Arch Gynecol Obstet DOI 10.1007/s00404-015-3629-x

REVIEW

Scientific evaluation of medicinal plants used for the treatment of abnormal uterine bleeding by Avicenna Masumeh Mobli • Marzieh Qaraaty • Gholamreza Amin • Ismaeil Haririan • Mannan Hajimahmoodi • Roja Rahimi

Received: 9 September 2014 / Accepted: 19 January 2015 Ó Springer-Verlag Berlin Heidelberg 2015

Abstract Purpose Abnormal uterine bleeding (AUB) is one of the prevalent gynecological disorders that cause considerable morbidity and management of that plays an important role in protecting women’s health. This review focuses on medicinal plants mentioned by Avicenna, a great Iranian philosopher and physician (A.D. 980–1037), in his book Canon for treatment of AUB. Methods Medicinal plants mentioned in Canon for treatment of AUB were elicited and searched in electronic databases including PubMed, Scopus, Google Scholar and Cochrane library to find studies that confirmed their efficacy. Data were collected for the years 1980–2014. Results The findings included 23 plants belonging to 18 families. Scientific findings have revealed that these plants control AUB through four mechanisms of action including

M. Mobli
G. Amin
M. Hajimahmoodi
R. Rahimi (&) Department of Traditional Pharmacy, School of Traditional Medicine, Tehran University of Medical Sciences, 1417653761 Tehran, Iran e-mail: [email protected] M. Qaraaty Traditional Medicine Clinical Trial Research Center, Shahed University, Tehran, Iran G. Amin Department of Pharmacognosy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran I. Haririan Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran M. Hajimahmoodi Department of Drug and Food Control, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

inhibition of inflammatory process, inhibition of prostaglandins production, antiproliferative activity on human cervical cancer cells (HeLa), and estrogenic activity. All of the plants exhibited anti-inflammatory activity in vitro and/ or in vivo. Cuscuta chinensis and Portulaca oleracea exhibited estrogenic activity. Boswellia carteri, Lens culinaris, Myrtus communis, Polygonum aviculare, Pistacia lentiscus, and Punica granatum have revealed inhibitory activity on biosynthesis of prostaglandins. Some of the mentioned plants including: Ceratonia siliqua, Cuscuta chinensis, Cuscuta epithymum, Cydonia oblonga, Paeonia sp., Portulaca oleracea, Solanum nigrum, Rumex acetosa and Onopordum acanthium have shown antiproliferative activity on HeLa cells. Conclusion Investigation of traditional Iranian medicine literatures can lead to the identification of effective natural medicines for the management of AUB; however, conclusive confirmation of the efficacy and safety of these treatments needs more evaluations. Keywords Abnormal uterine bleeding
Avicenna
Medicinal plants
Prostaglandin
Estrogenic
Antiproliferative
Anti-inflammatory

Introduction Abnormal uterine bleeding (AUB) is an important menstrual disorder covering 20 % of gynecological visits and creates considerable morbidity in women of reproductive age and imposes major medical, social, and economic problems to women, their families, the workplace, and health services [1–4]. The prevalence of AUB is estimated at 11–13 % in general population and increases with age, reaching 24 % in those aged 36–40 years [5]. Chronic and

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acute AUB and inter-menstrual bleeding are types of AUB [6, 7]. AUB has structural (organic) and non-structural (non-organic) causes. Polyp, adenomyosis, leiomyoma, malignancy and hyperplasia are structural causes. Coagulopathy, ovulatory disorders, endometrial disorders, iatrogenic causes and imbalance in the metabolism of local endometrial prostaglandins are non-structural causes [3, 8, 9]. Medical therapy is first-line treatment. However, certain situations may call for surgical management. Hormonal drugs such as IV conjugated equine estrogen, combined oral contraceptives, and oral progestins are considered as the first-line pharmacological treatments in the management of AUB. However, increased risk of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli and deep vein thrombosis in postmenopausal women during treatment with these medications has been reported [5, 7]. Because of these serious side effects, it seems logical to investigate other available sources to discover more effective and safe drugs. One of the most valuable ones to achieve this goal is traditionally used remedies. One of the advantages of traditionally used remedies is their use by people of a region for many years and this issue may confirm their efficacy and safety. Avicenna (A.D. 980–1037), a famous Iranian philosopher and physician, has described AUB by terms such as ‘‘Efrat-e Tams’’ or ‘‘Kesrat-e Tams’’ and also emphasized on its etiology and treatment. In treatment section, he has implied various herbs that could be used for the management of AUB [10–12]. The aim of present study is to review medicinal herbs claimed to be effective in ‘‘Canon of Medicine’’ for AUB to new source that may be used as complementary and/ or alternative to conventional treatment.

