Open Access
Review article
Relatos sobre a contribuição in vivo e in vitro de plantas medicinais na melhora da função reprodutiva feminina
- a Laboratório de Manipulação de Oócitos e Folículos Ovarianos Pré-antrais (LAMOFOPA), Faculdade de Veterinária (FAVET), Universidade Estadual do Ceará (UECE), Fortaleza, CE, Brazil
- b Laboratório de Análise Fitoquímica de Plantas Medicinais (LAFIPLAN I), Universidade Federal do Ceará (UFC), Fortaleza, CE, Brazil
- Received 26 October 2016, Accepted 26 November 2016, Available online 18 March 2017
- Open Access funded by Sociedade Brasileira de Reprodução Humana
- Under a Creative Commons license
Abstract
Medicinal plants are known as a prolific source of secondary metabolites which have important function both in vivo and in vitro
during the ovarian folliculogenesis and steroidogenesis in many animal
species. Some secondary metabolites can act as antioxidants generally
through their ability to scavenge reactive oxygen species (ROS) or can
regulate ovarian hormonal production. In general, these properties are
responsible for the medicinal functions to treat woman infertility
disorder. Some plants are constituted of biological actives substances
which have been used to treat reproductive dysfunction. However, until
recently, little was known about the implication of plants and/or their
secondary metabolites on in vitro folliculogenesis and
steroidogenesis. With the development of the technology, there is an
increase implication of those substances in assisted reproductive
technology (ART). The present review highlights some medicinal plants
used in the treatment of woman disorders related to infertility. In
addition, it provides an in vivo and in vitro overview
of herbs and their active compounds with claims for improvement of
ovarian activity thus showing their implication in female reproductive
health care.
Resumo
Sabe-se que as plantas medicinais são uma fonte abundante de metabólitos secundários que têm função importante tanto in vivo quanto in vitro
durante a foliculogênese e a esteroidogênese ovarianas em muitas
espécies animais. Alguns metabólitos secundários podem atuar como
antioxidantes, geralmente através de sua capacidade de eliminar espécies
reativas de oxigênio (ROS) ou podem regular a produção hormonal
ovariana. Em geral, essas propriedades são responsáveis pelas funções
medicinais usadas para tratar distúrbios da infertilidade feminina.
Algumas plantas contêm substâncias biológicas ativas que têm sido
utilizadas para tratar a disfunção reprodutiva. No entanto, até
recentemente, pouco se sabia sobre o efeito das plantas e/ou seus
metabólitos secundários na foliculogênese e na esteroidogênese in vitro.
Com o desenvolvimento da tecnologia, há uma implicação crescente dessas
substâncias na tecnologia de reprodução assistida (TRA). A presente
revisão destaca algumas plantas medicinais utilizadas no tratamento de
distúrbios femininos relacionados à infertilidade. Além disso, fornece
uma visão in vivo e in vitro de ervas e seus compostos
ativos com alegações de melhora da atividade ovariana, mostrando assim
seu envolvimento nos cuidados de saúde reprodutiva feminina.
Keywords
- Phytotherapy;
- Antioxidants;
- Women infertility;
- Ovarian follicles
Palavras-chave
- Fitoterapia;
- Antioxidantes;
- Mulheres infertilidade;
- Folículos ovarianos
Introduction
Infertility
is a disease of the reproductive system which affects both men and
women with almost equal frequency. It is a global phenomenon affecting
an average of 10% of human reproductive age population.1
Many conditions can be associated to this problem, including intrinsic
(anatomic, genetic, hormonal and immunological disorders) and extrinsic
factors such as sexually transmitted infections (STIs), infections after
parturition or surgery, tuberculosis of the pelvis, and obesity.2 ; 3
There
are a range of medical treatment options for infertility, such as the
use of commercial treatments to stimulate “superovulation” which
correspond to the development and release of more than one egg per
ovulatory cycle. In addition, ART is commonly applied to solve
infertility problems, including procedures to bring about conception
without sexual intercourse. Among the available techniques, in vitro maturation (IVM), in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI) and intrauterine insemination (IUI) 4
are frequently applied. As an alternative, medicinal plants can also be
used to solve part of the reproductive problems. Due to their chemical
composition, many plants have showed beneficial properties in the
folliculogenesis and steroidogenesis through their antioxidant
properties and regulation of some enzyme of the steroidogenesis. 5; 6; 7 ; 8
For
a better understanding of the medicinal properties of crude plant
extract or secondary metabolites on the regulation of reproductive
function (folliculogenesis and steroidogenesis), many in vivo studies have been performed. 5; 6; 8 ; 9
Several studies showed that the plant secondary metabolites act either
directly on ovarian cells to eliminate the ROS or through action on
several enzymes such as catalase, glutathione, superoxide dismutase and
glutathione peroxidase. 10; 11 ; 12
On the other hand, plants (infusion, decoction, beverages, crude
extracts) showed their implication during the steroidogenesis through
their capacity to mimic the biologic effects of endogenous hormones.
