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REVIEW ARTICLE
Year : 2023 | Volume
: 9
| Issue : 2 | Page : 111-122
Discussion on relationship between meridians and viscera of decreased ovarian reserve from the perspective of “preventive treatment of disease” by acupuncture
Si-An Pan, Zhi-Miao Murong, Yi-Lin Zhu, Jia-Wei Song, Xiao-Rong Chang, Yu Liu, Zeng-Hui Yue
Department of Professional Acupuncture and Moxibustion, College of Acupuncture, Moxibustion and Tuina, Hunan University of Chinese Medicine, Changsha, Hunan, China
Correspondence Address:
Dr. Yu Liu
College of Acupuncture and Tuina and Rehabilitation, Hunan University of Chinese Medicine, No. 300, Xueshi Road, Yuelu, Changsha
China
Dr. Zeng-Hui Yue
College of Acupuncture and Tuina and Rehabilitation, Hunan University of Chinese Medicine, No. 300, Xueshi Road, Yuelu, Changsha
China
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/2311-8571.378173
Based on extensive historical data, clinical experience, and modern scientific research, we discuss the relationship between meridians and viscera of decreased ovarian reserve (OR) from the perspective of “preventive treatment of disease” by acupuncture. It is believed that the endogenous protection mechanism of acupuncture in “preventive treatment of disease” lies in harmonizing Yin and Yang and dredging meridians; stimulating righteousness and rejecting the evil outside; preventing disease; co-cultivating body and spirit, and regulating emotions. The incidence of OR dysfunction is closely related to the uterus-related meridians and viscera. The mechanism of acupuncture treatment of OR dysfunction may be related to reproductive endocrine hormone levels, ovarian tissue morphology, immune system, granulosa cell apoptosis, and related signal transduction pathways. The clinical effect of acupuncture treatment of diminished OR is reflected in improving menstruation and ovulation; improving OR function, promoting pregnancy; improving local ovarian microenvironment; improving negative emotions, improving quality of life, and thus affecting pregnancy outcomes. This article summarizes the mechanism of action and clinical effect of acupuncture in the treatment of decreased OR function based on recent findings, analyzes the advantages and disadvantages of acupuncture in the treatment of disease, and provides the rationale for the clinical application of acupuncture in the treatment of decreased OR function.
Keywords: Acupuncture, ovarian reserve dysfunction, preventive treatment of disease, theoretical discussion
A decline in ovarian reserve (DOR) refers to a decline in the ability of the ovary to produce eggs, number of oocytes, quality of oocytes, and levels of sex hormones secreted, which results in a decline in female fertility.[1] The clinical manifestations include low menstrual volume, cycle disorders, abnormal uterine bleeding, and infertility. There are no medical terms in Chinese medicine strictly equivalent to DOR, and they are mainly considered to fall within the categories of “blood dryness,” “late menstruation,” “menorrhea,” and “infertility.” DOR is an progressive process characterized by an absence of significant symptoms at the early stage except for changes in menses or evidence of infertility. Failure of timely and effective interventions may lead to the development of premature ovarian insufficiency (POI) or even premature ovarian failure (POF). Early evaluation of ovarian function and diagnosis and treatment of DOR is of great significance in the prevention and treatment of POF and belongs to the Traditional Chinese medicine (TCM) category “prevention of disease.” Acupuncture treatment focuses on mobilizing the body's own disease resistance in the early stage of the disease, based on syndrome differentiation and treatment using a variety of methods of comprehensive conditioning; adjusting the body's organs, meridians, and blood; stimulating the body's internal potential to regulate Yin and Yang; and improving the body's disease resistance. The DOR is located in the uterus and changes Qi and blood. The uterus has a complex pathophysiological relationship with the meridians and zang-fu organs. Thus, the occurrence of DOR is presumed to be closely related to changes in Qi and blood in the uterus and the related meridians and viscera. Therefore, this article explores the relationship between the viscera and meridians of the uterus in cases of deficiency in OR function.
Acupuncture “Preventive Treatment”The TCM concept “prevention of disease” is embodied in the “Huangdi Neijing:” “It is the sacred man who does not treat his diseases and does not cure his diseases.” The history of acupuncture for the prevention of diseases goes back to the time of the warriors in the book “Lingshu nishun:” “The first worker punctures his unborn. Second, there are those who do not grow. Second, those who have failed to do so.” Physicians with the best medical skills were good at treating diseases without acupuncture.[2] The Eastern Jin Dynasty “Fan Wang Fang” first mentioned “inverse moxibustion;” the Sui Dynasty Chao Yuanfang's “various disease source syndrome theory” first mentioned “inverse acupuncture”; Ming Dynasty Gao Wu, in acupuncture Juying, proposed “no disease and inverse acupuncture.” Treatment before disease onset was the first to clarify the concept of inverse acupuncture.[3] The endogenous protective mechanism of acupuncture in disease prevention lies in the ability of the body to adjust to potential dysfunction, mitigate or counteract disease-induced damage, and enhance resistance to stress.[4]
Regulate Yin and Yang, dredge meridians
”Suwen Shengqi Tongtian theory” said: “Yin and Yang balance the human body in a healthy state; if Yin and Yang are separated, the body goes to death.” Under physiological conditions, the opposition and restriction, mutual root and use, mutual storage, growth, and declining transformation of Yin and Yang maintain a dynamic balance. Once this balance is disrupted, the body remains in a pathological state. Therefore, the adjustment of Yin and Yang is a basic principle of Chinese medicine.
