Application progress of traditional Chinese medicine in male infertility

Ai-min Zhang, Bin Yan

Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang 712000, Shaanxi Province,China

Introduction

Although assisted reproductive technology (ART) is of epoch-making significance for men and women with fertility problems to inherit their families, and is increasingly accepted, however, due to the inheritance of Chinese traditional ideas and the particularity of natural fertility, Chinese infertile patients tend to reproduce through natural reproduction with the help of drugs.Traditional treatment methods, such as drug therapy,surgical intervention, intrauterine insemination and intracytoplasmic sperm injection (ICSI), help many families with male reproductive problems to obtain clinical pregnancy. However, these treatments are sometimes ineffective, invasive, expensive, or associated with adverse reactions and high risk[1,2]. Due to the complexity of the etiology of infertility, there is still a lack of effective drug treatment. The use of alternative supplementary drugs including traditional Chinese medicine has aroused people’s attention. At present, Chinese medicine has made great efforts in the clinical study and basic research on the treatment of male infertility. Among them, the clinical application of traditional Chinese medicine includes the Chinese patent medicine which has been listed in China and conforms to the indications. There are also prescriptions sorted out by different doctors under the guidance of TCM theory according to their valuable experience. In this paper, we will review the widely used Chinese patent medicine in accordance with indications and modern doctors’ proven prescriptions in recent years.

Chinese Patent Medicine in Line with Indications

Wuzi Yanzong Pill

In 733 AD, Wuzi Yanzong Pill is firstly recorded in the book named Xuan Jie Lu and spreads throughout Northeast Asia regions for subsequent thousand years. It is formulated to treat infertility, impotence and premature ejaculation caused by kidney deficiency, and has been recognized as “the first prescription for strengthening Yang in ancient and modern times”[3]. Clinical study has found that Wuzi Yanzong Pill can improve semen quality, the effect is better than clomiphene citrate[4]and clomiphene[5], and there is no obvious adverse reaction.In addition, the effect of increasing fructose content and acrosin activity in seminal plasma is significantly better than that of the combination of vitamin C and vitamin E (100 mg each)[6]. It also has a positive effect on decreasing sperm fragmentation index (DFI),increasing sperm acrosin activity and repairing sperm DNA damage[7].Pharmacological studies show that Wuzi Yanzong Pill could improve the function of reproductive gland and accordingly improve semen quality by regulating the gonadal axis, increasing blood testosterone (T), follicle stimulating hormone (FSH)and luteinizing hormone (LH), and reducing estradiol(E2)[8]. Wuzi Yanzong Pill can improve the semen quality of rats by increasing the reduced cAMP content in testis and the up-regulated expression of CatSper1 protein and mRNA in testis tissue of model rats[9]. It can also protect the integrity of sperm outer membrane and mitochondrial outer membrane, inhibit the decline of MMP, and alleviate the damage of mitochondrial microstructure[10]. The prescription can also induce the differentiation of spermatogenic stem cells, and its serum containing medicine can resist the damage of testicular spermatogenesis caused by excessive oxidative stress,improve the quality of sperm, and protect sperm flagellum from oxidative stress damage[11].

Qilin Pill

Qilin Pill is a kind of Chinese patent medicine which is prepared on the basis of Zhudanxi Wuzi Yanzong Pill under the guidance of traditional Chinese medicine theory of “kidney governing reproduction”[12,13]. At present, it is widely used in the clinical treatment of male oligoasthenospermia, and its curative effect has been widely confirmed in clinical practice. Mao Jiaming et al[14]have designed a multicenter, randomized,double-blind, controlled study to verify the safety and effectiveness of Qilin Pill in the treatment of idiopathic oligoasthenospermia. After 12 weeks of treatment, Qilin Pill is more effective than Wuzi Yanzong Pill in improving sperm motility and sperm density (P< 0.01), and the improvement effect becomes more obvious along with the prolonging treatment time. Li Tao et al have found that Qilin Pill combined with Tamoxifen Citrate Tablets could significantly improve semen quality and hormone level of infertile patients, and the combined treatment is better than Tamoxifen Citrate Tablets alone (P< 0.05)[15]. Qilin Pill combined with Compound Ginseng and Vitamin Capsules can reduce sperm DNA fragmentation index(DFI)[16]. In terms of mechanism research, researchers have found that Qilin Pill can treat semen abnormalities in a variety of ways, including reducing the damage of sperm caused by oxidation products, improving the level of reproductive hormone, increasing the levels of acid phosphatase, α-glucosidase and fructose in seminal plasma, and decreasing phosphodiesterase, which can effectively optimize the internal environment of testis and restore sperm motility[17,18]. In addition, Qilin Pill can improve the level of anti-Mullerian hormone (AMH) in seminal plasma of infertile patients, which is related to the improvement of sperm motility[19]. For azoospermia mice, Qilin Pill can promote the paracrine function of sertoli cells in testis, improve the spermatogenic microenvironment and promote sperm production[20].Some scholars have established azoospermia mouse model[21]by using the mechanism of killing mouse stem cells and damaging reproductive function induced by busulfan (35 mg/kg body weight), and intervened with Qilin Pill. Western blot assay results show that, four sertoli cells specific proteins (GATA4, WT1, SCF and BMP4) in the testis of mice are lowly expressed in model group, while highly expressed in low-dose and highdose groups of Qilin Pill. The difference is statistically significant and positively correlates with the dose[22].

