Improvement of Sexual Behavior in Male Rats via Dietary Supplementation
with Panax ginseng Extract Standardized with Ginsenoside Rg3
Mosaad A. Abdel-Wahhab,
Aziza A. El-Nekeety,
Soher E. Aly,
Won J. Yoon,
Yong T. Kim
Myung H. Park
Korean ginseng (Panax ginseng CA Meyer) is important traditional medicinal
plants whose ginsenosides are generally accepted as serving to improve sexual
functions, such as penile erection. The aim of the current study was to utilize
panax ginseng extract standardized with ginsenoside Rg3 (PGRg3) to improve
the sexual behavior in rats. Male rats were categorized on the basis of seven
consecutive mating pre-tests as Sexually-Active (SA) and Sexually-Inactive (SI);
and stretching-yawning, penile erection, sedation and stereotyped behavior of
the same animals. The results indicated that PGRg3 at three tested doses (50,
150 and 450 mg kg-1 b.wt.) enhanced the copulatory pattern of both
SI and SA rats, ejaculation mechanisms, increase the sexual drive of SI rats.
The two groups of rats, exhibited different behavioral responses to PGRg3. Moreover,
PGRg3 was effective in SA rats at dose as low as 50 mg kg-1 b.wt.
however it was effective in SI rats at the higher doses (150 and 450 mg kg-1
b.wt.). It could be concluded that PGRg3 succeeded to enhance sexual behavior
and has beneficial effects as traditional medicinal herbal plant in male with
to cite this article:
Mosaad A. Abdel-Wahhab, Aziza A. El-Nekeety, Soher E. Aly, Won J. Yoon, Yong T. Kim and Myung H. Park, 2013. Improvement of Sexual Behavior in Male Rats via Dietary Supplementation
with Panax ginseng Extract Standardized with Ginsenoside Rg3. Journal of Medical Sciences, 13: 337-345.
Received: March 23, 2013;
Accepted: April 29, 2013;
Published: June 13, 2013
The sexual dysfunction is a common disease and with an increasing incidence
as a result of the longer lifespan, the increasing prevalence of degenerative
diseases as well as the increase in injuries and stress associated with industrialized
lifestyles. Both medical and surgical treatment modalities are available for
treating sexual dysfunction. Inspite of the availability of conventional medical
treatments, people are still seeking for alternative natural recourses derived
from plants and herbs to improve their sexual life (Rowland
and Tai, 2003). However, the efficiency of these agents in the treatments
of sexual dysfunction in not clear.
In recent years, the use of dietary supplements has been increased dramatically
(Ervin et al., 2004; Noonan
and Noonan, 2006). Supplements are becoming more important and more commonly
used by consumers in their personal healthcare regimens (Marinac
et al., 2007; Timbo et al., 2006).
Numerous products are currently promoted for enhancing erectile function and
sexual performance in men and are marketed with the implied assumption that
they are safe and natural. Yet reports of adulteration for products in this
category abound. Adulterants found in dietary supplements include, but arent
limited to, Active Pharmaceutical Ingredients (APIs) such as the PDE-5 inhibitors
sildenafil (Viagra®), vardenafil (Levitra®), tadalafil
(Cialis®) and, in an attempt to avoid detection, the unapproved
analogues of these drugs (FDA, 2007a-c,
2009; Reepmeyer et al., 2007).
This practice is illegal and places consumers at risk for potentially serious
side effects from these drugs such as abnormal vision, headaches, myalgia, dizziness,
flushing and dyspepsia (Fink et al., 2002; Sunwoo
et al., 2004). Of further concern is that these APIs may interact
with prescription medications such as nitrates, erythromycin and protease inhibitors
(Langtry and Markham, 1999). Interaction between PDE-5
inhibitors and nitrates, for example, can dangerously lower blood pressure.
Patients treated with nitrates for medical conditions often concomitantly suffer
from erectile dysfunction. Due to the potential for life-threatening drug interactions,
these patients may turn to natural products as alternatives
and unknowingly become exposed to pharmaceutical drugs (FDA,
Korean red ginseng is widely used in traditional medicine for the treatment
of many disorders (Goldstein, 1975; Bahrke
and Morgan, 1994). The root or root extract of P. ginseng has been
demonstrated to induce vasodilation (Chen et al.,,
1984), inhibit platelet aggregation (Kimura et al.,
1988; Teng et al., 1989), enhance learning
and memory (Abe et al., 1994), produce anxiolytic
effects (Bhattacharya and Mitra, 1991) and facilitate
male rat copulatory behavior (Kim et al., 1976).
