Etiology analysis and treatment progress of diminished ovarian reserve function in traditional Chinese and Western medicine

Shi-rong Liu, Nan Li, Jing Di, Chan-chan Li

1 Shaanxi University of Chinese Medicine, Xianyang 712000, Shaanxi Province, China

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

Funding: National Natural Science Foundation of China in 2016 (No. 81603656)

Abstract Nowadays, the low ovarian function caused by various reasons is gradually prevalent in younger population. The reproductive dysfunction caused by diminished ovarian reserve is a hot spot in the field of reproductive medicine in China and abroad at present, and it is also a difficult point in clinical treatment. At present, the pathogenesis and mechanism of diminished ovarian reserve are unknown. The existing treatment methods have certain effect on improving ovarian function.Under the guidance of dialectical treatment, starting from “kidney deficiency” and taking“regulating qi, blood and viscera” as the principle, TCM can slow down the ovarian function decline and restore ovarian ovulation function through multi-link and multi-system overall regulation. This paper reviews the progress of etiology and pathogenesis treatment of traditional Chinese and Western medicine for diminished ovarian reserve by reviewing the literature, aiming to provide some help for clinical treatment.

Key words: Diminished ovarian reserve; Etiology; Treatment; Review

Introduction

Diminished ovarian reserve (DOR) refers to the decrease in the number and quality of oocytes in the ovary. The reserve function of ovary is a good reflection of female reproductive function. DOR is limited by age, that is, before the age of 40 years, women show reduced menstruation volume, thin hair, or even amenorrhea,accompanied by menopause similar symptoms. The levels of FSH and LH in sex hormones are higher, while the level of E2 is lower than those in women of normal childbearing age. The levels of sex hormone 10 < FSH <40, FSH/LH > 2-3.6 are found twice or more, and serum AMH < 1.5 ng/ml. Only 5% of women with low ovarian function are likely to have spontaneous pregnancy,but these 5% cases also have the risk of spontaneous abortion and fetal chromosomal abnormalities. If ovarian dysfunction is not treated in time, it will further develop into premature ovarian failure, that is, “Plain Question- Yin Yang Classification of Natural Phenomena” says that: if you can know the seven evils and eight benefits,you can adjust them. If you don’t know how to use them,you will have premature senility. In traditional Chinese medicine, ovarian dysfunction is classified as “hemorrhagic amenorrhea, infertility, menstruation stops at young age,amenorrhea”.

Research Progress of Western Medicine on Ovarian Dysfunction

Understanding of etiology of this disease in Western Medicine

Genetic factors

Ovarian function caused by genetic factors accounts for 20%-25%, chromosomal abnormalities and gene mutation are two major aspects. Qin Ying-ying et al[1]have pointed out that the monosomic X chromosome mosaicism, X chromosome deletion and rearrangement, X chromosome autosomal heterotopia. Studies have shown that: X chromosome deletion plays an important role in maintaining ovarian development and function. Women with abnormal X chromosome number are more likely to suffer from ovarian dysfunction. Based on the candidate genes studies, at least a group of single gene interference can cause definite damage to the ovary. These monogenic interferences include changes in bone morphogenetic protein 15, progesterone receptor membrane component(PGRM) and fragile X mental retardation 1 (FMR1) in X chromosome pre-mutation (FMRI), growth differentiation factor 9 (GDF9), follicular development specific bHLH transcription factor (FGgla), new ovarian HOOBOX gene,nuclear receptor subfamily 5, nuclear receptor A, and NANOS homologous gene 3 (NANOS 3) mutations also seem to occur.

Iatrogenic injury

Radiotherapy, chemotherapy and surgery may deplete the ovarian follicle pool, increase the risk of ovarian failure and infertility. All kinds of ovarian surgery can destroy the normal ovarian tissue to varying degrees, which leads to DOR. Prostaglandins (PG) is closely related to reproduction and physiology, and non-steroidal anti-inflammatory drugs (NSAIDs) may inhibit normal ovarian reproductive function when they inhibit the anti-inflammatory effects of PG. Antitumor drugs such as cyclophosphamide, nitrogen mustard and other alkylating agents combine with DNA through chemical bonds, resulting in abnormal base pairing and irreversible cell damage. These drugs have obvious gonadal toxicity, easily cause ovarian damage and can accelerate follicular development and ovarian failure.Charlotte Sonigo et al[2]have proposed chemotherapy drugs can directly affect the primordial follicle DNA,promote the follicular atresia and at the same time cause damage to ovarian blood vessels and stromal chambers through animal model and ovary culture model.Radiotherapy and chemotherapy can induce oocyte apoptosis or destroy the function of granulosa cells, thus affecting the endocrine function of ovary.

