Natural Standard - Royal jelly.pdf

30/6/2014 Natural Standard - Royal jelly

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Royal jellyNatural Standard Professional Monograph, Copyright © 2014 (www.naturalstandard.com).

Synonyms/Common Names/Related Substances

10-Hydroxy-2-decenoic acid, amino acids, apilak, apisin, B vitamins, bee royal jelly, bee saliva, bee spit, bidro, biotin, carbohydrates,dipeptide YY, DNA, enzymes, flavonoids, gelée royale (French), gelatin, glycoprotein, honey bee milk, honey bee's milk, honeybeeroyal jelly, honeybee royal jelly-derived collagen production-promoting factor, honeybees (Apis mellifera), hormones, inositol, jaleareal (Spanish), jelleines, lait des abeilles (French), lipids, lyophilized royal mletsitse, major royal jelly protein 3, MEL 174 (final waterextract of RJ), MEL 247 (dry powder of RJ), minerals, natural royal jelly. neopterin, organic acid glycosides (monoglucosides of 10-hydroxy-2E-decenoic and 10-hydroxydecanoic acids), peptides, protein, RNA, royal bee jelly, royalisin, sterols (including (24Z)-stigmasta-5,24(28)-dien-3beta-ol-7-one, (24Z)-stigmasta-5,24(28)-diene-3beta,7beta-diol, (24Z)-stigmasta-5,24(28)-diene-3beta,7alpha-diol, and (24Z)-stigmast-24(28)-ene-3beta,5alpha,6beta-triol), vitamin A, vitamin C, vitamin D, vitamin E.

Combination Products: Pedyphar® (natural royal jelly and panthenol in an ointment base) (1), Melbrosia® (pollen, perga [fermentedpollen], hydroxypropylmethyl cellulose, lyophilized royal mletsitse [royal jelly], acerola extract), Lady 4 (evening primrose oil,damiana, ginseng, royal jelly).

Clinical Bottom Line/Effectiveness

Brief Background

According to secondary sources, royal jelly is a gelatinous secretion from hypopharyngeal and mandibular glands of young nurseworker bees (Apis mellifera). The secretion is used as food for the queen bee, resulting in an increased life span over other bees.Royal jelly is a milky-white liquid high in carbohydrates, protein, lipids, vitamins, minerals, antibiotic compounds, and enzymes.

Royal jelly is used commonly in general health maintenance. It is also used for gastrointestinal and hormonal uses, as well as toreduce signs and symptoms of aging, and to improve mood, inflammation, blood pressure, and cholesterol levels. It is occasionallyused in cosmetic products for skin problems.

There is insufficient clinical evidence supporting the use of royal jelly.

Due to a high risk of allergic potential and increased respiratory symptoms, royal jelly should be avoided in individuals with anyexisting allergies, as well in as those with asthma.

Scientific evidence for Common/Studied Uses

Indication Grade

Diabetic foot ulcers C

Exercise performance C

Hyperlipidemia C

Male infertility C

Menopause C

Hay fever D

Historical or Theoretical Uses That Lack Sufficient Evidence

Adrenal gland stimulation, aging (2), Alzheimer's disease (3), antibiotic (4;5;6), anemia, antioxidant (7;8), antiviral (9), anxiety,appetite stimulant, arrhythmia (10), arthritis, asthma (11), bone fractures, burns, cancer (12;13;14), cardiovascular disease (15),chronic fatigue syndrome (16), cognitive enhancement, cosmetic uses (17), depression, diabetes (18), endocrine disorders, generalhealth maintenance (mibyou) (19), growth (13), hair tonic (gray hair, growth), hepatoprotection, high blood pressure (20;18),immunomodulation (21;22;23;24;25), infections, inflammation, insomnia, kidney disease, malnutrition, mood (26), neuroprotection(18), ocular disorders (27), osteoporosis, pancreatitis, Parkinson's disease (3), premenstrual syndrome, quality of life (26), reducingside effects of chemotherapy or radiotherapy (28), respiratory tract infections (29), shivering (feeling cold) (30), skin problems,strength (asthenia), stress, systemic lupus erythematosus, ulcers, vasodilator (31), warts (32), weight loss, wound healing (33;34).

Expert Opinion & Historic/Folkloric Precedent

According to a review, when royal jelly is used as a food, filtering is lacking and particles are present; however, in wound care, royaljelly is passed through fine filters in order to remove pollen and other allergenic impurities (35).

Melbrosia®, a combination product containing royal jelly, was a frequently used herbal medication by surgery patients (36). Theconsumption habits of bee products, such as royal jelly, were examined in the elderly in Spain (37). Further details are lacking.

Various reviews on royal jelly have been published (details are lacking) (38;39;40).

Royal Jelly herb is not on the U.S. Food and Drug Administration (FDA) Generally Recognized as Safe (GRAS) list.

Brief Safety Summary

Possibly Safe: When used by otherwise healthy adults at commonly used doses.

Possibly Unsafe: When used in individuals with cardiovascular disease or blood coagulation disorders or those using hypotensives,antilipemics, or anticoagulant or antiplatelet agents, due to case reports of angioedema related to an anaphylactic reaction (41),decreased blood pressure in animal models (20;42;18), increased triglycerides following use of a combination product containing royaljelly (43), hemorrhagic colitis (including abdominal pain and bloody diarrhea) (44), hematuria and an elevated international normalized

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ratio (INR) in a man on stable warfarin (45), reduced arrhythmia in animal research (10), and heart palpitations, according tosecondary sources. When used in individuals with skin disorders, due to case reports of urticaria (41;46), facial pruritus anderythema, generalized pruritus, and wheals (47); facial edema and facial erythema (48); exacerbation of dermatitis (49); eczema (46);and skin irritations, according to secondary sources. When used in individuals with diabetes or those using agents that modulateblood sugar levels, due to a report in a diabetic animal model suggesting that there was a reduction in serum levels of insulin and thehomeostasis model assessment ratio (18;50), and in human research, royal jelly resulted in an increased insulinogenic index (26).When used in individuals with gastrointestinal disorders, due to case reports of hemorrhagic colitis, including abdominal pain andbloody diarrhea (44), eosinophilic gastroenteritis (51), and gastrointestinal discomfort, according to secondary sources. When used inindividuals with neurological disorders, due to a report of vertigo, numbness in fingers, and impaired consciousness related toanaphylaxis (47), as well as side effects related to the central nervous system symptoms and insomnia, according to secondarysources. When used in individuals with eye disorders, due to a report of congestion of the conjunctivae related to anaphylaxis (48).When used in individuals with psychiatric disorders, due to reports of agitation and anxiety, according to secondary sources. Whenused in individuals with hormonal imbalances or those using hormonal agents, according to in vitro research suggesting that royaljelly activated estrogen receptors (52) and inhibited the bisphenol A-induced proliferation of MCF-7 cancer cells (14), and in humanresearch, royal jelly resulted in increased testosterone (26); however, effects on hormone levels were lacking in other human research(53), and use of herbal combination products containing royal jelly reduced menopausal symptoms (54;43;53;55). When used inindividuals with immune disorders or those using immunomodulating agents, as immunological effects have been shown in bothanimal and in vitro research, such as delayed onset of systemic autoimmunity and decreased interleukin (IL)-10, as well asautoantibodies against ssDNA, dsDNA, and erythrocytes, and the number of splenic autoreactive B cells (21); induced proliferation oflymphocytes and alterations in interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha levels (22); and stimulated or inhibited Tcell proliferation and increased or decreased IL-2 production (depending on concentrations) (23). When used in children and pregnantor lactating women, due to insufficient safety and efficacy information.

Likely Unsafe: When used in individuals with asthma or other respiratory diseases, as well as in individuals with known allergy orsensitivity to royal jelly, honey, other bee products, bee stings, ragweed, mugwort, wheat or yeast, or conifer or poplar trees, or inthose with any other known previous allergies, due to reports of life-threatening respiratory distress, bronchospasm, wheezing,dyspnea, and asthma, including a fatal case, as well as many other reports of allergic reactions, and suggestions that the potentialfor allergic reactions increases in individuals with a previous known allergy, according to both published and secondary sources(56;57;58;41;59;60;61;47;48;62;63;46;64;65;49;66;67;68;69). When royal jelly is used that has not been preserved (dried orencapsulated), as, according to secondary sources, bacterial contamination is possible due to the difficulty of preserving the raw formof royal jelly.