These plant medicine derivatives can act by binding to their nuclear
receptor or regulating the activities of key enzymes of their
metabolisms. 6 ; 13
The
present review is an attempt to consummate the available scientific
information on various medicinal plants, which have been evaluated for
their effect on female reproduction. Among all the female reproductive
organs, only the ovary is discussed on this review since it is the site
of the folliculogenesis and steroidogenesis.14 The review also includes known evidences collected for the involvement of plant extracts in vivo and in vitro.
A number of plants and/or secondary metabolites have been discussed in
detail and a few others were only tabulated; a major criterion for this
arrangement was the ethnopharmacological relevance of the plant.
Mammalian ovary, folliculogenesis and ovarian follicles
The
mammalian ovary is the female gonad which contains germ cells
responsible for the perpetuation of the species. Furthermore, it is also
the reproductive gland controlling many aspects of female development
and physiology.15
That is why it is important for the reproductive biologists to
understand not only the normal functioning of the ovary but also the
pathophysiology and genetics of diseases such as infertility.
The
ovary consists of many types of differentiated cells, which work
together, promoting an ideal environment to perform the endocrine and
exocrine functions. Those functions are performed by different factors
such as autocrine, paracrine, juxtacrine and endocrine are essential for
ovarian folliculogenesis.16
Folliculogenesis is the result of a complex and closely integrated
series of events which start generally soon after conception. This
process can be defined as the formation, growth and maturation of
follicle, starting with the formation of the oocyte surrounding by the
granulosa cells which formed the primordial follicles.17
Besides
the granulosa cells, the thecal cells are recruited to the oocyte and
are directly or indirectly necessary for the oocyte development,
physiology and survival. The dynamic of the ovarian folliculogenesis is
classified in different stages known as: (a) formation of the primordial
follicles; (b) recruitment into the growing pool to form a primary,
secondary, and tertiary follicles; (c) lastly ovulation and subsequent
formation of a corpus luteum.18
In most species, the mammalian ovary shows extensive variation mainly
in relation to the interstitial tissue of the organ, the so-called
interstitial gland, and the degree of gonad regionalization, which
implies the existence of a cortex and a medulla.15
The internal part consists of fibroelastic connective tissues, nerve
and vascular tissues (medula) whereas the external part called the
cortex is located at the outer layer and is surrounded by the germinal
epithelium, which contains the ovarian follicles and corpora lutea in
various stages of development or in regression16 (Fig. 1).
- Fig. 1.Schematic representation of the ovarian structure. Adapted from http://faculty.southwest.tn.edu/rburkett/A&P2_reproductive_system_lab.htm.19
The
follicle which represents the morphological and functional unit of the
mammalian ovary consists of an oocyte surrounded by somatic cells
(granulosa and/or theca) organized or demarcaded by the basement
membrane.
