Research Progress in Molecular Mechanism Of Traditional Chinese Medicine in The Treatment Of Oligozoospermia And Asthenospermia
Mar 08, 2023
At present, the incidence of male infertility is on the rise. About 15% of couples of childbearing age are unable to have children, while the proportion of infertility caused by male factors is about 50% [1]. The factors that cause male infertility are very complex, and oligozoospermia is an important reason for male infertility. At present, the drugs for oligo asthenospermia mainly include the anti-estrogen drug clomiphene, L-carnitine levocarnitine, antioxidant vitamin E, etc. They are commonly used in combination with clinical practice, and the effective rate is not high. In recent years, traditional Chinese medicine has achieved good clinical effects by starting with the treatment methods of tonifying the kidney and essence, strengthening the spleen and soothing the liver, activating blood circulation and unblocking collaterals, and the basic research on its effective components and mechanism of action is also increasing. In this paper, the research progress of the molecular mechanism of the treatment of oligozoospermia and asthenospermia with traditional Chinese medicine in recent years is summarized as follows.
Chinese herb cistanche
1、 Chinese herbal medicine
（1） Morinda officinalis
Morinda officinalis has the effects of invigorating the kidney, consolidating the essence, and calming the nerves. Its extract can not only improve the number and survival rate of sperm but also reduce sperm deformity
It can also repair the damage to testicular microstructure and ultrastructure. Environmental pollution, genital tract infection, varicocele, and other factors can cause excessive reactive oxygen species (ROS) in semen. Excessive ROS can cause oxidative stress, which will not only damage the structure and function of the sperm membrane but also further damage sperm DNA, leading to sperm quality decline. The extract of Morinda officinalis can increase the content of superoxide dismutase (SOD) in testicular tissue, eliminate free radicals through SOD, inhibit lipid peroxidation of the cell membrane, and protect sperm from oxidative damage [2]. The extract of Morinda officinalis can act on the Sertoli cells of testis of rats with cyclophosphamide-induced spermatogenesis disorder, and increase the expression of FSHR mRNA and androgen binding protein (ABP) mRNA in Sertoli cells. The mechanism may be to increase the combination of follicle-stimulating hormone (FSH) and FSHR through cAMP-PKA, Ca+and other pathways, It can promote protein phosphorylation and increase the expression of protein product ABP. The specific combination of ABP and testosterone can maintain the level of testosterone in the seminiferous tubules and provide a suitable environment for spermatogenesis and maturation [3]. Morinda officinalis can also directly act on the pituitary, increase the quality of the pituitary, promote its synthesis and secretion of FSH, and then promote spermatogenesis; However, some studies found that there was no statistically significant difference in FSH levels among the treatment groups. It may be that Morinda officinalis does not directly act on the pituitary gland, but acts on the hypothalamus-pituitary-testis axis by affecting hormone levels and feedback mechanism [4]. In addition, Morinda officinalis contains zinc and other trace elements that play an important role in the process of spermatogenesis, maturation, and capacitation, which may be related to improving sperm quality.
（2） Cistanche deserticola
"Desert ginseng"Cistanche deserticola ma is a commonly used prescription for the treatment of male reproductive dysfunction. Its active ingredients mainly include phenylethanoid, polysaccharides, flavonoids, and other substances. Cistanche deserticola can protect the testicular tissue of mice, improve the microenvironment of the epididymis, standardize the morphology of the seminiferous tubules, increase the number of testicular interstitial cells, increase the level of testosterone, and enhance the spermatogenic function of the testis. Its mechanism may be that Cistanche deserticola can up-regulate the key enzyme of energy metabolism during spermatogenesis - lactate dehydrogenase (LDH), and StAR, CYP11A1, CYP17A1, CYP3A4 β- HSD and 17 β- HSD and other steroid-producing enzymes are expressed, thereby increasing the level of testosterone [5,6]. Cistanche phenylethanoid can improve the SOD activity of rat sperm suspension in vitro, reduce the content of malonaldehyde (MDA), and have an antagonistic effect on the oxidative stress damage of sperm membrane caused by ROS, and the antioxidant activity of Cistanche phenylethanoid in medium and high dose groups (0.25, 0.5g/mL) is significantly better than that of vitamin C [7].