A saying in “Lingshu Genjie” states, “the key to using the needle lies in knowing how to mediate Yin and Yang.” Preconditioning of acupuncture means using different acupuncture devices and techniques to stimulate the meridians, adjust the Qi and blood functions of the meridians, stimulate the potential of body tone and Yin and Yang, maintain homeostasis of the body environment, and achieve the goal of preventing diseases. The role of acupuncture in regulating Yin and Yang is primarily accomplished through the meridian Yin and Yang properties, acupoint compatibility, and acupuncture manipulation.[5]
Stimulation of vital Qi and resistance to pathogens
Strengthening vital Qi and eliminating pathogens are the fundamental principles of acupuncture for disease prevention and treatment. “Suwen Cifalun” states: “where healthy energy exists, evil cannot harm.” The development and outcome of a disease is a struggle between vital and pathogenic Qi. Only when the vital Qi is strong can it effectively prevent the intrusion of external pathogens or eliminate them. Then, the body has a strong adaptive and regulatory ability to adjust in a timely manner to potential or minor disturbances and abnormalities. Acupuncture preconditioning is designed specifically to prevent the disease from developing by various means of diarrhea, supporting and stimulating vital Qi.
Prevent disease, prevent the disease from worsening
Moxibustion is mainly used to preempt disease, focusing on its health-care effect, whereas acupuncture is mainly used to preempt and prevent disease, focusing on its anti-eradication effect. “If you want to be safe, three miles often do not dry,” that is, commonly used festering moxibustion Zusanli to strengthen the body, not disease prevention. ShangHanLun states: “Solar disease, headache of more than 7 days self-healing. Needle foot Yangming, the meridians are healed if not transmitted.” It has been pointed out that preconditioning of acupuncture and moxibustion has the goal of preventing degeneration through five-element system and meridian-collateral transformation, and prevention of diseases. “Jingui Yaolue” recorded: “moderate meridians, not spreading to the viscera, that is, treatment.” Limbs feel heavy stagnation; that is, guidance, vomiting, acupuncture, ointment massage, do not block the nine orifices, and it is believed that the treatment of the disease through acupuncture and massage during the meridians and collaterals can prevent the disease from spreading to the viscera. Due to the efficacy of acupuncture in preventing disease and disease-causing changes, acupuncture clinicians emphasize early intervention.
Body-spirit co-cultivation, regulating emotions
The acupuncture treatment of diseases should adopt the method of physical and mental treatment simultaneously. “Lingshu Benshen” says: “the essence of all healing must be in the deity;” “Suwen Baomingquanxinglun” says: “the essence of all healing must be in the deity first;” and “Lingshu Zhongshipian” says: “the essence of all healing must be in the deity and the intention of the deity must be in the needle,” which indicates that the deity is the foundation and prerequisite for the healing of the needle.[6] Clinically, by observing the deity before puncturing, curing the deity at the time of puncturing, and supporting the deity after puncturing, we can achieve the goal of form-deity mutual support and regulation of emotions.[7]
Relationship between Decreased Ovarian Reserve and Meridian VisceraHyporestorative ovarian disease occurs in the uterus, which is the most important reproductive organ of a woman and is responsible for menstruation and pregnancy. The first mention of the uterine tubes and the uterine nucleus is made in Shen's gynecology Jiyao Jianzheng: “The bottom of the uterus, from one uterine tube to the left and one uterine tube to the right, is continuous with a small hole, two and a half inches long, hanging on the side of the uterine nucleus; the nucleus, one inch to the right and one inch to the left of the uterus, has a stalk inside, which is continuous with the uterus; the fascia outside, which is continuous with the uterine tube, like a peacock egg, which is continuous with the uterine tube; and the pearl, which is continuous with the uterine tube.” Uterus is closely related to meridians and viscera. Therefore, the occurrence of diminished ORs is a result of changes in Qi and blood levels in the meridians and viscera.
Relationship between ovarian reserve dysfunction and meridians
From the perspective of meridians, the occurrence of decreased OR function is mainly associated with the Chong and Ren meridians and the three in meridians of the foot; Ren meridians in the abdominal circulation, Chong meridians, Du meridians with origin in the uterus, and Ren main generation. The Chong meridians are the “seas of the twelve meridians,” which pass through and permeate the Qi and blood of the 12 meridians, which run in parallel with the meridians of the kidneys and stomach. It is the “sea of five zang organs and six fu organs.” Only by allowing the Chong and Ren meridians to run smoothly can the Qi and blood of the five zang and six fu organs be gathered together, and the uterus can be induced to perform its normal physiological functions. This shows that the condition of “Renmaitong, Taichongmaisheng” is the external condition for the ovaries to perform their ovulation and endocrine functions. “Jingyue Encyclopedia·Women's Rules” says: “The menstrual cycle is formed by Yin blood, which drains the five zang organs and six fu organs into a sea of blood. Hence, the impulse is strong enough to form a menstrual period.” “Various disease source syndrome theory woman miscellaneous disease princes” pointed out that “Menstrual dysmenorrhea is most commonly caused by weakness of the body due to impairment of Qi and blood or by intrusion of pathogenic Qi onto the menstrual artery and impairment of the impulse artery.” Thus, the Chong and Ren meridians play an important role in the production and distribution of blood in Chong and Ren disorders, which are key factors in the development of POF. In addition, from the perspective of meridian circulation, the three Yin meridians of the foot can be indirectly connected to the uterus by a second meridian, which promotes harmony between Qi and the blood. If there is dysregulation of Qi and blood flow, and if there is insufficiency of the meridians, this may lead to a decrease in OR. Therefore, the occurrence of decreased OR function is closely related to the meridians.
