2022 Chemical Biology

9(1), 279 LETTERS

Panax ginseng as reproductive medicine in male infertility: with a brief

focus on 'herb-drug' interaction
Pallav Sengupta1,2*, Sulagna Dutta2,3
1Facultyof Medicine, Bioscience and Nursing, MAHSA University, Malaysia. 2School of Medical Sciences, Bharath Institute of Higher
Education and Research (BIHER), India. 3Faculty of Dentistry, MAHSA University, Malaysia
Submitted on: 25-Oct-2021, Accepted and Published on: 03-Jan-2022 Review Article

ABSTRACT

Male infertility is referred to as the lack of ability of the male to impregnate his fertile female partner even after 12 months of unprotected,
frequent sexual contact. It affects anywhere from 9% to 15.8% of the general population. Male infertility can be treated with a variety of
conventional methods, but the effectiveness of these therapies is still under research. Complementary and alternative medicine is frequently
sought by those suffering from infertility issues. In many cases, herbal medicine, for example maca, dang gui, or ginseng are applied to
improve male fertility, libido, and sexual functions. Ginseng comes from the Panax plant's root. Panax ginseng is known to contain
polysaccharides, ginsenosides, glucosides, alkaloids, and phenolic acid, among other chemicals. Ginseng's bioactivity, including antioxidant,
anti-inflammatory, neuroregulation, anti-cancer, anti-diabetic, anti-aging, metabolic, and antithrombotic properties, have been proven in
several research. Ginseng, as a cyclic adenosine monophosphate-responsive element modulator, has been shown in several preclinical
investigations to stimulate spermatogenesis, as well as to improve testicular functions, sperm quality, and motility. It acts as an aphrodisiac
and may influence estrogen and androgen activities. However, the particular mechanism through which Panax ginseng works to improve
male reproductive functions has not been completely revealed yet. The goal of this review is to analyze the current evidence pertaining to
the positive impact of Panax ginseng upon male reproductive functions, with an emphasis on the 'herb-drug' interaction.
Keywords: antioxidant; anti-inflammatory; testosterone; male infertility; Panax ginseng

which were based mostly on surveys from underdeveloped

INTRODUCTION nations, 80 percent of the world's population trusts herbal
Since thousands of years, herbal remedies have been used in therapies.2
medical care. It has sparked intense research interest in the Herbal resources have always piqued the interest of
etiology of many pathological conditions, particularly in Asia, researchers because of their wide range of applications and
South America, and Africa, in the current period of scientific potential as sources of innovative medications. Herbal medicine
revolution. The Western world is likewise turning more receptive is quickly rising in popularity throughout the world.3,4 In India,
to the use of herbal medicine.1 According to WHO estimates, Ayurveda, often known as the “science of life or longevity”,
refers to an ancient medicinal system that, according to some
sources, can be used in conjunction with more modern types of
*Corresponding Author: Dr. Pallav Sengupta, Associate Professor, Physiology Unit
Head of Services (Research), Faculty of Medicine, Biosciences and Nursing, MAHSA therapy. This pharmaceutical method asserts that it is complete
University, Malaysia enough to restore health and ensure a hale long life for the
Email: pallav_cu@yahoo.com individual.4 These medications were observed to be beneficial in
the management of a range of ailments including diabetes,
URN:NBN:sciencein.cbl.2022.v9.279 gastritis, hypertension, and even reproductive issues.1 According
© ScienceIn Publishing ISSN: 2347–9825 to reports from the Middle East, usage of herbal remedies
https://pubs.thesciencein.org/cbl
ameliorate fertility parameters in diabetic infertile men.5,6 Among

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 P. Sengupta & S. Dutta.

