Fenugreek

Fenugreek seeds and extract comes from the plant Trigonella foenum-graecum L and has been used historically for various uses such as antispasmodic, appetite stimulant, high cholesterol, wounds, blood cleanser, and expectorant effects.^[1][2] It is derived from both Ayurveda (mostly) and Traditional Chinese Medicine (to a lesser degree)^[2] and unlike most traditional medicines it also appears to be a condiment.^[2]

There are some other traditional usages of fenugreek seeds including using them in beer as an at-home remedy for anxiety and hopelessness (Danish).^[3]

Trigonella foenum-graecum seeds (Fenugreek seeds; the main active component of this plant) tend to contain:

• Trigonelline, a betaine molecule also found in high levels in alfalfa and coffee^[4]
• 4-hydroxyisoleucine^[5] and its precursor, 2-oxoglutarate.^[6]
• Protodioscin^[7] similar to Tribulus Terrestris
• The two Trigoneosides, Trigofaenoside A and Glycoside D^[8][7]
• Diosgenin^[7][9] and Yamogenin^[10][7][10]
• GII, a compound currently unnamed^[11]
• 3-hydroxy-4,5-dimethyl-2(5H)-furanone (HDMF; aka. sotolon), the causative agent for a maple syrup scent of body excretions^[12][13]
• Small phenolics such as Protocatechuic acid at 85.50ng/mg (ethyl acetate extract) or 31.25ng/mg (water extract),^[14] quinic acid at 15.97ng/mg (ethyl acetate extract) 165.55ng/mg (water extract),^[14] and gallic acid at 3.93ng/mg (ethyl acetate extract) or 3.10ng/mg (water extract)^[14]
• Apigenin-7-O-glycoside (1955.55ng/mg in the ethyl acetate extract^[14])
• Luteolin-7-O-glycoside (725.50ng/mg in the ethyl acetate extract^[14])
• Vitamin C at 576.50ng/mg (ethyl acetate extract^[14]) and less in the water extract (6.82ng/mg^[14])
• Minerals such as potassium (603+/-15mg/100g^[15]), Magnesium (42+/-5mg/100g^[15]), calcium (75+/-9mg/100g^[15]) Zinc (2.4+/-0.2mg/100g^[15]), Iron (25.8+/-1.2mg/100g^[15]), and both Manganese and Copper (0.9+/-0.1mg/100g^[15])

Fenugreek has been noted to also possess trypsin and chymotrypsin (protein digestive enzyme) inhibitors.^[16][17]

A fenugreek crude ethyl acetate extract appears to have the highest antioxidant properties of all fenugreek extracts.^[14]

Dietary carbohydrates and fibers (the latter of which constitutes 6.28-9.3% of total seed weight^[18]) include:

• Soluble fibers as galactomannins^[19], with a galactose:mannose ratio of 1.5:1^[20]

The fatty acid component of Fenugreek (4.51-7.1% of dry weight overall^[15][18]) consists of mostly oleic (16.3%), linoleic (50%), and linolenic acids (24.4%).^[21]

Fenugreek oil (aromatic component) contains Neryl acetate (17.32%), Camphor (16.32%), β-Pinene (15.05%), β-caryophyllene (14.63%), 2,5-dimethylpyrazine (6.14%), Geranial (4.81%), 6-methyl-5-hepten-2-one (4.48%), 3-octen-2-one (4.32%), α-selinene (4.04%), α-Terpineol (2.77%), α-Campholenal (2.63%), α-pinene (2.61%), and γ-Terpinene (2.08%).^[22]

The protein content of the seeds themselves appear to be 12.9-28.4%, but is highly variable.^[15][18]

A standardized hydroalcoholic extract of Fenugreek to isolated the bioactive Trigonelline is known as SFSE-T.^[23]

Fenugreek (300mg/kg of the seed powder for eight days with the final dose an hour before testing) has failed to significantly interact with CYP3A4 as assessed by a carbamazepine tracer test.^[24]

At this moment in time there are no known interactions with CYP3A4 enzymatic activity

Fenugreek (300mg/kg of the seed powder for eight days in rabbits with the final dose an hour before testing) has failed to significantly interact with P-glycoprotein function as assessed by a cyclosporine tracer test.^[24]

There does not appear to be any inhibitory nor inductive property on the P-glycoprotein efflux protein.

