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Treatments for male fertility are selected in function of the etiology. For instance, male hypogonadotropic hypogonadism is secondary to gonadotropin deficiency and is treated with hormone stimulation to replace the missing hormones. Therapeutic GnRH stimulates pituitary gonadotropin secretion. Gonadotropins imitate LH and FSH. Selective Oestrogen Receptor Modulators (SERMs) inhibit Oestrogen Receptors in the hypothalamus and pituitary and suppress the oestrogen-mediated negative feedback on the hypothalamic-pituitary-gonadal axis. Aromatase inhibitors inhibit the conversion of testosterone to oestradiol, thereby decreasing the oestradiol-mediated negative feedback (20). Although hormone stimulation has promising effects on animals, it is ineffective in human cancer patients (5).

In the case of male infertility due to cancer treatment in reproductive age, an alternative to preserve fertility is sperm cryopreservation followed by in vitro fertilization or intracytoplasmic sperm injection. These approaches are effective when sperm is collected for 2-3 ejaculates and before the cancer treatment. But, in some cases starting cancer treatment is an urgency that no contemplate time for sperm cryopreservation. Moreover, this option is expensive and difficult to develop in some centers (19). Furthermore, sperm cryopreservation and assisted-reproductive technology have 30% pregnancy and 25% live birth rates, respectively. Although being compared to general fertility treatment, is not effective in all the patients (3).

Cryopreserving sperm is impossible in prepuberal patients. The cryopreservation of testicular tissue obtained through a biopsy is possible in these patients (19). Moreover, cryopreserving testicular tissue is the only option in men unable to ejaculate and those with azoospermia (3). However, testicular biopsy has potential risks in leukemia patients. Furthermore, fertility restoration is still a problem in young cancer survivors for clinical reasons (19). In fact, the alternatives for using cryopreserving spermatogonia stem cells are under experimentation. For instance, testicular tissue auto- or xeno-grafting, spermatogonial stem cells transplantation and in vitro spermatogenesis are being studied in animals (5). However, culturing sperm and germ cells has been unsuccessful in humans. In addition, these approaches have some disadvantages: the small number of spermatogonia stem cells, contamination with cancer cells, surgical procedures, intracytoplasmic sperm injection and virus infection (3).

Regarding nutritional aspects, abnormal sperm parameters and hormone levels are associated with a high intake of alcohol, processed starchy and meat foods and foods rich in trans and saturated fatty acids (21–27). On the other hand, nutritional healthy habits such as high consumption of vegetables, fruits and seafood products have shown a positive association with the prevention of male infertility (28).

The Western diet is rich in saturated fatty acids, carbohydrates and proteins found in processed foods. It is also reduced in polyunsaturated fatty acids, dietary fibers and antioxidants, consequently having a negative effect on sperm quality. In this sense, the Western diet is associated with obesity, dyslipidemia, insulin resistance, oxidative stress, and aromatase activity. As a result, the Western diet reduces testosterone levels leading to a decrease in sperm count, motility and morphology. Moreover, the Western diet modifies the metabolism of sperm cells by decreasing glycolysis and mitochondrial respiration, reducing ATP content and sperm motility. Contrary, vegetarian diets are rich in plant-based antioxidants such as polyphenols with beneficial effects on sperm quality. For instance, quercetin is a flavonoid that interacts with mitochondrial membranes at the coenzyme Q-binding site, suppresses superoxide generation and promotes ATP synthesis (29). Similarly, the Mediterranean diet is characterized by a high intake of polyphenols, monounsaturated fatty acids, fiber, ω3 fatty acids, and vitamins, while being reduced in saturated and trans-fatty acids. Therefore, the Mediterranean diet is associated with a positive impact on male fertility, high sperm count and motility (28). Furthermore, the Mediterranean diet reduces oxidative stress and increases ATP generated through energetic metabolism, thus improving sperm quality (29).

As we previously described, there exists an intricate connection between nutritional habits and fertility. In vivo models have confirmed that administrating several bioactive compounds found in plant sources can help to mitigate the detrimental effects caused by unhealthy habits and environmental pollutants, thereby aiding in the recovery of fertility. Table 1 summarizes the nutritional habits known to prevent male infertility, classifying the sources and bioactive compounds that control the detrimental effects.