Previous studies have investigated the physiological effects of ginsenoside
saponins, the biologically active constituents of ginseng (Soldati
and Sticher, 1980) and determined that specific ginsenosides can elicit
significant effects on nitric oxide synthesis (Chen and
Lee, 1995), acetylcholine induced catecholamine secretion (Tachikawa
et al., 1995), maternal aggression (Yoshimura
et al., 1988) and glycemic activity (Ng and
Yeung, 1985). Although over 30 different ginsenosides have been identified
overall (Soldati and Sticher, 1980; Tachikawa
et al., 1995), the ginsenoside content between different strains
of ginseng is vastly different (Bahrke and Morgan, 1994),
suggesting that distinct ginseng strains may produce different physiological
effects. The aim of the current study was to utilize Panax ginseng extract
standardized with ginsenoside Rg3 (PGRG3) to improve the sexual behavior in
active and inactive male rats.
MATERIALS AND METHODS
Chemicals and hormones: Ketamine, xylazine (Bayer, Cairo, Egypt) was
freshly dissolved in saline at a concentration that allowed the administration
of 1 mL kg-1, subcutaneously (s.c.) for the females. Estradiol benzoate
and progesterone (Sigma Chemical Co., St. Louis, MO, U.S.A.) were dissolved
in corn oil and both injected S.C. in a volume of 0.2 mL/ female rat.
Ginseng materials: The standarized Panax ginseng extract EFLA400
(Phoenix ginseng) (Batch No. 303298) of Panax ginseng C.A. Mayer was
prepared according to the published procedure (Korean patent 0425022, PCT/KR2003/000003)
and was supplied by Lotte Group R&D Center (Seoul, Korea). The content of
ginsenoside Rg3 (PGRg3), a pharmacologically active ingredient of Phoenix ginseng,
was 3.6 % (w/w) (Panwar et al.,, 2005) as determined
by HPLC (i.e., 36 μg mg-1 P. ginseng extract). PGRG3
was dissolved just before treatment in a certain amount of saline to make 50,
150 and 450 mg mL-1 solutions. The solutions were sterilized by membrane
filtration and administrated orally to the rats at a volume of 1 mL kg-1
Experimental animals: Three months old male and female Sprague-Dawley
rats (140-150g.) were purchased from Animal House Colony, NRC, Giza, Egypt.
The animals were maintained on standard lab diet (Protein: 16.04%; Fat: 3.63%;
Fiber: 4.1% and metabolic energy: 0.012 MJ) and water ad libitum at the
Animal House Lab., National Research Center. After an acclimation period of
2 weeks, animals were maintained on a 12-h light cycle; from 7 am to 7 p.m.
The females were ovariectomized under intraperitoneally injection (i.p.) with
ketamine plus xylazine anesthesia (120±2 mg kg-1 b.wt.) and
were used as mating stimulus in the copulatory experiments. The experimental
protocol was approved by National Research Center Review Committee for the use
of human or animal Subjects.
Behavioral procedure: All the experiments were performed between 9 a.m.
and 2 p.m. in a soundproof, air-conditioned room, where the animals were monitored
by trained observers unaware of the experimental design. Sixty male rats were
divided into four treatment groups and treated orally with only one dose day-1
of PGRg3 for a period of one month as follow: (1) the control group, (2) the
group treated orally with PGRg3 at low dose (50 mg kg-1 b.wt), (3)
the group treated orally with PGRg3 at medium dose (150 mg kg-1 b.wt.)
and (4) the group treated orally with PGRg3 at high dose (450 mg kg-1
Evaluation of male sexual behavior: Evaluation of male sexual behavior
was carried out using the ovariectomized females which were brought into estrus
by subcutaneously (s.c.) injection with 30 μg estradiol benzoate and after
48 h they were injected with 0.5 mg progesterone and were used 4-5 h thereafter.
