Review on effects of obesity on male reproductive system and the role of natural products

1 Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia and Department of Science Laboratory Technology, Akanu Ibiam Federal Polytechnic, Unwana, Nigeria. 2Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia. 3Department of Physiology and Unit of Integrative Medicine, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia.


INTRODUCTION
Obesity is a disease condition associated with a significant disturbance in hormonal levels that can affect various systems leading to various diseases such as diabetes mellitus, hypertension, dyslipidemia, cardiovascular disease, lung diseases, osteoarthritis, some types of cancer, and certain reproductive and metabolic disorders (Hammoud et al., 2008). It can be caused by a combination of factors such as excessive food intake, lack of physical activity, medications, endocrine disorders, mental disorders, genes and genetic susceptibility (Guyenet and Schwartz, 2012). The prevalence of obesity has reached an alarming rate in many developing countries, including Malaysia, in which 29.1% were overweight while 14% were obese based on previous National Health and Morbidity Surveys (NHMSs) carried out in Malaysia (Chan et al., 2017;Mohamed, 2012;Nor et al., 2008). In men, the relationship between the male reproductive system and obesity is poorly understood (Fernandez et al., 2011;. Some reports have shown that obesity in men is associated with a decrease in serum levels of total and free testosterone leading to a low sperm count (Du Plessis et al., 2010;Fernandez et al., 2011). On the other hand, there is a negative correlation between obesity and various semen parameters (Oliveira et al., 2017), while a recent study has suggested that there is no relationship between increased body mass index (BMI) and sperm DNA (Bandel et al., 2015). Natural products are chemical compounds or substances produced by living organisms which could be from plants, animal, microorganisms, and marine sources. For many years, natural products have been used in the prevention of diseases and have also played a very important role in health. The ancient civilizations of the North Africans, Indians, and Chinese provide written evidence for the use of natural sources for treating various diseases (Moudgil and Khalil, 2016). In those early times, mandrake was prescribed for pain relief, turmeric possessed blood clotting properties, roots of the endive plant were used for the treatment of gallbladder disorders, and raw garlic was prescribed for circulatory disorders. These natural products are still being used in several countries as alternative medicines (Arafat and Rahman, 2017). The role of these products in the treatment of obesity and fertility has received increased attention owing to the recent and rapid increase in the prevalence of obesity in the developed world (Hruby and Hu, 2015). In this review, information on obesity, natural products, pre-testicular, testicular, and post-testicular mechanisms of obesity, and male reproductive impairment were obtained through the following search databases: PubMed, Google Scholar, ScienceDirect, EBSCOhost, SCOPUS, and SpringerLink from 2000 to 2018. The keywords in single or in combination were also searched in these various databases based upon which the effects of natural products on obesity and male reproductive system were reviewed.

Effects of Obesity on Male Reproductive System and their Mechanisms
Obesity has been studied using different obesity models. These include monogenic obesity models (ob/ob mouse, obese Zucker rats, and s/s mouse), polygenic obesity models [high fat diet (HFD)-induced obese rats, diet-induced obese (DIO) rats, and New Zealand Obese (NZO) mouse], surgical models, seasonal models (Syrian and Siberian hamsters), and lipodystrophy model. Generally, obesity affects the male reproductive system at pre-testicular, testicular, and the post-testicular levels leading to impaired male reproductive and fertility potentials, which are summarized in Figure 1.

