Phytoestrogen

A phytoestrogen is a plant-derived xenoestrogen (a type of estrogen produced by organisms other than humans) not generated within the endocrine system, but consumed by eating plants or manufactured foods.^[1] Also called a "dietary estrogen", it is a diverse group of naturally occurring nonsteroidal plant compounds that, because of its structural similarity to estradiol (17-β-estradiol), have the ability to cause estrogenic or antiestrogenic effects.^[2] Phytoestrogens are not essential nutrients because their absence from the diet does not cause a disease, nor are they known to participate in any normal biological function.^[2] Common foods containing phytoestrogens are soy protein, beans, oats, barley, rice, coffee, apples, carrots (see Food Sources section below for bigger list).

Its name comes from the Greek phyto ("plant") and estrogen, the hormone which gives fertility to female mammals. The word "estrus" (Greek οίστρος) means "sexual desire", and "gene" (Greek γόνο) is "to generate". It has been hypothesized that plants use a phytoestrogen as part of their natural defense against the overpopulation of herbivore animals by controlling female fertility.^[3][4]

The similarities, at molecular level, of an estrogen and a phytoestrogen allow them to mildly mimic and sometimes act as an antagonist of estrogen.^[2] Phytoestrogens were first observed in 1926,^[2][5] but it was unknown if they could have any effect in human or animal metabolism. In the 1940s and early 1950s, it was noticed that some pastures of subterranean clover and red clover (phytoestrogen-rich plants) had adverse effects on the fecundity of grazing sheep.^[2][6][7][8]

Chemical structures of the most common phytoestrogens found in plants (top and middle) compared with estrogen (bottom) found in animals

Structure

Phytoestrogens mainly belong to a large group of substituted natural phenolic compounds: the coumestans, prenylflavonoids and isoflavones are three of the most active in estrogenic effects in this class.^[1] The best-researched are isoflavones, which are commonly found in soy and red clover. Lignans have also been identified as phytoestrogens, although they are not flavonoids.^[2] Mycoestrogens have similar structures and effects, but are not components of plants; these are mold metabolites of Fusarium, especially common on cereal grains,^[9][10][11] but also occurring elsewhere, e.g. on various forages.^[12] Although mycoestrogens are rarely taken into account in discussions about phytoestrogens, these are the compounds that initially generated the interest on the topic.^[13]

Mechanism of action

Phytoestrogens exert their effects primarily through binding to estrogen receptors (ER).^[14] There are two variants of the estrogen receptor, alpha (ER-α) and beta (ER-β) and many phytoestrogens display somewhat higher affinity for ER-β compared to ER-α.^[14]

The key structural elements that enable phytoestrogens to bind with high affinity to estrogen receptors and display estradiol-like effects are:^[2]

• The phenolic ring that is indispensable for binding to estrogen receptor
• The ring of isoflavones mimicking a ring of estrogens at the receptors binding site
• Low molecular weight similar to estrogens (MW=272)
• Distance between two hydroxyl groups at the isoflavones nucleus similar to that occurring in estradiol
• Optimal hydroxylation pattern

In addition to interaction with ERs, phytoestrogens may also modulate the concentration of endogenous estrogens by binding or inactivating some enzymes, and may affect the bioavailability of sex hormones by depressing or stimulating the synthesis of sex hormone-binding globulin (SHBG).^[8]

Emerging evidence shows that some phytoestrogens bind to and transactivate peroxisome proliferator-activated receptors (PPARs).^[15][16] In vitro studies show an activation of PPARs at concentrations above 1 μM, which is higher than the activation level of ERs.^[17][18] At the concentration below 1 μM, activation of ERs may play a dominant role. At higher concentrations (>1 μM), both ERs and PPARs are activated. Studies have shown that both ERs and PPARs influence each other and therefore induce differential effects in a dose-dependent way. The final biological effects of genistein are determined by the balance among these pleiotrophic actions.^[15][16][17]

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Affinities of estrogen receptor ligands for the ERα and ERβ

