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Prevention Effects of Foeniculum vulgare (Fennel) Hydroalcoholic Extract for

Threatened Abortion by Misoprostol Induction in Experimental Mice

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 International Journal of Traditional and Natural Medicines, 2019, 9(1): 1-16
International Journal of Traditional and Natural Medicines ISSN: 2167-1141
Journal homepage: www.ModernScientificPress.com/Journals/IJTNM.aspx Florida, USA
Article

Prevention Effects of Foeniculum vulgare (Fennel)

Hydroalcoholic Extract for Threatened Abortion by Misoprostol
Induction in Experimental Mice

Mohammad Shokrzadeh1, Ayat Dashti1, Shaghayegh Aghajanshakeri1, Banafsheh Pourabbas2,

Nasrin Ghassemi barghi 1*

1
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mazandaran University of
Medical Sciences, Sari, Iran
2
MSc Student in Genetics, Sana Instituted of Higher Education, Sari, Iran

* Author to whom corresponding should be addressed; Email: ngeternal67@yahoo.com

Article history: Received 28 April 2019, Revised 28 June 2019, Accepted 25 July 2019, Published 15
August 2019.

Abstract: Fennel, a seed of Foeniculum vulgare, is used as a culinary spice and traditional
medicine. The present study was conducted to identify the preventive and therapeutic effects
of hydroalcoholic extract of fennel for threatened abortion by misoprostol in mice. A total
of 30 female balb/c mice were divided into five groups (n = 6). Groups 1 served as (negative
control) received normal saline. Groups 2, 3 and 4 (experimental groups) were administered
The Foeniculum vulgare hydroalcoholic extract at 2.5, 12.5 and 25 mg/kg concentration and
misoprostol injection at 100 mg/kg concentration, intraperitoneally on pregnancy 6th to 15th
day for continuous. Groups 5 (positive control) received misoprostol IP injection at 100
mg/kg concentration. On 16th day of pregnancy, embryos model were collected and the level
of estrogen, progesterone, skeletal abnormalities were analyzed. Data analysis revealed that
there is a significant difference in the mean level of serum estrogen, progesterone and also
skeletal abnormalities in embryos model between positive control group and experimental
groups were administered with different concentration of fennel extract (p<0.05). The
Foeniculum vulgare hydroalcoholic extract has a significant protective effect (especially at
dose of 25 mg/kg) on toxicity on embryos model were induced by misoprostol injection.

Keywords: Foeniculum vulgare; Misoprostol; Abortion; Estrogen; Progesterone

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Int. J. Trad. Nat. Med. 2019, 9(1): 1-16 2

1. Introduction

Abortion, spontaneous or induced, is a usual problem of pregnancy(Sedgh et al., 2015). The

World Health Organization stated that yearly about 79 million accidental pregnancies without
miscarriages are happening worldwide and annually, about 46 million persuaded abortions happen in the
world (Sedgh et al., 2014). Induced abortion can be accomplished by medical and surgical approaches.
Medical abortion is the induction of primary abortion by utilization of specific medications. Besides, the
medical method is a safe and effective substitute to surgical methods with an extreme rate of patient
gratification(Sedgh et al., 2014, Wasson et al., 2019).
Prostaglandins and their analogs are extensively used for medical induced abortion. Misoprostol,
a prostaglandin E1 analog, is used for primary abortion and has been shown to be a well alternative to
other prostaglandin substances because of achievability, easy administration, low cost, stability at room
temperature, and scarcer systemic side-effects (Yung et al., 2016, Singh et al., 2016). Sublingual and
vaginal are two usual ways of misoprostol administration with diverse pharmacokinetics and
efficiency(Watzer et al., 2015). The range of described successes rate of abortion provocation with
misoprostol is pretty different in numerous researches (between 37% and 86%) depending on the
regimen, way of administration, and dosage used(Gopal et al., 2017, Naghshineh et al., 2015).
Misoprostol is a synthetic prostaglandin E1 analogue, used to avert and treat gastro duodenal
harm caused by non-steroidal anti-inflammatory agents(Bazelle et al., 2018). The most common contrary
effects of misoprostol are nausea, vomiting, diarrhea, abdominal pain, chills, shivering, and fever, all of
which are dose-dependent. Misoprostol taken by pregnant women increases uterine tone and
contractions(Bulusu et al., 2017, Nankali et al., 2017).
In humans, a variety of congenital malformations have been verified after a failed finish of
pregnancy with exposure to misoprostol in early pregnancy(Auffret et al., 2016). The mechanism by
which misoprostol may cause malformations is based on the uterine contractions that it induced. These
contractions cause flexion of the embryo, particularly at cranial nerves VI and VII(Auffret et al., 2016,
Wax et al., 2018). Hemorrhage and/or cell death of the nuclei in these cranial nerves may occur, causing
Mobius sequence (characterized by paralysis of the eyes and facial muscles(Wu et al., 2015). Uterine
contractions may also cause decreased blood flow, leading to hypoxemia and ischemia, resulting in limb
defects, defective vascularization of the subclavian artery, and consequently to Poland sequence, club
foot, cranial nerve anomalies have also been described(Singhal and Singhal, 2017, Alexander and Koshy,
2018).
Fennel (Foeniculum vulgare) is a small green brown seed belonging to the family Umbelliferae.
It grows in the Mediterranean region and western Asia. It cultured in various areas of Europe and Asia,
and much is imported from India, China and Egypt(Diao et al., 2014, Rather et al., 2016). The fennel

