ETYMOLOGY AND HISTORY
Fennel, Foeniculum vulgare Mill., belongs to the family of Apiaceae, and is an annual, biennial, or perennial herbaceous plant, depending on the variety, which grows in good soils from sunny mild climatic regions and is a well-known aromatic plant species.
The word "fennel" developed from the Middle English fenel or fenyl. This came from, the Old English fenol or finol, which in turn came from the Latin feniculum or foeniculum, the diminutive of fenum or faenum, meaning "hay".
Foeniculum vulgare has two commercially important fennel types: bitter fennel, Foeniculum vulgare Mill. subsp. vulgare var. vulgare, and sweet fennel Foeniculum vulgare subsp. vulgare var. dulce. Several fennel parts are edible (bulbs, leaves, stalks, and fruits). Mature fruit (commonly known as seeds) and essential oil of fennel are used as flavoring agents in food products such as liqueurs, bread, cheese, and an ingredient of cosmetics and pharmaceutical products. Moreover fennel infusions are the classical decoction for nursing babies to prevent flatulence and colic spasms. Traditionally in Europe and Mediterranean areas fennel is used as antispasmodic, diuretic, anti-inflammatory, analgesic, secretomotor, secretolytic, galactagogue, eye lotion, and antioxidant remedy and integrator.
CHEMICAL CONSTITUENTS OF FENNEL
According to the 2nd edition of the European Pharmacopoeia monograph, sweet fennel contains not less than 2.0% v/m of essential oil, calculated with reference to the anhydrous drug. The essential oil is constituted mainly by anethole (80%) (a substance with supposed anticancer properties), it contains not more than 10% estragole and not more than 7.5% fenchone. Other minor constituents may be present including: R-pinene, limonene, β-pinene, β-myrcene, and p-cymene. Furthermore, sweet fennel contains other nonvolatile constituents such as flavonoids and coumarins, which have not received till now sufficient attention with regard to pharmacological properties.
Many phytochemical researches have been conducted so far to investigate the chemical composition of fennel essential oil with different results: depending on the time of harvests, conservation, region, and area of cultivation. The major components of fennel are phenylpropanoid derivatives: trans-anethole and estragole (methyl chavicol), and then alpha-phellandrene, limonene, fenchone, and alpha-pinene.
Can Estragole in Fennel Seed Decoctions Really Be Considered a Danger for Human Health? A Fennel Safety Update, 2012
USES OF FENNEL
Fennel is widely employed as a carminative, both in humans and in veterinary medicine (e.g., dogs), to treat flatulence by encouraging the expulsion of intestinal gas. Anethole is responsible for the carminative action.
Mrs. Eencher Herbal states:
On account of its carminative properties, fennel is chiefly used medicinally with purgatives to allay their side effects, and for this purpose forms one of the ingredients of the well-known compound liquorice powder. Fennel water has properties similar to those of anise and dill water: mixed with sodium bicarbonate and syrup, these waters constitute the domestic 'gripe water' used to correct the flatulence of infants. Volatile oil of fennel has these properties in concentration. Fennel tea, also employed as a carminative, is made by pouring boiling water on a teaspoonful of bruised fennel seeds.
Use of fennel against infant colics
Fennel can be made into a syrup to treat babies with colic (formerly thought to be due to digestive upset), but long-term ingestion of fennel preparations by babies is a known cause of thelarche.
Clinical inquiries. What is the best treatment for infants with colic?
Infantile colic, defined as excessive crying in an otherwise healthy baby, is a distressing phenomenon, but there is little evidence to support the many treatments offered. Several small studies report some benefit from use of a hypoallergenic (protein hydrolysate) formula, maternal diet adjustment (focusing on a low-allergen diet), and reduced stimulation of the infant. While dicyclomine has been shown to be effective for colic, there are significant concerns about its safety, and the manufacturer has contraindicated its use in this population. An herbal tea containing chamomile, vervain, licorice, fennel, and balm-mint was also effective in a small RCT, but the volume necessary for treatment limits its usefulness (strength of recommendation: B, inconsistent or limited-quality patient-oriented evidence). The one proven treatment is time, as this behavior tends to dissipate by 6 months of age.
Clinical inquiries. What is the best treatment for infants with colic?, 2006
The effect of fennel (Foeniculum Vulgare) seed oil emulsion in infantile colic: a randomized, placebo-controlled study.
Despite its benign, natural course, colic is a significant problem in infants and imparts a psychological, emotional, and physical burden to parents. Dicyclomine hydrochloride is the only pharmacological treatment for infantile colic that has been consistently effective. Unfortunately, 5% of infants treated with dicyclomine hydrochloride develop serious side effects, including death. Fennel seed oil has been shown to reduce intestinal spasms and increase motility of the small intestine. However, there have not been any clinical studies of its effectiveness.
