Women’s life stages are based on their reproductive cycle. This cycle begins with menstruation and ends with menopause. Ageing is a natural phenomenon that affects all people and is linked to a general decline in the body’s function. In women, ageing is linked to and starts with menopause. There is also a higher risk of various age-related diseases and complaints during the menopause and postmenopause. For this reason, researchers were directed to find effective measures that could promote healthy ageing and extend life expectancy. Apitherapy is an alternative medicine that uses natural products from bees, such as honey, hive honey, bee milk, etc. Bee milk is a natural yellowish-white substance secreted by both the hypopharyngeal and mandibular glands of bees and is commonly used for feeding. beekeepers and young workers. Over the centuries, this natural product has been regarded as the gold mine of traditional and natural medicine because of its miraculous properties. Bee milk has long been used in commercial medical products. It has been found to have a wide range of functional properties, such as antibacterial, anti-inflammatory, vasodilatory, hypotensive, anticancer, estrogen-like, antihypercholesterolemic and antioxidant effects. This product is commonly used as an adjunctive treatment for a variety of conditions such as cardiovascular disease, Alzheimer’s disease, sexual dysfunction, diabetes. The main objective of this study is to highlight the effectiveness of the bee mothers’ milk supplement in alleviating menopausal symptoms and age-related diseases. We also sought to review the latest scientific findings on the composition of beekeepers’ milk to better understand its impact on human health.

1. Introduction

Menopause is a transitional phase in a woman’s life, during which a variety of changes occur in metabolism, physiology, mental and physical well-being [1]. Menopausal symptoms usually have a significant negative impact on overall quality of life and become psychosocially detrimental. Most of these symptoms are the result of estrogen withdrawal or long-term estrogen deficiency [2]. Postmenopausal women are at increased risk of developing atherosclerosis, cardiovascular disease, diabetes, mood disorders such as anxiety and depression, vasomotor symptoms (hot flushes, night sweats), osteoporosis and vaginal atrophy [3]. These problems are usually treated with hormone replacement therapy, but the risk of unwanted side effects such as breast cancer, abnormal uterine bleeding or breast tenderness sometimes outweighs the benefits, which is why people tend to use natural alternatives [4,5]. Natural treatments for menopause-related symptoms and complaints include phytoestrogens, natural molecules similar to human oestrogens, which are thought to prevent post-menopausal symptoms. Soya beans and red clover are the best-known natural alternatives to conventional hormone replacement therapy, but their effectiveness is still debated [6]. Apitherapy is a type of alternative medicine that uses natural products derived from honey bees, such as honey, hive honey, bee milk, bee bread and bee venom, whose medicinal properties have been described for centuries [7]. These products also showed their usefulness in the treatment of post-menopausal complaints. Bee milk, known as “superfood”, is a creamy substance secreted by the mandibular and hypopharyngeal glands of bees, used to feed the queen bee throughout her life and to feed worker bees at the larval stage [8]. Consumption of this magical liquid by honeybee larvae provides many advantages, such as their size, which is double that of worker bees, longer lifespan and better functioning of their reproductive system [9]. Bee milk production has increased significantly in recent years. Although there is a wealth of medical data on the use of bee milk worldwide, it has been used mainly in Asia. Recent reports showed the great potential of this natural product to improve human health. The pharmaceutical properties of bees’ milk have been widely studied, from animal models to humans. Although the mechanisms are still under investigation, it has attracted the attention of many researchers worldwide. Bee milk improves reproductive health, neurological diseases and has several biological properties such as antibacterial, vasodilatory, anti-inflammatory, anti-hypotensive, anti-cancer, anti-estrogenic, anti-hypercholesterolemic and antioxidant effects [13]. In recent years, mother bee’s milk has been reported as a valuable therapeutic agent [7,14] for healthy ageing and longevity [15]. In this article, we focus on studies on the biological effects of royal jelly during menopause and its mechanisms of action. Our aim is to bring all these studies together to better understand whether and how beekeeper’s milk could be a natural remedy for menopausal complaints and age-related diseases. Figure 1 illustrates the main biological effects of bee milk.