Dosing/Toxicology

General

Doses may be based on those most commonly used in available trials, or on historical practice. However, with natural products it isoften not clear what the optimal doses are to balance efficacy and safety. Preparation of products may vary from manufacturer tomanufacturer, and from batch to batch within one manufacturer. Because it is often not clear what the active component(s) of aproduct is, standardization may not be possible, and the clinical effects of different brands may not be comparable.

Standardization

There is no well-known standardization for royal jelly. According to secondary sources, royal jelly may contain 60-66% water, withreduced water levels increasing the quality of the product. The authors also suggested that royal jelly is sensitive to oxidation andsudden temperature changes; consumption as a capsule is preferred, as the difficulty of preserving the raw form may result inbacterial contamination.

According to secondary sources, royal jelly is available in various forms, including its pure state, in honey, in freeze-dried form incapsules or tablets, as a liquid, or as an ingredient in ointments, salves, or other cosmetic or skin care products. According tosecondary sources, pure-state royal jelly must be kept refrigerated. According to secondary sources, freeze-dried products maintaintheir nutrient value. According to secondary sources, clinical benefits of synthetic royal jelly are lacking.

Adults (age ≥ 18)

Oral:

General: According to secondary sources, a small spoonful of royal jelly may be taken fresh daily (further details are lacking) (70).

Hyperlipidemia: 30-150mg of royal jelly was taken daily for 4-6 weeks orally or 30mg of royal jelly was given sublingually daily for anunclear duration (71;15). 10g of refrigerated royal jelly was taken daily each evening for 14 days (72).

Topical:

Insufficient available evidence.

Intravenous/Intramuscular:

Hyperlipidemia: 10-100mg of royal jelly was injected daily for 3-11 weeks (further details are lacking) (71).

Children (age < 18)

Oral:

Hay fever: 150mg of royal jelly was taken as capsules twice daily for 3-6 months during pollen season (73).

Toxicology

A fatal case of royal jelly-induced asthma has been reported (58). Anaphylactic reactions to royal jelly have been reported. Symptomshave included local angioedema, generalized urticaria, dysphonia and bronchospasm (41); severe facial pruritus and erythema,followed by vertigo, numbness in the fingers, generalized pruritus, wheals, dyspnea, wheezing, and impaired consciousness (47); anddyspnea, severe facial edema and erythema, and congestion of the conjunctivae (48). Khoury et al. reported on the investigation intothe death of an Australian woman with a history of asthma (74). It was concluded that the cause of death was acute anaphylaxis dueto royal jelly ingestion.

In humans, life-threatening respiratory distress, bronchospasm, wheezing, dyspnea, and asthma, including a fatal case, have beenrelated to royal jelly use (56;57;58;41;59;60;61;47;48;62;63;46). Allergic reactions to royal jelly were mentioned in a five-yeartoxicology study of traditional and herbal remedies and dietary supplements (64).

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Anaphylactic treatments have included antihistamines, corticosteroids, and fluid therapy (41;47).

The Australian government ordered a review of goods containing royal jelly following the death of a woman after consuming such aproduct (75).

According to secondary sources, due to difficulty preserving the raw form of royal jelly, bacterial contamination is possible (76).However, according to Fleche, the natural bacterial environment of royal jelly, as well as its physical and chemical properties, resultsin little bacterial or chemical contamination (77).

Precautions/Contraindications

Allergy

Avoid with known allergy or sensitivity to royal jelly, honey, or other bee products. According to secondary sources, royal jelly mayalso be harmful for individuals allergic to bee stings, honey, or ragweed pollen (present in bee pollen). According to secondarysources, oral royal jelly should be avoided by those allergic to bee pollen, honey, or conifer and poplar trees.

In humans, respiratory distress, bronchospasm, wheezing, dyspnea, and asthma, including a fatal case, have been related to royaljelly use (56;57;58;41;59;60;61;47;48;62;63;46).

Khoury et al. reported on the investigation into the death of an Australian woman with a history of asthma (74). It was concluded thatthe cause of death was acute anaphylaxis due to royal jelly ingestion.

An anaphylactic reaction to royal jelly in a 15 year-old girl included local angioedema, generalized urticaria, dysphonia, andbronchospasm (41). The patient was treated with antihistamines and corticosteroids. A non-commercially prepared specific IgE toroyal jelly was positive (0.8 KU/l) (further details are lacking). In other patients with asthma following ingestion of royal jelly IgE,antibodies to 18 royal jelly proteins (including a 55kDa protein) were detected in the sera (60;63). These authors also suggested thata direct relationship was lacking between IgE antibody reactivity to bee venom allergens and to royal jelly proteins; however, IgEantibody reactivity to royal jelly proteins was detected in about half of the subjects tested with allergies to inhalant and/or foodallergens. In a Japanese man, symptoms of anaphylaxis included severe facial pruritus and erythema, followed by vertigo, numbnessin his fingers, generalized pruritus, wheals, dyspnea, wheezing, and impaired consciousness (47). The patient was treated withcorticosteroid and fluid therapy; he tested positive in an allergy test to royal jelly. A 26 year-old Japanese woman who developedanaphylaxis after drinking a beverage of crude royal jelly and honey tested positive to royal jelly on a prick test (65). The major royaljelly protein 3 was suggested as the possible allergen in a case report of royal jelly-induced anaphylaxis in a 26 year-old woman (48).She presented with dyspnea, severe facial edema and facial erythema, and congestion of the conjunctivae.

According to the results of a questionnaire, 461 of 1,472 subjects had used royal jelly in the past; of those, nine subjects reported 14adverse reactions (46). The adverse reactions included urticaria, eczema, rhinitis, and acute asthma. Thirteen of 176 subjects and 23out of 300 consecutive asthma clinic attendees skin-tested positive to pure royal jelly. Of these 36 subjects in total who testedpositive to royal jelly, 35 were also atopic to other common allergens. The authors determined that there were positive associationsbetween a positive royal jelly skin test and atopy and between adverse reactions to royal jelly and a history of clinical allergy. Anassociation between royal jelly symptoms and previous royal jelly intake was lacking.

In a case report, a woman with previous exposure to royal jelly as a nutrient tested positive on patch testing following exacerbation ofdermatitis; two of 10 control subjects also tested positive to royal jelly (49).

Royal jelly allergy has been presented in other case reports (66). One of these patients was also allergic to mugwort. Harwood et al.determined that there was a link between allergies to royal jelly and to mugwort (67). Baldo et al. suggested a between ingestion andinhalation for allergies to wheat, yeast, and royal jelly (68).

In a separate study, severe anaphylaxis to royal jelly was attributed to cefonicid (69).

Allergic reactions to royal jelly were also mentioned in a five-year toxicology study of traditional and herbal remedies and dietarysupplements (64). According to secondary sources, the risk of allergy to royal jelly increases in individuals with a known previousallergy.

Adverse Effects/Post-Market Surveillance

General: The most common adverse reactions to royal jelly include allergic reactions, mainly respiratory symptoms associated withanaphylactic symptoms (56;57;58;41;59;60;61;47;48;62;63). Other adverse effects are mainly dermatological or gastrointestinal innature. In a clinical trial, adverse effects that occurred more often in the royal jelly group included difficulty or inability to swallow thecapsules (N=2 from the placebo group; N=4 from the treatment group); other adverse effects were equal between groups or were morecommon in the placebo group (73).

Cardiovascular: An anaphylactic reaction to royal jelly in a 15 year-old girl included local angioedema (41). In animal research,peptides from royal jelly decreased blood pressure in a hypertensive model (20;42). In a diabetic animal model, there was a tendencyto decrease blood pressure (18). According to secondary sources, side effects included heart palpitations. Use of Melbrosia®, acombination product containing royal jelly, reduced total and LDL cholesterol and increased HDL cholesterol and triglycerides (43).

Dermatologic: An anaphylactic reaction to royal jelly in a 15 year-old girl included generalized urticaria (41) which was also reportedelsewhere (46). In a Japanese man, symptoms of anaphylaxis included severe facial pruritus and erythema, generalized pruritus, andwheals (47). An anaphylactic woman presented with severe facial edema and facial erythema (48). In a case report of a woman whohad ingested royal jelly as a nutrient, there was an exacerbation of dermatitis when it was applied to her feet and she was found totest positive to royal jelly upon patch testing (49). According to secondary sources, skin irritations have been caused by topical useof royal jelly. According to a questionnaire, adverse effects related to royal jelly allergy included eczema (46).

Endocrine: In a diabetic animal model, there was a reduction in serum levels of insulin and the homeostasis model assessment ratio(used to quantify insulin resistance) (18;50).

