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    Topic review

    Plant Extract and Infertility

    Subjects: Others
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    Submitted by: Bonglee Kim

    Definition

    Infertility is a couple’s inability to conceive after one year of unprotected regular intercourse.

    1. Infertility

    Female infertility can be caused by failures at various steps, including ovulation, fertilization, embryo development, embryo transport, and implantation [1]. The different responses of environment toxicity include reduced fertility, spontaneous abortions, low birth weight, impaired folliculogenesis, and even damage to the ovaries [2]. OS induces infertility in woman through a variety of mechanisms [3], having a direct effect on the oocyte, embryo, and implantation by causing cell membrane lipid peroxidation, cellular protein oxidation, and DNA damage [4]. Excess ROS in the follicle may overwhelm follicular fluid antioxidant defense and hinder the endometrium which normally functions to support the embryo and its development [3]. Appropriate development of embryo and receptive endometrium are crucial factors for successful implantation [5]. Endometrial receptivity is critical for blastocyst adhesion and invasion during the complex process of implantation. Leukemia inhibitory factor (LIF) in particular is one of the major factors that regulates endometrial receptivity. Defects of LIF expression is involved in multiple implantation failures in patients with female infertility. OS is also associated with conditions such as endometriosis, hydrosalpinges, polycystic ovary syndrome (PCOS), and unexplained subfertility [4]. In addition, there is a lack of specific genetic markers because of the absence of an inherited syndrome that could implicate a gene in the pathogenesis of female infertility [6]. Mutations in the human LH P-subunit gene recently have been reported and linked with infertility. Endometriosis is noted in up to 30–40% of infertile women. Luteinizing hormone (LH) and its receptors have been linked with endometriosis-associated infertility. Reproduction is tightly controlled by hypothalamic–pituitary–gonadal axis [7]. Reproduction systems respond to hormonal signals from the pituitary gland which, in turn, is controlled by hormones produced in the hypothalamus [8]. Interruption of these processes, in any of the functional events in either sex, leads to fertility impairment [7] including gonadal dysgenesis, amenorrhea, premature ovarian failure [8]. Mammalian reproductive physiology is primarily regulated by the gonadotrophins luteinizing hormone (LH) and follicle stimulating hormone (FSH) secreted from the anterior pituitary which act on the gonads to produce sex steroids [9]. These pituitary hormones in turn enhance the proliferation of the follicular cells and the production of estrogens (principally estradiol) by ovarian cholesterol catabolism [10]. Additionally, they can lead to and restore spermatogenesis [11]. The initiation and maintenance of mammalian infertility are connected with G-protein coupled receptor 54 (GPR54) [12]. The mutation in GPR 54 is characterized by the absence of sexual maturation and low levels of gonadotropin releasing hormones (GnRH). Abnormal GnRH secretion induces anovulation, luteal insufficiency, and premature oocyte maturation, leading to menstrual disorders, polycystic ovary syndrome (PCOS), recurrent miscarriage, and infertility [6]. Additionally, it could affect the testicular function with decrease in T release [13]. Estrogen affects granulosa cells by promotion of proliferation, suppression of apoptosis, and augmentation of FSH effects. Homeostatic maintenance of prolactine (PRL) is essential since this hormone performs multiple physiological functions [14]. Increased PRL levels can cause infertility and bone loss in both women and men. It has been reported that E2 increases serum and pituitary PRL in ovariectomized rats. In addition, precursor of E2 and P4, pregnelone sulfate also increases prolactin production in the rat pituitary. On the other hand, compounds derived from natural food and herbal medicine showing promising antioxidant and antiapoptotic potentials have been considered an alternative therapy for disease [15].

    The antioxidant system plays an importance role in protecting reproductive and other biological tissues below a critical threshold of ROS, preventing negative effects on reproduction [16]. Herbal medicines possessing antioxidants reduced ROS levels, protecting germ cells from OS-mediated apoptosis [17]. They could be used as complementary, alternative medicines to promote pregnancy [18].

    2. Plant Extract and Infertility

    Several herbal extracts and plant-derived pure molecules have shown their protective effects in various types of diseases [19], including those that affect the reproductive system [20]. Recent studies have shown that the administration of plant extracts improve semen parameters, androgen status, fertility index, and have positive influence on sperm quality in male [21][22]. In female, herbal medicine affects the molecular mechanism and prevents estrogen-dependent endometrial hyperplasia improving ovarian dysfunction, ovarian follicle [23], and increased endometrial receptivity [1][5]. Additionally, herbal therapy that has actions on the hypothalamic–pituitary–gonadal axis may influence reproductive physiology and ameliorates some infertility problems [7]. The gonadotrophic-like effects of the extracts were characterized by the following biological parameters: increase in the weight of the ovary and uterus; induction of ovulation; increase in estradiol, progesterone, protein levels; decrease in cholesterol level, and so forth [10]. The antimutagenic or protective effects have been attributed to many classes of phytocompounds mainly flavonoids and phenolic compounds [24]. The natural antioxidants with free radical scavenging ability have received much attention as potential remedies to treat oxidative stress and abnormal hormone functions [8][25]. Antioxidants can directly scavenge ROS, inactivate them, and repair the damage [4]. Additionally, they showed diverse biological activities resulting from their ability to mimic endogenous estrogen actions, inhibit hormone actions, and modulate hormone productions [8]. The antioxidant capacity of phenolic compounds, flavonoids, and foods rich in these compounds, has been repeatedly demonstrated in various in vitro and in vivo systems. In this present study, we aimed to investigate the effects and mechanisms of various plants extracts and natural products on the reproductive system. A large number of plants have been used to treat infertility for thousands years worldwide, including Korea [26][27]. Additionally, numerous natural products, including plant extracts were discovered to possess potential effects in reversing reproductive activity in both males and females. Natural products originated from plants, animals, and fungi, and their forms varied from compounds, extracts, as well as multiple formulas. Studies have discovered structural and functional improvements in the reproductive system while identifying the specific mechanisms of effects. However, adverse effects were also observed to be related with the utilization of some natural products.