Autoimmunity

Immune ovaritis caused by herpes simplex virus and mumps virus infection can cause ovarian damage. Some potential immune targets in different parts of the ovary have been proposed as antigen antibody mediated autoimmune attack sites, thus affecting various functions of the ovary and leading to the decline of fertility. Andrea Weghofer et al[3]have investigated 225 infertile women due to thyroid autoimmune diseases, that is, the results showed that low thyroid hormone levels had a beneficial effect on follicular recruitment. Higher TSH levels have adverse effects on ovarian function to varying degrees.

Galactosemia and mitochondria

In recent years, studies have found that ovarian dysfunction is also associated with galactosemia. Galactosemia is a rare congenital metabolic error caused by the deficiency of enzymes involved in galactose metabolism[4]. The accumulation of galactose metabolites in ovarian cells can cause swelling and cell dysfunction, and the accumulation of reactive oxidants, such as methylenedialdehyde, can hinder the glutathione redox cycle and causes damage to ovarian cells. Galactose may also decrease the quality of mitochondria and oocytes. As the most abundant cell with mitochondria in human body, follicles rely on mitochondria to obtain the energy needed in various stages of development. Granulosa cells also contain a large number of mitochondria, which affect the process of division, metabolism, cell cycle and signal transduction.Mitochondrial dysfunction may cause the apoptosis of granulosa cells, stop the physiological activities of oocytes,cause follicular atresia or even failure, and then cause the decline of DOR. DOR also has a serious impact on the dynamic characteristics of mitochondrial biosynthesis in peripheral granulosa cells, forming a vicious cycle, and ultimately promoting the progress of POF[5].

Other

Western medicine psychology research shows that emotion is closely related to people’s health, and bad emotions will affect the central nervous system and gonadal axis function,resulting in abnormal secretion of FSH and LH, ovulation dysfunction, amenorrhea, and accordingly DOR or POF will occur. Long term stress, anxiety and depression will not only make the adrenal cortex sensitive and increase the secretion of adrenocortical hormone, but also disturb the HPO axis, resulting in the dysfunction of HPO axis and the decline of ovarian secretion function. Excessive weight loss leads to the rapid decrease of internal fat, so the main raw material for synthetizing estrogen is insufficient,which causes menstrual disorder, even amenorrhea, but abnormal amenorrhea can inhibit ovarian ovulation function, resulting in ovarian dysfunction.

Current situation of this disease in Western Medicine

Hormone replacement therapy

Ovarian dysfunction is an important factor leading to female ovarian hormone deficiency, in addition, to a large extent, it can lead to abnormal menstruation or even infertility. Ovarian dysfunction is associated with a variety of health risks, including a range of menopausal symptoms, decreased bone density and increased risk of fractures, decreased cognitive ability, and dry eye disease.At present, estrogen and progesterone replacement therapy is the main treatment for premature ovarian dysfunction.The mechanism of treatment of ovarian dysfunction has two aspects: (1) promote the development and maturation of follicles and excretion by acting on the target organs, so as to adjust the menstrual cycle and improve the symptoms of estrogen deficiency; (2) regulate the function of human pituitary gonadotropin to regulate reproductive endocrine,and then improve the quality of life of patients. The mechanism of hormone replacement therapy in improving fertility rate is to inhibit long-term elevated FSH and restore FSH receptor, so as to enhance the response of residual follicles to exogenous gonadotropin, promote follicular development and ovulation, and improve clinical pregnancy rate[6].