All females were screened with non-experimental sexually experienced males and
only those exhibiting good sexual receptivity (solicitation behavior and lordosis
in response to mounting) and no rejection behavior were used. The males were
transferred singly to an observation cage (40x30x34 cm) and after a 3-min adaptation
period, a receptive female were introduced. Male copulatory behavior was evaluated
according to the method described by Dewsbury (1972)
by calculating the (1) The time from the introduction of the female until the
first mount and intromission [mount latency and intromission latency (ML and
IL)], (2) The number of mounts and intromissions preceding ejaculation [mount
and intromission frequency (MF and IF)], (3) The interval between the first
intromission and ejaculation [ejaculation latency (EL)] and (4) The time between
the first ejaculation and the next intromission [post-ejaculatory interval (PEI)].
After the PEI, the test was considered complete.
Tests were discontinued when IL or PEI was >15 min or EL was>30 min.
Only those animals which were completed at least the last five or four mating
tests out of the seven conducted at 4-day intervals were considered Sexually
Active (SA) (n = 28). Whereas, those which never mounted or intromitted during
the training tests were considered Sexually Inactive (SI) (n = 25). Animals
which were displayed discontinuous activity were discarded (n = 7). In addition,
the following parameters were evaluated in the 6 and 7th test: (1) Latency to
the first contact (CL) as the time from the introduction of the female on the
opposite side of the cage until the first voluntary contact by the male and
(2) Total time spent in genital exploration by the male (GET), which were recorded
from the introduction of the female until the first ejaculation or the end of
the test in the event of its being discontinued.
Evaluation of sex penile erection (PE), sedation and stereotyped behavior
(SB): Stretching-Yawning (SY) and PE episodes were counted up for each animal.
Sedation and Stereotyped Behavior (SB) were scored as described by Ferrari
and Giuliani (1993). In brief, every 5 min, starting immediately in the
test period (30 min), each rat was observed for 30 sec sedation was graded:
0 = absent, 1 = immobility of the animal for at least 25 sec with open eyes,
2 = immobility of the animal for at least 25 sec with closed eyes. SB was graded:
0 = absent, 1 = low (intermittent or continuous sniffing), 2 = high (continuous
sniffing and/or intermittent or continuous licking and biting). Sedation and
SB values were represented for each rat by the sum of all the scores attributed
to the animal during the test period.
Experimental protocol: After having verified the consistency of the
SA rats copulatory behavior in the 6 and 7th tests, twenty four animals from
the selected SA rats were divided into four groups (6 rats/ group; not statistically
different for any of the parameters considered), which were orally received
saline, PGRg3 at 50, 150 and 450 mg kg-1 b.wt. Another twenty four
of the selected SI rats were randomly divided into four groups and were treated
orally as previously described. SA and SI rats were transferred in groups of
three homogeneous as regards treatment and sexual typology to the glass observation
cages which they were accustomed singly. The tests (Experiment 1) were started
immediately after the oral treatment with PGRg3 and were lasted 30 min. During
this period, SY, PE, sedation and SB were evaluated for each rat. Immediately
after the completion of the recording of the above behavioral parameters, the
second experiment was started and the male rats were placed singly in other
cages where their sexual behavior towards a receptive female, presented 3 min
later, were observed.
Statistical analysis: All data were subjected to statistical analyses
using the General Linear Models (GLM) Procedure of the Statistical Analysis
System (SAS, 1982). The significance of the differences
among treatment groups with variable means was determined by Waller-Duncan k-ratio
T test (Waller and Duncan, 1969). All statements of
significance were based on a probability level of p< 0.05.
Experiment 1: The effects of oral administration of PGRg3 (50, 150 and
450 mg kg-1) on SY, PE, sedation and SB are depicted in (Fig.
1, 2, 3 and 4), respectively.
These results indicated that SY episodes of the control animals in SA and SI
groups were sporadic during the test period and did not differ significantly.
Treatment with PGRg3 at 50 mg kg-1 b.wt. stimulated SY in all rats
however, no significant difference was observed between the two types of animal.
On the other hand, at 150 or 450 mg kg-1 b.wt., PGRg3 showed to be
effective in SA rats, whereas, SI animals received PGRg3 at 450 mg kg-1
showed a significant increase in SY compared to those of control SI (Fig.
