Advances in Health Sciences Research, volume 22

4th International Symposium on Health Research (ISHR 2019)

The Effect of Anastatica hierochuntica L. Extract on

the Histology of Myometrial Cells and Prostaglandin
Levels (PGE2, PGF2α) in Pregnant Mice
Heny Astutik1,*, Budi Santoso2, Mangestuti Agil3
1
2
Department of Midwifery, Poltekkes Kemenkes Malang, Malang, Indonesia
Department of Medicine Science, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
3
Department of Pharmacognosy and Phytochemistry, Faculty of Pharmacy, Universitas Airlangga, Surabaya, Indonesia
*
Corresponding author. Email: [email protected]

ABSTRACT
Anastatica hierochuntica L. is well known as a traditional medicine which brings benefit to the final trimester
of pregnancy by increase uterine contractions. This study aimed to analyze the effect of A. hierochuntica L.
extract on the histology of myometrial cells and prostaglandin levels (PGE2 and PGF2α) of pregnant mice. The
mice were divided into three groups: (1) control group, treated by 0.5% CMC solution 10 ml/kg bw/day; (2)
two treatment groups that treated by A. hierochuntica L. extract with 100 and 150 mg/kg bw/day doses,
respectively. Uterine tissue was collected for histological analysis and blood serum was collected to examine
the PGE2 and PGF2α levels. It obtained that myometrial hypertrophy increased significantly in the treatment
groups (p = 0.001) than in the control group. Moreover, there were significant differences in the PGE2 levels
(p = 0.001) and PGF2α levels (p = 0.000) between the control group and the treatment groups. The 100 mg/kg
bw/day dose had a greater effect on myometrial hypertrophy than 150 mg/kg bw/day, which resulted in a higher
increase of PGE2 and PGF2α levels. Hence, it was concluded that the 100 mg/kg bw/day dose of A.
hierochuntica L. extract was the appropriate dose for increasing prostaglandin levels.
Keywords: Anastatica hierochuntica L., myometrial cells, prostaglandins, pregnant mice

pharmacology studies, A. hierochuntica L. contains

phenolic substances (51.97 mg/g d.w), flavonoids (42.53 to
1. INTRODUCTION 46.28 mg/g d.w)10, sterol11, and several minerals including
Mg, Ca, Cr, Mn, Fe, Co, Cu and Zn.9 A. hierochuntica L.
Nowadays, advanced technology and medical science still is considered a phytoestrogen plant, with estrogenic
utilizing plant-based medicines [1]. Herbal medicine is activity, due to the presence of flavonoids and another
considered safe since they are derived from natural products compound.9,11-14 Phytoestrogen—a member of the
and has fewer side effects. In brief, herbal medicines are polyphenols family—is derived from herbal and it functions
mostly utilized in developing countries for routine health similar to estrogen in the human reproductive system [15].
care [2] and treatment of gynecological health issues, A study by Nani [4] resulted that drinking the soaking water
including Indonesia [3]. A.hierochuntica L. is well known containing a dose of 40 grams of A. hierochuntica L.
as a traditional medicine and in Indonesia, it has been increased the frequency of uterine contractions [4].
extensively consumed by expectant mothers during the final However, until now, the mechanism that regulates
trimester of their pregnancy to increase uterine contractions myometrial contraction activity during pregnancy, labor,
to initiate labor. Indonesian pregnant women used to drink and birth has not been fully observed [16]. Several studies
the soaking water of A. hierochuntica L [4]. Nevertheless, have obtained an overview of the estrogenic effect of
there is no much research about the biological activity of phytoestrogens [17]. The uterine tissue undergoes changes
this plant. in histological structure that are dynamic based on estrogen
A. hierochuntica L., also known as Rose of Jericho, Fatimah levels [18]. Estrogen also increases a series of myometrial
grip, [5] Kaff Maryam—or in Indonesia—as Rumput changes, including elevated production of the
Fatimah, is found in the Sahara-Arab desert where it is prostaglandins, PGE2 and PGF2α, with a high expression
widely consumed as an herbal tea drink [6]. It was claimed of prostaglandin receptors [19].
to be very useful in the antepartum treatment [6] and has Prostaglandins, especially those produced in intrauterine
been used as a traditional medicine during the end of tissue, play a central role in the initiation and development
pregnancy, since it is popularly believed to facilitate the of labor, including myometrial contraction stimulation,
delivery process, [5] reduces uterine bleeding, [7] and treats metabolism management of the extracellular matrix related
various health problems [2][6][8][9]. Based on to cervical maturation, and upregulation of the fetal HPA-

Copyright © 2020 The Authors. Published by Atlantis Press SARL.

