The most important medicinal plants affecting sperm and testosterone production: a systematic review

Objective Infertility, defined as the inability to conceive after one year of intercourse without the use of contraception, affects 15% of couples. Many factors, such as genitourinary tract infections, endocrine disorders, immunological factors and drug-related injuries, affect the male reproductive system and cause infertility. Due to men's fear of infertility, it is very important to pay attention to medicinal plants that are effective in male fertility. Therefore, the aim of this study was to evaluate the medicinal plants that affect sperm and testosterone production in men. Methods In this review, we used the following search terms, consisting of herbal medicine, traditional medicine, traditional therapies, sperm, testosterone, testicles and Iran were used to retrieve the relevant articles published in the journals indexed in the Information Sciences Institute, Science Direct, PubMed, Scopus, PubMed Central and Scientific Information Databases. We searched and used papers published between 2000 and 2020. Then, we analyzed the eligible papers. We collected and analyzed 35 papers from the databases. We selected only the articles about herbs that affect sperm and testosterone production. Results Based on the results, herbs Apium graveolens, Cinnamomum camphora, Cornus mas, Satureja khuzestanica, Withania somnifera, Fumaria parviflora, zingiber officinale, cinnamomum zeylanicum and Phoenix dactylifera are used in the male reproductive system. Conclusions Plants can probably be useful in increasing fertility due to their antioxidant power and low side effects.


INTRODUCTION
Infertility, defined as the inability to conceive after one year of intercourse without the use of contraception, affects 15% of couples (Kim et al., 2013). About 30-50% of infertility is related to male infertility and 30-40% of the causes of male infertility are related to sperm disorders (Godmann et al., 2009). The most common cause of infertility in men is their inability to produce enough healthy, active, and highly motile sperm (Bastampoor et al., 2014;Oyeyemi et al., 2008). Lack of testicular development, diseases of the reproductive system, increased scrotal temperature, immunological problems, endocrine disorders, lifestyle choices, environmental and nutritional factors are considered as the main causes of male infertility having a negative effect on sperm parameters (Marbeen et al., 2005;Sharpe & Franks, 2002;Low et al., 2013;Singh & Jemal, 2017;Chyou et al., 1993;De Rosa et al., 1981). Many factors, such as genitourinary tract infections, endocrine disorders, immunological factors, and drug-related issues, affect the male reproductive system and cause infertility (Wang et al., 2018;Jiang et al., 2017;Kesari et al., 2018;Agarwal et al., 2018). Disorders affecting spermatogenesis, hormone regulation, oxidative stress, and regulation of spermatogenesis-related genes cause infertility (Zhou et al., 2019;Moghbelinejad et al., 2018;Zhang et al., 2020;Hu et al., 2006;Ma et al., 2015). Infertility can be due to excessive consumption of natural plant compounds (phytoestrogens). These compounds can affect the reproductive system and reduce fertility (Csupor-Löffler et al., 2009). Sperm plasma membranes are exposed to oxidative damage due to large amounts of unsaturated fatty acids, which ultimately decrease sperm motility and viability. Antioxidant compounds increase sperm function and can improve fertility (Kooti et al., 2014).
According to several studies, oxidative stress can cause molecular and genetic defects causing infertility (Agarwal et al., 2006). Oxidative stress is usually associated with aerobic metabolism producing prooxidant molecules or reactive oxygen species (ROS). Some cells have specific mechanisms for producing the ROS required for cellular function at low concentrations. Depending on the tissue concentration of ROS, they can have beneficial physiological effects and play a role in the fertilization process. Free radicals can affect the ova, sperm, and embryos in their small environment. Free radicals can also damage cellular components, including lipids, proteins, and nucleic acids. There is a complex interaction of cytokines, hormones and other stressors that affect the production of free radicals (Gupta et al., 2007). ROS can be neutralized by a complex antioxidant defense system consisting of enzymes such as catalase, superoxide dismutase and glutathione peroxidase/reductase, and several non-enzymatic antioxidants such as vitamin C, vitamin E, vitamin A, pyruvate, glutathione, taurine (Safarnavadeh & Rastegarpanah, 2011). Whenever the level of ROS is pathologically elevated, antioxidants begin to work, helping to minimize oxidative damage, repair, or prevent it. The male and female reproductive organs are rich in both enzymatic and non-enzymatic antioxidants. Increased ROS levels can damage the ovum, the zygote/embryo, and most importantly, the sperm. Sperm are very sensitive to oxidative stress. Oxidative stress appears to be due to increased ROS production rather than a decrease in antioxidants (Safarnavadeh & Rastegarpanah, 2011). The WHO recommends the use of traditional medicines in the medical health care system. However, there has been a great deal of interest in finding natural antioxidants from herbal materials to replace synthetic drugs recently (Hasani-Ranjbar et al., 2009). There are many medicinal plants in the world with anti-fertility and fertility-enhancing properties (Jain et al., 2015;Modaresi et al., 2008). Many people now use herbs or their derivatives to increase or decrease fertility as well as libido (Kachroo & Agrawal, 2011). Some of these plants have spermicidal properties, others increase the number of sperm and change sperm motility. Some plants also alter testicular hormones (Khaki et al., 2014).
The World Health Organization reports that despite the increasing use of herbal medicines, there is still a significant lack of research on it, and the role of studies examining herbal medicines is crucial. Due to the clear negative effects of chemical drugs on humans, the tendency to use herbal medicines is increasing among women and men. We need to study the use of biologically active plant materials in the field of male fertility and to identify natural plant materials with estrogenic and anti-estrogenic properties (Marbeen et al., 2005). Due to men's fear of infertility (Hosseini & Abdi, 2012), it is very important to pay attention to medicinal plants that affect male fertility. Therefore, the aim of this study was to evaluate the medicinal plants that affect sperm and testosterone production in men.