Shengjing Capsule

Shengjing Capsule has been confirmed by clinical study in improving sperm density and motility[23], and it is better than Wuzi Yanzong Pill alone[24]or vitamin E[25]. Shengjing Capsule has been widely used in assisted reproductive process. The results show that the fertilization rate, excellent embryo rate and clinical pregnancy rate of male infertility patients after taking Shengjing Capsule are significantly increased (P< 0.05)[26]. Studies have demonstrated that, Shengjing Capsule significantly improves the endocrine disorders in SD rats induced by adenine;Compared with the model group, Shengjing Capsule could significantly increase the contents of serum FSH,LH and T (P< 0.05)[27]. Shengjing Capsule extract can reduce sperm DNA damage, reduce the content of malondialdehyde (MDA) in testis and epididymis, enhance the activity of superoxide dismutase (SOD), protect antioxidant enzyme system, repair pathological damage of testis and epididymis, and promote spermatogenesis[28].

Huangjing Zanyu Capsule

Huangjing Zanyu Capsule has the effect of tonifying kidney and filling essence, strengthening spleen and replenish Qi, nourishing Yin and moistening lung.It is used for the treatment of asthenospermia due to kidney deficiency and essence deficiency. Studies have shown that Huangjing Zanyu Capsule can significantly improve sperm density, total sperm count, motility and activity rate of patients with asthenospermia after regular oral administration of Huangjing Zanyu Capsule for 3 months, and can significantly reduce sperm deformity rate. For patients with weak sperm and abnormal DFI,Huangjing Zanyu Capsule can significantly improve sperm DNA integrity[29]. A network pharmacology study has speculated that, Huangjing Zanyu Capsule may treat oligoasthenospermia by acting on protein targets and pathways related to hormone regulation, cell apoptosis, cell structure, metabolism, inflammation and immunity[30].Huangjing Zanyu Capsule can increase sperm MMP value,improve mitochondrial function, effectively increase sperm motility and PR% and improve sperm morphology, which is safe and effective in the treatment of asthenospermia[31].

Shengjing Tablet

Shengjing Tablet is a kind of commonly used traditional Chinese patent medicine with the function of tonifying kidney and essence, strengthening Yang and nourishing Yin. It contains a variety of effective ingredients including ginseng, pilose antler, Cordyceps sinensis, and Ginkgo biloba leaves. Xu Ji-xiu et al[32]compared the semen analysis data of patients with oligozoospermia and asthenospermia before and after using Shengjing Tablet,and have found that after 3 months of treatment, the sperm motility of oligozoospermia patients is significantly improved, and the plasma testosterone content is also increased. Cheng Guo-long[33]have found that Shengjing Tablet can effectively reduce sperm DFI of infertile patients, and promote the outcome of IVF for L-carnitine,and improve the clinical excellent embryo rate and pregnancy rate.

Experiential Effective Recipe

Wang Quan-sheng et al[34]have seld-made a seed prescription of Dipsacus asperata. The prescription is composed of Dipsacus asperata, Eucommia ulmoides,Achyranthes bidentata, Drynaria fortunei, Cuscuta chinensis and so on. It has the effects of strengthening spleen and tonifying kidney, promoting blood circulation and generating essence, and dredging collaterals. Clinical studies have confirmed that the prescription can significantly improve the sperm quality of oligoasthenospermia patients, the effective rate is as high as 80.3%, and the effect is better than levocarnitine alone. At the same time, it can regulate the levels of serum T and E2 hormones in male infertility patients.Animal experiments have shown that the prescription can also regulate the activity of antioxidant enzymesin vivo, eliminate excessive free radicalsin vivo, reduce the oxidative damage of spermatogenic cells, and improve the sperm quality of rats with reversible spermatogenesis disorder induced by ornidazole[35]. Gu Yu-neng[36]studied the mechanism of seld-made Shengsui Yulin Decoction in the treatment of oligozoospermia and asthenospermia in rats. It was confirmed that Shengsui Yulin Decoction could improve the sperm quality indexes such as sperm density,progressively motile sperm ratio and sperm activity rate,reduce the apoptosis rate of spermatogenic cells, decrease the expression of Caspase-3 and Bax, and increase the expression of Bcl-2, which is positively correlated with the concentration of traditional Chinese medicine. Therefore,it can regulate gene expression of spermatogenic cells,inhibit cell apoptosis and improve semen quality of rats.Luo Shao-bo[37]used cyclophosphamide intraperitoneal injection to create a mouse model of oligoasthenospermia,and treated the model with “Yijing Decoction” by drench,which was composed of Cuscuta chinensis, Angelica sinensis, mulberry, Radix Rehmanniae and cuttlebone. The results showed that large dose of Yijing Decoction could improve the quality of semen by increasing the expression of Catsper 1 in sperm tail and increasing the concentration of intracellular Ca2+in sperm.

