The administration of 100 mg/kg bw/day of bee pollen on streptozotocin (STZ)-induced diabetic rats for 4 weeks caused significant increases in testis weight, testosterone, LH, and FSH as well as sperm count, motility, and viability, which is suggested partly by scavenging toxic and mutagenic electrophiles and free radicals/modification of antioxidant pathways due to the presence of flavonoids [12]. Algerian bee pollen (100 mg/kg bw) administered for 15 days showed an increase in spermatogenesis and a decline in Sertoli cells destruction by lowering lipids, and it also showed anti-inflammatory and protective effects against testis cell injury due to the potentiated synthesis of proteins. Similarly, 60 mg/animal/day of Turkish bee pollen over a 30-day period showed increases in testosterone level and sperm counts in a rats model via its antioxidant activity [70].

Furthermore, the Indian bee pollen of 100 mg/kg/bw caused a decrease in MDA levels, while there were increases in SOD, GR, GPx, GST, CAT, and GSH in rifampicin and isoniazid-induced toxicity in rats through its antioxidant activity. In addition, lead-induced rats treated with 100 mg/kg bw of Algerian bee pollen showed an increase in spermatogenesis and a decline in the destruction of Sertoli cells (Table 1).

Few studies have been reported on the effects of bee venom on the testicular damage; Egyptian bee venom at doses of 0.1, 0.2, and 0.3 mg/rabbit twice weekly administered over 20 weeks showed increases in TAC, GST, GSH, testosterone spermatogenesis, and fertility. These may be due to the stimulation of the pituitary gland to release the adrenocorticotropic hormone, which causes release of the sex hormones such as testosterone in blood circulation, which have significant effects on spermatogenesis and fertility [73]. In a related study carried out in mice treated with Iraqi bee sting, it provided protection and the maintenance of some sexual efficiency parameters via its ability to release cortisol that inhibits Sertoli cells from releasing activin-B, which normally stimulates spermatogonia to induce mitosis to form spermatocytes [10] (Table 2).

Studies carried out in Nigeria revealed that 100, 200, and 400 mg/kg of honey administered on rats and 2.5, 5, and 7.5 mg/kg of testosterone i.p. showed increases in sperm count; this might be due to the fact that chrysin (5,7-dihydroxyflavone) blocked the conversion of androgens into estrogens with a consequent increase in testosterone [75]. On the other hand, 70 g of Iranian honey supplementation administered on humans for 8 weeks showed significantly less elevation in seminal IL-1β, IL-6, IL-8, TNF-α, ROS, and MDA levels and increases in seminal SOD, catalase, and TAC concentrations through its antioxidant, anti-inflammatory, and anti-apoptotic properties due to the presence of phenols and flavanoids [76]. Similarly, 1.0 mL/100 g body weight of honey administered in nicotine-induced old rats showed increases in the fertility of juvenile male rats by increasing sperm motility and the number of morphologically normal sperm; however, the exact mechanisms require further study [77].

In addition, 0.05 mL of honey administered for 4 weeks showed diminished degenerative changes of seminiferous tubules and increased plasma levels of testosterone significantly in CCL-induced rats via reduction of the elevated levels of free radicals and an increased antioxidant defense system [78]. Furthermore, rats treated with 1.0 mL/100 g of Egyptian honey for 60 days showed significant increases in sperm count and the number of sperm with normal morphology, the honey acted as a physiologic modulator of spermatogenic cells proliferation, which influence the cell cycle of the seminiferous epithelium; thereby, it increases spermatogenesis [14]. Similarly, studies carried out in Iran by Hadi and Mohammed [79,80] revealed that 10% of honey (1 mL of honey and 9 mL of IVF culture medium) with doses of 1.2 and 1.8 g/kg bw enhances sperm motility, increases testosterone, FSH, and LH hormones as well as diameters of seminiferous tubules; this might be a result of the antioxidant properties of honey.

Conversely, 1.2 g/kg of Malaysian honey showed increases in the percentages of rats achieving intromission, ejaculation, mating, and fertility indexes as well as increases in testis, epididymis weights, percentages of abnormal spermatozoa, and sperm motility; in this case, the mechanism through which honey acts is by its counteraction on oxidative stress within penile tissues via its antioxidant property due to the possession of phenols [81,82].

Likewise, 0.2, 1.2, and 2.4 g/kg⁻¹ of Malaysian honey administered for 4 weeks in rats revealed increases in epididymal sperm count without affecting spermatid count and reproductive hormones [83,84]. Furthermore, 1, 2, and 2.5 mL of Nigerian honey administered to rats for 21 days improved the sperm quality and spermatogenesis rate, and there was no sign of degeneration or cellular loss in the testicular histoarchitecture. It is imperative to note that the presence of zinc in honey and its accumulation in the testis during early spermatogenesis may be important in DNA synthesis and regulate spematogonial proliferation [85]. In other similar studies, 1 mL/100 g of bw of Nigerian honey administered for 65 days increases the sperm count and sperm motility, and it also improves the sperm morphology through the reduction of lipid peroxidation and oxidative stress on the sperm cells by reactive oxygen species such as superoxide and hydrogen peroxide. The authors of [86,87,88] revealed that rats treated with 100 mg/kg bw of Nigerian honey for 35 days had improvements in sperm motility, viability, morphology, counts, FSH, LH, and testosterone. The rats treated with 5% Palestinian honey for 20 days induced spermatogenesis in rats by increasing epididymal sperm count, relative weight of the epididymis, SDH activity, and reducing LDH activity; however, the mechanisms require further study [89].