the ancient medicinal systems, Chinese traditional medicine A variety of herbal medicines have been reported to be
holds a significant place with various therapeutic options, mainly effective in the treatment and amelioration of male infertility,
the acupuncture, and natural remedies for a variety of ailments.7 most of which are derived from ancient medicinal systems,
In the medical community in the United States, complementary Ayurveda, Chinese Medicine, as well as more contemporary,
and alternative medicines are gaining high acceptances among Western Alternative Medicines.7 Sheng Jing, a herbal mixture of
the general public.8 15 plants, has been shown to be effective in restoring hormone
Male infertility is a disorder whose processes are still unknown levels and improving the quality of sperm in oligozoospermic
in the majority of instances, and the precise diagnosis and therapy men.19 Botanical medicine is also widely used in South Africa for
are currently under investigation. Numerous herbal medicines primary healthcare and reproductive issues.20 Typha capensis
have been found to have the ability to improve male reproductive (love reed), a plant native to southern Africa, demonstrated
health. These herbs include Panax ginseng (PG), Eurycoma antioxidant activity as well as the ability to increase testicular
longifolia (Tongkat Ali), Tribulus terrestris (Gokhru or land steroidogenesis.21, 22
caltrops), Withania somnifera (Aswagandha or the ‘Indian For male infertility therapy, Ayurvedic medicine employs a
ginseng’), Allium cepa (onion), Allium sativum (garlic), Centella combination of herbs. The mostly used herbs include Mucuna
asiatica, Cannabis sativa (marijuana), Capsicum frutescens pruriens (velvet bean), Withania somnifera (Indian ginseng),
(chilli pepper), and Zingiber officinale (ginger).9-13 Their Phyllanthus emblica (Indian gooseberry or amla), Tribulus
effectiveness in treating oligozoospermia, disorders in terrestris (land caltrops), Piper longum (Indian long pepper),
reproductive hormones, erectile dysfunction, etc. have been Terminalia arjuna (Arjuna tree), Glycyrrhiza glabra (licorice),
proved via clinical trials. Polysaccharides, ginsenosides, and Zingiber officinale (ginger).1 To ensure that such therapeutic
glucosides, alkaloids, and phenolic acid are among the chemical combinations are effective, they ought to be thoroughly
components found in Panax ginseng. Ginseng's bioactivity has investigated and verified for their precise actions and
been demonstrated in various studies, including anti- mechanisms before they are used.
inflammatory, antioxidant, neuroregulation, anti-cancer, anti- Herbal constituents have lately been employed in assisted
diabetic, anti-aging, lipid regulatory, and antithrombotic reproduction, including cryopreservation and in vitro fertilization
properties. Ginseng, a cyclic adenosine monophosphate- (IVF) research.23, 24 Preparation of seminal plasma for assisted
responsive element modulator, has been proven to enhance reproduction is the most vital process of sperm preparation for
spermatogenesis as well as improve testicular functions, sperm IVF. Because seminal plasma acts as nutrient and antioxidant
quality, and motility in multiple preclinical studies. It has medium for spermatozoa survival in the body, when they are
aphrodisiac properties and may impact estrogen and androgen exposed to the medium of assisted reproductive technologies,
levels. However, the specific mechanism through which Panax they are stripped of their own antioxidative defense, placing them
ginseng acts as a male fertility enhancer has yet to be fully at a greater risk of OS induction and oxidative damage.14, 23
researched. The purpose of this review is to look at the current Spermatozoa can also be cryopreserved to maintain their fertility
evidence that Panax ginseng improves male reproductive for an extended period of time, but this is associated with
functions, with a focus on the 'herb-drug' interaction. increased ROS production, lipid peroxidation (LPO), as well as
reduced sperm functions.14 Numerous studies were conducted to
HERBS AS REPRODUCTIVE MEDICINE determine whether polyphenol-rich grape pomace extract
‘Infertility’ has been defined as a couple's inability to be (obtained from Vitis vinifera) and crocin, a plant-derived
pregnant even after 12 months of unprotected regular vaginal antioxidant, could improve sperm quality (the principal
intercourse. Infertility is suffered by approximately 8.5 million apocarotenoids of Crocus sativus).23 Because of the antioxidant
couples worldwide, with male factors accounting for almost half capabilities and polyphenol content of grape seed extracts,
of all cases.14 Treatments for infertility mostly include stress bovine sperms treated in the extract demonstrated enhanced
management, hormonal therapy, other pricey drugs, and assisted motility and viability.23, 25 It has also been found that Crocin
reproductive technologies, among other managements. Despite lowers ROS and LPO levels, which correlates with an increase in
the high expense, the success rate is only approximately 10% to cryopreserved sperm viability and motility.26 Bushen Shengjing
30%, depending on the circumstances. As a result, herbal Decoction, a Chinese herbal concoction, was supplied to men
remedies for male infertility are being evaluated for their with azoospermia oligozoospermia for two months prior to ICSI.
efficacy. These therapies offer cost-effectiveness as well as cure It has been demonstrated that the treatment increases sperm
with minimal or no adverse effects.15 concentration, sperm viability, and motility, resulting in
Male infertility bears a multifactorial causatives, that include enhanced fertilization and pregnancy rates.24 Herbal supplements
hormonal imbalance, reproductive tract infections, varicocele, for assisted reproduction, on the other hand, have been the focus
disorders of sexual behavior and many others, while nearly half of more in-depth research.
of the cases of male infertility remain idiopathic.16 Oxidative
stress (OS) may be a common mechanism by which a variety of PANAX GINSENG: CHEMICAL CONSTITUENTS
causative agents can result in male infertility.17 OS occurs when Approximately 200 different compounds are recognized from
reactive oxygen species (ROS) produced in excess overwhelms ginseng to date. Ginsenosides, amino acids, polysaccharides,
the total antioxidant capacity.18