The current results also indicated that PE was similar in the control SA and
SI animals (Fig. 2). However, stimulation of PE was apparent
after PGRg3 treatment at all doses only for SI animals in dose dependent fashion
||Stretching-Yawning (SY) in SI and SA rats treated orally with
PGRg3 extract (n)
||Penile Erection (PE) in SI and SA rats treated orally with
PGRg3 extract (n)
On the other hand, both SA and SI rats displayed significant increased sedation
after PGRg3 treatment (Fig. 3). The comparative analysis between
SI and SA rat sedation observed in the control animals and after the oral administration
of PGRg3 at the three tested doses showed that sedation was significantly different
in the two types of animal. Moreover, the sedation was found to be increased
in SI and SA rats in a dose dependent manner although this increase was pronounced
in the SI than the SA animals. A similar degree of SB was also scored in SI
and SA rats only after PGRg3 administration (Fig. 4).
Experiment 2: Data presented in Table 1 revealed
that all SI rats scored a higher CL (185 ±75) compared to those values
for SA rats (4.3±0.9) in the 7th test. On the other hand, in the 8th
test, oral treatment with PGRg3 at the three tested doses (50, 150, 450 mg kg-1
b.wt.) resulted in significant decreases in both CL (175±62, 130±22,
90±12, respectively) and GET (50±2.1, 42±3.9, 30±0.9,
respectively) for SI animals.
||Sedation in SI and SA rats treated orally with PGRg3 extract
||Stereotyped Behavior (SB) in SI and SA rats treated orally
with PGRg3 extract (score)
||Effect of oral treatment with different doses of PGRg3 on
contact latency (CL) and genital exploration (GET) of sexually inactive
(SI) and active (SA) male rats
|Within each column, means superscript with different letters
(a, b, c, d) are significantly different (p = 0.05), CL: Contact latency;
GET: Genital exploration; SA: Sexual active; SI: Sexual inactive
|| Effect of oral treatment with PGRg3 extract on copulatory
behavior of sexually inactive (SI) rats
|Within each column, means superscript with different letters
(a, b, c, d) are significantly different (p = 0.05), ML: mount latency;
IL: Intromission latency, MF: Mount frequency; IF: Intromission frequency;
EL: Ejaculation latency; PEI: Post-ejaculatory interval
|| Effect of oral treatment with PGRg3 extract on copulatory
behavior of sexually active (SA) rats
|Within each column, means superscript with different letters
(a, b, c, d, e) are significantly different (p = 0.05), ML: Mount latency;
IL: Intromission latency, MF: Mount frequency; IF: Intromission frequency,
EL: Ejaculation latency; PEI: Post-ejaculatory interval
This decrease was pronounced in the animals received the higher doses of PGRg3
which indicated that the PGRg3 is effective on SI rats. In SA rats, these parameters
were also affected by the treatment with PGRg3 at the three tested doses and
the recorded CL values were 4.2±0.9, 3.±0.9 and 2.6±0.4
for 50, 150 and 450 mg kg-1 b.wt., respectively. However, the recorded
GET values for the SA rats were 3.8±1.1, 2.1 ±0.2 and 1.6±0.7
for the three tested doses, respectively. It is clear from the data presented
in Table 1 that CL and GET were significantly decreased by
the treatment with PGRg3 in a dose dependent manner which also indicate that
PGRg3 was also effective in SA rats although these effects were pronounced in
SI rats than SA group.
