Ginseng and male reproductive function

Abstract

Ginseng is often referred to as the King of all herbs, and is found to be a promising agent to improve general well-being. Ginseng has also been reputed as an aphrodisiac, and is used to treat sexual dysfunction as well as to enhance sexual behavior in traditional Chinese medical practices. Data from animal studies have shown a positive correlation among ginseng, libido, and copulatory performances, and these effects have been confirmed in case-control studies in human. In addition, ginseng is found to improve the sperm quality and count of healthy individuals as well as patients with treatment-related infertility. These actions are mostly attributed to ginsenosides, the major pharmacological active components of ginseng. This review compiles the current knowledge about the multifaceted effects of ginseng on male reproductive function, and also focuses on its mechanisms of action that may represent novel therapeutic strategies for the treatment of male reproductive diseases or disorders.

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REVIEW
Introduction
Infertility is a growing problem in the world. In 2010, an esti-
mated 48.5 million couples worldwide were infertile.1 In approxi-
mately 40% of these couples, the male partner has been either
the sole or a contributing cause of infertility.2,3 Herbal therapy is
increasingly popular worldwide as a way to treat infertility. In the
United States, 17% constantly visited herbal therapist in the past
18 mo out of the 29% of infertile couples who use complementary
and alternative medicine.3 In a clinic-based survey conducted in
Jordan, 44% of infertile patients use herbal medicine as part of
their infertility treatment.4 Among them, 8% went for Chinese
medication.4 In South Australia, 29% of interviewed infertile
subjects use herbal remedies, in which 4.2% uses ginseng.5
Ginseng is one of the most precious herbs in traditional
Chinese medicine. There are at least nine species of ginseng and
are mostly named by their geographical origins, such as Asian
ginseng (Panax ginseng), American ginseng (Panax quinquefo-
lium), and Japanese ginseng (Panax japonicus). The genus name
“Panax” is given to ginseng by the Russian botanist Carl A Meyer
in 1843. “Panax” means “all-healing” in Greek, and Panax gin-
seng is conventionally referred to the Asian ginseng. Ginseng has
been reported to have diverse physiological effects in multiple
systems, including cardiovascular, immune, and neuronal. It has
also been used to enhance sex performance and satisfaction. In
this review, we will summarize the effects of ginseng on male sex
performance and spermatogenesis. Recent evidences on its mech-
anisms of action that may represent novel therapeutic strategies
for the treatment of male reproductive diseases or disorders will
be discussed.
Sex Performance
Erection
Ginseng is commonly taken by itself or with an herbal for-
mula to enhance sexual performance in traditional Chinese
medical practices. The beneficial effects have been scientifically
evaluated and confirmed in meta-analyses of randomized clinical
trials.6 For example, in a double-blind, placebo-controlled study,
45 men with moderate to severe erectile dysfunction had found
improvement in their scores on erectile performance and sexual
satisfaction after treated with three times daily doses of 900 mg
Korean red ginseng for 8 wk.7 A similar study on 60 men with
erectile dysfunction also reported marked improvement in erec-
tile function including rigidity, penetration, and maintenance of
erection after taking Korean red ginseng (1000 mg) three times
daily for 12 wk.8
In animal studies, treatment with Korean red ginseng and
ginseng berry extract has been shown to significantly relax the
pre-contracted penile corpus cavernosum smooth muscles of rab-
bits in vitro, and increase the intracavernosal pressure of rats in
vivo.9,10 Data from studies on ginseng berry extract suggest that
this action is nitric oxide (NO) dependent. The pharmacologi-
cally active components of ginseng, ginsenosides, are known to
be able to induce NO synthesis in endothelial cells and perivascu-
lar nerves, and to augment vascular smooth muscle cell’s sensitiv-
ity to NO.11,12 This release of NO causes smooth muscle to relax,
thus allowing more blood to enter the erectile bodies known as
corpus cavernosum and causing erection.13 Among the ginsen-
osides, Rg1 has been found for NO production in endothelial
cells by glucocorticoid receptor (GR)-dependent, non-genomic
*Correspondence to: Alice ST Wong; Email: awong1@hku.hk
Submitted: 09/04/2013; Accepted: 09/05/2013
http://dx.doi.org/10.4161/spmg.26391
Ginseng and male reproductive function
Kar Wah Leung and Alice ST Wong*
School of Bi ological Sciences; Uni versity of Hong Kong; H ong Kong, PR China
Keywords: ginseng, ginsenosides, sexual behavior, sperm, spermatogenesis, steroid receptor
Abbreviations: ACh, acetylcholine; AR, androgen receptor; cGMP, cyclic guanosine monophosphate; CREM, cAMP-responsive
element modulator; CP, cyclophosphamide; DA, dopamine; ER, estrogen receptor; GABA, gamma-aminobutyric acid; GDNF,
glial cell-derived neurotrophic factor; GR, glucocorticoid receptor;LH, luteinizing hormone; NO, nitric oxide; NOS, nitric oxide
synthase; PR, progesterone receptor; ZEA, zearalenone
Ginseng is often referred to as the King of all herbs, and is
found to be a promising agent to improve general well-being.
