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Panax ginseng Improves Senile Testicular Function in Rats

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Abstract

We reported previously that the administration of Korean red ginseng water extract (KRG-WE) protected the guinea pig testis against damage induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (a potent endocrine disruptor). We also found that crude saponin from ginseng was the active ingredient responsible for this protection. Here, we examined the biological role of KRG-WE in an animal model of age-induced dysfunction of spermatogenesis. Twenty-four male Sprague-Dawley (six 2-month-old and eighteen 12-month-old) rats were used. The young and old control groups received only vehicle. The ginseng saponin (GS)- and KRG-WE-treated groups received GS (40 mg/kg body weight/day) and KRG-WE (200 mg/kg body weight/day), respectively, for 4 months. The number of cells, Sertoli cell index, Johnsen's score, and sex hormone levels decreased significantly with age. However, the administration of KRG-WE and GS markedly improved the number of germ cells, seminiferous tubular size, and Johnsen's score in the old rats. Ginseng produced a distinct testicular histological improvement in old rats. KRG-WE and GS elevated testosterone levels, while attenuating the aberrant increase in follicle stimulating hormone and luteinizing hormone levels. Sperm kinematics evaluated by a computer-assisted sperm analyzer demonstrated improvement in the percentage of motile sperm, progressive sperm motility, and curvilinear velocity associated with sperm quality, supporting the beneficial role of red ginseng in senile spermatogenesis. Overall, the total water extract had a more potent effect than the corresponding saponin fraction. In conclusion, Korean red ginseng rejuvenated age-induced testicular dysfunction. Additionally, the total water extract was more potent than the corresponding saponin fraction.
The Korean Society of Ginseng
327
http://ginsengres.org pISSN: 1226-8453 eISSN: 2093-4947
Research Article
J. Ginseng Res. Vol. 34, No. 4, 327-335 (2010)
DOI:10.5142/jgr.2010.34.4.327
E-mail: skkim@kku.edu
Tel: +82-43-840-3574, Fax: +82-43-840-3929
*
Corresponding author
INTRODUCTION
Increasing life expectancy has raised issues concern-
ing the impact of aging on the male endocrine system
and sexuality. While female fertility ends at the entrance
to menopause around the age of 50 years, men generally
do not experience a clear-cut end to their reproductive
capacity. A reduction in sperm motility may be due to in-
creased latency and decreased frequency of intercourse
with aging. Age-associated histomorphological altera-
tions of the testis include a reduction in the number of
Leydig cells [1], thickening and protrusions of the basal
membrane of the seminiferous tubules [2], small areas
of disturbed spermatogenesis, and malformed sperma-
tids [3]. Decreased numbers of Leydig cells could be
related to lower serum testosterone levels, which were
decreased by approximately 0.4% annually starting at
the age of 50 years [4]. Additionally, decreased testicular
Panax ginseng Improves Senile Testicular Function in Rats
Seock-Yeon Hwang1, Sang-Hyun Sohn2, Jae-Joon Wee3, Jin-Bae Yang1, Jong-Soo Kyung3,
Yi-Seong Kwak3, Sung-Won Kim2, and Si-Kwan Kim2*
1Department of Clinical Pathology, Daejeon University, Daejeon 300-716, Korea
2Department of Life Science, College of Biomedical and Health Science, Konkuk University, Chungju 380-701, Korea
3Korea Ginseng Corporation, Daejeon 305-805, Korea
We reported previously that the administration of Korean red ginseng water extract (KRG-WE) protected the guinea pig
testis against damage induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (a potent endocrine disruptor). We also found that crude
saponin from ginseng was the active ingredient responsible for this protection. Here, we examined the biological role of KRG-
WE in an animal model of age-induced dysfunction of spermatogenesis. Twenty-four male Sprague-Dawley (six 2-month-
old and eighteen 12-month-old) rats were used. The young and old control groups received only vehicle. The ginseng saponin
(GS)- and KRG-WE-treated groups received GS (40 mg/kg body weight/day) and KRG-WE (200 mg/kg body weight/
day), respectively, for 4 months. The number of cells, Sertoli cell index, Johnsen’s score, and sex hormone levels decreased
significantly with age. However, the administration of KRG-WE and GS markedly improved the number of germ cells,
seminiferous tubular size, and Johnsen’s score in the old rats. Ginseng produced a distinct testicular histological improvement
in old rats. KRG-WE and GS elevated testosterone levels, while attenuating the aberrant increase in follicle stimulating
hormone and luteinizing hormone levels. Sperm kinematics evaluated by a computer-assisted sperm analyzer demonstrated
improvement in the percentage of motile sperm, progressive sperm motility, and curvilinear velocity associated with sperm
quality, supporting the benecial role of red ginseng in senile spermatogenesis. Overall, the total water extract had a more
potent effect than the corresponding saponin fraction. In conclusion, Korean red ginseng rejuvenated age-induced testicular
dysfunction. Additionally, the total water extract was more potent than the corresponding saponin fraction.