Pre-testicular Mechanisms of Obesity
Obesity has been recognized to interfere with the hypothalamic-pituitary-gonadal axis leading to secondary hypogonadism. Studies have also revealed that increased adipose tissue results in increased aromatase activity and a consequent elevation in estradiol levels, which inhibits gonadotropin folliclestimulating hormone (FSH) and luteinizing hormone (LH) secretion from the anterior pituitary (Dimitriadis et al., 2017;Rosenblatt et al., 2017;Roth et al., 2008), Studies in experimental models in animals indicate that the most common cause of leptin insensitivity in the hypothalamus is obesity, which is responsible for the decreased KISS1 expression, and consecutively changes the release of gonadotropin-releasing hormone (GnRH) (Stefater et al., 2010). Pre-testicular mechanism involves two conditions, Figure 1. Summary of mechanisms of obesity on the male reproductive system. namely hypergonadotropic hypogonadism and hypogonadotropic hypogonadism.
Hypogonadotropic hypogonadism/primary hypogonadism is caused by testicular deficit leading to reduced testosterone level and impaired spermatogenesis (Condorelli et al., 2015;Dimitriadis et al., 2017). This attenuates the attenuation of the testosterone-induced negative feedback loop to the secretory activities of the hypothalamus and pituitary, which in turn leads to increased amounts of GnRH and FSH/LH secretions. On the other hand, hypogonadotropic hypogonadism/secondary hypogonadism is caused by the deficit at the hypothalamus and/or pituitary. FSH and LH are secreted at reduced levels, which also lead to decreased stimulation of Leydig cells to secrete testosterone (Santi et al., 2017).

Testicular Mechanisms of Obesity
Testis is an important site of hormone production and metabolism, and accumulation of large amounts of body fat may interfere with the hormonal regulation of testicular function. Several studies on obesity suggest that high levels of plasma cholesterol and/or triglycerides have direct adverse effects on testicular function, leading to poor semen quality and infertility (Teerds et al., 2011). Kasturi et al. (2008) have reported the presence of 65% incidence of dyslipidemia as defined by isolated hypercholesterolemia, triglyceridemia, or both, in 106 male partners from infertile couples. Reactive oxygen species (ROS) resulting in lipid peroxidation, are extremely toxic to human spermatozoa, implicating a significant role of oxidative stress in causing of male infertility as spermatozoa from infertile men show signs of greater oxidative injury compared with normal fertile controls (Agarwal et al., 2003). Elevated DNA fragmentation index noted in obese men may reflect an abnormal oxidative state in the testicular microenvironment (Aitken et al., 2014). Similarly, in vitro study suggests that endogenously generated ROS in the adipocytes lead to an increase in sperm DNA fragmentation. This finding also suggests that oxidative stress may result in lipid peroxidation in the sperm plasma membrane. This may, in turn, lead to decreased motility, membrane dysfunction, and excessive oxidative stress in DNA of the affected sperm (Zhou et al., 2014).

Post-Testicular Mechanisms of Obesity
Over the years obesity has been linked to posttesticular etiology that may cause male infertility by affecting the male genital system after sperm production. The affected post-testicular structures include defects of the genital tract like vas deferens obstruction, congenital absence of vas deferens, prostatitis, ejaculatory duct obstruction, retrograde ejaculation, hypospadias, and impotence. In a study carried out by Ouvrier et al. (2011), 3-month-old male mice are fed with a lipid-enriched diet containing 1.25% cholesterol for 4 weeks. The result shows complete infertility in dyslipidemic male mice (the Liver X Receptor-deficient mouse model). The infertility results from posttesticular defects affecting the fertilizing potential of spermatozoa which are less viable and motile and highly susceptible to undergo a premature acrosome reaction. It suggests that obesogens may also cause erectile dysfunction (ED), apart from inflammatory responses, androgen deficiency, and endothelial dysfunction (Petrakis et al., 2017). Researchers suggest that visceral obesity contributes to ED via three interdependent (overlapping) pathophysiological mechanisms: i. inflammatory cytokines that contribute to endothelial dysfunction and microvascular disease and reduced androgen levels, ii. the insult on the endothelium resulting in endothelial injury and reduced nitrogen oxide (NO) synthase activity and NO production, leading to reduced tissue relaxation and poor hemodynamics, and iii. disruption of the endocrine milieu, with a concomitant decrease in testosterone levels and increased E2 level, thus disrupting tissue homeostasis, tissue histo-architecture, and erectile tissue compliance (Siragusa and Fleming, 2016).

Natural Products and Obesity-induced Impairment in Male Reproductive Function
Natural products are used for the treatment of various diseases including to improve male reproductive health for several decades. They are shown to be effective, inexpensive, and available. The extraction and development of several drugs and chemotherapeutics from these natural products have been widely observed. Several researchers have suggested that two-thirds of the world's plant species have medicinal value and many of them have great antioxidant potential. These products have shown to have significant effects at the pre-testicular, testicular, and posttesticular levels which are listed in Tables 1 and 2 (whole extracts and pure compounds isolated from plants, respectively).