2. Chemical composition of bees’ milk

Bee milk is a rich source of proteins, peptides, sugars, fatty acids and other bioactive substances. Its variability generally depends on the vegetation biodiversity [16] and seasonal feeding conditions specific to each geographical area. The water content of bees’ milk accounts for 60-70% of the final composition. Bee milk is an acidic liquid and its pH ranges between 3.6 and 4.2 [17]. 2.1. Proteins and peptides Proteins are the most dominant milk constituents of the queen bee, after water. Almost 50% of the final composition is made up of proteins and various peptides. Of these, 80-90% are made up of MRJPs (the main milk proteins of the queen bee), also known as apalbumins [18]. MRJPs represent nine major protein families with molecular weights ranging from 49 to 87 kDa. They are called MRJP1-MRJP9 and are encoded by nine different genes [19]. MRJP1 is the most dominant of all the major protein families. It contains a monomeric glycoprotein known as royalactin, which activates the p70 S6 kinase. This kinase is responsible for increasing levels of juvenile hormone, which is essential for normal ovarian development and function [20]. Most of the health and metabolic benefits of bee milk are due to the glycosylated proteins in its composition [21,22]. The MRJP family is not the only protein family in bee milk. It contains small amounts of peptides such as aspirin, royal jelly and gels (character-I to character-IV) [23]. Of these, royalisin and gelsins exert antimicrobial effects and enhance the effectiveness of the immune response to common infections. 2.2. Amino acids Bee milk contains high levels of amino acids, especially essential amino acids [24]. The most expressed free amino acid in bees’ milk is lysine (62.43 mg/100 g). This is followed by varying amounts of cysteine, proline and aspartic acid. Recent studies [25] have shown that long-term supplementation with leucine, isoleucine and valine extracted from royal milk increases sirtuin 1 expression, mitochondrial biogenesis and reduces reactive oxygen species (ROS) production in skeletal muscle and myocardium. Under these conditions, supplementation with bees’ milk may alleviate age-related muscle dysfunction. 2.3. Sugars Carbohydrates make up almost 15% of the total composition of bees’ milk [26]. The main sugars are glucose and fructose and together they make up almost 90% of the final composition. Depending on the beekeeping diet, botanical origin, time of year and species of bee, glucose can account for almost 50-70% of total sugars, while sucrose only 0.8-3.6%. Other small amounts of oligosaccharides such as erlosin, trehalose, ribose, raffinose, gentiobioos or melibose can be found in the composition of bee milk [27]. 2.4. Lipids and fatty acids Lipids make up 7-18% of the bees’ milk content and 80-85% are dicarboxylic acids and hydroxy acids [28]. The most common fatty acids in bees’ milk are 10-hydroxy-2-decenoic acid (10H2DA), sebacic acid (SA) and 10-hydroxydecanoic acid (10-HDA). 10-HDA makes up 3.5% of freeze-dried bees’ milk and is the most stable compound [29]. In addition, it acts as a potent antibacterial agent, protecting bee larvae from bacterial infections in beehives [30]. It was reported that 10-HDA is a potent inhibitor of matrix metalloproteinases (MMPs), which promote tissue ageing and cause a number of inflammatory diseases such as arthritis. SA, 10-HDA and 10H2DA are able to mediate oestrogen signalling by increasing the activity of oestrogen receptors (ER). Suzuki et al. [31] reported that a number of lipid compounds extracted from the lactic acid of the bees (trans-2-decenoic acid, 10-hydroxy-trans-2-decenoic acid, 10-HDA and 24-methylene cholesterol) inhibited the binding of 17β-estradiol to ERβ. However, they had no effect on ERα binding. These findings provide strong evidence for the oestrogenic effects of milk compounds in the mother bee. 2.5. Other ingredients: vitamins, minerals, acetylcholine, polyphenols. Vitamins and minerals make up 0.8-3% of the fresh matter in milk products from bees. Vitamin B5 is the most abundant vitamin in the composition of bees’ milk, followed by niacin and minor amounts of vitamins A, C, E and vitamins B1, B2, B6, B8, B9 and B12 [17]. The main minerals are K, Ca, Na, Mg, Zn, Fe, Cu and Mn, in descending order. Bee milk also contains trace elements such as Co, Hb, Ba, W, Cr, Ni, V, Pb, Mo, whose concentrations are very stable [32]. Bees’ milk also contains nucleotides (e.g. guanosine, adenosine and uridine) and phosphates such as adenosine monophosphate, adenosine diphosphate and adenosine triphosphate. Adenosine N1-oxide is an oxidized molecule of adenosine [33, 34], which showed its neurogenicity and tropism on the central nervous system. It stimulates neurite outgrowth by inducing differentiation of PC12 cells into neuronal cells [34] and contributes to normal neuronal development [33]. Acetylcholine, known as a neurotransmitter, can also be found in the composition of bee milk (1 mg/g dry weight). Its consumption may prevent neurogenerative dysfunctions such as Alzheimer’s disease [35]. The flavonoids described in bee silicon can be divided into the following five categories: isoflavonoids (genistein and formononetin), flavones (apigenin, chrysin and luteolin), flavonols (kaemferol), flavonones (hesperetin, naringerin, isosacuranetin) and isoflavonoids (genistein). The phenolic content of bees’ milk is based on organic acids such as octanoic or dodecanoic acid and pinobanksin [36]. Figure 2 schematically illustrates the composition of bees’ milk and the main functional activities of its compounds.