Keywords: Red ginseng, Crude saponin, Sperm quality, Spermatogenesis, Aging
This is an Open Access article distributed under the terms of the Cre-
ative Commons Attribution Non-Commercial License (http://creativecom-
mons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial
use, distribution, and reproduction in any medium, provided the original
work is properly cited.
Received 30 Jul. 2010, Revised 26 Nov. 2010, Accepted 29 Nov. 2010
DOI:10.5142/jgr.2010.34.4.327
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J. Ginseng Res. Vol. 34, No. 4, 327-335 (2010)
perfusion [5], reduced Sertoli cell function [6], and in-
creased testicular connective tissue deposition have been
suggested to be age-related changes that might impair
spermatogenesis and reduce feedback from the testes to
the pituitary, resulting in elevated luteinizing hormone
(LH) and follicle stimulating hormone (FSH) levels [7].
Consistent with this, sperm morphology analyses show a
reduced percentage of normal spermatozoa in men older
than 50 years of age.
Drugs used to treat sexual dysfunction include phos-
phodiesterase-5 inhibitors [8], dopamine agonists [9],
synthetic prostaglandins [10], and α‑adrenergic receptor
antagonists [11]. However, these drugs focus primarily
on erectile dysfunction and only temporarily improve
that symptom. Additionally, they are accompanied by
side effects, including headache, flushing, dyspepsia,
nasal congestion, and impaired vision. Rare, but serious,
adverse effects found through post-marketing surveil-
lance include priapism, severe hypotension, myocardial
infarction, ventricular arrhythmias, stroke, increased
intraocular pressure, and sudden hearing loss [12]. Con-
sequently, agents with fewer side effects that improve
sexual function are desirable.
Korean red ginseng (KRG) has been taken orally to
improve physical strength by people in East Asia for more
than 2,000 years. Studies have shown that KRG helps
prevent diabetes mellitus [13], atherosclerosis [14], erec-
tile dysfunction [15], immune dysfunction [16], carci-
nogenesis [17], and physicochemical stress [18] among
other disorders. Additionally, we reported that the ad-
ministration of KRG water extract (KRG-WE) protects
testicular function [19], and improves sperm survival
rate and quality in guinea pigs exposed to 2,3,7,8-tet-
rachlorodibenzo-p-dioxin [20]. KRG is used for many
reasons, including its reasonable price, ready availabil-
ity, and safety. In light of its long history of use and the
results of modern scientific research, Korean ginseng
appears to alleviate testicular dysfunction, including
erectile dysfunction and stress-induced sexual dysfunc-
tion. However, no attempt has been made to examine the
effects of Korean ginseng on age-related testicular dys-
function, or to compare the efcacy of the whole extract
and crude saponin, which is the main active ingredient
of Panax ginseng. Thus, we examined the benets of KRG
in age-induced testicular dysfunction.
MATERIALS AND METHODS
Materials
Six-year-old KRG-WE was procured from a local KRG
distributor. The crude ginseng saponin (GS) was pre-
pared as reported previously [21]. Briey, 1 kg of KRG‑
WE was diluted in distilled water to make a 10% solu-
tion and passed through a glass column (5 L) containing
Diaion HP-20 resin (3.5 L; Mitsubishi Chemical, Tokyo,
Japan). The resin was subsequently washed with four
bed volumes of distilled water. The crude GS fraction
was obtained by eluting the water-washed resin with
absolute ethanol. The ethanol eluate was dried in vacuo
to obtain a dark brown powder (350 g). The ginsenoside
contents of the ginseng preparations were determined as
described in ‘European pharmacopoeia (supplement 5.1
to the 5th edition)’ with slight modications. Briey, the
ginsenosides were analyzed using reverse phase HPLC
with an ultraviolet detector using the following gradient
of acetonitrile (CH3CN) and water: 0 min, 20% CH3CN;
40 min, 35% CH3CN; 52 min, 45% CH3CN; 62 min,
70% CH3CN; and 80 min, 100% CH3CN. The standard
reference ginsenosides Rb1, Rb2, Rc, Rd, Re, Rf, Rg1,
Rg2(S), Rg2(R), Rg3(S), Rg3(R), and Rh1 were isolated
by our laboratory. Identication and purity tests were car-
ried out as described in ‘Herbal medicinal products’ [22].
