Fructus Agni Casti consists of the dried, ripe fruits of Vitex agnus-castus L. (Lamiaceae).
Agnus-castus vulgaris Carr., Vitex verticillata Lam.
Selected vernacular names
Abraham’s balm, Abrahamsstrauch, agneau-chaste, agnocasto, agnos-casto cumune, agnus-castus, angarf, ârbol casto, ârbolde la castidad, arbre au poivre, athlak, banjankusht, barátcserje, bish barmagh aghaji, chaste tree, chasteberry, common chaste tree, daribrahim, felfele barry, fanfangosht, gatileira comum, gattilier, gattilier commun, hab an nasl, hab el fakd, hab a khouraf, hayit, hemp tree, jurema, kaff maryam, kef-meriem, kerwa, Keuschbaum, Keuschlamm, kyskhedstrae, lilac chastetree, lygos, Mönchspfeffer, Mönchspfeller, monk’s pepper, monk’s pepper tree, Müllen, non’s peppertree, panj angosht, panjangusht, pape falso, peperella, petite poivre, pimiento menor, poivre de moine, poivre sauvage, ranukabija mah, sagetree, sauzgatillo, seiyo-ninzin-boku, shajerat Ebrahim, shagareh Ibrahim, sinduvara, tree of chastity, true chaste tree, vitex, vitiu, wild lavender, Yemen safrani.
A small tree or deciduous shrub, approximately 1–6 m in height, with aromatic odour.
Leaves: opposite, long-petiolate, palmately-compound with 3–9 stipulate leaﬂets; leaﬂet blade linear-lanceolate, apex and base acuminate, 1.5–10.0 cm long, 0.5–2.0 cm wide; the central leaﬂet is the longest, dark green and glabrous above, velvety white-tomentose below; margin entire to sparsely toothed.
Inﬂorescence: terminal panicle, 12.0–17.5 cm long, and composed of many sessile-subsessile cymes.
Flower: perfect, campanulate symmetric, white-tomentose; calyx 5-toothed, campanulate, 2.0–2.5 cm long; corolla blue, pink, yellowish or white, salverform, tube 6–7 mm long, limb 2-lipped, upper lip 2-lobed, lower lip 3-lobed; stamens 4, exerted, 2 long, 2 short, inserted near top of corolla tube, alternate with corolla lobes; ovary superior, style exerted, stigma biﬁd. Fruit: drupe, globose to subglobose, 2–4 mm in diameter, reddish.
Mature fruit is round to ovoid, 2–4 mm in diameter, glandular hairy, extremely hard, reddish-brown to black, slightly rough, and usually accompanied by a short pedicel and some smaller, immature fruits in close groups of up to six.
The apex has a slight depression with 4 faint grooves at right angles to one another. A tubular persistent calyx with 5 short, often indistinct, teeth covers half to three quarters of the surface. The calyx is grey-green and tomentose.
Odour: faintly aromatic; taste: slightly aromatic and bitter.
Fruit: The exocarp is brown and narrow, consisting of parenchymatous cells with thin walls and partially ligniﬁed cells with many pitted thickenings on the inside. In surface view, the exocarp shows an epidermis of polygonal cells with thickened walls and some with large, conspicuous, simple pits; among the cells are short-stalked glandular trichomes with unicellular or multicellular heads and some short covering trichomes.
In cross-section, the fruit shows small epicarp cells covered with a thick cuticle.
The mesocarp consists of several layers of isodiametric parenchyma cells with slightly thickened and pitted cell walls; occasionally these cells have brownish granular contents.
The walls of the outer mesocarp cells are brown whereas those of the inner cells lack colour. The inner mesocarp consists of ﬁnely pitted sclerenchymatous cells, some with moderately thickened walls, others consisting of isodiametric stone cells with a small lumen.
