Diagnosis and treatment strategy of acupuncture-moxibustion for advanced-age infertility in vitro fertilization and embryo transfer based on the temporal rhythm theory of traditional Chinese medicine ✩

Abstract

The ability of natural conception decreases with age, leading many advanced-age women with fertility desire begin to attempt in vitro fertilization and embryo transfer (IVF-ET) technique nowadays. Traditional Chinese medicine (TCM) believes that human body undergoes periodic changes corresponding to the natural rhythms. Women exhibit distinct physiological lunar rhythms of the thoroughfare vessel and the conception vessel, as well as pathological rhythms during the menstrual cycle and IVF-ET cycle. Based on the theory of TCM temporal rhythm, this paper discusses the pathogenesis characteristics of infertility in advanced-age women at different stages. It believes that acupuncture intervention should comply with the following ideas: determining main acupoints based on disease differentiation, with a preference for the acupoints on the thoroughfare vessel, the conception vessel, spleen meridian and kidney meridian, as well as the back-shu points of the liver, spleen and kidney; determining the supplementary acupoints based on syndrome differentiation and symptoms; determining the supplementary acupoints based on time differentiation of lunar rhythm of the thoroughfare vessel and the conception vessel, and ing both and reducing techniques. During the process of intervention, the physical and mental states were balanced simultaneously.

Headnote

ABSTRACT

The ability of natural conception decreases with age, leading many advanced-age women with fertility desire begin to attempt in vitro fertilization and embryo transfer (IVF-ET) technique nowadays. Traditional Chinese medicine (TCM) believes that human body undergoes periodic changes corresponding to the natural rhythms. Women exhibit distinct physiological lunar rhythms of the thoroughfare vessel and the conception vessel, as well as pathological rhythms during the menstrual cycle and IVF-ET cycle. Based on the theory of TCM temporal rhythm, this paper discusses the pathogenesis characteristics of infertility in advanced-age women at different stages. It believes that acupuncture intervention should comply with the following ideas: determining main acupoints based on disease differentiation, with a preference for the acupoints on the thoroughfare vessel, the conception vessel, spleen meridian and kidney meridian, as well as the back-shu points of the liver, spleen and kidney; determining the supplementary acupoints based on syndrome differentiation and symptoms; determining the supplementary acupoints based on time differentiation of lunar rhythm of the thoroughfare vessel and the conception vessel, and ing both and reducing techniques. During the process of intervention, the physical and mental states were balanced simultaneously.

Keywords:

Acupuncture-moxibustion

Infertility

Temporal rhythm

In vitro fertilization and embryo transfer

Advanced age

Infertility refers to the inability to achieve clinical pregnancy for women of reproductive age with normal sexual activity over 12 months [1]. One of the important factors of infertility is the age [2]. At present, there is no universally defined threshold for the advanced age of female fertility; however, multiple studies have shown a significant decline in fertility rates among women over the age of 35 [3]. The study indicates that women over 35 years old who have attempted to conceive for 6 months without success should undergo relevant tests and treatment as soon as possible [4,5]. As age increases, women's endometrial receptivity, ovarian reserve function, oocyte number and quality are declined, resulting in a reduced natural conception ability [6]. In recent years, an increasing number of women with age-related infertility have sought assistance from assisted reproductive technologies (ART), and in vitro fertilization-embryo transfer (IVF-ET) as one of the ART technologies has been developed and applied worldwide [7,8].

The theory of "correspondence between nature and human" in traditional Chinese medicine (TCM) holds that the human and nature are an integrated whole, and physiological and pathological changes in yin and yang, qi and blood in the human body exhibit rhythmic changes in response to natural phenomena. The temporal rhythm theory of TCM is based on observing these periodic changes between the human body and nature, providing guidance for clinical diagnosis and treatment [9]. Throughout the menstrual cycle and IVF-ET cycle, women experience corresponding physiological and pathological rhythms, with fluctuations in qi and blood in the uterus (baogong), the thoroughfare vessel and the conception vessel. The temporal rhythm theory of TCM aids in understanding the disease patterns manifested at different stages, playing a crucial role in guiding the staging-based treatment of acupuncture-moxibustion. Professor Jeffrey C. Hall, Michael Rosbash and Michael W. Young, the Nobel Prize winners in physiology or medicine in 2017, discovered the molecular mechanism for regulating circadian rhythm [10], and it suggests the existence of circadian rhythm changes within the human body. Circadian rhythm, also known as biological clock or biorhythm, plays a crucial role in regulating physiological functions. Disruptions in circadian rhythm can have adverse effects on hormone regulation, making it a potential risk factor for infertility [11]. Based on the theory of TCM temporal rhythm, this paper discusses the treatment of acupuncture-moxibustion in the IVF-ET cycles for infertile women at advanced age.

1. Syndrome differentiation of infertility in females at advanced age

The core pathogenesis of advanced-age infertility is kidney essence deficiency and the dysfunction of the thoroughfare vessel (chongmai) and the conception vessel (renmai). The disease location is the uterus (baogong); the affected zangfu organs are mainly the kidney, liver and spleen; the affected meridians are closely related to the thoroughfare vessel and the conception vessel, and the foot-shaoyin kidney meridian, the foot-jueyin liver meridian and the foot-taiyin spleen meridian.