3. Studies on the utility of bee milk as a therapeutic agent for post-menopausal symptoms and age-related diseases

Hormone replacement therapy is the most common treatment used by most women to reduce post-menopausal symptoms and improve their quality of life during this period. The most important drawback of this type of treatment is the high incidence of side effects, which is why its replacement by natural alternatives has been emphasised. The use of non-hormonal methods to reduce menopause-related symptoms and treat various pathologies is known as complementary medicine. It consists of the administration of plant products, phytoestrogens or food supplements [44]. Royal jelly is a traditional and natural product used by postmenopausal women [45] to improve and treat menopause-related complications and age-related pathologies due to its similarity to estrogens. The effects of breast milk during menopause are a real issue and many studies have been carried out on this topic. Unfortunately, there are only a small number of clinical trials in humans, and most of the trials have been carried out with ovaries removed in fetal models. 3.1. Oestrogen-like activity Royal jelly has shown estrogenic activity both in vitro and in vivo. This effect is mediated by interaction with estrogen receptors (ER). Daily administration of bees’ milk supported ovarian hormones and follicle development and improved fertility parameters in a rat model. Bee milk also improved oocyte maturation, improved redox status and activated oophorus glucose pathways [46]. Moreover, a recent study [47] showed that the administration of queen bee jelly in combination with exogenous progesterone similarly increased pregnancy rate and estrogenic response in Awassi ewes. Luteinising hormone (LH) and follicle-stimulating hormone (FSH) are sex hormones involved in reproduction. Their levels are controlled by oestrogen and inhibin. In addition, these hormones are involved in the natural ageing process. In young women, high levels of oestrogen decreased FSH and LH. During menopause, the reduction in follicle size associated with luteal remission affects the regular release of oestrogen and inhibin, leading to abnormal secretion of FSH. Supplementary consumption of bees’ milk with food was very beneficial in this process as it contains fatty acids, in particular 10-hydroxyl-2-decenoic acid. This compound increases the synthesis of oestrogens and keeps serum FSH and LH levels low. In addition, 10-hydroxyl-2-decenoic acid is highly effective in preventing age-related follicular depletion and enhancing hormonal regulation [48]. Studies in ovariectomized rats showed that bee milk competes with E2 for ERα and ERβ binding, but its affinity is weaker compared to phytoestrogens or diethylstilbestrol. Similarly, bee milk can restore VEGF expression in the uterus by increasing gene transcription in MCF-7 cells, while 20 mg/kg 17β-estradiol can restore expression of this factor in both the uterus and brain [45]. Clinical studies have shown that oral administration of bee milk (1 g/day) is able to reduce the severity of premenstrual syndrome and improve the quality of life of women of reproductive age [49]. In addition, during menopause and post-menopause, bee milk improves genitourinary syndrome, one of the most common complaints of women during these periods [50]. One of the aims of supplementing with bees’ milk is to improve quality of life in the post-menopausal period. Sharif et al. [51] carried out a survey of 200 women aged 45-60. Each subject was given either bee milk capsules (1 g per day) or a placebo for 2 months and the results were compared. The researchers observed a significant reduction in menopause scores after 8 weeks of consuming bee milk compared to the placebo group. Therefore, bee milk may alleviate post-menopausal symptoms such as hot flushes, night sweats and other menopause-related complaints, but research on this is conflicting. Quality of life during menopause is also affected by urinary incontinence or vulvovaginal atrophy, both of which are called urogenital syndrome. These complications have a negative impact on postmenopausal women’s psychosocial and partner relationships. To observe the therapeutic effect of bee milk in alleviating vulvovaginal atrophy, 90 postmenopausal women were randomly allocated to receive bee milk, conjugated estrogens or lubricated vaginal cream for 12 weeks [50]. After this period, vaginal cytology was assessed among the quality of life scores. The results showed an improvement in the quality of life scores of the first group receiving vaginal formula. In terms of vaginal cytology, the Pap test showed better results in the group treated with topical oestrogens compared with the other two groups. During menopause, a sudden drop in oestrogen levels affects the autonomic nervous system, leading to