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Int. J. Trad. Nat. Med. 2019, 9(1): 1-16 3

fruit has a long history of use as both food and medicine. It has been reported that this plant can also
increase libido, facilitate birth, relieve the symptoms of the male climacteric, stimulate menstrual flow,
and soothe indigestion and cough(Rather et al., 2016, Rahimikian et al., 2017). Fennel seed contains of
trans-anethole, estragole, fenchone, and α-phellandrene and the relative concentration of these
compounds differs noticeabily due to the phenological state and origin of the plant(Diao et al., 2014).
Foeniculum vulgare commonly shows strong antioxidant properties(Chang et al., 2018,
SHOKRZADEH et al., 2018). So, has the ability to be used as a neuroprotective agent; as it may reduce
the toxic effects of oxidative stress(Bhatti et al., 2018). It contains some potential chemical entities
including phenols, flavonoids, minerals calcium, Sodium, potassium, iron, copper, magnesium and zinc
and vitamins along with protein, fat, fiber and carbohydrate(Diao et al., 2014). Besides, it has also
exhibited various pharmacological effects including antibacterial, antimicrobial antithrombotic,
antioxidant and anti-inflammatory(Diao et al., 2014). It also possesses emmenagogue and galactagogue
properties. It has been formerly reported that fennel used in the pediatric colic and some respiratory
disorders due to its anti-spasmodic effects. Seeds of fennel are used in folk medicine for treatment of
dysmenorrhea due to its probable anti-spasmodic effects(Anheyer et al., 2017, Amini et al., 2016).
Fennel has shown numerous effects in vivo and in vitro, including anti-inflammatory and
antioxidant activity. Fennel has a long history as an estrogenic agent with low toxicity and lack of
documented carcinogenicity(Rather et al., 2016, Chang et al., 2016).
Hence, the aim the present study is to determine whether the administration of hydroalcoholic
extract of fennel can alter the serum level of estrogen, progesterone and skeletal abnormalities on
embryos model were induced by misoprostol injection.

2. Materials and Methods

2.1. Chemicals

Misoprostol was purchased from sigma Aldrich and all other chemicals were obtained from
local supplier (Sari, Iran).

2.2. Animals and Mating

7-weeks-old female BALB/c mice were procured from the Experimental Animal Center,
Mazandaran University of Medical Science. All animals were maintained under a standard
environmental conditions of temperature of 25 ± 2 o C with a 12/12 h light-dark cycle. The animals
allowed free access to commercial rodent feed and drinking water. Adult female mice mating was taking
place with fertile male mice in same cages for pregnancy establishment. Checking the vaginal plugs next

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Int. J. Trad. Nat. Med. 2019, 9(1): 1-16 4

morning were conducted in order to confirm successful mating and its presence were defined as the day
0.5 of pregnancy. All animal procedures were carried out in according to the principle of laboratory
animal care guidelines of the National Institutes of Health and approved by the local Research and
Ethical Committee, Pharmacy faculty; Mazandaran.