Gastrointestinal: In a case report, royal jelly intake was associated with hemorrhagic colitis, including abdominal pain and bloodydiarrhea (44). A case of eosinophilic gastroenteritis induced by royal jelly was discussed; however, further details are lacking (51).According to secondary sources, adverse effects include gastrointestinal discomfort.

Hematologic: In a case report, royal jelly intake was associated with hemorrhagic colitis, including abdominal pain and bloodydiarrhea (44). Hematuria and an elevated INR occurred in an 87 year-old African-American man on stable warfarin for three monthswho had started taking royal jelly (45).

Neurologic/CNS: In a Japanese man, symptoms of anaphylaxis included vertigo, numbness in his fingers, and impairedconsciousness (47). According to secondary sources, side effects include central nervous system symptoms and insomnia.

Ocular/Otic: An anaphylactic woman presented with congestion of the conjunctivae (48).

Psychiatric: According to secondary sources, side effects include agitation and anxiety.

Pulmonary/Respiratory: In humans, respiratory distress, bronchospasm, wheezing, dyspnea, and asthma, including a fatal case,have been related to royal jelly use (56;57;58;41;59;60;61;47;48;62;63;46). In a Japanese man, symptoms of anaphylaxis included

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dyspnea and wheezing (47). An anaphylactic woman presented with dyspnea (48). According to a questionnaire, adverse effectsrelated to royal jelly allergy included rhinitis (46).

Other: An anaphylactic reaction to royal jelly in a 15 year-old girl included dysphonia (41). According to secondary sources, adverseeffects include anecdotal weight gain.

Precautions/Warnings/Contraindications

Use cautiously in individuals with cardiovascular disease or blood coagulation disorders or those using hypotensives, antilipemics, oranticoagulant or antiplatelet agents, due to case reports of angioedema related to an anaphylactic reaction (41), decreased bloodpressure in animal models (20;42;18), increased triglycerides following use of a combination product containing royal jelly (43),hemorrhagic colitis (including abdominal pain and bloody diarrhea) (44), hematuria and an elevated international normalized ratio (INR)in a man on stable warfarin (45), reduced arrhythmia in animal research (10), and heart palpitations, according to secondary sources.

Use cautiously in individuals with skin disorders, due to case reports of urticaria (41;46); facial pruritus and erythema, generalizedpruritus, and wheals (47); facial edema and facial erythema (48); exacerbation of dermatitis (49); eczema (46); and skin irritations,according to secondary sources.

Use cautiously in individuals with diabetes or those using agents that modulate blood sugar levels, due to a report in a diabetic animalmodel suggesting that there was a reduction in serum levels of insulin and the homeostasis model assessment ratio (18;50), and inhuman research, royal jelly resulted in an increased insulinogenic index (26).

Use cautiously in individuals with gastrointestinal disorders, due to case reports of hemorrhagic colitis, including abdominal pain andbloody diarrhea (44), eosinophilic gastroenteritis (51), and gastrointestinal discomfort, according to secondary sources.

Use cautiously in individuals with neurological disorders, due to a report of vertigo, numbness in fingers, and impaired consciousnessrelated to anaphylaxis (47), as well as side effects related to the central nervous system symptoms and insomnia, according tosecondary sources.

Use cautiously in individuals with eye disorders, due to a report of congestion of the conjunctivae related to anaphylaxis (48).

Use cautiously in individuals with psychiatric disorders, due to reports of agitation and anxiety, according to secondary sources.

Use cautiously in individuals with hormonal imbalances or those using hormonal agents, according to in vitro research suggestingthat royal jelly activated estrogen receptors (52) and inhibited the bisphenol A-induced proliferation of MCF-7 cancer cells (14), and inhuman research, royal jelly resulted in increased testosterone (26); however, effects on hormone levels were lacking in other humanresearch (53), and use of herbal combination products containing royal jelly reduced symptoms of menopause (54;43;53;55).

Use cautiously in individuals with immune disorders or those using immunomodulating agents, as immunological effects have beenshown in both animal and in vitro research, such as delayed onset of systemic autoimmunity and decreased IL-10, production ofautoantibodies against single- and double-strand DNA, and erythrocytes, and the number of splenic autoreactive B cells (21);induction of proliferation of lymphocytes and alterations in IFN-gamma and TNF-alpha levels (22); and stimulation or inhibition of T cellproliferation and increased or decreased IL-2 production (depending on concentrations) (23).

Use cautiously in children and pregnant or lactating women, due to insufficient safety and efficacy information.

Avoid use in individuals with asthma or other respiratory diseases, as well as in individuals with known allergy or sensitivity to royaljelly, honey, other bee products, bee stings, ragweed, mugwort, wheat or yeast, or conifer or poplar trees, or in those with any otherknown previous allergies, due to reports of life-threatening respiratory distress, bronchospasm, wheezing, dyspnea, and asthma(including a fatal case), as well as many other reports of allergic reactions, and suggestions that the potential for allergic reactionsincreases in individuals with a previous known allergy, according to both published and secondary sources(56;57;58;41;59;60;61;47;48;62;63;46;64;65;49;66;67;68;69).

Avoid consumption of royal jelly that has not been preserved by drying or encapsulation, as, according to secondary sources, there isdifficulty preserving the raw form of royal jelly, and therefore there is a potential for bacterial contamination.

Pregnancy & Lactation

Not recommended due to a lack of sufficient data.

Information on royal jelly's effects on lactation is lacking in the National Institute of Health's Lactation and Toxicology Database(LactMed).

Interactions

Most herbs and supplements have not been thoroughly tested for interactions with other herbs, supplements, drugs, or foods. Theinteractions listed below are based on reports in scientific publications, laboratory experiments, or traditional use. You should always readproduct labels. If you have a medical condition, or are tak ing other drugs, herbs, or supplements, you should speak with a qualifiedhealthcare provider before starting a new therapy.

Royal jelly/Drug Interactions

Antiallergy agents: In animal research, royal jelly had antiallergic effects in a mouse model of immediate hypersensitivity (78).However, anaphylaxis and other allergic reactions to royal jelly have been shown in numerous human case reports and other reports(56;57;58;41;59;60;61;47;48;62;63;65;49;66;67;68;69;64).

Antiarrhythmic agents: In animal research, royal jelly protected against and reduced adrenaline induced arrhythmia (10).

Antibiotics: In vitro, royalisin, a protein in royal jelly, had antibacterial activity against Gram-positive bacteria, but not Gram-negativebacteria (4;79). In vitro, the minimum inhibitory concentration (MIC) of royal jelly against Pseudomonas aeruginosa was 4% (5), androyal jelly blocked the fucose>fructose/mannose-binding lectin (PA-IIL) (involved in biofilm formation and animal cell adhesion) ofPseudomonas aeruginosa (6). In vitro, jelleines-I-III had antimicrobial effects (80).

Anticoagulants and antiplatelets: In a case report, royal jelly intake was associated with hemorrhagic colitis, including abdominalpain and bloody diarrhea (44). Hematuria and an elevated INR occurred in an 87 year-old African-American man on stable warfarin forthree months who had started taking royal jelly (45).

Antidiabetic agents: In a diabetic animal model, there was a reduction in serum levels of insulin and the homeostasis modelassessment ratio (18;50). In human research, royal jelly resulted in an increased insulinogenic index (26).

Antihypertensives: In animal research, peptides from royal jelly decreased blood pressure in a hypertensive model (20;42). In adiabetic animal model, there was a tendency to decrease blood pressure (18).

Anti inflammatory agents: In vitro, royal jelly inhibited the production of proinflammatory cytokines by activated macrophages (81).

Antilipemic agents: In human research, royal jelly decreased levels of total cholesterol and increased levels of serum phospholipids,resulting in a reduction of the ratio of cholesterol to phospholipids (71). In healthy adults, royal jelly decreased total and low-densitylipoprotein (LDL) cholesterol, perhaps by decreasing levels of very-low-density lipoprotein (VLDL) (82). Effects on high-density

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lipoprotein (HDL) cholesterol and triglycerides were lacking. In separate human research, nonsignificant decreases in blood lipidsoccurred (15), or changes were limited (details are lacking) (72). Use of Melbrosia®, a combination product containing royal jelly,reduced total and LDL cholesterol and increased HDL cholesterol and triglycerides (43).

Antineoplastic agents: According to secondary sources, anticancer effects of royal jelly have been shown in animal models. In vitro,protein fractions of royal jelly were cytotoxic to cancer cells (13). In vitro, royal jelly inhibited the bisphenol A-induced proliferation ofMCF-7 cancer cells; however, it was without effect in the absence of bisphenol A (14). In animal research, royal jelly protectedagainst the mutagenic effects of Adriamycin® (doxorubicin) and/or cobalt gamma radiation (28).