An ethanolic extract of fenugreek seeds appears to inhibit monoamine oxidase A (MAO-A) with an IC₅₀ of 4µg/mL^[3] and an extract containing high levels of trigonelline (84%) has shown MAOI properties with an IC₅₀ of 528µg/mL (2.81µM assuming pure trigonelline).^[23]

A high trigonelline extract (84%) has been noted to inhibit monoamine oxidase B (MAO-B) with an IC₅₀ of 391µg/mL (2.1µM assuming pure trigonelline).^[23]

Fenugreek seeds have a potential to inhibit both forms of the monoamine oxidase (MAO) enzyme with no apparent sensitivity. This may be related to the trigenolline content in part although there may be a more potent molecule able to inhibit MAO-A in the ethanolic extract

An in vitro study using crude fenugreek extract noted acetylcholinesterase inhibitory properties^[25] with an IC₅₀ value between 9.23+/-6.08µg/mL (pure alkaloids) and 53+/-17.33µg/mL (ethyl acetate extract).^[25]

Oral ingestion of 10-100mg/kg of a fenugreek seed extract (82% trigonelline) has failed to show anticholinergic effects in rats (a Parkinsons model).^[23]

An ethanolic extract of fenugreek has failed to show affinity to the serotonin transporter (SERT) at concentrations up to 10mg/mL, suggesting no potential usage as an SSRI.^[3]

Fenugreek does not appear to have any affinity for the serotonin transporter

Fenugreek is known to exert analgesic properties when injected into the periphery, and when the serotonergic system of the spine is irreversibly damaged (injections of 5,7-dihydroxytryptamine) the analgesic properties of low doses of fenugreek were abolished and higher doses were attenuated.^[26]

Serotonergic signalling appears to be involved in the analgesic properties of fenugreek in the periphery

A study in rats using 42mg/kg of Fenugreek suggests an increase in appetite^[27] which has been replicated in humans at 40mg/kg bodyweight of the aqueous extract in otherwise healthy volunteers.^[28]

In obese persons, fenugreek (1176mg) taken daily appeared to reduce spontaneous fat intake without significantly affecting appetite overall^[29][30] while the isolated fibers (4-8g) daily seem to induce satiety in obese persons.^[31]

Has been implicated in modulating appetite, with an increasing effect in persons of normal weight (association, not known if normal weight is a mandatory prerequisite) and either satiating or no stimulating effect in obese persons. At least one study has noted a preferential switch of appetite away from dietary fatty acids

Injections of fenugreek (500-2,000µg intrathecally or 1g intraperitoneally) appear to have analgesic properties in rats mediated via the spinal serotonergic system,^[26] which is a mechanism of action similar to NSAID drugs such as aspirin^[32][33] and can be inhibited by damaging the spinal serotonergic system with injections of 5,7-dihydroxytryptamine^[26] or preventing synthesis of serotonin with parachlorophenylalanine.^[33]

A seed extract of fenugreek (IND01) given orally to rats at 50-200mg/kg for one month following spinal nerve damage (either a partial sciatic nerve ligation (PSNL) or a sciatic nerve crush injury (SNCI) injury) appear to reduce the hyperalgesia induced by the injuries following two weeks or supplementation, but not two days.^[34] The magnitude of analgesia with 200mg/kg of IND01 was comparable to the reference of 100mg/kg pyridoxine HCl.^[34]

In the intestines, the fiber component of fenugreek seeds can suppress uptake of cholesterol and bile acids.^[35]

Fenugreek as a whole can attenuate the absorption of carbohydrates by acting as an alpha-amylase and maltase inhibitor (starch and maltose digestive enzymes, respectively).^[35][36]

This has been noted in vivo with Fenugreek Oil (15% Fish Oil by weight) at 5% of feed in diabetic rats is associated with a 51% reduced AUC of plasma glucose following a meal associated with reduced carbohydrate enzyme activity (46% and 37% reduction for pancreatic α-amylase and maltase, respectively; 52% and 35% for plasma).^[22]