In the outer part, very small brown-coloured vascular bundles are arranged in a circle. Towards the endocarp the cells become smaller and their cell walls thicker; the innermost cell layers consist of small sclereids with a small branched lumen. The seeds are small, having large cotyledons surrounded by thin-walled, large parenchymatous cells that have ribbed thickenings.
The nutritive tissue and the cells of the germ contain aleurone grains and oil globules. Calyx: composed of outer epidermis of small, isodiametric polygonal cells, densely covered by short, bent or undulate, unicellular or bicellular covering trichomes of fairly uniform length; inner epidermal cells a little larger, walls slightly wavy, some thickened; trichomes absent.
Powdered plant material
Greyish to dark brown, with a musty, slightly aromatic odour and unpleasant, bitter taste, reminiscent of sage; abundant, more or less isodiametric stone cells with walls of varying thickness and degree of pitting; ovoid ligniﬁed cells with thin bands of reticulate thickening; fragments of calyx with closely-spaced, short covering and glandular trichomes on the outer side and birefractive elongated sclereids on the inner side; epicarp cells with large pits in the outer wall; thin-walled parenchymatous cells and globules of ﬁxed oil; small glandular trichomes.
Uses supported by clinical data
Orally for the symptomatic treatment of gynaecological disorders including corpus luteum insufﬁciency and hyperprolactinaemia , premenstrual síndrome , menstrual irregularities, cyclic mastalgia and also to treat hormonally-induced acné.
Uses described in pharmacopoeias and well established documents
Orally for the treatment of endometrial hyperplasia and secondary amenorrhoea; endocrine-dependent dermatoses (dermatitis symmetrica dysmenorrhoica (Matzenauer-Polland syndrome)) acne vulgaris, eczema, acne rosacea), hypermenorrhoea, infertility due to hyperprolactinaemia and luteal phase defect.
Used to treat ﬁbroid cysts and infertility, to stop miscarriages due to progesterone insufﬁciency, to help expel the placenta after birth and also as a digestive aid, sedative, anti-infective and for the treatment of hot ﬂushes.
Uses described in traditional medicine
Used as an anaphrodisiac, calefacient, contraceptive, emmenagogue, sedative and as a tonic.
Receptor binding Numerous mechanisms have been proposed for the many activities of the crude drug.
Extracts of the fruit have been shown to act as dopamine agonists in vitro and in vivo. The binding of an 80% ethanol extract of the fruit and various fractions of the extract to the dopamine D2and other receptors was evaluated both by radioligand binding studies and by superfusion experiments.
The extract bound to the dopamine D2 and opioid (μ and K subtype) receptors with a range of median inhibitory concentrations between 40 and 70 μg/ml. Binding was not observed for the histamine H1 and benzodiazepine receptor or the serotonin transporter.
Two diterpenes isolated from the hexane fraction of the extract, rotundifuran and 6B,7B-diacetoxy-13-hydroxy-labda-8,14-diene, exhibited inhibitory actions on dopamine D2 receptor binding with a median inhibitory concentration of 45 and 79 μg/ml, respectively.
While lipophilic fractions of the extract bound to the μ- and K-opioid receptors, binding to D-opioid receptors was inhibited mainly by an aqueous fraction of the extract.
In superfusion experiments, the aqueous fraction of a methanol extract inhibited the release of acetylcholine in a concentration-dependent manner. In addition, the D2 receptor antagonist, piperone, antagonized the effect of the extract suggesting a dopaminergic action mediated by D2receptor activation. A labdane diterpene, A-acetoxy-13-hydroxylabdadiene, isolated from a fruit extract, was found to displace 125I-sulpiride from recombinant human D2 receptor binding sites in a dose-dependent manner.
This group also demonstrated that rotundifuran, at a concentration of 100 MM, signiﬁcantly inhibited the secretion of prolactin from cultured rat pituitary cells (p < 0.05). In addition, rotundifuran inhibited forskolininduced prolactin and cyclic adenosine monophosphate secretion in rat pituitary cells, when added to the medium at a concentration range of 10– 100 MM.