DHEA

DHEA is a hormone with androgen activity, which is secreted in adrenal cortex, central nervous system and endometrial cells of follicle. With the growth of age,DHEA becomes decline, and it relates to human aging.Clinical studies have shown that DHEA can up-regulate the receptor expression of follicle-stimulating hormone(FSH), enhance the sensitivity of ovarian follicles on FSH stimulation, so the androgen of follicles in the ovarian microenvironment plays an important role in early follicular development and granulosa cell proliferation and it can obviously promote the primordial follicle recruitment and initiation[7]. Through up-regulating the expression of AR, FSHR and insulin-like growth factor-1 in GCS, it can induce the development of primary, presinus and sinusoidal follicles, induce paracrine regulation,reduce follicular atresia, improve ovarian reserve function,enhance ovarian responsiveness, and improve a series of perimenopausal symptoms caused by poor ovarian function.

Coenzyme Q10 + vitamin E

In order to conform to the trend of the times, more and more women advocate the later marriage and later child-bearing, as the growth of the age, women of childbearing age are aging, ovarian function is also declining. Recent studies have shown coenzyme Q10 +vitamin E can improve ovarian reserve function and the ovarian reactivity to a certain extent. Zou Yu-jie et al[8]have believed that exogenous application of antioxidants can improve mitochondrial function, clear free radicals,and resist to apoptosis, which is conducive to improve the pregnancy outcome. Good function of mitochondria provides enough ATP to help finish meiosis in the oocyte development. Zuo Yin-hua[9]gave oral vitamin E and vitamin E + coenzyme Q10 for 3 months to patients with ovarian dysfunction before the implementation of IVFET. The results showed that the days of Gn and the total amount of Gn were lower than those of the control group.Coenzyme Q10 + vitamin E had a positive effect on the ovaries of women with IVF-ET.

Growth hormone

Growth hormone has always regarded as a kind of metabolic hormones secreted by the pituitary gland,which plays an important physiological role in the process of human growth and development. It also plays a physiological role by binding to growth hormone receptor on the surface of the target cells. Many reports in China and abroad have pointed out that, the growth hormone can be found in the fetus and adult ovary, which plays an important role in oocyte maturation and embryo development and other reproductive aspects. Jesus et al[10]have suggested that growth hormone acts directly on Kisspeptin neurons located around the periventricular nuclei and anteroventral periventricular nuclei by the signal transduction and transcriptional activation factor 5 (STAT5). These neurons play a critical role in regulating activities of GnRH neurons. The interaction between growth hormone and growth hormone receptor in ovary promotes the synthesis of sex steroids, enhances the response of granulosa cells to gonadotropin, induces the production of oocytes, inhibits follicular apoptosis, and up-regulates the expression of IGF-1 receptor gene in the ovary, and increases the sensitivity of follicles to FSH.

Assisted reproduction

In vitro fertilization (IVF) and embryo transplantation has become a routine method for the treatment of ovarian dysfunction. In IVF cycle, patients are faced with the risk of low ovarian reactivity, and attain lower egg rate, highquality embryo rate than normal women. Therefore it is critical to explore an appropriate ovarian stimulation program to get enough quantity of high-quality ovum.

Progress of Etiology and Treatment of Ovarian Dysfunction in Traditional Chinese Medicine

In traditional Chinese medicine, there is no term for ovarian dysfunction, according to the corresponding clinical symptoms, it belongs to “advanced menstruation,hemorrhagic amenorrhea, low menstrual blood volume,menstruation stops at young age, amenorrhea, infertility”.TCM holds that kidney-menstruation-Chong-Ren-uterus reproductive axis certain parts suffer from the transformation imbalance of Yin and Yang because of the intrusion of disease-causing pathogens, which contributes to ovarian dysfunction. Modern physicians demonstrate the disease derives from the kidney. Taking the kidney as a starting point, they combine the syndrome differentiation of zang-fu organs, qi and blood and discuss it from liver,spleen and kidney. Much attention should be attached on the treatment with essence-qi-blood. Others will also cooperate with acupuncture treatment to improve the sensitivity and reactivity of the ovaries to drugs.