Experimental animals
Eighteen 12-month-old (750±20 g) and six 2-month-
old (280±10 g) male Sprague-Dawley rats were pur-
chased from Hanil Experimental Animal Breeding
(Yeumsung, Korea) and acclimatized to the facility for
at least 1 week before the experiment. They were fed a
standard pellet diet and water ad libitum and kept at a
constant temperature (23±2°C) and relative humidity
(55±10%) on a 12/12-h light/dark cycle.
The rats were maintained in the Regional Innovation
Center Experimental Animal facility in accordance with
the Institutional Animal Care and Use Committee guide-
lines of Konkuk University. The study was approved by the
Animal Ethics Committee in accordance with the 14th
article of the Korean Animal Protection Law.
The rats were divided into four groups of six rats each:
the young (YC) and old control (OC) groups received
vehicle only; the GS and KRG-WE groups received the
crude ginseng saponin fraction and Korean red ginseng
water extract for 4 months at daily doses of 40 mg/kg
body weight and 200 mg/kg body weight, respectively.
The GS and KRG-WE were mixed evenly with steril-
ized standard diet and administrated orally after pel-
letization. The appropriate contents of GS and KRG-
WE were controlled by weighing the rats weekly and
the daily dietary intake. At the end of the experiment,
all food was removed for 24 h before sacrice. The rats
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Hwang et al. Panax ginseng Improves Senile Testicular Function in Rats
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were euthanized under general anesthesia with diethyl
ether. Blood samples were collected from the abdominal
vein for blood chemistry panels and sex hormone level
analysis. The liver, kidney, spleen, epididymides, and
testes were isolated and weighed after removing any ad-
hering adipose tissue.
Blood chemistry panels
To measure biochemical parameters, blood was col-
lected in a SST® gel and clot activator tube (Becton
Dickinson, Franklin Lakes, NJ, USA). Serum was sepa-
rated by centrifugation (1,500× g, 10 min, room temper-
ature). An automated chemistry analyzer (Hitachi-747,
Hitachi Medical, Tokyo, Japan) was used to measure
serum levels of aspartate transaminase (AST), alanine
aminotransferase (ALT), alkaline phosphatase (ALP),
γ‑glutamyl transpeptidase (γ‑GTP), albumen (Alb), cal-
cium (Ca), phosphorus (P), blood urea nitrogen (BUN),
and uric acid (UA). Serum testosterone, LH, and FSH
contents were analyzed using a radioimmunoassay kit
(Diagnostic Product Corporation, LA, USA).
Measuring sperm motility
Sperm samples were extracted from the left caudal epi-
didymis by cutting it with scissors; one drop of caudal
uid was immediately placed in a culture dish contain-
ing 5 mL of Hanks’ balanced salt solution prewarmed to
37°C and supplemented with 10 mg/mL bovine serum
albumin (fraction V). After incubation for 5 min at 37°C,
an aliquot of the suspension was collected with a mi-
cropipette and diluted to contain 40±10 sperm under the
defined microscopic field (×100 magnification); then,
10 μL of the suspension were added to a 2X‑CEL slide
(depth, 80 μm; thickness, 0.15 mm; Hamilton Thorne Re-
search, Beverly, MA, USA) that had been prewarmed in
a CO2 incubator (Sanyo, Osaka, Japan) at 37°C. Sperm
motility was recorded using a computer-aided sperm
analyzer (Hamilton Thorne Research) with a ×4 objec-
tive lens and a charge-coupled device camera. At least
200 sperm in each sample were monitored for motility
pattern analysis.
Analysis of spermatogenesis-related parameters
To analyze the stages of spermatogenesis, germinal
cells were divided into three broad morphological cat-
egories according to the developmental process: sper-
matogonia, spermatocytes, and spermatids in the semi-
niferous epithelium. Testes were stained with periodic-
acid Schiff and hematoxylin and examined under a light
microscope for categorization according to the criteria
proposed by Hankinson [23] and developed by Russell
et al. [24]. The Sertoli cell index (SCI, the ratio of the
total number of germinal cells to the total number of
Sertoli cells) was calculated and the numbers of sperm
at different stages of maturation in the seminiferous epi-
thelium were analyzed, as recommended by Russell et
al. [24].