Table 1 Medicinal plants used for treatment of AUB mentioned in ‘‘Canon of Medicine’’ Scientific names

Family

Name(s) in ‘‘Canon of Medicine’’ book

Boswellia sacra Flueck.

Burseraceae

Kondur

Ceratonia siliqua L.

Fabaceae

Kharnub

Cuscutachinensis Lam. Cydonia oblonga Mill.

Convolvulaceae Rosaceae

Kashus Safarjal

Cymbopogon schoenanthus (L.) Spreng.

Poaceae

Izkher

Hyoscyamus sp.

Solanaceae

Banj

Juglansregia L.

Juglandaceae

Juz

Lens culinaris Medik.

Fabaceae

Adas

Myrtus communis L.

Myrtaceae

Aas

Nymphaea alba L. Oleae uropaeaL.

Nymphaeaceae Oleaceae

Nilufar Zeitun

Onopordum acanthium L.

Asteraceae

Shukaei

Paeonia officinalisL.

Paeoniaceae

Ood-al- Saleeb, Favania

Paeonia emodi Wall. ex Royle Pistacia lentiscus L.

Anacardiaceae

Mastaki

Polygonum aviculare L.

Polygonaceae

Asi-al-raei

Portulaca oleracea L. Punica granatum L.

Portulacaceae Lythraceae

Boghla-al-homgha Jolnar

Rhus coriaria L.

Anacardiaceae

Somagh

Rumex acetosa L.

Polygonaceae

Hommaz

Solanum nigrum L.

Solanaceae

Enab-al-saalab

Symphytum sp.

Boraginaceae

Samghuton

Tragopogon sp.

Asteraceae

Lahyat-al-tis

Ziziphus spina-christi (L.) Willd.

Rhamnaceae

Sedr

Methods Medicinal herbs used for the treatment of AUB were extracted from ‘‘Canon of Medicine’’ (Table 1) [12]. Electronic databases including PubMed, Scopus, Google Scholar and Cochrane library were explored for each of these herbs and all retrieved articles were evaluated to achieve any in vitro, animal, or clinical evidence for their efficacy and pharmacological mechanisms related to AUB. Studies either demonstrate direct efficacy of these medicinal herbs or effect of them in mechanisms involved in AUB was considered. Data were collected for the years 1980 to June 2014. The search terms were ‘‘uterine bleeding’’ or ‘‘menstrual cycle’’ or ‘‘menstruation’’ in title and abstract and the name of each herb in the whole text. Results from primary search were screened by two independent investigators. References of finally included articles were reviewed for more relevant studies. Included articles were reviewed to extract plant’s scientific name,

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medicinal part and active components (if mentioned), and animal model and species for in vivo studies. In human studies, study design, number of patients, interventions, duration of treatment and efficacy and tolerability of the herbal treatment were also collected. Results are shown in Tables 2, 3 and 4.

Findings and results Below, the medicinal herbs mentioned for the management of AUB in ‘‘Canon of Medicine’’ and all evidence confirming their efficacy are described individually. Boswellia species Oleogum resin from various Boswellia species has been claimed to be effective for the management of AUB in

Arch Gynecol Obstet Table 2 In vitro studies on plants used for treatment of AUB mentioned in ‘‘Canon of Medicine’’ Plant

Part/extract

Active constituent

Result

Reference

Boswellia carteri Birdw.

Gum resin

C(28)-hydroxylated lupeolic acid

Suppression of eicosanoids biosynthesis through inhibition of cytosolic phospholipase A2

[15]

Ceratonia siliqua L.

Pods/crude polyphenol fraction

Polyphenols

Antioxidant activity

[16]

Sapwood/methanol extract

Gentisic acid and (-)epicatechin

Antitumor activity; ;intracellular ROS production by HeLa cells after treatment with H2O2

[21]

Leaves/methanol extract

Gallic acid, (?)-catechin and quercetin

Cytotoxic effects and apoptosis induction on human cancer cell line

[22]

Aerial parts/chloroform and hydroalcoholic extracts

–

; Viability of Hela and MDA-MB-468 cells

[26]

Seeds/ethanol extract

Kaempferol and isorhamnetin

Estrogenic activity

[30]

Cuscuta epithymum L.