The reduction of serum glucose following a meal has been noted in otherwise healthy humans.^[37]

It has been noted that the steroidal saponins per se do not possess significant influence on glucose metabolism^[27] and that de-gumming Fenugreek (removing soluble fibers) reduces the ability of Fenugreek to attenuate post-prandial blood glucose spikes.^[37]

In diabetic rabbits, purified GII at 50mg/kg is able to reduce blood glucose to near normal concentrations and reduce HbA1c.^[38]

A protective effect on pancreatic beta-cells has been noted with fenugreek seed ingestion in diabetic rats^[22] which has been noted with the isolated steroidal saponin content.^[39]

4-hydroxyisoleucine (henceforth 4OH-Ile), mostly exclusive to fenugreek (beyond some bacterial synthesis either naturally^[40][41] or via modification^[42]) can induce insulin secretion from pancreatic beta-cells under conditions of high glucose concentration^[43] with little to no efficacy at normal serum glucose concentrations.^[43] 4OH-ILE does not appear to interfere with other inducers of insulin secretion such as leucine^[43] and in doses of 50mg/kg bodyweight can reduce glucose, LDL, and insulin in diabetic mice.^[44][45][46]

In streptozotocin-induced diabetic rats, 1,500mg/kg of fenugreek seeds daily for 21 days was associated with a 58% reduction in blood glucose levels (still 116% higher than true control) with no significant influence on insulin.^[47] Reduction in blood glucose have also been noted in Alloxan-induced diabetic rats (2-8g/kg of the seeds).^[48]

21 days of 1,500mg/kg Fenugreek is associated with improvements in the hepatic enzymes G6P (59% of the change seen via diabetes was reversed) and G6P dehydrogenase (30%) as well as improving hepatic glycogen storage; phosphofructokinase, reduced during diabetes, was unaffected.^[47] A beneficial alteration of hepatic enzymes has also been noted in Alloxan-induced diabetic rats in both the kidneys and liver (5% of the rat diet)^[49]

Appears to hold some promise in reducing biochemical markers of diabetes in diabetic rats

One study using high doses of Fenugreek (2-8g daily) in alloxan induced diabetic rats noted that the healthy control rats also experienced a reduction in blood glucose.^[48]

This appears to be relevant in humans with Type I diabetes (100g defatted Fenugreek)^[50] as well as Type II diabetics, where a 53% increase in insulin sensitivity was noted via HOMA relative to the control group using 1g daily of a hydroalcoholic extract.^[51]

Benefits for glycemic control have been seen with the seeds themselves,^[52][53] defatted seed extract^[54] and whole seed powder.^{[48][37][55][56]} Fenugreek has been successfully incorporated into a bread product at 5% fenugreek flour by weight without exerting adverse taste effects onto the bread, this has been used in vivo to lower the glucose spikes after eating the bread in diabetics.^[57]

One study using fenugreek at 2,500mg twice a day for 3 months noted no changes to blood sugars or blood lipids in healthy individuals, but a reduction in blood sugar in persons with Type II diabetes and a reduction in blood lipid parameters (cholesterol and triglycerides) in persons with both Coronary Artery Disease and diabetes.^[58] This suggests that fenugreek has the ability to lower blood lipids, but it works vicariously though fixing problems in glucose metabolism.^[58]

When administered at 900mg and in conjunction with 3.5g Creatine monohydrate, fenugreek+creatine appears to be as effective at increasing lean body mass and strength over 8 weeks as creatine alongside 70g dextrose.^[59] A few problems with this latter study include no true control group (comparative study), the Fenugreek group weighting less and pressing more at baseline (possibly poor randomization), and funding from Indus Biotech.

A review^[60] notes its pluripotent effects of the above in addition to activating muscular uptake of glucose by activating PI3K, an intermediate in insulin signalling.^[61] This increase of muscular uptake may enhance glycogen replenishment after exhaustive exercise^[62] but has been contested.^[63] The difference may lay in benefits being seen after HIIT training (80% VO² max intervals) compared with aerboic exercise (50% VO² max constant).

