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Received: 18 September 2019    Revised: 27 November 2019    Accepted: 17 December 2019

DOI: 10.1111/and.13509

INVITED REVIEW

Plants in the management of male infertility

Sunny O. Abarikwu1  | Chigozie Linda Onuah1 | Shio Kumar Singh2

1
Department of Biochemistry, University
of Port Harcourt, Choba, Port Harcourt,
Nigeria
2
Department of Zoology, Banaras Hindu
University, Varanasi, India
Correspondence
Sunny O. Abarikwu, Department of
Biochemistry, University of Port Harcourt,
Choba, P.M.B. 5323 Port Harcourt, Nigeria.
Shio Kumar Singh, Department of Zoology,
Banaras Hindu University, Varanasi, India.
Email: abarikwus@gmail.com;
shioks53@gmail.com
Abstract
This review attempts to collate existing data and provide the perspectives for future
studies on the effects of plants on the male gonads. For many of these medicinal
plants such as Lepidium meyenii, Rupus coreanus, Tribulus terrestres, Panax ginseng,
Petasites japonicas, Apium graveolens, Eurycoma longifólia, Pedalium murex, Corchorus
depressus, Mucuna pruriens, Astragalus membranaceus, Nigella sativa, Crataegus mo-
nogyna, Fagara tessmannii, Phaleria macrocarpa, Anacyclus pyrethrum, Cynomorium
songaricum and Morinda officinalis, the mechanism of actions of their active principles
and crude extracts has been shown in both laboratory animals, in vitro, and human
studies, and includes their antioxidant, anti-inflammatory, spermatogenesis-induc-
ing, aphrodisiac, smooth muscle relaxing and androgenic properties. Several active
chemical leads including glucosinolates, anthocyanins, protodioscin, ginsenosides,
sesquiterpenes, phyto-oestrogens, quassinoids, diosgenin, thymoquinone, proantho-
cyanidins and bajijiasu isolated from these plants are known to have target effects
on the testis, but efforts have been limited in their application at the clinical level.
There still appear to be many more extracts of medicinal plants that have not been
characterised to determine the phytochemicals unique to them that have target ef-
fects on the gonads. Further, collaborative efforts at isolating pro-drug candidates
from medicinal plants for studies at the molecular, cellular and clinical level towards
elucidating their mechanisms of action on the testes are therefore warranted in the
light of the current male fertility crisis.

KEYWORDS

androgens, male infertility, medicinal plants, plant extracts, testis

especially in Africa, the social status of infertile couples is usually stig-

1 |  I NTRO D U C TI O N
The contribution of male factor infertility is now recognised as import-
ant as female factor and in some cases accounts for almost 60% of
all cases of infertility (Abarikwu, 2013; Araoye, 2003). Globally, defi-
cient sperm production is reported as the major source of male fac-
tor contribution to the incidence rate of infertility (Yang et al., 2010).
In the Western countries, sperm counts had decreased at the rate of
1% over the last 5 decades (Yang et al., 2010). The inability to have a
child can be a major life crisis for infertile couples especially when they
are unsuccessful at their many efforts to conceive (Dyer, Abrahams,
Mokoena, & Spuy, 2004). In most parts of the developing countries and
matised. Anecdotal evidence claims that plants are rich in novel chem-
ical entities that could enhance the fertility health of the males and
this has been demonstrated in experimental animal models and in man
(Nantia, Moundipa, Monsees, & Carreau, 2009). Consequently, the use
of botanical medicines among men with infertility cases is common
in most developing countries and with outcomes such as improved
sperm quality, sexual functions, libido and testosterone level being
reported (Agrawal & Kulkarni, 2003; Chen, Xu, & Chen, 1999; Devi,
Laxmi, Charulata, & Rajyalakshmi, 2004; Kolahdooz, Nasri, Modarres,
Kianbakht, & Huseini, 2014; Xu, Yin, Tang, Zhang, & Gosden, 2003).
For this purpose, many plants with aphrodisiac and testicular effects
(e.g. sperm counts, motility, viability) and which play important role in

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© 2020 Blackwell Verlag GmbH     1 of 22
https://doi.org/10.1111/and.13509
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herbal practice and in our social life's have been screened for male fer-
tility effects in most countries of the world and especially in developing
countries, but with limited systematic data available on the molecular
basis of their actions on the gonads.
In most developing countries, infertile couples use both herbal
medicines and contemporary therapies as treatment. Because of the
limited access to orthodox medicines, traditional medicine is often
the first treatment alternative of infertile couples in developing and
underdeveloped countries (Nantia et al., 2009). Consequently, the pa-
tronage of herbal medicines especially in remote areas of developing
and undeveloped countries continues to rise even when the claims of
many of the plants or natural products are without scientific evidence.
Medicinal plants that are used to treat infertility problems are empir-
ically used as extracts, decoctions or partially purified compounds.
These herbal remedies are applied in the treatment of impaired libido,
sexual weakness, erectile dysfunction, ejaculatory disorders and de-
fective sperm production (azoospermia, oligospermia).
For the purpose of this review, scientific literatures were searched
for plants used in herbal medicines to obtain information on their phar-
macological mechanisms that validate their positive effects on male
reproductive health including sexual behaviour, sexual desire, perfor-
mance and fertility. Scientific articles and review papers published on
Google Scholar, Wiley Online Library, PubMed and Scopus from 1996
to 2019 were identified using keywords such as male infertility, plant
extracts and sperm quality, plant extracts and testosterone, medici-
nal plants and androgens, plant extracts and male infertility, medici-
nal plants and incidence of male infertility. Information obtained from
identified published materials was organised according to the plant
part used, observed pharmacological effects on the testis, dosage and
duration of treatment, experimental model (human and rodent) used
to evaluate the potential action of a plant extract and characterised
natural product on the testis (Table 1). It seems that promising bioac-
tive pro-drug candidates isolated from some medicinal plants, for ex-
ample Lepidium meyenii, Rupus coreanus, Tribulus terrestres, Korean red
ginseng (Panax ginseng Meyer), Petasites japonicas, Celery (Apium gra-
veolens), Eurycoma longifólia, Pedalium murex Linn., Corchorus depressus
Linn., Mucuna pruriens Linn, Astragalus membranaceus, Nigella sativa L.,
Crataegus monogyna, Fagara tessmannii, Phaleria macrocarpa, Anacyclus
pyrethrum, Cynomorium songaricum and Morinda officinalis, might form
the basis for further studies at the molecular, cellular and clinical level
for elucidating their mechanisms of action on the testis. The present
study therefore presents a survey of medicinal plants with claims for
the management of male infertility, progress of work done to validate
their traditional believes in fertility management and the deficits of
information that has precluded further studies of the effects of their
active metabolites, if any, on the gonads of animal models and at the
clinical level.
2 |  LE PI D I U M M E Y E N I I
Lepidium meyenii known as maca is a member of the family of the
flowering plants, Brassicaceae. It grows between 4,000 and 4,500 m
above sea level in the Central Andes of Peru (Clément, Diaz Grados,
et al., 2010; Gonzales et al., 2006). The hypocotyls are edible and
are used traditionally in Peru to enhance fertility. There are different
varieties of the hypocotyls characterised by different colours, yel-
low, red and black.
The oral gavage of the aqueous extract of black maca in rats at the
dose of 2 g/kg increased epididymal sperm count at day 1 and much
more following 42 days of treatment, suggesting that the action of
maca was at the epididymal level at the beginning of treatment and
then most beneficial effects on spermatogenesis at the level of the
testis after a longer administration (Gonzales et al., 2006; Gonzales,
Nieto, Rubio, & Gasco, 2006). These effects on spermatogenesis were
less obvious in the testis of rats treated with extracts of yellow and
red maca than in those treated with extract of black maca (Gonzales
et al., 2006). There are studies that have shown that extracts of yellow
maca prevented malathion-induced arrest of spermatogenesis in mice
and that both black and yellow maca extracts blocked high altitude-in-
duced reduction of spermatogenesis and spermiation in rats (Bustos-
Obregon, Yucra, & Gonzales, 2005; Gonzales et al., 2004).
At the clinical level, there were no noticeable differences in
serum hormonal concentrations in healthy men who received 1,500
or 3,000 mg maca gelatinizada both before treatment and after
treatment (Gonzales et al., 2003). The unchanged hormonal profiles
of healthy men consuming maca (1.7  g/day) despite the beneficial
effects on the sperm quality were also confirmed after a 12-week
clinical trial in healthy men (Melnikovova, Fait, Kolarova, Fernandez,
& Milella, 2015), suggesting that maca might directly stimulate
sperm quality already stored in the epididymides of healthy men by
mechanism not related to steroidogenesis. Additionally, several clin-
ical studies have demonstrated that maca increases the number and
the motility of spermatozoa and increases sexual function in humans
(Gonzales et al., 2001, 2002; Lee, Lee, You, & Ha, 2016). In studies
that were done with mammalian experimental models, maca admin-
istration was also found to improve sperm quality and spermato-
genesis (Chung, Rubio, Gonzales, Gasco, & Gonzales, 2005; Gasco,
Aguilar, & Gonzales, 2007; Gonzales et al., 2006, 2004; Gonzales,
Gonzales-Castaneda, & Gasco, 2013; Gonzales, Rubio, Chung,
Gasco, & Villegas, 2003; Sanchez-Salazar & Gonzales, 2018; Yucra,
Gasco, Rubio, Nieto, & Gonzales, 2008; Zhang, Zhou, & Ge, 2019)
and the steroidogenic capacity of rat's Leydig cells (Ohta et al., 2016).
Furthermore, the ejaculate volume, erection, mounting activity,
sperm quality and the number of bulls that had undamaged plasma
membrane acrosome after maca supplementation were increased
after two spermatogenic cycles (Clement, Kneubühler, Urwyler,
Witschi, & Kreuzer, 2010). Semen isolated from maca-treated horses
was found to have better sperm quality and preserved acrosome,
progressive motility and DNA integrity, resulting in more artificial in-
semination doses per ejaculate (Del Prete et al., 2018). The effect on
the stallion semen was thought to be due to the potent antioxidant
effect of maca because of the improvement of the systemic antiox-
idant capacity of stallions after dietary supplementation, although
the antioxidant status of seminal plasma after maca supplementa-
tion has not been confirmed (Del Prete et al., 2018).
TA B L E 1   Plants that can be used as male anti-infertility agents