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 P. Sengupta & S. Dutta.

volatile oils, and polyacetylenes are among the compounds found concentration of 28.56 percent, according to a study by Wang et
in the plant.27 al.37
Saponins Amino acids
The total ginsenosides (TGS) are the most important and Ginseng contains 18 amino acids38 among which 14 are
distinctive components of these herbs. TGS can be divided into substantially accumulated: arginine, glutamic acid, glycine,
three types: dammarane-type, ocotillol-type, and oleanane-type aspartic acid, alanine, leucine, serine, lysine, threonine,
oligoglycosides. Dammarane-type oligoglycosides have the phenylalanine, proline, isoleucine, and tyrosine.39 Arginine is the
highest concentrations, while ocotillol-type oligoglycosides have amino acid that is most abundant in the blood. Ginseng has a
the lowest concentration.28 To be more specific, the saponins higher total amino acid content than notoginseng, which makes it
found in ginseng are predominantly of the dammarane type a more complete supplement. There may be a relationship
(which includes the protopanaxadiol-type and protopanaxatriol- between differences in the amounts of different amino acids and
type), ocotillol-type, and oleanane-type. According to current differences in the composition of different areas, harvest periods,
estimates, ginseng has a total saponin concentration of roughly and different portions of the plants.
4%, which varies depending on the species and harvest season as Volatile oil
well as the age of the plant and the section of the plant used in the Aldehydes, sesquiterpenoids, heterocycles, fatty acid esters,
preparation.29 fatty acids, and alkane hydrocarbons are found in the chemical
Polysaccharides composition of ginseng's volatile oil. There are several types of
Polysaccharides, which are a major pharmacodynamically sesquiterpenoids, with n-hexadecanoic acid (32.28%) and
active component in ginseng, have attracted a great deal of study falcarinol (29.64%) being the most numerous.40 Ginseng volatile
in recent years. Generally speaking, ginseng polysaccharides oil contains a significant amount of n-hexadecanoic acid
(GPS) can be separated into two types according to their (32.28%) and falcarinol (29.64%). According to the growth cycle
monosaccharide composition, which are starch-like glucans and and the time of year, the volatile oil concentration of ginseng
pectin, respectively. Dextran and arabinogalactan are examples ranges from 0.081% to 0.223%, depending on the variety.
of glucans that resemble starch (AG). Ginseng pectin is mostly Polyacetylene
made of galactose (Gal), galacturonic acid (GalA), arabinose Polyacetylene is an organic molecule made up of single and
(Ara), and rhamnose (Rham). Ginseng pectin is a natural triple bonds that alternate in the same direction. The term
preservative (Rha).30 Two homogenous ginseng polysaccharide "polyyne" refers to the existence of many alkynes in a single
fractions, GPII and GPIII, have been isolated, with both fractions compound. The total amount of polyacetylene found in ginseng
containing glucose as their primary component.31 Through water are found to be 0.020–0.073%41, with the diacetyl alcohol,
extraction, Zhang et al.32 were able to obtain the entire sugar of triacetyl alcohol, linolenic acid, and acetic acid.42 Reports on the
ginseng, with the predominant component being amyloid dextran polyacetylene chemicals suggest that the polyacetylene content
and a tiny quantity of AG. Pectin is a polysaccharide that contains of ginseng is approximately 0.04%.
a high concentration of GalA. Pectin was divided into distinct Other constituents
domains based on the ratio of Rha to GalA. The Additionally, ginseng has been used to isolate and identify
rhamnogalacturonan I (RG-I) and rhamnogalacturonan II (RG-II) salicylic acid amine, maltol and its glucoside, ten different
domains were the most abundant (RG-II).33 These forms of pectin organic acids types, and glycosides (non-saponin water-soluble),
are rarely found alone; instead, they are frequently seen in in addition to the previously stated compounds. There are over
combination with RG-I, homogalacturonan (HG), and AG twelve alkaloids found in ginseng, comprising spermine,
structures. Sun et al.34 isolated by using alkali saponification in adenosine, and choline, to name a few. Aside from these
conjunction with endo-polygalacturonase hydrolysis, we were components, ginseng has a variety of trace minerals, enzymes as
able to extract a sequence of RG-I and RG-II domains from well as vitamins that benefit health.43
ginseng pectin. Gao et al. identified and purified four types of
acid pectins from ginseng that were rich in RG-I and HG domains
PANAX GINSENG AND MALE FERTILITY
and contained AG side chains as well as a modest quantity of Ginseng, often known as the "King of Herbs," is renowned for
GalA.35 By using fractional purification, Zhang et al.36 were able its power to enhance overall health, comprising cardiovascular,
to obtain four homogeneous, HG-rich pectin fractions. Pectins neurological, and immunological systems. Ginseng is also
with a high concentration of RG-I domains have fewer or no HG recognized for its ability to improve the circulatory, neuronal,
domains, and side chains are made of AG-I and AG-II domains, and immune systems. Moreover, it has been demonstrated to be
either alone or in combination. Pectins with a high concentration an effective aphrodisiac, and it has found widespread use in the
of HG domains frequently exhibit varying degrees of methyl management of sexual disorders and the enhancement of sexual
esterification and acetylation, and the side chain frequently behavior, mostly in traditional Chinese medicines. Carl A Meyer,
contains a minor amount of AG or dextran. The entire content of a Russian botanist, introduced the term 'Panax' to ginseng in
ginseng pectin Ara and Gal, which is rich in AG domains and 1843, arisen from the Greek and means 'all-healing'. PG is a term
often contains few RG-I domains, which may exist as the core that is commonly used to refer to the Asian ginseng.44, 45
domain of the molecule, exceeds 50% of the total content of PG can boost sexual activities and contentment, as indicated
ginseng pectin Ara and Gal. Ginseng has a polysaccharide by research in human and animals. The effects of PG therapy on