Aerial parts/chloroform and hydroalcoholic extracts

–

; Viability of Hela, HT-29 and MDA-MB-468 cells by chloroform extract; ; viability of MDA-MB468 cells by hydroalcoholic extract

[26]

Cydonia oblonga Miller.

Peel/polyphenolic extract

–

Inhibition of LPS-mediated activation of three major cellular proinflammatory effectors, NF-jB, p38MAPK and Akt

[31]

Lipophilic wax extract and aqueous fermented extract

–

Antioxidant properties and cytotoxic effects on human HeLa cell lines

[32]

Cuscuta chinensis Lam.

Cymbopogon citratus Stapf.

Leaves

Polyphenols

iNOS expression

[34]

Leaves

Chlorogenic acid

Inhibition of proteasome and NF-jB pathway

[35]

Leaves/aqueous extract

–

Inhibition of iNOS expression, NO production and various LPS-induced pathways; Inhibition of LPSinduced PGE2 production

[36]

Leaves/phenolic acid-rich fraction

Polyphenols

Inhibition of LPS-induced PGE2 production

[36]

Cymbopogon martinii (Roxb.) Wats.

Essential oils

–

; TNF-c, IL-1b, and IL-8 secretion levels of THP-1 cells

[38]

Juglansregia L.

Bark/aqueous, chloroform and alcoholic extracts

–

Anti-inflammatory activity

[44]

Lens culinaris Medik.

Seed/methanol extracts

–

Inhibition of COX-2

[48]

Myrtus communis L.

Leaves

Myrtucommulone

Suppression of typical proinflammatory cellular responses

[102]

Leaves

Myrtucommulone

Inhibition of microsomal PGE2 synthase-1

[103]

Nymphaea alba L.

Rhizome/ethanol extract

Alkaloids, tannins, glycosides and flavonoids

Antioxidant activities

[54]

Onopordum acanthium L.

Flower, fruit and leaves

–

Antiproliferative activity against Hela and MCF7 cell line

[60]

Onopordum Macracanthum Schousboe.

Aerial parts

–

Inhibition of TNFa and NO synthesis, as well as VCAM1 surface expression

[61]

Onopordum cynarocephalum Boiss. and C.I.Blanche.

Aerial part/aqueous extract

–

Inhibition of fetal bovine serum derived gelatinase A and B; ; expression of endotoxin-induced inflammation markers IL-6 protein and mRNA, as well as gelatinase A and B -activity via NF-jB. suppressed mRNA and protein levels of b-casein

[62]

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Arch Gynecol Obstet Table 2 continued Plant

Part/extract

Active constituent

Result

Reference

Paeonia suffruticosa Sndr.

Aerial part/aqueous extract

Polyphenols, flavonoids and trace metal

Inhibition of NO and TNF-a production

[64]

Aerial part/aqueous and ethanol extracts

Polyphenols, flavonoids and trace metal

Antioxidant activity

[64]

Root/hydroalcoholic extract

Paeonol

Regulation of TNF-a, IL-1b, IL-6, and IL-10 production

[65]

Paeonia species

Root

Paeoniflorin

Induction of apoptosis of HeLa cells

[66, 67]

Pistacia lentiscus L.

Resin

–

Inhibition of NO and PGE2 production

[69]

Polygonum aviculare L.

Aerial part

–

Inhibition of PGs biosynthesis and platelet activating factor and induction of exocytosis

[71]

Aerial part

Flavonol glucuronides

Inhibition of ROS production

Portulaca oleracea L.

Aerial part

Polysaccharides

Inhibition of cervical cancer cell growth

[76]

Punicagranatum L.

Leaves/methanol extract

Phenols, flavonoids, tannins and anthocyanins

Antioxidant activity; cytotoxic activity

[78]

Leaves/ethanol extract

Phenols, flavonoids, tannins and anthocyanins

Inhibition of 5-lipoxygenase, AChE and BuChE

[78]

Leaves/ethanol and methanol extracts

Phenols, flavonoids, tannins and anthocyanins

Anti-inflammatory activity

[78]

Flower/80 % ethanol extract

Phenols, flavonoids, tannins and anthocyanins

Antioxidant, anti-inflammatory and antiproliferative activities

[79]

Peel

Punicalagin, punicalin, strictinin A, and granatin B –

Inhibition of NO production and iNOS expression; COX-2 and PGE2 inhibitory effect

[84]

Anti-inflammatory activity

[85]

Fruit

Polyphenols

Inhibition of COX2 activity and PGE2 production

[86]

Leaves

2-Methyl-pyran-4-one-3O-b-D-glucopyranoside

Blockage of both the TNFa-induced translocation and activation of NF-jB

[87]

Rumex acetosa L.