Name of plant Plant part Animal model Observed effects Dose Duration References

Garcinia kola Seed Albino rats Improves the antioxidant system, increases in 250, 500, 1,000 mg/ 6 weeks Farombi, Adedara, Oyenihi, Ekakitie,
testosterone level kg and Kehinde (2013)
ABARIKWU et al.

Garcinia kola Seed Albino rats Increases in testis weight, mount frequency, number of 200, 400 mg/kg 28 days Ralebona, Sewani-Rusike, and Nkeh-
ejaculation, intromission frequency Chungag (2012)
Ajuga iva Leaf Diabetic albino Increases in testosterone and 17β-oestradiol levels, and 50 mg/kg 3 weeks Hamden et al., (2008)
rats testicular antioxidant capacity
Morinda Leaf Albino mice Increases in testosterone level and improves sperm 160 mg/kg 30 days Wu et al., (2015)
officinalis quality
Pedalium murex Fruit Albino rats Improves sexual performance 50, 100, 150 mg/kg 28 days Sharma, Arya, Bhagour, & Gupta,
(2019)
Corchorus Whole plant Albino rats Aphrodisiac property 100, 200, 400 mg/kg 45 days Kataria et al., (2013)
depressus
Mucuna pruriens Leaf Albino rats Aphrodisiac activity 150, 200, 250 mg/kg 45 days Suresh et al., (2009)
Vitis vinifera Fruit Albino rats Antioxidant properties, improves the gonado-somatic 2.36 g/kg 56 days Pires et al., (2013)
(Grape) index and increases in testosterone level
Petasites Leaf Mice Promotes the proliferation of mouse (spermatogonial 0.1, 1, 10 μg/ml 2 months Kang et al., (2015)
japonicas stem cells) in vitro
Withania Root Infertile men Improves metabolic pathways and energy metabolism 5 g/day 3 months Gupta et al., (2013)
somnifera in semen, improves semen quality and reproductive
hormones
Astragalus Root Mice Improves sperm count and sperm activity 100, 200, 400 mg/kg 28 days Kim et al., (2013)
membranaceus
Ferula harmonis Root Mice Improves sexual behaviour 600 mg/kg 30 min Hadidi, Aburjai, and Battah (2003)
Annona muricata Fruit Albino rats Improves sperm count 5, 10 ml/kg 65 days Ekaluo, Ikpeme, Ibiang, and Omordia
L (2013)
Basella alba Leaf Albino rats Increases in the production of testosterone 1 mg/kg 2 months Nantia et al., (2012)
Fumaria Leaf Albino rats Improves epididymal sperm density 200, 400 mg/kg 70 days Dorostghoal, Seyyednejad,
parviflora Khajehpour, and Jabari (2013)
Psidium guajava Leaf Albino rats Improves sperm motility 250, 500 mg/kg 65 days Ekaluo, Ikpeme, Uno, Umeh, and
Erem (2016)
Kaempferia Whole Albino rats Increases blood flow to the testis, aphrodisiac property, 40 mg/kg 5 weeks Chaturapanich, Chaiyakul,
parviflora plant rhizome   sexual performance 140, 280, 420 mg/kg Verawatnapakul, and Pholpramool
  6 weeks (2008); Lert-Amornpat, Maketon,
and Fungfuang (2017)
Ginkgo biloba Whole plant Wistar rats Improves sperm production 50 mg/kg 40 min before Ahmed, Lasheen, and El-Zawahry
detorsion (2016)
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      3 of 22

(Continues)
TA B L E 1   (Continued)

Name of plant Plant part Animal model Observed effects Dose Duration References
|

Lycium barbarum Fruits Albino rats Improves sperm production 10, 20, 40 mg/kg 62 days Shi et al., (2017)
4 of 22      

Date palm Pollen Albino rats Improves spermatogenesis 150 mg/kg 56 days El-Kashlan, Nooh, Hassan, and Rizk
(2015)
Guibourtia Stem bark Albino rats Induces ejaculation 20 mg/kg 30 s Deeh-Defo et al. (2017)
tessmannii Watcho et al., (2013)
Ionidium Whole plant Albino rats increases in sperm count 250 mg/kg 28 days Chenniappan and Murugan, (2017)
suffruticosum
Black pepper Fruit Mice Increases in testosterone level 25 mg/kg 9 months Kanedi, (2016)
Hygrophila Seed Albino rats increases testosterone level and stimulates Leydig cells 50 mg/kg 28 days Vyas and Raval, (2016)
spinosa T.
Ander
Apium graveolens Leaf Wistar rats Increases in seminiferous tubule diameter, testis volume, 100, 200 mg/kg 30 days Hardani et al., (2015)
number of spermatogonia, primary spermatocytes,
spermatozoa, and spermatids and epididymal weight
Myrciaria dubia, Fruit Holtzman rats Increases spermatogenesis, daily sperm and sperm count 50 mg/day 7 days Gonzales, Vasquez, and Gasco (2013)
camu
Lophira Stem bark Albino rats Increases in sperm number and spermatogenesis 100, 200, 300 mg/kg 7 days Etuk and Muhammad (2009)
lanceolata
Tinospora Whole plant Rams Increases in semen cholesterol and antioxidant 1 g/kg 6 months Jayaganthan et al., (2013)
cordifolia parameters
Tetracarpidium Leaf Albino rats Reduces the oxidative damage of ethanol on the 50, 500, 1,000 mg/kg 21 days Akomolafe, Oboh, Akindahunsi, and
conophorum treated with testis, epididymis, seminal vesicle and prostate gland; Afolayan (2015), Akomolafe, Oboh,
ethanol improves sperm quality Akindahunsi, and Afolayan (2017)
Mucuna pruriens Seed Albino rats Increases in mounting frequency, erections intromission 150, 200, 250 mg/kg 45 days Suresh et al., (2009)
Linn. frequency and ejaculation latency, and decreases
in mounting latency, intromission latency, post-
ejaculatory interval and inter-intromission interval
Glycyrrhiza - Testis culture of Promotes the proliferation of spermatogonia and the 0.2, 2, 20 μmol/L 3 days Wang, Jin, and Jin (2016)
uralensis mouse differentiation of spermatocytes
(Licorice)
Phlegmariurus Aerial parts Wistar rats Stimulates sexual arousal and facilitates sexual 1, 3, 10, 30 mg/kg 30 min Birri, Vallejo, Carro-Juárez, and
saururus execution, induces copulation Agnese (2017)
Huperzia Whole plant Spinal cord Activates fictive ejaculation 3 μg/animal Immediately Birri, Franco, Vallejo, Carro-Juárez,
saururus transected and Agnese (2014)
Albino Wistar
rats
ABARIKWU et al.

(Continues)
TA B L E 1   (Continued)

Name of plant Plant part Animal model Observed effects Dose Duration References

Epimedium Leaf Sprague Dawley Enhances penile erection 300, 1,000, 2 hr after Chen and Chiu, (2006)
Brevicornum rats 3,000, 6,500, administration
ABARIKWU et al.

