Royal Jelly

Scientific Name(s):Produced by the honeybee, Apis mellifera L.

Common Name(s): Royal jelly

Uses

Royal jelly has been studied for a variety of actions, including antimicrobial, antitumor, antihypertensive, and immunoregulatory activity. Additionally, effects on lipid profile, insulin-like action, and neurological and estrogenic effects have been demonstrated. However, clinical trials are lacking.

Dosing

Clinical trials are generally lacking in dosage recommendation. Small clinical trials have used 6 to 10 g royal jelly per day for 14 to 28 days in trials evaluating the effect on the lipid profile.

Contraindications

Contraindications have not been identified. Allergy to bee venom is considered a relative contraindication.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. Royal jelly possesses some estrogenic activity.

Interactions

Case reports of hematuria due to potentiation of warfarin have been documented.

Adverse Reactions

In many allergy patients, skin tests were positive for royal jelly. There have been case reports of allergy, acute exacerbation of asthma, anaphylaxis, and death.

Toxicology

Data are limited.

Royal jelly is a milky-white secretion produced by the hypopharyngeal and mandibular glands of worker honeybees of the species A. mellifera L . to induce differentiated growth and development of the queen bee. Royal jelly is the principal food of the honeybee queen. Because of this specialized nutrition, queen bees differ from workers in several ways; the queens are approximately twice the size, they lay approximately 2,000 eggs a day (female worker bees are infertile), and they live 5 to 8 years (approximately 40 times longer than worker bees). 1 These differences have led to the marketable assumption that ingestion of this product will do as much for humans as it does for bees; that is, increase size, improve fertility, and enhance longevity.

History

In many countries, royal jelly has been promoted widely as a commercially available medicine, health food, and cosmetic (as an emollient, moisturizer, and nourishing substance). It is used in traditional medicine for longevity in Europe and Asia. Royal jelly has been sold as a skin tonic and hair growth stimulant. 1 , 2 , 3

Chemistry

Royal jelly is composed of a complex mixture of water (50%), proteins (approximately 15%), sugars, lipids, vitamins, pheromones, amino acids, and minerals. 3

Other bioactive compounds have been identified using high performance liquid chromatography with fluorescence detection, and other electrophoretic and chromatographic techniques. 4 , 5

Fatty acids (including hydroxydecanoic acids) and sterols (including sitosterol, desmosterol, and methylenecholesterol), tryptophan, organic acid glycosides and monoglucosides glycopeptides, N-glycans, adenosine monophosphate N-oxide, apisimin, and a variety of major royal jelly proteins (including MRJP 1 to 9) have been identified. 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13

Uses and Pharmacology

Recent clinical trials are lacking and suggested pharmacologic effects are largely based on in vitro and animal model experiments.

Antibacterial activity

The protein royalisin found in royal jelly has potent in vitro antibacterial activity against gram-positive bacteria, but not against gram-negative bacteria. Hydroxydecanoic acid has in vitro bacteriostatic activity against Streptococcus aureus and Escherichia coli . These antibacterial components are believed to modestly enhance host defenses in honeybees. Additive or synergistic effects have been demonstrated in vitro with starch and honey. 14 , 15 , 16

Antioxidant activity

Antioxidant activity has been demonstrated with royal jelly using different in vitro and plant models, 17 , 18 , 19 , 20 while protection against oxidative stress-induced injury has been demonstrated in animal experiments. 18 , 21 , 22 , 23 Lipid peroxidation was inhibited in vitro and in experiments in rats; however, clinical data are lacking. 24

Antitumor activity

Royal jelly exhibited antitumor activity in experimental mouse leukemias, 25 and antiangiogenesis activity has also been demonstrated in vitro. 8 In human cervico/uterine carcinoma cells, some royal jelly fractions actively inhibited tumor growth and some did not. 10 One study found that royal jelly inhibited the growth-promoting effect of bisphenol on breast cancer MCF-7 cell lines, although another study showed that royal jelly enhanced MCF-7 proliferation. 13 , 26