Histomorphological study
The left testis was cut into small pieces (5 mm3) and
fixed in Bouin’s solution (saturated solution of picric
acid, 40% formaldehyde and glacial acetic acid) for his-
topathological study. Fixed testicular tissues were dehy-
drated and embedded in parafn wax using an automatic
tissue processor (Leica ASP300; Leica Microsystems,
Wetzlar, Germany), sectioned to 4‑6 μm thickness with
a microtome (Leica RM2245, Leica Microsystems),
stained with hematoxylin and eosin, and examined using
light microscopy (Olympus CX31; Olympus, Tokyo,
Japan). More than 100 horizontally sectioned seminifer-
ous tubules per group were analyzed to determine the
spermatogenesis-related histology. All seminiferous
tubules in one histological section of the testicular speci-
men were evaluated and scored on a scale of 1 to 10
using Johnsen’s scoring system [25]. Briey, the scoring
is as follows: 10) complete spermatogenesis with many
spermatozoa, determined by head form, and an orga-
nized germinal epithelium of regular thickness, leaving
an open lumen; 9) many spermatozoa present, but with a
disorganized germinal epithelium and marked sloughing
or obliteration of the lumen; 8) only a few spermatozoa
present; 7) no spermatozoa, but many spermatids pres-
ent; 6) no spermatozoa and only a few spermatids pres-
ent; 5) no spermatozoa and no spermatids, but several
or many spermatocytes present; 4) only a few spermato-
cytes (<5), but no spermatids or spermatozoa present; 3)
spermatogonia were the only germ cells present; 2) no
germ cells, but Sertoli cells were present; and 1) no cells
in a tubular section.
Statistical analyses
Results are expressed as the mean±SD. Statistical
analysis was performed using ANOVA followed by
Duncan’s t-test (p<0.05 and p<0.01). Analyses were per-
formed using the SAS ver. 9.1 (SAS Inc., Cary, NC, USA).
RESULTS
Ginsenoside content of the ginseng preparations
The ginsenoside content of the KRG-WE determined
DOI:10.5142/jgr.2010.34.4.327
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J. Ginseng Res. Vol. 34, No. 4, 327-335 (2010)
on a dry weight basis was as follows: Rb1 10.44 mg/g, Rb2
4.61 mg/g, Rc 5.19 mg/g, Rd 3.30 mg/g, Re 3.08 mg/g, Rf
2.63 mg/g, Rg1 1.90 mg/g, Rg2S 3.30 mg/g, Rg2R 2.45 mg/
g, Rg3S 4.19 mg/g, Rg3R 1.84 mg/g, and Rh1 1.40 mg/g.
The amount of each ginsenoside in the GS fraction was ap-
proximately 19 times higher than that in KRG-WE.
Eects on organ weight and blood chemistry panels
As shown in Table 1, the liver, kidney, and spleen
were about twice as heavy in old rats versus young rats
(p<0.01), but no signicant change in testicular weight
was observed. However, the epididymides of old rats
were signicantly lighter than those of young rats. Inter-
estingly, the ginseng treatments increased the epididymis
weights of old rats, particularly the KRG-WE treatment.
The blood chemistry panels worsened with aging, but
there were no significant changes in the Alb, Ca, P, or
UA levels. Liver function marker enzymes (AST, ALT,
ALP, and γ‑GTP) and BUN (a kidney function marker)
were signicantly increased in old rats (p<0.05). Gener-
ally, treatment with ginseng, especially KRG-WE, im-
proved the changes in organ weight and blood chemistry
panels in old rats, particularly epididymides weight and
the AST, ALT, ALP, γ‑GTP, and BUN levels.
Eects on sperm movement parameters
Sperm motility ratios in young and old rats were
84.6±10.0% and 38.5±18.9%, respectively (p<0.05)
(Table 2). The progressive sperm motility ratios were
35.4±1.8% and 12.0±3.6% in young and old rats, respec-
tively (p<0.01). Overall, sperm quality decreased with
increasing age, while the average path velocity, straight
line velocity, and curvilinear velocity (VCL) of old rats
were markedly lower than in young rats (p<0.05-0.01).
However, the parameters associated with sperm motility
were improved signicantly by treatment with ginseng
preparations (p<0.05-0.01). There was no significant
difference in sperm motility-related parameters between
the GS and KRG-WE groups. The linearity, straightness,
and wobbling of swimming sperm were the same in
both young and old rats.