Ginseng has also been reputed as an aphrodisiac, and is used
to treat sexual dysfunction as well as to enhance sexual behav-
ior in traditional Chinese medical practices. Data from animal
studies have shown a positive correlation among ginseng,
libido, and copulatory performances, and these effects have
been confirmed in case-control studies in human. In addition,
ginseng is found to improve the sperm quality and count of
healthy individuals as well as patients with treatment-related
infertility. These actions are mostly attributed to ginsenosides,
the major pharmacological active components of ginseng.
This review compiles the current knowledge about the multi-
faceted effects of ginseng on male reproductive function, and
also focuses on its mechanisms of action that may represent
novel therapeutic strategies for the treatment of male repro-
ductive diseases or disorders.

e26391-2 Spermatogenesis Volume 3 Issue 3
mechanisms,14 and administration of Rg1 (10 mg/kg) signifi-
cantly enhances NO release and cyclic GMP (cGMP) accumula-
tion in corpus cavernosum of mice.15
Libido
Studies on rodents reveal that both Asian ginseng (Panax
ginseng)16 and American ginseng (Panax quinquefolium)17 can
facilitate copulatory behavior. Daily treatment of Asian ginseng
(25–100 mg/kg) or ginsenoside Rg1 (2.5–10 mg/kg) demon-
strates a dose-dependent increase in mounting, intromission, and
penis licking in mice which are exposed to estrous females.18 Such
effects are not observed in mice treated with ginsenoside Rb1,
Rb2, and Ro.
Sex drive in higher mammals involves a complex coordina-
tion between the hormonal and neuronal components. The male
sex steroid, testosterone, is synthesized in the Leydig cell under
the control of luteinizing hormone (LH), which is produced by
the anterior pituitary.19 Testosterone levels are strongly correlated
with libido and testosterone is therefore one of the main forms of
prescription given to men with reduced sex drive.20 Interestingly,
rats fed with 5% Panax ginseng in their diet for 60 d have shown
significantly increased blood testosterone levels, whereas treat-
ment with 1% Panax ginseng had no effect.21 Ginsenoside Rg1
(10 mg/kg), the major active constituent in Panax ginseng,
is responsible for the increase of serum testosterone levels and
improvement of copulatory behavior observed.15 Ginsenoside
Rb1 (10 µg/kg), a key ginsenoside found in American ginseng,
is found to increase the secretion of LH by acting directly on
the anterior pituitary gland.22 In a clinical study that involves 66
participants, the use of Asian ginseng extract has been shown to
significantly increase the levels of plasma total and free testos-
terone, follicle stimulating hormone, and LH.23 However, oral
administration of American ginseng (10–100 mg/kg) for 28 d
does not seem to alter testosterone and LH levels in rats,18 sug-
gesting that type of ginseng and treatment duration could make
a difference in the libido-enhancing ability.