Estrogenic activity

A number of studies evaluated royal jelly for relief of menopausal symptoms in the 1970s. However, recent clinical trials are lacking. Binding to estrogenic receptors (weak in comparison with diethstilbesterol and phytoestrogens), stimulation of mRNA expression in estrogen-responsive genes, and enhanced MCF-7 cell proliferation (which could be blocked by tamoxifen) have all been demonstrated in vitro. 13 , 27 Animal experiments in rats and ewes have also been conducted. Mild hypertrophy of the uterine luminal epithelium was achieved in rats supplemented with royal jelly, 13 while effects in ewes were varied. The effect of royal jelly supplementation on the onset of estrus has shown mixed results in ewes, with one trial showing no effect, while another exhibiting a shorter time to estrus compared with control and no difference compared with gonadotropin. 28 , 29 , 30 In both experiments, positive effects on pregnancy and lambing rates were demonstrated.

In tissue culture models and ovariectomized rats, a positive effect on osteoporosis was demonstrated. Increased calcium content and recovered bone mass were suggested to be the results of enhanced intestinal calcium absorption, rather than antagonism of the parathyroid hormone. 31

Hypertension

As a result of GI enzymatic hydrolysis, peptides derived from royal jelly demonstrated angiotensin 1–converting enzyme inhibitory activity in the spontaneously hypertensive rat. Other studies suggest trans-2-octenoic acid and hydroxydecanoic acid may account for the antihypertensive activity, but different fractions exert lesser or greater effects on duration of action. Royal jelly also was associated with a protective action and therapeutic activity in adrenaline-induced arrhythmia; however, no effect on heart rate has been observed. 32 , 33 , 34 , 35

Immunoregulatory activity

Various in vitro experiments have examined the actions of royal jelly and its constituents on the immune system. 4 , 36 , 37 , 38 , 39 , 40 Experiments in animals have demonstrated immunoregulatory activities, with the administration of royal jelly (500 to 1,500 mg/kg body weight/day) increasing survival in tumor-bearing mice and demonstrating positive effects on bone marrow stem cells and tumor-induced splenic hematopoiesis. 41 Additionally, auto-immunity was inhibited in systemic lupus erythematous-prone mice, with a delay in disease progression, decreased proteinuria, and increased survival. 42 Increased healing rates were observed in guinea pig tympanic membrane perforation. 43

In an in vitro study using lymphocytes from healthy volunteers and patients with Graves disease, royal jelly caused lymphocytes to proliferate and certain cytokines to be secreted, suggesting a potential immunomodulatory role in the management of this disease. 44

Insulin-like activity

In rats and in vitro experiments, insulin-like activity has been shown with royal jelly, and components may be structurally and functionally related to insulin. In an insulin-resistance model in rats, royal jelly reduced plasma insulin and triglycerides without affecting plasma glucose levels. 10 , 35

Lipid profile

Small clinical trials have demonstrated mixed effects on the lipid profile in humans. Royal jelly administered at 10 g/day for 14 days increased serum high-density lipid (HDL) levels in elderly participants, while a trend toward improved low-density lipid (LDL) levels was seen with no effect on serum triglycerides. 45 In another trial, 6 g/day for 4 weeks resulted in decreased serum total cholesterol and LDL, but had no effect on HDL or triglycerides. 46

Neurological activity

Traditional use of royal jelly in preventing aging has led to experiments regarding neuronal activities. Stimulation of production of glial cell line-derived neurotrophic factor has been demonstrated in the adult mouse brain, with a prediction of a neuroprotective role for royal jelly. 47 In addition, 10-hydroxy-trans-2-decanoic acid increased the generation of neurons from neural stem (progenitor) cells in vitro, 48 while adenosine monophosphate stimulated neuronal differentiation of pheochromocytoma PC12 cells. 49