Saudi Arabian honey (20 mg/kg bw/day) ameliorates octylphenol toxic effects and reduces the histopathological stress toxicity on the testis in rats; also, the combined administration of honey and royal jelly reduces sperm abnormality and chromosomal aberrations as well as ameliorates GSH and MDA in cyclophosphamide toxicity in mice; therefore, the presence of CAPE served as a protective agent against chemotherapy-induced oxidative stress [9,90]. The honey drone milk is a product that is secreted by honey bees through their hypopharyngeal and mandibular glands; thus, the Hungarian honey drone milk (110 mg/kg/day) increases the relative weights of the androgen-dependent organs and the plasma testosterone level in castrated rats and then increases the tissue mRNA and protein level of SLAP (Spot14-like androgen-inducible protein). This was done through the scavenging of free radicals by polyphenols before they can interact with DNA [91], while 70 g of honey supplement administered to humans for 8 weeks in Iran increases seminal IL-1b, IL-6, IL-8, TNF-α, ROS, and MDA levels and significantly decreases the levels of seminal SOD, catalase. Kelulut honey 2.0 g/kg weight administered 28 days to diabetic rats revealed significant increases in SOD activity and GSH level as well as significant decreases in protein carbonyl and MDA levels in sperm and testis, whereas the histology of the epididymis showed a decrease in spermatozoa and spermatogenic cells density in the testis of the diabetic group [11] (Table 3).

Iraqi propolis of 200 mg/kg bw decreases the sperm concentration, sperm motility, rate of viability, and normal sperms as well as decreases the weights of testes, epididymis, prostate gland, seminal vesicles, serum testosterone, FSH, and LH levels with a significant increase in sperm abnormalities in acrylamide-induced toxicity in rats through the antioxidative effectiveness of propolis mainly by its flavonoids and phenolic content [92]. Egyptian propolis extract (50 mg/kg bw) decreases LPO levels and normalizes CAT, SOD, GPx, and GST activities, while GSH content was increased in testicular tissue in chlorpyrifos-induced toxicity in rats. The protective effect can be due to scavenging MDA molecules by propolis active ingredients or inhibition of mitochondrial and cytosolic lipoperoxidation chain reactions [93]. Egyptian propolis of 200 mg/kg p.o. for 3 weeks decreases testicular oxidative stress, inflammatory, and apoptotic markers in doxorubicin-induced toxicity in rats due to its possession of phenolic compounds [15]. Egyptian propolis (50 mg/kg bw/day extract decreases dead and abnormal sperm and TBARS, and it increases testosterone, GSH, 17-ketosteroid reductase, CAT, and GST in aluminum chloride-induced toxicity in rats through its antioxidant properties [94].

Turkish propolis (100 mg/kg/day) prevented the rise in malondialdehyde, xanthine oxidase levels, and HSP-70 expression and improved testicular morphology and JTBS in methotrexate-induced toxicity in rats through scavenging free radicals and thereby protected against lipid peroxidation [95]. Similarly, the combination of Turkish propolis (200 mg/kg/days, gavage) and pollen (100 mg/kg/days, by gavage) decreases levels of TOS, NF-κB, and MDA using L-NAME (40 mg/kg, i.p.) for induction of hypertension in rats; this was done by inhibiting the functioning of inflammatory pathways [96]. The in vitro study carried out by [97] shows that Chilean propolis protects sperm membrane from the deleterious action of oxidative attack, reducing TBARS formation and LDH release by exhibiting a strong antioxidant activity of propolis. Similarly, 1 uL of Czech Republican propolis maintains sperm motility and improves the total mitochondrial respiratory efficiency in human spermatozoa through its antioxidant properties [98]. Egyptian propolis (50 mg/kg bw/day) improves the structure of seminiferous tubules, and their lumens were full of bundles of sperms. In addition, all the parameters of seminiferous tubules and total numbers of Sertoli cells, round spermatids, daily sperm production, and Leydig cells were ameliorated through decreases in the levels of free radicals and lactate dehydrogenase as a result of the presence of flavonoids [99]. Egyptian propolis administered to rabbits at 100, 200, and 300 mg/kg bw/day, respectively for two weeks (one week before and after mating) for five consecutive times shows that the bunnies belong to rabbits treated with bee propolis, which shows the best improvement for all the studied traits due its antioxidant nutrients, including vitamins, minerals, phenolic constituents, and enzymes [100].

