Icariin, A Novel Promising Complementary Therapeutic
Strategy in the Management of Female Infertility:
A Literature Review
Sima Mosavi 1, Amirabbas Rostami 2, Marzieh Pooladi 3, Mahdie Shojaei Baghini 4, Sahar Poudineh 5, Maryam
Poudineh 5, Esmaeil Behzadi 6
1 Department of Obstetrics and Gynecology, School of medicine, Urmia University of Medical Sciences, Urmia, Iran
2 Department of Internal Medicine, Faculty of General Medicine, Yerevan State Medical University aer Mkhitar Heratsi, Yerevan,
Armenia
3 Department of Anatomical Sciences, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
4 Medical Informatics Research Center, Institute for Futures Studies in Health, Kerman University of Medical Sciences, Kerman, Iran
5 School of Medicine, Mashhad Azad University, Mashhad, Iran
6 School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
GMJ.2023;12:e2528
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Correspondence to:
Amirabbas Rostami, Department of Internal Medicine,
Faculty of General Medicine, Yerevan State Medical
University after Mkhitar Heratsi, Yerevan, Armenia.
Telephone Number: +14168901910
Email Address: Dr.amirabbasrostami@gmail.com
Received 2022-07-13
Revised 2022-08-02
Accepted 2022-08-22
GMJ
Copyright© 2021, Galen Medical Journal.
This is an open-access article distributed
under the terms of the Creative Commons
Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/)
Email:info@gmj.ir
Abstract
The prevalence of pre-menopausal female infertility is increasing considerably due to various
causes such as environmental pollutants, increased administration of chemotherapeutics and
radiation exposure, microbial infections, and genetic/epigenetic alterations. However, the cur-
rent therapeutical strategies remain unfavorite as the disadvantages are strongly challenging.
Icariin (ICI) is a phytoestrogen that exerts some promising properties in order to alleviate fe-
male infertility. Therefore, the current literature review aimed to evaluate the conducted studies
regarding the benecial impacts of ICI on the female reproductive system and female fecundity.
The ndings of the present study revealed that ICI is able to modulate the levels of reproductive
hormones as it causes a signicant decrement in the levels of luteinizing hormone (LH) and
follicle-stimulating hormone (FSH) while increasing the levels of estrogen and progesterone.
Furthermore, the administration of ICI results in a dramatic alteration in the expression of sex
steroids’ receptors, particularly in female reproductive tissues. In addition, preserving ovarian
follicular reserve, improving the ovarian and uterine histoarchitecture, elongating the estrous
cycle duration, and eventually advancing the female fecundity are other major eects of ICI on
the female reproductive system. Despite these desired benecial properties, the current knowl-
edge appears to be insucient, hence further investigations, particularly on humans, are en-
couraged. To the best of our knowledge, this review provides a comprehensive information re-
garding the benecial eects of ICI on female infertility for the rs time.[GMJ.2023;12:e2528]
DOI:10.31661/gmj.v12i.2528
Keywords: Icariin; Female Infertility; Female Reproductive System
Introduction
Infertility, an integral part of reproductive
health which is become a priority global
health issue, is dened by the world health
organization as a failure of a couple to con-
ceive a known pregnancy after twelve months
or longer of regular unprotected sexual inter-
course [1-3].
It is documented that approximately 30 per-
Mosavi S, et al. Icariin and Female Infertility
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cent of couples in western countries are suf-
fering from infertility.
Females exert a more critical role in the prev-
alence of infertility since 20-70 percent of
infertility-related factors are associated with
women [4, 5].
A number of factors could cause female in-
fertility including reproductive system disor-
ders (e.g. endometriosis and polycystic ovary
syndrome) [4, 6], toxicants and environmental
pollutants (e.g. organophosphates and carba-
mates) [7, 8], chemotherapies and pharma-
ceutics (doxorubicin and irinotecan) [9, 10],
radiation, etc. [11].
The current therapeutic strategies include sex
hormone therapy such as follicle-stimulating
hormone (FSH) therapy, human chorionic
gonadotropin, estrogen replacement therapy,
etc., assisted reproductive technology, and
tubal plastic surgery which despite some de-
sired advances, these strategies are invasive,
expensive, and are faced with unavoidable ad-
verse eects like increasing the risk of ovari-
an hyperstimulation syndrome (OHSS), men-
tal disorders, and so on [1, 12, 13].
Regarding the two principal aspects of female
infertility, one of which is the misregulation
of sex hormone levels, especially estrogen,
and the other is the involvement of oxidative
stress [14, 15], researchers have been eorting
in recent years to nd an ideal phytoestrogen
to support the ability of couples to re-create.