Activity on the pituitary gland in middle-aged rats has also been demonstrated, 50 and orally administered royal jelly increased granule cell content in the hippocampus, with an observed improvement in induced cognitive impairment in mice. 48

Dosage

Clinical trials are generally lacking to recommend dosage. Small clinical trials have used 6 to 10 g/day for 14 to 28 days in trials evaluating the effect on hyperlipidemia. 45 , 46

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. Estrogenic effects of royal jelly and its constituents have been demonstrated in animals. 13 , 27 , 28 , 29 , 30 , 31

Interactions

Case reports of hematuria due to potentiation of warfarin have been documented. 51 Based on a few animal experiments, a theoretical potentiation of the activity of insulin exists. 10 , 35

Adverse Reactions

In many allergy patients, skin tests were positive for royal jelly. There have been reports of allergy, acute exacerbation of asthma, anaphylaxis, and death. 51 , 52 , 53 , 54 , 55 , 56

Toxicology

Toxicological assessments are lacking. A case report described mucosal hemorrhage, edema, and inflammation attributed to royal jelly consumption. A drug-induced lymphocyte stimulation test for royal jelly was positive. 57

Bibliography

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6. Schmitzová J, Klaudiny J, Albert S, et al. A family of major royal jelly proteins of the honeybee Apis mellifera L. Cell Mol Life Sci . 1998;54(9):1020-1030.
7. Bíliková K, Hanes J, Nordhoff E, Saenger W, Klaudiny J, Simúth J. Apisimin, a new serine-valine-rich peptide from honeybee ( Apis mellifera L.) royal jelly: purification and molecular characterization. FEBS Lett . 2002;528(1-3):125-129.
8. Izuta H, Chikaraishi Y, Shimazawa M, Mishimas, Hara H. 10-Hydroxy-2-decenoic acid, a major fatty acid from royal jelly, inhibits VEGF-induced angiogenesis in human umbilical vein endothelial cells. Evid Based Complement Alternat Med . 2009;6(4):489-494.
9. Zhang JZ, Xue XF, Zhou JH, et al. Determination of tryptophan in bee pollen and royal jelly by high-performance liquid chromatography with fluorescence detection. Biomed Chromatogr . 2009;23(9):994-998
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11. Hattori N, Nomoto H, Mishima S, et al. Identification of AMP N1-oxide in royal jelly as a component neurotrophic toward cultured rat pheochromocytoma PC12 cells. Biosci Biotechnol Biochem . 2006;70(4):897-906.
12. Kodai T, Umebayashi K, Nakatani T, Ishiyama K, Noda N. Compositions of royal jelly II. Organic acid glycosides and sterols of the royal jelly of honeybees ( Apis mellifera ). Chem Pharm Bull (Tokyo) . 2007;55(10):1528-1531.
13. Suzuki KM, Isohama Y, Maruyama H, et al. Estrogenic activities of fatty acids and a sterol isolated from royal jelly. Evid Based Complement Alternat Med . 2008;5(3):295-302.
14. Supabphol R. Antibacterial activity of royal jelly royalisin: potent antibacterial protein from royal jelly. Warasan Phesatchasat . 1995;22:33-38.
15. Boukraâ L, Meslem A, Benhanifia M, Hammoudi SM. Synergistic effect of starch and royal jelly against Staphylococcus aureus and Escherichia coli . J Altern Complement Med . 2009;15(7):755-757.
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17. Jamnik P, Goranovic D, Raspor P. Antioxidative action of royal jelly in the yeast cell. Exp Gerontol . 2007;42(7):594-600.