Decreased ovarian reserve function in relation to the viscera
Relation with the kidneys
TCM maintains that the kidneys contain the essence, dominate reproduction, are enriched with kidney gas, become increasingly mature, and have menstrual periods to produce a child. “Huangdi Neijing” says: “a woman at 7 years of age is rich in kidneys and teeth. At 14 years old when the kidney is strong, conception and pulse are open, menarche begins, then she can become pregnant.” The kidney contains spermatozoa first, then the kidney contains essence-generating Qi, the kidney is filled with Qi, and the Qi of origin is vigorous. They grow rapidly and reproduce continuously. Thus, deficiency of spermatozoon in the kidney, deficiency of Qi, deficiency of blood in the ovary, deficiency of impetuosity, deficiency of warming of the uterus affect the normal development of the follicle, resulting in decreased OR.
Relation with the liver
”LingShu JingMai” says: “the meridians of the liver and foot and anus. Follow the femoral and vaginal divisions, enter the hairs, return via the vaginal apparatus, and cover the abdomen.” The liver meridians run through the genitals. Reproductive organs are closely related to the liver through the meridian system. The catharsis of the liver was considered appropriate or moderate. In women, ovulation and menstruation are timely and sexual desire is normal. If the liver's catharsis is abnormal, Qi movement is disturbed or Qi and blood cannot nourish the uterus, which leads to menstrual blood deficiency and poor blood flow, disrupting the regulatory function of the kidney-Tiangui-Chongren-uterus reproductive axis and resulting in abnormal ovarian ovulation function. Therefore, liver Qi stagnation is the initial stage of the disease.
Relationship with the spleen
Zhang Jingyue stated that the key to regulating menstruation is to nourish the spleen and stomach to enrich the source of blood and nourish the kidney Qi to tranquilize the blood room. He noted that if the spleen Qi is healthy, the water and grain essence is slightly filled with the essence of the kidney, and the kidney essence is sufficient to promote the transportation and transformation of the spleen so that the spleen and stomach are nourished at the same time. Spleen and stomach deficiency for a long time, weak body win, blood and body fluid lacking biochemical resource, and blood sea emptiness, results in no blood in the uterus.[8] Evidence suggests that splenic-gastric deficiency leads to amenorrhea and consequently affects OR function.[9]
Relation with the heart
The heart governs the blood vessels, and the heart Qi drives the blood to run through the peripheral vessels. The heart Qi is connected to the kidney. Therefore, regular menstruation predicts successful pregnancy. From the heart-kidney-uterine axis point of view, this is closely related to the heart, although the disease is inadequate in the renal column and is prematurely exhausted. It occurs mainly because the patient's prolonged mental stress leads to the restlessness of the heart and mind and to dark depletion of the heart's blood divisions, which in the long run depletes the Yin of the kidneys, fails to refine the marrow to feed the heart and mind, and causes malignant circulation.
Mechanism of Acupuncture in Treating Diminished Ovarian ReserveOR function refers to the ability of follicles in the ovarian cortex to grow, develop, and form fertilizable oocytes; that is, the number and quality of follicles retained in the ovary can reflect the fertility potential and reproductive endocrine function of women. Clinically, DOR was evaluated based on a decrease in anti-Müllerian hormone (AMH) levels, a decrease in antral follicle count (AFC), and an increase in follicle-stimulating hormone (FSH) levels. Multiple meta-analyses[10],[11],[12],[13],[14],[15] showed that acupuncture for both POI and POF was significantly more effective and superior to western medications, improving the level of the patient's reproductive endocrine hormones and returning the menstrual cycle to normal. Acupuncture for assisted reproduction also improves serum sex hormone levels and increases the number of antral follicles, oocytes, and fertilization in patients with DOR, thereby increasing embryo seeding and clinical pregnancy rates.[16],[17] However, the mechanism of action is unclear and may improve OR in several ways [Table 1].
Table 1: Mechanism of acupuncture in treating decline in ovarian reserveRegulating the function of hypothalamic-pituitary-ovarian axis
In the female reproductive endocrine system, hormonal changes are regulated by the hypothalamic-pituitary-ovarian axis (HPOA), which secretes gonadotropin-releasing hormone (GnRH) to regulate the release of FSH and luteinizing hormone (LH) from the pituitary gland, thereby controlling the ovarian secretion of estradiol (E2) and progesterone (P); in turn, the level of secreted ovarian hormones regulates the secretion levels of the pituitary gland and hypothalamus by negative feedback. Decreased numbers and quality of oocytes in the ovaries of patients with DOR lead to disorders of ovarian secretion, with decreased levels of E2 and P-inhibitors, thus decreasing the level of estrogen that promotes FSH and LH secretion through negative feedback.