Aerial parts

–

Antiproliferative activity against Hela and MCF7 cell line

[90]

Symphytum officinale L.

Root

Glycopeptides

Inhibition of PGs and leukotriens release via ; expression of phospholipase A2

[96]

Ziziphus spinachristi (L.) Willd.

Bark/ethanol extract

–

Inhibition of PG synthesis by COX-2

Leaves/methanol and ethanol extracts

AChE acetylcholinesterase, Akt protein kinase B, BuChE butyrylcholinesterase, COX cyclooxygenase, Hela human uterine cervical carcinoma, IL Interleukin, iNOS inducible NO synthase, LPS lipopolysaccharide, MCF7 breast epithelial adenocarcinoma, MDA-MB-468 human breast carcinoma cell line, NF-jB nuclear factor-kappa B, NO nitric oxide, p38MAPK p38 mitogen-activated protein kinase, PG prostaglandin, ROS reactive oxygen species, THP-1 human acute monocytic leukemia cell line, TNF tumor necrosis factor, VCAM1 vascular cell adhesion protein 1

‘‘Canon of Medicine’’. B. carteri dried gum resin water extract showed significant anti-inflammatory and analgesic activities and also exhibited remarkable inhibitory activity on production of Prostaglandin (PG) E2 [13, 14]. Triterpene acids isolated from B. carteri resin exhibited marked antiinflammatory activity in inflammation in mice [14]. C(28)hydroxylated lupeolic acid from the gum resin of B. carteri suppressed eicosanoid biosynthesis in intact cells [15].

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Ceratonia siliqua L. Ceratonia siliqua, commonly known as carob, is a plant of the Mediterranean regions. The crude extract of the plant pod exhibited antioxidant properties higher than certain known polyphenols such as catechin, quercetin and gallic acid alone [16, 17]. This antioxidant activity may be related to the presence of carotenoids and phenolic

Coumarinolignan

–

Seeds/ methanol extract

Seeds/ alcoholic extract

Hyoscyamus niger L.

Myrtucommulone Tannins, alkaloids, and flavonoids

Leaves

Aerial parts/ aqueous and ethanol extracts

–

Leaves/ ethanol extract

Myrtus communis L.

–

Leaves/ ethanol and aqueous extract

Juglans regia L.

–

Aerial parts/ methanol extract

Hyoscyamus reticulatus L.

Essential oil

Leaves

Cymbopogonwinterianus Jowitt.

Essential oil

Flavonoids

Seed

Leaves

–

Seed/ methanol extract

Cymbopogon flexuosus (D.C) Stapf.

Cuscuta chinensis Lam.

Acetic acid-induced writhing and hot plate tests/xylene-induced ear edema and a cotton pellet test

Carrageenan-induced paw edema and carrageenan-Induced pleurisy

Carrageenan-induced hind paw edema

P-Benzoquinone-induced abdominal constrictiontest

Acetic acid-induced writhing test and hot plate test

Formalin test

Writhing test and Hot plate method/ carrageenin-induced paw oedema and cotton pellet granuloma methods

Acute carrageenan-induced paw edema and the chronic granuloma pouch models/acetic acidinduced writhing and tail-flick model acetic acid-induced writhing and formalin tests/carrageenan-induced neutrophil migration

Sound, light, and electricity were combined into psychological stress for endocrine dysfunction model

Acetic acid-induced writhing response and formalin-induced paw licking methods/kcarrageenan-induced paw edema

TPA-induced inflammation

Resin/ methanol extract

Triterpene acids

Formalin-and carrageenan-induced paw edema/oxytocin-induced dysmenorrhea

Gum resin/ – water extract

Model

Boswellia carteri Birdw.