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（3） Cynomorium songaricum
Cynomorium has the effect of tonifying kidney yang, benefiting blood essence, moistening intestines, and relieving constipation. Cynomorium solarium can significantly increase the sperm quantity and vitality of oligozoospermia and asthenospermia model rats and increase the testicular quality. Its carbohydrates, flavonoids, and polyphenols have good scavenging effects on oxygen free radicals and can prevent the decline of sperm number and vitality caused by oxidative stress caused by excessive ROS. Cynomorium solarium contains zinc, manganese, and other trace elements, which have positive effects on sperm morphology and vitality. Cynomorium solarium can induce the expression of glial cell line-derived neurotrophic factor (GDNF), GDNF, and GFR on the surface of spermatogonial stem cells in rat testis Sertoli cells α After specific binding, Ret protein tyrosine kinase is activated, and then PI3K/Akt, Src, Ras/ERK1/2, and other signal pathways are activated, resulting in the up-regulation of corresponding transduction factors downstream of the pathway, promoting the proliferation of spermatogonial stem cells, and then promoting the spermatogenesis process; GDNF can also promote the division and maturation of Sertoli cells in an autocrine manner, and participate in the development of testis; In addition, GDNF can act on capillary endothelial cells in the form of paracrine, promote their proliferation and form tight connections, and participate in the formation of blood-testis barrier [8].
（4） Astragalus membranaceus
The effective components of astragalus include total astragalus ketone (TFA), total astragalus polysaccharide (TPA), total astragalus saponins (TSA), etc. Astragalus membranaceous as an additive in vitro has been widely used in assisted reproductive technology, such as intrauterine artificial insemination (IUI), in vitro fertilization (IVF), and sperm cryopreservation
It has application value. After adding astragalus injection, human sperm motility, linear velocity (VSL), curve velocity (VCL), and average path velocity (VAP) are significantly increased, which may be related to the antioxidant activity of astragalus and its ability to increase the concentration of Ca+in sperm and enhance sperm mitochondrial activity [9]. CAMP-responsive element regulator (CREM) and test-specific CREM activator (ACT) play an important role in cell differentiation after sperm meiosis. Astragalus can also promote sperm development by increasing the expression of CREM and ACT proteins in rat testis [10]. In addition, TPA can inhibit platelet aggregation, promote fibrinolytic activity, expand blood vessels, improve the activity of antioxidant enzymes, reduce the content of lipid peroxide, reduce oxidative damage caused by free radicals, and improve sperm quality.
Superman herbs cistanche
（5） Epimedium
Epimedium can enhance sperm vitality, increase sperm quantity and stimulate penis erection. Icariin is the total flavonoid extracted from the stems and leaves of Epimedium and is the main bioactive component of Epimedium. Maintaining a high concentration of testosterone in the seminiferous tubules of the testis plays an important role in promoting spermatogenesis. Icariin has a sex hormone-like effect and can directly stimulate the gonads to increase the secretion of testosterone. In addition, icariin can also regulate the level of testosterone by regulating the expression of peripheral benzodiazepine receptor (PBR) and steroidogenic acute regulatory protein (StAR), which play an important role in testosterone synthesis and acting on the hypothalamus-pituitary-gonad axis [11]. Icariin can improve the SOD activity of rat sperm suspension, reduce the content of MDA, help reduce the oxidative damage of sperm DNA, and protect the normal morphology and function of sperm [12]. Some studies have shown that in the model rats with testicular damage caused by adenine, the antioxidant effect of total flavones of Epimedium is better than that of methyltestosterone, but the improvement of serum testosterone value is weaker than that of the former; Compared with vitamin E, its improvement of serum testosterone value is better than that of vitamin E, while its antioxidant effect is weaker than that of vitamin E [13]. In addition, icariin can also promote the proliferation of Sertoli cells by activating the ERK1/2 signal pathway [14], and Sertoli cells have important functions such as providing support for spermatogenic cells, participating in the formation of the blood-testis barrier, secreting a variety of substances necessary for sperm differentiation and maturation, which may be one of the mechanisms of icariin improving reproductive function, but whether it can promote the proliferation of Sertoli cells in vivo remains to be further studied.
（6） Wolfberry fruit
Lycium barbarum polysaccharide (LBP) is the main active component of Lycium barbarum fruit, and LBP is mainly composed of xylose
It is composed of galactose, arabinose, glucose, rhamnose, and mannitol. LBP can maintain the balance between T, TSH, and LH and maintain the normal spermatogenic environment by regulating the pituitary-gonadal axis. LBP has antioxidant activity, which can increase the SOD activity of sperm suspension of mice with oligozoospermia and asthenospermia induced by radiation, reduce the content of MDA, reduce the oxidative damage of testicular tissue, promote the development and recovery of reproductive glands, and increase the number and vitality of sperm [15]. Sperm reduction is related to spermatogenic cell apoptosis. The main genes regulating spermatogenic cell apoptosis are Fas/Fasl gene, Bcl-2/Bax gene family, P53 gene, HSP gene, etc. The study found that LBP can reduce the expression of caspase-3 by up-regulating the protein expression of anti-apoptotic genes Bcl-2, Bcl-w, and Hsp70, down-regulating the protein expression of proapoptotic genes Bax, Fas, and P53, and inhibiting the release of cytochrome C (cytC) from mitochondria, thereby reducing the apoptosis of spermatogenic cells [16, 17]. In addition, some studies found that in the cyclophosphamide-induced oligospermia mouse model, the proportion of primary spermatocytes (4C cells) in the testes of the treatment group with different doses of Lycium barbarum decoction increased to a certain extent compared with the control group, so it is speculated that the mechanism of Lycium barbarum in treating oligospermia is related to its ability to promote the division and differentiation of spermatogonia, and thus promote the proliferation of 4C cells [18].