Antipsychotic agents: According to secondary sources, side effects include agitation and anxiety.

Cardiovascular agents: In human research, nonsignificant decreases in fibrinolytic activity occurred (15).

Corticosteroids: The effect of royal jelly on the exertion of corticoids has been discussed (83). Further details are lacking.

Dermatologic agents: In animal research, royal jelly inhibited the development of atopic dermatitis-like skin lesions (84). In animalresearch, royal jelly lacked benefit on healing following tympanic membrane perforation; however, use of royal jelly increased thethickness of the membranes by increasing the organization of the connective tissue (33). A component originally labeled honeybeeroyal jelly-derived collagen production-promoting factor (HRJ-CPF) was found to be 10-hydroxy-2-decenoic acid; 10-hydroxy-2-decenoic acid increased collagen production in vitro (34). However, allergic reactions to royal jelly have resulted in generalizedurticaria (41); severe facial pruritus and erythema, generalized pruritus, and wheals (47); severe facial edema and facial erythema (48);and an exacerbation of dermatitis (49). According to secondary sources, skin irritations and eczema have also been reported.

Exercise performance agents: In animal research, a protein from royal jelly reduced fatigue and accumulation of serum lactate andammonia associated with a forced swim (85). In human research, a combination product containing royal jelly improved exerciseperformance (86;87).

Gastrointestinal agents: In a case report, royal jelly intake was associated with hemorrhagic colitis, including abdominal pain andbloody diarrhea (44). A case of eosinophilic gastroenteritis induced by royal jelly was discussed; however, further details are lacking(51). According to secondary sources, adverse effects include gastrointestinal discomfort.

Growth hormone: In vitro, protein fractions of royal jelly stimulated the growth of insect cells (13).

Hepatoprotective agents: In animal research, royal jelly protected against acetaminophen-induced liver damage (88).

Hormonal agents: In vitro, royal jelly activated estrogen receptors (52) and inhibited the bisphenol A-induced proliferation of MCF-7cancer cells; however, it was without effect in the absence of bisphenol A (14). The estrogenic activities of royal jelly and its fatty acidand sterol constituents have been the topic of discussion (89;19;90). In human research, royal jelly resulted in increased testosterone(26); however, effects on hormone levels were lacking in other human research (53). The influence of royal jelly on the excretion ofgonadotropins in healthy males has been discussed (91).

Immune agents: Immunological effects have been shown in both animal and in vitro research, such as delayed onset of systemicautoimmunity and decreased IL-10, as well as autoantibodies against ssDNA, dsDNA, and erythrocytes, and the number of splenicautoreactive B cells (21); induced proliferation of lymphocytes and alterations in IFN-gamma and TNF-alpha levels (22); andstimulated or inhibited T cell proliferation and increased or decreased IL-2 production (depending on concentrations) (23).

Menopausal agents: Use of herbal combination products containing royal jelly reduced symptoms of menopause (54;43;53;55). Theeffect of royal jelly alone is not clear.

Neurologic agents: In isolated and perfused mesenteric vascular beds of a diabetic animal model, royal jelly reduced thesympathetic nerve-mediated vasoconstrictor response to periarterial nerve stimulation, as well as the potentiation of the calcitoningene-related peptide nerve-mediated vasodilator response to periarterial nerve stimulation (18). Also, in vitro, royal jelly and 10-hydroxy-trans-2-decenoic acid increased the generation of neurons and decreased the generation of astrocytes from neuralstem/progenitor cells (92). However, in a Japanese man, symptoms of anaphylaxis included vertigo, numbness in his fingers, andimpaired consciousness (47), and according to secondary sources, side effects include central nervous system symptoms andinsomnia.

Ophthalmic agents: An anaphylactic woman presented with congestion of the conjunctivae (48).

Radioprotective drugs: In animal research, royal jelly protected against the mutagenic effects of Adriamycin® (doxorubicin) and/orcobalt gamma radiation (28).

Respiratory agents: In humans, respiratory distress, bronchospasm, wheezing, dyspnea, and asthma, including a fatal case, havebeen related to royal jelly use (56;57;58;41;59;60;61;47;48;62;63). In a Japanese man, symptoms of anaphylaxis included dyspneaand wheezing (47). An anaphylactic woman presented with dyspnea (48). According to secondary sources, adverse reactions to royaljelly have included rhinitis.

Vasodilators: In animal research, a water-soluble fraction of royal jelly had vasodilating effects on dog femoral artery (31).

Warfarin: In a case report, royal jelly intake was associated with hemorrhagic colitis, including abdominal pain and bloody diarrhea(44). Hematuria and an elevated INR occurred in an 87 year-old African-American man on stable warfarin for three months who hadstarted taking royal jelly (45).

Wound healing agents: In animal research, royal jelly lacked benefit on healing following tympanic membrane perforation; however,use of royal jelly increased the thickness of the membranes by increasing the organization of the connective tissue (33). Acomponent originally labeled honeybee royal jelly-derived collagen production-promoting factor (HRJ-CPF) was found to be 10-hydroxy-2-decenoic acid; 10-hydroxy-2-decenoic acid increased collagen production in vitro (34).

Royal jelly/Herb/Supplement Interactions

Antiallergy agents: In animal research, royal jelly had antiallergic effects in a mouse model of immediate hypersensitivity (78).However, anaphylaxis and other allergic reactions to royal jelly have been shown in numerous human case reports and other reports(56;57;58;41;59;60;61;47;48;62;63;65;49;66;67;68;69;64).

Antiarrhythmics: In animal research, royal jelly protected against and reduced adrenaline induced arrhythmia (10).

Antibacterials: In vitro, royalisin, a protein in royal jelly had antibacterial activity against Gram-positive bacteria, but not Gram-negative bacteria (4;79). In vitro, the minimum inhibitory concentration (MIC) of royal jelly against Pseudomonas aeruginosa was 4%(5), and royal jelly blocked the fucose>fructose/mannose-binding lectin (PA-IIL) (involved in biofilm formation and animal cell adhesion)of Pseudomonas aeruginosa (6). In vitro, jelleines-I-III had antimicrobial effects (80).

Anticoagulants and antiplatelets: In a case report, royal jelly intake was associated with hemorrhagic colitis, including abdominalpain and bloody diarrhea (44). Hematuria and an elevated INR occurred in an 87 year-old African-American man on using ananticoagulant for three months who had started taking royal jelly (45).

Hypoglycemics: In a diabetic animal model, there was a reduction in serum levels of insulin and the homeostasis model assessmentratio (18;50). In human research, royal jelly resulted in increased insulinogenic index (26).

Anti-inflammatory herbs and supplements: In vitro, royal jelly inhibited the production of proinflammatory cytokines by activatedmacrophages (81).

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Antineoplastics: According to secondary sources, anticancer effects of royal jelly have been shown in animal models. In vitro,protein fractions of royal jelly were cytotoxic to cancer cells (13). In vitro, royal jelly inhibited the bisphenol A-induced proliferation ofMCF-7 cancer cells; however, it was without effect in the absence of bisphenol A (14). In animal research, royal jelly protectedagainst the mutagenic effects of Adriamycin® (doxorubicin) and/or cobalt gamma radiation (28).

Antioxidants: Enzymatic hydrolysates of royal jelly had antioxidant effects in vitro (7). In vivo and in vitro, peptides from royal jellyinhibited lipid peroxidation (8). Further details are lacking.

Antipsychotics: According to secondary sources, side effects include agitation and anxiety.

Cardiovascular herbs and supplements: In human research, nonsignificant decreases in fibrinolytic activity occurred (15).

Dermatologic agents: In animal research, royal jelly inhibited the development of atopic dermatitis-like skin lesions (84). In animalresearch, royal jelly lacked benefit on healing following tympanic membrane perforation; however, use of royal jelly increased thethickness of the membranes by increasing the organization of the connective tissue (33). A component originally labeled honeybeeroyal jelly-derived collagen production-promoting factor (HRJ-CPF) was found to be 10-hydroxy-2-decenoic acid; 10-hydroxy-2-decenoic acid increased collagen production in vitro (34). However, allergic reactions to royal jelly have resulted in generalizedurticaria (41); severe facial pruritus and erythema, generalized pruritus, and wheals (47); severe facial edema and facial erythema (48);and an exacerbation of dermatitis (49). According to secondary sources, skin irritations and eczema have also been reported.