Active constituent

Part/extract

Plant

Table 3 In vivo studies on plants used for treatment of AUB mentioned in ‘‘Canon of Medicine’’

Antinociceptive activity/anti-inflammatory activity

Anti-inflammatory activity

Mouse Mouse

Anti-inflammatory activity

Antinociceptive activity

Antinociceptive activity

Analgesic effect on acute and chronic pain thresholds

Antinociceptive activity/anti-inflammatory activity

Antinociceptive activity/anti-inflammatory activity

[105]

[104]

[45]

[45]

[43]

[42]

[41]

[37]

[33]

[28]

: Estrogen receptor expression in the hippocampus, hypothalamus and pituitaries, as well as luteinizing hormone receptor expression in ovaries Anti-inflammatory activity/analgesic activity

[27]

[14]

[13]

Reference

Antinociceptive activity/anti-inflammatory activity

Anti-inflammatory activity

Anti-inflammatory activity/analgesic activity

Result

Mouse

Mouse

Mouse

Rat

Rat and mouse

Mouse/ rat

Rat

Rat

Mouse

Mouse

Mouse

Species

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Punica granatum L. –

–

Flower/petroleum ether, dichloromethane and methanol fractions

Fruit rind, flower and leaves/aqueousethanol (50 %) extract

–

Arial part –

Polysaccharides

Aerial part

Fruit peel/methanol extract

–

Portulaca oleracea L.

–

–

Leaves/aqueous, chloroform, ethyl acetate and methanol extract

Pistacia lentiscus L.

Paeonol

–

Aerial part/10 % ethanol extract

Root/80 % aqueous-ethanol extract

Paeonia suffruticosa Andrews.

Aerial parts/ethanol extract

Flowers and roots/ethanol extracts

Paeonia peregrina Mill.

–

Hydroxytyrosol and oleuropein

Leaves

Aerial parts/aqueous extract

–

Oil

Onopordum cynarocephalum Boiss. & C.I.Blanche.

– –

Fruits/n-hexane extract

Leaves/chloroform and methanol extracts

–

Flower/ethanol extract

Olea europaea L.

Alkaloids, tannins, glycosides and flavonoids

Rhizome/ethanol extract

Nymphaea alba L.

Active constituent

Part/extract

Plant

Table 3 continued

Carrageenan-induced paw edema/tail-flick method

Hind paw egg albumin test/writhing, formalin, hot plate and tail-immersion tests Carrageenan-induced paw edema/acetic acid-induced writhing test

Wound healing model

Carrageenan-induced paw edema assay/hot plate method and tail-flick response In vitro assay on HeLa cell/in vivo assay on U14 tumor-bearing mice

Animal model

Carrageenan-induced paw edema

Lipopolysaccharide-induced endotoxemia

Paw edema

Endotoxin-induced paw edema

Carrageenan-induced paw edema/acetic acid abdominal constriction test

Xylene ear edema test/formalin, hot plate and writhing tests

Carrageenan-induced paw edema/acetic acid-induced writhing test

Carrageenan-induced hind paw edema

Acetic acid-induced vascular permeability and cotton pellet-induced granuloma

Acetic acid-induced writhing test and formalin-induced paw licking method

Model

Rat/ mouse

Rat/ mouse

Rat

Mouse

Rat/ mouse Mouse

Rat

Rat

Mouse

Mouse

Rat

Rat/ mouse

Mouse

Rat/ mouse

Mouse

Mouse

Mouse

Species

Anti-inflammatory activity/ analgesic activity

Anti-inflammatory activity/ analgesic activity Anti-inflammatory activity/ analgesic activity

Accelerating wound healing process

Anti-inflammatory activity/ analgesic activity Antitumor activity against cervical carcinoma

Estrogenic activity

Anti-inflammatory activity

Regulation of pro- and antiinflammatory cytokines

Anti-inflammatory activity

Anti-inflammatory activity

Anti-inflammatory activity/ analgesic activity

Anti-inflammatory activity/ analgesic activity

Anti-inflammatory activity/ analgesic activity

Anti-inflammatory activity

Anti-inflammatory activity

Analgesic activity

Result

[83]

[82]

[81]

[77]

[76]

[75]

[74]

[68]

[65]

[63]

[62]

[59]

[58]

[57]

[106]

[55]

[54]

Reference

Arch Gynecol Obstet

–

Root bark/ aqueous extract

Acetic acid-induced writhing, formalin and thermal (hot plate) tests

Writhing test

Rat and mouse

Rat

Mouse

Rat

Mouse

Mouse

Rat/mouse

Rat

Analgesic activity

Analgesic activity

Anti-inflammatory activity

Anti-inflammatory activity

Growth inhibition effect on U14 cervical cancer and protective effect on thymus tissue

Inhibition of growth of cervical carcinoma by inducing apoptosis in tumor cells

Anti-inflammatory activity/analgesic activity

Anti-inflammatory activity

Anti-inflammatory activity/analgesic activity

[88]

; K?-induced contraction in uterus Rat/mouse

Anti-inflammatory activity

Result

Mouse

Species

HeLa human uterine cervical carcinoma, TPA 12-O-tetradecanoylphorbol-13-acetate, U14 mouse cervical carcinoma

–

Leaves/ aqueous extract

Ziziphus spinachristi (L.) Willd.