Icariin (ICI) (2-(4′-methoxylphenyl)-3-rham-
nosido-5-hydroxyl-7-glucosido-8-(3′-meth-
yl-2-butylenyl))-4-chromanone) is a well-
known phytoestrogen extracted from Epi-
medium pubescens. Chemical structure of
ICI is shown in Figure-1.
This pentenylated avonoid glycoside mono-
mer exerts a number of desired biological
properties such as antioxidant, anti-inamma-
tory, and anti-tumor activities.
Therefore, some recent studies have investi-
gated its therapeutic eects on human disor-
ders such as cancer, asthma, cardiovascular
disease, osteoporosis, etc. [16-19].
Regarding the documented experimental
studies that revealed the benecial eects of
ICI on the female reproductive system, the
current literature review aimed to assess the
potential therapeutic properties of ICI on fe-
male infertility by considering the eects it
has on the biosynthesis of reproductive hor-
mones, the structure of uterine and ovarian
tissues, the expression of sex steroid recep-
tors, and fecundity.
The search was performed in Web of Science,
PubMed, Scopus, and Embase databases
without time limitation.
Icariin Modulates Reproductive Hormones
Synthesis
The hypothalamic-pituitary-ovarian (HPO)
axis, a highly regulated system, controls
female reproduction through cyclic biosyn-
thesis of gonadotropic and steroid hormones
[20].
Due to the vital role of hormones secreted by
the HPO axis in preparing reproductive tissues
Figure 1. Chemical structure of icariin.
Icariin and Female Infertility Mosavi S, et al.
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3
for healthy reproduction, any dysregulation
will result in impaired reproductive function,
reproductive-related disorders such as prema-
ture ovarian failure (POF), polycystic ovarian
syndrome (PCOS), ovarian and uterine can-
cer, endometriosis, etc., and consequently in-
fertility [21-23].
Due to the vital importance of reproductive
hormones in regulating the development of
involved cells such as sertoli cells and granu-
losa cells, proliferation or apoptosis of ovari-
an follicles, preparation of ovarian and uterine
tissues, supporting fetal growth, etc., several
studies have investigated the potential desired
eects of ICI on the biosynthesis of these hor-
mones.
In Eriocheir sinensis, for example, treatment
with dierent doses of ICI resulted in a sig-
nicant increment in hemolymph estrogen
content [24].
Moreover, the study by Nie et al. revealed
that ICA was able to promote the production
of both sex steroids, estrogen, and progester-
one, in rat-derived granulosa cells [25]. Sim-
ilarly, prepubertal administration of ICI, as
well as icaritin (ICT), advanced pubertal de-
velopment in female Sprague-Dawley rats by
aecting estrogen and estrogen response gene
expression levels [26].
POF is an ovarian complication that results in
amenorrhea, ovarian failure, and eventually
infertility.
POF is characterized by premature depletion
of ovarian follicles in approximately 3% of
women younger than 40 years old which is
diagnosed by high levels of gonadotropins
such as luteinizing hormone (LH) and FSH,
and low levels of gonadal hormones including
estrogens and inhibins [27, 28].
Interestingly, the administration of ICI to
animal models of D-galactose-induced POF
caused a signicant reduction in LH and
FSH levels, promotion of estrogen and an-
ti-Müllerian hormone (AMH) production, and
increased viability of granulosa cells, which
were all assumed to be the result of strength-
ening the DNA repair system indicated by
altered levels γH2AX and 53BP1 expression
upon treatment with ICI [29].
Furthermore, in mice models of D-galac-
tose-induced ovarian aging, in which ovarian
aging itself is a causative agent in many ovar-
ian dysfunctions [30-32], ICI was capable of
inhibiting ovarian follicular atresia, lowering
the levels of LH and TSH, improving estrogen
biosynthesis and AMH expression, and there-
by restoring ovarian function and enhancing
fertility in aging mice [33].
In addition to the common abnormalities in
the secretion of reproductive hormones, there
are rare diseases such as perimenopausal de-
pression, which are mediated by an imbalance
in the levels of sex steroids, particularly es-
trogen.
Interestingly, Cao et al. revealed that admin-
istration of ICI is followed by a signicant in-
crement in the levels of estrogen, testosterone,
serotonin, dopamine, and noradrenaline, and
lowering the levels of LH and FSH through
modulating the phosphatidylinositol 3-kinase
(PI3K)/serine-threonine protein kinase (AKT)
signaling pathway in a rat model of perimeno-
pausal depression-like [34].
Along with PI3K/AKT signaling pathway, ICI
is able to aect other signaling pathways in
order to modulate reproductive hormones bio-
synthesis.
The cyclic adenosine monophosphate
(cAMP)/protein kinase A (PKA)/cAMP re-
sponse element-binding (CREB) protein path-
way, for example, is modulated by ICI which
is resulted in alteration in estrogen levels and
leads to resolving the problem of delayed
ovarian maturation [24].