Eects on spermatogenesis-related parameters in
the testis
There was no significant difference in the percent-
age of seminiferous tubules with sperm when compar-
ing young and old rats (Table 3). However, the sperm
counts per tubule, Sertoli cell counts per tubule, SCI,
and seminiferous tubule size were signicantly lowered
in old than young rats. There was no marked difference
in these spermatogenesis-associated parameters between
the GS and KRG-WE groups. Tubular cross-sections of
young rat testis showed the typical arrangement of cells
at different stages (Fig. 1). Spermatogonia and Sertoli
Table 1. Effects of ginseng saponin and Korean red ginseng water extract (KRG-WE) on organ weights and blood chemistry panels
Variable
Group
Young control goup Old control group Ginseng saponin KRG-WE
Organ weight (g)
Liver 6.2±1.7 16.9±3.1†† 17.0±1.6 19.7±2.3
Kidney 1.8±0.2 3.5±0.3†† 3.6±0.3 3.5±0.4
Spleen 0.4±0.2 0.9±0.1†† 1.0±0.1 1.0±0.1
Epididymides 1.8±0.3 1.0±0.2†† 1.2±0.2 1.5±0.2*
Testes 3.5±0.2 3.6±0.2 3.5±0.4 3.4±0.5
Liver and kidney-related blood chemistry
Aspartate aminotransferase (U/L) 138.4±75.1 351.8±72.9242.9±47.2*258.2±61.5*
Alanine aminotransferase (U/L) 89.5±7.1 179.9±37.7163.7±44.4 134.2±48.3
Alkaline phosphatase (U/L) 113.8±12.4 176.3±75.1207.4±60.8 145.6±26.4
γ‑ glutamyl transpeptidase (U/L) 2.2±4.1 7.8±4.52.1±1.4* 1.8±1.1*
Albumin (g/dL) 4.2±0.4 4.1±0.2 3.7±0.4 3.5±0.3*
Calcium (mg/dL) 8.9±0.7 9.7±0.5 9.1±0.4 8.9±0.2*
Phosphorus (mg/dL) 5.1±0.5 5.0±0.6 5.5±0.7 5.2±0.9
Blood urea nitrogen (mg/dL) 10.8±2.4 16.9±0.817.9±10.3 11.9±3.2*
Uric acid (mg/dL) 1.1±0.3 1.3±0.2 1.3±0.6 1.2±0.4
Data are expressed as the mean±SD.
p<0.05, ††p<0.01, compared with the young control group; *p<0.05, **p<0.01, compared with the old control group.
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Hwang et al. Panax ginseng Improves Senile Testicular Function in Rats
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cells rested on the basement membrane, surrounded by a
concentric myobroblast layer similar to that of the hu-
man testis. In particular, the tubules were densely packed
with sperm cells at various stages. In contrast, the tu-
bules of old rats were loosely packed. The number of
fully mature spermatozoa at the center of the tubules was
low, demonstrating late maturation arrest, degeneration
around the tubule, and a decrease in the number of cells
lining the tubular membrane. Sperm number per tubule
in the OC (p<0.05), GS, and KRG-WE groups accounted
for 75.2% (p<0.05), 84.5%, and 98.3% (p<0.05), respec-
tively, compared with the number in the YC group,
demonstrating that KRG-WE increased spermatogenesis
significantly in old rats. The germ cell counts per tu-
bule also increased markedly with KRG-WE treatment
(p<0.05). The marked decrease in seminiferous tubular
size and Johnsen’s score in OC (p<0.05) were signifi-
cantly elevated in the KRG-WE group (p<0.05). Rats in
the GS and KRG-WE groups had denser tubule packing
than those in the OC group (Fig. 1). Additionally, degen-
erated Leydig cells were rejuvenated by treatment with
GS and KRG-WE, and were uniformly scattered within
the interstitium. The rejuvenating effect of KRG-WE on
spermatogenesis in old rats was more potent than the ef-
fect of GS.
Eects on serum sex hormone levels
Serum testosterone was not lowered by aging, but the
FSH and LH levels increased almost two-fold in old rats
(Table 3). KRG‑WE signicantly reduced the abnormal
Table 2. Effects of ginseng saponin and Korean red ginseng water extract (KRG-WE) on sperm movement parameters
Variable
Group
Young control goup Old control group Ginseng saponin KRG-WE
Motility (%) 84.6±10.0 38.5±18.969.3±4.9*73.3±8.0*
Progressive (%) 35.4±1.8 12.0±3.6†† 24.3±1.2** 24.8±2.3**
Average path velocity (um/s) 382.8±45.9 173.9±74.7229.1±69.4 242.2±81.8
Straight line velocity (um/s) 258.7±31.2 129.7±53.5156.2±57.9 154.8±65.8
Curvilinear velocity (um/s) 524.2±84.5 258.8±106.3†† 389.4±93.8 406.4±88.7*
Linearity (%)1) 49.4±0.8 49.3±2.5 42.3±1.5 42.0±1.2
Straightness (%)2) 67.6±2.6 69.7±1.2 65.7±0.5 66.0±1.2
Wobble (%)3) 73.0±1.5 66.8±4.0 58.8±2.7 58.3±1.6
Data are expressed as the mean±SD.