10,000 μg/0.1 ml
Acanthopanacis Whole plant Human Activates sperm motility 10μg/L 1 and 3 hr Wu, Liu, Yin, and Zhang (2009)
senticosi
Vanda tassellata Flower Swiss albino Increases in nitric oxide in blood and activation of corpus 50 mg/kg 30 min Subramoniam, Gangaprasad,
mice cavernosum nitric oxide synthase Sureshkumar, Radhika, and Arun
(2013)
Chrysactinia Aerial parts Wistar rats Increases in proportion of ejaculation 80, 160, 320 mg/kg 60 min Estrada-Reyes, Ferreyra-Cruz,
mexicana A. Jiménez-Rubio, Hernández-
Gray Hernández, and Martínez-Mota
(2016)
Turnera diffusa Aerial parts Wistar rats Increases in proportion of ejaculation 80 mg/kg 60 min Estrada-Reyes et al., (2016)
Wild
Asparagus Roots Albino rats Increases in sperm count, nitric oxide activity and 100 mg/kg 14 days Thakur et al., (2011)
racemosus improves penile erection
Willd
Curculigo Roots Albino rats Increases in sperm count and nitric oxide activity and 100 mg/kg 14 days Thakur et al., (2011)
orchioides improves penile erection
Dactylorhiza Roots Albino rats Increases in sperm count and nitric oxide activity and 100 mg/kg 14 days Thakur et al., (2011)
hatagirea improves penile erection
Syzygium Flower bud Parkes mice Increases in testosterone level and testicular 15 mg/kg 30 days Mishra and Singh, (2016)
aromaticum hydroxysteroid dehydrogenase and activity, improves
sperm motility, sperm morphology and secretory
activity of epididymis and seminal vesicle
Montanoa Leaf Wistar rats Increases in ejaculatory potency 50 mg/kg Immediate Carro-Juárez, Franco, and Rodríguez-
frutescens observation Peña (2014)
Montanoa Leaf Wistar rats Increases in ejaculatory potency 50 mg/kg Immediate Carro-Juárez et al. (2014)
grandiflora observation
Montanoa Leaf Wistar rats Increases in ejaculatory potency 50 mg/kg Immediate Carro-Juárez et al. (2014)
tomentosa observation
Epimedium Whole plant Albino Wistar Improves erectile function 300, 750 mg/kg 10 days Makarova et al. (2007)
koreanum rats
Casimiroa edulis Seeds Wistar rats Aphrodisiac activity 250 mg/kg 7 days Ali and Rakkah, (2008)
Dracaena Root barks Albino Wistar Aphrodisiac activity and improves erectile function 100, 500 mg/kg 4 weeks Wankeu-Nya et al., (2014)
arborea rats
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(Continues)
TA B L E 1   (Continued)

Name of plant Plant part Animal model Observed effects Dose Duration References
|

Fadogia agrestis Stem Albino rats Increases in testes-body weight ratio, testicular 18 mg/kg 28 days Yakubu, Akanji, and Oladiji (2008)
6 of 22      

cholesterol, sialic acid, glycogen levels and acid

phosphatase, y-glutamyl transferase activities
Massularia Roots Wistar rats Increases mount and intromission frequencies increased 50, 100, 200 mg/kg 30 min Yakubu, Awotunde, Ajiboye, Oladiji,
acuminate male sexual behaviour parameters and prolonged and Akanji (2011)
ejaculatory latency
Satureja Aerial parts Albino Wistar Improves sperm count, sperm viability, fertilisation and 225 mg/kg 45 days Najafi, Farokhi, Jalali, and
khuzestanica rats blastocyst development Akbarizadeh (2016)
Zingiber Root Albino rats Increases in volume of seminiferous tubule, sperm count 50, 100, 150 mg/kg 48 days Bordbar, Esmaeilpour, Dehghani, and
officinale treated with and testosterone level Panjehshahin (2013)
busulfan
Sesamum – Infertile men Improvement of semen parameters (sperm count, motile 0.5 mg/kg 3 months Khani, Bidgoli, Moattar, and Hassani
indicum sperm percentage and normal morphology sperm (2013)
percentage) Uno-Ubarei Uno, Ndifon, Esua, and
Ekaluo (2019)
Salvia Root Rat Increases testicular spermatids, daily sperm production, 5, 50 300 mg/kg 30 days Bansode, Rajendran, and Singh (2015)
haematodes epididymal sperm count, tubular diameter and sexual
behavioural performance
Punica Fruit Albino rats Increases daily sperm production and epididymal sperm 500 mg/kg 35 days Leiva, Rubio, Peralta, and Gonzales
granatum L. treated with number and spermatogenesis (2011)
(pomegranate) lead acetate
Trichopus Leaf Swiss mice Increases in number of mounts and mating performance 200 mg/kg 6 days Subramoniam, Madhavachandran,
zeylanicus Rajasekharan, and Pushpangadan
(1997)
Vanda tessellate Flowers Albino mice Stimulate mounting behaviour, increases in mating 50, 200 mg/kg 1 hr Kumar, Subramoniam, and
performance Pushpangadan (2000)
Turnera diffusa Leaf impotent male Improves copulatory performance and number of rats 1 ml/kg 2 hr Arletti, Benelli, Cavazzuti, Scarpetta,
rats achieving ejaculatory performances and decreases and Bertolini (1999)
mount, intromission and ejaculation latencies, post-
ejaculatory interval and inter-copulatory interval.
Terminala Seeds Rats Increases in sexual vigour, sexual performance and 1.5 g/kg 7 days Ratnasooriya and Dharmasiri, (2000)
catappa ejaculation latency
Myristica Kernel Albino rats Increases in sexual activity, mounting and intromission 500 mg/kg 7 days Tajuddin, Ahmad, Latif, Qasmi, and
fragrans Houtt. frequencies, intromission latency, frequency of Amin (2005)
(nutmeg) erections, quick flips, long flips and the aggregate of
penile reflexes with penile stimulation
Syzygium Flowers Albino rats Increases in mating and intromission frequencies, 500 mg/kg 7 days Tajuddin, Latif & Qasmi, (2004)
aromaticum decreases in the intromission and post-ejaculatory
latencies
ABARIKWU et al.

(Continues)
TA B L E 1   (Continued)

Name of plant Plant part Animal model Observed effects Dose Duration References
ABARIKWU et al.

Dactylorhiza Root Albino rats Stimulates rat libido, mating and ejaculatory frequencies, 200 mg/kg 28 days Thakur and Dixit, (2007)
hatagirea increases in testosterone level and decreases in the
intromission and post-ejaculatory latencies
Ruta chalepensis Leaf Sprague Dawley Increases in the weight of testes, epididymides and the 0.5, 1, 2 g/kg 30 days Al-Qarawi, (2005)
rats testicular index, sperm number, sperm motility and
viability and the levels of testosterone and FSH
Massularia Stem Albino rats Increases in testis weight, serum concentrations of 250, 500, 1,000 mg/ 7 and 21 days Yakubu, Akanji, Oladiji, and Adesokan
acuminate testosterone, LH, FSH and cholesterol kg (2008)
Fadogia agrestis Stem Albino rats Increases in testosterone, mount frequency intromission 18, 50, 100 mg/kg 1, 3, 5 days Yakubu, Akanji, and Oladiji (2005)
(Schweinf. Ex frequency and prolonged ejaculatory latency and
Hiern) reduced mount and intromission latency.
Chlorophytum Root Albino rats Increases in libido, sexual vigour sexual arousal and 125, 250 mg/kg 1, 7, 21, 14, 28, Kenjale, Shah, and Sathaye (2008)
borivilianum sperm count 60 days Das et al., (2016)
Cinnamomum - Lead treated Increases in weight of sexual organs, sperm 30, 250 mg/kg 60 days Elgawish and Abdelrazek, (2014)
zeylanicum albino rats concentration and viability and inhibits oxidative stress
Butea superba Root Albino rats Increases in testis weight and sperm count 250, 1,250 mg/kg 60 days Manosroi, Sanphet, Saowakon, and
Aritajat., S, & Manosroi, J. (2006)
Butea superba Root Sprague Dawley Enhances penile erection 1, 10, 1,000 mg/kg 1 hr Tocharus, Smitasiri, and Jeenapongsa
rats (2006)
Cynomorium Stem and root Wistar rats Increases in spermatogenesis, sperm count, percentage 47 mg/100 g 14 days Abd El-Rahman et al.. (1999)
coccineum of live sperm and motility and decreases in number of
abnormal sperm
Solanum nigrum Leaves Sprague Dawley Improves sperm quality, testis histology, hormonal levels, 100, 300, 500 mg/kg 28 days Adelakun, Ogunlade, Olawuyi, Aniah,
rats testis and epididymis weights, haematology parameters and Omotoso (2018)
Lepidium meyenii Hypocotyl Healthy men Increases sperm concentration and motility 1.75 g/day 12 weeks Melnikovova et al. (2015)
(Maca)
Lepidium meyenii Hypocotyl Holtzman rats Sperm count, daily sperm production 1, 3, 5, 7, 12 days 2 g/kg Gonzales et al. (2006)
(Black Maca)
Pfaffia Roots Sprague Dawley Improves copulatory performance, decreased mount, 0.25, 0.5, 1 ml/kg 1 hr Arletti et al., (1999)
paniculata rats intromission and ejaculation latencies, post-ejaculatory
interval and inter-copulatory interval
Anthocleista Roots Albino rats Increases in spermatogenesis 200 mg/kg 60 days Ezirim, Abarikwu, Uwakwe, and
djalonensis treated with Mgbudom-Okah, Abarikwu,
busulfan Uwakwe and Mgbudom-Okah
(2019)
|