18. El-Nekeety AA, El-Kholy W, Abbas NF, Ebaid A, Amra HA, Abdel-Wahhab MA. Efficacy of royal jelly against the oxidative stress of fumonisin in rats. Toxicon . 2007;50(2):256-269.
19. Nagai T, Inoue R, Suzuki N, Nagashima T. Antioxidant properties of enzymatic hydrolysates from royal jelly. J Med Food . 2006;9(3):363-367.
20. Liu JR, Yang YC, Shi LS, Peng CC. Antioxidant properties of royal jelly associated with larval age and time of harvest. J Agric Food Chem . 2008;56(23):11447-11452.
21. Silici S, Ekmekcioglu O, Eraslan G, Demirtas A. Antioxidative effect of royal jelly in cisplatin-induced testes damage. Urology . 2009;74(3):545-551.
22. Kanbur M, Eraslan G, Silici S, Karabacak M. Effects of sodium fluoride exposure on some biochemical parameters in mice: evaluation of the ameliorative effect of royal jelly applications on these parameters. Food Chem Toxicol . 2009;47(6):1184-1189.
23. Kanbur M, Eraslan G, Beyaz L, et al. The effects of royal jelly on liver damage induced by paracetamol in mice. Exp Toxicol Pathol . 2009;61(2):123-132.
24. Guo H, Ekusa A, Iwai K, Yonekura M, Takahata Y, Morimatsu F. Royal jelly peptides inhibit lipid peroxidation in vitro and in vivo. J Nutr Sci Vitaminol (Tokyo) . 2008;54(3):191-195.
25. Townsend GF, Morgan JF, Hazlett B. Activity of 10-hydroxydecenoic acid from royal jelly against experimental leukaemia and ascitic tumours. Nature . 1959;183(4670):1270-1271.
26. Nakaya M, Onda H, Sasaki K, Yukiyoshi A, Tachibana H, Yamada K. Effect of royal jelly on bisphenol A-induced proliferation of human breast cancer cells. Biosci Biotechnol Biochem . 2007;71(1):253-255.
27. Mishima S, Suzuki KM, Isohama Y, et al. Royal jelly has estrogenic effects in vitro and in vivo. J Ethnopharmacol . 2005;101(1-3):215-220.
28. Kridli RT, Al-Khetib SS. Reproductive responses in ewes treated with eCG or increasing doses of royal jelly. Anim Reprod Sci . 2006;92(1-2):75-85.
29. Husein MQ, Haddad SG. A new approach to enhance reproductive performance in sheep using royal jelly in comparison with equine chorionic gonadotropin. Anim Reprod Sci . 2006;93(1-2):24-33.
30. Kridli RT, Husein MQ, Humphrey WD. Effect of royal jelly and GnRH on the estrus synchronization and pregnancy rate in ewes using intravaginal sponges. Small Rumin Res . 2003;49(1):25-30.
31. Hidaka S, Okamoto Y, Uchiyama S, et al. Royal jelly prevents osteoporosis in rats: beneficial effects in ovariectomy model and in bone tissue culture model. Evid Based Complement Alternat Med . 2006;3(3):339-348.
32. Matsui T, Yukiyoshi A, Doi S, Sugimoto H, Yamada H, Matsumoto K. Gastrointestinal enzyme production of bioactive peptides from royal jelly protein and their antihypertensive ability in SHR. J Nutr Biochem . 2002;13(2):80-86.
33. Librowski T, Czarnecki R. Comparative analysis of Apistmul Crataegi Forte and royal jelly in the experimental heart action disturbance. Herba Pol . 2000;46(3):145-150.
34. Takaki-Doi S, Hashimoto K, Yamamura M, Kamei C. Antihypertensive activities of royal jelly protein hydrolysate and its fractions in spontaneously hypertensive rats. Acta Med Okayama . 2009;63(1):57-64.
35. Zamami Y, Takatori S, Goda M, et al. Royal jelly ameliorates insulin resistance in fructose-drinking rats. Biol Pharm Bull . 2008;31(11):2103-2107.
36. Okamoto I, Taniguchi Y, Kunikata T, et al. Major royal jelly protein 3 modulates immune responses in vitro and in vivo. Life Sci . 2003;73(16):2029-2045.