2.3. Preparation of Plant Extraction

Aerial parts of F. vulgare were collected from Sari city, Mazandaran, Iran. The plant was
authenticated and a voucher specimen (E1-218-2111) was deposited in herbarium of department of
pharmagenesis. Parts of plant completely were dried in the open air and crushed air-dried plants into the
fine powder using an electric grinder. One hundred of gram powdered whole plant was suspended in a
liter of ethanol (95%) for 48 h under continuous stirring at room temperature. The extraction was filtered
to remove residue particle using filter papers and then all the collected filtrate was concentrated using
vacuum rotary evaporator. The dried extract was weighed and stored at 4 ºC (Shokrzadeh et al., 2014).

2.4. Treatment Protocol and Groups

Pregnant mice were randomly divided to the followings five group (n=6): group 1(negative
control) received saline solution; group 2 received misoprostol (100 mg/kg, i.p); group 3-5 including
extract (2.5, 12.5 and 25 mg/kg, i.p) + misoprostol (100 mg/kg, i.p). Extract administration was
intraperitoneally conducted from the 6th to 15th day of pregnancy, misoprostol was dissolved in saline
solution and injected in a single dose (100 mg/kg, i.p) after 24 h of the extract administration. At the end
of the experiment (on 17th day), blood was collected from pregnant anesthetized mice and scarified by
chloroform. After removing the fetus were recorded the parameters of weight, height, number live and
dead fetuses, and number of aborted mice. And fetuses were also evaluated in terms of the morphological
and skeletal abnormalities in different parts of the body using stereomicroscope (Nikon SMZ 800
Japan)(Saravi et al., 2016).

2.5. Determination of Hormonal Levels

Serum levels of hormone were measured by direct chemiluminescence using acridinium ester
technology as per manufacturer's instructions (Snibe Maglumi 600 immunoassay system).

2.6. Histopathological Examinations

The mice fetuses were fixed in 10% buffered formalin for 24 h at 4 ºC. mixtures of Alison blue
and Alizarin red staining were performed in accordance with the standard process. In this method, bone
and cartilage parts are perceived under the stereomicroscope the colors of red and blue, respectively.

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Int. J. Trad. Nat. Med. 2019, 9(1): 1-16 5

2.7. Statistical Analysis

The results were expressed as Mean ± SD. Statistical compressions were performed using one-
way ANOVA followed by Turkey’s test and P-values < 0.05 were statistically considered
significant(Shokrzadeh and Ghassemi-Barghi, 2018).

3. Results

3.1. Effects of Extract and Misoprostol on Body Weight and Height

In this study, pregnant mice were treated with misoprostol and different doses of extract from 6th
day to 15th day of pregnancy, as shown in figs. 1a & b, there were significant differences in the body
weight and height of the fetuses (p <0.05) among groups. Misoprostol caused significant increase in all
the fetuses' height and weight as compared to control group. Extract pre-treatment significantly reversed
the misoprostol induced decreasing body height and weight in fetuses.

Fig. 1. Effects of pretreatment with F. vulgare hydroalcoholic extract on the fetus length and weight. A:
fetus length; B: fetus weight.
(All data are shown as mean ± SD. ** p < 0.01 compared to control group; # p < 0.05 compared to misoprostol group.)

3.2. Effects of Extract and Misoprostol on Estrogen Level in the Serum

Figure 2 depicts the effects of Foeniculum extract on the misoprostol induced alteration in the
estrogen level. Data analysis showed that misoprostol was significantly increased (p<0.0001) the serum
level of estrogen in comparison to control that incremental effects of misoprostol on the serum estrogen
significantly reduced dose-dependent by hydroalcoholic extract pre-treatment in the pregnant mice.

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Int. J. Trad. Nat. Med. 2019, 9(1): 1-16 6

****
####
15

E s tr o g e n le v e l (n g /m l)

10

C o n tr o l + - - - -
M is o p r o s t o l - + + + +
E x t r a c t ( 2 .5 m g /k g ) - - + - -
E x tr a c t( 1 2 .5 m g /k g ) - - - + -
E x t r a c t ( 2 5 m g /k g ) - - - - +

Fig. 2. Effects of pretreatment with F. vulgare hydroalcoholic extract on serum estrogen level in
pregnant mice.
(All data are shown as mean ± SD. **** p < 0.0001 compared to control group; #### p < 0.0001 compared to misoprostol
group.)