Daa presented in Table 2 showed the effects of PGRg3 on copulatory
behavior in SI rats and indicated that PGRg3 have a significant improvement
in the copulatory behavior in SI rats. The results revealed that these parameters
were decreased significantly in the three tested doses and the recorded values
were 200±12, 170± 22 and 98 ±14, respectively for ML; 260±29,
195±18 and 123±16, respectively for IL; 450±32, 340±26
and 204±45, respectively for EL and 430±25, 340±32 and
201±39, respectively for PEI. Whereas, MF and IF were significantly increased
in this group in the 8th test compared to the same parameters in the same SI
rats in the 7th pre-test and the recorded values for MF in this test were 5±1.6,
8±1.8 and 15±3.4 for the three tested doses respectively. However,
the recorded V of IF were 3±0.8, 5±1.5 and 11±2.5 for the
tested doses, respectively. In the same concern, data presented in Table
3 showed that PGRg3 had a significant improvement on the various parameters
regarding the copulatory behavior for SA rats in a dose dependent manner. The
results also suggested that PGRg3 enhanced libido and copulatory performance
as indicated by the increased of IL (60 ±9, 75±8 and 116±9),
MF (26±6, 32±7 and 46±3), IF (16±1, 19±3
and 22±1) and EL (430±42, 440 ±20 and 460±38) with
the significant decrease in ML (14±2, 10±2 and 8±4) and
PEI (411±35, 405±22 and 317±28) for the three tested doses,
respectively. Moreover, there were significant differences between the data
collected in the 7th per-test and those collected in the 8th test for the same
SA group of rats.
Ginseng is well known herb used for the treatment of sexual dysfunction. Several
studies on laboratory animals have shown that ginseng enhance libido and copulatory
performance. These effects of ginseng may not be due to changes in hormone secretion,
but to the direct effects of ginseng, or its ginsenoside components, on the
central nervous system and gonadal tissues (Kang et
al., 2002; Tsai et al., 2003). Indeed,
there is good evidence that ginsenosides can facilitate penile erection by directly
inducing the vasodilatation and relaxation of penile corpus cavernosum (Hong
et al., 2002). Moreover, the effects of ginseng on the corpus cavernosum
appear to be mediated by the release and/or modification of release of nitric
oxide from endothelial cells and perivascular nerves (Murphy
and Lee, 2002). Treatment with ginseng extract also affects the central
nervous system and has been shown to significantly alter the activity of hypothalamic
catecholamines involved in the facilitation of copulatory behavior and hormone
secretion. The findings that ginseng treatment decreased prolactin secretion
also suggested a direct nitric oxide-mediated effect of ginseng at the level
of the anterior pituitary (Kang et al., 2002).
Thus, animal studies lend growing support for the use of ginseng in the treatment
of sexual dysfunction and provide increasing evidence for a role of nitric oxide
in the mechanism of ginsenoside action.
The present study demonstrated that PGRg3 exerts a sexual stimulation in both
SI and SA rats which seems to involve ejaculation mechanisms and sex-arousal.
It has already been shown that these independent aspects of sexual behavior
are variously modulated by pharmacological agents (Beach,
1956). In the current study, all sexual parameters tested including CL,
GET, which reflect interest towards the female (Ferrari
and Giuliani, 1995) and certain measures of copulatory pattern (mount and
intromission latencies, post ejaculatory interval), which resemble human libido,
were significantly affected by the PGRg3 treatment.
The modulatory effect of PGRg3 on sexual drive was further confirmed in SI
rats by the enhancement effects of the extract to stimulate copulatory behavior,
to modify GET or to reduce CL. Moreover, CL was significantly decreased in these
animals after PGRg3 treatment at the three tested doses although these effects
were pronounced in the groups received the higher doses (i.e 450 mg kg-1
b.wt.), probably as a consequence of the anti-sedative effects exerted by PGRg3
at high doses.
A previous study showed that CL and GET are useful indicators of rat copulatory
activity (Ferrari and Giuliani, 1995). But while it
seems obvious that CL will be different in SA and SI rats, one would hardly
expect a similarly low GET in the two types of rat. However, it has been demonstrated
that, after repeated copulatory training tests, low GET reflects opposite situations
in SI and SA rats, namely, sexual indifference in the former and high sexual
drive culminating in copulation in the latter (Ferrari
and Giuliani, 1995). The second significant finding which emerges from the
current study was that the animals categorized as SA and SI on the basis of
their sexual behavior were also markedly different in their behavioral response
to the same doses of the PGRg3. In the SA rats, treatment with PGRg3 induced
a moderate sedation that was significantly lower than that induced in SI rats.