Natural Products with Pre-Testicular hypothalamic-pituitary gonadal axis (HPG axis) Beneficial Effects in Obesity
The administration of Argyreia nervosa Bojer (Convolvulaceae) in DIO rats increased the synthesis and release of FSH (Galani et al., 2010). On the other hand, the messenger ribonucleic acid (mRNA) levels of GnRH mRNA and LH are significantly increased in HFD mice treated with Epimedium Herb (Zhang et al., 2011). In addition, administration of Nigella sativa increases testosterone and FSH in HFD-induced obese mice (Barakat and El-Masry, 2016) (Tables 1 and 2).

Natural Products with Testicular Beneficial Effects in Obesity
There are also studies showing the beneficial effects of natural products at the testicular level. A study on the seed of Achyranthes aspera Linn. (Amaranthaceae) has shown an increase in spermatogenesis in HFD-induced obese mice (Rani et al., 2012). In another study, the leaf of Aloe vera significantly increases the number of stem cells and primary spermatocytes in HFDinduced obese rats (Misawa et al., 2012). The rhizome of Alpinia galanga Linn. also increases the number of spermatozoa HFD mice (Ongwisespaiboon and Jiraungkoorskul, 2017). The root of Angelica gigas Nakai (Apiaceae) administered in HFD-induced obese mice increased sperm count, motility, and spermatogenic cell density (Bae et al., 2016).

Natural Products with Post-Testicular Beneficial Effects in Obesity
Many natural products have also shown their potential beneficial effects in treating post-testicular impairment in male obesity as shown in Tables 1 and 2. A study carried out on HFDinduced obese mice for 30 days shows that Achyranthes bidentata Blume (Kamble et al., 2017) decreases spermatogenesis and inhibits testicular function without any side effects suggesting its potential contraceptive property (Rani et al., 2012). Another study carried out by Wu et al. (2009) on glucose challenged db/ db mice treated with Acorus calamus Linn. (Araceae) for 3 weeks has shown an improved sexual performance, i.e., improved mount, intromission, and ejaculatory latencies, and their frequencies and inhibits prostaglandins E 5 (PDE-5) synthesis. Allium sativum Linn. administered on HFD-induced obese mice for 28 days also increases sexual behavior (Focho et al., 2009). Defo et al. (2017 have reported an improvement in sexual behavior and performance when Guibourtia tessmannii (Caesalpiniaceae) is administered in HFD-induced obese rats for 21 or 56 days. In addition, Icariside II (Epimedium) administered on Zuckers rat for 4 weeks also improves erectile function and pathologic changes through endogenous progenitor cell preservation and proliferation (Ruan et al., 2018).

Effects of Natural Products on Adipose Tissue and Lipid Profile
A large number of the natural products studied in this review demonstrated significant effects in reducing total cholesterol (TC), triacylglycerides (TG), high-density lipoprotein (HDL) (Jung et al., 2012), low-density lipoprotein (LDL) as well as fasting blood glucose (Table 1). Some pure isolated compounds also reduced the accumulation of ROS, attenuated adipogenesis (Zhang et al., 2011), and decreased expression of adipogenesisrelated factors and enzymes (Table 2).

CONCLUSION AND FUTURE DIRECTION
There is enough evidence to show that male obesity has an impact on fertility through its effects on pre-testicular, testicular, and post-testicular mechanisms. Natural products, on the other hand, have been used over the years to improve obesity-induced male infertility at the aforementioned levels. This review identifies some selected natural products, with their effects and mechanisms on male reproductive functions in obesity. What does the future hold for the effect of natural products on the male reproductive system in obese men at these levels? With the exponential increase in the number of experiments in this area, it seems likely that many more will be conducted in the nearest future on natural plants, herbs, and other natural products emphasizing on new technologies which could help manage health and weight/energy balance more effectively and analyze the future impact of new technologies on lifestyle, dietary habits, thereby improving male fertility. However, the inclusion of studies on their phytochemical compounds and toxicity would further help appreciate their potentials to reduce obesity-induced impairment in the male reproductive system.