Studies[18] have demonstrated that acupuncture can activate the brain dopamine system and modulate the function of the HPOA, thereby restoring the reproductive endocrine system and normal physiological dynamic balance. Cheng and Tian[19] found that acupuncture effectively improved low estrogen levels and lowered high gonadotropin levels by observing the modulation of HPOA in ovariectomized rats through the retrograde acupuncture “Guanyuan” and “Sanyinjiao.” This suggests beneficial regulation of HPOA function and endocrine levels against this disorder in ovariectomized rats. Li et al.[20] observed the effect of electroacupuncture “Sanyinjiao” on naturally peri-menopausal rats and found that the E2 levels in the electric needle group were significantly higher and the FSH, LH, and GnRH levels were decreased to varying degrees compared with those in the model group. After 4 weeks of treatment, Jin et al.[21] detected decreased serum FSH, elevated E2, and increased AMH in the DOR rats, and found that the effects differed by the timing of the moxibustion onset, in which predisease plus early treatment was the most effective, followed by early treatment. This conclusion is consistent with TCM's “prevention of disease” thesis, which emphasizes the importance of protecting ovarian function and early detection and treatment of patients with DOR. Acupuncture regulates the function of the HPOA, thereby regulating the changes in hormone levels to improve the OR, which is an important mechanism for the overall regulatory effect of acupuncture.
Improving the histological morphology of the ovaries and uterus
Normal ovarian morphology is essential for the maintenance of ovarian function. When follicles, corpus luteum, and granulosa cells are damaged within the ovary, reproductive endocrine function is inevitably affected. Ovarian arterial hemodynamics showed decreased peak systolic velocity (PSV) an increased resistive index (RI) and pulsatility index (PI), indicating high ovarian and uterine blood flow resistance, poor perfusion, and dysfunctional blood supply, resulting in follicular hypoxia, which affects follicular development, hormone secretion, and ultimately ovarian prematurity.[22],[23]
In recent years, there has been increasing evidence that acupuncture can modulate ovarian function by restoring the morphology of ovarian tissue cells, thereby increasing the number and quality of ovarian cells. Xie Zijing et al.[24] observed the protective effect of acupuncture on the ovaries of mice in a model of ovarian dysfunction caused by Tripterygium wilfordii, selecting bilateral Shenshu, Guanyuan, and Zhongwan acupoints and administering acupuncture every other day; the results showed that in the acupuncture group, the corpus luteum and follicle numbers increased, and the number of closed follicles decreased. Electron microscopy demonstrated less damage to organelles in the acupuncture group, tighter arrangement of granule cells, less damage to organelles, and more lipid droplets. These results show that acupuncture improves ovarian tissue structure, increases the number of follicles, and promotes follicular growth and development. Hua et al.[25] observed morphological changes in the uterus and ovary after 16 days of treatment with acupuncture in rats with impaired OR function and found that the ovaries in the acupuncture group were large, the number of follicles at all levels was markedly increased, the corpus luteum developed well, and the amount of follicle fluid was high, reaching normal levels in the control group. They believed that acupuncture could improve ovarian morphology and prevent impaired OR function. Xiaoguang et al.[26] in a study on a model of premature failure in female rats, found that compared with the model group, the rats in the acupoint catgut embedding combined with TCM group had a marked increase in endometrial and uterine wall thickness, increased normal glands and blood vessels, increased ovarian follicle growth and mature follicle number, and reduced interstitial cells, indicating that the combination of acupoint catgut embedding and TCM improves OR function and has a positive effect on preventing OR function decline and the treatment of POF. Shengjia et al.[27] showed bilateral ovarian enlargement, bilateral ovarian basal sinus follicle count, and endometrial thickness after 3 months of electroacupuncture treatment in patients with DOR, promoting blood circulation and regulating menstruation at the acupoints of Zigong, Luanchao, Guanyuan, Qihai, Tianshu, Sanyinjiao, Pishu, and Shenshu, and significantly more than in the hormone drug treatment group. It can be seen that acupuncture can not only improve the tissue morphology of the uterus and ovaries, but also increase the thickness of endometrium, increase the volume of ovary, improve the environment of follicular growth and development, and thus improve the OR function.
Influence on the neuroendocrine-immune system and enhancement of body immunity
Immune dysfunction is an important contributor to DOR, and the synergistic effects of cellular immunity and proinflammatory cytokines may be important immunological mechanisms in DOR. In addition, autoimmune antibodies, such as anti-ovarian antibody (AOAb), anti-hyaline band antibody (AZPA), and antinuclear antibodies (ANA) can destroy ovarian tissues, inhibit ovarian maturation, and increase follicular atresia.[28] Acupuncture has been shown to modulate ovarian tissue damage caused by autoimmune diseases, cellular immune imbalances, and autoantibody abnormalities, thereby improving the OR.[29]
Regulation of cellular CD4+ and CD8+ levels
Patients with DOR exhibit a proportional imbalance in T-cell subpopulations in terms of cell immunity, manifested by a decrease in CD4+ cells, an increase in CD8+ cells, and a decrease in the CD4+/CD8+ ratio. Wang Qin et al.[30] determined that CD4 and CD4/CD8 were significantly increased, and CD8 was significantly decreased after 3 and 6 months of treatment with abdominal acupuncture combined with moxibustion therapy in patients with POF, suggesting that acupuncture promotes the restoration of ovarian function by modulating cellular immune function.