Carrageenan-induced paw edema model

b-amyrin acetate

Aerial parts/ methanol extracts

Tragopogon porrifolius L.

Carrageenan-induced paw edema

Tumor-bearing animal

Tumor-bearing animal

Carrageenan-induced paw edema model/ abdominal constriction, hot plate and formalin tests

Carrageenan-induced paw edema model

Carrageenan-induced paw edema model/acetic acid-induced writhing test

Rat

Carrageenan-induced paw edema model

Model

Glycopeptides

Polysaccharides

Aerial part

Root

–

Aerial part/ aqueous extract

Symphytum officinale L.

–

–

–

Leaves/ chloroform extract

Fruit/ methanol extract

Solanum

nigrum L.

Leaves/ ethanol extract

Rhus retinorrhaea Steud. ex A.Rich.

Animal model

Punicalagin, punicalin, strictinin A, and granatin B

Peel

–

Active constituent

Part/extract

Flower/aqueous and hydroalcoholic extract

Plant

Table 3 continued

[101]

[100]

[98]

[96]

[94, 95]

[93]

[92]

[91]

[89]

[84]

Reference

Arch Gynecol Obstet

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Arch Gynecol Obstet Table 4 Clinical studies on plants used for treatment of AUB mentioned in ‘‘Canon of Medicine’’ Plant

Treatment group

Control group

Study design

Number of patients

Treatment duration

Result

Reference

Myrtus communis L.

Fruit syrup

Placebo syrup

Randomized double-blind, placebocontrolled pilot study

30

3 months

; Mean number of bleeding days from 10.6 ± 2.7 days to 8.2 ± 1.9 days and ; use of pads in Myrtus group

[53]

Portulaca oleracea L.

Seed powder

No preparation

Uncontrolled pilot clinical trial

10

3 days

; Duration and volume of bleeding and normalization of patterns of periods; The seed powder was ineffective in two (20 %) patients

[73]

compounds [18–20]. Extracts from different parts of C. siliqua as well as their main compounds, gentisic acid and (-)-epicatechin, significantly decreased viability of cervical cancer cells [21, 22].

C. martini showed anti-inflammatory activity by reducing proinflammatory cytokines in human acute monocytic leukemia cells [38]. Hyoscyamus species

Cuscuta species Anticancer activity of Cuscuta species was evaluated in different human cancer cell lines [23–25]. Different extracts from C. chinensis and C. epithymum demonstrated significant reduction in viability of cervical cancer cells [26]. C. chinensis seeds exhibited antinociceptive and antiinflammatory effect in animal model through reducing inflammatory cytokines and oxidative stress [27]. Flavonoids of C. chinensis seeds were effective in the treatment of ovarian endocrine dysfunction in psychologically stressed rats [28]. C. chinensis seeds also showed estrogenic activity [29]. Flavonoids, kaempferol and isorhamnetin seem to be responsible for this estrogenic activity [30].

Hyoscyamus niger seeds have revealed anti-inflammatory and analgesic activity in various animal models. Cleomiscosin A, a coumarino lignin present in seeds, is responsible for anti-inflammatory activity [41, 42]. Aerial parts of H. reticulates exhibited a significant antinociceptive activity in animal model [43]. Juglans regia L. Anti-inflammatory and antinociceptive activities of different parts of J. regia have been demonstrated in different studies [44, 45]. Lens culinaris Medik.

Cydonia oblonga Mill. Cydonia oblonga peel polyphenolic extract exhibited potent anti-inflammatory activity by inhibition of proinflammatory effectors [31]. Lipophilic extract of C. oblonga was a valuable anti-lipoperoxidant agent, but it was ineffective as radical scavenger; however, its aqueous extract exhibited marked antioxidant capacity. Both extracts inhibited proliferation of cervical cancer cells, although aqueous extract is more potent in this manner [32].

Lens culinaris, commonly known as lentil, is an edible plant and is one of the most nutritious and healthimproving foods. Lentil contains essential macronutrients such as functional proteins and carbohydrates, essential micronutrients such as iron, selenium, zinc and other trace minerals, and bioactive phytochemicals such as phytates and polyphenols [46, 47]. L. culinaris markedly inhibited COX-2 and PGE2 production [48]. Myrtus communis L.