Monomers of Traditional Chinese Medicine

Lycium barbarum L. has the effect of nourishing liver and kidney. Its water extract can directly remove hydroxyl radical and superoxide radical, and reduce the effect on sperm. Lycium barbarum polysaccharide, the main effective component of Lycium barbarum L., can improve the proliferation of spermatogonial stem cells in vitro,significantly increase the number of high spermatogonial stem cells, protect the reproductive system of male diabetic rats and improve their reproductive ability[38,39,40].Schisandra chinensis has the effect of nourishing kidney and astringent essence. Its water extract can directly capture antioxidant free radicals and improve the activity of antioxidant enzymes, so as to protect sperm.Schisandra chinensis can also reduce the content of serum corticosterone in stress rats, reduce its effect on testis, thus protecting the ultrastructure of testis[41]. Epimedium, with the effect of tonifying kidney and strengthening Yang, is a common Yang promoting medicine in traditional Chinese medicine, which has good reproductive effect. It can inhibit the synthesis of prostaglandin, thus inhibiting inflammation. Icariin extracted from Epimedium has androgen-like effect, can promote the development of male sexual organs and increase the amount of semen secretion[42]. Cuscuta chinensis has androgen-like effects, which can protect the reproductive organs of male animals, prevent oxidative damage and apoptosis of spermatogenic cells, promote testicular development and semen secretion, and improve semen quality[43].Ginsenoside is known as the King of Herbs. Ginsenoside Rg1 is one of the main active components of ginsenoside.Ginsenoside Rg1 can significantly reduce the level of reactive oxygen species in the damaged testis tissue, and improve the structure damage of testicular tissue caused by gossypol to certain extent[44]. It can significantly increase the expression of Bcl-2 and down-regulate the expression of Caspase-3, reduce the apoptosis of spermatogenic cells caused by varicocele, and repair the damage of testicular tissue[45]. Rhodiola[46]extract can enhance the antioxidant capacity of testis tissue, reduce the activity of nitric oxide synthase (NOS), and reduce the damage of oxidative stress on the body function in strongly restraint stress mice.This evidence shows that Rhodiola has a certain effect on improving the reproductive function of male mice, and the effect may be achieved through enhancing the antioxidant capacity of the body and preventing over-oxidation damage caused by ROS under oxidative stress, which accordingly alleviate the stress load of the body. Tribulus terrestris saponin[47]can increase the activities of catalase(CAT) and GSH-PX in whole blood of aging mice induced by D-galactose, and increase the sperm density, sperm motility and percentage of living sperm in epididymis.These results indicate that Tribulus terrestris saponin has anti-effect on testicular spermatogenesis in aging mice induced by D-galactose. The mechanism may be related to the fact that Tribulus terrestris saponins increases the antioxidant capacity of the body, scavenges free radicals and promotes the repair of damaged cells.

Epilogue

With the development of modern society, there are increasing problems that affect the quality of male sperm, and the male reproductive ability is declining obviously. More and more attention has been paid to male infertility. Traditional Chinese medicine is one of the oldest medical systems in the world, which is rooted in ancient Chinese Taoist philosophy. In western countries,traditional Chinese medicine is considered to be a very popular complementary and alternative medicine, because traditional Chinese medicine is usually extracted from natural products and does not need artificial additives, so it produces small side effects. There are increasing modern means in Chinese medicine treatment of male infertility,and various treatments such as Chinese medicine decoction, Chinese patent medicine, acupuncture, and integrated Chinese and Western medicine have achieved good clinical efficacy. Syndrome differentiation and treatment is a major principle and magic weapon of traditional Chinese medicine. It is a common treatment method of Chinese medicine decoction to formulate prescriptions based on syndrome differentiation treatment, which is also the characteristics of traditional Chinese medicine in treating diseases. Therefore, whether it is a Chinese patent medicine, self-made prescription by doctors or other intervention means of traditional Chinese medicine, we should follow this principle for rational use. Contemporary scholars combine traditional Chinese medicine with modern medicine to investigate the possible therapeutic mechanism of traditional Chinese medicine at the molecular level, and some achievements have been made. However, the mechanism of traditional Chinese medicine in the treatment of male infertility still remains unclear. How to better use modern technology and experimental means and methods to explore the therapeutic effect and mechanism of traditional Chinese medicine in treating such diseases is still a very important and arduous work.