Bicyclic clerodane diterpenes have also been isolated from extracts of the fruit and were found to have a 10-fold higher activity than rotundifuran for inhibiting synthesis of cyclic adenosine monophosphate and release of prolactin in prolactin secreting cells of the rat pituitary by binding directly to the D2 receptors.
In membrane preparations from rat corpus striatum, a lyophilized 60% ethanol extract of the fruit at a concentration of 0.5mg/ml displaced 125I-sulpiride from dopamine D2 receptor binding sites in a dose-dependent manner.
An extract of the fruit as well as the synthetic dopamine agonist (lisuride) signiﬁcantly inhibited basal and thyroid releasing hormone-stimulated secretion of prolactin by rat pituitary cells in vitro.
A reduction in the concentrations of endogenous opioids during the late luteal phase has also been proposed as one of the mechanisms which may induce the symptoms of premenstrual syndrome, such as mood swings, headaches and water retention.
A number of fruit extracts and chromatographic fractions have been tested in vitro for their ability to displace receptor binding ligands to the M-,K-, and D-opioid receptors.
The extract and butanol, chloroform and hexane fractions bound to the M- and K-receptors, while the aqueous extract was more active in the D-opioid receptor.
No binding in the orphan opioid receptor was noted. Rat brain striatal tissue was preincubated with 3H-choline. Treatment of the preincubated tissue with a fruit extract inhibited electrically stimulated release of 3H-acetylcholine with a median inhibitory concentration of 30 Mg/ml.
The inhibitory effect was reduced by co-incubation of the tissues with spiroperidol. Atropine partially reduced the inhibitory effects of the fruit extract suggesting that the extract may also work on the cholinergic receptors.
Several extracts of chaste berry have been shown to bind to the estrogen receptor and have weak estrogenic effects, suggesting that chaste berry may also affect the estrogen/progesterone balance.
A fruit extract dose-dependently bound to both estrogen receptor isotypes, but binding appeared to be more selective for estrogen receptor B than estrogen receptor A.
The extract also dose-dependently inhibited the secretion of progesterone from human granuloma cells, an effect that is mediated by estrogen receptor B, as it can be blocked by tamoxifen.
Furthermore one in vivo study has shown that treatment of ovariectomized rats with an undeﬁned extract of the fruit (dose not stated) increased uterine growth, and the expression of uterine c-myc mRNA levels and liver ceruloplasm mRNA levels, indicating an estrogenic effect.
A methanol extract of the crude drug bound to both estrogen receptor A and estrogen receptor B, and induced the expression of estrogendependent genes, progesterone receptor, and pS2 (presenelin-2) in Ishikawa cells (an estrogen-dependent endometrial adenocarcinoma cell line).
Signiﬁcant binding afﬁnity for both estrogen receptor A and estrogen receptor B, with a median inhibitory concentration of 46.3 μg/ ml and 64.0 μg/ml, respectively, and the afﬁnity for estrogen receptor A and estrogen receptor B was not signiﬁcantly different.
Breast cancer cells
In Ishikawa cells, the extract exhibited weak estrogenic activity, as indicated by upregulation of the progesterone receptor mRNA; however alkaline phosphatase activity was not changed. In S30 breast cancer cells, the presenelin-2 gene was up-regulated in the presence of 20.0 μg/ml of the same extract.
Based on bioassay-guided isolation, the “estrogenic” component from the fruit extract was identiﬁed as linoleic acid, which also bound to estrogen receptor A and estrogen receptor B.
Like the extract, linoleic acid also induced expression of the progesterone receptor mRNA in Ishikawa cells, at a concentration of 1 μg/ml, indicating that binding produced a biological estrogenic effect in vitro. In addition, low concentrations of the extract or linoleic acid (10 Mg/ml) up-regulate the expression of estrogen receptor B mRNA in the estrogen receptor+
16hormone-dependent T47D:A18 cell line, a further indication of estrogenic activity.