Cymbopogon sp. Anti-inflammatory and analgesic activity of different species of Cymbopogon were demonstrated in different studies [33–38]. The anti-inflammatory activity of C. citratus has been attributed to their polyphenolic compounds, particularly chlorogenic acid, as well as its monoterpenes, citronellol and citral [35, 36, 39, 40]. Essential oil from

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Myrtucommulone (non-prenylated acyl phloroglucinol) from M. communis leaves potently suppressed the biosynthesis of eicosanoids by inhibition of COX-1 and 5-lipoxygenase [49, 50]. It has been also shown to inhibit PGE2 formation without significant inhibition of the COX enzymes [51]. The aqueous and ethanol extracts of M. communis aerial parts showed significant antinociceptive

Arch Gynecol Obstet

activity and also anti-inflammatory effects against chronic inflammation in animal model [52]. The efficacy of M. communis in AUB has been also confirmed during a clinical trial [53]. Nymphaea alba L. Ethanol extract of rhizome of N. alba has shown more potent analgesic activity compared to that of paracetamol in animal models [54]. Moreover, ethanol extract of N. alba flower showed anti-inflammatory activity [55]. Olea europaea L. Fruits, leaves and oil of O. europaea have revealed antiinflammatory activity in different studies [56–58]. Oleuropein and hydroxytyrosol are phenolic compounds found in olive leaves exhibiting marked anti-inflammatory and analgesic activities in animal models [59]. Onopordum acanthium L. Flowers, fruit and leaves of O. acanthium showed antiproliferative activities against cervix epithelial adenocarcinoma cells [60]. Extracts from O. cynarocephalum and O. macracanthum exhibited anti-inflammatory activity [61, 62].

Portulaca oleracea L. In a pilot clinical trial, the effectiveness of P. oleracea seeds on AUB was studied. 80 % of patients reported that duration and volume of bleeding had reduced and their patterns of periods had normalized without any serious adverse events [73]. The aerial parts of P. oleracea aerial part exhibited estrogenic activity in ovariectomized rats [74]. It also showed significant analgesic and anti-inflammatory properties [75].Water-soluble polysaccharide from P. oleracea inhibited cervical cancer cell proliferation and significantly inhibited tumor growth in tumor-bearing mice [76]. Aerial parts of P. oleracea have accelerated the wound-healing process by decreasing the surface area of wound and increasing the tensile strength [77]. Punica granatum L. Anti-inflammatory and antinociceptive activity of different parts of P. granatum including leaves, flowers and fruit were demonstrated in various studies [78–85]. Polyphenol-rich extract of pomegranate fruit exerted an anti-inflammatory effect in animal model by inhibiting the production of PGE2 and NO [86]. 2-Methyl-pyran-4-one-3-O-b-D-glucopyranoside, a compound isolated from leaves of P. granatum, blocked inflammatory pathways [87]. Extracts of P. granatum flower exhibited antispasmodic effect on the uterus of non-pregnant rats and diminished contraction of uterus [88].

Paeonia species Rhus coriaria L. Ethanol extracts of flowers and roots from P. peregrina showed anti-inflammatory activity in acute inflammatory models [63]. P. suffruticosa showed anti-inflammatory activity through inhibition of proinflammatory cytokines. Presence of significant level of phenolics mainly paeonol, as well as trace metal contents in P. suffruticosa may be associated with its anti-inflammatory activity [64, 65]. Paeoniflorin, a glycoside from Paeonia root, showed antiproliferative and apoptotic effects on human cervical cancer cells [66, 67].

However, there is no evidence in Rhus coriaria; ethanol extract of another species of Rhus, R. retinorrhaea, exhibited anti-inflammatory and analgesic activity in animal model [89]. Rumex acetosa L. Antiproliferative activity of R. acetosa extracts against cervix epithelial adenocarcinoma cell line has been confirmed in vitro [90].

Pistacia lentiscus L.

Solanum nigrum L.

Oleogum resin from P. lentiscus showed anti-inflammatory activity via inhibition of NO and PGE2 [69, 70]. The leaf extract caused an inhibition of gastric lesions in animal models [68].

Solanum nigrum berries and leaves showed significant antiinflammatory antinociceptive activity in animal models [91, 92]. Aqueous extract as wells as polysaccharides isolated from S. nigrum exert antitumor activity on cervical cancer bearing mice [93–95].

Polygonum aviculare L. Symphytum sp. Polygonum aviculare exhibited inhibitory activity on PGS biosynthesis [71]. Flavonol glucuronides may be responsible for this anti-inflammatory activity [72].