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 P. Sengupta & S. Dutta.

libido and copulatory performance, as well as on sexual outcomes.59 The active PG constituent, Ginsenoside Rg1, when
satisfaction, have been documented in these investigations. It also administered at a dose of 10 mg/kg, has been shown to
has the additional effect of improving the quality and quantity of dramatically enhance serum testosterone levels and improve
sperm in both healthy individuals and infertile patients. The copulatory behaviour.54 It has also been demonstrated that several
ginsenosides, which are the primary pharmacological active ginseng species have the ability to stimulate LH secretion
component of PG, are responsible for the majority of its actions.44 through their direct actions on the anterior pituitary gland.60 PG
Panax ginseng and penile erection therapy, according to a clinical trial conducted on 66 patients,
To boost sexual performance, PG is a traditional Chinese significantly boosted the plasma levels of total and free
medicine that can be used in conjunction with a herbal mix or testosterone, as well as the levels of follicle stimulating hormone
consumed on its own.44, 46 Ginseng medication has been shown to (FSH) and LH.61
have favorable benefits on male reproductive functioning in It is believed that dopamine (DA) is responsible for desire,
randomized clinical trials, according to meta-analyses of these acetylcholine (ACh) is responsible for awakening, and the
studies. Via a double-blinded placebo-controlled-study, neurotransmitter gamma-aminobutyric acid (GABA) is
researchers suggested that Ginseng may improve the conditions responsible for eliciting orgasm. A number of ginsenosides,
of erectile dysfunction and increase sexual contentment in 45 notably Rg1, which is unique to the PG, have been demonstrated
male individuals.47 The results of another study, which included to be agonists of the GABA(A) receptor in receptor-ligand
60 males with erectile dysfunction, revealed that twelve weeks of binding studies.62 It appears that PG has direct effects on the
ginseng medication resulted in significant improvements in hypothalamic-pituitary-testicular (HPT) axis, which is involved
erectile functions such as penile hardness, penetration, and in both hormonal and neuronal regulation of male reproduction,
sustained erection.48 In addition, animal studies have indicated according to these studies.
that ginseng mediates relaxation of smooth muscles in the pre- Panax ginseng on semen quality
contracted penile corpus cavernosum of rabbits in vitro and The first published reports on the favourable effects of ginseng
increased intracavernosal pressure in rats in vivo, both of which on spermatogenesis were published in 1977, and they were
have been demonstrated in humans.49, 50 The antioxidant and anti- groundbreaking.63 The findings of the study indicated that
inflammatory properties of ginseng, as per the evidence, are ginseng extracts might promote DNA and protein synthesis in rat
mediated by nitric oxide (NO). In vitro studies have shown that testicles.63 Researchers have discovered that ginseng can increase
ginsenosides, the principal active ingredients of ginseng, can sperm count in humans and animals, and they have conducted
increase the sensitivity of vascular smooth muscle cells to NO by numerous experiments to support this claim.64 In rats, it has been
stimulating the generation of NO in perivascular neurons and demonstrated that ginseng therapy increases the spermatogenic
endothelial cells.19, 51 NO release relaxes smooth muscles leading rate via stimulating the expression of glial cell-derived