Several neurotransmitters have been implicated in libido, such
as dopamine (DA) for desire, acetylcholine (ACh) for arousal,
and (GABA) for orgasm. Ginsenoside Re has been shown to
increase extracellular DA and ACh levels in rat brain.24 The
action of ginsenoside Rb1 on ACh release is associated with an
increase of choline uptake into nerve endings.25 American gin-
seng extracts were shown to modulate GABAgeric neurotrans-
mission in rat brainstem neurons.26 Receptor-ligand binding
assays have demonstrated that ginsenosides Rb1, Rb2, Rc, Re,
Rf, and Rg1 are agonists of GABA(A) receptor, and Rc is also
an agonist for GABA(B) receptor.27 These findings suggest that
ginseng may regulate the pituitary-testis axis at both hormonal
and neuronal levels.
Sperm Production and Quality
Researches over the past 20 y have shown sperm counts
declining in many countries across the world. For instance, a
study on 26000 French males has shown a continuous decrease
in sperm concentration over a 17-y period.28 A 32% reduction is
found when comparing the average sperm level of a 35-y-old man
between 1989 and 2005.28 The reasons are not fully known, but
the reduction in fertility worldwide could indicate a general dete-
rioration of male’s well-being, which is becoming a major health
concern. Thus, there is a need to further understand the causes
and to establish measures to prevent it.
Sperm count and motility
The initial evidence that ginseng may have positive effects on
spermatogenesis was first published in 1977. Here it was demon-
strated that the stimulatory effect of ginseng extracts on DNA
and protein syntheses in rat testes.29 Later studies in both rodents
and humans have shown that ginseng can increase sperm count.
Ginseng-treated rats have demonstrated an increased rate of sper-
matogenesis via glial cell-derived neurotrophic factor (GDNF)
expression elevation in Sertoli cells,30 and activation of testicu-
lar cAMP-responsive element modulator (CR EM).31 GDNF is a
possible regulator of the survival and cell fate decision of undif-
ferentiated spermatogonial cells,32,33 and CREM is essential for
spermatid maturation.34 Men with little or no CREM protein/
mRNA show specific arrest of round spermatids, which could be
a possible cause of infertility.35 Both oligoastenospermic patients
and age-matched healthy counterpart showed an increase in sper-
matozoa density and motility after the use of Panax ginseng.23
Asthenospermia patients treated with ginseng also showed a sig-
nificant increase in progressive sperm motility.36 The aqueous,
organic, and polysaccharide fractions of Panax notoginseng have
been shown to enhance the directional motility of human sperms
in 60–120 min.37 Similarly, ginsenosides Rc and Rb2 (0.01 mg/
ml) have been shown to enhance sperm progression in vitro.38
To pinpoint on specific active components for this action, these
effects are found to be mediated through induction of nitric oxide
synthase (NOS) activities and NO production.39 NO is also
closely related to sperm function. Ginsenoside Re (1–100 µM)
has been shown to facilitate human sperm capacitation and acro-
some reaction through enhancing intracellular NO production.40
Sperm preservation
Ginseng is also found to help preserve the ejaculated sperms.
It has been shown that the sperm count of ejaculated sperms that
were incubated with ginseng extract was significantly higher
than those treated with vehicle.41 Treatment with ginsenoside
Rg1 (50 µg/ml) significantly increases sperm motility and mem-
brane integrity of post-thawed sperms as compared with fresh
and untreated thawed sperms.42 These findings suggest that the
addition of ginseng extract to the cryogen for sperm storage could
en h a nc e fertility.
Effects of Ginseng on Spermatogenesis
During Disease States
It is known that conventional cancer treatments often lead to
various degrees of reproduction impairment, and that these effects
could be either temporary or permanent. Cyclophosphamide
(CP) is an alkylating agent that shows cytostatic effects by form-
ing covalent DNA adducts. Since CP targets rapidly dividing
cells, it is extensively used to suppress tumor malignancy, and
as an immunosuppressant for organ transplantation patients.