Exercise performance agents: In animal research, a protein from royal jelly reduced fatigue and accumulation of serum lactate andammonia associated with a forced swim (85). In human research, a combination product containing royal jelly improved exerciseperformance (86;87).

Gastrointestinal herbs and supplements: In a case report, royal jelly intake was associated with hemorrhagic colitis, includingabdominal pain and bloody diarrhea (44). A case of eosinophilic gastroenteritis induced by royal jelly was discussed; however, furtherdetails are lacking (51). According to secondary sources, adverse effects include gastrointestinal discomfort.

Ginseng: Zhang et al. published the analysis of ginseng royal jelly with respect to constituents specific to ginseng, as well as 10-hydroxy-2-decenoic acid (93). According to secondary sources, royal jelly and ginseng may be used in combination.

Growth agents: In vitro, protein fractions of royal jelly stimulated the growth of insect cells (13).

Hepatoprotective agents: In animal research, royal jelly protected against acetaminophen-induced liver damage (88).

Honey: In vitro, honey increased the antibacterial effects of royal jelly against Pseudomonas aeruginosa (5). According to secondarysources, royal jelly and honey may be used in combination.

Hormonal herbs and supplements: In vitro, royal jelly activated estrogen receptors (52) and inhibited the bisphenol A-inducedproliferation of MCF-7 cancer cells; however, it was without effect in the absence of bisphenol A (14). The estrogenic activities of royaljelly and its fatty acid and sterol constituents have been the topic of discussion (89;19;90). In human research, royal jelly resulted inincreased testosterone (26); however, effects on hormone levels were lacking in other human research (53). The influence of royal jellyon the excretion of gonadotropins in healthy males has been discussed (91).

Antilipemics: In human research, royal jelly decreased levels of total cholesterol and increased levels of serum phospholipids,resulting in a reduction of the ratio of cholesterol to phospholipids (71). In healthy adults, royal jelly decreased total and low-densitylipoprotein (LDL) cholesterol, perhaps by decreasing levels of very-low-density lipoprotein (VLDL) (82). Effects on high-densitylipoprotein (HDL) cholesterol and triglycerides were lacking. In separate human research, nonsignificant decreases in blood lipidsoccurred (15), or changes were limited (details are lacking) (72). Use of Melbrosia®, a combination product containing royal jelly,reduced total and LDL cholesterol and increased HDL cholesterol and triglycerides (43).

Hypotensives: In animal research, peptides from royal jelly decreased blood pressure in a hypertensive model (20;42). In a diabeticanimal model, there was a tendency to decrease blood pressure (18).

Immunomodulators: Immunological effects have been shown in both animal and in vitro research, such as delayed onset ofsystemic autoimmunity and decreased IL-10, as well as autoantibodies against ssDNA, dsDNA, and erythrocytes, and the number ofsplenic autoreactive B cells (21); induced proliferation of lymphocytes and alterations in IFN-gamma and TNF-alpha levels (22); andstimulated or inhibited T cell proliferation and increased or decreased IL-2 production (depending on concentrations) (23).

Menopausal agents: Use of herbal combination products containing royal jelly reduced symptoms of menopause (54;43;53;55). Theeffect of royal jelly alone is not clear.

Neurologic herbs and supplements: In isolated and perfused mesenteric vascular beds of a diabetic animal model, royal jellyreduced the sympathetic nerve-mediated vasoconstrictor response to periarterial nerve stimulation, as well as the potentiation of thecalcitonin gene-related peptide nerve-mediated vasodilator response to periarterial nerve stimulation (18). Also, in vitro, royal jelly andits 10-hydroxy-trans-2-decenoic acid increased the generation of neurons and decreased the generation of astrocytes from neuralstem/progenitor cells (92). However, in a Japanese man, symptoms of anaphylaxis included vertigo, numbness in his fingers, andimpaired consciousness (47), and according to secondary sources, side effects include central nervous system symptoms andinsomnia.

Ocular agents: An anaphylactic woman presented with congestion of the conjunctivae (48).

Radioprotective agents: In animal research, royal jelly protected against the mutagenic effects of Adriamycin® (doxorubicin) and/orcobalt gamma radiation (28).

Respiratory agents: In humans, respiratory distress, bronchospasm, wheezing, dyspnea, and asthma, including a fatal case, havebeen related to royal jelly use (56;57;58;41;59;60;61;47;48;62;63). In a Japanese man, symptoms of anaphylaxis included dyspneaand wheezing (47). An anaphylactic woman presented with dyspnea (48). According to secondary sources, adverse reactions to royaljelly have included rhinitis.

Vasodilator herbs and supplements: In animal research, a water-soluble fraction of royal jelly had vasodilating effects on dogfemoral artery (31).

Wound-healing agents: In animal research, royal jelly lacked benefit on healing following tympanic membrane perforation; however,use of royal jelly increased the thickness of the membranes by increasing the organization of the connective tissue (33). Acomponent originally labeled honeybee royal jelly-derived collagen production-promoting factor (HRJ-CPF) was found to be 10-hydroxy-2-decenoic acid; 10-hydroxy-2-decenoic acid increased collagen production in vitro (34).

Royal jelly/Food Interactions

Honey: In vitro, honey increased the antibacterial effects of royal jelly against Pseudomonas aeruginosa (5). According to secondarysources, royal jelly and honey may be used in combination.

Royal jelly/Lab Interactions

Blood lipids: In human research, royal jelly decreased levels of total cholesterol and increased levels of serum phospholipids,resulting in a reduction of the ratio of cholesterol to phospholipids (71). In healthy adults, royal jelly decreased total and low-densitylipoprotein (LDL) cholesterol, perhaps by decreasing levels of very-low-density lipoprotein (VLDL) (82). Effects on high-density

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lipoprotein (HDL) cholesterol and triglycerides were lacking. In separate human research, nonsignificant decreases in blood lipidsoccurred (15), or changes were limited (details are lacking) (72). Use of Melbrosia®, a combination product containing royal jelly,reduced total and LDL cholesterol and increased HDL cholesterol and triglycerides (43).

Blood pressure: In animal research, peptides from royal jelly decreased blood pressure in a hypertensive model (20;42). In a diabeticanimal model, there was a tendency to decrease blood pressure (18).

Coagulation parameters: In a case report, royal jelly intake was associated with hemorrhagic colitis, including abdominal pain andbloody diarrhea (44). Hematuria and an elevated INR occurred in an 87 year-old African-American man on stable warfarin for threemonths who had started taking royal jelly (45).

Fibrinolytic activity: In human research, nonsignificant decreases in fibrinolytic activity occurred (15).

Hormones: In human research, royal jelly resulted in increased testosterone (26); however, effects on hormone levels were lacking inother human research (53). The influence of royal jelly on the excretion of gonadotropins in healthy males has been discussed (91).Further details are lacking. In human research, royal jelly resulted in increased testosterone (26).

Immune parameters: Immunological effects have been shown in both animal and in vitro research, such as delayed onset ofsystemic autoimmunity and decreased IL-10, as well as autoantibodies against ssDNA, dsDNA, and erythrocytes, and the number ofsplenic autoreactive B cells (21); induced proliferation of lymphocytes and alterations in IFN-gamma and TNF-alpha levels (22); andstimulated or inhibited T cell proliferation and increased or decreased IL-2 production (depending on concentrations) (23). In animalresearch, royal jelly had antiallergic effects in a mouse model of immediate hypersensitivity, and the major royal jelly protein 3(MRJP3) was found to suppress IL-4 production, IL-2, and IFN-gamma by T cells (78).

Inflammatory parameters: In vitro, royal jelly inhibited the production of proinflammatory cytokines by activated macrophages (81).

Insulin: In a diabetic animal model, there was a reduction in serum levels of insulin and the homeostasis model assessment ratio(18;50).

Red blood cells: In human research, royal jelly resulted in increased red blood cell counts and hematocrit (26).

Serum ammonia: In animal research, a protein from royal jelly reduced fatigue and accumulation of serum lactate and ammoniaassociated with a forced swim (85).

Serum lactate: In animal research, a protein from royal jelly reduced fatigue and accumulation of serum lactate and ammoniaassociated with a forced swim (85).

Royal jelly/Nutrient Depletion

Cholesterol: In human research, royal jelly decreased levels of total cholesterol (71;82). In separate human research, nonsignificantdecreases in blood lipids occurred (15), or changes were limited (details are lacking) (72). Use of Melbrosia®, a combination productcontaining royal jelly, reduced total cholesterol and increased triglycerides (43).