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 Advances in Health Sciences Research, volume 22

axis [20]. Prostaglandin (PGs), a uterotonic agent [21] and The fetus was removed from the uterus, then one side of the
a stimulator of uterine contractions [3] is synthesized from uterine cornu was excised, fixed in a 10% formalin buffer
arachidonic acid by cyclooxygenases and prostanoid solution for 24 hours, and planted in paraffin. The tissue was
synthases [22]. Prostaglandins act by binding to certain G stained with Hematoxylin-Eosin (HE staining) and the
protein-coupled receptors [23] thereby activating intra- staining results were observed using a Nikon H600L
cellular signals and gene transcription [24]. microscope with a DS Fi2 300 megapixel of a digital
In addition to having estrogenic activity, A. hierochuntica camera. The Examination of prostaglandin levels, PGE2
L. also has gastroprotective activity, [13] hepatoprotective and PGF2α, were measured in intracardiac blood serum of
activity, [24] antioxidants activity [9]. Several studies have pregnant mice using a sandwich ELISA kit.
been conducted to identify the various activities of this All the myometrial cell histology for each sample was
plant, but only a few studies are available regarding the assessed semiquantitatively according to the modified
histological effects of A. hierochuntica L. and its activity Billingham method [25]. The myometrial cell histology was
during labor. Ethnobotany research aims to investigate and measured within a 0–5.5 score based on histological
report the herbs for gynecological health problems and their changes, which was a percentage of hypertrophic myocytes
uterotonic activities in several countries, including of all observed myocytes. The hypertrophic cells were
Indonesia [3]. However, studies related to the biological determined based on the size or diameter of myocyte cells,
activity of A. hierochuntica L. during labor have not been which more than 6 μm.
reported. Therefore, this study aimed to evaluate the effect The data were analyzed using the Kruskal Wallis test to
that A. hierochuntica L. has on histological changes in identify the differences in myometrial histology. Moreover,
myometrial cells and prostaglandin levels (PGE2, PGF2a) a one-way ANOVA was conducted to analyze the
in pregnant mice. Understanding the histological effects of prostaglandin level (p < 0.05). Then, the post-hoc test with
this herb is essential since, in many cases, there is no LSD was used to determine the differences between the
scientific evidence on the use of A. hierochuntica L. plants treatments of each group.
as a facilitator of labor during childbirth.
3. RESULTS AND DISCUSSION
2. METHOD Myometrium is one of the essential reproductive organs that
The material used in this study is the whole A. hierochuntica regulate contractions. This regulation is controlled by
L. was obtained from the local market of Saudi Arabia. This estrogen and progesterone.26 Estrogen has a direct or
plant determined by plant taxonomists from the Indonesian indirect ability to change the myometrium, as it increases
Institute of Science (LIPI), Plant Conservation Center of the capacity of contraction power in myometrial cell
Bogor and it has also been identified using the liquid hypertrophy27, the contractile potential of myometrium
chromatography-mass spectrometry (LCMS) method. cells, uterotonic receptors, and cell to cell communication
The plant was extracted with 96% ethanol using maceration [21][28].
method. The sample was sonicated in an ultrasonic bath for Table 1 shows the results of the microscopic examination of
10 minutes, then filtered, using a Burger funnel which was myometrium obtained from the uterine tissue of pregnant
connected to a vacuum pump to obtain residue and solution. mice. This identification aimed to determine the
The solution obtained from each filtration step was hypertrophic degree of myometrial myocytes associated
evaporated using a rotary evaporator at 50 ºC. Furthermore, with an estrogenic activity of A.hierochuntica L. extract in
the extract was weighed and stored in a closed bottle at 4 pregnant mice. It was also expected to have an effect on
ºC. prostaglandin production (PGF2a and PGE2). The
The research protocol for this study was approved by the alteration of myometrial cells is related to the
local ethics committee. Healthy adult female mice (Mus administration of A. hierochuntica L. extract, as presented
musculus strain Balb C), 12–14 weeks old and 25–35 grams in Figure 1.
in weight, were used for this research. The mice were
acclimated for a week then their estrus period was
synchronized using 5 IU 0.1 mL of Prostaglandin and 5 IU
0.1 mL of HCG. Afterward, the female mice were placed
with fertile male mice, 1:1 (monogamy), for breeding.
All pregnant mice were divided into three groups—the
control group (P0) and two treatment groups (P1 and P2).
Each group consisted of seven random mice. Treatment was
Figure 1. The size difference in the nucleus of
treated on day 14 to 18 of pregnancy. Mice within the
control group were treated by 0.5% CMC Na solution 10
hypertrophic myocyte cells (arrows) between
mL/kg bw/day for 5 days. Mice belonged to P1 and P2 treatment groups (μm): (a) Myometrial tissue of the
treatment groups were treated by A. hierochuntica L. control group (P0), (b) Myometrial tissue of the
extract, 100 and a 150 mg/kg bw/day dose of, respectively, treated groups (P1) (H= hypertrophy; V=
for 5 days. On the 19th day, mice were dislocated for the vacuolization), and (c) P2. (M=400x; Nikon
preparation of uterine organ tissue and blood serum microscope 600l; camera ds fi2 300 megapixels).
collection.