A glycopeptide isolated from roots of S. officinale showed a remarkable, dose-dependent anti-inflammatory effect via

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Fig. 1 Mechanisms involved in the management of abnormal uterine bleeding by medicinal plants

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decreasing the expression of phospholipase A2 [96]. The extract of S. officinale suppressed leukocyte infiltration at the 3rd and 4th hour of the induced inflammation [97]. Tragopogon sp. Acute anti-inflammatory activity of different extracts from T. porrifolius was evaluated in animal model. The methanol extract exhibited maximum anti-inflammatory activity. b-Amyrin acetate has been demonstrated to be responsible for its anti-inflammatory effect [98]. Ziziphus spina-christi (L.) Willd. Ziziphus spina-christi bark extract showed anti-inflammatory activity by inhibition of COX-2 enzyme [99]. It also exhibited antinociceptive properties in animal models [100, 101].

Conclusion Medicinal plants used in traditional and folk medicine of different areas may be valuable sources for discovering new drugs [107–110]. In ‘‘Canon of Medicine’’, a precious book written in 11 AD by the great Iranian physician Avicenna, variety of medicinal plants with different pharmacological activities has been introduced. In this paper, the medicinal plants claimed to be effective in AUB have been collected from ‘‘Canon of Medicine’’ and their possible efficacy and pharmacodynamics in modern medicine were surveyed. Some of them such as Cydonia oblonga, Juglans regia, Lens culinaris, Olea europaea, and Punica granatum have nutritional value and are routinely used in human diets. Different mechanisms of action could be considered for these medicinal plants including antiinflammatory and antinociceptive properties, antiproliferative activity on cervical cells, and estrogenic activity (Fig. 1). Since all of the surveyed plants had been shown in vitro and/or in vivo anti-inflammatory effects, it could be concluded that their major mechanism of action is inhibition of the inflammatory process. Endometrial prostaglandins have important role in the management of menstruation. In AUB, synthesis of endometrial PGS is increased. Endometrium from women with AUB synthesizes more PGE2 than PGF2a (vasoconstricting PG) [3]. Some of the mentioned plants and phytochemicals including gum resin of Boswellia carteri, Myrtucommulone, an acylphloroglucinol compound from Myrtus communis, resin of Pistacia lentiscus and polyphenol-rich fruit extract of Punica granatum have revealed significant inhibitory activity on production of PGE2. Moreover, aerial parts of P. aviculare have exhibited inhibitory activity on

PG biosynthesis. Ceratonia siliqua L., Cuscuta chinensis Lam., Cuscuta epithymum L., Cydonia oblonga Mill., Paeonia sp., Portulaca oleracea L., Solanum nigrum L., Rumex acetosa L. and Onopordum acanthium L. have shown antiproliferative activity on human cervical cancer cells. Extract of Cuscuta chinensis and Portulaca oleracea exhibited estrogenic activity in vitro and in vivo, respectively. Furthermore, flavonoids of Cuscuta chinensis seeds have been effective in the treatment of ovarian endocrine dysfunction in psychologically stressed rats. Only two clinical trials on the efficacy of investigated herbal medicines were found: one on Myrtus communis fruits and another on Portulaca oleracea seeds. The results of two studies showed that duration and volume of bleeding had reduced after treatment with these herbs. If we want to introduce the most effective herbal remedies for the management of AUB among these 23 investigated medicinal plants, Myrtus communis, Portulaca oleracea, and Punica granatum. could be suggested because of finding higher levels of evidence for them. The main active constituents of most of investigated plants are polyphenolic compounds especially flavonoids and tannins. Flavonoids have been reported from Ceratonia siliqua leaves [111], Cuscuta chinensis seeds [30], Cymbopogon citratus leaves [112], Juglans regia leaves [113], Lens culinaris seeds [114], Myrtus communis fruits [115], Nymphaea alba flowers [116], Olea europaea oil and leaves [117, 118], Paeonia sp. [119], Portulaca oleracea aerial parts [120], and Punica granatum fruits [121]. Efficacy of micronized purified flavonoid fraction (MPFF) on treatment of AUB was demonstrated in clinical studies. It seems that suppression of endometrial prostaglandins is its possible mechanism of action [122]. Overall, investigation of TIM literatures can lead to the identification of effective natural medicines for the management of different ailments such as AUB; however, conclusive confirmation of the efficacy and safety of these treatments needs more evaluations. Conflict of interest

We declare that we have no conflict of interest.

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