to higher blood volume to flow to the erectile units, known as the neurotrophic factor (GDNF) in the Sertoli cells65 and activating
corpus cavernosum. This followed the occurrence of erection.52 the cAMP-responsive element modulator (CREM) in the testis.66
The recognized PG ginsenoside is the ginsenoside Rg1, which GDNF has the potential to operate as a regulator of
operates through non-genomic, glucocorticoid receptor- spermatogonial survival and differentiation67, and it is essential
dependent-pathways to stimulate NO production in endothelial for the maturation of spermatids.68 It has been demonstrated that
cells acting on the blood vessel wall.53 Rg1 treatment to mice at low or absent expression of the CREM protein or mRNA results
a dose of 10 mg/kg, have been shown to greatly increase the NO in a specific arrest of the development of round spermatids, which
released and the amount of cyclic GMP (cGMP) present in corpus may result in male sterility in some cases.69 When
cavernosum.54 oligoastenospermic patients are compared to healthy age-
Panax ginseng and sex drive matched controls, it has been found that PG use had a favorable
Study on murine models have demonstrated that PG has anti- impact on sperm density and motility in the patients.61 It has also
inflammatory properties55 and also enhances sexual behavior. been demonstrated to improve progressive sperm motility in
Treatment with PG at doses ranging from 25–100 mg/kg or patients suffering from asthenospermia.70 To be more specific,
ginsenoside Rg1 (2.5–10 mg/kg) has been demonstrated to the polysaccharide, aqueous, and organic components of PG all
improve copulatory activity patterns in mice who came in contact correlate positively with improved directional sperm motility in
to estrous females, with mounting, penile licking, and humans within 60–120 minutes after administration.71 Some of
intromission all showing a dose-dependent increase.56 these functions may be mediated by the activation of the nitric
Sex drive is coordinated in higher mammals through oxide synthase (NOS) and the production of NO72, which has a
complicated interactions between hormonal and neural significant impact on sperm physiology, boosting capacitation as
constituents. Testosterone is synthesized by the Leydig cells in well as acrosome reactions.73
response to anterior pituitary hormone and luteinizing hormone Panax ginseng and preservation of spermatozoa
control (LH).57 The level of testosterone levels is a critical factor Numerous ginseng species are extremely useful in preserving
in maintaining a proper libido.58 An interesting finding was that ejaculated sperms. There is evidence that incubating ejaculated
a 5% PG dose administered to rat (along with their regular meal) spermatozoa with ginseng extracts dramatically improves sperm
for two months, have shown increased serum testosterone levels, count in comparison to a vehicle-treated control.74 Active
while the same dose administered at 1% PG did not have the same constituent of PG, ginsenoside, Rg1, was observed to significan-

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 P. Sengupta & S. Dutta.

Figure 1. Mechanism of actions of ginsenosides (Rb1, Rg1, and Rg3) on male reproductive functions. AR, androgen receptor; MAPK, mitogen-activated
protein kinase; PI3K/AKT, phosphatidylinositol 3-kinase/AKT; eNOS, endothelial nitric oxide synthase; Bax, Bcl-2-associated X protein; Bcl2, B-cell
lymphoma 2; Cyt-C, cytochrome c; ERK1/2, extracellular signal-regulated protein kinases 1 and 2; GnRH, gonadotropin releasing hormone; FSH, follicle
stimulating hormone; LH, luteinizing hormone.