Before
formation of an ovarian follicle, oocytes are present within germ cell
clusters. Primordial follicle formation occurs when oocytes that survive
the process of germ cell cluster breakdown are individually surrounded
with squamous pre-granulosa cells. This process takes place during the
latter half of fetal development in humans and in the days immediately
following birth in mice.18 ; 20
In mammals, the population of primordial follicles serves as a resting
and finite pool of oocytes available during the female reproductive life
span. Germ cell cluster breakdown, primordial follicle formation, and
subsequent recruitment remain the least understood steps of
folliculogenesis, that is why key regulators of these initial stages of
follicle development continue to be identified. Furthermore, despite
many unanswered questions during this crucial period, the concept of
ovarian cross talk between oocytes and somatic cells is apparent from
the formation of primordial follicles onward.21 ; 22
After differentiation of the primordial germ cells, oogonia undergo
mitotic proliferation with incomplete cytokinesis, leaving daughter
cells connected by intercellular bridges. The majority of germ cells in a
cluster divide synchronously such that a single germ cell cluster
contains 2n germ cells.23
Germ cells subsequently enter meiosis, becoming oocytes. Individual
oocytes within these nests lack surrounding somatic cells, and the
majority of the oocytes will undergo apoptosis as the germ cell clusters
break down to give rise to primordial follicles.
The
primordial follicles represent the first category of follicles. After
their formation, the granulosa cells stopped multiplying and enter a
period of quiescence. Throughout the life of the female, a small group
of follicles is stimulated to grow gradually, forming the activation
follicular phase. The first sign of activation of primordial follicles
is the resumption of proliferation of granulosa cells. Upon activation, a
series of events that increases the number of granulosa cells,
formation of the zona pellucida and oocyte diameter increased leading to
the formation of other categories of preantral follicles, primary and
secondary follicles occurs. Once activated, the follicles enter a
pre-programmed course of development and maturation which is necessary
for successful ovulation and fertilization or alternatively are lost
through the process of atresia.24
The second category of follicles is characterized by the organization
of granulosa cells in several layers and formation of a cavity filled
with follicular fluid called antrum. This follicular fluid consists of
water, electrolytes, serum proteins and high concentrations of steroid
hormones secreted by granulosa cells.25 However, throughout the life of the female, only a small group of follicles, approximately 0.1%, reached ovulation,26
thus reducing the reproductive potential of the female. In several
pathological conditions, the woman can suffer of premature ovarian
failure (POF) caused by different factors: endocrine, paracrine, genetic
and metabolic factors such as high production of ROS.27 ; 28
ROS production in the ovary
Oxidative
metabolism is indispensable for energy production of ovarian follicle,
which in turn results in generation of ROS (oxygen hydroxide, superoxide
ion, heavy metals and free radicals). Although a critical amount of ROS
is essential for their physiological activities, excessive amount of
them causes oxidative stress,29 damage to mitochondria and also to cellular structures such as the membrane lipids, damage to nucleic acids and proteins.27 It does become necessary to use antioxidants to counteract this overproduction of ROS.30
Prevention of oxidative stress is vital in order to maintain normal reproductive function.31 Sources of ROS during ART procedures could either be endogenously from gametes or via exogenous environmental factors. 32
However, unless measures are taken to curb ROS production, both the
endogenous and exogenous sources of ROS will ultimately lead to the
development of oxidative stress, which would then have negative impact
on follicles development, oocyte maturation, fertilization rates and
pregnancy outcome. Valorization of natural compounds of plants could
improve and be an alternative to reduce the cost of ART.
Phytotherapy
Phytotherapy
can be defined as the use of medicinal plants in the prevention, relief
or cure of diseases. A plant can be considered as medicinal when the
whole plant or at least one of its parts has one or more medical
properties.33
Medicinal plants are used by the people to treat several diseases,
including to solve infertility problems. In this context, some plants
are rich in compounds which exhibit regulator effect on reproductive
function acting directly or indirectly on the
hypothalamic–pituitary–ovarian axis by induction or inhibition of
ovulation and steroidogenesis disrupting hormonal functioning of the
hypothalamus and pituitary gland.5 Their use can bring direct answers to some health problems such as reproductive disorders. The use of medicinal plants (Fig. 2)
in response to reproductive problems can be seen as an alternative to
manufactured drugs, especially in developing countries where they are
expensive and/or inaccessible.34
- Fig. 2.General scheme and sequence (from 1 to 8) of studying the in vitro and in vivo effects of plant extracts.