OBJECTIVES: To determine the effectiveness of fennel seed oil emulsion in infantile colic.
DESIGN: Randomized placebo-controlled trial.
SETTINGS: Two large multi-specialty clinics.
SUBJECTS: 125 infants, 2 to 12 weeks of age, who met definition of colic.
INTERVENTION: Fennel seed oil emulsion compared with placebo.
OUTCOME MEASURE: Relief of colic symptoms, which was defined as decrease of cumulative crying to less than 9 hours per week.
RESULTS: The use of fennel oil emulsion eliminated colic, according to the Wessel criteria, in 65% (40/62) of infants in the treatment group, which was significantly better than 23.7% (14/59) of infants in the control group (P < 0.01). There was a significant improvement of colic in the treatment group compared with the control group [Absolute Risk Reduction (ARR) = 41% (95% CI 25 to 57), Number Needed to Treat (NNT) = 2 (95% CI 2 to 4)]. Side effects were not reported for infants in either group during the trial.
CONCLUSION: Our study suggests that fennel seed oil emulsion is superior to placebo in decreasing intensity of infantile colic.
The effect of fennel (Foeniculum Vulgare) seed oil emulsion in infantile colic: a randomized, placebo-controlled study, 2003
- PREGNANCY AND GENITAL EFFECTS
The galactagogue property of Foeniculum vulgare Mill
There are historical anecdotes that fennel is a galactagogue, improving the milk supply of a breastfeeding mother. This use, although not supported by direct evidence, is sometimes justified by the fact that fennel is a source of phytoestrogens, which promote growth of breast tissue. However, normal lactation does not involve growth of breast tissue. A single case report of fennel tea ingested by a breastfeeding mother resulted in neurotoxicity for the newborn child.
Effect of Foeniculum vulgare Mill. seed extract on the genital organs of male and female rats
Following the oral administration of acetone extract of Foeniculum vulgare (fennel) seeds for 15 days is male rats, total protein concentration was found to be significantly decreased in testes and vas deferens and increased in seminal vesicles and prostate gland. There was a decrease in activities of acid and alkaline phosphatase in all these regions, except that alkaline phosphatase was unchanged in vasa. In female rats, oral administration of the extract for 10 days led to vaginal cornification and oestrus cycle. While moderate doses caused increase in weight of mammary glands, higher doses increased the weight of oviduct, endometrium, myometrium, cervix and vagina also. The results confirm the oestrogenic activity of the seed extract.
Effect of Foeniculum vulgare Mill. seed extract on the genital organs of male and female rats, 1985
The effect of fennel essential oil on uterine contraction as a model for dysmenorrhea, pharmacology and toxicology study
Increasing the ectopic uterine motility is the major reason for primary dysmenorrhea. This motility is the basis for several symptoms including for pain is the main complaints of patients with primary dysmenorrhea. There are several mechanisms, which initiate dysmenorrhea. Therefore, different compounds can be employed to control its symptoms. In long-term therapy, combination of oestrogens and progestins may be useful. In short-term therapy, dysmenorrhea sometimes non-steroidal anti-inflammatory drugs (*NSAIDs*) are used. Most of NSAIDs in long-term therapy show severe adverse effects. In an attempt to find agents with less adverse effect the fennel essential oil (*FEO*) was chosen for this investigation. In this article, effects of FEO on the uterine contraction and estimation of LD in rat were described. For assessment of pharmacological effects on the isolated rat uterus, oxytocin (0.1, 1 and 10 mu/ml) and prostaglandin E(2) (PGE) (5×10(-5) M) were employed to induce muscle contraction. Administration of different doses of FEO reduced the intensity of oxytocin and PGE induced contractions significantly (25 and 50 microg/ml for oxytocin and 10 and 20 microg/ml PGE, respectively). FEO also reduced the frequency of contractions induced by PGE but not with oxytocin. LD of FEO was obtained in the female rats by using moving average method. The estimated LD was 1326 mg/kg. No obvious damage was observed in the vital organs of the dead animals.