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The histological analysis of myometrium cells of pregnant

mice treated with 100 mg/kg bw/day of A.hierochuntica L.
extract showed that there was an increasing number of
hypertrophy cells (H) with larger myocyte cell diameter
compared to the control group and the treatment group
treated 150 mg/kg/day of the extract (P2) (Figure 1).

Table 1. Microscopic Changes within

Myometrial Myocytes Cells in Pregnant Mice
Treated Different Doses of Anastatica hierochuntica
L. (Ah) Extract

Figure 2 The PGE2 level among groups.

Figure 2 shows that the PGE2 levels in group P1 (100 mg/kg

bw/day) increased 1.7× (X1 = 414.36) and in group P2 (150
mg/kg bw/day) 1.4× (X2 = 336.50) higher than the control
group (X0 = 239.14). Group P1 also had PGE2 levels that
were 1.2× higher than group P2. Furthermore, Table 3
presents the results of the one-way ANOVA test that was
performed, with α = 0.05.

* Group 1 = control, pregnant mice were treated 0.5% CMC Table 3. ANOVA Test of PGE2 Level among the
solution, Group 2 = Pregnant mice treated with AH extract dose of Groups.
100mg/kg bw/day, Group 3 = Pregnant mice treated with AH extract
dose of 150mg/kg bw/day.

Table 1 shows that the average number of hypertrophic

myocyte cells in the control group was < 5% of all observed
myocytes cells, while in the pregnant mice group treated Note: *significance =0.05 (one-way ANOVA)
a,b,c
with A. hierochuntica L. (AH) extract, the number of superscript showed difference among group (multiple
hypertrophic myocyte cells increased up 36–50% both in comparisons LSD)
the P1 and P2 groups—and some of the cells underwent
vacuolization. The difference in the hypertrophic scores of The results displayed in Table 3 presented that Anastatica
the myometrial cells between the three groups of pregnant hierochuntica L. treatment affects the PGE2 levels within
mice is shown in Table 2. pregnant mice. The significance level of PGE2 levels
among the control group, group P1 (100 mg/kg bw/day),
Table 2. The Results of the Hypertrophic Score and group P2 (150 mg/kg bw/day) (P2), through one-way
of Myometrial Myocytes Cells in the Treatment ANOVA statistical analysis, showed a significance level
Groups Treated Different Doses of Anastatica with p = 0.000 (p < 0.05). This result means there were
hierochuntica L. Extract. significant differences in the levels of PGE2 between the
control group and the treatment group. The results of the
post-hoc tests, multiple comparisons of LSD, showed that
there was a significant difference in the levels of PGE2
between the control group and group P1, the control group
and group P2, and between the P1 and P2 groups.
The average level of PGF2α between the control group,
Note: *significance α = 0.05 (Kruskal Wallis) group P1, and group P2 is presented in Figure 3.
a,b
It showed differences among the group (Mann-Whitney test)