MATERIALS AND METHODS
We used the following search terms: herbal medicine, traditional medicine, traditional therapies, sperm, testosterone, testicles and Iran, to retrieve the relevant papers published in the journals indexed in the Information Sciences Institute, Science Direct, PubMed, Scopus, PubMed Central and Scientific Information Databases. Papers published in 2000-2020 were searched and used in the review. Then, we analyzed the findings of the eligible papers.
We assessed the abstracts for the pre-determined inclusion and exclusion criteria. We collected 35 papers from the databases, and 15 papers were taken out due to repeatability, irrelevance, lack of a summary, non-native Iranian plants, invalid papers and invalid journals. Papers without an abstract in English, without a full text and books were excluded from the analysis. Only the papers about herbs that affect sperm and testosterone hormone production were selected for the study (Flowchart 1). There was a significant increase in the number of sperms, sertoli cells, and primary spermatocyte in groups receiving extract; however, structural changes were not observed in the groups. It seems that celery increases spermatogenesis in male rats but has no destructive effects on testicular tissue. Perhaps this plant could be used to treat infertility in men. Kooti et al., 2014 Cinnamomum camphora Lauraceae The active ingredient is prepared from plant stem Significant improvements in potency, fecundity, fertility index, and litter size and significant decrease in post implantation loss. Satureja khuzestanica essential oil protected reproductive system from toxicity of Cyclophosphamide through its antioxidant potential and androgenic activity. The application of ginger plus Cinnamon compared with ginger and cinnamon alone in diabetic rats significantly improved the damaging effects of oxidative stress on spermatogenesis and fertility parameters. It seems that the antioxidant content of herbs could be increased dramatically when used in combination.

Different doses in different routes
This review showed that phoenix dactylifera pollen is a very suitable supplement for infertility and can reduce free radicals and increase sperm motility. Thus: control group (normal saline). CdCl2 (2 mg/kg single dose IP); CdCl2 + 200 mg/kg vitamin E; CdCl2 + 100 or 200 mg / kg PC; And CdCl2 + 25 or 50 mg / kg DDMP. The biochemical parameters of malondialdehyde, nitric oxide, antioxidant enzymes and proton pumps were measured by spectrophotometry. Reproductive hormones were measured using ELISA. In the treated groups, a significant increase in sperm count, motility and viability was observed. Malondialdehyde and nitric oxide levels were significantly reduced. Significant increases in antioxidant enzymes, proton pump and testosterone were observed in the treated groups.

Olaniyan et al., 2018
Continued used organs, participants, intervention protocol, and the important findings. Also, the active ingredients of these herbs plus their chemical and molecular formula are listed in Table 2.