neurodegenerative diseases (e.g. Alzheimer’s disease), mood disorders (e.g. anxiety, depression) or headache, lower back or back pain. 42 postmenopausal women who blamed anxiety, back and lower back pain were recruited and randomly assigned to receive either 800 mg dextrin or 800 mg enzyme-treated bee milk for 3 months [52]. After this period, both the anxiety and back pain scores in the breast milk group decreased significantly compared to the placebo group. No adverse reactions were reported during the administration of enzyme-treated bees’ milk. 3.2. Action against cancer Other beneficial effects of bees’ milk include inhibition of tumour cell growth, tumour-related angiogenesis and activation of immune functions. Cancer is a common pathology in the elderly and cancer-related fatigue is a complication that further worsens the quality of life of these patients. In such cases, complementary medicine can be a valuable option to alleviate symptoms with minimal side effects. According to Mofid et al. [53] up to 50% of cancer patients experience cancer-related fatigue, and ingestion of both bees’ milk and processed honey can alleviate symptoms. They administered 5 ml of bees’ milk and processed honey twice daily to 26 patients and compared the results with 26 patients who received only 5 ml of honey for one month on the same regimen. The conclusion of this clinical trial was that the addition of bees’ milk to honey consumption is more effective in alleviating cancer-related fatigue. In women, the most common cancers are gynaecological cancers. Breast cancer is the most common during menopause and bee milk has shown its potential as a complementary cancer treatment. Bisphenol A (BPA) is one of the most common chemicals in the world that has structural similarities with oestrogens. This property allows BPA to bind strongly to human estrogen receptor y (ERRγ) [54]. Under these conditions, BPA is a risk factor for breast cancer in a time- and dose-dependent manner. Nakaya et al. [55] reported that bee milk inhibited the growth-promoting effect of BPA in vitro using MCF-7 cell lines. In the absence of BPA, bees’ milk had no effect on cell proliferation. RJP30 is a fraction of royal jelly obtained by precipitation with ammonium sulphate. In vitro, this fraction was cytotoxic to human cervical carcinoma cells (HeLa cell line). Only 7 days after the first treatment, cell density decreased by about 2.5 times [56]. Shirzad et al. [57] tumour cells were inoculated into 28 male Balb/c mice, and after inoculation the animals were orally administered different doses of honeydew jelly (100, 200 or 300 mg/kg). The tumour size was measured every 2 days from day 5 and the researchers observed a significant reduction in tumour size. 3.3. Hypocholesterolemic effect Menopause is a period associated with a high risk of cardiovascular disease. Dyslipidaemia is a major risk factor for the development of cardiovascular pathology. Because bee milk is rich in fatty acids with hypolipidemic properties, it is used in the post-menopausal population to rebalance the lipid profile. Despite the fact that bee milk is a powerful hypocholesterolemic and hypolipidemic agent, its active compounds and mechanisms of action that lower cholesterol levels have yet to be discovered. MRJP1 exerts the most potent hypocholesterolemic effect [43]. MRJP1 interacts with bile acids and increases the excretion of bile acids in faeces. It also induces an increased propensity to excrete cholesterol in faeces. This key protein in bee milk also increases the catabolism of cholesterol by the liver. Another mechanism of hypocholesterolaemia in beekeepers’ milk is an increase in the gene expression of the low-density lipoprotein receptor (LDLR). This molecule regulates the entry of cholesterol into the liver. In addition, in mice, bees’ milk reduced gene expression of a protein that binds the regulatory elements of squalene epoxidase and sterol, key factors in cholesterol biosynthesis [58]. Lambrinoudaki et al. [59] included 36 postmenopausal subjects in a prospective study and analysed their circulating cardiovascular risk markers and bone tissue metabolic parameters after three months of daily intake of 150 mg of bee milk. No significant changes in bone turnover parameters or circulating cardiovascular risk markers (protein S, protein C, antithrombin III and plasminogen activator inhibitor-1) were recorded. However, significant changes in the lipid profile were recorded. HDL-C (high-density lipoprotein cholesterol) values increased after daily consumption of bees’ milk, while LDL-C (low-density lipoprotein cholesterol) and total cholesterol (TC) values decreased significantly. Therefore, the supplementation of bee milk may offer a valuable alternative method to counterbalance the dyslipidemia associated with menopause. In healthy volunteers, daily consumption of bee milk (6 g per day for 4 weeks) resulted in a significant reduction in LDL-C and TC. No significant differences were observed between cases and controls in serum concentrations of HDL-C and TG [60]. A recent meta-analysis [61] reported that bee milk reduced TC and increased serum HDL-C levels in studies with long-term follow-up. In the same study it was mentioned that TG and LDL-C levels did not improve significantly. These findings suggest that this natural product may play an important role in protecting cardiovascular health by mitigating the damaging effects of elevated cholesterol. 