Moreover, the CYP17 and CYP19 protein
expression, and aromatase levels, are upreg-
ulated by ICI that causing elevated steroid
hormone secretion in ovarian granulosa cells
[25].
In addition to the mentioned mechanisms, ICI
is able to modulate the expression of hormone
receptors in target tissues and thus regulate
the eects of reproductive hormones [35].
Icariin Regulates the Expression of Repro-
ductive Hormones’ Receptors
Although estrogen, the primary female sex
hormone, is attributed to be responsible for
the regulation of reproductive system func-
tion and development of secondary sexual
characteristics, it exerts its actions by binding
to specic receptors, known as the estrogen
receptors (ERs), which in turn activate tran-
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Mosavi S, et al. Icariin and Female Infertility
scriptional processes and signaling pathways
via genomic or non-genomic eects [36].
Therefore, any irregularity or dysfunction
of these receptors will have the same conse-
quences as the disruption of estrogen levels. A
growing body of evidence strongly suggests
that the majority of estrogenic actions are me-
diated by nuclear estrogen receptors, in which
two subtypes of ERs, Esr1, known as ERα,
and Esr2, known as ERβ, have been generally
conserved [37]. Furthermore, the progesterone
hormone, which is suggested to be responsi-
ble for the human menstrual cycle, pregnancy,
and parturition regulation, exerts its function
via its nuclear receptors [38] whose activation
results in transcriptional regulation [39].
Because of the vital importance of steroid hor-
mone receptors in regulating the function of
these hormones, a number of studies have ex-
amined alterations in the expression of these
receptors upon ICI and/or its derivatives ad-
ministration. In this regard, it is suggested that
ICI, and ICT, aected the levels of ERs and
PR in both uterus and ovaries which in turn
led to the advancement of pubertal develop-
ment in female rats [26].
Moreover, ICI is reported to be capable of
regulating the expression levels of ERs in
both bone and reproductive tissues in ovariec-
tomized rats suering from estrogen decien-
cy [40].
The Benecial Eects of Icariin on the
Ovarian and Uterine Histoarchitecture
Histomorphology of the major tissues in-
volved in the reproductive process, the ovaries
and the uterus, is directly aected by sex ste-
roids through their receptors; Therefore, the
physiological structure of these tissues on the
one hand indicates the potential fertility and
guarantees the eective production of sex ste-
roids and on the other hand, is a manifestation
of the suitable functioning of sex hormones
and their receptors in these tissues [41-43].
The mammalian ovary contains dierent fol-
licles such as primordial, primary, secondary,
antral, and graaan, which are classied based
on their stages of development.
It is well established that the number of pri-
mordial follicles is determined during the
embryonic period and stays permanent until
puberty, referred as an ovarian reserve. In this
regard, damage to this ovarian reserve is fol-
lowed by a pathologic state known as POF or
premature ovarian insuciency (POI).
Due to the renewal inability of these follicles,
depletion of the ovarian reserve could result
in permanent infertility [10, 44, 45]. In this re-
gard, researchers reported that ICI improved
the diameter and proportion of ovarian folli-
cles and induced mature follicle development
in rodents’ models of aging [33]. In addition,
ICI was able to protect the histomorphology
of ovarian follicles against an induced state of
POF [29].
Similarly, ICI alleviated the pathological al-
terations such as the number of layers of gran-
ulosa cells, the mature ovarian follicle, and
the corpus luteum caused by perimenopausal
depression [34].
The promotion of DNA damage repair via
altering the expression level of γH2AX and
53BP1, the inhibition of apoptosis through
upregulation of Bcl2, and suppression of Bax
expression, thus improving the development
of ovarian follicles and reducing the num-
ber of atretic follicles are the most important
mechanisms by which ICI aects the histo-
morphology of the ovary [25, 29, 33, 34].
In addition to the ovaries, uterine histomor-
phology is strongly associated with fertility
and the possibility of giving birth to a healthy
newborn. Thin endometrium, for example, is
well documented that is related to a signicant
decrease in pregnancy rates [46, 47].
In this regard, Le et al. reported that ICI is
a promising therapeutic strategy to increase
the thickness of the endometrium which ex-
erts its benecial eects through modulating
the expression of VEGF (vascular endothelial
growth factors) , CD31, and factor VIII [48].
In ovariectomized animals, which is a mod-
el of estrogen depletion, a study suggests that
administration of ICI, although it had no eect
on uterine tissue weight, increased the thick-
ness of the uterus, endometrial, and luminal
epithelium, and the numbers of endometrial
glands [40].