However, this drug often leads to gonadal toxicity, and infertility

www.landesbioscience.com Spermatogenesis e26391-3
as a consequence discourages many patients from choosing CP
treatment. It has been shown that intake of American ginseng
(500 mg/kg/day) can protect sperms, in particular by increasing
the sperm count, reducing sperm death and abnormalities, and
resuming sperm motility from CP insult in adult male Wistar
rats as compared with CP treatment alone.43 Furthermore, treat-
ment of protopanazatriol saponin is shown to markedly reduce
the chemotherapeutic agent (busulfan)-induced structural defect
of the testis in mice, suggesting that ginseng may have applica-
tions in the recovery of male infertility after cancer treatments.44
Radiation therapy is sometimes given to patients as part of
the cancer therapy. However, the unselective action of radiation
therapy can also damage normal cells, leading to side effects.
Amifostine (WR-2721) is one of the radioprotectants that is
registered for human use, but its usage leads to many negative
side effects, such as hypertension, nausea, and vomiting.45 This
compound is also cytotoxic to stem spermatogonia, thus limit-
ing its clinical use.46 It is interesting to note that intraperitone-
ally injection of Panax ginseng extract (10 mg/kg) given to adult
male Swiss albino mice for 4 d can protect germ cell popula-
tion and function against γ-radiation, and dramatically reduce
γ-radiation-associated sickness, including anorexia, diarrhea,
weight loss, lethargy, and epilation.47
Zearalenone (ZEA) is an estrogenic mycotoxin that commonly
contaminates the environment as its presence in the crops, which
causes reproductive disorders in farm animals. The consumption
of Korean red ginseng (300 mg/kg) for 4 wk every other day has
been shown to be able to prevent ZEA-induced spermatogenesis
impairment in rats via modulating Fas/Fas-L expression.48
Males with non-insulin-dependent diabetes mellitus (type 2
diabetes) often suffer from sexual dysfunction.49 Studies have
found the benefits of ginseng intake. For example, the admin-
istration of standardized ginseng extract (100 mg/kg) daily for
90 d in streptozotocin-induced diabetic rats has been shown to
result in a significant improvement of fertility parameters and
decrease in testicular pathological signs, such as degenerative
changes of the seminiferous tubules.50 Furthermore, the con-
sumption of Korean red ginseng (30 mg/kg, three times a week
for 1 mo) can help streptozotocin-induced type 2 diabetic male
rats to improve on libido and sexual performance.51 In addition,
ginseng has been shown to be able to stabilize diabetes disease
progression. In a double-blinded, placebo-controlled study, it has
been shown that daily ginseng intake (100 or 200 mg) among
type-2 diabetic patients demonstrated significant reduction in
fasting blood glucose and body weight, and improvement in gly-
cated hemoglobin, serum N-terminal propeptide concentration,
psychological performance, and physical activities.52 Si m i l a rly,
Korean red ginseng has been shown to be able to enhance cGMP
levels of the corpus cavernosum in rats with metabolic syndrome
and may therefore improve erectile function.53
A continuous exposure to environmental toxins is considered
to be a cause of fertility decline. Ginseng has been demonstrated
to have a cytoprotective effects against these toxins, in which
administration of Panax ginseng extract is reported to signifi-
cantly reduce the 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced
pathological and genotoxical damages in rat testes.54 In addition,
treatment of Panax ginseng is found to protect Sertoli cells from
the cytotoxic effects of bisphenol A.55
Mechanisms of Action on Spermatids
Ginsenosides are triterpenoid saponins that structurally
resemble the steroid hormones. Thus, it is tempting to spec-
ulate that the effects of ginsenosides on sexual function and
spermatogenesis are a result of activation of steroid receptors.