3.3. Effects of Extract and Misoprostol on Progesterone Level in the Serum

Benefit effects of extract against alterations of progesterone hormone induced by misoprostol is

presented in figure 3. The serum progesterone level was remarkably decreased (p<0.0001) in groups
treated with misoprostol as compared to control pregnancy mice, while it almost was increased by extract
pre-administration in comparison to misoprostol group.

60
P r o g e s te r o n e le v e l (n g /m l)

**** ####

40
##

20

C o n tr o l + - - - -
M is o p r o s t o l - + + + +
E x t r a c t ( 2 .5 m g /k g ) - - + - -
E x tr a c t( 1 2 .5 m g /k g ) - - - + -
E x t r a c t ( 2 5 m g /k g ) - - - - +

Fig. 3. Effects of pretreatment with F. vulgare hydroalcoholic extract on serum progesterone level in
pregnant mice.
(All data are shown as mean ± SD. **** p < 0.0001 compared to control group; ## p < 0.01 compared to misoprostol group;
#### p < 0.0001 compared to misoprostol group.)

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Int. J. Trad. Nat. Med. 2019, 9(1): 1-16 7

3.4. Exposure of Pregnant Mice to Misoprostol and Fetus Viability

As shown in table 1, there were a significant increase (p<0.0001) in the number of dead fetuses
in mice of pregnant female after administration of misoprostol in compared with control group. Fetus
death rate in pretreatment groups with hydroalcoholic extract were effectively diminished in compared
to the misoprostol-treated groups.

Table 1. Number of live and dead fetuses related to misoprostol administration

Group Live fetuses Dead fetuses

Control 6.25 ± 0.05 0.333 ± 0.517
****
Misoprostol (100 mg/kg) 0.75 ± 0.11 5.45 ± 0.895 ****
Extract (2.5 mg/kg) 2.55 ± 0. 12 ****, ## 2.75 ± 0.5 **, ##
Extract (12.5 mg/kg) 5.150 ± 1.43 *, ### 1.95 ± 0.63 **, ###
Extract (25 mg/kg) 6.050 ± 0.72 #### 1 ± 0.633 ###
All data expressed as mean ± SD. * p < 0.05 compared to control group; ** p < 0.01 compared to control group; **** p <
0.0001 compared to control group; ## p < 0.01 compared to misoprostol group; ### p < 0.001 compared to misoprostol
group; #### p < 0.0001 compared to misoprostol group.

3.5. Misoprostol-mediated Structural Abnormalities in Fetus

Pathological analyses revealed no changes in the fetus structure in control mice (fig. 4a), while
misoprostol administration resulted in significant changes in the pathology of various parts of fetus body
including spinal cord disorders, petechiae, skeletal limb abnormalities (shortness of limb) and
impairment of internal organs (liver and kidney) (fig. 4b). Pretreatment with different doses of extract
significantly prevented misoprostol-induced damages and pathological alterations in fetus (fig. 4c-e).

Fig. 4: Misoprostol-mediated structural abnormalities in fetus. Control (A), misoprostol administration

(B), Pretreatment with different doses of extract(C-E).

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Int. J. Trad. Nat. Med. 2019, 9(1): 1-16 8