Mice fed with a high-fat diet develop a metabolic syndrome-like condition (increased body weight, hypercholesterolemia, hyperglycemia and glucose intolerance) associated with deleterious reproductive status. For instance, high-fat diet-fed mice have an increment in gonadal fat, associated with a reduction in epididymis weight and sperm count (54). However, switching from a high-fat diet to a normal diet recovers the fertility potential in obese male mice. In this sense, obese mice changing to a normal diet have a reduction in gonadal fat content, and an increment in FSH serum levels and fertility potential (55). In addition, the impact of a high-fat diet on semen parameters has been studied in a rabbit model of diet-induced hypercholesterolemia. In fact, a high-fat diet is associated with a reduction of semen volume, sperm count and motility, but an increment in sperm cholesterol content, lipid droplets, functional (acrosomal reaction) and morphological abnormalities. The testicular inefficiency is associated with reduced testosterone levels, decreased differentiation from spermatogonia to sperm cells, and increased apoptosis of germ cells. On the other hand, the addition of olive oil to the diet recovered the semen quality and sperm function dismissed by hypercholesterolemic diet in rabbits Table 1 ) (30–32).

Plants-based diets are alternative and sustainable approaches managing male infertility. Active principles and crude extracts of medicinal plants are used because of their antioxidant, anti-inflammatory, and positive effects on the testis. They have bioactive compounds such as polyphenols (anthocyanins, proanthocyanidins), phyto-oestrogens, diosgenin and thymoquinone (56). For instance, Lepidium meyenii (Maca), administrated to healthy men at 1.75 g/day for 3 months, increases sperm count and motility (33). Furthermore, Acanthopanacis senticosi activates sperm motility when administrated in humans (34). Moreover, Sesamum indicum, administrated at 0.5 mg/kg during 3 months, improves sperm count, motility and normal morphology (35, 36). In addition, roots of Withania somnifera administrated 5 g/day during 3 months improve energy metabolism and quality of semen and reproductive hormone levels in infertile men (37). Zingiber officinale (Ginger) powder or root are used because of their antioxidant, anti-inflammatory, anti-tumorigenic and androgenic activity. In fact, ginger contains gingerdiol, gingerol, shogaols,zingerone, zingibrene, folic acid, sesquiterpenes and vitamin C (57).

Morinda officinalis-Lycium barbarum coupled herbs are traditional Chinese medicines that reduce oxidative stress and apoptosis, thereby improving male fertility. These herbs contain ohioensin-A, quercetin and sitosterol that target androgen and estrogen receptors, MAPK, PI3K/Akt and glyceraldehyde-3-phosphate dehydrogenase (38). Camellia sinensis (green tea) leaves contain flavonol and epigallocatechin gallate and increase sperm concentration and viability when administrated for 52 days in rats (39, 57). Microalgae such as Chlorella vulgaris and Spirulina platensis improve spermatogenesis and steroidogenesis and protect against oxidative stress in rats (40–45). Algae such as Halopteris scorapia and Laminaria japonica increase sperm count, motility and testosterone levels, meanwhile decreasing sperm abnormalities, inflammation and oxidative stress, in mice and rats, respectively (46, 47, 57).

Vitis vinífera (grape) contains resveratrol and flavonoids (catechin, quercetin, anthocyanin and pro-anthocyanidins) with protective effects on testicles. In this sense, grape seed extracts reduce oxidative stress and apoptosis, meanwhile improve testicular histology, hormone levels, and sperm count and morphology (57). In mice, resveratrol reduces the toxic effects of cadmium and lead at the testicular level. Moreover, resveratrol prevents the development of testicular germ cell neoplasia in situ promoted by heavy metals. In this sense, resveratrol improves sperm parameters, redox balance, testicular histology, and reduces signaling pathways such as Akt (48). Moreover, resveratrol supplementation in a cryopreservation medium improves the post-thawed sperm quality and fertility of roosters. Indeed, rooster semen cryopreserved with 40 µM resveratrol-loaded nanostructured lipid carriers has higher motility, viability, membrane function, mitochondrial activity, antioxidant capacity and lower apoptosis than non-treated frozen sperm (49). In human cryopreserved semen samples, 15 µM resveratrol decreases DNA fragmentation mean increases markers of male fertility (protamine 1 and 2) and pregnancy success (adducin 1 alpha) by activating 5’ AMP-activated protein kinase (50).

Antioxidants lead the list of natural products that are protective agents for male infertility. In this regard, oxidative stress damages sperm membranes and DNA, thereby promoting infertility. Curcumin is a bioactive compound present in the turmeric plant Curcuma longa that reduce oxidative stress, lipid peroxidation and oxidative DNA damage. Curcumin increases the levels of GSH, glutathione peroxidase, superoxide dismutase and catalase. In addition, curcumin increases testosterone, FSH and LH levels in mice (51–53). Ellagic acid is a polyphenol with similar effects to curcumin. Vitamin C protects spermatogenesis, prevents sperm agglutination, and increases testosterone, FSH and LH levels. Moreover, vitamin C induces antioxidant enzymes, and reduces LDL cholesterol and lipid peroxidation. Vitamin E is an antioxidant that protects cell membrane components from oxidative damage. At reproductive level, vitamin E also protects spermatogenesis and testosterone levels (57).