Regulating the expression of inflammatory cytokines
Increased levels of proinflammatory cytokines, such as interleukin (IL), tumor necrosis factor, and interferon-gamma, cause excessive follicle failure due to increased immune challenge.[31] Ge et al.[32] treated DOR model rats with acupuncture at Shenshu, Guanyuan, and Zhongwan points, the results showed that in the acupuncture group, serum IL-10 increased and IL-21 decreased, follicle growth volume increased, granulocyte layer increased, and follicle atresia decreased, indicating that acupuncture significantly reduced ovarian inflammatory response and attenuated inflammatory damage to favor the growth of oocytes.
Decrease in the number of anti-ovarian antibodies
Abnormal autoantibodies have been found in some patients with DOR, and when Ab is abnormally abundant in AOAb and ANA, an overreactive antigen reacts, resulting in damage to ovarian tissue and failure of normal follicular maturation. Wang Jingbin[33] observed the effect of warm acupuncture combined with TCM on the immune system in patients with DOR, and the comparison of immune function before and after treatment showed that AOAb positivity was significantly reduced after treatment, and ovarian damage due to abnormal immune reactions was reduced; acupuncture and TCM have been shown to be effective in enhancing immune function, improving ovarian function, and reducing clinical symptoms. The neuroendocrine-immune system is an important element for the body to maintain homeostasis in the internal environment. The parts of this system are closely related and interact with each other to participate in various physiological and pathological processes. Regulation of the neuroendocrine immune system by acupuncture and moxibustion is a hot topic of current research. In this study, the regulation of DOR immune abnormalities by acupuncture and moxibustion confirmed their importance.
Effects on proteins related to granulocyte apoptosis
The differentiation of granule cells into thalamic and is closely related to the development of ovarian cells. Parietal granule cells regulate the growth and development of ovarian cells and their own differentiation, proliferation, and apoptosis in paracrine and autocrine manners.[34] In contrast, thalamic cells interact with oocytes to transmit and receive signals that contribute to oocyte development, maturation, and fertilization.[35] Granulocyte proliferation and apoptosis are mediated by interactions between survival factors and apoptosis-inducing factors, and acupuncture can modulate the gene expression of these factors, thereby inhibiting granulocyte apoptosis and delaying ovarian decline.
Regulating the expression of B-cell lymphoma-2 and Bax
Apoptotic factor B-cell lymphoma-2 (Bcl-2) suppresses granule cell apoptosis and reduces follicular atresia, whereas the proapoptotic factor Bcl-associated X protein (Bax) exerts a pro-apoptotic effect. Fang et al.[36] showed that after 14 days of acupuncture at bilateral Shenshu or Guanyuan and Zhongwan in DOR rats, the expression of the Bax gene was reduced in the acupuncture group and the expression of the Bcl-2 gene was increased, with increased E2 and decreased FSH and LH compared with the model group, suggesting that acupuncture reduced granulocyte apoptosis and delayed ovarian decline by regulating Bax and Bcl-2 expression. Zhang Hua et al.[37] randomly divided 72 rats with DOR into equal groups. After 16 days of intervention, Bax levels significantly decreased, and Bcl-2 levels significantly increased in the acupuncture, drug, and acupuncture-drug groups. Acupuncture and TCM are believed to synergistically upregulate the expression of the Bcl-2 protein in the ovary and downregulate the Bax protein, thereby reducing ovarian granule cell apoptosis and follicular atresia.
Decreased p53 and Bad mRNA expression
Upregulation of apoptosis-inducing factors p53 and Bad promotes granulocyte apoptosis and increases follicular atresia.[38] Xiangshan et al.[39] explored the effects and mechanisms of electroacupuncture on granulosa cells in the ovary and found that the granulocyte apoptosis rate and p53 and Bad mRNA expression were significantly lower in the treated group than that in the control group, while the embryo rate and high-quality embryo rate were higher than those in the control group. Electroacupuncture is thought to downregulate p53 and Bad expression, reduce excessive apoptosis in granulosa cells, and improve oocyte maturation and fertilization.
Decreased Fas protein expression
As a death receptor on the cell surface, Fas can induce apoptosis by binding to its ligand FasL. Increased expression of Fas accelerates granulocyte apoptosis and increases follicular atresia, resulting in ovarian immune damage. However, decreased expression of Fas promotes follicular growth and development and contributes to the restoration of ovarian function.
According to Junhong,[40] 15 days after treatment with acupuncture at the Shenshu, Zusanli, and Sanyinjiao points in premenopausal rats, the results showed that acupuncture increased the expression of Bcl-2 protein and decreased the expression of Fas protein in the ovaries, thereby inhibiting granulocyte apoptosis and slowing the process of follicular atresia, providing a favorable environment for follicular maturation and enabling normal ovarian function.