Anthocleista Roots Albino rats Increases in testosterone and follicle-stimulating 200 mg/kg 60 days Ezirim, Abarikwu, and Uwakwe (2019)
djalonensis hormone post-treatment
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8 of 22       ABARIKWU et al.
A group of secondary metabolites known as macamides and ma-
caenes and other lipid-extractable fractions of maca are believed
to directly act on the reproductive tract by affecting the antioxi-
dant–oxidant balance to increase semen quality (Gasco et al., 2007;
Melnikovova, Havlik, Fernandez-Cusimamani, & Milella, 2012; Wang,
Wang, McNeil, & Harvey, 2007). Additional information from studies
with the aqueous extract of L. meyenii established that the action of
maca on the testis of adult rats was due to the stimulation beyond the
androgen receptor by glucosinolates (Bogani et al., 2006; Chung et al.,
2005). The fact that macamides, macaenes and glucosinolates have
been described as responsible for the medicinal effects of maca on the
male gonads cannot be confirmed due to paucity of data (Beharry &
Heinrich, 2018). Although quite a bit is known on the role of gluco-
sinolates in reducing the risk for prostate cancer, further studies on
'macamides' and the glucosinolates that are unique to maca and their
activation of androgen signalling especially on the basis of their differ-
ent structures can be of interest (Chiao et al., 2002; Yu et al., 2013).
3 |  RU B U S CO R E A N U S
Rubus coreanus (Raspberry) popularly called Bokbunja is native to South
Korea (Eu et al., 2008). Ripe R. coreanus is regularly used in Korea for
the manufacturing of wine (Jeon et al., 2008). It is used commonly in
Korea for the treatment of erectile dysfunction, spermatorrhoea, bed-
wetting, asthmatic attack and also allergic diseases (Jeon et al., 2008).
Rubi Fructus is the unripe fruit of R. coreanus and is reported
to contain many important active principles including niga-ichigo-
side F1 and F2, 23-hydroxytormentic acid, 19-α-hydroxyursolic acid,
coreanoside-F1, suavissimoside, polyphenols, gallic acid, 2,3-(S)-
hexahydroxydiphenoyl (HHDP)-d-glucopyranose and sanguine (Oh
et al., 2007).
The use of boiled unripe fruit of R. coreanus on 2-month-old male
Wistar rats for 14 months appears to be nontoxic and enhances sper-
matogenesis and sperm quality (sperm count, sperm motility) through
increased gene and protein expressions of cAMP-responsive element
modulator in the testis (Figure 1) (Oh et al., 2007). In an ex vivo exper-
imental model that was performed using isolated corpus cavernosum
tissue obtained from the penis of the New Zealand white rabbits, it was
observed that fermented reddish-purple R. coreanus was more potent
than the green R. coreanus at relaxing the smooth muscle and arteri-
oles of the corpus cavernosum and increasing the testosterone level
and epididymal sperm counts of the experimental animals (Jeon et al.,
2008). This was thought to be related to the artery-dilatating effect
of the anthocyanin-rich contents in reddish-purple (Jeon et al., 2008).
This appears to act through the up-regulation of the NO-cGMP path-
way in the testis induced by the anthocyanins present in Rubus species
(Jeon et al., 2008).
4 | TR I B U LU S TE R R E S TR I S
Tribulus terrestris, a common weed, found mostly in the tropics are from
the family of Zygophyllaceae. The leaves of T. terrestris are used in the
native Chinese medicine for the treatment of stomach problems, blad-
der stones and male reproductive disorders (Kumari & Singh, 2015).
Fruit extract of T. terrestris increased testis weight and sperm count and
recovered the spermatogenic cycle in mouse (Kumari & Singh, 2015).
The findings of Singh, Nair, and Gupta (2012) validated the herbal use
of T. terrestris in the improvement of sexual functions.
Protodioscin, the most abundant saponin in Tribulus genus, stim-
ulates Sertoli cells and induces the proliferation of germ cells and
the growth of seminiferous tubules by converting testosterone into
dihydrotestosterone through 5-α reductase activity supporting the
use of T. terrestris as male fertility-enhancing agent (Salgado et al.,
2017). At the clinical level, androsten capsule containing 250 mg of
T. terrestris dried extract presented normal semen parameters and
increased free testosterone, dihydrotestosterone and dehydroepi-
androstenedione in men undergoing infertility treatment (Adimoelja
& Adaikan, 1997; Salgado et al., 2017). Similar improvement in sexual
functions and sperm quality parameters has been observed in animal
models including rabbits, aged rats, young rats and rhesus monkeys
treated with T. terrestris extracts (Adaikan, Gauthaman, Prasad, & Ng,
2000; Gauthaman & Ganesan, 2008; Singh et al., 2012). The antioxi-
dative flavonoids present in the extracts were thought to be respon-
sible for the recovery of spermatogenesis in metronidazole-induced
azoospermic experimental model (Kumari & Singh, 2015).
5 | KO R E A N R E D G I N S E N G ( PA N A X
G I N S EN G M E Y E R )
Korean red ginseng is a perennial herb from the family, Araliaceae.
It is traditionally considered as one of the most valuable herbal
F I G U R E 1   Reverse transcription–PCR
analysis of CREM gene expression in
testes of Rubi Fructus (RF)-treated rats.
The left panel shows the expression of
CREM and β-actin mRNA. On the right,
CREM mRNA levels are expressed as
a ratio of those of the control group.
Adapted from Oh et al. (2007) with
permission
ABARIKWU et al.
medicines in Far East Asia because of its many health-promoting
effects. The root of ginseng is traditionally used to boost mental
efficiency, combat weakness, relieve fatigue and normalise body
functions and systems that are compromised by stress (Lee et al.,
2015; Oliynyk & Oh, 2013). Scientific data have also established the
usefulness of Korean ginseng in the boosting of sex hormone levels
of several experimental models (Kopalli et al., 2015).
Korean red ginseng could also improve spermatogenesis and
sperm numbers and restore Leydig and Sertoli cell numbers and the
Sertoli cell index of aged rats (Kopalli et al., 2015). The increased con-
centrations of testicular antioxidants including glutathione, ascorbic
acid and α-tocopherol and the up-regulated expressions of phospha-
tidylinositol transfer protein, fatty acid-binding protein 9 and triose-
phosphate isomerase 1 proteins (Kopalli et al., 2015) were thought
to be responsible for the positive effects of Korean red ginseng on
spermatogenesis in rats. Furthermore, different ginsenosides such
as the dammarane-type triterpene saponin constituents isolated and
characterised from Korean red ginseng roots (Park, 1996; Ramesh et
al., 2012) possess antioxidant effects and exhibit significant effects in
re-establishing the sperm maturation process (Ramesh et al., 2012). It
was therefore proposed that Korean red ginseng could be developed
as a potential therapeutic target against male infertility problems.
6 | PE TA S ITE S JA P O N I CU S
Petasites japonicus known as Japanese butterbur is an herbaceous plant
from the compositae family. The Japanese butterbur is found mainly in
Korea, Japan and Taiwan (Cui, Kim, & Sok, 2005; Kang et al., 2015). In
many European countries, Japanese butterbur is consumed as a food
and used for therapeutic purposes (Cui et al., 2005; Wang et al., 2013).
Petasites japonicus was shown to stimulate spermatogonial stem
cell proliferation and through its antioxidant effects improved the
capacity of the stem cells to colonise recipient mouse testes (Kang
et al., 2015). The presence of sesquiterpenes especially eremophi-
lane-type sesquiterpenoids in extracts of P. japonicus that have an-
tioxidant properties and the fact that no side effects of P. japonicus
have been reported are expected to lead to the development of new
botanicals that might find application in the treatment of male infer-
tility (Kang et al., 2015).
7 | A PI U M G R AV EO LEN S (C E LE RY )
Apium graveolens commonly called celery is a biennial herbaceous
plant of the parsley descent (Umbelliferae). The plant is native to
Europe, but the wild type is found mostly in Algeria, the Caucasus,
Iran, India and America (Kooti et al., 2014).
The aqueous leaf extract of Apium graveolens increased the diam-
eter of the seminiferous tubules and the number of spermatocytes,
spermatogonia and spermatozoids (Hardani, Afzalzadeh, Amirzargar,
Mansouri, & Meamar, 2015). The weight of the testes, cauda epidid-
ymides and vas deferens of rats were also reported to be increased
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by the leaf extract of celery (Hardani et al., 2015). Celery oil was
also reported to increase body and testis weight, sperm motility and
count and the messenger RNA expression of the CYP19 enzyme in
the rat testes (Madkour, 2014).
The leaves and seeds of Apium graveolens are rich in phytochem-
icals and phyto-oestrogens (Sameh, Ibtissem, Mahmoud, Boukef, &
Boughattas, 2011), which could be responsible for the stimulating
effects on testosterone levels and spermatogenesis (Kooti et al.,
2014). However, there is yet no effort at profiling and identifying
the phyto-oestrogens and antioxidant phytochemicals present in the
leaves and seeds of Apium graveolens responsible for their biologic
effects on the testis.
8 | EU RYCO M A LO N G I FO LI A
Eurycoma longifolia Jack commonly called ‘Tongkat Ali’ is a small
Simaroubaceae tree that is native to Malaysia and ‘Pasak Bumi’ in
Indonesia, where it is locally used as a sexual tonic (Low, Das, &
Chan, 2013). The decoction of the roots of ‘Tongkat Ali’ yields a
herbal mixture that is traditionally used to enhance sexual activity
and fertility (Ang & Sim, 1998a, 1998b).
Eurycomanone and related quassinoids in the methanol extract
of E. longifolia were reported to increase sperm count, plasma and
testicular testosterone concentrations of rats compared to the con-