Moreover, PGRg3 stimulated PE and SY to a great extent. As regards SY, an impressive
effect was seen in SI animals not only at the low dose but also at the high
It is well documented that SY is stimulated by certain receptors including
the dopamine receptors. If SY is evoked by a selective stimulation of a particular
dopamine receptor subtype, namely the DA D2 autoreceptor (Ferrari,
1985) or alternatively the DA D3 receptor (Kostrzewa
and Brus, 1991), it may be hypothesized that this kind of receptor is particularly
sensitive in SI rats. Although, any interpretation regarding the underlying
mechanisms is at present highly speculative, several possibilities can be proposed.
The first possibility is that there are basic, a priori, behavioral and biochemical
differences between the animals classified as SA and SI. The second possibility
is that in SA rats the sensitivity of DA receptors is changed by repeated copulatory
tests because of the release of DA into certain brain area during the copulation
(Damsma et al.,, 1992).
The sexual-stimulant properties of PGRg3 are not surprising, as one of the
major actions of the extract may be the block of the reuptake of dopamine (DA)
and so increase its synaptic availability (Oh et al.,
1997; Nah et al., 2009; Hwang
and Jeong, 2010). The key role of DA in sexual behavior is well documented
(Ferrari and Giuliani, 1995; Lee
et al., 2008). Other mechanisms for the sexual properties enhancement
of the PGRg3 may be involved the improvement of the testicular function and
the increase of testosterone secretion as well as increase the sperm counts
(Kim et al., 1999; Hassan
et al., 2006; Qinna et al., 2009).
In this regards, Hwang et al. (2004) reported
that ginseng improves the survival rate and sperm quality in guinea pigs exposed
to TCDD and stimulates the spermatogenesis (Yamamoto et
al., 1977). This action may be attributed to the increase in LH secretion
which acts directly on the pituitary gland (Tsai et
al., 2003). Furthermore, the current study revealed that treatment with
PGRg3 resulted in a significant decrease in mount and intromission latency (ML
and IL). These results were in agreement with those reported by other investigators
(Murphy et al., 1998). Similar to these findings,
Hong et al. (2002) reported that erectile function
scores were significantly higher in patients treated with Korean red ginseng
than in those who received placebo. Moreover, Wang et
al., (2010) proved that ginsenoside Rg1 from panax ginseng could
be a promising new drug for erectile dysfunction and low libido.
Although, ginsengs exact mechanism of action remains elusive, its physiological
effects are thought to be due to the presence of tetracyclic triterpenoid saponins
known as ginsenosides in the Panax species (Murphy
and Lee, 2002). These ginsenosides appear to have an effect both on the
neurotransmitters involved in sexual arousal and on the NO/cGMP pathways involved
in erection (Park et al., 2006; Lin
et al., 2007). Although there is also a possible impact on the Hypothalamus-Pituitary-Adrenal
(HPA) axis with a corresponding impact on cortisteroid and prolactin levels
(Kim et al., 1976).
The big question is does ginseng live up to its reputation as a male sexual
tonic? From the obtained data, the answer appears to be a qualified yes, but
dosage and length of administration appear to be important (Choi
et al., 1995). In a sixteen week, double-blind study using three
grams of ginseng per day versus a placebo in men suffering from erectile dysfunction,
the ginseng treatment offered significant improvement in erectile quality over
placebo (Hong et al., 2002). Another study also
found a significant improvement over placebo only after several weeks of administration
(Choi et al., 1999). The same study also found
no changes in sexual response after acute, short-term ginseng administration.
Moreover, Shamloul (2010) recommended ginseng as an
It would appear; therefore, that PGRg3 has the potential to be useful as a
sexual enhancer in SA rats at dose as low as 50 mg kg-1 b.wt. However,
in SI rats the dose should be increased to at least 150 mg kg-1 to
induce a significant sexual enhancement. Similar to the current observations
were reported by Ellis and Reddy (2002) and Coleman
et al. (2003) however, they recommended a higher dose reached 1 g
per day for a period of several weeks.
From the current study, we can conclude that PGRg3 succeeded to improve male
sexual behavior in both active and inactive rats. Moreover, these results demonstrated
that PGRg3 significantly facilitates male copulatory behavior and lend growing
support for the use of PGRg3 extract as traditional medicinal in the treatment
of male sexual dysfunction.
This work was full supported by Lotte R and D Center, Lotte Group, Seoul, 150-964,
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