3.4. Hypertensive effects Hypertension is one of the most common cardiovascular risk factors in older people. It can lead to myocardial infarction, heart failure, stroke and is usually associated with metabolic syndrome. Three peptides (Ile-Val-Tyr, Val-Tyr and Ile-Tyr) in bee milk inhibit angiotensin I converting enzyme activity and normalise systolic blood pressure after only 28 days of treatment in hypertensive rats. [62]. The antihypertensive and vasodilatory effects of breast milk were studied in hypertensive rats and isolated rabbit thoracic aortic rings [63]. UHT reduced systolic and diastolic blood pressure and increased NO levels in vivo. In addition, bee milk induced vasodilatation in the aortic rings of isolated rabbits. In addition, bee milk increased nitric oxide (NO) TC and cyclic guanosine monophosphate (cGMP) levels in the aortic rings. In conclusion, the antihypertensive effect of bee milk is related to NO production and vasodilatation is secondary to the action of muscarinic receptor agonists via the NO/cGMP pathway. 3.5. Effect on bone metabolism During menopause, the parameters of bone metabolism are usually altered and osteoporosis is one of the most common menopause-related complications. Bisphosphonates are the gold standard treatment for post-menopausal osteoporosis. These substances have a high affinity for bone minerals and bind to hydroxyapatite crystals on bone surfaces. Their effect is to down-regulate osteoclast-mediated bone resorption [64]. Bee milk is a natural alternative used to prevent osteoporosis and improve bone strength, and a number of studies have been carried out using animal models. Royal jelly was administered to ovariectomized rats daily for 3 months to analyse its effects on bone metabolism [65]. After this period, it was reported that femoral bone mineral density had not improved significantly. However, femur stiffness was higher in the study group compared with the control group, suggesting that beekeeper’s milk cannot prevent the onset of menopause-related osteoporosis, but it can improve bone strength. Contrary to these results, another study [66] confirmed that both enzyme-treated and bee milk can prevent osteoporosis. The explanation lies in the increased absorption of calcium in the gut. Hidaka et al. 17β-oestradiol or bees’ milk was administered to rats that had had their ovaries removed. Their findings showed that bee milk is almost as effective as hormone replacement therapy in preventing osteoporosis. In addition, the inability of royal jelly to inhibit calcium loss induced by parathyroid hormone and the development of osteoclast-like cells induced by the same hormone was highlighted using a mouse bone marrow culture model. 3.6. Anti-ageing effects Consumption of bees’ milk is associated with increased lifespan of bees and other species. This natural product may slow the onset of natural ageing and some age-related disorders. In addition, it has been shown that bee milk can extend life span through its components and is useful in improving quality of life during ageing [67]. The proteins and lipids in bees’ milk can prolong the lifespan of different species such as bees, nematodes, slugs or mice. Xin et al. [68] reported that MRJPs increased the longevity of Drosophila melanogaster by promoting an epidermal growth factor receptor-mediated pathway. In addition, roylactin had the same effect on Caenorhabditis elegans by facilitating EGF (epidermal growth factor) and EGFR (epidermal growth factor receptor) signalling pathways [69]. Regarding the effect on lifespan extension in mice, studies have shown that prolonged intragastric administration of milk from a mother bee prevented age-related weight loss, improved memory and slowed age-related thymus atrophy [70]. In addition, the treated animals had better physical performance compared to the control group: muscle stem cell progenitors increased and muscle atrophy decreased [70]. In addition, bee milk can significantly delay age-related motor functions [67]. It was reported that the lipid components of bee milk inhibit the natural ageing process of human cell cultures through two mechanisms: upregulation of EGF signalling and downregulation of insulin-like growth factor (IGF) [15]. 