Etiology and pathogenesis

Kidney deficiency

Kidney is a congenital origin, kidney governs the reproduction and is dominant in the “kidneymenstruation-Chong-Ren-uterus” reproductive axis.The ovum is the essential substance for reproduction.Its maturation is closely related to kidney essence filling and the normal discharge of follicles depends on the stimulation of kidney Yang. Professor Cai Lian-xiang[11]believed that the essence and blood are homologous and mutual breeding, and the kidney essence is refined to produce qi and blood. If the kidney essence is sufficient,the Yin blood generated by the transformation of kidney essence is sufficient, which can provide a certain material basis for the development of follicles. Ovarian dysfunction is caused by the deficiency of kidney essence and vital blood, as well as malnutrition of Chong-Ren, then the follicular development is blocked or stopped, leading to infertility. Professor Xia Gui-cheng[12]believed that women with ovarian dysfunction are mostly suffering from heart-kidney-uterus axis dysfunction, which is mainly due to kidney deficiency and partial Yin. When this disease occurs, it firstly appears in the heart, and the premise is kidney, which explains that some women have symptoms such as dysphoria, insomnia, fatigue when they know that their ovarian function is low. Liu Hai-hong et al[13]classified 72 patients with ovarian dysfunction according to their TCM clinical symptoms. The results showed that Yin deficiency of liver and kidney was the main syndrome type of the disease. Therefore, the adequacy of kidney qi determines whether the ovary can play a normal physiological function.

Liver depression

Women are born with liver. Nowadays, women’s emotions are subjected to great fluctuations in the face of pressure from work, family and others aspects. The liver prefers free activity and dislikes the depression, it belongs to Yin in physique and Yang in function. Liver is the hinge of regulating qi and blood. Among the five zang viscera, the liver blood and kidney essence are the same origin and can be simultaneously supplemented, and they regulate each other by dredging and storing, which has an important impact on menstruation. Under the effect of depression qi, the liver is poorly responsible for the dredging, and the qi mechanism of the whole body is out of balance. If the qi doesn’t work, it is easy to generate water, dampness,phlegm, drink and blood stasis. The blood stored in the liver cannot flow downwards the uterus, thus disturbing the normal physiological function of the reproductive axis, and the poor circulation of qi and blood in the Chong-Ren, thus affecting the development of the follicle and menstruation. Liver subjugating spleen leads to the deficiency of qi and blood transformation, even the deficiency of blood sea eventually. Feng Jing-hua et al[14]propose that patients with ovarian dysfunction caused by psychological stress were randomly divided into control group and treatment group. The control group was treated with western medicine, while the treatment group was treated with Bushen Shugan decoction and psychological intervention. The results showed that Bushen Shugan decoction combined with psychological intervention could reduce FSH, increase AMH, E2 and AFC, and the study showed that it had obvious protection and improvement effect on ovary.

Blood stasis

Women are based on blood, and blood is used in menstruation, pregnancy, childbirth and lactation. If a woman’s qi and blood are harmonious, the five zang viscera will be peaceful and the Chong-Ren will be prosperous. If the blood and qi are out of balance, the qi will be released with the blood, then the Chong-Ren is instable. Qi and blood are the material basis of human body living in the world. Similarly, the generation and smooth operation of qi and blood are also essential for female reproduction. Women’s menstruation, belt, fetus and birth are closely related to qi and blood. The loss and deficiency of qi and blood affect Chong Ren, resulting in blood sea emptiness, blood stasis blocking the uterus.If the old blood does not go, new blood will not be produced, and retarded menstruation and amenorrhea will occur. If the ovary is not nourished by qi and blood,follicle growth and ovulation will be affected. Professor You Zhao-ling[15]believed that long-term kidney deficiency, liver dysfunction, or Yin blood cold can lead to the formation of blood stasis. Therefore, blood stasis is the key pathogenesis. Uterine vessels are blocked by blood stasis, which cannot absorb sperm and become pregnant,eventually leading to infertility.

Advances in the treatment of TCM

TCM holds that the cause of ovarian dysfunction mainly includes the kidney deficiency, liver depression and blood stasis, and disharmony of thoroughfare and conception channels. The liver can’t reserve and regulate blood;dysfunction of spleen in transportation causes the failure of absorb and produce blood; a deficiency in the kidney essence can’t transform qi to regulate reproduction.Therefore, the treatment mainly starts with tonifying the kidney, centers on the liver, spleen and kidney, and uses the tonifying method from the deficiency point of view.At the same time, the elimination of pathogenic factors is embodied in strengthening the body, so as to balance Yin and Yang and adjust the rhythm of menstrual cycle. In the follicular phase, the treatment should nourish kidney and Yin, increase estrogen and promote follicular development;in the ovulation phase, it promotes ovulation by activating blood circulation and dredging collaterals; in luteal phase,it warms kidney Yang to increase progesterone secretion and improve luteum function; in menstrual phase, it promotes menstrual blood discharge, improves and restores ovarian function to prepare for the development of primordial follicles into antral follicles.