trol and infertile animals (Chan, Low, The, & Das, 2009). Interestingly,
it was only eurycomanone that was found in the rat testis and was
thought to have contributed to the improvement of the animal
sperm quality (Chan et al., 2009). There are also several animal stud-
ies to support the aphrodisiac and testosterone-enhancing proper-
ties of E. longifolia root extract (Ang & Ngai, 2001; Ang & Sim, 1998a,
1998b). Furthermore, clinical trials have provided additional data on
the potential of E. longifolia to improve serum testosterone level and
in the treatment of erectile dysfunction, and appeared to be use-
ful in the management of diseases related to androgen deficiency
(George & Henkel, 2014; Jayusman, Mohamed, Alias, Mohamed, &
Shuid, 2018; Kotirum, Ismail, & Chaiyakunapruk, 2015; Tambi, Imran,
& Henkel, 2012). To understand the androgen secretion-promoting
ability of E. longifolia root extract, it was reported that the euryco-
manone constituent acts at the level of Leydig cells by inhibiting
aromatase-mediated conversion of testosterone to oestrogen (Low,
Choi, Abdul Wahab, Das, & Chan, 2013). There is also the possibil-
ity that phosphodiesterase action is inhibited resulting in high local
level of cAMP needed to drive the steroidogenesis cascade for the
up-regulation of testosterone synthesis (Low et al., 2013). To confirm
this hypothesis, Chan et al. (2009) earlier reported that testosterone
level in the testis of rats receiving methanol extract of E. longifolia
was higher than the level in the plasma compared to the untreated
control animals, suggesting a target effect of E. longifolia on the tes-
tis of experimental animals (Low et al., 2013).
Further studies with animal models have shown that a glycopeptide
with molecular weight of 4.3 kDa found in the aqueous preparation of
E. longifolia was responsible for its aphrodisiac and fertility-enhancing
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10 of 22       ABARIKWU et al.
properties (Asiah, Nurhanan, & Ilham, 2007; Tambi, 2006; Tambi,
Imran, & Henkel, 2012). However, no further studies to identify this
peptide have been reported in the literature. Some authors have
claimed that the quassinoid extract from the root of E. longifolia im-
proves sperm quality and sexual performance and reverses oestro-
gen-induced infertility and increases the fecundity index of male rats
(Wahab, Mokhtar, Halim, & Das, 2010; Zanoli, Zavatti, Montanari, &
Baraldi, 2009). Furthermore, human trial study with 200 mg of pro-
prietary standardised extract of E. longifolia improves the quality of
spermatozoa in men with idiopathic infertility and increases the tes-
tosterone concentration in men with late-onset hypogonadism (Tambi
& Imran, 2010; Tambi et al., 2012). It was assumed that the quassinoids
especially eurycomanone in the standardised extract of E. longifolia
might be responsible for the improved sperm quality and testosterone
and are a potential pro-drug candidate for treating androgen-deficient
idiopathic male sterility (Low et al., 2013; Tambi et al., 2012). Future
research studies that focus on chemical modifications are expected to
generate more active and less toxic quassinoids that might represent
source of promising drug molecules that will target pathways relevant
to spermatogenesis and steroidogenesis.
9 |  PE DA LI U M M U R E X
Pedalium murex Linn is a shrub belonging to the family Pedaliaceae
and found abundantly in the southern part of India, Sri Lanka, some
parts of Ceylon, Mexico and tropical Africa (Patel, Laloo, & Kumar,
2011). It is commonly known as Large Caltrops and Gokhru in India.
Pedalium murex has a long history as an aphrodisiac and mainly used as
a tonic in the traditional Indian medicine (Patel, Kumar, Laloo, Sairam,
& Hemalatha, 2012). The plant is locally used to treat impotency in
men, and spermatorrhoea, gonorrhoea, dysuria, nocturnal emissions
and leucorrhoea in women (Patel et al., 2011). It has the reputation in
the Indian Ayurvedic medicine for improving testosterone concentra-
tion and sexual performance in men (Singh & Gupta, 2011).
Several studies on the ethanolic extract of P. murex showed
that the plant contains diosgenin, a saponin that can be converted
to testosterone and other sex hormones, for example progesterone
and anti-inflammatory steroids, such as cortisone (Norton, 1998;
Raju, Patlolla, Swamy, & Rao, 2004; Sato, Fujita, & Iemitsu, 2014).
Saponins are known to have stimulating effects on androgen syn-
thesis (Kostova & Dinchev, 2005). Diosgenin is structurally similar to
dehydroepiandrosterone (DHEA) and is thought to replenish DHEA
in vivo in rats (Raju et al., 2004; Sato et al., 2014) and regulate sex
hormones in humans (Komesaroff, Black, Cable, & Sudhir, 2001;
Wu, Liu, Chung, Jou, & Wang, 2005). The generated DHEA is then
converted to other sex steroid hormones including testosterone
and oestradiol (Norton, 1998; Raju et al., 2004; Sato et al., 2014).
However, it is not known where in the body is diosgenin converted
to DHEA (Sato et al., 2014), but the effects of diosgenin could be
blocked by a 5α-reductase inhibitor that inhibits synthesising dihy-
drotestosterone from testosterone (Sato et al., 2014) confirming that
in vivo, diosgenin serves as substrate for 5α-reductase.
Many other studies have elucidated that extracts of P. murex
have aphrodisiac and curative effects in infertile male rats and
could elevate penile erection index, sperm quality, sexual be-
haviour and fertility rate (Ankita, Prava, Kunal, & Sekhar, 2017;
Balamurugan, Muralidharan, & Polapala, 2010; Patel et al., 2012;
Sharma et al., 2019). Probably the application of diosgenin to rel-
evant experimental biologic models will shed more light on its
mechanism of action on the testis that leads to the improvement
of androgen synthesis, spermatogenesis and testicular function.
10 | CO RC H O RU S D E PR E S S U S
Corchorus depressus is a herbaceous plant of the Tiliaceae family
that is long used as an aphrodisiac in Indian systems of traditional
medicine (Kakrani, Kakrani, & Raval, 2018). It is usually blended
with sugar candy and taken orally with goat's milk (Jain, Katewa,
Chaudhary, & Galav, 2004). Diosgenin, a pharmacologically active
steroid saponin obtained from C. depressus, has androgenic and
aphrodisiac properties in normal male rats (Kataria, Kaur, Rao, &
Khajuria, 2013). The plant is also rich in several secondary me-
tabolites including apigenin, luteolin, depressonol A, depressonol
B, depressoside A, depressoside B, β-sitosterol, quercetin and
kaempferol, which might contribute to the effect on the testis
(Zahid et al., 2002).
The chloroform fraction of C. depressus stimulated the relax-
ation of corpus cavernosum smooth muscle in vitro and elevated
the frequency of erections, quick flip, long flip and total reflex in
vivo in experimental animals and was the most potent compared to
the petroleum ether, ethyl acetate, n-butanol and aqueous fractions
of the methanol extract in enhancing the sexual activity of the ani-
mals (Kataria et al., 2013). After 45 days of treatment, a period that
covers complete spermatogenic cycle in rats, the weight of the tes-
tis and accessory sex glands and the number of spermatozoa and
serum testosterone level of the animals were increased (Kataria et
al., 2013). The in vitro and in vivo data provided the evidence that
the chloroform fraction of C. depressus extract possesses aphro-
disiac property (Singh, Sarkar, Tripathi, & Rajender, 2013) and jus-
tifies the traditional use of C. depressus as a sexual invigorator in
men. However, the exact mechanism of action of the saponins and
other phytosterols that are present in the active chloroform frac-
tion to validate the aphrodisiac activity of C. depressus is currently
unknown. Therefore, future efforts at characterising these phy-
to-constituents and applying same to relevant experimental models
will elucidate our understanding on the effect of C. depressus on the
testis and drive efforts on the pharmaceutical development of med-
icines with aphrodisiac property.
11 | M U C U N A PRU R I E N S
Mucuna pruriens (velvet bean) is a tropical leguminous plant be-
longing to the Papilionaceae family. It is grown widely in Africa,
ABARIKWU et al.
America, Malaysia, Sri Lanka, India and South-East Asia (Suresh,
Prithiviraj, & Prakash, 2009). In the Indian traditional medicine,
the beans are used for treating male sexual disorders (Suresh et
al., 2009).
The roots and seeds of M. pruriens are rich in alkaloids (pru-
rienine, prurieninine and prurienidine), triterpenes, saponins, ste-
rols especially β-sitosterol and ursolic acid (Misra & Wagner, 2004;
Suresh et al., 2009) and several proteins and amino acids including
globulins, albumins and L-Dopa (Suresh et al., 2009) along with fatty
acids, carbohydrates and related compounds such as oleic acid, lin-
oleic acid and palmitic acid (Adebowale, Adeyemi, & Oshodi, 2005;
Suresh et al., 2013).
Mucuna pruriens seed extract has been demonstrated to in-
crease mounting frequency and frequency of erections, intromis-
sion frequency, ejaculation latency, quick flip, long flip, total reflex
and testosterone and oestradiol concentrations in normal male rats
(Suresh et al., 2009). Treatment of rats with the ethanolic extract
of M. pruriens increases the weight of the testes and epididymides
and sperm count and motility, and the effects were close to those
of the reference drug, sildenafil citrate, confirming that the aphrodi-
siac activity and spermatogenic potential of the plant are controlled
at the hormonal level (Suresh et al., 2009). The aphrodisiac activ-
ity of M. pruriens might also be through the dopaminergic pathway
because of the high presence of L-DOPA in M. pruriens (Suresh et
al., 2009). The fact that L-DOPA largely accounted for the pro-sper-