Ligand	Other names	Relative binding affinities (RBA, %)^a		Absolute binding affinities (Ki, nM)^a		Action
		ERα	ERβ	ERα	ERβ
Estradiol	E2; 17β-Estradiol	100	100	0.115 (0.04–0.24)	0.15 (0.10–2.08)	Estrogen
Estrone	E1; 17-Ketoestradiol	16.39 (0.7–60)	6.5 (1.36–52)	0.445 (0.3–1.01)	1.75 (0.35–9.24)	Estrogen
Estriol	E3; 16α-OH-17β-E2	12.65 (4.03–56)	26 (14.0–44.6)	0.45 (0.35–1.4)	0.7 (0.63–0.7)	Estrogen
Estetrol	E4; 15α,16α-Di-OH-17β-E2	4.0	3.0	4.9	19	Estrogen
Alfatradiol	17α-Estradiol	20.5 (7–80.1)	8.195 (2–42)	0.2–0.52	0.43–1.2	Metabolite
16-Epiestriol	16β-Hydroxy-17β-estradiol	7.795 (4.94–63)	50	?	?	Metabolite
17-Epiestriol	16α-Hydroxy-17α-estradiol	55.45 (29–103)	79–80	?	?	Metabolite
16,17-Epiestriol	16β-Hydroxy-17α-estradiol	1.0	13	?	?	Metabolite
2-Hydroxyestradiol	2-OH-E2	22 (7–81)	11–35	2.5	1.3	Metabolite
2-Methoxyestradiol	2-MeO-E2	0.0027–2.0	1.0	?	?	Metabolite
4-Hydroxyestradiol	4-OH-E2	13 (8–70)	7–56	1.0	1.9	Metabolite
4-Methoxyestradiol	4-MeO-E2	2.0	1.0	?	?	Metabolite
2-Hydroxyestrone	2-OH-E1	2.0–4.0	0.2–0.4	?	?	Metabolite
2-Methoxyestrone	2-MeO-E1	<0.001–<1	<1	?	?	Metabolite
4-Hydroxyestrone	4-OH-E1	1.0–2.0	1.0	?	?	Metabolite
4-Methoxyestrone	4-MeO-E1	<1	<1	?	?	Metabolite
16α-Hydroxyestrone	16α-OH-E1; 17-Ketoestriol	2.0–6.5	35	?	?	Metabolite
2-Hydroxyestriol	2-OH-E3	2.0	1.0	?	?	Metabolite
4-Methoxyestriol	4-MeO-E3	1.0	1.0	?	?	Metabolite
Estradiol sulfate	E2S; Estradiol 3-sulfate	<1	<1	?	?	Metabolite
Estradiol disulfate	Estradiol 3,17β-disulfate	0.0004	?	?	?	Metabolite
Estradiol 3-glucuronide	E2-3G	0.0079	?	?	?	Metabolite
Estradiol 17β-glucuronide	E2-17G	0.0015	?	?	?	Metabolite
Estradiol 3-gluc. 17β-sulfate	E2-3G-17S	0.0001	?	?	?	Metabolite
Estrone sulfate	E1S; Estrone 3-sulfate	<1	<1	>10	>10	Metabolite
Estradiol benzoate	EB; Estradiol 3-benzoate	10	?	?	?	Estrogen
Estradiol 17β-benzoate	E2-17B	11.3	32.6	?	?	Estrogen
Estrone methyl ether	Estrone 3-methyl ether	0.145	?	?	?	Estrogen
ent-Estradiol	1-Estradiol	1.31–12.34	9.44–80.07	?	?	Estrogen
Equilin	7-Dehydroestrone	13 (4.0–28.9)	13.0–49	0.79	0.36	Estrogen
Equilenin	6,8-Didehydroestrone	2.0–15	7.0–20	0.64	0.62	Estrogen
17β-Dihydroequilin	7-Dehydro-17β-estradiol	7.9–113	7.9–108	0.09	0.17	Estrogen
17α-Dihydroequilin	7-Dehydro-17α-estradiol	18.6 (18–41)	14–32	0.24	0.57	Estrogen
17β-Dihydroequilenin	6,8-Didehydro-17β-estradiol	35–68	90–100	0.15	0.20	Estrogen
17α-Dihydroequilenin	6,8-Didehydro-17α-estradiol	20	49	0.50	0.37	Estrogen
Δ^8-Estradiol	8,9-Dehydro-17β-estradiol	68	72	0.15	0.25	Estrogen
Δ^8-Estrone	8,9-Dehydroestrone	19	32	0.52	0.57	Estrogen
Ethinylestradiol	EE; 17α-Ethynyl-17β-E2	120.9 (68.8–480)	44.4 (2.0–144)	0.02–0.05	0.29–0.81	Estrogen
Mestranol	EE 3-methyl ether	?	2.5	?	?	Estrogen