Several
studies have shown the beneficial implication of natural compounds on
the woman reproduction acting directly on the reproductive organs or
indirectly regulated physiological process. For example, studies by
Telefo et al.35 showed that the aqueous extract of the mixture of Aloe buettneri, Dicliptera verticillata, Hibiscus macranthus and Justicia insularis, is used in traditional medicine to normalize the menstrual cycle increasing female fertility. In addition, Acanthus montanus, Aloe vera, Carica papaya, Citrus aurantifolia, Elaeis guineensis, and Panax quiquefolius, Eremomastax speciosa are used in Nkam (Littoral region in Cameroon) with the same purpose. 36Asystasia vogeliana, Crinum distichum, Crinum jagus, Crassocephalum biafrae, Scoparia dulcis, Solanum torvum, Aframomum letestuanum, Aloe buettneri and Eremomastax speciosa make part of the cast of plants most widely used to treat diseases of the reproductive system. 37 Generally, medicinal plants used for the improvement of the reproductive functions have more than one property. Table 1 illustrates some traditional medicinal plants used in the treatment of female reproductive disorders.
- Table 1. Medicinal plants and their in vivo therapeutic utilization on female reproductive function.
Plants Family Major phytochemical compounds Used parts Therapeutic utilization References Moringa oleifera Moringaceae Lutein, carotene xanthins, kaempferol, quercetin Leaves Sexual libido Cajuday and Pocsidio,38 2010 Adiantum concinnum Adiantaceae No report Leaves and stems Menstrual regulation Bussmann and Glenn,39 2010 Petroselinum crispum Apiaceae Flavonoids Whole plant Menstrual regulation Nielsen et al.,40 1999; Bussmann and Glenn,39 2010 Musa sapientium Musaceae No report Leaves Menstrual regulation Chifundera,41 1998 Scabiosa atropurpurea Dipsacaceae No report Leaves Menstrual regulation Bussmann and Glenn,39 2010 Cassia alata Fabaceae Tannins, saponins, flavonoids, steroids, terpenoids, alkaloids Root Infertility Ramaraj et al.,42 2014; Koch et al.,43 2015 Ximenia americana Olacaceae Saponins, glycosides anthraquinones Whole plant Menstrual regulation James et al.,44 2007, Bussmann and Glenn,39 2010 Eremomastax speciosa Acanthaceae Flavonoids, alkaloids, saponins, tannins Leaves Infertility Adjanohoun et al.,45 1996; Priso et al.,36 2006 Justicia insularis Acanthaceae Flavonoids, alkaloids, glycosides Leaves and stem Infertility, menstruation unrest Adjanohoun et al.,45 1996; Telefo et al.,5 1998 Crinum distichum Amaryllidaceae No report Whole plant Amenorrhea infertility Priso et al.,36 2006 Ageratum conyzoides Asteraceae Flavonoids, alkaloids, benzofuranes, terpenes Leaves Infertility, infections of the genital device Adewole,46 2002 Senecio biafrae Asteraceae Dihydroisocoumarins, terpenoids, sesquiterpens, amino acids, mineral salts Leaves and stem Infertility Tabopda et al.,47 2009; Tacham,37 2000 Emilia coccinia Asteraceae No report Whole plant Dysmenorrhea Adjanohoun et al.,45 1996 Zehnaria scabra Cucurbitaceae No report Leaves and stem Infertility, dysmenorrhea Adjanohoun et al.,45 1996 Euphorbia tirucalli Euphorbiaceae No report Stem Gonorrhea Arbonnier,48 2002 Jatropha curcas Euphorbiaceae No report Leaves and stem Infertility Igoli et al.,49 2002 Aloe buettneri Liliaceae Glycosides, quinines, coumarins, anthraquinonic derivatives Leaves Infertility, painful menstruations, dysmenorrhoea Telefo et al.,6 2004; Tacham,37 2000 Paulinia pinnata Sapindaceae No report Leaves Infertility, amenorrhea, gonorrhea Arbonnier,48 2002 Solanum torvum Solanaceae Flavonoids, alkaloids, saponins, glycosides, tannins Fruit Infertility, genital infections Tacham,37 2000 Ampelocissus Pentaphylla Vitaceae No report Leaves Infertility Tacham,37 2000 Pelargonium odoratisimum Geraniaceae No report Whole plant Inflammation of the ovaries and womb Bussmann and Glenn,39 2010 Pelargonium roseum Geraniaceae No report Flowers and leaves Hemorrhages, uterus pain Bussmann and Glenn,39 2010 Krameria lappacea Krameriaceae No report Leaves and root Inflammation of the ovaries Bussmann and Glenn,39 2010
