Infertility means the inability to conceive after one year of unprotected sexual intercourse. Male factor infertility is the cause of 40-50% of cases and has become a significant health problem (Ayaz et al., 2018). Diagnosis occurs when seminal parameters such as sperm concentration, motility and morphology are abnormal. In these cases, it is recommended to start medical treatment (Duca et al., 2019; Vander Borght and Wyns, 2018).

Current treatments for male infertility, such as assisted reproduction techniques, have high  costs  and  often  low successful rates (10-30%) (Nejatbakhsh et al., 2016). Although hormonal (FSH-follicle replacement) and nutritional therapies (with carnitine, arginine, zinc, selenium, vitamin E, glutathione and coenzyme Q10) may be used to treat semen alterations (Duca et al., 2019), a new modality of treatment has contributed to improving the management of this issue (Nejatbakhsh et al., 2016). Alternative medicine, essentially herbal, has been projecting with the purpose of improving sperm parameters in male infertility (Sengupta et al., 2018).

The use of medicinal herbs has persisted for thousands years and continues to represent a considerable area of ​​medical treatment in many countries, particularly in Asia, Africa and South America (Tahvilzadeh et al., 2016). According to an estimate by the World Health Organization (WHO), 80% of the world's population trust on herbal medicines for their care (Gadelha et al., 2015).

Essentially, the effect of medicinal plants on male reproductive function is associated with their antioxidant activity, since they present in their compositions phytochemical compounds able to inhibit spermatic membrane lipid peroxidation. Among these compounds are polyphenols, flavonoids and tannins, which act in various processes of the male reproductive system, such as spermatogenesis and steroidogenesis (Ahmadi et al., 2016; Lohiya et al., 2016; Mansouri et al., 2016). Withania somnifera, locally known as Aswagandha or "Indian Ginseng" is an Indian-origin herb that has been widely used in Brazil for its adaptogenic potential (Lohiya et al., 2016). Although commonly used in its countries of source as part of the treatment of erectile dysfunction, oligozoospermia, endocrinological reproductive problems and other male reproductive problems (Gupta et al., 2013; Kumar et al., 2015), in Brazil, it is still rarely used as complementary treatment for male infertility. Knowing that medicinal plants are recognized as a safe, effective and economical alternative and considering that W. somnifera has been used in the treatment of reproductive disorders, the aim of this study was to review the available data in literature on its effectiveness in improving male infertility.

A literature review was performed  using three databases: Pubmed, Lilacs and Medline, in order to identify scientific articles published from 2009 to 2019. Search was performed based on the descriptors "Male Infertility" or "Infertile Men" to describe the population, "W. somnifera" "Aswagandha" or "Indian Ginseng" to describe the intervention, and "Sperm Parameters" "Sexual Dysfunctions or “Men's Sexual Health” for the outcome.

Human intervention studies were included, as well as systematic reviews and meta-analyzes. Male reproductive disorders with the following diagnoses were included: Oligozoospermia (reduced sperm count in semen), asthenozoospermia (decreased sperm motility), azoospermia (absence of sperm), oligoastenozoospermia (low sperm concentration and motility) or teratozoospermia (altered sperm morphology). Animal studies were not included.

The publications were pre-selected by titles, which had to include the full terms and/or references to male infertility and W. somnifera; thereafter the abstracts were read. Articles that met the inclusion criteria entered the study, otherwise, they were excluded. After searching, Endnote X8 was used to remove duplicate articles.

The flowchart (Figure 1) describes the study selection process. Finally, 9 articles were selected for discussion.

General features

Found in hot, dry regions of the semi-arid climate, W. somnifera originates from South Africa, the Middle East, India, and China (Dar et al., 2015). In India, W. somnifera is a medicinal plant and both the whole plant and its parts are used in medicinal treatments. From ancient times, W. somnifera root has been used as adaptogen, diuretic, sedative, antioxidant and aphrodisiac (Narinderpal et al., 2013). Other parts of the plant, such as leaves and fruits, have been used as an analgesic, memory stimulant, anti-neoplastic, antimicrobial and anti-inflammatory agent (Sengupta et al., 2018).

W. somnifera contains a wide variety of phytochemicals giving rise to a range of biological implications. In preclinical studies, it has demonstrated antimicrobial, anti-inflammatory, anti-tumor, anti-stress, neuroprotective, cardioprotective and antidiabetic properties (Dar et al., 2015).

In addition, this plant is known for its potential to promote health and longevity by preventing the aging process, enhancing defense against disease, revitalizing the body in debilitated conditions, enhancing an individual's ability to resist environmental effects and creating a sense of mental well-being (Durg et al., 2015).

Due to its pronounced anti-stress qualities, this species of plant is named "somnifera", which means "sleep inducer". The pharmacological effects and folk uses of W. somnifera are like those of Korean ginseng tea. For this reason, it is also known as Indian ginseng (Dar et al., 2015).

W. somnifera extract is one of the widely used herbal medicines for the treatment of infertility and sexual dysfunction. It contains more than 80 types of phytochemicals,   among    which     are    alkaloids    and flavonoids. Its root is the most used part for certain purposes, as it has antioxidant, anti-apoptosis and anti-inflammatory properties and exerts positive effects on the male reproductive system, improving semen quality by regulating sex hormone levels and inhibiting lipid peroxidation (Azgomi et al., 2015).