matogenic properties of M. pruriens was supported by the fact that
both L-DOPA and M. pruriens exhibited similar capacity to recover
spermatogenesis in oestrogen-treated rat model with compromised
spermatogenesis (Singh et al., 2013). Under patho-physiological sit-
uations such as diabetes, M. pruriens also improved the sexual be-
haviour and sex hormone concentrations of male rats (Suresh et al.,
2013). At the clinical level, infertile men receiving M. pruriens seed
have their semen quality significantly improved (Ahmad et al., 2008;
Shukla et al., 2010).
Considering the interesting findings on M. pruriens with re-
spect to spermatogenesis and especially that it has no significant
toxic effect (Suresh et al., 2009), it will be important to explore
other signalling pathways associated with the spermatogenic po-
tential of this wonderful plant in order to understand better the
mechanism of action. Furthermore, efforts at characterising and
identifying other phyto-constituents in the ethanolic seed ex-
tract of M. pruriens and to determine their possible spermatogenic
activities in both animal model and infertile human subjects are
warranted.
12 | A S TR AG A LU S M E M B R A N AC EU S
Astragalus membranaceus BUNGE is a flowering plant in the family
Fabaceae that is native to northern China including the provinces of
Inner Mongolia, Shanxi, Gansu and Heilungkiang (Auyeung, Han, &
Ko, 2016). It is commonly called milk-vetch root or Huangqi (China)
and is one of the most important tonifying adaptogenic traditional
|
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herbs from the Chinese Materia Medica (Auyeung et al., 2016; Wang
et al., 2019). It is widely used in East Asia to treat general weak-
ness and chronic illnesses and to increase overall vitality (Auyeung
et al., 2016). The root of A. membranaceus has been traditionally used
to treat diabetic nephropathy (Li, Wang, Xue, Gu, & Lin, 2011). The
genus Astragalus has a wide range of potential therapeutic applica-
tions in immunodeficiency conditions, as an adjunct cancer therapy
and for its adaptogenic effect on the heart and kidneys (Auyeung et
al., 2016). This is believed to be due to the presence of the immune-
stimulating polysaccharides in extract of the plant (Auyeung et al.,
2016; Wang et al., 2019). Interestingly, decoction of A. membrana-
ceus or its main constituents has not been associated with toxicity
so far in both in vitro and in vivo studies, and is generally regarded
as a safe drug (Auyeung et al., 2016; Upton, Graff, Jolliffe, Langer, &
Williamson, 2011).
Astragalus membranaceus has a complex chemical profile. Its
major active constituents include saponins, flavonoids and polysac-
charides (Liu et al., 2015; Ma, Shi, Duan, Dong, & Tsim, 2002). Other
components found in the herb include phytosterols, amino acids and
trace elements (Auyeung et al., 2016; Ma et al., 2002; Wang et al.,
2019).
With respect to male fertility heath, only scanty information is
available in the literature. For example, the motility of human sper-
matozoa in vitro and the sperm parameters (sperm count, motility)
of cyclophosphamide-treated mice were increased after treatment
with A. membranaceus (Kim, Kim, Park, & Chang, 2012; Liu et al.,
2004). In one study that tested the sperm motility-enhancing activ-
ity in vitro of water extracts of 18 major Chinese medicinal plants,
it was found that only A. membranaceus demonstrated a significant
stimulatory effect on the spermatozoa of healthy donors, such that
when a concentration of 10 mg/ml was applied, the sperm motil-
ity was increased to 147% compared to control values (Hong, Ku,
& Wu, 1992). From the study with the cyclophosphamide-treated
mice model, it was speculated that A. membranaceus activated the
gene and translational expressions of cAMP-responsive element
modulator as possible mechanism for the observed positive effects
on the sperm parameters of mice (Kim, Chang, & Park, 2016; Kim et
al., 2012).
Because A. membranaceus contain many secondary metabolites,
it may be possible that these compounds can be converted into each
other in vivo. For example, the saponin, astragaloside I and astragalo-
side II may be converted into astragaloside IV, and the flavonoid, ca-
lycosin-7-O-β-D-glycoside, can be hydrolysed to produce calycosin
(Liu et al., 2015; Wang et al., 2019). Thus, metabolic transformation
studies to identify the metabolites in the testis or semen after in vivo
administration in animal models and human subjects will elucidate
our understanding on the mechanism of action of A. membranaceus.
Therefore, it is important to identify the metabolites in the testis
responsible for the positive effect on sperm motility. Furthermore,
studies that apply the astragaloside saponins or calycosin flavonoids
on targeted experimental models that focus on understanding the
effect of A. membranaceus on the spermatozoa are still missing in the
scientific literature.
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13  | N I G E LL A SATI VA
Nigella sativa, commonly called black seed, is an annual flowering
plant belonging to the family of Ranunculaceae (Malhotra, 2004).
It is native to southern Europe, North Africa and South-west Asia
and widely cultivated in Middle Eastern Mediterranean region,
South Europe, India, Pakistan, Syria, Turkey and Saudi Arabia
(Ahmad et al., 2013). The seeds and oil have a long history of folk-
lore usage in various traditional system of medicine and in the
treatment of infertility (Salehi Surmaghi, 2008). Because of its rich
history and religious background and its wide spectrum of phar-
macological potentials, it is often called the miracle herb (Ahmad
et al., 2013).
In a randomised double-blind, placebo-controlled clinical
trial, administration of N. sativa oil to infertile men twice a day for
8 weeks resulted in an increase in sperm count and motility and im-
provement in the morphology of the sperm cells (Kolahdooz et al.,
2014). Beneficial effects of N. sativa oil have been demonstrated on
the reproductive traits of hyperlipidaemic and normal rats (Samir
Bashandy, 2007), and on sperm quality, spermatogenesis and fer-
tility of male rats and chickens (Abdulkarim & Al-Sardary, 2009; Al-
Sa'aidi, 2009; Mukhallad, Mohamad, & Dradka, 2009). Studies on the
seed extract reported an increase in testis and epididymis weights,
epididymal sperm reserve, sperm count, daily sperm production,
serum testosterone, luteinising hormone and the fertility index of
male rats (Parandin, Yousofvand, & Ghorbani, 2012). The favourable
effect on the sperm parameters was due to the excellent ability of
N. sativa to inactivate free radicals and prevent oxidative stress in
the semen of infertile subjects (Kolahdooz et al., 2014). To support
this assumption, thymoquinone, the major pharmacologically active
component of N. sativa oil was also tested in different animal models
and was found to re-establish spermatogenesis and protect against
testicular ischaemia–reperfusion injury and chemically induced tes-
ticular injury through an antioxidant mechanism (Erboga et al., 2016;
Kanter, 2011; Salahshoor, Haghjoo, Roshankhah, Makalani, & Jalili,
2018).
The alkaloid and phenol components in N. sativa can trigger the
increase in sperm concentration through stimulating the secretion
of testosterone and follicle-stimulating hormone (FSH) in rats (Cho
Ping, Hashim, & Hasan Adli, 2014). Although N. sativa oil appears to
be the best form of N. sativa for therapeutic interventional studies
in animal models, extracts of N. sativa have also been reported to
have favourable effects on the male gonads and sperm quality. For
instance, the alcoholic extract of N. sativa, which was rich in vitamins
and minerals (zinc, copper, magnesium), could increase the size of
testis and epididymis and improve the quality of spermatozoa along
with sex hormone concentrations in rats (Al-Sa'aidi, Al-Khuzai, & Al-
Zobaydi, 2009; Parandin et al., 2012).
Apparently, there are yet no clinical trials conducted in infertile
men treated with thymoquinone except the only one study that
evaluated the effects of N. sativa oil in childless men (Kolahdooz
et al., 2014). Consequently, to date there is insufficient evidence
to make recommendations for the use of thymoquinone as an
adjunct therapy in infertile men (Mandavi, Heshmati, & Namazi,
2015). However, based on the promising effects of black seed on
the fertility health of different animal models, more clinical trials
are required to further demonstrate the efficacy of N. sativa on
male infertility.
14 | C R ATA EG U S M O N O G Y N A
Crataegus monogyna (Hawthorn) is one of the most important ed-
ible plants of the Rosaceae family that is grown mainly in East Asia,
in eastern America and in most Asian countries where it is com-
monly found as a small tree 5–10 m tall and with several applica-
tions in folk medicine including treatment of infertility (Nabavi et
al., 2015). The small dark-red fruit is commonly called haw, which
is used for several culinary purposes, including preparation of jel-
lies, jams and syrups (Kumar, Arya, Bhat, Khan, & Prasad, 2012;
Nabavi et al., 2015).
Treatment with aqueous extract of C. monogyna fruit to male rats
protected against doxorubicin toxicity on the male gonads and in-
creased the concentrations of testosterone and the gonadotrophins
(FSH, LH) and the quality of the produced spermatozoa (Jalali &
Hasanzadeh, 2013). The medicated serum prepared with the aque-
ous decoction of the root of the plant could significantly increase the
progressive motility of sperm specimen of asthenospermic patients
even after 60 and 120 min when compared with the control samples
(Hu & Xiong, 2006).
Growing evidence has shown that the plant interesting pharma-
cological activities are due to the presence of proanthocyanidins and
flavonoids (Jalali & Hasanzadeh, 2013). Additional constituents of