Mechanism of Action

Pharmacology

Constituents: Biotin was measured in royal jelly (94). According to secondary sources, royal jelly contains B vitamins (including highlevels of B5 and B6), as well as vitamins A, C, D, and E, DNA, minerals, enzymes, hormones, 18 amino acids, and gelatin (95;96).According to secondary sources, 1g of royal jelly contains the following: vitamin B1: 1.5-7.4mcg; vitamin B2: 5.3-10.0mcg; vitaminB6: 2.2-10.2mcg; niacin: 91.0-149.0mcg; pantothenic acid: 65.0-200.0mcg; biotin: 0.9-3.7mcg; inositol: 78.0-150.0mcg; folic acid:0.16-0.50mcg; and vitamin C (trace). Vitamin E was lacking in this report, and vitamins A and D are claimed to be lacking in royaljelly, according to other secondary sources. According to secondary sources, royal jelly contains antibacterial and antibioticcomponents. According to secondary sources, minerals in royal jelly include calcium, copper, iron, phosphorus, potassium, silicon,and sulfur.

According to secondary sources, royal jelly is 60-70% water, 10-16% carbohydrates, 3-6% lipids, and 12-15% protein.

Components isolated from royal jelly include organic acid glycosides (monoglucosides of 10-hydroxy-2E-decenoic and 10-hydroxydecanoic acids) and sterols (including (24Z)-stigmasta-5,24(28)-dien-3beta-ol-7-one, (24Z)-stigmasta-5,24(28)-diene-3beta,7beta-diol, (24Z)-stigmasta-5,24(28)-diene-3beta,7alpha-diol, and (24Z)-stigmast-24(28)-ene-3beta,5alpha,6beta-triol) (97).

Both protein and nonprotein nitrous substances have been isolated, including 12 different types of proteins, oligopeptides high inhistidine, and high concentrations of lysine, proline, beta-alanine, and glutamic acid (98).

A component originally labeled honeybee royal jelly-derived collagen production-promoting factor (HRJ-CPF) was found to be 10-hydroxy-2-decenoic acid (34).

Royalisin was purified from royal jelly (79). Dipeptide YY was isolated from royal jelly (20). Jelleine-I, jelleine-II, jelleine-III, and jelleine-IV were purified from royal jelly (80).

The effects of royal jelly may be related to constituent flavonoids (99).

According to a review, neopterin was found in royal jelly (24). According to secondary sources, royal jelly is rich in nucleic acids,RNA, and DNA, and contains gelatin.

Zhang et al. published the analysis of ginseng royal jelly with respect to constituents specific to ginseng, as well as 10-hydroxy-2-decenoic acid (93).

Kimura et al. analyzed the structures of N-linked sugar chains from 350kDa royal jelly glycoprotein found to stimulate the proliferationof human monocytes (100). The structures fell into the category of oligomannose-type sugar chains.

Nakajin et al. published the methods involving high-performance liquid chromatography using a reversed-phase stationary phase toquantify 10-hydroxy-2-decenoic acid in raw royal jelly, and granules and tablets containing royal jelly (101). Feng et al. developed athin-layer chromatographic method for the determination of 10-hydroxy-2-decenoic acid in gel preparations (102).

Adipocyte effects: In vitro, protein fractions of royal jelly increased the percent of mature adipocytes in a preadipocyte culture (13).

Antiaging effects: In animal research, royal jelly reduced tissue DNA oxidative damage and increased life span (2).

Antiallergy effects: In animal research, royal jelly had antiallergic effects in a mouse model of immediate hypersensitivity (78). Themajor royal jelly protein 3 (MRJP3) was found to suppress IL-4, IL-2, and IFN-gamma production by T cells.

Antiarrhythmic effects: In animal research, royal jelly protected against and reduced adrenaline-induced arrhythmia (10).

Antibacterial effects: In vitro, royalisin, a protein in royal jelly, had antibacterial activity against Gram-positive bacteria, but notGram-negative bacteria (4;79). In vitro, the minimum inhibitory concentration (MIC) of royal jelly against Pseudomonas aeruginosawas 4% (5). The addition of honey increased the antibacterial effects. In vitro, royal jelly blocks the fucose>fructose/mannose-bindinglectin (PA-IIL) (involved in biofilm formation and animal cell adhesion) of Pseudomonas aeruginosa (6). The mannosylatedglycoproteins of royal jelly were thought to play a role. In vitro, jelleines-I-III had antimicrobial effects (80).

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The antibacterial effects of bee products were the scope of a review (35).

Antidiabetic effects: In a diabetic animal model, there was a tendency to decrease blood pressure and a significant reduction inserum levels of insulin and the homeostasis model assessment ratio (18;50). In isolated and perfused mesenteric vascular beds ofthese animals, royal jelly reduced the sympathetic nerve-mediated vasoconstrictor response to periarterial nerve stimulation, as wellas the potentiation of the calcitonin gene-related peptide nerve-mediated vasodilator response to periarterial nerve stimulation. Effectson norepinephrine-induced vasoconstriction and calcitonin gene-related peptide-induced vasodilation were lacking.

Anti-inflammatory effects: In vitro, royal jelly inhibited the production of proinflammatory cytokines by activated macrophages (81).

Antineoplastic effects: According to secondary sources, anticancer effects of royal jelly have been shown in animal models. Intumor cells in vitro, royal jelly inhibited N-acetylation and metabolism of 2-aminofluorene (2-AF) (12). In vitro, protein fractions of royaljelly were cytotoxic to cancer cells (13). In vitro, royal jelly inhibited the bisphenol A-induced proliferation of MCF-7 cancer cells;however, it was without effect in the absence of bisphenol A (14).

In animal research, the role of 10-hydroxy-2-decenoic acid from royal jelly was investigated on the nude mice solid tumor model NHG-1 from human glioma cell line (103). Further details are lacking.

Antioxidant effects: Enzymatic hydrolysates of royal jelly had antioxidant effects in vitro (7). In vivo and in vitro, peptides from royaljelly inhibited lipid peroxidation (8). Further details are lacking.

Cardiovascular effects: In human research, nonsignificant decreases in fibrinolytic activity occurred (15).

Chemoprotective effects: In animal research, royal jelly protected against the mutagenic effects of Adriamycin® (doxorubicin)and/or cobalt gamma radiation (28). Royal jelly reduced DNA fragmentation and chromosomal aberrations.

Dermatological effects: In animal research, royal jelly inhibited the development of atopic dermatitis-like skin lesions (84).

Exercise performance effects: In animal research, a protein from royal jelly reduced fatigue and accumulation of serum lactate andammonia associated with a forced swim (85).

Growth effects: In vitro, protein fractions of royal jelly stimulated the growth of insect cells (13).

Hepatoprotective effects: In animal research, royal jelly protected against acetaminophen-induced liver damage (88).

Hormonal effects: In vitro, royal jelly activated estrogen receptors, resulting in enhanced transcription of a reporter gene through anestrogen-responsive element and stimulated the expression of mRNA coding for estrogen-responsive pS2 and vascular endothelialgrowth factor (VEGF) (52). Tamoxifen blocked the royal jelly-induced enhancement of MCF-7 cell proliferation. In an ovariectomizedrat model, royal jelly restored VEGF expression in the uterus. In vitro, royal jelly inhibited the bisphenol A-induced proliferation ofMCF-7 cancer cells; however, it was without effect in the absence of bisphenol A (14).

The estrogenic activities of both fatty acids and a sterol isolated from royal jelly have been the topic of discussion (89). Further detailsare lacking. The estrogenic effects of royal jelly were discussed in a review (19;90). In human research, royal jelly resulted inincreased testosterone (26); however, effects on hormone levels were lacking in other human research (53). The influence of royal jellyon the excretion of gonadotropins in healthy males has been discussed (91).

In animal research, estrogenic effects of Melbrosia®, a combination product containing royal jelly, were lacking (104).

Hypolipidemic effects: In human research, royal jelly decreased levels of total cholesterol and increased levels of serumphospholipids, resulting in a reduction of the ratio of cholesterol to phospholipids (71). In healthy adults, royal jelly decreased totaland LDL cholesterol, perhaps by decreasing levels of VLDL (82). Effects on HDL cholesterol and triglycerides were lacking. Inseparate human research, nonsignificant decreases in blood lipids occurred (15), or changes were limited (details are lacking) (72).

Use of Melbrosia®, a combination product containing royal jelly, reduced total and LDL cholesterol and increased HDL cholesteroland triglycerides (43).