Moxestrol	RU-2858; 11β-Methoxy-EE	35–43	5–20	0.5	2.6	Estrogen
Methylestradiol	17α-Methyl-17β-estradiol	70	44	?	?	Estrogen
Diethylstilbestrol	DES; Stilbestrol	129.5 (89.1–468)	219.63 (61.2–295)	0.04	0.05	Estrogen
Hexestrol	Dihydrodiethylstilbestrol	153.6 (31–302)	60–234	0.06	0.06	Estrogen
Dienestrol	Dehydrostilbestrol	37 (20.4–223)	56–404	0.05	0.03	Estrogen
Benzestrol (B2)	–	114	?	?	?	Estrogen
Chlorotrianisene	TACE	1.74	?	15.30	?	Estrogen
Triphenylethylene	TPE	0.074	?	?	?	Estrogen
Triphenylbromoethylene	TPBE	2.69	?	?	?	Estrogen
Tamoxifen	ICI-46,474	3 (0.1–47)	3.33 (0.28–6)	3.4–9.69	2.5	SERM
Afimoxifene	4-Hydroxytamoxifen; 4-OHT	100.1 (1.7–257)	10 (0.98–339)	2.3 (0.1–3.61)	0.04–4.8	SERM
Toremifene	4-Chlorotamoxifen; 4-CT	?	?	7.14–20.3	15.4	SERM
Clomifene	MRL-41	25 (19.2–37.2)	12	0.9	1.2	SERM
Cyclofenil	F-6066; Sexovid	151–152	243	?	?	SERM
Nafoxidine	U-11,000A	30.9–44	16	0.3	0.8	SERM
Raloxifene	–	41.2 (7.8–69)	5.34 (0.54–16)	0.188–0.52	20.2	SERM
Arzoxifene	LY-353,381	?	?	0.179	?	SERM
Lasofoxifene	CP-336,156	10.2–166	19.0	0.229	?	SERM
Ormeloxifene	Centchroman	?	?	0.313	?	SERM
Levormeloxifene	6720-CDRI; NNC-460,020	1.55	1.88	?	?	SERM
Ospemifene	Deaminohydroxytoremifene	0.82–2.63	0.59–1.22	?	?	SERM
Bazedoxifene	–	?	?	0.053	?	SERM
Etacstil	GW-5638	4.30	11.5	?	?	SERM
ICI-164,384	–	63.5 (3.70–97.7)	166	0.2	0.08	Antiestrogen
Fulvestrant	ICI-182,780	43.5 (9.4–325)	21.65 (2.05–40.5)	0.42	1.3	Antiestrogen
Propylpyrazoletriol	PPT	49 (10.0–89.1)	0.12	0.40	92.8	ERα agonist
16α-LE2	16α-Lactone-17β-estradiol	14.6–57	0.089	0.27	131	ERα agonist
16α-Iodo-E2	16α-Iodo-17β-estradiol	30.2	2.30	?	?	ERα agonist
Methylpiperidinopyrazole	MPP	11	0.05	?	?	ERα antagonist
Diarylpropionitrile	DPN	0.12–0.25	6.6–18	32.4	1.7	ERβ agonist
8β-VE2	8β-Vinyl-17β-estradiol	0.35	22.0–83	12.9	0.50	ERβ agonist
Prinaberel	ERB-041; WAY-202,041	0.27	67–72	?	?	ERβ agonist
ERB-196	WAY-202,196	?	180	?	?	ERβ agonist
Erteberel	SERBA-1; LY-500,307	?	?	2.68	0.19	ERβ agonist
SERBA-2	–	?	?	14.5	1.54	ERβ agonist
Coumestrol	–	9.225 (0.0117–94)	64.125 (0.41–185)	0.14–80.0	0.07–27.0	Xenoestrogen
Genistein	–	0.445 (0.0012–16)	33.42 (0.86–87)	2.6–126	0.3–12.8	Xenoestrogen
Equol	–	0.2–0.287	0.85 (0.10–2.85)	?	?	Xenoestrogen
Daidzein	–	0.07 (0.0018–9.3)	0.7865 (0.04–17.1)	2.0	85.3	Xenoestrogen
Biochanin A	–	0.04 (0.022–0.15)	0.6225 (0.010–1.2)	174	8.9	Xenoestrogen
Kaempferol	–	0.07 (0.029–0.10)	2.2 (0.002–3.00)	?	?	Xenoestrogen
Naringenin	–	0.0054 (<0.001–0.01)	0.15 (0.11–0.33)	?	?	Xenoestrogen
8-Prenylnaringenin	8-PN	4.4	?	?	?	Xenoestrogen
Quercetin	–	<0.001–0.01	0.002–0.040	?	?	Xenoestrogen
Ipriflavone	–	<0.01	<0.01	?	?	Xenoestrogen
Miroestrol	–	0.39	?	?	?	Xenoestrogen
Deoxymiroestrol	–	2.0	?	?	?	Xenoestrogen
β-Sitosterol	–	<0.001–0.0875	<0.001–0.016	?	?	Xenoestrogen