As can be seen from Table 1,
various medicinal, plants belonging to different families showed
therapeutic effects. Traditionally, rural women have used plant
medicines rather than modern medicine for their personal ailments due to
lack of modern facilities in the regions. Bannu region in Pakistan was
ranked first having large number of gynecological plant to medical
treatment of female reproductive system: uterus, vagina, and ovaries.50
Moreover, many women in Costa Rica consider menopause as a natural
phenomenon and treat the symptoms with herbs. Interestingly, Latina
women in the United States also tend not to use hormone therapy
(estrogenic and/or progesteronic compounds) opting for natural remedies
for menopause such as diet, exercise and herbal remedies.51
More detailed scientific studies are desperately needed to evaluate the
efficacy and safety of the remedies employed traditionally.
Secondary metabolites of plants: description and medicinal properties
Description
Secondary
metabolites are structurally diverse; their classification is mainly
derived from their biosynthetic pathways. In pharmacognosy, secondary
metabolites are classifying in: (a) phenolic; (b) alkaloids and (c)
terpenoids compounds,52 as described below.
Phenolic compounds
Phenolic
compounds are among the most widespread class of secondary metabolites
in nature. This class of compounds are synthesized from a common
precursor: the amino acids phenylalanine or tyrosine. Phenolic compounds
consist of flavonoids, tannins, coumarins, quinones and anthocyanins
and are regarded as the widest spread phytochemicals. Phenolic compounds
may assume a wide range of structures from simple ones containing one
aromatic ring only, to very complex polymeric forms.53 The term flavonoid is a collective name for plant pigments, mostly derived from benzo-δ-pyrone. 54 They are widely distributed in plants contain free hydroxyl groups attached to the aromatic rings (Table 2). Flavonoids such as rutin, present in certain buckwheat (Fagopyrum esculentum) species are known to inhibit lipid oxidation by radicals scavenging. 55
Alkaloids compounds
Alkaloids are nitrogenated compounds synthesized by living organisms. In general, they contains heterocyclic rings (Table 2)
and due the presence of one or more nitrogen atoms, they present basic
properties. The name alkaloid is directly related to the fact that
nearly all alkaloids are basic (alkaline) compounds. Derived from amino
acids, in general, they are pharmacologically active. Alkaloids
constitute ‘a very large group of secondary metabolites, with more than
12,000 substances isolated. A huge variety of structural formulas,
coming from different biosynthetic pathways and presenting diverse
pharmacological poperties.56
Terpenoids compounds
The
terpenoids comprising monoterpenes, sesquiterpenes, sesterterpenes and
triterpenes, besides steroids, saponins and cardiac glycosides. They are
considered be the phytochemicals having the most diverse chemical
structures.57
Terpenoids are the largest and most diverse family of natural products,
ranging in structure from linear to polycyclic molecules and in size
from the five carbon hemiterpenes to natural rubber, comprising
thousands of isoprene units (Table 2). The monoterpenes and sesquiterpenes are common in essential oils produced by plants.58
Medicinal properties
Crude
extracts or secondary metabolites from medicinal plants can act as
antioxidant agents generally through their ability to scavenge ROS or as
a regulator of ovarian hormonal production. These properties can be
responsible for their medicinal functions.