There was a significant difference in the hypertrophy of

myometrial myocyte cells (p < 0.05 ) (Table 2) between the
control group compared to the treatment groups treated a
100 mg/kg bw/day and 150 mg/kgbw/day dose of
Anastatica hierochuntica L. extract. However, there was no
significant difference between the treatment groups in the
hypertrophy of myocyte cells.
The average PGE2 level within the control group treated
0.5% CMC and the treatment group treated with A.
hierochuntica L. extract presented in Figure 2.

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test results, using the LCMS method, presented that A.

hierochuntica L. contained flavonoid compounds.
Therefore, it is considered to be a phytoestrogen, which is
structurally and functionally similar to estradiol, [15][29]
with estrogenic function [30].
The administration of A. hierochuntica L. affects the
increased number of hypertrophic myometrial myocytes
cells. The results showed that A. hierochuntica L. extract
increased hypertrophic myometrial myocyte cells in
pregnant mice, which was characterized by a bigger cell size
(7 μm–12 μm) compare to the control group (4 μm–6 μm).
Moreover, it also increased the number of hypertrophic
Figure 3. Level of PGF2α among groups. myocyte cells 36–50% of all observed myocytes. Based on
these results, it obtained that the A. hierochuntica L. plant
Figure 3 shows that the average level of PGF2α within- has the potential to induce myometrial cell hypertrophy at
group P1 (100 mg/kgb w/day) and group P2 (150 mg/kg the end period of pregnancy. This change in process is
bw/day) increased 2× (X1 = 325.76) and 1.6× (X2 = normal since, physiologically, uterine tissue undergoes
266.57), respectively, and both groups had higher levels dynamic changes in the histological structure based on
than the control group (X0 = 160.54). Whilst, the levels in estrogen hormone levels [18]. Based on the study of Gaete
group P1 was 1.2× higher than group P2. Furthermore, et al., the administration of Genistein (0.5 mg/kg body
Table 4 shows the results of the one-way ANOVA (α = weight, subcutaneously) causes myometrial cell
0.05). hypertrophy and uterine luminal epithelium as estradiol
[31]. During hypertrophy, the contractile element enlarges
Table 4. ANOVA Test of PGF2α Levels among and the extracellular matrix expands for growth [32].
Groups. The administration of Anastatica hierochuntica L. extract
also increased the mean PGE2 and PGF2α levels within the
blood serum of pregnant mice. The administration of 100
mg/kgbw/day of Anastatica hierochuntica L. extract
increased the levels of PGE2 and PGF2α by 1.7 and 2×,
respectively, compared to the control group. The results
Note: *significance α=0.05 (one-way ANOVA)
a,b,c following the previous theory that estrogen and
superscript showed difference among groups (multiple
comparisons LSD) progesterone involve in regulating uterine contractions. The
membrane is depolarized, increasing the prostaglandin
The results in Table 4 demonstrated A. hierochuntica L. did production of PGE2, PGF2α, and oxytocin receptors. 33
have an effect on the PGF2α within pregnant mice. The Previous research stated that prostaglandin F2α increased in
level of significance of the difference in PGF2α levels the proestrus phase of the rat cycle when estrogen levels
between the control group and the A.hierochuntica L. were maximum.
extract treatment group was p = 0.000 (p < 0.05), This result proved that estradiol-17β caused an increase in
demonstrating that there were significant differences of the prostaglandin F2α levels in uterine ovariectomized rats.
levels of PGF2α between the control group and the Estrogen acts to control prostaglandin synthesis by
treatment group. The results of the post-hoc tests, multiple regulating the prostaglandin synthetase complex, as it
comparisons of LSD, demonstrated that there were produces a pattern change in the ratio of prostaglandin F to
significant differences in PGF2α levels between the control prostaglandin E [34].
group and the treatment group, and between treatment The Anastatica hierochuntica L. treatment presented a
groups (P1 and P2). significant difference in PGE2 levels (Table 3) and PGF2α
Hypertrophy of myometrial myocyte cells occurs levels (Table 4). These results indicated that the 100
physiologically within pregnancy. It is associated with mg/kgbw/day dose was more effective to induce the PGE2
increased myometrial growth during late pregnancy. and PGF2α levels within pregnant mice. Increased levels of
Smooth muscle cell hypertrophy is caused by the prostaglandin are expected to be related to cell hypertrophy
mechanical stretch of uterine tissue due to fetal growth [27]. and the stretching process (Mechanical Stretch) that has an
However, the estrogen hormone also has an essential role impact on NFkB activation [35]. The NFkB activation
within the growth of reproductive tissue cells, including the process will trigger prostaglandin production via the Cox-2
myometrium. pathway [36]. The results in this study showed that the
As explained in the previous studies, estrogen stimulation administration of Anastatica hierochuntica L. extracts at
can cause hypertrophy at the end of pregnancy. Several doses of 100 mg/kg bw/day and 150 mg/kgbw/day
potential mechanisms that regulate myometrial hypertrophy increased prostaglandin levels compared to the control
have been proposed within the literature. It has been group—according to the increase of myometrial cell
reported that ovarian hormones, estrogen, and progesterone, hypertrophy in the group. The association of an increase in
could induce myometrial hypertrophy [27]. Phytochemical prostaglandins, with myometrial cell hypertrophy, needs
further analysis.