Furthermore, ICI was able to justify the uter-
ine epithelial heights and myometrium thick-
ness. However, other studies have shown that
ICI improves uterine weight in almost identi-
cal pathological conditions, too [49, 50].
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Icariin and Female Infertility Mosavi S, et al.
Table 1. Icariin Exerts Desired Benecial Eects on the Female Reproductive System.
Year Type Cell/ Animal Dose Duration Finding Ref
2020 In
vivo
Eriocheir
sinensis
0, 50, 100,
and 200
mg/Kg
8 weeks Icariin was able to increase the levels of vitellogenin, GSI, oocyte volumes,
estrogen, and aromatase through the cAMP/PKA/CREB pathway.
[24]
2018 In
vitro
Rat Ovarian
Granolusa
Cells
10 μg/l 72 h ICI caused a dramatic increase in the levels of estrogen and progesterone and the
proliferation of granulosa cells. Furthermore, it increased the levels of CYP17 and
CYP19.
[25]
2012 In
vivo
SD rats 20 mg/Kg 20 days The increased duration of the estrous cycle and increased weight of ovarian tissue
resulted after the administration of ICI.
[26]
2019 In
vivo
C57BL/6
mice
10, 50 and
100 mg/Kg
42 days ICI improved ovaries weight, ovarian histoarchitecture, decreased LH and FSH
levels, upregulated AMH and estrogen, and increased granulosa cell viability
through promoting the DNA repair system.
[29]
2018 In
vivo
Kunming
white mice
50, 100, and
200 mg/Kg
30 days Improved follicular content, reduced apoptosis, decreased LH and FSH levels,
increased levels of estrogen, and promoted fertility rates resulted from the
administration of ICI.
[33]
2019 In
vivo
SD rats 12.5, 25, and
50
mg/Kg
30 days ICI was able to modulate sex-steroid levels as it elevated estrogen and testosterone
levels, reduced LH and FSH levels, upregulated ESR1, and decreased apoptosis
through PI3K/ AKT pathway.
[34]
2017 In
vivo
SD rats 50, 100, and
200 mg/Kg
3
respective
estrous
cycles
ICI could improve the thickness of the thin endometrium via modulating the levels
of VEGF, CD31, and factor VIII.
[48]
LH:luteinizing hormone; FSH:follicle-stimulating hormone; GSI:Gonado Somatic Index; SD:Sporgue Dawley; cAMP/PKA/CREB:Cyclic adenosine monophosphate/
protein kinase A/cAMP-responsive element binding protein; CYP17: Cytochrome P450 17; AMH:Anti-Mullerian Hormone; PI3K:Phosphoinositide 3-kinase; A K T:Protein
kinase B; VEGF:Vascular endothelial growth factors; CD3:1cluster of dierentiation 3.1; C57BL:C57 black 6.
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Mosavi S, et al. Icariin and Female Infertility
ICI benecial eects on the female reproduc-
tive system are shown in Table-1.
Conclusion
The current literature review demonstrated
that ICI could be assumed a novel promising
therapeutic strategy in the management of
female infertility due to its desired properties
such as modulation of the levels of hormones
involved in the HPO axis including LH, FSH,
estrogen, and progesterone, the regulation
of sex-steroid receptors expression in
reproductive tissues, preserving of ovarian
follicular reserve and the histomorphology of
ovarian and uterine tissues, and ultimately the
regulation of estrous cycle.
However, the present studies appeared to be
insucient and the design and conduct of
further studies, especially clinical trials, are
strongly recommended by the ndings of the
present study.
Conict of Interest
The authors declare that there are no conicts
of interest.
The Impact of Icariin on the Estrous
Cycle and Fertility
In rodents, the secretion of reproductive hor-
mones, the development of ovarian follicles,
and the maturation of oocytes are highly reg-
ulated processes that occur during a regular
cycle, referred as the estrous cycle, that con-
sists of four phases named proestrus, estrus,
metestrus, and diestrus.
This cycle, particularly in rodents like rats
and mice, lasts for a 4-5 days period which is
characterized to be a repetitive but dynamic
process as it exerts dierent types of cells and
levels of hormones [38, 51, 52].
In a study by Kang et al. it was found that ICI
administration signicantly increased the du-
ration of the estrous cycle in rats which leads
to advanced pubertal development [26].
The benecial eects of ICI on the estrous
cycle, which was accompanied by alleviat-
ed POI, have been attributed to aecting the
Nrf2/HO-1/Sirt1 pathway in the mice ovary
[53]. More importantly, the administration
of ICI to the induced aging led to increased
pregnancy rate, improved average litter sizes,
elevated average litter birth weight, average
weaning weight of litters, and weaning rate
revealing the benecial eects of ICI on fe-
male fertility and newborn health [33].
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