In animal research, royal jelly decreased the gene expression of squalene epoxidase (cholesterol biosynthesis) and sterol regulatoryelement-binding protein (SREB)-1, and increased the gene expression of low-density lipoprotein receptor (105).

Hypotensive effects: In vitro, a royal jelly-derived peptide (dipeptide YY) inhibited human renin activity with an inhibition constant (Ki)of 10mcM when the Km was 0.16mcM (20). In animal research, peptides from royal jelly decreased blood pressure in a hypertensivemodel (20;42). In a diabetic animal model, there was a tendency to decrease blood pressure (18).

Immune effects: In animal research, royal jelly delayed the onset of systemic autoimmunity, including decreased proteinuria andreduced renal symptoms (21). There was a decrease in serum level of IL-10, as well as autoantibodies against ssDNA, dsDNA, anderythrocytes, and the number of splenic autoreactive B cells.

In vitro, royal jelly induced proliferation of lymphocytes (22). Royal jelly also increased the release of IFN-gamma and decreased TNF-alpha. There were also significant differences in the ratios of IFN-gamma/IL-4 and IFN-gamma/IL-10. When lymphocytes from patientswith Graves' disease were used, the T-helper (Th)1:Th2 cytokine ratio was shifted to the side of Th1 cytokine, and there was adecrease in the TSHR antibody levels in lymphocyte cell culture supernatants.

In vitro, royal jelly stimulated T cell proliferation and increased IL-2 production at lower concentrations (23). Higher concentrations,however, inhibited T cell proliferation and decreased IL-2 production.

According to a review, neopterin was found in royal jelly, and it has immunological effects (24).

The effect of royal jelly on mitotic activity of lymphocytes has been discussed (106). Further details are lacking.

A synthetic derivative of the royal jelly organic acid 10-hydroxy-2-decenoic acid, 1-(2-methoxyethoxymethyl)2,3-(10-hydroxy2-decenoyl)(E) glycerol, was found to induce NF-kappaB translocation following IkappaB-alpha proteolysis, and it also activatedsphingomyelinase (107). The effects of royal jelly, or its natural component itself, are not clear.

Neuroprotective effects: In isolated and perfused mesenteric vascular beds of a diabetic animal model, royal jelly reduced thesympathetic nerve-mediated vasoconstrictor response to periarterial nerve stimulation, as well as the potentiation of the calcitoningene-related peptide nerve-mediated vasodilator response to periarterial nerve stimulation (18). In vitro, royal jelly and its 10-hydroxy-trans-2-decenoic acid increased the generation of neurons and decreased the generation of astrocytes from neural stem/progenitorcells (92).

Radioprotective effects: In animal research, royal jelly protected against the mutagenic effects of Adriamycin® and/or cobaltgamma radiation (28). Royal jelly reduced DNA fragmentation and chromosomal aberrations.

Vasodilating effects: In animal research, a water-soluble fraction of royal jelly had vasodilating effects on dog femoral artery (31).

Wound-healing effects: In animal research, royal jelly lacked benefit on healing following tympanic membrane perforation; however,use of royal jelly increased the thickness of the membranes by increasing the organization of the connective tissue (33). Acomponent originally labeled honeybee royal jelly-derived collagen production-promoting factor (HRJ-CPF) was found to be 10-hydroxy-2-decenoic acid; 10-hydroxy-2-decenoic acid increased collagen production in vitro by a mechanism using TGF-beta 1(34).

Pharmacodynamics/Kinetics

In vitro, the minimum inhibitory concentration (MIC) of royal jelly against Pseudomonas aeruginosa was 4% (5). The addition of honey

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increased the antibacterial effects.

In vitro, a royal jelly-derived peptide (dipeptide YY) inhibited human renin activity with an inhibition constant (Ki) of 10mcM when theKm was 0.16mcM (20).

History

According to secondary sources, royal jelly has been used for centuries in East Asia. Historically, it has only been available to thosethat could afford it.

According to a review, bee products such as royal jelly have only recently become the subject of medical research (108).

Evidence Table

ConditionStudyDesign

Author,Year

NStatisticallySignificant

Quality OfStudy

0-2=poor3-4=good

5=excellent

Magnitudeof Benefit

ARR NNT Comments

Hyperlipidemia

Systematic

review and

meta-analysis

Vittek, 1995 Nine trials NA NA NA NA NA

Overall

improvements

in lipid levels

from mainly

poorly

designed

studies.

Hay feverRandomized

controlled trial

Anderson,

200580 No 4 NA NA NA

Lack of effect

in children.

Evidence Discussion

Diabetic foot ulcers

Summary: Evidence from available combination studies using an ointment containing royal jelly suggest benefits in the healing ofdiabetic foot ulcers (1). Further research on royal jelly alone is needed.

Select combination studies (not included in the Evidence Table): Abdelatif et al. conducted a study to examine theeffectiveness and safety of Pedyphar® ointment in the treatment of patients with diabetic foot ulcers (N=60) (1). The patients hadlimb-threatening diabetic foot infections of Wagner grades 1-5 (full-thickness skin ulcer to gangrenous lesions). The ointmentconsisted of royal jelly and panthenol in an ointment base that was applied and covered with dressings following irrigation andcleansing with normal saline, and surgical debridement if required. Patients were followed up for six months or until full healingoccurred. Insulin treatment for diabetes control was also used. The primary endpoint was clinical response at weeks 3, 9, and 24. Theauthors indicated that in patients with grades 1-2 ulcers, 96% responded well, with a complete cure by week 9 (defined by theauthors as a complete closure of the ulcer without signs of underlying bone infection). The more serious patients (grade 5) also allhealed following surgical excision, debridement of necrotic tissue, and conservative treatment with the ointment. The effect of royaljelly alone is not clear from this study. Limitations included the lack of control and randomization.

Exercise performance

Summary: Information from animal research, a clinical trial involving royal jelly in combination with other agents, and a reviewsuggests that a potential for improved exercise performance is associated with royal jelly (85;86;87). Further research is needed.

Hyperlipidemia

Summary: Cholesterol reduction was evident based mainly on poorly designed clinical trials included in a systematic review andmeta-analysis (71); however, effects were limited in a more recent study not in the available systematic review (72). Further well-designed research is necessary in order to draw conclusions.

Systematic review and meta-analysis: Vittek et al. conducted a systematic review and meta-analysis to assess the effects ofroyal jelly on atherosclerosis (71). The effects of royal jelly on both humans and animals were assessed in this review. However,results regarding the effects of treatment in animals are excluded from this summary focusing on the effects in humans. Nine studiesincluded in the review assessed the effects of royal jelly on lipid parameters in humans (109;110;111;15;112;113;114;115;116).Articles published through 1994 that assessed the effects of royal jelly on the cardiovascular systems of animals and humans werepooled from MEDLINE. The references of the pooled articles were reviewed to identify additional relevant studies. Nine human studies,in which subjects presented with either hypercholesterolemia or atherosclerosis, were included in the review. All nine studies wereused to calculate the effect size of treatment, while five of these studies were used for the meta-analysis regarding the effect of royaljelly on serum lipids and cholesterol. To treat atherosclerosis, participants in some of the included studies were administered 30-150mg of royal jelly daily for 4-6 weeks. In one study, sublingual doses of 30mg of royal jelly daily were given, but the duration of thetreatment was unclear. In another study, participants were injected with 10-100mg of royal jelly daily for 3-11 weeks. Informationregarding standardization, allergies, adverse effects, toxic effects, dropouts, and interactions was lacking. Outcome measuresincluded differences in levels of serum total cholesterol, lipids, phospholipids, and lipoproteins. When all nine studies were used todetermine a pooled-effect size, a significant cholesterol-lowering effect was observed with royal jelly treatment (-30.3mg/dL, 95% CI:-19.0 to -41.5mg/dL). In addition, when only the five placebo controlled trials were compared, a significant mean decrease incholesterol was also observed (-34.0mg/dL, 95% CI: -25.1 to -42.9mg/dL, p<0.001). The mean reduction in the level of serum lipidswas significant as well (-52.00mg/dL, 95% CI: -37.8 to -66.2mg/dL, p<0.05). In two out of four trials where serum phospholipids wereassessed, these levels increased significantly (p<0.05). The ratio of cholesterol to phospholipids decreased in three out of four trialsthat assessed this parameter (p<0.05). Lipoprotein levels decreased significantly in three out of four trials (p<0.05). The authorsconcluded that royal jelly may decrease serum total cholesterol and lipid levels and may impact other lipid parameters as well.However, the authors stated that some of the trial designs were lesser quality, the number of subjects and baseline characteristics(including disease status) of these subjects differed greatly and/or were poorly characterized, different forms and administrations ofroyal jelly were used, and some trials lacked a placebo group. Additional trials are needed before conclusions may be made.