In rats, oral intake of 10-35mg/kg Fenugreek furostanols for 4 weeks has caused an increase in the weight of the levator ani muscle (thought to be indicative of anabolic actions in males) with no significant influence on circulating testosterone levels.^[64] Prostate weight was not altered in this study.

Possible androgenic effects independent of testosterone, although no evidence exists to support the notion that this is at all a powerful androgenic effect (if it is replicated)

Fenugreek has once been shown at 500mg (brand name Testofen) to increase serum testosterone over a period of 8 weeks in resistance trained males relative to placebo (experiencing a decline in testosterone relative to baseline)^[65] although another study (which noted a decrease in DHT, a testosterone metabolite) failed to find any significance influence on total or free testosterone using similar methodology^[66] and a study using 600mg of Testofen for a period of 6 weeks in otherwise healthy man has similarly failed to find an increase in testosterone.^[67]

In regards to DHT, the one study to measure DHT noted a 9.42% decrease relative to baseline over 8 weeks supplementation of 500mg Fenugreek.^[66]

Mixed results on an increase in testosterone in otherwise healthy men, although there appears to be support for the 5alpha-reductase properties of Fenugreek via the reduction in DHT

In rats given exogenous thyroid hormones (T4 and T3) in order to induce high blood sugar, 220mg/kg of the seeds of Fenugreek was able to suppress the rise in blood glucose and the rise of thyroid hormones; the potency of which being comparable to 500mg/kg Allium sativum and 10mg/kg propyl thiouracil (known anti-thyroid as active control).^[68]

Fenugreek has been noted to protect against oxidative liver pathology at 5% of male rat feed against Aluminum Chloride toxicity.^[69]

Fenugreek appears to be recommended for alcohol-related complications according to its traditional usage, similar to such herbs as Pueraria Lobata and Hovenia Dulcis.^[70]

An in vitro study using Chang liver cells (non-malignant cell model for studying EtOH toxicity^[71]) incubated with 30mM alcohol, the reduction of cell viability to 45% was attenuated in a concentration dependent manner to 48% (20mcg/mL), 52% (40mcg/mL), and 75% (60mcg/mL) with simultaneous incubation; the active control of Silymarin (from Milk Thistle) at 30mcg/mL preserved 79% of cells.^[72] Silymarin and the highest dose of Fenugreek polyphenols were similarly effective in preserving lipid peroxidation, LDH leakage, and mitochondrial permeability.^[72]

A water extract of Fenugreek seeds concurrently during 60 days of alcohol ingestion was associated with a reduction in the rise of oxidation and liver enzymes noted in the serum of rats given ethanol alone, suggesting protective effects.^[73]

May protect liver cells in response to ethanol ingestion (coadministration), although there is not a large amount of evidence for this claim. One study, comparing Fenugreek to Silymarin, suggest the potency is not remarkable either

An alcoholic extract of fenugreek seeds at 2,000mg/kg daily in alloxan-induced diabetic rats was able to reduce diabetes-induced cataract formation, although to a lesser protective effect when compared to Pterocarpus marsupium bark at 1,000mg/kg.^[74]

At least one study in diabetic rats has noted that ingestion of Fenugreek saponins was associated with preservation of steroidal synthesis enzymes in the testes of rats (HMG-CoA redutase, 3β-HSD, Malic enzyme and G6P-DH)^[39] which are reduced during diabetes.

Intakes of up to 35mg/kg of the furostanol component are not associated with any adverse effects to the testes (or prostate) as assessed by histology or organ weight.^[64]

Fenugreek may also enhance male libido when ingested at 600mg a day (Testofen brand name, 50% Fenusides) in two divided doses for 6 weeks.^[67] The primary measurement was the self-reported score on the Derogatis interview for sexual functioning-self report (DISF-SR^[75]) and there was a reported global improvement as well as significant improvements on the subscales of satisfaction with orgasm and sexual desire; this study was not affiliated with the producer of the supplement.^[67]

Fenugreek is a commonly recommended herb for increasing milk production in pregnant women,^[76] and is seen by some as one of the few herbs with promising evidence.^[77][78] It is told (traditionally) that fenugreek 'stimulates sweat production' and that this influences milk production as the two structures (sweat glands and milk glands) are similar.^[79][80]

A few trials have been conducted on the matter, and fenugreek seems to be able to enhance milk production in recent mothers more than placebo.^[79] In which control and placebo had 31.1+/-12.9mL and 38.8+/-16.3mL respectively, the fenugreek group was able to produce 73.2+/-53.5mL after consuming at least 3 cups (200mL) of fenugreek tea (Still tea, Humana) for three days.