The effect of fennel essential oil on uterine contraction as a model for dysmenorrhea, pharmacology and toxicology study, 2001
Evaluation of the teratogenicity of fennel essential oil (FEO) on the rat embryo limb buds culture
The use of FEO as a remedy for control of primary dysmenorrhea increases concern about its potential teratogenicity due to its estrogen-like activity. Limb bud mesenchymal cells, when grown in high-density cultures, can be differentiated into a number of cell types including cartilage and muscle. These cells have been used extensively for in vitro studies of chondrogenesis. Therefore, we used limb bud cells and Alcian blue staining method that is specific for staining cartilage proteoglycan, to determine the teratogenic effect of FEO. Limb bud cells obtained from day 13 rat embryo were cultivated and exposed to various concentrations of FEO for 5 days at 37 degrees C and the number of differentiated foci were counted. Retinoic acid (90 microg/ml) was chosen as positive standard control. The differentiation was also evaluated using limb bud micromass culture using immunocytochemical techniques and BMP-4 antibody. The results showed that FEO at concentration as low as 0.93 mg/ml produced a significant reduction in the number of stained differentiated foci. However, this reduction was due to cell loss, determined by neutral red cell viability assay, rather than to be related to decrease in cell differentiation. These findings suggest that the FEO at the studied concentrations may have toxic effect on fetal cells, but there was no evidence of teratogenicity.
Evaluation of the teratogenicity of fennel essential oil (FEO) on the rat embryo limb buds culture, 2004
A striking and frequent cause of premature thelarche in children: Foeniculum vulgare
Isolated premature thelarche is a common disorder characterized by breast development, usually younger than 2 years, with no other signs of puberty. Although it is usually associated with adrenal or ovarian disorders, hypothyroidism, and use of exogenous hormones or drugs, it may also be associated with long-term use of herbal medicine. Thus, long-term use of preparations such as Foeniculum vulgare, which is used to eliminate gas and regulate intestinal function in children, may cause premature thelarche, and thus, the use of such preparations should be limited.
A striking and frequent cause of premature thelarche in children: Foeniculum vulgare, 2008
In the Indian subcontinent, fennel seeds are also eaten raw, sometimes with some sweetener, as they are said to improve eyesight. Ancient Romans regarded fennel as the herb of sight. Root extracts were often used in tonics to clear cloudy eyes. Extracts of fennel seed have been shown in animal studies to have a potential use in the treatment of glaucoma.
Blood and urine
Fennel may be an effective diuretic and a potential drug for treatment of hypertension.
FENNEL TEA and CANCER: can they be correlates?
Fennel tea: risk assessment of the phytogenic monosubstance estragole in comparison to the natural multicomponent mixture
For centuries, fennel fruits have been used as traditional herbal medicine in Europe and China. For the treatment of infants and sucklings suffering from dyspeptic disorders, fennel tea is the drug of first choice. Its administration as a carminativum is practiced in infant care in private homes and in maternity clinics as well where it is highly appreciated for its mild flavor and good tolerance. The long standing positive experience is astonishingly contrasted by a recent statement of the German 'Bundesinstitut für gesundheitlichen Verbraucherschutz und Veterinärmedizin' (BgVV, May 11, 2001), where consumers are advised to reduce their intake of foods containing estragole and methyleugenol, e.g. tarragon, basil, anis, star anis, jamaica pepper, nutmeg, lemon grass as well as bitter and sweet fennel fruits for reasons of health. These warnings are based on experiments with rats and mice where ESTRAGOLE, a natural ingredient of fennel fruits, proved to be carcinogenic. Meanwhile, criticism arose amongst experts concerning the interpretation of these studies. The crucial points of criticism concern the transfer of data obtained in animal models to the human situation as well as the high doses of the applied monosubstance, which do not at all represent the amounts humans are exposed to as consumers of estragole-containing foods and phytopharmaceuticals. Furthermore, studies on estragole metabolism revealed at least quantitative differences between the estragole metabolism of mice and men. In addition, it has been shown that an agent when administered in its isolated form may have significantly different effects and side effects than the same agent applied as a constituent in naturally occurring multicomponent mixtures. Thus, a multicomponent mixture such as fennel tea contains various antioxidants known to be protective against cancer. These differences were not considered in the risk assessment. A well done risk assessment should be based on appropriate data collected in humans. Considering the long traditional use of fennel tea and the total lack of epidemiological and clinical studies indicating a well founded cancerogenic potential, the probability of a serious risk connected with the consumption of fennel tea seems to be negligibly small.
Fennel tea: risk assessment of the phytogenic monosubstance estragole in comparison to the natural multicomponent mixture, 2004
Estragole Carcinogenicity In Vitro and Its Metabolic Pathways
For flavonoids formation of reactive intermediates proceeds by their enzymatic and/or chemical oxidation to quinone/quinone methide type metabolites, that are reactive alkylating intermediates. For alkenylbenzenes, including estragole, methyleugenol, elemicin, safrole, and myristicin the ultimate carcinogenic metabolites are their 1′-sulfooxy derivatives which degrade to alkylating carbocations that transformed in reactive substance, can give rise to DNA adducts.