Resveratrol	–	<0.001–0.0032	?	?	?	Xenoestrogen
α-Zearalenol	–	48 (13–52.5)	?	?	?	Xenoestrogen
β-Zearalenol	–	0.6 (0.032–13)	?	?	?	Xenoestrogen
Zeranol	α-Zearalanol	48–111	?	?	?	Xenoestrogen
Taleranol	β-Zearalanol	16 (13–17.8)	14	0.8	0.9	Xenoestrogen
Zearalenone	ZEN	7.68 (2.04–28)	9.45 (2.43–31.5)	?	?	Xenoestrogen
Zearalanone	ZAN	0.51	?	?	?	Xenoestrogen
Bisphenol A	BPA	0.0315 (0.008–1.0)	0.135 (0.002–4.23)	195	35	Xenoestrogen
Endosulfan	EDS	<0.001–<0.01	<0.01	?	?	Xenoestrogen
Kepone	Chlordecone	0.0069–0.2	?	?	?	Xenoestrogen
o,p'-DDT	–	0.0073–0.4	?	?	?	Xenoestrogen
p,p'-DDT	–	0.03	?	?	?	Xenoestrogen
Methoxychlor	p,p'-Dimethoxy-DDT	0.01 (<0.001–0.02)	0.01–0.13	?	?	Xenoestrogen
HPTE	Hydroxychlor; p,p'-OH-DDT	1.2–1.7	?	?	?	Xenoestrogen
Testosterone	T; 4-Androstenolone	<0.0001–<0.01	<0.002–0.040	>5000	>5000	Androgen
Dihydrotestosterone	DHT; 5α-Androstanolone	0.01 (<0.001–0.05)	0.0059–0.17	221–>5000	73–1688	Androgen
Nandrolone	19-Nortestosterone; 19-NT	0.01	0.23	765	53	Androgen
Dehydroepiandrosterone	DHEA; Prasterone	0.038 (<0.001–0.04)	0.019–0.07	245–1053	163–515	Androgen
5-Androstenediol	A5; Androstenediol	6	17	3.6	0.9	Androgen
4-Androstenediol	–	0.5	0.6	23	19	Androgen
4-Androstenedione	A4; Androstenedione	<0.01	<0.01	>10000	>10000	Androgen
3α-Androstanediol	3α-Adiol	0.07	0.3	260	48	Androgen
3β-Androstanediol	3β-Adiol	3	7	6	2	Androgen
Androstanedione	5α-Androstanedione	<0.01	<0.01	>10000	>10000	Androgen
Etiocholanedione	5β-Androstanedione	<0.01	<0.01	>10000	>10000	Androgen
Methyltestosterone	17α-Methyltestosterone	<0.0001	?	?	?	Androgen
Ethinyl-3α-androstanediol	17α-Ethynyl-3α-adiol	4.0	<0.07	?	?	Estrogen
Ethinyl-3β-androstanediol	17α-Ethynyl-3β-adiol	50	5.6	?	?	Estrogen
Progesterone	P4; 4-Pregnenedione	<0.001–0.6	<0.001–0.010	?	?	Progestogen
Norethisterone	NET; 17α-Ethynyl-19-NT	0.085 (0.0015–<0.1)	0.1 (0.01–0.3)	152	1084	Progestogen
Norethynodrel	5(10)-Norethisterone	0.5 (0.3–0.7)	<0.1–0.22	14	53	Progestogen
Tibolone	7α-Methylnorethynodrel	0.5 (0.45–2.0)	0.2–0.076	?	?	Progestogen
Δ^4-Tibolone	7α-Methylnorethisterone	0.069–<0.1	0.027–<0.1	?	?	Progestogen
3α-Hydroxytibolone	–	2.5 (1.06–5.0)	0.6–0.8	?	?	Progestogen
3β-Hydroxytibolone	–	1.6 (0.75–1.9)	0.070–0.1	?	?	Progestogen
Footnotes: ^a = (1) Binding affinity values are of the format "median (range)" (# (#–#)), "range" (#–#), or "value" (#) depending on the values available. The full sets of values within the ranges can be found in the Wiki code. (2) Binding affinities were determined via displacement studies in a variety of in-vitro systems with labeled estradiol and human ERα and ERβ proteins (except the ERβ values from Kuiper et al. (1997), which are rat ERβ). Sources: See template page.