10-HDA is a major lipid compound in bee milk and has been shown to prolong the lifespan of Caenorhabditis elegans through nutritional signalling and TOR components [71]. An interesting question is whether the effects of bee milk on animal models can be extended to humans. Despite the paucity of studies in this area, the results showed that the anti-ageing effects of beeswool milk and its compounds on human cell lines support previous findings reported in model organisms. It has been shown that bee milk and its specific lipid compound 10-HDA can reduce cell senescence and stimulate the production of type I procollagen and transforming growth factor β1 (TGF-β1) [72,73]. Moreover, a recent study [74] using human fibroblast cells showed that MRJP induce increased cell proliferation, longer telomeres and slowed senescence. The skin is the body’s largest organ. During menopause and the natural ageing process, it is affected by a drop in oestrogen levels. In addition, changes in skin collagen levels cause oily skin to lose elasticity and firmness [75]. Royal jelly has been reported as an anti-ageing skin protectant that increases collagen production in rats that have had their ovaries removed [76]. It has been reported that after the administration of a 1% beeswax jelly to oestrogen-deficient Sprague-Dawley rat dams, type I procollagen protein levels in the skin of the animals increased. In addition, the restored collagen levels were very close to normal. In conclusion, bee milk can be considered as a valuable and effective dietary supplement against the natural ageing process of the skin in the post-menopausal period, but future clinical trials in humans are certainly needed. 3.7. Neuroprotective effect Menopause is a normal milestone associated with many hormonal changes. In this context, a number of neurological diseases can develop, which usually have a serious impact on the psychosocial life of post-menopausal women [77]. Anxiety, depression or loss of spatial memory are the most common complaints of postmenopausal women. In order to investigate the effects of bee milk on neurological disorders, a number of studies were carried out on animal models. Poor mental performance and neurodegenerative diseases such as Alzheimer’s are common among older people as a result of the ageing process. Royal jelly appears to stimulate mental functions through its neuroprotective effects. It was reported that daily consumption of bee milk strengthens memory and learning skills in honey bees and rats [78]. In addition, this natural product stimulates neurite outgrowth, induces hippocampal granule cell regeneration and protects the central nervous system from oxidative damage [33,79]. Consumption of breast milk is effective in alleviating menopause-related neurological disorders, but the mechanisms of action remain to be further elucidated. However, lowering cholesterol and beta-amyloid levels, increasing oestrogen levels and improving the haematoencephalic barrier appear to be the most cited mechanisms by which bee milk fulfils its neuroprotective role [34]. Zhang et al. [80] showed that purified bee milk peptides can inhibit β-amyloid 40 and 42 through the regulation of beta-secretase, being useful in alleviating diseases such as Alzheimer’s disease. In addition, bee milk improved structural brain imaging and behavioural abnormalities in cholesterol-fed rabbits. It acted by lowering levels of body weight, lipids, beta-amyloid, and acetylcholinesterase, which is linked to an increase in choline acetyltransferase in the brain [80]. Pyrzanowska et al. [81] showed that Greek bee milk was able to improve the memory of aged Wistar rats. They were administered to animals at 50 or 100 mg bee mother jelly powder/kg twice daily by gavage for 8 weeks. After this period, rats receiving 50 mg powder/kg showed a significant improvement in memory compared to controls. Another study [82] assessed spatial memory and depression-like behaviour in rats that had their ovaries removed after 82 days of ingestion of bee milk. This natural product improved memory and anti-depressive behaviour. In addition, brain weights and myelin galactolipids increased slightly after beekeeping compared to hormone replacement therapy. 3.8. Anti-diabetic effects Diabetes mellitus is a very common pathology in post-menopausal women. In recent years, new dietary supplements have been investigated for the treatment of these patients, with high therapeutic benefits and minimal side effects. In healthy humans, bee milk significantly lowered serum glucose and increased insulin concentrations [83]. Yoshida et al. [84] recently did a study with obese KK-Ay mice with 2. type of diabetes. 