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In the process of labor, prostaglandin has three actions, antioxidant flavonoids , chlorogenic acids and phenolic
myometrial contraction stimulation, cervical softening, and compounds. Phytochemistry. 2011; 72(2-3): 248-254.
gap junction induction [33][37]. Prostaglandin acts by [7] Gamal EEG, Khalifa SAK, Gameel AS, Emad MA.
binding to certain G-protein-coupled receptors, thereby Traditional medicinal plants indigenous to Al-Rass
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Prostaglandins (PGs) invove in the initiation and 2680-2683.
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or contractile receptors in the myometrium. This study
Aqueous Extract Of Anastatica Hierochuntica On Some
obtained that A. hierochuntica L. is an herbal plant that has
Hormones In Mouse Females. Ibn Al-Haitham J. Pure Appl.
a role in the reproductive system due to its potential to
Sci. 2013; 26(2): 198-205.
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Kaff Maryam ( Anastatica hierochuntica L .) and its relation
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A. hierochuntica L. plant extract had a greater effect on the [10] Mohamed AA, Khalil AA, El-beltagi HES.
histology of myometrial cells in pregnant mice and Antioxidant and antimicrobial properties of kaff maryam
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to the 150 mg/kg/day dose. These results provide new [11] Rizk A, Hammouda F, Ismail S, Hassan NM.
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ACKNOWLEDGMENT geocarpa. Food Chem. Toxicol. 2000; 38: 555-564.
[13] Shah AH, Bhandari MP, Al-harbi NO, Al-ashban RM.
The author thank the Center for Quality Improvement and
Kaff-E-Maryam (Anastatica hierochuntica L .): Evaluation
Educator Certification for Lecturers in the Indonesian
of Gastro-Protective Activity and Toxicity in Different
Ministry of Health for providing the funding in this
Experimental Models. Biol. Med. 2014; 6(1): 1-10.
research. The authors also expressed gratitude to Dr. Djoko
Legowo, M.Kes for technical assistance and discussion. [14] Daoowd WS. In vitro antifungal activity of extracts of
Anastatica Hierochuntica. or Vet. Med. Sci. 2013; 4(1):
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