Effects on related signaling pathways
Phosphatidylinositol 3-kinase/protein kinase B/mTOR Signaling
Phosphatidylinositol 3-kinase (PI3K) regulates cell growth, proliferation, and apoptosis in vivo, with protein kinase B (Akt) as its downstream target. PI3K/Akt signaling is mainly mediated by the Akt phosphorylation of downstream target proteins.[41] Zhang et al.[42] explored the mechanism of action of moxibustion in rats with ovarian injury and found that compared with the model group, the rats in the moxibustion group had reduced ovarian tissue injury, reduced expression of phospho PI3K, Akt, and mTOR proteins, reduced serum FSH and LH levels, and increased E2, suggesting that moxibustion may improve hormone levels and promote ovarian recovery by inhibiting PI3K/Akt/mTOR signaling. In an experimental study on DOR rats, Zhang et al.[43] found that the expression of PI3K, Akt, and mTOR mRNA in the acupuncture group increased. Acupuncture can promote follicular development and maturation, and regulate ovarian secretion, and its therapeutic effect is similar to that of estrogen. This mechanism may be related to the activation of PI3K and Akt activities and the inhibition of granulosa cell apoptosis.
Nuclear factor-erythroid 2-related factor 2/heme oxygenase 1 (HO-1) Signaling
Nuclear factor-erythroid 2-related factor 2 (Nrf2) regulates heme oxygenase 1 (HO-1), downstream, and activated Nrf2 protects oocytes by influencing the antioxidant and anti-inflammatory pathways.[44] The Nrf2/HO-1 signaling pathway has been linked to antioxidant stress and modulation of inflammatory responses.[45],[46]
Wang et al.[47] showed that 14 days after a moxibustion intervention in DOR model rats, serum FSH, LH, malondialdehyde in the moxibustion group decreased compared to that in the model group, E2, AMH, superoxide dismutase, Nrf2, and HO-1-associated proteins were increased in ovarian tissues, and it is believed that moxibustion can restore ovarian function by modulating molecular expression of the Nrf2/HO-1 signaling pathway and by enhancing antioxidant stress and sex hormone levels in rats. Lu Geet et al.[32] showed that after 14 days of acupuncture treatment in DOR rats, the acupuncture group not only improved the serum hormonal response but also upregulated Nrf2 and HO-1 protein and gene expression and downregulated NLRP3 mRNA expression, thereby reducing ovarian inflammation and protecting ovarian tissues and function.
Follicle stimulating hormone-cyclic adenosine monophosphate signaling
FSH is an important sex hormone in the reproductive endocrine system that promotes the developmental maturation of follicular exocytosis, luteinization, and steroidogenesis. Specific binding of FSH to granulosa cells by FSHR activates adenylate cyclase, which converts ATP to cyclic adenosine monophosphate (cAMP) and further activates PKA to exert biological effects.[48] Yaqian[49] selected the Guanyuan, Baihui, and Ciliao acupoints for acupuncture treatment in DOR rats. Compared to the control group, the expression of FSHR protein, mRNA, and cAMP content in the ovarian tissue of the acupuncture group was significantly increased, FSH was significantly reduced, and AMH and E2 were significantly increased. It is believed that acupuncture can regulate the expression of signaling molecules in the FSH-cAMP signal transduction pathway and improve ovarian function in DOR rats.
miR-223/AKT/glucose transporter 4 signaling
miR-223 is involved in the pathogenesis of a variety of gynecological disorders; when miR-223 is upregulated, cells undergo G1 arrest, and granulocyte apoptosis increases.[50] Glucose transporter 4 (GLUT4) provides energy to endometrial cells under the control of AKT. miR-223 has been shown to function by influencing GLUT4 and AKT expression.[51] Tingyu[52] showed that ovarian tissue morphology was significantly improved in DOR rats treated with acupuncture combined with medicine 3 weeks after treatment; AMH was elevated, GLUT4 and AKT expression was upregulated, and miR-223 expression was downregulated. Acupuncture combined with medicine can modulate the miR-223/AKT/GLUT4 signaling pathway expression, improve endometrial glucose availability, reduce granulocytic apoptosis, and thus improve uterine and ovarian function. There is increasing evidence that many signaling pathways regulate the growth, proliferation, and apoptosis of oocytes and granulosa cells, thereby influencing the development of DOR. Acupuncture can modulate the expression of genes involved in cell signaling pathways that affect the growth and apoptosis of ovarian cells and improve the OR through individualized therapies.
Clinical ResearchMenstruation and ovulation
In modern medicine, menstrual changes are not only important clinical manifestations of poor ovarian function but also sensitive indicators of aging.[53] A study[54] found that women with a relatively short menstrual cycle (22–25 days) had significantly lower OR function, natural fertility rate, and pregnancy outcome after in vitro fertilization (IVF) than women with a relatively long menstrual cycle (28–31 days and 32–35 days), and that cycle duration shortening may be an early sign of ovarian senescence. At the same time, some patients with diminished OR after treatment of ovarian function recovery are mainly characterized by normal menstruation, and even successful conception. Acupuncture has been shown to improve symptoms of predominantly abnormal menstruation,[55],[56],[57] help restore menstrual resurgence, restore ovulation, regulate ovulation regularity, and regulate the menstrual cycle.
Ovarian reserve
OR is defined as the quality and quantity of OR in the female ovary and is an important indicator of fertility potential; early reduction in OR may occur in approximately 10% of patients for a variety of reasons, irrespective of age.[58] Patients with DOR have significantly reduced odds of ovarian ovulation due to decreased total and quality follicles and are prone to adverse pregnancy outcomes such as spontaneous abortion, recurrent abortion, and fetal chromosomal abnormalities.[59] Currently, the clinical assessment of OR function is based on the comprehensive screening of ovarian-related hormones and ultrasonography. There is no single reliable indicator of OR function, with the key indicators being AFC, AMH, and basal hormones, including FSH, LH, and E2.