Dragon herbs cistanche
（7） Dodder seed
The semen auscultate mainly contains flavonoids, glycosides, trace elements, etc., of which the flavonoids of semen cuscutae are its main pharmacological component, which can promote the development of the reproductive system, and improve sperm vitality and survival rate. Cuscuta chinensis flavonoids are also widely used in gynecological endocrine diseases, which shows that Cuscuta chinensis is not a substitute for some hormones, but can act on the hypothalamus-pituitary-gonadal axis, with a gonadotropin-like effect. Cuscuta chinensis extract has good antioxidant activity, and the antioxidant activity of 0.25g/mL crude drug Cuscuta chinensis extract is significantly better than vitamin C, which can improve the SOD activity of sperm suspension, reduce MDA content, improve sperm antioxidant capacity, and protect the structure and function of sperm membrane [19]. Cuscuta flavonoids can repair the S phase of spermatogenic cells, interfere with the division cycle of spermatogenic cells, protect the proliferation ability of spermatogenic cells, and reduce the apoptosis of spermatogenic cells by down-regulating the expression of apoptotic genes Fas and Fasl [20]. Cuscuta chinensis extract can increase the expression of cytochrome P450 aromatase (P450arom) and CYP19 in rat testis. P450arom is the rate-limiting enzyme of testicular estrogen synthesis, and CYP19 is the key gene of estrogen synthesis, while the abnormal level of endogenous estrogen can cause damage to the vas deferens, epididymis, and tubules of the testicular reticulum, leading to germ cell apoptosis and differentiation disorder. Therefore, Cuscuta chinensis may affect spermatogenesis by regulating estrogen synthesis [21]. The appropriate concentration of Cuscuta chinensis can significantly improve the sperm activity and motility in vitro of patients with asthenospermia, enhance the activity of the important proteolytic enzyme acrosin in the process of fertilization, facilitate the decomposition of sperm to the cumulus of egg cells and the penetration of the zona pellucida, and facilitate fertilization, which may be one of the mechanisms of its action on asthenospermia, and also indicate that Cuscuta chinensis may have application value in the in vitro fertilization technology [22].
（8） Schisandra chinensis
Schisandra chinensis is a commonly used Chinese medicine for the treatment of male reproductive dysfunction. Its main components are polysaccharides, lignans, flavonoids, etc. Schisandra chinensis polysaccharide can increase the number of spermatogenic epithelial layers, clear cell layers, and orderly arrangement of spermatogenic cells in mice with the cyclophosphamide-induced spermatogenic disorder; Compared with the control group, sperm concentration, and sperm survival rate increased, sperm deformity rate decreased, serum FSH and LH levels decreased, and T content in testicular tissue increased. The mechanism may be related to restoring the regulation of the hypothalamus-pituitary-gonad axis and regulating the level of reproductive hormone [23]. In addition, Schisandra polysaccharide and lignans have strong antioxidant effects, can improve the activities of antioxidant enzymes such as SOD, and GSH-PX, and have certain scavenging effects on superoxide anion free radicals, hydroxyl free radicals, and DPPH free radicals, which may be related to the protective function of Schisandra chinensis [24, 25].
Cistanche male benefits
（9） Salvia miltiorrhiza
Salvia miltiorrhiza is a commonly used clinical Chinese medicine, which is currently widely used in the treatment of cardio-cerebrovascular diseases. Salvia miltiorrhiza drugs also have good effects on male reproductive system diseases such as male infertility, epididymitis, and varicocele. Salvia miltiorrhiza water extract can improve sperm concentration, survival rate, and the total activity of oligozoospermic and hypozoospermic mouse models constructed by cyclophosphamide damage, increase the percentage of sperm moving forward (PR), average sperm movement speed (CVP), and linear movement speed index (VSL), and reduce early chromosome aberration and sperm DNA damage of spermatogenic cells, which may be related to its antioxidant activity [26]. In addition, salvia miltiorrhiza has inhibitory effects on Escherichia coli and Staphylococcus aureus. Compound salvia miltiorrhiza injection can significantly increase the sperm number and sperm survival rate of mice infected with Escherichia coli reproductive system, and reduce sperm deformity rate [27].
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