Gouveia et al.61 identified and quantified five substances from Amburana cearensis,
namely: protocatechuic acid (PCA), epicatechin, p-coumaric acid, gallic
acid and kaempferol, which were identified by high performance liquid
chromatography (HPLC) from the crude ethanolic extract of A. Cearensis. Gallic acid is a well known antioxidant compound, was the main compound found in A. cearensis. 62 Gallic acid prevents in vivo and in vitro
DNA oxidative increasing the activities of antioxidant enzymes
(superoxide dismutase, GPx and glutathion-S-transferase-π) and
decreasing the intracellular ROS concentrations. 63 Another compound found in the A. cearensis extract was the PCA, commonly found in several vegetables and fruits. 64 PCA acts in vitro
by increasing the activities of antioxidant enzymes such as superoxide
dismutase, scavenging ROS or inhibiting their formation, and
consequently reducing oxidative stress damage. 64; 65 ; 66 One of the prominent and most useful properties of the flavonoids is their ability to scavenge ROS.67 They are considered more efficient antioxidants than vitamins C and E.68
Coumarins, another group of phenolic compound (1,2-benzopyrone) are
natural antioxidant compounds widely distributed in plants. 69 ; 70
Studies have reported that coumarins inhibit lipid peroxidation,
decreasing the injury caused by oxidative stress and decreasing the
levels of ROS in different types of cells. 71 ; 72 Likewise, anethole a constituent of essential oil (terpenoids) from Croton-zehntneri,
a medicinal plant popularly known as “canela de cunhã” or “canelinha”
in the Northeast of Brazil, decreased the levels of ROS both in vivo 73 ; 74 using mice model, and in vitro during culture of cell lines isolated from the peripheral blood of male patient with acute myeloblastic leukemia. 75 Sá et al.76 showed that addition of anethole (300 and 2000 μg/mL) to the in vitro
culture medium was able to improve the development of goat preantral
follicles by reducing concentrations of ROS and increasing the
percentage of oocytes able to resume meiosis. In addition to their
antioxidant activity, compounds from plant can have an important role
during the steroidogenesis.
Many
compounds (flavonoids, lignans, coumestans) derived from plants have
ability to mimic the biologic effects of endogenous hormones by binding
to their nuclear receptor or regulating the activities of key enzymes of
their metabolisms such as cytochrome P450 aromatase, and
17β-hydroxysteroid dehydrogenase which is a key enzyme of the
steroidogenesis.13
The estrogenic effects of some compounds are often related to the
stimulation of the hypothalamus–pituitary complex increasing the
follicle stimulating hormone (FSH), which will thereafter induce ovarian
steroidogenesis. Flavanoids with estrogenic potential have been
reported to inhibit aromatase activity in various tissues.77
The
best-described property of almost plants is their capacity to act as
antioxidants. For instance, flavones and catechins seem to be the most
powerful flavonoids for protecting the body against ROS. Follicular
cells are continuously threatened by the damage caused by free radicals
and ROS, which are produced during normal oxygen metabolism or are
induced by exogenous damage.78
The mechanisms and the sequence of events by which free radicals
interfere with cellular functions are not fully understood, but one of
the most important events seems to be the lipid peroxidation, which
results in cellular membrane damage. This cellular damage causes a shift
in the net charge of the cell, changing the osmotic pressure, leading
to swelling and eventually cell death.79 The ROS produced during the metabolism are made inactive according the following equation, where R• is a free radical and O• is an oxygen free radical.
Flavonoid (OH) + R• → flavonoid (O•) + RH
Nowadays,
medicinal plants are widely used around the world as an alternative to
pharmaceutical drugs. Although herbal products are considered to have
fewer adverse effects compared with synthetic drugs, they are not
completely free of indesejable effects. The volatile terpenoids camphor,
a compound of the essential oil of Artemisia kopetdaghensis crosses the placenta and may lead to abortion. 80 In another study, Linjawi81
reported that camphor induces significant structural changes on uterus
of pregnant rats. Therefore, it is rational to assume that camphor is
involved in the abortifacient effect of A. kopetdaghensis. Results from Oliaee et al. 82 using female rats as animal model showed that continuous consumption of 800 μg/mL of A. kopetdaghensis
in pregnancy may increase the risk of abortion and also may have toxic
effect on some cells of body. Therefore, its continuous use is not
recommended in pregnancy.