1)VSL/VCL×100; 2)VSL/VAP×100; 3)VAP/VCL×100.
p<0.05, ††p<0.01, compared with the young control group; *p<0.05, **p<0.01, compared with the old control group.
Table 3. Effects of ginseng saponin and Korean red ginseng water extract (KRG-WE) on spermatogenesis and serum sex hormone levels
Variable
Group
Young control goup Old control group Ginseng saponin KRG-WE
Spermatogenesis
% tubules with sperm 83.2±6.3 82.5±9.7 87.4±10.3 93.5±15.5
Sperm counts/tubule 3,632±342 2,730±2873,070±216 3,570±266*
Sertoli cell counts/tubule 25.3±1.3 21.6±3.320.8±2.7 22.8±3.7
Germ cell counts/tubule 505.4±96.4 437.8±96.3 489.5±71.4 544.7±62.5*
Sertoli cell index 32.0±3.3 20.3±2.0†† 23.5±3.0 23.9±2.5
Seminiferous tubule size (μm) 294.6±23.2 246.7±47.4255.5±38.7 279.6±47.3*
Johnsen’s score1) 9.5±0.7 8.9±1.19.1±1.1 9.5±1.4*
Sex hormone level
Testosterone (ng/ml) 5.1±0.6 5.6±1.3 7.3±1.7 8.5±2.1**
Follicle stimulating hormone (mIU/ml) 10.6±2.6 22.6±3.219.5±3.9 15.5±4.7*
Luteinizing hormone (mIU/ml) 12.5±2.0 25.6±3.0†† 21.3±3.6 17.3±2.7*
Data are expressed as the mean±SD.
1)Johnsen’s score was dened as the degree (1–10) of male fertility calculated from testicular biopsy specimens.
p<0.05, ††p<0.01, compared with the young control group; *p<0.05, **p<0.01, compared with the old control group.
DOI:10.5142/jgr.2010.34.4.327
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J. Ginseng Res. Vol. 34, No. 4, 327-335 (2010)
production of FSH and LH in old rats (p<0.05). Interest-
ingly, the testosterone level was increased signicantly
by treatment with the ginseng preparations, particularly
by KRG-WE (p<0.01).
DISCUSSION
The age-related degenerative change that occur in the
testis influences sperm quality, semen volume, sperm
count, sperm motility, morphology and fertility. The
changes are reected by increases of FSH and LH in the
serum, leading to a decline in fertility. These characteris-
tics vary among individuals, and are strongly inuenced
by endogenous or exogenous stress and lifestyle. Age-
related changes in male fertility are different from the
female menopause, which is marked by the cessation of
reproductive capacity connected with a sudden loss in
endocrine function. To date, some drugs derived from
natural products have been reported to improve sexual
dysfunction in males. These drugs include yohimbine
[26], krausianone [27], berberine [28], papaverine [29],
and forskolin [30].
Panax ginseng is one of the oldest and best-known
medicinal plants used to prevent sexual dysfunction.
Ginseng has several pharmacological properties and
potential therapeutic applications, and some studies sug-
gest that the antioxidant and organ protective actions of
ginseng are associated with enhanced nitric oxide (NO)
synthesis in the endothelium of the lung, heart, kidney,
and corpus cavernosum [31]. Enhanced NO synthesis
causes vasodilatation and might be responsible for the
aphrodisiac properties of ginseng. Although many re-
searchers have recognized that Panax ginseng reverses
erectile dysfunction [15,32], few attempts have been
made to determine its effects on age-associated sexual
function. Moreover, no reported trial has compared the
efficacy of the whole KRG-WE and crude GS, which
contains the main active ingredients of ginseng.
Here, we investigated the benecial role of KRG on
organ weight, blood chemistry panels, serum sex hor-
Fig. 1. Cross-sections of seminiferous tubules in the rat testis. All specimens were sectioned at 4 to 6-μm thick with a microtome, stained with
hematoxylin and eosin, and examined using light microscopy (×200 magnication). Scale bar, 45 μm. LY, Leydig cell; ST, Sertoli cell; SG, sper-
matogonium; SC, spermatocyte; SM, spermatid; SP, spermatozoa.