Because of their availability, safety and low cost, bioactive compounds contained in fruits, vegetables and spices are potential agents for the prevention and treatment of cancer. Even though they have limitations (low bioavailability, high metabolism, poor water solubility), these molecules have antitumorigenic effects against a wide range of cancers: colon, lung, prostate, breast, gastric, liver, and brain cancer (58). Moreover, contrary to current cancer treatments, bioactive compounds are potential chemo-preventive and -therapeutic agents with low side effects on the health of patients (59, 60).

Bioactive compounds target cancer cells, macrophages and adipocytes in the tumor microenvironment, thereby preventing cancer development and progression (61). In this way, curcumin, myricetin, geraniin, genistein, tocotrienol, fucoxanthin, anthocyanin, epigallocatechin gallate, gallic and ellagic acids have anti-proliferative, pro-apoptotic and anti-metastatic effects. For instance, curcumin, in nanoparticles, piperine, phospholipid complexes and liposomes, inhibits PI3K/Akt and NF-κB pathways, but upregulates p53 and Bax expression, thereby promoting apoptosis of cancer cells. In addition, curcumin downregulates MMP-9 expression and reduce the metastatic potential of cancer cells (59). Furthermore, Tripterygium wilfordii used in the Chinese medicine contains bioactive compounds such as triptolide, celastrol and tripchlorolide that also inhibit PI3K/Akt and NF-κB pathways thereby exerting anticancer and anti-inflammatory effects (62).

As previously mentioned, several plant-derived bioactive compounds are effective in improving male infertility. In addition, these compounds have been shown to reverse cancer-induced infertility. Table 2 summarizes the sources and bioactive compounds known to prevent cancer-associated male infertility by controlling the detrimental effects of cancer therapy.

For instance, ginger and algae extracts have beneficial reproductive effects post cancer-therapy (57). Rats treated with a single intraperitoneal (IP) injection of 5mg/kg busulfan (chronic myelogenous leukemia treatment) and with 100-150 mg/kg ginger extract for 48 days have increased volume of seminiferous tubules, sperm count and testosterone levels, previously impair by busulfan ( Table 2 ) (63). Another group demonstrated that oral administration of 300-600 mg/kg ginger extract recovers the epithelium thickness and germ cell count of rat testis affected after a single IP dose of 100 mg/kg cyclophosphamide treatment by increasing antioxidant and testosterone serum levels (64). In addition, oral administration of fucoxanthin-rich brown algae Sargassum glaucescens extract ameliorates cisplatin-induced testicular damage in hamsters. Hamsters were intraperitoneal injected with 7 mg/kg cisplatin and treated with 100, 200 and 500 mg/kg fucoxanthin extract orally administrated. In fact, fucoxanthin-enriched extract recovers the testosterone level, seminiferous tubules morphology and sperm number, motility and morphology affected by cisplatin treatment (65).

Additionally, several bioactive compounds such as curcumin, ellagic acid and vitamin E are involved in reverting cancer-induced male infertility (57). For instance, rats treated with a single IP dose of 5 mg/kg cisplatin and 100 mg/kg/day curcumin during 7 days reverse testicular damage by reducing NF-κB and caspase-3 activated by cisplatin (66). Rats treated with a single IP dose of 7 mg/kg cisplatin and orally administrated 200 mg/kg/day curcumin for 10 days recover oxidative stress and testicular damage induced by cisplatin via mitogen-activated protein kinase and nuclear factor-kappa B signaling pathways (67). Mice treated with 4 mg/kg curcumin nanocrystals recover the negative effects of cyclophosphamide in sperm activity, sperm chromatin condensation, and seminiferous tubule architecture, meanwhile have a reduction in germ cells apoptosis induced by the treatment with 200 mg/kg cyclophosphamide (IP) (68). Mice with colon cancer treated with 5 mg/kg cisplatin (IP) have a reduction in sperm count which is recovered after 5 weeks of treatment with 10 mg/kg ellagic acid (oral) (69). Rats receiving 250 mg/kg vitamin E with 500 mg/kg L-carnitine control the oxidative stress induced by the treatment with 20 mg/kg methotrexate (IP) via reducing malondialdehyde and increasing superoxide dismutase (70). In rabbits, the treatment with 4 mg/kg resveratrol (intravenous) for 8 weeks ameliorates the DNA fragmentation and abnormal DNA integrity in epididymal sperms induced by 5 mg/kg paclitaxel (71). In addition, 20 µM resveratrol induces the proliferation of spermatogonia stem cells in vitro. In mice, 100 mg/kg/day resveratrol for 2 weeks promotes the proliferation of germ cells thereby reversing the loss of spermatogenic cells in the testis and sperm cells in the epididymis induced by 30 mg/kg busulfan treatment (gavage) (72).