Mechanisms of action

The exact mechanisms underlying the reproductive effects of W. somnifera are not yet well elucidated however, several studies have shown that its phytochemical components may exert major effects on the male reproductive system through antioxidant and detoxicant properties, regulation of sex hormones, GABA-mimetic action (Tahvilzadeh et al., 2016; Kumar et al., 2015; Ambiye et al., 2013). The mechanisms by which W. somnifera is capable of exerting effects on the male reproductive system and fertility can be divided into oxidative and non-oxidative mechanisms as shown in Figure 2 (Sengupta et al., 2018; Mahdi et al., 2011).

Oxidative mechanism

First, it is important to note that reactive oxygen species cannot be only harmful as several biological reactions at the chemical level are by then catalyzed. From fertility point of view, an optimal concentration of reactive oxygen species (ROS) is required for sperm maturation, capacitation, hyperactivation, acrosome reaction, zona pellucida binding and sperm-oocyte interaction (Agarwal et al., 2014).

However, excessive production of reactive oxygen species (ROS) may be among the main causes for the onset of male reproductive dysfunction, as the sperm membrane presents high amounts of polyunsaturated fatty acids, making them susceptible to lipid peroxidation (LPO) (Bisht and Dada, 2017). A high concentration of ROS or low antioxidant intake can lead to the process known as oxidative stress, resulting in the disruption of sperm cell DNA and/or RNA molecules (Esmaeili et al., 2015). Thus, antioxidants in seminal plasma protect germ cells against such damage and prevent the formation of ROS (Aitken, 2016).

The antioxidant action of W. somnifera has been determined by the amount of LPO produced. It has been observed that compounds extracted from W. somnifera are able to donate electrons and stop the destructive chain reaction of free radicals, thus decreasing the general charge of ROS (Gadelha et al., 2015). Withania flavonoids have been reported to have potent antioxidant activity that can counteract the formation of ROS in infertile men. Two alkaloids, sitoindosides VII-X and withaferin A, have been shown to activate the major free radical scavenging enzymes in vivo (Ahmad et al., 2010).

Metal ions, such as Cu²⁺, Zn²⁺ and Fe²⁺ are cofactors for the antioxidant enzymes superoxide dismutase (SOD) and catalase and their deficiency has been observed in the sperm of infertile men (Shukla et al., 2011). Treatment with W. somnifera significantly improved SOD activity, catalase activity and glutathione level, eventually reducing protein peroxidation and carbonyl levels in infertile men (Durg et al., 2015).

W. somnifera root has also been shown to increase alanine concentration in semen. Alanine has a protective role against oxidative stress and can reduce LPO and thus increase sperm concentration and motility (Tahvilzadeh et al., 2016; Gupta et al., 2013).

Thus, the ability of W. somnifera root extract to decrease ROS can be inferred from two factors: its potent antioxidant activity and its ability to improve the concentration of metal ions that act as enzymatic cofactors (Shukla et al., 2011).

Non-oxidative mechanism

In  addition   to  oxidative  stress,  other  causes, such  as hormonal imbalance caused by physiological or psychological factors, are also related to male infertility. Stress-related hormones, particularly glucocorticoids, have a deleterious effect on the hypothalamus-pituitary-gonadal axis (HPG) and subsequently on spermatogenesis (Chandra et al., 2012). The hypothalamus gonadotropin-releasing hormone (GnRH) stimulates the anterior pituitary to release the Stimulating Hormone Follicle (FSH) and the Luteinizing Homonium (LH); both subsequently act on the gonads, regulating spermatogenesis and testosterone production. Therefore, when the HPG axis is disrupted by hormones such as gonadotropin inhibitor hormone, prolactin (PRL) and cortisol, spermatogenesis is negatively affected (Nargund, 2015).

Furthermore, stress increases production and release of epinephrine, norepinephrine and cortisol. These hormones can have a detrimental effect on male reproductive function with two main mechanisms altering local blood flow and causing vasoconstriction in target tissues; reducing LH functional activity and testosterone level, which leads to decreased libido and oligospermatogenesis (Mahdi et al., 2011).

Due to its adaptogenic effects, W. somnifera can promote homeostasis, reducing stress response and normalizing cortisol levels. These characteristics were confirmed in a study that analyzed its effects on infertile men with normozoospermia who were under psychological or environmental stress (smoking) or had infertility of unknown cause (Sengupta et al., 2018).

Ambiye et al. (2013) noted that treatment with Ashwagandha root extract resulted in higher levels of testosterone and LH among infertile men, which had suboptimal values ​​prior to therapy. Thus, they postulated that the probable reason for increased sperm concentration and motility was the higher testosterone levels provided by treatment with the extract.

In addition to these mechanisms of action, the roots of W. somnifera contain substantial amounts of lactate and lactate dehydrogenase (LDH). The stimulation of Krebs cycle and the consequent increase in ATP and cAMP levels observed after 3 months of treatment could help explain the achieved improvement in sperm concentration and motility (Tahvilzadeh et al., 2016).

Based on the intervention studies already performed the Table 1 was elaborated upon which summarizes the administered treatments and the effects of W. somnifera on sperm quality. The main conclusions of the systematic review studies are summarized in Table 2.

The authors have not declared any conflict of interests.