Implication of plant extracts or compounds in ovarian cells cultured in vitro
With
the aim to elucidate their properties, plant extracts or its secondary
metabolites have been used in the culture of various types of cells
including follicles and granulosa cells. Hsia et al.83 demonstrated that the partitioned fractions of Coix lachryma-jobi (Adlay), a traditional Chinese medicine used for the dysfunction of endocrine system extracts possess hypogonadal effect in vitro
conditions. This plant shows a great capacity to reduce the production
of progesterone (P4) and estradiol (E2) by decreasing the activity of
cholesterol side-chain cleavage enzyme (P450scc) and
3beta-Hydroxysteroid dehydrogenase (3β-HSD). In contrary, the use of
leaves mixture of Aloe buettneri, Justicia insularis, Dicliptera verticillata and Hibiscus macranthus (ADHJ) in vitro
attest the direct effects of some chemical components on rat ovarian
steroidogenesis. Indeed, alkaloids, coumarins glycosides, flavonoids and
quinones from ADHJ are more effective when the plant extract (130 g/ml)
is combined to 0.1 IU/mL of human chorionic gonadotropin (hCG) during
2 h of incubation. In these conditions, estradiol production increased
by 13-fold compared to the medium without hCG and the plant extract; and
by 5-fold compared to the medium containing only the plant extract
(130 g/ml) or hCG (0.1 IU/mL).6
Studies with quercetin, a flavonoid present in several plants, as well as nonsteroidal compounds known as phytoestrogens84
affects porcine granulosa cell function by interfering with
steroidogenic activity and redox status as well as by inhibiting
vascular endothelial growth factor output.85 This phytoestrogen represents a potential modulator of ovarian functions through inhibition of steroidogenic enzymes.77 ; 86
Suppressive
action of phytoestrogen on cytochrome P450 (enzyme that catalyzed the
conversion of cholesterol to pregnenolone) represents a rate-limiting
step in the steroidogenic pathway. Several studies87 ; 88
showed that phytoestrogen induced decrease of P4 production in
granulosa cells. This decrease is due to the inhibition of
3β-hydroxysteroid enzyme. Furthermore, Santini et al.89
revealed the inhibitory effect of quercetin on aromatase activity. It
has been suggested that the action of phytoestrogen on aromatase
activity could be mediated by nitric oxide (NO). In fact, this free
radical seems to represent an autocrine regulator of granulosa cells E2
production.90
However, molecular studies should be done to better understand the
mechanism of action of phytoestrogen on steroidogenic enzymes.
Implication of plants extract or compounds on oocyte maturation
During in vitro oocyte culture, the levels of antioxidants are lower than in vivo because the oocytes are divorced from the donor body and do not benefit from the maternal antioxidant protection. 90 The addition of an antioxidant to the medium, therefore, may be important for in vitro oocyte maturation.
Reports from Rajabi-Toustani et al.91 shows that supplementation of appropriate concentrations of Papaver rhoeas
extract (50 μg/mL) in maturation medium (bicarbonate-buffered TCM 199
supplemented with 10% FBS, 0.2 mM sodium pyruvate 0.1 IU/mL hMG,
100 IU/mL penicillin and 100 μg/mL streptomycin) improve the sheep
oocyte maturation rate. Similar results have been obtained when
maturation medium of mouse oocyte was supplemented with 5 μg/mL of Crocus sativus 92 or when supplemented with 20 μg/mL of Phoenix dactylifera pollen grain. 93 Improvement maturation rate of oocytes treated with P. rhoeas extract may be partly due to increase of intracellular glutathione (GSH) levels in oocytes 91 or super oxide dismutase (SOD) activity.94
Anthocyanins protect cells against free radicals by
gamma-glutamylcysteine synthetase (γ-GCS) activation, while of γ-GCS
elevates GSH levels in medium.95 Increased GSH levels through oocyte maturation are associated with improvement in subsequent embryo development.96 On the other hand, the reduction on in vitro maturated oocytes to metaphase II stage might be due to deleterious effects of excessive concentrations (200 μg/ml of P. rhoeas extract), because some flavonoids displayed toxic effects 91 ; 97 by changing the cell membrane structure and consequently damage cell polarization.98 Locklear et al.99 demonstrated that extract of Justicia pectoralis acts as an E2 and P4 agonists on the cellular membrane and inhibits the activity of the cyclooxygenase 2 (COX-2) enzyme in vitro.