Estragole is known to be metabolized along a number of pathways including O-demethylation (to give chavicol), epoxidation of the double bond, 1′-hydroxilation, and oxidative degradation of the side chain to carboxylic acids. Zangouras et al. indicate that at least two pathways, namely, O-demethylation and 1′-hydroxylation exhibit dose-dependency in both mouse and rat. Thus the proportion of the dose that undergoes O-demethylation declines in a dose-dependent fashion and is accompanied by an increase in the proportion of the dose that undergoes urinary elimination. This change presumably arises from saturation of the enzyme systems responsible for O-dealkylation.
The well-known bioactivation pathway of estragole proceeds by initial metabolic hydroxylation by cytochrome P450 enzymes, leading to the production of the proximate carcinogen 1′-hydroxyestragole, that by involvement of sulfotransferases is converted to the ultimate 1′-sulfooxyestragole; an instable substance that degrades to a reactive carbocation binding to different endogenous nucleophiles and inducing the production of DNA adducts, in particular hepatic macromolecular adducts; and these as shown in rodents when given as a pure compound and at high dose-levels-induced hepatomas.
Bioactivation pathway of estragole
To study bioactivation and detoxification of suspect toxic substance derived from estragole the PBK (Physiologically based kinetic) model was extended to a physiologically based dynamic (PBD) model, by which predict the formation of DNA adducts in the liver of male rats. A PBD model was developed by extending the PBK model through linking the area under the curve for 1′-hydroxyestragole formation predicted by the PBK model to the area under the curve for 1′-hydroxyestragole in in vitro incubations with rat hepatocytes exposed to 1′-hydroxyestragole. The PBD model thus obtained, was validated by in vivo experimental data on DNA adducts formation in the liver of mice exposed to estragole, since data from rat were not available.
Literature reports the formation of 1 adduct in 10.000–15.000 DNA nucleotides after a single i.p. injection of about 400 mg estragole/kg bw/day to female CD-1 mice. At this dose the PBD model predicts the formation of E-3′-N2-dGuo, the major estragole DNA adduct formed in the liver of rat at a level amounting to 4 adducts in 10.000 nucleotides. Thus, levels of DNA adducts formation in the two studies are within the same order of magnitude. The slight difference can be explained by the difference in the experimental design of the two studies. At dose levels that match the available estimates for the daily intake of estragole, amounting to 0.01 mg/kg bw and 0.07 mg/kg bw estragole, the PBD model predicted amounts of E-3′-N2-dGuo DNA adduct formed of, respectively, 2 and 12.8 in 108 nucleotides.
Consideration of some issues (dose, administration form, and differences in metabolism between species) raises doubts about the conclusion that fennel seed can be “reasonably anticipated to be a human carcinogen”, It is clear that human and animal metabolism cannot be directly compared but we think data should deserve attention.
Recently has been demonstrated that formation of DNA adducts by 1′-hydroxyestragole and cofactor for SULT-mediated conversion could be inhibited by basil extract, the same result was then confirmed in intact human hepatoma cells. This result suggests the likelihood that bioactivation and carcinogenicity may be much lower when estragole is administered at low dose and in a natural matrix.
In summary, according to the results obtained, it seems that the genotoxicity of estragole in vitro at high doses may ensue in part from direct adduction of DNA which can lead to alkali-labile sites in DNA, resulting in tails in the comet assay, and SCE, due to DNA strand-breaks. Nevertheless, the authors state that doses necessary to induce a genotoxic response are far from physiologically relevant human doses, and therefore the relevance of these adducts for tumor induction in humans in vivo needs to be further clarified.
In all of the animal studies reviewed, isolated, purified estragole was used. Thus the findings give a toxicological profile of this only molecule and not the profile risk of the entire decoction. In humans estragole usually enters the body as a component of fennel tea, or as a food that has been seasoned with herb that contains many other substance like nevadensin, epigallocatechine, other flavonoids, and anethole, that have a protective role and so counterbalance to the possible effect of pure estragole. In this context estragole occurs in the form of an extremely complex phytochemical mixture. If data about single constituent in vivo can be used as basis for statements about a herb, then data about other constituents should also be fully considered, because we think it is the only way to establish definitively if a substance is dangerous or not; and if it is a substance used from many years and in particular subsets of consumers or patients epidemiological data, when available, can help in establishing, together with the real mode of use, the effective risk for consumers.
Can Estragole in Fennel Seed Decoctions Really Be Considered a Danger for Human Health? A Fennel Safety Update, 2012