Androgens are sex steroids that are essential for the develop-
ment and maintenance of male sexual characteristics, and
regulate normal spermatogenesis. Androgen receptor (AR) is
abundantly expressed in male genital tissues and in spermato-
zoa,56 and its expression is significantly decreased in infertile
men.57 Ginsenoside Rb1 and Re have been reported to be AR
agonists, through which these ginsenosides stimulate NO pro-
duction via the activation of NOS.58,59 Ginseng berry extract
GB0710, of which ginsenoside Re is the key ingredient, could
improve erectile dysfunction in rats by inducing NO produc-
tion.10 Re-induced NO production in sperm has also been
shown to be involved in capacitation and acrosome reaction,
and that these effects could be a result of the non-genomic
activities of the Re-AR interaction.40
Estrogen is another hormone with profound effects on sexual
function of both male and female. Estrogen supplements have
been shown to improve sexual function of testosterone defi-
ciency men.60 In this regard, although estrogen receptor (ER)
α-knockout mice have undisrupted reproductive tract develop-
ment, these mice display less masculine sexual behavior61 and
have a much lower fertility rate.62 Several ginsenosides, including
Rb1, Re, Rg1, Rg3, and Rh1, are agonists of ERα that have been
shown to elicit both receptor-dependent transcriptional and non-
transcriptional estrogenic actions in multiple cell types.58,63-66 In
this regard, ER has been reported on human spermatozoa and
that it is located mainly on the plasma membrane,67-70 suggesting
that ginsenosides may modulate male sexual function through
non-genomic interactions of ER.
Expression of progesterone receptor (PR) was observed on
human sperms, and a strong correlation between PR expres-
sion and sperm function has been demonstrated.71 Intriguingly,
unlike estrogens, progesterone promotes the capacitated sperm
to undergo acrosomal reaction.72,73 In concordance, a handful of
in vitro studies have demonstrated an inhibitory action of pro-
gesterone on estrogens and vice versa. For example, the estro-
gen-induced forward movement of human spermatozoa into the
oviduct could be effectively suppressed by progesterone.74-7 7 In
addition, it was shown that progesterone, which was secreted by
the culumus cells surrounding the oocyte to induce sperm hyper-
activation, was inhibited in the presence of estrogen.78 On the
other hand, estrogen and progesterone may cooperate to opti-
mize their effects on fertilization.79,80 Ginseng extracts contain a
mixture of ginsenosides that can activate either or both ER and/
or PR, and, hence, may modulate different aspects of sperm func-
tion. The ginsenoside Re-induced motility enhancement effect in
spermatozoa could be related to the findings that Re is found to
be both ER and PR agonists.58

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Concluding Remarks and Future Perspectives
Ginseng is a vital constituent of traditional Chinese medi-
cine and has been used to treat various physical conditions for
thousands of years, importantly as an aphrodisiac and is used to
treat sexual dysfunction as well as to enhance sexual behavior
and gonada l functions (Fig. 1). Therefore, use of ginseng appears
to be important for the development of novel therapeutics or to
increase the effectiveness of the current treatment strategies for
male reproductive diseases or disorders. However, its molecu-
lar mechanisms of action remain elusive. Research in this area
should be carried further. A versatile assay for high-throughput
expression profiling will prove useful to reveal the molecular
functions of different ginsenosides and how the different signal
networks are orchestrated. Further evaluations are also needed
to validate some of the medicinal benefits using modern analyt-
ical tools and technology-based analyses. Different approaches
to synthesize and/or modify natural ginsenosides can also be
considered to increase the efficacy/potency, metabolic stability,
and oral bioavailability for clinical applications.
Disclosure of Potential Conflicts of Interest
No potential conf licts of interest were disclosed.
Funding
This work was supported by the Health and Medical
Research Fund 11121191, Hong Kong Jockey Club Charities
Trust (HKJCCT), HKU Strategic Research Theme on
Drug, and Croucher Senior Research Fellowship to Alice ST
Wong.
Figure 1. Summary of the ginseng’s effects on male sexual function.
Ginseng enhances sexual per formance, improves male fertility through
modulating the neuronal and hormonal systems, promotes spermato-
genesis, and acts directly on sperms via steroid receptors. Ginseng also
preserves male fertility during disease states.

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