the plant include triterpenes, polysaccharides and catecholamines
(Kumar et al., 2012). However, there is yet no information about
the possible effect of the phenolic compounds that are unique to
C. monogyna on the testis.
15 |  FAG A R A TE S S M A N N I I ( Z A NTH OX Y LU M
TE S S M A N N I I )
Fagara tessmannii (Syn. Zanthoxylum tessmannii) is locally known
as ‘Uziza (Nigeria)’, as ‘Trade olon (Liberia)’ and as ‘Ewoungea’ or
‘Bongo’ in the littoral region of Cameroon where it is found as a
shrub from the family of Rutaceae. It grows mostly in the African
rainforests found in South-West, Centre, South and East prov-
inces of Cameroon (Mbaze et al., 2007; Tankeo et al., 2015). The
roots and aerial parts of the plant are used in folk medicine to
treat infertility and sexual weakness (Ayofor, Ngadjui, Sondengam,
& Tsamo, 1984).
In herbal practice among the native people in Cameroon,
200 g of stem bark of F. tessmannii is usually macerated in 1 L of
alcohol and the person with the sexual problems drinks 150 ml of
the solution three times a day. This volume is equivalent to about
0.9 g of extract for a 70-kg individual, which is about 0.01 g/kg
ABARIKWU et al.
body wt. (Lembe et al., 2011). When this dose was applied to
healthy rats for 14 days, the daily sperm production (DSP) was
reduced to about 76% compared to control values (Lembe et al.,
2011). The authors further observed that low doses of F. tess-
mannii extract facilitated epididymal sperm transit, a mechanism
thought to be responsible for the decrease in sperm quality and
DSP of rats, whereas higher doses could normalise the transit
sperm time and increase the DSP, sperm count and testoster-
one concentration (Fernande, Porto, Arena, & Kempinas, 2008;
Lembe, Gasco, & Gonzales, 2014; Lembe et al., 2011). Enhanced
spermatogenesis was also observed especially at the length of
stages VII-VIII and IX-XI of the seminiferous tubule, suggesting
that F. tessmannii must act at the initial stages of spermatogen-
esis (Lembe et al., 2014, 2011). The observed deficit in gonadal
weights along with decreased sperm count, DSP and testoster-
one concentration especially with the lowest dose of F. tessman-
nii (0.01 g/kg body wt.) was also observed when F. tessmannii
was administered to rats in combination with Lepidium meyenii
(black maca), but not at the highest dose of F. tessmannii (1 g/
kg body wt.) where testosterone concentration and spermato-
genesis were enhanced. The higher testosterone level that was
associated with the high dose of F. tessmannii was responsible for
normalising the sperm transit time (Lembe et al., 2014). It is be-
lieved that the combination of L. meyenii (black maca) with F. tess-
mannii improves gonadal activities of rats only at higher doses of
F. tessmannii irrespective of whether F. tessmannii was adminis-
tered alone (Lembe et al., 2011) or in combination with L. meyenii
(Lembe et al., 2014). This information appears to contradict the
traditional belief that F. tessmannii is used for infertility treatment
(Ayofor et al., 1984), except if doses of the alcohol extract up to
1 g/kg body wt. were used in folk medicine, which is currently
not the case. These suggest that higher doses of the ethanolic
extract ought to be recommended in herbal practice among the
native people of Cameroon for the cure of sexual weakness and
erectile dysfunction.
In addition to vanillic acid, some triterpenes unique to F. tess-
mannii have been shown to have inhibitory effects on α-gluco-
sidase, a marker of epididymal function that is linked to sperm
quality (Elzanaty, Richthoff, Malm, & Giwercman, 2002; Gupta et
al., 2005; Mbaze et al., 2007) and could be the mechanism for
the anti-fertility effects of the plant. For instance, two pentacyclic
triterpene acetates, 3β-acetoxy-16β-hydroxybetulinic acid and 3β,
16β-diacetoxybetulinic acid, have been isolated from F. tessman-
nii. However, only diacetoxybetulinic acid has been shown to have
inhibitory effects on α-glucosidase activity (Mbaze et al., 2007).
Other chemical constituents of the stem bark of F. tessmanni that
have inhibitory effects on spermatogenesis and gonadal functions
include lupeol (Gupta et al., 2005; Mbaze et al., 2007). However,
these chemical constituents have not yet been tested in an infer-
tile rat model or at the clinical level and the attempt to further
understand the ‘hormesis’-type effect of the ethanol extract of
F. tessmannii could lead to the development of molecules with in-
teresting contraceptive properties.
|
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16  | PH A LE R I A M AC RO C A R PA
Phaleria macrocarpa, commonly called Mahkota dewa or Pau, is a
medicinal plant that is native to Indonesia. The plant belongs to the
family of Thymelaeaceae and is widely cultivated at Papua Island
where it is commonly found as a shrub or small tree 1–18 m tall (Altaf,
Asmawi, Dewa, Sadikun, & Umar, 2013). It is traditionally used in
Indonesia to improve fertility in males and to treat other ailments
such as skin and blood diseases, migraine, acne, stroke, allergies,
diabetes mellitus, haemorrhoids, heart, liver and kidney diseases
(Zhang, Xu, & Liu, 2006).
It is believed that all parts of the plant including the fruits,
seeds, stems and leaves have medicinal properties and can be used
in treatment (Altaf et al., 2013). For instance, the aqueous extract
of the fruit of P. macrocarpa was reported to increase the number
of spermatogonial cells and thickness of the seminiferous tubules
without changing the testis volume and size (Parhikar, Zulkifli,
& Dollah, 2014). The authors claimed that P. macrocarpa extract
could pass through the blood–testis barrier and gain access to
the germ cells in the seminiferous tubules but that a longer treat-
ment time is required to induce effects on testis volume and size.
Additional studies with the aqueous extract of P. macrocarpa have
demonstrated that the plant increases the mounting frequency,
testosterone level and sperm viability of rats without affecting the
number of motile spermatozoa and counts along with mounting
latency (Parhizkar, CheZainudin, & Dollah, 2013; Parhizkar, Yusoff,
& Dollah, 2013). It is assumed that the alkaloid, phenol and sa-
ponin constituents of the extract acting either by increasing the
synthesis and secretion of androgens or through the serotoniner-
gic action of serotoninergic agents were responsible for the stim-
ulating effect on testosterone level. Since most of this information
were from data on the aqueous extract, it would also be interest-
ing to consider other forms of the extracts that might have better
spermatogenic effects.
The major chemical constituents that have been found in dif-
ferent parts of P. macrocarpa include phalerin, flavicordin-A, flavi-
cordin-D, mahkoside A, icariside C3, mangiferin, lignans and many
flavonoids such as gallic acid, rutin (Ali et al., 2012; Altaf et al., 2013;
Zhang et al., 2006), which might contribute to its positive effects on
the male gonads. However, there is a need to apply these biologically
active compounds especially those that are unique to the plant with
the purpose of relating them to the spermatogenic potentials and
the folk reputation of the plant as sexual stimulants.
17 | A N AC YC LU S PY R E TH RU M
Anacyclus pyrethrum DC (family, Asteraceae) is a perennial herb that
is native to the North African countries, South-western Europe,
India and Arabian countries (Usmani et al., 2016). The dried roots
of A. pyrethrum are commonly called Akarkara and are one of the
most popular drugs of the traditional Indian medicine that is widely
used as a ‘Vajikaran Rasayana’ medicine for rejuvenation and vitality
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14 of 22       ABARIKWU et al.
(Sharma, Boonen, Spiegeleer, & Dixit, 2013). Oral administration of
this powder is used in the Ayurvedic system of medicine to arouse
sexual desire and improve ejaculatory time (Shamloul, 2010; Sharma,
Thakur, Chauhan, & Dixit, 2010).
The petroleum ether extract of A. pyrethrum was shown to increase
the penile erection index, mount and intromission frequency along
with decreased mount latency, intromission latency period of male rats
(Sharma et al., 2010). Additional study further demonstrated the an-
drogenic potential and increased sperm quality (sperm count, motility
and viability) along with the fertilising capacity of the semen sample
of rats treated with ethanol extract of A. pyrethrum after 28 days of
treatment (Sharma et al., 2013). Other effects caused by the etha-
nol-rich extract include increased weight of the testis and accessory
sex glands (prostate, seminal vesicles and epididymis) and spermato-
genic activities and reproductive hormone (luteinising hormone and
follicle-stimulating hormone) concentrations (Sharma et al., 2013). The
aqueous extract of the roots of A. pyrethrum also has the capacity to
improve the sexual behaviour of treated rats along with pronounce an-
abolic and spermatogenic effects. The sperm count and seminal fruc-
tose concentration were also increased in a dose-dependent manner
at the end of the 28-day duration of treatment, thereby confirming the
traditional claim of the plant as a herbal remedy for improving sexual
function (Sharma, Thakur, Chauhan, & Dixit, 2009).
It was assumed that increased spermatogenic activities were due
to the high androgenic potential of the alkylamide-rich extract of the
plant (Sharma et al., 2011, 2013; Thakur et al., 2011). Therefore, one
of the mechanisms by which the plant extract may improve male fer-
tility is by enhancing spermatogenesis through a pituitary–gonadal
axis. Further understanding on this process may lead to the develop-
ment of novel drugs to treat male infertility.
18  | C Y N O M O R I U M S O N G A R I C U M
Cynomorium songaricum Ruprecht is a fleshy holoparasitic herba-