    2.1. Natural Products That Reverse Male Infertility

    2.1.1. Plant Derived Natural Products for Treatment of Male Infertility

    In Vitro Studies

    Several studies reported the efficacy of plant derived natural products through in vitro examination (Table 1).

    Table 1. Plant derived natural products and male infertility (in vitro studies).

    Classification Compound/Extract System Source Cell Line/Animal Model Dose; Duration Efficacy Mechanism Reference
    Plant Date palm pollen extract In vitro Phoenix dactylifera Linn. Sertoli cells, spermatogonial stem cells from mice 0.06, 0.25, 0.62 mg/mL; 14 days Increase of proliferation of spermatogonia   [28]
    Plant 5H-purin-6-amine, Sedum sarmentosum extract In vitro Sedum sarmentosum Spermatogonial stem cells C57BL. 6-TG-EGFP 0.01, 0.1, 1, 10 mg/mL; 1 week Increase of self-renewal in SSCs ↑ PLZF, GFRα1, VASA, Lhx1
    ↓ Pgk2
    [29]
    Plant Licorice extract In vitro Glycyrrhiza uralensis Fisch. Testis tissue from C57BL/6N mice 0.2, 2, 20 μmol/L; 72 h Increase of proliferation of spermatogonia ↑ PCNA, SCP3, Spo11 [30]
    Plant Lycium barbarum polysaccharide In vitro Lycium barbarum Linn. Leydig MLTC-1 50 μg/mL; 48 h Increase of cell viability ↑ Testosterone,
    ↓ p-PERK/PERK, p-elF2α/elF2α, ATF4/β-actin,
    apoptosis rate, LC3II/I, Atg5/β-actin
    [31]
    Plant Morindae radix aqueous extract In vitro Morinda officinalis TM3 cells, mouse Leydig cells 10, 50, 100, 250 mg/mL; 24 h Increase of testosterone production.
    Decrease of H2O2 induced cytotoxicity, and lipid peroxidation
    ↑ SOD, CAT
    ↓ MDA
    [32]
    Plant Taraxacum officinale aqueous extract In vitro Taraxacum officinale TM3, ATCCNoCRL 1, 10, 25, 50 mg/mL; 12, 48 h Increase of the levels of steroidogenic enzymes ↑ STAR, CYP11A1, CYP17A1 [33]
    Plant Typha capensis rhizome extract F1 fraction In vitro Typha capensis (Rohrb.N.E.Br. TM3-Leydig cells 10, 100 μg/mL; 96 h   ↑ Testosterone [34]

    PCNA, proliferating cell nuclear antigen; PERK, protein kinase-like endoplasmic reticulum kinase; p-PERK, phospho-PERK; elF2α, eukaryotic initiation factor 2; p-elF2α, phospho-elF2α; ATF4, activating transcription factor 4; SCP3, synaptonemal complex protein 3; SOD, superoxide dismutase; CAT, catalase; MDA, malondialdehyde; StAR, steroidogenic acute regulatory protein; CYP17A1, cytochrome P450 17A1; CYP11A1, cytochrome P450 11A1.

    In Vitro and in Vivo Studies

    Seveal studies were conducted both in vitro and in vivo to prove the effectiveness of natural substances of plant origin (Table 2). 

    Table 2. Plant derived natural products and male infertility (in vitro and in vivo studies).

