH. More work is needed to identify estrogens and associated signaling pathways in BPH in order to target BPH with dietary and therapeutic SERMs.
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• To investigate the influence of baseline variables on the 4-year incidence of acute urinary retention (AUR), benign prostatic hyperplasia (BPH)-related surgery and overall clinical progression in men treated with tamsulosin, dutasteride, or a combination of both. • The 4-year Combination of Avodart® and Tamsulosin (CombAT) study was a multicenter, randomized, double-blind, parallel-group study of clinical outcomes in men aged ≥ 50 years with symptomatic (International Prostate Symptom Score [IPSS]≥ 12) BPH, with prostate-specific antigen (PSA) levels of ≥ 1.5 ng/mL and ≤ 10 ng/mL, and a prostate volume (PV) of ≥ 30 mL. • Eligible patients received tamsulosin 0.4 mg, dutasteride 0.5 mg, or a combination of both. • The primary endpoint was time to first AUR or BPH-related surgery. Secondary endpoints included clinical progression of BPH and symptoms. Posthoc analyses of the influence of baseline variables (including age, IPSS health-related quality of life [HRQL], PV, PSA, IPSS, peak urinary flow rate [Q(max) ] and body-mass index [BMI]) on the incidence of AUR or BPH-related surgery, clinical progression of BPH, and symptoms were performed. • There were 4844 men in the intent-to-treat population. Overall baseline characteristics were similar across all patient groups. • Regardless of baseline subgroup, the incidence of AUR or BPH-related surgery was higher in men treated with tamsulosin than in those treated with dutasteride or combined therapy. • Combined therapy was statistically better than tamsulosin in reducing the risk of AUR or BPH-related surgery in subgroups of baseline PV > 42.0 mL, in all subgroups of baseline PSA level, and all other baseline subgroups (P ≤ 0.001). • Across treatment groups, the incidence of clinical progression was highest in men with a baseline IPSS of < 20 or IPSS HRQL score of < 4. The incidence of clinical progression was also higher in men receiving tamsulosin than dutasteride or combined therapy in all baseline subgroups, except for men with a baseline PV of < 40 mL. Combined therapy reduced the relative risk (RR) of clinical progression compared with tamsulosin across all baseline subgroups and compared with dutasteride across most baseline subgroups. • Symptom deterioration was the most common progression event in each treatment group regardless of baseline subgroup, except in those men with an IPSS of ≥ 20 at baseline. Combined therapy reduced the RR of symptom deterioration compared with tamsulosin across all but one baseline subgroup (the reduction was not significant for men with a baseline PV of < 40 mL) and compared with dutasteride in most subgroups. • Men with a baseline PV of ≥ 40 mL and any baseline PSA level of ≥1.5 ng/mL had greater reductions in the RR of AUR or BPH-related surgery and greater reductions in the RR of clinical progression and symptom deterioration on combined therapy or dutasteride monotherapy than on tamsulosin monotherapy. • These analyses support the long-term use of combined therapy with dutasteride plus tamsulosin in men with moderate-to-severe BPH symptoms and a slightly enlarged prostate.