Acupuncture treatment has been shown to improve ovarian AFC and oocyte retrieval in DOR and significantly improve embryo embedding and pregnancy rates.[60] Zhou et al.[61] explored the effects of sequential acupuncture treatment on IVF - embryo transfer outcomes in patients with DOR. The results showed that the E2 values, AFC, number of oocytes obtained, number of fertilized embryos, quality of embryos, and clinical pregnancy rates in the acupuncture group were significantly higher than those in the control group, suggesting that acupuncture treatment can improve OR function, promote follicular excretion and fertilization, and positively affect pregnancy outcomes. Dong et al.[62] showed that by increasing AMH and AFC levels and reducing FSH, LH, and E2 levels in patients after a 3-month menstrual cycle, acupuncture at Guanyuan, Taixi, Sanyinjiao, and Taichong as the main acupoints, provided a favorable ovarian environment for pregnancy, thereby increasing the number of oocytes and quality embryos. Li and Yinping[63] used sequential acupuncture to treat a patient with 13 assisted reproductive failures with DOR, and the results showed that AFC increased from 4 to 8, the number of oocytes increased to 7, and healthy embryos were successfully implanted and delivered.
Acupuncture can modulate the HPOA through multiple targets, thereby improving the OR to varying degrees. Zhang Jinwen et al.[64] used the “Tiao Ren Tong Du acupuncture method” with bilateral Guanyuan, Zhongwan, Baihui, Zhongji, Qihai, Mingmen, and Yaoyangguan as the main points. After 3 months of treatment of elderly patients with DOR, the level of E2 increased, the levels of FSH and FSH/LH decreased, and the clinical symptoms of hot flashes, night sweats, and irritability significantly improved. An increase in endometrial thickness is helpful for conception. This mechanism may improve hormone levels by regulating the endocrine function of the HPO axis. Xiaotong et al.[65] randomly assigned 40 patients with DOR to either a control group or a group treated with acupuncture to regulate menstruation and promote pregnancy based on the principle of filling the kidney essence, regulating Chong and Ren, and tranquilizing the mind. The results showed that FSH levels decreased, AFC increased, and anxiety improved. Wang yi et al.[66] applied the heat supplement method with acupuncture at the Guanyuan, Dahe triangle, Shenque, Zigong triangle, and other points, combined with TCM to treat patients with DOR; the control group was treated with TCM alone. The results showed that the total efficacy was 86.7% in the treatment group and 66.7% in the control group, and the E2 was elevated whereas the FSH, LH, and FSH/LH were all markedly decreased. This study demonstrated that acupuncture improves serum hormone levels, delays ovarian aging, and better regulates HPO axis function.
Uterine microcirculation
The developmental maturation and elimination of follicles in the ovary depend mainly on the interstitial blood flow to provide nutrients and hormones; if the local microcirculation of the ovary is disturbed, the blood supply is blocked and the normal function of the ovary is affected, resulting in the developmental maturation of follicles and disturbance of hormone secretion.[67] Hu Jing et al.[68] showed that after three cycles of combined acupuncture with pelvic floor rehabilitation in patients with DOR, PSV increased, RI and PI decreased, ovarian volume increased, AMH and AFC increased, and FSH and FSH/LH decreased, indicating that acupuncture can increase the intraovarian blood supply, optimize the local ovarian microenvironment, and regulate the serum hormone level, thus improving clinical efficacy.
Vascular endothelial growth factor (VEGF), a multifunctional cytokine that is closely related to female reproductive function, promotes neovascularization and vascular permeability in the ovary. When VEGF secretion is decreased, follicular and luteal growth is restricted, and ovarian hormone secretion is dysfunctional.[69] Feng Xiaoling et al.[70] used electroacupuncture combined with the Yuyin Pill to treat patients with DOR and hypomenorrhea. After 3 months, the menstrual volume increased, and the serum VEGF level increased significantly. Menstrual volume reduction is considered a common and significant symptom in patients with DOR. The mechanism of improvement in menstrual status in this study is based on the synergistic action of electroacupuncture and the Yuyin Pill, which enhances ovarian function by upregulating VEGF and improving the circulatory status in the ovary.
Improvement of negative emotions
Research[71] shows that there is a close relationship between mood and human health. Patients with ovarian dysfunction often suffer from anxiety, depression, and other negative emotions that greatly affect their overall health-related quality of life as a result of the diagnosis and progression of the disease. Among infertile couples receiving help using modern assisted reproductive technology, 17.9% of women and 6.9% of men were depressive, and 14.7% of women and 4.5% of men were anxious.[72]
Negative emotional stress activates the hypothalamic-pituitary-adrenal axis, leading to high levels of cortisol secretion, which inhibits the pulsed release rhythm of the hypothalamic GnRH. This affects pituitary gonadotropin secretion and, hence, ovarian function, causing ovarian dysfunction and POF.[73] Approximately half of the patients with POI experience anxiety, anger, guilt, depression, and other negative feelings.[74]
Acupuncture therapy has a significant advantage in ameliorating negative moods.[75] The acupuncture method of regulating menstruation and promoting pregnancy reduced the anxiety self-rating anxiety scale (SAS) score and improved the DOR-related quality of life along multiple dimensions of psychological, physiological, and partial sexual life symptoms, suggesting that the acupuncture method of regulating menstruation and promoting pregnancy improves a wide range of unpleasant feelings[76] and persists until the end of treatment.[77]
In summary, acupuncture as an adjuvant therapy can treat multiple aspects of OR dysfunction. First, menstruation and ovulation are improved; by improving AFC, AMH, and basic sex hormone levels, including FSH, LH, and E2, OR function is improved and pregnancy is promoted. Ovarian function is improved by improving RI and PI of ovarian local microcirculation. Finally, acupuncture can also adjust the negative emotions of patients and improve their quality of life, thereby improving the overall therapeutic effect. Representative clinical studies are presented in [Table 2].