333
Hwang et al. Panax ginseng Improves Senile Testicular Function in Rats
http://ginsengres.org
mone levels, histology, and parameters related to sper-
matogenesis in old rats. Testis weight was not changed
by aging, but epididymis weight was reduced nearly
55% compared with the YC group (Table 1). KRG-WE
increased the weight of the epididymides, but not the
testes (p<0.05). As fully mature sperm cells are recruited
from the seminiferous tubules to the epididymides, and
wait there for ejaculation, the weight of the epididymi-
des reects the rate of sperm cell production. Our data
indicate that ginseng improves the release of spermato-
zoa from spermatogonia in testicular gonocytes.KRG-
WE signicantly decreased AST, γ‑GTP, and BUN lev‑γ‑GTP, and BUN lev‑-GTP, and BUN lev-
els. These results indicate that ginseng plays a benecial
role in liver and kidney function (Table 1). In traditional
Asian medicine, kidney function is believed to be close-
ly related to sexuality. No references demonstrating a
direct relationship between organs other than the kidney
are available. However, it can be deduced that decreases
in the function of the liver and other organs may play
a negative role in general physical condition, including
sexual function.
The age-related declines in sperm motility were sig-
nicantly improved by the GS and KRG‑WE treatments
(p<0.05) (Table 2), to levels equivalent to about 80%
of the YC. Progressiveness and VCL were increased
markedly in the KRG‑WE group compared with the OC
group (p<0.05). Thus, it seems reasonable to conclude
that KRG counteracts the decline of spermatogenesis
caused by aging, resulting in increased total distance of
sperm movement in a unit period and the production of
sufcient spermatozoa to cope with a competitive mat-
ing system. Moreover, KRG-WE was more effective
than crude saponin in improving various parameters
related to spermatogenesis, such as the Johnsen’s score,
seminiferous tubular size, percentage of tubules contain-
ing sperm, sperm count, and germ cell count. KRG-WE
signicantly improved the FSH and LH levels (p<0.05)
(Table 3) and increased testosterone levels in old rats
(p<0.01), consistent with an earlier report [33]. The age-
related decline of Leydig cell steroidogenesis has po-
tential implications for the decline of male fertility, and
high testicular testosterone concentrations are required
to maintain spermatogenesis [34]. Our results indicate
that KRG-WE improves the reduced feedback from the
testes to the pituitary gland with aging, resulting in an
increase in the amount of testosterone secreted from LH-
stimulated Leydig cells. In the histological study, the
degeneration of spermatogonia and Sertoli cells caused
by aging was improved by treatment with KRG-WE (Fig.
1). Spermatogonia and Sertoli cells rested on the basement
membrane, surrounded by a concentric myofibroblast
layer. Additionally, degenerating Leydig cells were reju-
venated by treatment with KRG-WE and were scattered
uniformly within the interstitium.
We postulated that the ginseng saponin fraction would
be more potent than KRG-WE. Surprisingly, our results
demonstrated that KRG-WE was more effective than
GS, which is thought to be the active fraction of KRG-
WE. Ginsenosides may be the main active compounds
in ginseng; nevertheless, the total extract was more po-
tent than the saponin fraction alone. This suggests that
the saponin and non-saponin fractions act in harmony
to achieve their physiological effects. These results pro-
vide evidence that KRG plays a benecial role in sexual
dysfunction induced by aging. Our animal experiment
results suggest that men with oligospermia or astheno-
spermia could benet from taking KRG. However, this
evidence is anecdotal, and a placebo-controlled clinical
experiment should assess this hypothesis. We also dem-
onstrated that KRG improved liver and kidney function,
sperm motility, testosterone levels, and spermatogenesis
in old rats. From these results, together with our previ-
ous reports [19-21], we conclude that KRG effectively
overcomes the testicular dysfunction of aging. These
physiochemical results lead us to propose additional bio-
chemical studies and further development of ginseng for
sexual dysfunction, especially to promote spermatogen-
esis in men.
ACKNOWLEDGEMENTS
This study was supported by the Regional Innovation
Center Program of the Ministry of Commerce, Industry
and Energy through the Bio-Food & Drug Research
Center at Konkuk University, Republic of Korea.
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Pharmacotherapy of erectile dysfunction comprises oral and local application of drugs. Today, Yohimbin is the only drug listed for this indication. Yohimbin acts via central alpha-receptor blockade and showed a significant effect in a recent double blind study compared to placebo. The centrally acting substances Apomorphin and Trazodone were also tested for their potential use with Apomorphin showing promising results. The orally active phosphodiesterase-V inhibitor Sildenafil acts predominantly on the peripheral side; broad clinical studies demonstrated a significant effect of the drugs compared to placebo. For local use, intraurethral (MUSE) and intracavernous applications are available with PGE1 being the drug the most widely used for the moment. Since many different drugs with various modes of action and different modes of application are being developped at the moment, future pharmacological treatments will allow a more refined approach towards an individually adapted regimen.