37. Taniguchi Y, Kohno K, Inoue S, et al. Oral administration of royal jelly inhibits the development of atopic dermatitis-like skin lesions in NC/Nga mice. Int Immunopharmacol . 2003;3(9):1313-1324.
38. Oka H, Emori Y, Kobayashi N, Hayashi Y, Nomoto K. Suppression of allergic reactions by royal jelly in association with the restoration of macrophage function and the improvement of Th1/Th2 cell responses. Int Immunopharmacol . 2001;1(3):521-532.
39. Vucevic D, Melliou E, Vasilijic S, et al. Fatty acids isolated from royal jelly modulate dendritic cell-mediated immune response in vitro. Int Immunopharmacol . 2007;7(9):1211-1220.
40. Gasic S, Vucevic D, Vasilijic S, Antunovic M, Chinou I, Colic M. Evaluation of the immunomodulatory activities of royal jelly components in vitro. Immunopharmacol Immunotoxicol . 2007;29(3-4):521-536.
41. Bincoletto C, Eberlin S, Figueiredo CA, Luengo MB, Queiroz ML. Effects produced by royal jelly on haematopoiesis: relation with host resistance against Ehrlich ascites tumour challenge. Int Immunopharmacol . 2005;5(4):679-688.
42. Mannoor MK, Shimabukuro I, Tsukamotoa M, Watanabe H, Yamaguchi K, Sato Y. Honeybee royal jelly inhibits autoimmunity in SLE-prone NZB x NZW F1 mice. Lupus . 2009;18(1):44-52.
43. Calli C, Tugyan K, Oncel S, et al. Effectiveness of royal jelly on tympanic membrane perforations: an experimental study. J Otolaryngol Head Neck Surg . 2008;37(2):179-184.
44. Erem C, Deger O, Ovali E, Barlak Y. The effects of royal jelly on autoimmunity in Graves' disease. Endocrine . 2006;30(2):175-183.
45. Münstedt K, Henschel M, Hauenschild A, von Georgi R. Royal jelly increases high density lipoprotein levels but in older patients only. J Altern Complement Med . 2009;15(4):329-330.
46. Guo H, Saiga A, Sato M, et al. Royal jelly supplementation improves lipoprotein metabolism in humans. J Nutr Sci Vitaminol (Tokyo) . 2007;53(4):345-348.
47. Hashimoto M, Kanda M, Ikeno K, et al. Oral administration of royal jelly facilitates mRNA expression of glial cell line-derived neurotrophic factor and neurofilament H in the hippocampus of the adult mouse brain. Biosci Biotechnol Biochem . 2005;69(4):800-805.
48. Hattori N, Ohta S, Sakamoto T, Mishima S, Furukawa S. Royal jelly facilitates restoration of the cognitive ability in trimethyltin-intoxicated mice. [published online ahead of print April 17, 2009] Evid Based Complement Alternat Med . doi:10.1093/ecam/nep029.
49. Hattori N, Nomoto H, Fukumitsu H, Mishima S, Furukawa S. Royal jelly and its unique fatty acid, 10-hydroxy-trans-2-decenoic acid, promote neurogenesis by neural stem/progenitor cells in vitro. Biomed Res . 2007;28(5):261-266.
50. Narita Y, Ohta S, Suzuki KM, Nemoto T, Abe K, Mishima S. Effects of long-term administration of royal jelly on pituitary weight and gene expression in middle-aged female rats. Biosci Biotechnol Biochem . 2009;73(2):431-433.
51. Lee NJ, Fermo JD. Warfarin and royal jelly interaction. Pharmacotherapy . 2006;26(4):583-586.
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53. Testi S, Cecchi L, Severino M, et al. Severe anaphylaxis to royal jelly attributed to cefonicid. J Investig Allergol Clin Immunol . 2007;17(4):281.
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57. Yonei Y, Shibagaki K, Tsukada N, et al. Case report: haemorrhagic colitis associated with royal jelly intake. J Gastroenterol Hepatol . 1997;12(7):495-499.

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