The COX-2, is the rate-limiting enzyme in the biosynthesis of
prostaglandins (PGs) which are considered to participate in follicular
rupture during ovulation. 100J. pectoralis
is a medicinal plant commonly used by women in Costa Rica to treat
symptoms associated with premenstrual syndrome (common forms of hormonal
imbalance affecting women) and menopause. Table 3 shows some in vitro implications of medicinal plants from different species on folliculogenesis and steroidogenesis process.
- Table 3. In vitro implication of some medicinal plants on folliculogenesis and steroidogenesis in different species.
Plants Chemicals compounds Used parts Effects Species References Amburana cearensis Protocatechuic acid, epicatechin, p-coumaric acid gallic acid, kaempferolin Leaves Maintained follicular survival and promoted the development of isolated secondary follicles. Ovine Barberino et al.,11 2015 Moringa oleifera β-Carotene, protein, vitamin C, calcium, potassium Leaves Improved the oocyte maturation rate Ovine Ibrahim et al.,101 2015 Croton zehntneri Anethole Leaves Improved the development and oocyte maturation rate of isolated secondary preantral follicles. Caprine Sá et al.,76 2015 DPP Flavonoids, phenolic acid, diterpenes Grain Improved the oocyte maturation rate Mice Abdollahi et al.,93 2015 Yucca shidigera Sarsapogenin, milagenin, markogenin, samogenin, gitogenin, neogitogenin Bark Reduced ovarian cell proliferation, promoted ovarian cell apoptosis, stimulated P4 and inhibited testosterone release. Swine Štochmaľová et al.,102 2014 Gundelia tournefortii Phenolic compounds Leaves Improved oocyte maturation rate Murine Abedi et al.,103 2014 Crocus sativus Crocin, crocetin, dimethyl crocetin, safranal, flavonoids. Stigmas Improved the IVM, IVF, and early embryo development Murine Maleki et al.,104 2012 Coix lachryma-jobi Coixenolides, coixans A, B, and C Seed Decreased P4 and E2 levels. Murine Hsia et al.,83 2007 ADHJ Alkaloids, flavonoids, glycosides, coumarins and quinones Leaves mixture Induced E2 synthesis Murine Telefo et al.,6 2004 - IVM, in vitro maturation; IVF, in vitro fertilization; ADHJ, mixture of Aloe buettneri, Dicliptera verticillata, Hibiscus macranthus and Justicia insularis; DPP, Phoenix dactylifera pollen grain.
Final considerations
Female
reproductive problems continue to be a major health challenge
worldwide. An impressive number of plant species is traditionally used
to remedy such disorder. Those plants mainly constituted of secondary
metabolites have been used over decades for the treatment of diseases
which affect woman reproduction leading to infertility. These substances
widely distributed over the world are constituted of compounds whose
concentrations and compositions vary among plants and between the same
genus. Several factors affect the plants composition among which the
season, site and time of harvest. With the development of technology, an
interest of plant is reported due to their antioxidant capacity and
their ability to mimic the effect of steroidogenic enzymes. But little
remain unknown about their implication in vitro which represents alternative studies of the in vivo
studies. Finally, further studies should be performed to better
understand the mechanism of action of plant and/or secondary
metabolites. The discovery may also help to reduce the cost and improve
the results of treatments normally applied.
Conflicts of interest
The authors declare no conflicts of interest.
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