4. Discussion

A miscarriage is the impulsive loss of a fetus before 20 weeks' gestation that is before it can
endure outside the womb. Miscarriage can occur before a woman is alert that she is pregnant and it has
been approximated that 1- 5% pregnancies end in miscarriages(Wahabi et al., 2018). Numerous factors
can dispose a pregnant woman to a miscarriage. According to a miscarriage may be because of the
presence of abnormal chromosomes in the fetus, abnormal structure of the uterus, inept cervix,
infections, hormonal imbalances, immune system disorders, diseases like poorly controlled diabetes and
imbalances in diet(Bardos et al., 2015). The focus of this study was evaluation of the effect of fennel on
misoprostol induced-abortion and different relative factors in mice.
Misoprostol is a drug used to start labor, induction of abortion, avert treat stomach ulcers and
treat postpartum bleeding owing to poor contraction of the uterus(Morris et al., 2017, Chen and Creinin,
2015). Misoprostol stimulates prostaglandin receptors, it is a prostaglandin analogue specifically, a
synthetic prostaglandin E1 (PGE1)(Li et al., 2017). Misoprostol is considered a teratogen. Inherited
defects following prenatal exposure in early pregnancy to misoprostol include skull defects, bladder
exstrophy, arthrogryposis, cranial nerve palsies, facial malformations and terminal transverse limb
defects(Stevenson, 2015, Auffret et al., 2016).
Prostaglandins play a crucial role in cervical ripening by enhancing inflammatory mediators in
the cervix and inducing cervical altering. Prostaglandin E1 and prostaglandin E2 show various effects
on these processes and on myometrial contractility (Park et al., 2016, Pierce et al., 2018).
Recently, use of alternatively remedies, predominantly herbal medicine, has been deliberated
widely in the treatment of infertility and other relevant disorders due to their scarcer side-effects and
lower costs(Organization, 2015, Mohammadi et al., 2019). The presence of proteins and carbohydrates
in most of the herbal plants may be a vital reason in obstructing threatened miscarriage which is
specifically due to malnutrition or infections(Otimenyin, 2018). Malnutrition as a factor in abnormal
progress of a pregnancy has been reported by many studies(Otimenyin, 2018). Herbs such as Fructus
lycii, Radix Morindae officinalis, Epimedii and many others have been used, for this overcome to this
problem(Chen et al., 2015). F. vulgare is a traditionally identified plant, which is being used for its anti-
inflammatory, anti-spasmodic, analgesic, and laxative effects in folk medicine(Sadeghpour et al.,
2015b).
Due to above mentioned results, this study has been designed to find more details about the
possible mechanism of this plant seed extract on serum level of estrogen, progesterone, skeletal
malformation and some other factors. As shown in fig2 and fig 3 the serum progesterone level was
remarkably decreased (p<0.0001) in groups treated with misoprostol as compared to control pregnancy
mice, while it almost was increased by extract pre-administration in comparison to misoprostol group.

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Int. J. Trad. Nat. Med. 2019, 9(1): 1-16 9

Besides misoprostol was significantly increased (p<0.0001) the serum level of estrogen in comparison
to control that incremental effects of misoprostol on the serum estrogen significantly reduced dose-
dependent by Hydroalcoholic extract pre-treatment in the pregnant mice.
Fennel contains different ingredients such as anol or dimethylatedanethole, which may have
some estrogenic activity. More than 80% of the components of Fennel is composed of trans-Anatole.
trans-Anatole seems to have an estrogenic activity(Stob, 2018, Sadeghpour et al., 2015a, Ghassemi-
Barghi et al., 2017, Ghassemi-Barghi et al., 2016). Another component of this seed is flavonoids, a type
of phytoestrogen. Several studies reported the estrogenic actions of phytoestrogens both in in vivo and
in vitro treatment conditions(Yaralizadeh et al., 2016). The results of some studies have been revealed
that fennel can decrease the gravity of dysmenorrheal and in another study reported that fennel has the
similar effect as Mefenamic acid in dysmenorrheal pain respite(Ardela et al., 2017). Results of another
study showed that fennel considerably increased the number of graafian, antral and multilaminar follicles
at concentration of 100 and 200 mg/kg(Sadeghpour et al., 2015a).
In the current study, Pretreatment with different doses of extract significantly prevented
misoprostol-induced damages and pathological alterations in fetus. Besides as shown in table 1 fetus
death rate in pretreatment groups with hydroalcoholic extract were effectively diminished in compared
to the misoprostol-treated groups. Preceding studies revealed that fennel seed extract at concentration of
100 and 200 mg/kg can increased the number of different ovarian follicles and sex hormones which
possibly are responsible for this ovulation-induction effect of the plant. In addition, different doses of
fennel essential oil (25 and 50 µg/ml) significantly decreased level of oxytocin and prostaglandin E and
induced uterine contractions in primary dysmenorrhea(Sadeghpour et al., 2015a).
The results of our study showed that misoprostol administration resulted in significant changes
in the pathology of various parts of fetus body including spinal cord disorders, petechiae, skeletal limb
abnormalities (shortness of limb) and impairment of internal organs (liver and kidney) (fig. 4b).
Pretreatment with different doses of extract significantly prevented misoprostol-induced damages and
pathological alterations in fetus (fig. 4c-e). The integrity of the skeleton requires a dynamic balance
between bone formation and bone resorption, which are controlled by hormones and cytokines. Estrogen
plays a crucial role in physiological redevelopment of bones and decreasing level of serum estrogen is
associated with osteoporosis after menopause in elderly women(Cauley, 2015). Several studies revealed
the effect of estrogen as antiosteoporotic agent. The effects of estrogen on osteoblasts and osteoclasts
are arbitrated by moderating the production of target proteins. Phytoestrogens, with similar structure to
17β-estradiol (E2), are recognized to produce a protective effect on osteoporosis in post-menopausal
women(Cauley, 2015, Klein-Nulend et al., 2015). These agents are proposed to have not only estrogenic
activities such as stimulation of uterus growth and inhibition of bone loss, but also anti-estrogenic