Summary and OutlookThe clinical advantages and treatment concepts of the preventive treatment of diseases by acupuncture are relevant to the health needs of modern society. Acupuncture treatment for DOR starts from the perspective of the “preventive treatment of disease.” By dredging the Qi movement of the meridians and viscera, regulating the rise and fall of Yin Yang in Qi and blood, nourishing the body and spirit, improving negative emotions, the body's OR function is stimulated. The pathogenesis of DOR is located in the uterus, and various pathogenic factors can interfere with the pathogenesis of the uterus by Chong Ren Meridians and Three Foot Yin Meridians. Visceral disorders of the kidneys, liver, spleen, and heart can lead to the occurrence of this disease. Acupuncture treatment of DOR can be achieved by the following mechanisms: Regulating the function of the reproductive endocrine system, improving hormonal levels; restoring the normal morphology of ovarian tissue cells, providing a favorable environment for follicular growth and development; regulating the imbalance of immune cells, inflammatory factors, and autoantibodies; reducing ovarian tissue damage; inhibiting the apoptosis of granule cells, promoting follicular maturation and reducing follicular atresia; regulating the expression of signaling molecules in various signaling pathways; improving ovarian secretion and synthetic function; increasing the rate of neovascularization and blood flow; improving the local circulatory supply of the ovaries; increasing the frequency of ovulation and fertilization during assisted reproduction; and improving clinical pregnancy outcome. Thus, acupuncture therapy has the advantages of a multisystem, multilayered, and multitargeted treatment of DOR. In line with the theory of the “preventive treatment of disease” in TCM, early intervention will help acupuncture achieve more pronounced therapeutic outcomes.
To summarize the current literature on the mechanisms and clinical outcomes of acupuncture DOR and acupuncture for disease prevention, several limitations have been identified. First, the pathogenesis of DOR is linked to genetic mutations and mitochondrial abnormalities, but this area has not been studied, and relatively little is known about the immune system. Second, clinical studies have mostly examined the level of reproductive hormones, protein deficiencies, molecular relationships, and multisystem cross-relationships. Experimental studies have focused on correlations that require further elucidation of specific processes of action between pathways, cells, and molecules. Third, clinical studies have confirmed the short-term efficacy of acupuncture with few adverse effects. However, because the study sample sizes are generally small, the results are not sufficiently generalizable; because the observation time is short, long-term follow-up is absent, and long-term effect cannot be assessed. Last but not least, many clinical studies in acupuncture do not follow the TCM principles of selecting acupoints. The lack of uniform standards for stimulating the number of acupoints, duration at acupoints, and number of treatment cycle makes it difficult to elucidate phenomena and laws from existing results and is not conducive to clinical application and widespread use.
Suggestions for Future ResearchAcupuncture is an important method for the prevention of diseases. The treatment of DOR can be improved in the following aspects by proceeding from a theory related to the meridian and viscera. Theoretical aspects: It is possible to understand the theoretical origins and therapeutic methods of acupuncture for the treatment of uncomplicated diseases, but the relationship between the uterus and the acupoint effect needs to be further confirmed. Fundamental research: Focusing on the protein and molecular levels of DOR mechanisms in acupuncture and multisystem cross-relationship studies based on the relatively large spatial dimension of acupuncture for disease prevention, combined with modern systems biology technology and multi-site time-point data acquisition, it is possible to explore the underlying mechanisms of complexity and key pathways or targets, which may be an effective way to reveal the scientific principles of acupuncture and acupuncture for disease prevention. Clinical studies: In the future, rigorous large-sample, multi-center, multisystem randomized controlled studies should be conducted to standardize the selection of acupoints, extent of acupoint stimulation, time of needle retention, and treatment cycle. We should adopt individualized, precision medicine, real-world research, data acquisition, and analysis methods; scientifically determine the clinical efficacy of acupuncture for preventing disease; establish internationally accepted clinical research norms (or criteria) for acupuncture to prevent disease; and formulate clinical guidelines (or pathways) or a consensus of clinical experts for acupuncture in the prevention of disease.[83]
Data availability
The data used to support the findings of this study have been included in this article.
Authors' contributions
Si-An Pan and Yu Liu designed the study. Zhi-Miao Murong, Yi-Lin Zhu, and Jia-Wei Song reviewed the research and drafted the manuscript. Si-An Pan, Xiao-Rong Chang, and Zeng-Hui Yue critically revised the figures and the manuscript. All authors approved the final version of the manuscript.
Acknowledgments
This study was supported by the National Natural Science Foundation of China (No. 82004490) and the Innovation Platform Open Fund Project of the Hunan Education Department (No. 20K091).
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
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