ceous plant that is used to treat sexual dysfunction and impotence in
the traditional Korean medicine (Nickrent, Der, & Anderson, 2005).
Treatment of 2-month-old male Wistar rats with the aqueous
extract of C. songaricum at 1.0 g kg-1 day-1 for 56 days increases
the sperm quality (Abdel-Rahman, El-Badry, Mahmoud, & O., &
Harraz, F.A., 1999; Yang et al., 2010). Further study showed that
the aqueous extract of C. songaricum exerted a testosterone-like
effect on the seminiferous tubules that led to the increase in testis
weight (Abdel-Magied, Abdel-Rahman, & Harraz, 2001). The sper-
matogenesis-enhancing properties of the extract are through the
signalling of the Sertoli cell-derived factor and glial cell-derived
neurotrophic factor (Figure 2; Yang et al., 2010). When decoction
of C. songaricum was tested in oligoasthenospermic rat model, it
was also observed to increase the sperm count and motility along
with testosterone concentration (Cao et al., 2016). The mRNA ex-
pression of spermatogonial stem cell markers such as Oct4, Thy1,
PLZF and GDNF genes was remarkably higher in the low-dose
C. songaricum-treated rats compared to the values obtained from
the oligoasthenospermic rat model (Cao et al., 2016). The authors
speculated that the spermatogenesis-enhancing effect of C. son-
garicum was by inducing the expression of GDNF in the rat Sertoli
cells required to promote the proliferation of undifferentiated
spermatogonial cells (Cao et al., 2016). The expression of these
germ cell markers was recently detected at the protein levels and
was found to be significantly increased in the testis of the infertile
rat model treated with different concentrations of decoction of
C. songaricum (Han et al., 2019).
F I G U R E 2   Effects of Cynomorium
songaricum (CS) treatment on sperm count
(a) and glial cell-derived neurotrophic
factor (GDNF) transcriptional (b and c) and
translational (d) expressions in rat testes.
Results are presented as mean ± SD.
*The mean differs significantly between
the control group and CS-treated group
(p < .05). RT-PCR was performed on RNA
and protein isolated from rat testis using
actin and β-tubulin primers, respectively.
Adapted from Yang et al. (2010) with
permission
ABARIKWU et al.
All of these effects might be a result of the antioxidative proper-
ties of C. songaricum, which help to restore the imbalance in exces-
sive levels of testicular reactive oxygen species (Jo & Jerng, 2016).
So far, some studies have reported that C. songaricum contain a vari-
ety of ingredients with potent antioxidant effects including steroids,
triterpenes, fructosides, flavonoids, polyphenols and tannins (Jiang,
Tanaka, Sakamoto, Jiang, & Kouno, 2001). Recently, two new wa-
ter-soluble polysaccharides, CSP-1 and CSP-2, with α-glucopyrano-
sidic linkages similar to those of starch (Tuvaanjav et al., 2016) and a
flavanol, songarin A (Xie et al., 2013), were isolated from C. songar-
icum. Although these new compounds have not yet been tested in
relevant infertile experimental models, information on the other in-
dividual chemical constituents found in the plant and how it affects
in vivo spermatogenesis has not yet been reported. Furthermore,
studies that focus on the research and development of the mono-
meric components of the polysaccharides constituent of the plant
and how it potentially influences spermatogonia stem cell prolifera-
tion in vitro could be interesting.
19 | M O R I N DA O FFI C I N A LI S
Morinda officinalis is a famous herbaceous plant in southern China
where it is traditionally used to treat male infertility and kidney yang
deficiency diseases (An, 2009).
Administration of M. officinalis extract protects the membrane
of human sperm suspension from oxidative injury (Yang, Zhang,
Ding, Yan, & Du, 2006). The aqueous extract of M. officinalis in-
creases sperm count and germ cell numbers in the seminiferous
tubules of rats (Song, Wang, & Wang, 2015; Wang et al., 2013).
Spermatogenesis was improved, and the secretion of GnRH was
stimulated in experimental varicocele rats treated with water-solu-
ble polysaccharides obtained from M. officinalis (Zhang, Hao, Wang,
Lin, & Wang, 2016; Zhu et al., 2017; Zhu, Zhao, Huang, Wang, &
Wang, 2019). Morinda officinalis extract also attenuated seminifer-
ous epithelium structures and inhibited germ cell apoptosis (Zhu et
al., 2019). In experimental varicocele rats that were administered
M. officinalis extract, testosterone and inhibin levels were increased
and TGF-β3 and TNF-α cytokine levels were decreased allowing for
the improved spermatogenesis (Zhang et al., 2016). Both the aque-
ous and alcoholic extracts of M. officinalis could also repair testicular
injury and increase spermatogenesis in microwave radiation-ex-
posed rats (Wang et al., 2013). Additional study by Song et al. (2015)
observed that the sexual performance of the animals was improved
and their sperm numbers both in the testis and in the epididymis
were increased. The hormonal profiles of these animals were char-
acterised by high testosterone level along with decreased LH and
GnRH levels (Song et al., 2015). Furthermore, experimental rat mod-
els showing impaired spermatogenesis by intraperitoneal injection
of cytoxan were also repaired in a dose-dependent manner by ex-
tract of M. officinalis (Chen & Wang, 2015).
The identified active ingredient of the plant, bajijiasu, was
also shown to enhance the sexual behaviour of mice, improve the
|
      15 of 22
testosterone concentration and sperm quality, and protect the
sperm DNA from damage by reactive oxygen species (Wu et al.,
2015). Bajijiasu is suggested to possess androgenic properties,
which increased the libido and physical sexual activity of mice (Lin,
Lin, Xiao, Liu, & Wang, 2008; Wu et al., 2015). It was also found that
water-soluble polysaccharides extracted from M. officinalis stim-
ulated gonadotrophin secretion via up-regulating the kisspeptin
1-GPR54 pathway and activation of MAPK phosphorylation. This
pathway was thought to be responsible for the improved sperm
quality and serum hormonal parameters along with better morpho-
logic structure of the seminiferous epithelial elements (Zhu et al.,
2017). Further studies on the effect of bajijiasu on kisspeptin path-
way will shed more light on the mechanism of action of these natural
oligosaccharides on male fertility.
2 0 |  CO N C LU S I O N S
The patronage of botanical medicines has been transmitted by gen-
erations among people of different cultures in different parts of the
world and will still continue for a long time. The pro-drug candidates
that are found in many medicinal plants have been well established
by experimental findings to potentially regulate the function of the
testis. But there is need to further scientifically support the tradi-
tional claims of the reproductive health effects of isolated extracts
from medicinal plants before moving onto clinical efficacy and safety
data. To progress in this direction, the efficacy of the plant extract
and/or its drug preparation must be tested in humans themselves
after a series of standardised safety trials in animal models. The
benefit of this to humanity will be promising considering the large
numbers of infertile people who wish to have their own biological
children. This paradigm shift has become necessary because of the
high cost of synthetic medicines for treating various forms of deficits
in the function of the testes such as impaired sexual performance
and desire and suboptimal sperm function and production along
with germ cell development. It is also important for andrologists and
clinicians treating male infertility to have some background infor-
mation about the medicinal plants whose scientific information has
been validated, and to consider whether therapeutic outcomes will
be more beneficial when botanical medicines are combined with or-
thodox medicines. The incorporation of policies into the healthcare
delivery system that makes this combinatorial therapeutic approach
a possibility will be necessary. Furthermore, because of the multiple
clinical signs for male infertility that might be complex, the phar-
macological effects of single extract of medicinal plants that target
the testis might be different when used in the form of formulations.
For example, in rats, the formulation of hydro-alcoholic extracts of
L. meyenii and F. tessmannii could increase spermatogenesis and tes-
tosterone level much more when administered together (Lembe et
al., 2014). Similarly, men with poor semen quality who had received
standardised extracts of the combination of Punica granatum and
Alpinia galanga showed increased total number of motile spermato-
zoa after three months of daily treatment (Fedder et al., 2014). All
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16 of 22       ABARIKWU et al.

these interesting findings are expected to drive the development of
new botanical medicines for the treatment of male infertility.
AC K N OW L E D G E M E N T
We tender apologies to all authors whose works were not cited in
this review owing to a lack of space.
C O N FL I C T O F I N T E R E S T S
The authors declare no conflict of interests regarding the publication
of this paper.
AU T H O R C O N T R I B U T I O N S
Conceived the study and approved the final version of the manu-
script: SKS; Coordinated the study, and wrote and approved the final
version of the manuscript for submission: SOA; Wrote the draft ver-
sion of the manuscript: CLO.
ORCID
Sunny O. Abarikwu  https://orcid.org/0000-0003-3378-2689
Shio Kumar Singh  https://orcid.org/0000-0002-8222-2429
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How to cite this article: Abarikwu SO, Onuah CL, Singh SK.
Plants in the management of male infertility. Andrologia.
2020;00:e13509. https​://doi.org/10.1111/and.13509​