Ecology

Phytoestrogens are involved in the synthesis of antifungal benzofurans and phytoalexins, such as medicarpin (common in legumes), and sesquiterpenes, such as capsidiol in tobacco.^[19] Soybeans naturally produce isoflavones, and are therefore a dietary source for isoflavones.

Phytoestrogens are ancient naturally occurring substances, and as dietary phytochemicals they are considered to have coevolved with mammals. In the human diet, phytoestrogens are not the only source of exogenous estrogens. Xenoestrogens (novel, man-made), are found as food additives^[20] and ingredients, and also in cosmetics, plastics, and insecticides. Environmentally, they have similar effects as phytoestrogens, making it difficult to clearly separate the action of these two kind of agents in studies.^[21]

Avian studies

The consumption of plants with unusual content of phytoestrogens, under drought conditions, has been shown to decrease fertility in quail.^[22] Parrot food as available in nature has shown only weak estrogenic activity. Studies have been conducted on screening methods for environmental estrogens present in manufactured supplementary food, with the purpose of aiding reproduction of endangered species.^[23]

Food sources

According to one study of nine common phytoestrogens in a Western diet, foods with the highest relative phytoestrogen content were nuts and oilseeds, followed by soy products, cereals and breads, legumes, meat products, and other processed foods that may contain soy, vegetables, fruits, alcoholic, and nonalcoholic beverages. Flax seed and other oilseeds contained the highest total phytoestrogen content, followed by soybeans and tofu.^[24] The highest concentrations of isoflavones are found in soybeans and soybean products followed by legumes, whereas lignans are the primary source of phytoestrogens found in nuts and oilseeds (e.g. flax) and also found in cereals, legumes, fruits and vegetables. Phytoestrogen content varies in different foods, and may vary significantly within the same group of foods (e.g. soy beverages, tofu) depending on processing mechanisms and type of soybean used. Legumes (in particular soybeans), whole grain cereals, and some seeds are high in phytoestrogens.

A more comprehensive list of foods known to contain phytoestrogens includes:

• Soybeans and soy products
• Tempeh
• Linseed (flax)
• Sesame seeds
• Wheat berries
• Fenugreek (contains diosgenin, but also used to make Testofen, a compound taken by men to increase testosterone).
• Oats
• Barley
• Beans
• Lentils
• Yams
• Rice
• Alfalfa
• Mung beans
• Apples
• Carrots
• Pomegranates^[25]
• Wheat germ
• Rice bran
• Lupin
• Kudzu
• Coffee
• Licorice root
• Mint
• Ginseng
• Hops,^[26]
• Bourbon whiskey
• Beer,^[27]
• Fennel
• Anise.^[28]
• Red clover (sometimes a constituent of green manure).
• Spinach^[29]

Food content of phytoestrogens is very variable and accurate estimates of intake are therefore difficult and depends on the databases used.^[30] Data from the European Prospective Investigation into Cancer and Nutrition found intakes between 1 mg/d in Mediterranean Countries and more than 20 mg/d in the United Kingdom.^[31] The high intake in the UK is partly explained by the use of soy in the Chorleywood bread process.^[32] An epidemiological study of women in the United States found that the dietary intake of phytoestrogens in healthy post-menopausal Caucasian women is less than one milligram daily.^[33]

Effects on humans

In humans, phytoestrogens are digested in the small intestine, poorly absorbed into the circulatory system, circulate in plasma, and are excreted in the urine. Metabolic influence is different from that of grazing animals due to the differences between ruminant versus monogastric digestive systems.^[21]

As of 2020, there is sufficient clinical evidence to determine that phytoestrogens have effects in humans.^[34]