-tly enhance the post-thawed sperm membrane integrity and dihydrotestosterone (5-DHT), are two of the most important
motility in comparison to untreated freshly thawed spermatozoa androgens, and they mediate their actions via the
at a dose of 50 g/ml (Table 1).75 T This suggests that PG may be androgen receptors (ARs) induced signalling pathways.77
a powerful herbal agent capable of improving the quality of A number of studies were carried out to investigate the effects
cryogen used for sperm preservation and, consequently, of Asian ginseng on testosterone levels in the body.78-81 All of the
improving the outcomes of assisted reproductive technologies. research used Asian ginseng (PG) fruit or root extracts, with the
Panax ginseng and androgens root being referred to as Korean red ginseng, which is a processed
Androgens have key roles in male sexual differentiation, variety of the herb.82
pubertal maturation, spermatogenesis maintenance, and Depending on the hydrophobicity of the ginsenoside, the
gonadotropin regulation.76 Testosterone and its metabolite, 5- molecular target of ginsenosides can be found either at the

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 P. Sengupta & S. Dutta.

cellular membrane or inside the cell.27 The steroidal backbone of Kim et al., P. ginseng contains anti-inflammatory qualities,
most ginsenosides allows them to pass through cell membranes 197655 and it also has the added benefit of enhancing
by diffusion and influence cellular processes by binding to sexual behavior.
particular intracellular target cytosolic proteins and also in Yoshimura A study conducted on mice exposed to estrous
the nucleus. Binding to membrane-associated receptors initiates et al., females found that treatment with P. ginseng at
phosphorylation signaling cascade and the production of second 199856 doses ranging from 25–100 mg/kg or ginsenoside
messengers in the non-genomic route of ginsenoside action. Rg1 (2.5–10 mg/kg) improved copulatory activity
Ginsenosides first bind to intracellular nuclear hormone receptors patterns, with mounting and penile licking all
such the progesterone receptor (PR), glucocorticoid receptor increasing in response to the treatment.
(GR), androgen receptor (AR), mineralocorticoid receptor (MR),
Fahim et A 5% P. ginseng dose administered to rat (along
and estrogen receptor (ER) to activate the genomic pathway.83-85
al., 198259 with their regular meal) for two months, have
shown increased serum testosterone levels, while
Table 1. Studies on the effects of P. ginseng on male fertility. the same dose administered at 1% PG did not have
Study P. ginseng effects of male reproduction the same outcomes
Leung & P. ginseng therapy has been shown to improve Salvati et In a clinical experiment conducted on 66 patients,
Wong, libido, copulatory performance, and sexual al., 199661 it was discovered that using P. ginseng therapy
201344 satisfaction. The majority of these effects are a dramatically increased the plasma levels of total
result of the ginsenosides, which are the principal and free testosterone, as well as the levels of FSH
pharmacologically active component of P. ginseng. and LH. When oligoastenospermic patients are
Hong et P. ginseng was found to be effective in improving compared to healthy age-matched controls, it has
al., 200247 the symptoms of erectile dysfunction and been discovered that the usage of P. ginseng has a
increasing sexual satisfaction in 45 male beneficial effect on sperm density and motility.
participants. Lee et al., P. ginseng can boost sperm count in both humans
Andrade et An experiment involving 60 men with erectile 202064 and animals.
al., 200748 dysfunction indicated that twelve weeks of P. Yang et A study found that P. ginseng therapy increased the
ginseng administration led to significant al., 201165 spermatogenic rate in the Sertoli cells by increasing
improvements in erectile functions such as penile the expression of glial cell-derived neurotrophic
hardness, penetration and the ability to maintain an factor (GDNF) in the cells.
erection for an extended period of time.
Kim et al., After being treated with 50 g/ml ginsenoside, the
Choi et al., In vitro, P. ginseng causes smooth muscle 201375 active ingredient of P. ginseng was found to
199949, relaxation in the pre-contracted penile corpus dramatically improve the membrane integrity and
Cho et al., cavernosum of rabbits, and in vivo, P. ginseng motility of post-thawed spermatozoa in contrast to
201350 causes an increase in intracavernosal pressure in untreated newly thawed spermatozoa at the same
rats, both of which have been proven in humans. dose.
Murphy & By promoting the production of NO in perivascular
Lee, neurons and endothelial cells, the ginsenosides, the
In these reproductive tissues, PG preferentially binds to ER.85
200251, primary active constituents in P. ginseng, have been
In reproductive organs such as the breast, ovary, prostate, and
Leung et shown to improve the sensitivity of smooth muscle
al., 200653 cells in the vascular system to NO. The ginsenoside
uterus, however, ER antagonises ER-mediated actions.86 In vitro
Rg1 is the most widely characterized P. ginseng investigations have consistently shown that PG inhibits apoptosis
ginsenoside, and it acts on the blood vessel wall by potentiating PI3K/Akt signalling through ER upregulation.75,
87
through non-genomic, glucocorticoid receptor- Stress-induced TNF-α-converting enzyme and nuclear factor-
dependent mechanisms to promote NO generation B appear to be suppressed by PG, reducing the generation of
in endothelial cells. reactive oxygen species and preserving cells from apoptosis.88
In testicular tissue from aged and doxorubicin-sensitized
Wang et When administered at a dose of 10 mg/kg, Rg1
Sprague Dawley rats, the mRNAs and protein expressions for sex
al., 201054 therapy in mice has been demonstrated to
hormone receptors (AR, LHR, FSHR) were investigated.
significantly increase the quantity of NO released
Laboratory animal models stressed by intermittent immobility (2
and the amount of cyclic GMP (cGMP) present in
the corpus cavernosum. Ginsenoside Rg1, when hours/day for 8 weeks/6 months) and heat (32oC, 2hour/day for 8
provided at a dose of 10 mg/kg, has been weeks/6 months), had downregulated protein and mRNA
demonstrated to significantly increase serum expression levels. The downregulation of these receptors was
testosterone levels while also improving copulatory significantly reduced after pretreatment with PG.89 A comparable
behavior in rats and mice. experiment with cold-stressed rats was carried out by Wang et al.
at the Center for Disease Prevention and Control in Shenyang
Command, Shenyang, China.54 Ginseng polysaccharides were