Studies of lesser methodological quality (not included in the Evidence Table): Münstedt et al. conducted a study to examinethe effect of royal jelly on blood lipids in older patients (N=50) (72). Patients in the study had hypercholesterolemia and totalcholesterol >200mg/dL; an absence of diabetes mellitus, endocrine disorders, allergy to royal jelly, or asthma; and consistent

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medication use for hypercholesterolemia for the previous three months. Patients consumed 10g of refrigerated royal jelly daily eachevening for 14 days. The authors concluded that effects of royal jelly on cholesterol levels in this population were limited. Furtherdetails are lacking.

Male infertility

Summary: Midcycle pericoital vaginal applications of Egyptian bee honey and royal jelly improved pregnancy rates in patients treatedwith standard intrauterine insemination for infertility due to asthenozoospermia in the male (117). Further research investigating royaljelly alone is needed.

Select combination studies (not included in the Evidence Table): Abdelhafiz et al. conducted a crossover study to evaluate theefficacy of a mixture of Egyptian bee honey and royal jelly for the treatment of infertility due to asthenozoospermia (N=99) (117). Inone group, patients were treated midcycle with pericoital vaginal applications of Egyptian bee honey and royal jelly along withstandard intrauterine insemination for three cycles or until conception. The control group was given standard intrauterine inseminationalone. After a washout period of two months, the groups crossed over if pregnancy had not yet occurred. Pregnancies per cycle were23 (8.1%) and 7 (2.6%) in the Egyptian bee honey and royal jelly vs. control groups (p<0.001). Further details are lacking. The effectof royal jelly alone is not clear.

A simple treatment for asthenozoospermia-related subfertility using midcycle pericoital vaginal micronized progesterone, bee honey,and royal jelly was also discussed (118). Further details are lacking.

Menopause

Summary: Use of herbal combination products containing royal jelly reduced symptoms of menopause (54;43;53;55). Women whoused Melbrosia® stated they did so because it helped their climacteric discomfort (119). The effect of royal jelly alone is not clear,and further research is needed.

Select combination studies (not included in the Evidence Table): Yakoot et al. conducted a study to examine the effectivenessof an herbal formula in women with menopausal syndromes (N=120) (54). The women were treated with two capsules of Lady 4(containing evening primrose oil, damiana, ginseng, royal jelly) daily. The main outcome was measurements on the MenopauseRating Scale II (MRS-II). After two and four weeks of treatment, there was a statistically significant improvement in the MRS-II scorein both groups, with a significantly better improvement in the treatment group (p<0.001), with 86.7% vs. 56.7% indicating that theywere "much improved" or "very much improved." Further details are lacking. The effect of royal jelly alone is not clear.

Georgiev et al. conducted an open uncontrolled study to examine the effect of Melbrosia® on menopausal symptoms andcardiovascular disease risk factors in menopausal women (N=55) (43). Women were treated for three months. Endpoints includedKupperman score, Zerssen Symptom List, Zung Depression Score, Frankfurt Self-Concept Scale, blood lipid levels, C-reactiveprotein, and vascular cell adhesion molecule (VCAM)-1. There was a statistically significant reduction in Kupperman score, ZerssenSymptom List, and Zung Depression Score, and significant improvements in the problem-solving score of the Frankfurt Self-ConceptScale. Total and LDL cholesterol were significantly reduced, and HDL cholesterol and triglycerides were significantly elevated. Othersignificant changes were lacking. Further details are lacking. The effect of royal jelly alone is not clear.

Kolarov et al. conducted a study to examine the effect of Melbrosia® on menopausal symptoms (N=66) (53). Endpoints included theKupperman Menopausal Index and hormone levels. There was a decrease in the Kupperman index, whereas effects on hormones andlipid parameters were lacking. Further details are lacking. The effect of royal jelly alone is not clear.

Szanto et al. conducted a placebo controlled study to examine the effect of Melbrosia® on menopausal symptoms (55). The authorsindicated that biochemical parameters were limited but that menopausal symptoms were reduced (headache, urinary incontinence,dry vagina, decreasing vitality). Further details are lacking. The effect of royal jelly alone is not clear. This study was commented on(120).

Hay fever

Summary: In children, use of the royal jelly product Bidro lacked effect on hay fever prevention or treatment (73). Although the studywas well randomized, the methods of blinding were not clear, and only one marketed product was studied. In addition, anaphylaxisand other allergic reactions to royal jelly have been shown in numerous human case reports and other reports(56;57;58;41;59;60;61;47;48;62;63;65;49;66;67;68;69;64). Further research is needed; however, until safety is established in thisspecific population, royal jelly should be avoided.

Evidence: Andersen et al. conducted a randomized, double-blind, placebo controlled parallel-group study to assess the effects ofroyal jelly (Bidro) on hay fever symptoms in children with documented rhinoconjunctivitis caused by allergy to birch, grass, or ragweedpollen (N=80) (73). Participants in this study were children aged 5-16 years who had clinically verified hay fever diagnoses on thebasis of birch, grass, or mugwort pollen allergies. All included participants had been diagnosed at least one year prior to the study.Participants were excluded from the study if they had a chronic need for antihistamine, cromoglycate, or steroids (nasal or systemic);if they had received immunotherapy within two years of the study; or if they had nasal abnormalities with displacement of the nasalseptum, polyps, atrophic rhinitis, or chronic infectious sinusitis. Participants were randomized by a computer-generatedrandomization schedule to receive 150mg of Bidro or identical placebo capsules twice daily, once in the morning and once in theevening, for 3-6 months during pollen season. Information on standardization was lacking. Adverse effects that occurred during thisstudy included deterioration of atopic dermatitis (N=4 for each treatment group), respiratory infections (N=15 from the placebo group;N=8 from the treatment group), and difficulty or inability to swallow the capsules (N=2 from the placebo group; N=4 from the treatmentgroup). Information on toxic effects was lacking. Sixteen participants dropped out of the study before completion: four withdrewconsent (N=2 from the placebo group; N=2 from the treatment group), six withdrew due to inability to swallow the capsules (N=2 fromthe placebo group; N=4 from the treatment group), three were excluded due to lack of compliance (N=2 from the placebo group; N=1from the treatment group), two participants from the treatment group withdrew due to deterioration of atopic dermatitis, and oneparticipant withdrew from the placebo group due to suspicions on the part of the participant's mother. Information regardinginteractions was lacking. The primary outcome measure was the occurrence of rhinoconjunctivitis symptoms during pollen season.Secondary outcome measures included symptom severity and the need for any medical treatment. Compared to the control group,treatment with Bidro lacked preventative or curative effects on the occurrence of hay fever symptoms. A statistically significantdifference in symptom severity was lacking between the two study arms (p=0.45). Limitations of this study included a lack ofadequate description of blinding, which may have allowed for the introduction of bias or confounding variables. In addition, there was a20% dropout rate, which reduced the sample size from 80 to 64.

Products Studied

Brands Used in Clinical Trials

Not applicable.

Brands Reviewed for Claimed Ingredients Through Third-Party Testing

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Consumer Lab: Not applicable.

Consumer Reports: Not applicable

Natural Products Association: Not applicable

NSF International: Not applicable

U.S. Pharmacopeia: Not applicable

Selected Patents Outside of the United States

CN102793733 Ginseng royal jelly chewable tablets and preparation method thereof

KR20120108637 Royal jelly convenient to store and dose and method for manufacturing thereof

CN102772345 All-natural bee pollen facial mask paste and production method thereof

KR101227309 Auto-grafting apparatus for the production of royal jelly

United States Patents

20110318293 Hair Preparation Comprising Royal Jelly

EP 1824350 A1 Dietetic product based on royal jelly, particularly for health protection and improving immunity. Prepared royal jellywith caloric value

20060159834 Refined royal jelly

EP 2437853 A2 Cosmetic cleansing agent containing surfactant and royal jelly

1048222 A2 Royal jelly composition with low calorific value

8,263,157 - Pelletization method for raw royal jelly

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89. Suzuki, K. M., Isohama, Y., Maruyama, H., Yamada, Y., Narita, Y., Ohta, S., Araki, Y., Miyata, T., and Mishima, S. Estrogenicactivities of Fatty acids and a sterol isolated from royal jelly. Evid.Based.Complement Alternat.Med. 2008;5(3):295-302. ViewAbstract

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