    Classification Compound/Extract System Source Cell Line/Animal Model Dose; Duration Efficacy Mechanism Reference
    Plant Echinacea purpurea ethanol extract (encapsulated chitosan/silica nanoparticle) In vitro and in vivo studies Echinacea purpurea Linn. (1) LC540
    (2) SD rats
    (1) 25 µg/mL; 24 h
    (2) 279, 465 mg/kg; 7 weeks
    (2) Increase of seminiferous tubules diameter, germinal cell layer thickness, area of seminiferous tubules, area of seminiferous lumen, sperm motility, sperm DNA integrity
    Decrease of sperm abnormality
    (1) ↓ NO
    (2) ↓ TNF-α, IL-1β
    [35]
    Plant Echinacoside In vitro and in vivo studies Cistanche tubulosa (Schrenk) Hook. f. II. (1) LC-540, TM3
    (2) SD rats
    (1) 5, 10 μM
    (2) 160, 320 mg/kg; 6 weeks
    (1) Increase of cell viability
    (2) Increase of sperm number, sperm motility, seminiferous tubule thickness
    Decrease of sperm abnormality
    (1) LC-540, TM3: ↓ Superoxide anion,
    LC-540: ↑ StAR, CYP11A1, CYP17A1, HSD17β3
    ↓ RAGE, NF-κB, H2O2
    (2) ↑ LH, KISS1, SIRT1, GPR54, SOCS -3, SOD, CAT
    ↓ NO, TNF-α, IL-6, superoxide, MDA
    [12]

    NO, nitric oxide; TNF-α, tumor necrosis factor α; IL-1β, interleukin 1 beta; CYP17A1, Cytochrome P450 17A1; CYP11A1, cytochrome P450 11A1; HSD17β3, hydroxysteroid dehydrogenase 17β3; RAGE, receptor for advanced glycation end products; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; H2O2, hydrogen peroxide; LH, luteinizing hormone; Kiss1, kisspeptin 1; SIRT1, sirtuin 1; GPR 54, G protein-coupled receptor; SOCS-3, suppressor of cytokine signaling 3; SOD, superoxide dismutase; CAT, catalase; IL-6, interleukin 6.

    2.1.2. Animal Derived Natural Products for Treatment of Male Infertility

    Natural products from animal origin were also mentioned to have profertility effects upon males in various studies (Table 3).

    Table 3. Animal derived natural products and male infertility.

    Classification Compound/Extract Source Cell Line/Animal Model Dose; Duration Efficacy Mechanism Reference
    Insect Drone milk Apis mellifera SD rats 110 mg/kg; 5, 10 days Increase of weight of androgen-sensitive organs (glans penis, seminal vesicle, muscles) ↑ Testosterone, SLAP [36]
    Animal Gelam Honey Apis mellifera SD rats 1.0 mL/100 g; 60 days Increase of fertility ↑ Fructose [11]
    Insect Hydroethanolic extract of Indian propolis Apismellifera Swiss albino mice 400 mg/kg; 4 weeks Increase of testis weight, sperm count, total motility, spermatozoa with normal head morphology, spermatozoa with normal DNA, number of tubules with complete spermatogenesis, diameter of seminiferous tubule, number of germ cells
    Decrease of sperm DNA damage, chromatin immaturity, apoptosis in spermatogonial germ cell
    ↑ Testosterone, GSH, CAT
    ↓ MDA, RAD51
    [37]
    Animal Spermaurin Scorpion Scorpio maurus palmatus (1) Bovine sperm
    (2) Monkey sperm
    (3) Mouse oocytes
    (1) dilution 1/20; 10 min (2) dilution 1/40; 10 min
    (3) dilution 1/40; 4 h
    Improvement of sperm motility   [38]

    SD, Sprague Dawley; SLAP, spot14-like androgen-inducible protein; TBRAS, thiobarbituric acid-reactive substances; LDH, lactic dehydrogenase; GSH, glutathione; CAT, catalase; MDA, malondialdehyde.

    2.1.3. Fungus Derived Natural Products for Treatment of Male Infertility

    One study was found to elucidate the efficacy in male fertility of fungus derived natural product (Table 4). 

    Table 4. Fungus derived natural product and male infertility.

    Classification Compound/Extract Source Cell Line/Animal Model Dose; Duration Efficacy Mechanism Reference
    Fungi Antrodia cinnamomea ethanol extract Antrodia cinnamomea
    Chang.
    SD rats 385, 770, 1540 mg/kg; 5 weeks Increase of total sperm count, motility rate
    Decrease of abnormal sperm count, DNA damage in sperm
    ↑ LH, testosterone, StAR, CYP11A1, 17β-HSD, SOD
    ↓ RAGE, GRP-78, H2O2, NO, MDA
    [39]

    SD, Sprague Dawley; LH, luteinizing hormone; StAR, steroidogenic acute regulatory; CYP11A1, cytochrome P450 11A1; 17β-HSD, 17β-hydroxysteroid dehydrogenase; SOD, superoxide dismutase; RAGE, receptor for advanced glycation end products; GRP-78, glucose-regulated protein-78; H2O2, hydrogen peroxide; NO, nitric oxide; MDA, malondialdehyde.

    2.2. Natural Products That Reverse Female Infertility

    2.2.1. Animal Derived Natural Products for Treatment of Female Infertility

    A single study mentioned a natural product from an animal that showed the capacity to recover infertility problems in females (Table 5). Royal jelly is a dietary substance originated from Apis mellifera [40]. Elham Ghanbari et al. demonstrated that administration of royal jelly to Wistar rats (100, 200, 400 mg/kg for 14 days) resulted in the folliculogenesis by a significant increase of uterine and ovarian weights, the serum levels of progesterone, estradiol, FRAP, and a decrease in NO level.

    The entry is from 10.3390/antiox9100957

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