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 P. Sengupta & S. Dutta.

found to increase androgen receptor mRNA expression and herbal drug and LPV-r is therefore unlikely to occur in HIV-
testosterone levels. These findings suggest that Panax ginseng is infected individuals who choose to use these agents at the same
vital in maintaining healthy levels of steroid hormone receptors, time as the herbal treatment.100 Another study on rat model
especially androgen receptors, which guarantees that androgens reported that saffron was found to be a potent inducer of the
operate properly. enzymes CYP1A2 and CYP2C11, as well as a potent inhibitor of
CYP3A in a common Chinese concoction (Sailuotong)
PANAX GINSENG: MECHANISM OF ACTION combining PG, Ginkgo biloba (ginkgo), and Crocus sativus
A chemically triterpenoid saponin with a structure that (saffron).101,102
resembles that of steroid hormones, ginsenosides are the active
constituent of ginseng.90, 91 CONCLUSION
Androgens regulate male sexual behavior, reproductive Since ancient times, herbal medicines have been used to treat
growth, and testicular functions. Because ginsenosides are male infertility, and in recent decades, this practice has seen a
structurally similar to steroid hormones, they may be able to resurgence in popularity. In contrast, it appears that the research
stimulate steroid-hormone-receptors in reproductive tissues, into the efficacy of herbal therapy is the result of a rediscovery of
which are involved in the regulation of steroidogenesis, ancient traditional treatments. The information presented in this
gametogenesis, and other gonadal processes. The androgen review supports the diverse pharmacological effects of PG on the
receptor (AR) is expressed at high levels in both the male gonadal quality of sperm and the production of sex hormones, as well as
tissues and the spermatozoa of fertile men92, but both expressions other findings. In order to have a better knowledge of the herbs'
are dramatically reduced in infertile men.93 effects on male fertility, the molecular mechanisms of action of
The fundamental mechanism used by the ginsengs to improve these herbs are described too. The findings of this study suggest
overall sperm activities, including sperm capacitation and that future research ought to focus further on the synergistic
acrosome responses, is by increasing the intracellular levels of benefits of herbal extracts in combination with mainstream
NO in the spermatozoa. Ginsenosides may activate NOS and medications in the management of male infertility. It would also
induce intracellular NO generation by acting as AR agonists. be good to conduct additional research into the usage of herbal
Ginseng may also act as an AR antagonist.73, 94-96 A rodent model components in assisted reproduction. In light of recent
of erectile dysfunction shown that ginseng enhanced NO developments in research, a combination of herbal therapy,
production, which helped to ameliorate the condition.50 standard medical therapy, and lifestyle change may be able to
increase the efficacy of treatment for male infertility.
PANAX GINSENG: HERB-DRUG INTERACTION
In a recent publication, effects of PG on cytochrome P-450 ACKNOWLEDGMENTS