DISCUSSION
Having children is one of the concerns of every couple after marriage, when it does not happen, it causes concerns for the couple and their families. Due to the support of the World Health Organization for maintaining public health and reproductive health, today the use of medicinal plants as a substitute or supplement to synthetic drugs affecting fertility is considered. This is a systematic study of Iranian medicinal plants effective in the treatment of male infertility.
Recent studies have shown that, under physiological conditions, reactive oxygen species play a very important role in the intracellular messaging processes. On the other hand, over the past decade, reactive oxygen species have been implicated in the development of male infertility due to their overproduction or a reduced ability of the reproductive system and sperm to deal with it. In pathological conditions, reactive oxygen species cause male infertility through impaired spermatogenesis, sperm function and structure, motility, viability, acrosome reaction, spermovum mating, and even reduced fertilization and implantation (Dare et al., 2021;Bentrad et al., 2017;Fanaei et al., 2013).
There is a growing demand for herbal medicines around the world. Studies have shown that some medicinal plants may have fertility-enhancing properties in men by improving antioxidant activity, prevent the formation of free radicals and lipid peroxidation, and reduce oxidative stress, preventing damage to sperm cells (Moher et al., 2009). They also increase the number of testicular vessels, the lifespan and number of sperm, increasing sperm quality and protecting germ cells. On the other hand, these plants can enhance the activity of the hypothalamic-pituitary-gonadal axis on different levels, affecting the secretion of LH and testosterone (Oi et al., 2001;Ralebona et al., 2012). These medicinal plants affect male fertility, parameters such as sperm survival and mortality, pituitary hormone levels, histological changes in the testes and sperm depletion. Therefore, these herbs can help improve sperm parameters in infertile men, but this requires further clinical studies.
Some herbs inhibit the uptake of 5 alpha-reductase (a factor that converts testosterone into dihydrotestosterone), reducing gonadotropins and testosterone, increasing the affinity for sex-specific proteins, thickening the basement membrane, reducing germinal epithelial cells and reducing the irregular placement of these cells, reducing sperm count, motility, and sperm viability, but causing side effects such as infertility, at certain doses (Roozbeh et al., 2016). Some plants, such as garlic, inhibit the enzyme caspase 3 and cytochrome P450 2E1 (CYP2E1), which have a toxic effect on the testes, reducing testicular function and improving spermatogenesis by reducing these two enzymes (Vickers, 2017). Garcinia cola polyphenolic sections showed prophylactic effects on the histology and hormones of the pituitary-testicular axis of male Wistar rats (Omotola et al., 2017). Another study from Nigeria found that an injection of Cissus populnea root into male Wistar rats increased the secretion of male sex hormones such as testosterone and gonadotropins, thereby increasing the fertility of these rats (Olaolu et al., 2018). Similarly, Cocos nucifera water improved reproductive indices in Wistar rats (Kunle-Alabi et al., 2014). A study conducted in Iraq showed that Cyperus esculentus has a protective effect on testicular and sperm abnormalities caused by lead acetate in Wistar rats (Al-Shaikh et al., 2013). The aqueous extract of Cyperus esculentus, administered to Wistar rats for nine weeks, increased testicular and epididymal weight, increased sperm count and motility. These studies show that the medicinal properties of these plants are related to polyphenolic components, especially flavonoids, which can neutralize free radicals -the source of oxidative stress (Methorst & Huyghe, 2014). Flavonoids in plant samples have antioxidant power and can optimize the function of the body's antioxidant system. Reactive oxygen species are produced in a chain of reactions that alter male reproductive cells quantitatively and qualitatively; antioxidants act by interrupting these chain reactions (Methorst & Huyghe, 2014). In Iranian herbal medicine, many medicinal plants are used to treat various disorders and diseases. One of the most important reasons for the effectiveness of medicinal plants is the presence of effective medicinal substances (Solati et al., 2021;Bahmani et al., 2020;Aidy et al., 2020;Karimi et al., 2019;Abbasi et al., 2016;. The effect of medicinal plants on sperm production and testosterone is due to the presence of secondary medicinal compounds. According to researchers, methods for standardizing medicinal plants, quality control, information on safety and effectiveness are needed to properly understand the use of herbal medicines. Finally, we recommend more experimental and clinical studies using modern scientific principles and methods in this field.

CONCLUSION
Plants can probably be useful in increasing fertility due to their antioxidant power and lower side effects. The use of medicinal plants with the property of enhancing male fertility can be used as a substitute or supplement to chemical drugs that affect male fertility. On the other hand, it is recommended that plants with fertility reduction properties be used less or not at all in men with infertility disorders.