Egyptian propolis (50 mg/kg bw) revealed significant decreases in CAT, SOD, GPx, and GST in chlorpyrifos-induced toxicity [93]. Rats treated with 3, 6, and 10 mg/kg/day of green Brazallian propolis show higher sperm production and greater epithelium height of the epididymis initial segment and no induction of oxidative stress, and the exact mechanism is still under investigation [101]. The co-administration of Turkish propolis (200 mg/kg/days, gavage) and pollen (100 mg/kg/days, by gavage) that lasted 14 of 28 days showed decreases in TOS, NF-κB, MDA, TAS levels, PON1, and CAT activities in testis tissue; it acted through its protective effect of antioxidant mechanisms [96]. Furthermore, Malaysian propolis (300 mg/kg bw) administered on streptozotocin-induced rats caused increases in testosterone level, steroidogenic, and sperm parameters by increasing penile cGMP and serum testosterone levels due to the presence of phenols [102] (Table 4).

Egyptian bee honey (100 g) mixed with 3 g of royal jelly and 1 teaspoon of bee bread intravaginally in humans shows an increase in pregnancy rate due to increase in sperm capacitation through its antioxidant and scavenging activities against free oxygen species [104]. The administration of Egyptian royal jelly (1 g/kg bw) for 1 month increased the testicular weight and the body of epididymus, sperm count, testosterone hormone, and glutathione level, and it also caused a decrease in sperm deformity percentage, while there were no significant differences in the prostate weight, seminal vesicles, percentage of live sperm, malondialdehyde level, and body weight through the central effect of royal jelly because it contains acetylcholine [105] in hydrogen peroxide (0.5%) in drinking water induced rats. Meanwhile, 100 mg/kg of royal jelly causes a decrease in the toxic effect of cyclosporine in testis of rats due to its antioxidant property [106]. Egyptian royal jelly administered at 200, 400, or 800 mg/kg body weight once a week (6 weeks) significantly boosts testosterone level, ejaculated volume, and seminal plasma fructose; improves sperm motility and sperm total output; reduces abnormal sperm and dead sperm due to the presence of vitamin C and amino acids; and increases spermatic concentration [107].

Turkish royal jelly (50 and 100 mg/kg) for 10 days decreases the malondialdehyde level and increases superoxide dismutase, catalase, and glutathione–peroxidase activities and increases the weights of testes, epididymis, seminal vesicles, and prostate along with epididymal sperm concentration and motility in cisplatin-induced in rats. Similarly, 50, 100, or 150 mg of Chinese royal jelly/kg twice per week, respectively, administered over a 20-week period shows a significant increase (p < 0.05) in rabbits’ sperm concentration, total sperm output, sperm motility, live sperm, and normal sperm in rabbits; it was suggested that amino acids and vitamins might have played a role [108]. Egyptian royal jelly (0.4%) and heparin administered to buffalo induces sperm acrosome reaction but also is effective for the in vitro fertilizing capacity of the cryopreserved buffalo spermatozoa as a result of possessing motility stimulants such as adenosine and adenosine monophosphate [7].

Iranian royal jelly (100 mg/kg bw) increases testicular weight, sperm count, motility, viability, and serum testosterone levels and decreases observed sperm deformity, DNA integrity, chromatin quality, and tissue MDA levels in streptozotocin-induced diabetic rats. This might be because of its antioxidant properties due to the presence of vitamins E and C [109]. Similarly, bleomycin-induced rats treated with Iranian royal jelly (100 mg/kg/day) for 48 days improved sperm parameters and testosterone levels as well as decreased MDA levels due to its antioxidant properties [110]. On the other hand, Iranian royal jelly of 0, 50, 100, and 150 mg/kg bw increases sperm and causes a significant upregulation of transcription factor E2f1 mRNA in taxol-induced toxicity [111]. Japanese royal jelly of 50 μg/g diet or 500 μg/g diet for 12 weeks increases the intensity of spermatogenesis and testosterone levels in hamsters via its antioxidant activity [112]. Japanese royal jelly (300 mg) administered for 6 months accelerates the conversion of DHEA-S to testosterone [113], while Turkish royal jelly of 400 mg/kg daily for 4 weeks caused caspase-3-positive cells to be significantly decreased in testicular apoptosis via its anti-apoptotic activity [114]. Twenty-eight adult Wistar rats administered with royal jelly (100 mg/kg bw) for 6 weeks showed increases in CAT and FRAP activities [115]. Rats induced with hydroxylurea (225 or 450 mg kg/bw/day) followed by administration of royal jelly (100 mg kg/bw/day) for 60 days revealed improved sperm quality, hormonal, and antioxidant status as well as histology architecture [116] (Table 5).

The administration of 0.5 g/kg/bw Malaysian bee bread for 12 weeks caused increases in testicular antioxidant enzymes, downregulated inflammation and apoptosis, and increased PCNA immunoexpression, as well as improved lactate transport, through its antioxidant, anti-inflammatory, and antiapoptotic properties [118,119] (Table 6).