was investigated and the clinical test was performed on healthy Authors declared no conflict of interest.
human volunteers.97 It was demonstrated that consumption of
caffeine, debrisoquine, midazolam, and chlorzoxazone, rendered
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94. T. Furukawa, C.-X. Bai, A. Kaihara, E. Ozaki, T. Kawano, Y. Nakaya, et AUTHORS BIOGRAPHIES
al. Ginsenoside Re, a main phytosterol of Panax ginseng, activates
cardiac potassium channels via a nongenomic pathway of sex hormones. Dr. Pallav Sengupta is the Head of
Mol Pharmacol 2006, 70(6), 1916-1924. Services (Research) and an Associate
95. J. Yu, M. Eto, M. Akishita, A. Kaneko, Y. Ouchi, T. Okabe. Signaling Professor in the School of Medicine,
pathway of nitric oxide production induced by ginsenoside Rb1 in human MAHSA University, Malaysia and had
aortic endothelial cells: a possible involvement of androgen receptor.
served as the Head of Physiology Unit in
Biochem Biophys Res Comm 2007, 353(3), 764-769.
96. A.T.S. Yee, L.T. Chan. Effectiveness of Ginseng in Treating Erectile the Faculty of Medicine, Lincoln
Dysfunction: A Review Paper. Open Access Library Journal 2021, 8(10), University College, Malaysia. He has
1-17. obtained his PhD in Reproductive
97. S. Shi, U. Klotz. Drug interactions with herbal medicines. Clin Endocrinology from the University of Calcutta, India. His key
Pharmacokinet 2012, 51(2), 77-104.
research interests include Infertility and Reproductive Medicine. His
98. T. Lynch, A. Price. The effect of cytochrome P450 metabolism on drug
response, interactions, and adverse effects. Am Fam Physician 2007, research has yielded a substantial number of publications including
76(3), 391-396. several research articles, books and book chapters. He has been listed
99. C.Y. Malati, S.M. Robertson, J.D. Hunt, C. Chairez, R.M. Alfaro, J.A. among the World’s top 2% researchers by Stanford University in
Kovacs, et al. Influence of Panax ginseng on cytochrome P450 (CYP)3A 2020 and 2021
and P-glycoprotein (P-gp) activity in healthy participants. J Clin
Pharmacol 2012, 52(6), 932-939.
100. M.M. Calderón, C.L. Chairez, L.A. Gordon, R.M. Alfaro, J.A. Kovacs, Dr. Sulagna Dutta is the Head of Services
S.R. Penzak. Influence of Panax ginseng on the steady state (Research) and a Senior Lecturer in the
pharmacokinetic profile of lopinavir-ritonavir in healthy volunteers. School of Dentistry, MAHSA University,
Pharmacotherapy 2014, 34(11), 1151-1158. Malaysia. Following her Masters in
101. P. Singh, P.P. Sharma. Medicinal applications of Saffron plant in
Physiology, Dr. Dutta has earned her PhD
Neurological disorders. Chem. Biol. Lett. 2020, 7 (4), 242–246.
102. Y. Zhang, L. Miao, L. Lin, C.Y. Ren, J.X. Liu, Y.M. Cui. Repeated in Immunology from the University of
administration of Sailuotong, a fixed combination of Panax ginseng, Calcutta, India. Her research interests are
Ginkgo biloba, and Crocus sativus extracts for vascular dementia, alters in the realms of Immunology and
CYP450 activities in rats. Phytomedicine 2018, 38, 125-134. Reproductive Physiology. She has published numerous research
articles and book chapters. She has been listed among the World’s
top 2% researchers by Stanford University in 2020 and 2021

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