The mechanism of action is not specifically known, but may be related to phytoesteogens or diosgenin.^[79] Not many studies have detected the presence of Fenugreek bioactives in breast milk, but one assessing the anti-oxidant capacity of breast milk from mothers drinking Fenugreek tea failed to find a significant difference relative to placebo.^[81]

Limited evidence to support Fenugreek enhancing milk production, but Fenugreek Tea does have preliminary evidence in support of this traditional usage.

Fenugreek, at dosages of 800mg/kg bodyweight or above in rats (128mg/kg human estimated dose), is potentially a teratogenic substance^[82] that may cause birth defects when consumed by a pregnant woman; the mechanism of teratogenesis is hypothesized to be through inhibiting stem cell differentation.^[83]

Fenugreek is sometimes used as a breast enhancing substance;^[84] there is no evidence to support this notion.

Fenugreek has traditionally (and currently via non-medical associations) been recommended as a treatment for menopause with regard to lessening vaginal dryness;^[85] there is currently insufficient evidence to support these claims.

A single oral dose of 10-100mg/kg SFSE-T given to rats prior to 6-Hydroxydopamine toxicity (damages a similar area of the brain observed to be damaged in Parkinson's and thus is an animal model of research) and MPTP neurotoxicity noted that pretreatment of 30mg/kg was associated with less signs of neural toxicity when pretreated, but not when SFSE-T followed neurotoxicity.^[23]

Fish oil appears to increase the efficacy of fenugreek in reducing post-prandial blood sugar spikes, as a mixture (5%) of half fish oil and half fenugreek showed a greater attenuation of blood sugar than the same amount (5%) of fenugreek alone.^[22]

Arcabose is an alpha-glucosidase inhibitor that is used for treatment of diabetes by attentuating the release of glucose into the blood. In 1:0.8-1.2 weight ratios of Arcabose:Fenugreek Gum (the soluble fiber aspect), fenugreek is able to increase the release of arcabose from being fully absorbed in one hour and delay complete absorption for up to 8 hours, suggesting that fenugreek gum can enhance intestinal half-life.^[20]

Due to fenugreek's own ability to be anti-diabetic, it works in synergism on drug delivery and additive on attentuating glucose spikes.^[20]

An oral dose of 3g/kg bodyweight of ethanol-extract fenugreek failed to show adverse effects in one study, and higher doses were not studied as this was above the most hypoglycemic dosage of 1g/kg.^[86] In another study, the LD⁵⁰ was established at 3.5g/kg in female mice and 4.1g/kg in males.^[83]

Allergies to fenugreek have been noted, and seem to be tied in with the entire Leguminoseae family, and both subjects noted responsiveness to chickpeas as well; if one is allergic to chick peas, they may react to fenugreek.^[87]

Fenugreek has been historically used as an abortifacient, or a compound capable of inducing abortions.^[88] The proposed mechanisms are through contractions of the uterine wall, which would also induce birth in the late third trimester.

When overfed to rats (800mg/kg bodyweight), fenugreek also has shown teratogenic potential by possibly interfering with stem cell division.^[82]. This dose roughly translates to 128mg/kg in humans.

Maple Syrup Urine Disease (MSUD) is a condition that results from improper metabolism of branched-chain amino acids. The aromatic in fenugreek, sotolon, may be used as a diagnostic criteria for MSUD as it exists in the urine of those persons with this metabolic defect and gives the characteristic sweet-scent.^[13] It normally does not appear in healthy person's urine due to no dietary intake, but may appear in those who drink or consume fenugreek, leading to a false diagnosis.^[89] Maternal consumption of sotolon can also transfer into the baby after birth, and cause trans-generational false diagnosis.^[90]

A few human interventions note a side-effect of 'peculiar' or 'sweet' smell in the urine.^[30]