10 mg/kg of bees’ milk was administered by oral gavage. Insulin levels, body weight and plasma glucose were analysed after 4 weeks of daily treatment. The results showed partially suppressed body weight, which was associated with reduced glycaemia in the study group. But insulin resistance did not improve. The explanation lies in the inhibition of gluconeogenesis by bees’ milk through the reduction of glucose-6-phosphatase mRNA expression. In addition, this natural product induced the expression of adiponectin receptor-1, adiponectin, and phosphorylated AMP-activated protein kinase, resulting in the suppression of glucose-6-phosphatase, an enzyme essential for gluconeogenesis. Contrary to the results of Yoshida et al. [84], who do not mention a reduction in insulin resistance among the effects of bee milk, Zamami et al. [85] claimed that this food supplement could be very effective in preventing insulin resistance. After 8 weeks of daily administration at doses of 100 mg/kg or 300 mg/kg, plasma levels of TG and insulin decreased significantly and systolic blood pressure tended to decrease in ovariectomized rats. Thirty-two male Wistar rats with streptozotocin-induced diabetes were given 100 mg per kg of milk from the mother bee every day [86]. After six weeks, there was a significant improvement in urine levels of urea, creatinine, uric acid, albumin and histopathological findings in kidney and liver tissues. In addition, bee milk significantly improved TG, LDL-C, HDL-C, VLDL-C, total cholesterol and ApoA-1 levels in diabetic patients, thereby promoting glycaemic balance [87]. In view of all the studies and findings presented, we can consider bee milk as a golden supplement that can be used to alleviate post-menopausal symptoms and treat many age-related pathologies. However, further clinical studies in humans are needed to better monitor the beneficial effects, molecular mechanisms of action and potential side effects of this valuable natural and traditional product. In Tables 1 and 2, we summarised separately the studies conducted in humans and animals/cultures over the last 20 years to investigate the effectiveness of bee milk in the treatment of postmenopausal problems and complications. Figure 3 is a schematic representation of the beneficial effects of bee milk in alleviating menopausal symptoms and age-related diseases.

4. Side effects of bees’ milk

Bee milk is a natural product that is widely used around the world. However, a number of side effects of its consumption have been described. The main allergens in this product are MRPJ 1 and MRPJ2 [100] and these are common bee venom allergens. MRJPs can cause a number of allergic reactions in certain situations, such as asthma, dermatitis, skin rashes, eczema, bronchospasm, anaphylaxis, haemorrhagic colitis [101] or even anaphylactic shock and death [102]. A positive diagnosis of bee milk anaphylaxis is made on the basis of a positive prick test and systemic clinical signs. Oral allergy syndrome due to bee milk consumption has also been mentioned in the literature [103]. There were no reports of possible interactions between bee milk supplements and other medicinal products used concomitantly. However, Lee et al. [104] presented the case of an 87-year-old man who was on long-term warfarin treatment with the addition of bee milk capsules. He was referred to hospital because of haematuria and the most likely explanation for his symptoms was a possible interaction between warfarin and bee milk. For this reason, doctors should repeatedly inform their patients about possible drug interactions with food supplements.

5. Conclusions and future perspectives

Bee milk is widely used for a variety of medical and commercial purposes. Its biologically active compounds give this natural product a wide range of pharmaceutical applications with very few side effects. Accumulating evidence from recent studies has shown that bee pollen plays an important role in modulating natural ageing mechanisms. This product has demonstrated its effectiveness in relieving post-menopausal complaints. In addition, post-menopausal women could successfully use it as a dietary supplement for the treatment of age-related pathologies such as neurodegenerative diseases, diabetes, obesity, cancer, osteoporosis or cardiovascular pathologies. Unfortunately, there is a paucity of human clinical studies on the effects of royal jelly in the post-menopausal period, most of which have been conducted in animal models. We believe that this article paves the way for further research in this area. We think it is very important to investigate whether and by what mechanisms bee milk could improve sleep disturbances, hot flushes, post-menopausal headaches, anxiety or depression. In addition, the dosage and the period of administration are of greatest interest, as this can have a major impact on the final results. Therefore, further clinical studies are urgently needed to clarify the real value of this natural product as a dietary supplement during menopause. Source : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397171/