TCM method of regulating the cycle

Professor Kong Ling-shen believed that the sequential therapy of liver-spleen-kidney, namely regulating the liver,tonifying the kidney and strengthening the spleen, are the three magic weapons for treating menstrual diseases. In the prophase of menstruation, Xiaoyao Powder is mainly used to disperse stagnated liver qi. During menstruation period, Xiaoyao Powder is used to remove the old blood stasis and generate new blood as the main prescription.According to concomitant symptoms it is timely combined with traditional Chinese medicine of warming kidney,promoting blood circulation and relieving pain to promote qi and blood circulation. Yin blood is released in the late menstrual period, and the blood in the uterus is deficient. Dingjing decoction is used to tonify the kidney and regulate qi and blood. The intermenstruation is an important period of Qi and blood generation, Guipi decoction can replenish spleen and qi to generate blood and promote qi and blood activity in uterus. Guo Wenwen[16]applied Professor Kong’s liver-spleen-kidney cycle regulation method to 40 of 78 patients with ovarian dysfunction, and the other 38 cases were treated with climen. The results showed that the total effective rate of the treatment was 90.0%, and the menstrual condition,reproductive endocrine and ovarian function of the patients were significantly improved.

Tonifying kidney and promoting blood circulation method

Based on the pathological mechanism of kidney deficiency and blood stasis, Ma Kun[17]used kidney tonifying and follicle promoting decoction to treat infertile patients with ovarian dysfunction, 43 patients in the experimental group were treated with oral traditional Chinese medicine,and the other 43 patients in the control group were treated with oral western medicine. The results showed that there were significant differences in the improvement of FSH,AMH and AFC in the experimental group. Chen Ruixue[18]believed that the main cause of this disease are the deficiency of kidney Yang, cold coagulation and blood stasis, and invasion of chronic disease into the collaterals.Therefore, the treatment principles are to tonify kidney Yang, activate blood circulation and remove blood stasis.Yanghe decoction is used to warm the kidney and warm the uterus, and activate blood circulation to dredge the collaterals, so as to strengthen the pelvic blood circulation and improve the ovarian reserve function.

Tonifying kidney, dispersing liver and nourishing blood method

Based on the pathogenesis of deficiency of kidney Yin, liver depression and qi stagnation, Yin and blood deficiency, Chai Song-yan[19]proposed the treatment principle of regulating menstrual cycle mainly and nourishing Yin and blood, dispersing stagnated liver qi for relieving stagnation. Huang Ye-fang[20]believed that the method of tonifying the kidney, dispersing the liver,promoting blood circulation and dredging collaterals combined with bathing feet using traditional Chinese medicine can achieve the balance of Zang Fu viscera, the balance of Yin and Yang in the kidney, the normal liver function and the state of Yin and Yang in equilibrium following internal and external treatment, so as to restore normal menstrual cycle and menstrual volume in patients with ovarian dysfunction due to kidney deficiency, liver depression and blood deficiency. Yang Ji-ke[21]explored the mechanism of tonifying kidney and dispersing liver method in the treatment of ovarian dysfunction, and finally concluded that: the serum levels of SOD, GSH, E2 and AMH in the TCM group rats were higher than those in the model group, while the levels of FSH, LH, MDA and ROS were lower than those in the model group. The results of morphological examination of ovary showed that it was significantly improved compared with the model group, which also suggested that the method of tonifying the kidney and dispersing the liver could weaken the oxidative stress state of rats with ovarian dysfunction, thus improving the ovarian reserve function.

Tonifying the kidney and tranquilizing method

Based on the method of tonifying the kidney, calming the heart and regulating menstrual cycle, Professor Xia Guicheng[22]pointed out that nourishing Yin and descending fire, calming the heart and tranquilizing the mind, and treating according to the clinical symptoms of patients were the basic treatment principles. Based on the pathogenesis described by Professor Xia, Li Jia-hui[23]applied self-drafted Qingxin Zishen Decoction and Yueju Erchen decoction to treat DOR patients. The results showed that the total treatment rate, TCM symptom score, AFC and hormone levels of the study group were significantly improved compared with the treatment group, indicating that the functions of nourishing the kidney and calming the heart, resolving phlegm and regulating qi can regulate the hormone secretion of the body and improve the ovarian dysfunction.