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The impact of male age on fecundity remains controversial. Here, a large population study was used to investigate the effect of paternal age on time to conception. All couples in the Avon Health district expecting a baby between 1 April 1991 and 31 December 1992 were eligible. Questionnaires completed by both the man and the woman at 18 weeks gestation covered specific fertility factors, e.g. parity, paternity, cohabitation and oral contraception; and non-specific factors, e.g. educational achievement, housing, cigarette smoking, alcohol consumption, obesity. Logistic regression was used to identify factors independently related to conception in ≤6 or ≤12 months. Of 8515 planned pregnancies, 74% were conceived in ≤6 months, 14% in the second 6 months and 12% after more than a year. Nine variables, including the age of the woman, were independently related to time to conception. After adjustment for these, the likelihood of conception within 6 or 12 months was lower in older men. Compared to men <25 years old, the adjusted odds ratios (95% confidence interval) for conception in ≤12 months were 0.62 (0.40, 0.98), 0.50 (0.31, 0.81) and 0.51 (0.31, 0.86) in men aged 30–34, 35–39 and ≥40 years respectively.
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The phosphodiesterase-5 inhibitors (PDE5i) sildenafil, vardenafil, and tadalafil are considered first-line therapy for the treatment of patients with erectile dysfunction (ED). In addition to the classical pro-erectile-effect, clinical findings have suggested that they can also influence vascular tone in pulmonary, coronary and other vascular tissues, as well as improving symptoms associated with benign prostatic hyperplasia. Therefore, considering the hypothetical widespread application of PDE5i, the potential for drug-drug interactions emerges as a relevant factor in determining the safety profile of PDE5i. Review of relevant literature was conducted using data sources from MEDLINE (1998, to June 2007). The use of nitrates remains the only contraindication for all 3 PDE5i. Vardenafil is also not recommended in patients taking type 1A (such as quinidine, or procainamide) or type 3 antiarrhythmics (such as sotalol, or amiodarone) while no other major limitations have been reported for tadalafil and sildenafil. In contrast to previously reported labeling, recent studies have suggested only a precaution, but not contraindication with the concomitant use of alpha-blockers agents. In addition, precaution is also suggested in the presence of potent CYP3A inhibitors, such as azole antifungals, antiretroviral protease inhibitors, or macrolid antibiotics. This is because sildenafil, vardenafil, and tadalafil are metabolized mainly via the CYP3A4 pathway. On the other hand, statins and testosterone seem to have synergic effects with PDE5i on sexual activity.
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To evaluate the hypothesis that endocrine profiles change with aging independently of specific disease states, we examined the age trends of 17 major sex hormones, metabolites, and related serum proteins in 2 large groups of adult males drawn from the Massachusetts Male Aging Study, a population-based cross-sectional survey of men aged 39-70 yr conducted in 1986-89. Group 1 consisted of 415 men who were free of obesity, alcoholism, all prescription medication, prostate problems, and chronic illness (cancer, coronary heart disease, hypertension, diabetes, and ulcer). Group 2 consisted of 1294 men who reported 1 or more of the above conditions. Each age trend was satisfactorily described by a constant percent change per yr between ages 39-70 yr. Free testosterone declined by 1.2%/yr, and albumin-bound testosterone by 1.0%/yr. Sex hormone-binding globulin (SHBG), the major serum carrier of testosterone, increased by 1.2%/yr, with the net effect that total serum testosterone declined more slowly (0.4%/yr) than the free or albumin-bound pools alone. Among the major androgens and metabolites, androstane-3 alpha,17 beta-diol (androstanediol; 0.8%/yr) and androstanediol glucuronide (0.6%/yr) declined less rapidly than free testosterone, while 5 alpha-dihydrotestosterone remained essentially constant between ages 39-70 yr. Androstenedione declined at 1.3%/yr, a rate comparable to that of free testosterone, while the adrenal androgen dehydroepiandrosterone (3.1%/yr) and its sulfate (2.2%/yr) declined 2-3 times more rapidly. The levels of testosterone, SHBG, and several androgen metabolites followed a parallel course in groups 1 and 2, remaining consistently 10-15% lower in group 2 across the age range of the study. Subgroup analyses suggested that obese subjects might be responsible for much of the group difference in androgen level. Serum concentrations of estrogens and cortisol did not change significantly with age or differ between groups. Of the pituitary gonadotropins, FSH increased at 1.9%/yr, LH increased at 1.3%/yr, and PRL declined at 0.4%/yr, with no significant difference between groups 1 and 2.(ABSTRACT TRUNCATED AT 400 WORDS)