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Int. J. Trad. Nat. Med. 2019, 9(1): 1-16 10

activities such as inhibition of breast cancer cell growth(Klein-Nulend et al., 2015, Fribbens et al., 2016).
Fennel extract are a rich source of phytochemicals and many of these compounds have useful effects on
human health. The resemblance in action between phytoestrogen and estradiol indorsed us to examine
whether Fennel extract phytochemicals might show estrogenic activity in cell culture system. Stem cells
can promote bone healing through extensive proliferation, differentiation, and growth factor secretion in
the local microenvironment at the site of injury(Mansourabadi et al., 2015). Alkaline phosphatase (ALP)
activity is one of the osteoblastic markers and has considerable function in mineralization. ALP activity
meaningfully increased in presence of Fennel extract. Its activity, along with other specialized bone
proteins, concentrates extracellular matrices appropriate for mineral deposition(Al-Amoudi, 2017,
Mannaa et al., 2015).
Besides fennel is known as an important source of natural antioxidants. This plant can restrain
free radicals due to the high content of polyphenols and flavonoids. Phenolic contents in this herb such
as caffeoylquinic acid, rosmarinic acid, eriodictyol-7-orutinoside, quercetin- 3-O-galactoside,
kaempferol-3-O-glucoside showed antioxidant activity(Marín et al., 2016).The results of prior study
showed that fennel extracts could inhibit free radicals and act as primary antioxidant. In another study,
the antioxidant activity of aqueous and ethanol extracts of fennel seeds was assessed by using a variety
of antioxidant methods such as total antioxidant, free radical scavenging, superoxide anion radical
scavenging, hydrogen peroxide scavenging, metal chelating activity(Alemán et al., 2018, Chang et al.,
2018).
Of the pharmacological effects of fennel plant, anti-inflammatory activity can be renowned.
Several studies have shown that the methanol extract of fennel has anti-inflammatory effects. It
significantly reduced the level of malondialdehyde as a marker of lipid peroxidation. These results reveal
that the methanol extract of fennel fruit is effective in reducing inflammation. The methanol extract of
fennel seeds inhibits inflammation through cyclooxygenase and through lipoxygenase pathways. Also
Choi et al. evaluated fennel methanol extract anti-inflammatory effects(Pacifico et al., 2018, Rabalais et
al., 2018).Furthermore, anti-inflammatory, anti-diabetic, anti-tumor, anti-fungi, anti-bacterial and many
other activities of this plant have been revealed in different studies(Pacifico et al., 2018).

5. Conclusion

In this study, we reported that fennel extract at a concentration of 2.5- 25 mg/kg can significantly
increase the serum level of steroid hormones such as estrogen and progesterone in mice. Our data are in
accordance to the results described by other researchers. Therefore, Fennel seed extract has been shown
to have estrogenic, antioxidant, and anti-inflammatory activities. Fennel has a long history as an

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Int. J. Trad. Nat. Med. 2019, 9(1): 1-16 11

estrogenic agent with low toxicity and absence of verified carcinogenicity, therefore it can be re-
introduced into modern medical practice.

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