Acupuncture and Moxibustion therapy

A meta-analysis[24]suggests that acupuncture can improve menstruation and reduce FSH and LH levels by regulating qi and blood, tonifying liver and kidney,coordinating meridians, while acupuncture will not cause adverse reactions such as abnormal vaginal bleeding,acute liver injury, liver damage and vascular embolism.Acupuncture and moxibustion can effectively regulate the hypothalamus-pituitary-ovary axis and then affect the secretion of various hormones, thus affecting the function of female reproductive organs. Li Qing[25]randomly divided 78 patients with ovarian dysfunction into the control group and the treatment group. The control group was treated with acupuncture at related acupoints, while the treatment group was treated with half moxibustion of governor vessel. After treatment, FSH in both groups decreased and E2 increased, but the improvement of FSH/LH and E2 in the treatment group was better than that in the control group. Studies have shown that acupuncture can improve ovarian function, and the moxibustion of governor vessel can also improve ovarian function.

Treatment according to age

Professor Lian Fang pointed out[26]that the treatment can focus on nourishing the kidney, warming yang and dispersing the liver for patients with ovarian dysfunction under 35 years old, so as to stimulate the growth of qi. It is appropriate to use sentient flesh and blood products,mainly to tonify the kidney and disperse the liver, and add traditional Chinese Medicine such as prepared rhizome of rehmannia, Chinese yam, cornus officinalis, Rhizoma Polygonati and colla plastri testudinis to nourish kidney Yin, regulate immunity and delay aging. For patients older than 35 years old with ovarian dysfunction, it is advisable to nourish the kidney and invigorate the spleen in succession. “Huangdi Internal Classics” has discussed“in case of Yang Ming meridian decline, the face began to aging, and the hair began to fall”, describing the gradual decline of human function, of course, including ovarian dysfunction. The beginning of all aging is due to the decline of Yang Ming meridian, that is, the decline of spleen and stomach function, so we can supplement the medicine of nourishing spleen and stomach at the same time of tonifying kidney.

Integrated Traditional Chinese and Western Medicine Therapy

Li Jing et al[27]randomly divided 106 infertile patients caused by ovarian dysfunction into a treatment group(54 cases were treated with western medicine and decoction of tonifying kidney and dispersing liver) and a pure western medicine treatment group (52 cases were treated with estrogen). The results showed that tonifying kidney and dispersing liver decoction combined with western medicine has obvious effect on improving ovarian reserve function, and can reduce FSH, FSH/LH,increase E2, increase ovulation rate and pregnancy rate.Zhang Ling et al[28]retrospectively studied 35 cases of successful pregnancy after the treatment of traditional Chinese medicine of tonifying the kidney and activating blood circulation and Western Medicine of estrogen. The results showed that on the one hand, kidney tonifying and blood activating herbs can nourish the kidney essence,enrich the essence and blood, and provide a certain material basis for the growth of follicles. At the same time,traditional Chinese medicine of tonifying the kidney and promoting blood circulation can eliminate the thrombotic diseases caused by long-term administration of estrogen.Integrated traditional Chinese and Western medicine treatment of the disease can benefit from each other and make up for each other’s deficiencies, maximize their respective therapeutic role, and ultimately relieve the pain caused by the disease for patients.

Conclusion

Infertility caused by diminished ovarian function is a difficult problem in clinical treatment. Because the exact cause of the disease is still unclear, the treatment is limited to symptomatic treatment. Hormone replacement therapy, ovulation induction and assisted reproduction are the representative treatments to solve the problems of irregular menstruation and infertility. Although it has certain curative effect, there are many problems that cannot be ignored. Traditional Chinese medicine has obvious advantages in regulating menstruation, helping pregnancy and protecting pregnancy, and integrated traditional Chinese and Western medicine treatment is more predominant. Traditional Chinese medicine has a long history in regulating menstruation and helping pregnancy, but the treatment cycle is long, which affects the dependence of patients’ treatment. The combination of traditional Chinese and Western medicine, can complement each other in the treatment of the disease to maximize their own role. It is believed that in the near future, the treatment of ovarian dysfunction will have further development, so as to open a new chapter.