Females

It is unclear if phytoestrogens have any effect on the cause or prevention of cancer in women.^[1][35] Some epidemiological studies have suggested a protective effect against breast cancer.^[1][35][36] Additionally, other epidemiological studies found that consumption of soy estrogens is safe for patients with breast cancer, and that it may decrease mortality and recurrence rates.^[1][37][38] It remains unclear if phytoestrogens can minimize some of the deleterious effects of low estrogen levels (hypoestrogenism) resulting from oophorectomy, menopause, or other causes.^[35] A Cochrane review of the use of phytoestrogens to relieve the vasomotor symptoms of menopause (hot flashes) stated that there was no conclusive evidence to suggest any benefit to their use, although genistein effects should be further investigated.^[39]

Males

It is unclear if phytoestrogens have any effect on male sexuality, with conflicting results about the potential effects of isoflavones originating from soy.^[1] Some studies showed that isoflavone supplementation had a positive effect on sperm concentration, count, or motility, and increased ejaculate volume.^[40][41] Sperm count decline and increasing rate of testicular cancers in the West may be linked to a higher presence of isoflavone phytoestrogens in the diet while in utero, but such a link has not been definitively proven.^[42] Furthermore, while there is some evidence that phytoestrogens may affect male fertility, more recent reviews of available studies found no link,^[43][44] and instead suggests that healthier diets such as the Mediterranean diet might have a positive effect on male fertility.^[44] Neither isoflavones nor soy have been shown to affect male reproductive hormones in healthy individuals.^[43][45]

Infant formula

Some studies have found that some concentrations of isoflavones may have effects on intestinal cells. At low doses, genistein acted as a weak estrogen and stimulated cell growth; at high doses, it inhibited proliferation and altered cell cycle dynamics. This biphasic response correlates with how genistein is thought to exert its effects.^[46] Some reviews express the opinion that more research is needed to answer the question of what effect phytoestrogens may have on infants,^[47][48] but their authors did not find any adverse effects. Studies conclude there are no adverse effects in human growth, development, or reproduction as a result of the consumption of soy-based infant formula compared to conventional cow-milk formula.^[49][50][51] The American Academy of Pediatrics states: "although isolated soy protein-based formulas may be used to provide nutrition for normal growth and development, there are few indications for their use in place of cow milk-based formula. These indications include (a) for infants with galactosemia and hereditary lactase deficiency (rare) and (b) in situations in which a vegetarian diet is preferred."^[52]

Ethnopharmacology

In some countries, phytoestrogenic plants have been used for centuries in the treatment of menstrual and menopausal problems, as well as for fertility problems.^[53] Plants used that have been shown to contain phytoestrogens include Pueraria mirifica^[54] and its close relative kudzu,^[55] Angelica,^[56] fennel,^[28] and anise. In a rigorous study, the use of one such source of phytoestrogen, red clover, has been shown to be safe, but ineffective in relieving menopausal symptoms^[57] (black cohosh is also used for menopausal symptoms, but does not contain phytoestrogens^[58]).

See also

• Ethnopharmacology
• Isoflavones
• Lignan
• Mycoestrogens
• Phytoandrogens
• Plant hormone
• Soy

References

1. "Isoflavones". Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis. October 2016. Retrieved 6 August 2022.
2. Yildiz F (2005). Phytoestrogens in Functional Foods. Taylor & Francis Ltd. pp. 3–5, 210–211. ISBN 978-1-57444-508-4.
3. Hughes CL (Jun 1988). "Phytochemical mimicry of reproductive hormones and modulation of herbivore fertility by phytoestrogens". Environmental Health Perspectives. 78: 171–4. doi:10.1289/ehp.8878171. PMC 1474615. PMID 3203635.
4. Bentley GR, Mascie-Taylor CG (2000). Infertility in the modern world: present and future prospects. Cambridge, UK: Cambridge University Press. pp. 99–100. ISBN 978-0-521-64387-0.
5. Varner JE, Bonner J (1966). Plant Biochemistry. Academic Press. ISBN 978-0-12-114856-0.
6. Bennetts HW, Underwood EJ, Shier FL (1946). "A specific breeding problem of sheep on subterranean clover pastures in Western Australia". Australian Veterinary Journal. 22 (1): 2–12. doi:10.1111/j.1751-0813.1946.tb15473.x. PMID 21028682.
7. Cunningham IJ, Hogan KG (1954). "Oestrogens in New Zealand pasture plants". N. Z. Vet. J. 2 (4): 128–134. doi:10.1080/00480169.1954.33166.
8. Johnston I (2003). Phytochem Functional Foods. CRC Press Inc. pp. 66–68. ISBN 978-0-8493-1754-5.
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