1.1. Pathogenesis identification: kidney deficiency is the root cause; the disharmony of the thoroughfare vessel and the conception vessel are the key pathological mechanism, and the disease located in the uterus

As women age, the congenital essence gradually depletes, resulting in kidney essence deficiency and the dysfunction of the thoroughfare vessel and the conception vessel; thus, baogong fails to retain the essence/sperms and achieve conception, manifesting as infertility. The most common syndromes of advanced-age infertility are kidney essence deficiency, liver gi stagnation, blood stagnation, and kidney yang deficiency with phlegm dampness [12]. Kidney deficiency is manifested by irregular menstrual cycle or amenorrhea, scanty menstrual flow, and soreness and weakness of the lumbar region and knee joint. Kidney yin deficiency is combined with feverish sensation of the palms and soles, dry mouth, insomnia and dream-disturbed sleep. For the patients of kidney deficiency combined with liver gi stagnation, the additional symptoms are emotional depression, irritability, hot temper, and breast distention. For kidney deficiency combined with blood stagnation, the patients may have dark menstrual flow, menses with clots and dysmenorrhea. For kidney yang deficiency combined with phlegm and dampness, profuse leukorrhea, obesity, chest oppression and abdominal distention are combined.

The baogong in TCM includes the uterus and bilateral fallopian tubes and ovaries. The treatment of acupuncture-moxibustion emphasizes "needles reaching the location of illness" or "qi conducting to the illness site". It shows that the disease location is indispensable in the treatment of acupuncture-moxibustion [13]. The modern medicine believes that the main reason of the decrease in pregnancy rate in the advanced-age women is the reduced ovarian reserve function [14]. By integrating both TCM and modern medicine perspectives, the disease location in acupuncturemoxibustion treatment for infertility can be understood as the baogong.

1.1.1. Taking the priority of zangfu differentiation and qi-blood differentiation, determining the zangfu location of infertility and distinguishing between blood deficiency and blood stagnation

Regarding zangfu differentiation, the baogong refers to the extraordinary organ in TCM, and is most closely related to the kidney, liver and spleen. Kidney, as the foundation of innate essence, governs reproduction. Baogong relies on kidney essence and kidney ут for nourishment and kidney gi and kidney yang for warmth to maintain its function. The prosperity of kidney essence determines whether the baogong can regularly store and release essence, facilitating conception. Liver stores blood and governs the free flow of gi; when gi and blood are abundant, baogong can be nourished. Spleen, as the foundation of acquired essence, is the source of qi and blood.

Concerning gi and blood differentiation, blood is the foundation for females. Throughout their lives, women undergo menstruation, pregnancy, and childbirth, making them prone to blood deficiency syndromes characterized by "excess of gi and deficiency of blood". It is mentioned in Zhenjiu Jiayi Jing (The Systematic Classic of Acupuncture and Moxibustion) that blood stagnation is one of etiology and pathogenesis of infertility. Therefore, it can be inferred that advanced-age women with infertility are more likely to present with blood deficiency or blood stasis syndromes in clinical practice.

1.1.2. Integrating with meridian differentiation, focusing on meridian and acupoint examination and exploring the relationship between acupoint reaction and advanced-aged infertility

Meridian differentiation is important in gynecological disease. Based on meridian theory, in association with the running course of meridian, indications, pathological and physiological characteristics of meridian, as well as the meridian and acupoint detection, the affected meridian and disease characteristic can be determined. In clinical practice of acupuncture-moxibustion, the meridian-acupoint examination is conducted along the running courses of the thoroughfare vessel and the conception vessel of the lower abdomen and along the paths of the three yin meridians of foot of the lower limbs. By palpation, the temperature and elasticity of the skin, the muscular softness of the lower abdomen, the positive reactions at the acupoints such as tenderness, striplike cord and clustered nodules, can be detected; and the location of illness, and the nature of disease such as cold, heat, deficiency and excess can be determined [15].

TCM attaches great importance to the effect of the thoroughfare vessel and the conception vessel on menstruation, vaginal discharge, pregnancy and childbirth. These two meridians originate from the baogong. The conception vessel starts from the site below Zhongji (CV3), thoroughfare vessel is regarded as the "sea of blood", while the conception vessel governs the fetus. Blood is considered the foundation for women. The abundance of gi and blood in the thoroughfare vessel and the conception vessel are closely related to the women' ability to conceive. In gynecology of modern TCM, the theory of "heart (brain)-kidney-uterus reproductive axis" [16] pointed by Gui-cheng XIA integrates the baogong and the above two meridians of TCM with the modern medical concept of the "hypothalamic-pituitary-ovarian axis". According to this theory, the heart houses mind (shen), the brain is the residence of primary shen, corresponding to the functions of hypothalamus and pituitary gland. The kidney dominates reproduction and sexual functions, produces the Tiangui (a vital essence related to puberty and fertility), and regulates the thoroughfare vessel and the conception vessel, which encompass the ovarian functions of modern medicine. The author's research team also found a relationship between acupoint reactions and advanced-age infertility through long-term clinical experience, for instance, the cold skin of the lower abdomen with poor elasticity, soft lower abdomen, is mostly identified as deficiency and cold syndrome. The team also discovered that in patients with primary dysmenorrhea and adenomyosis, the positive response rate on the running course of spleen meridian in the lower limb was significantly higher than that of the foot-jueyin liver meridian and foot-shaoyin kidney meridian. Since acupoints act as treatment points for diseases as well as external manifestations of the disease, this suggests a closer relationship between the foot-taiyin spleen meridian and gynecological disease [17]. Furthermore, meridian point reaction is also closely related to the lunar rhythmic changes of the thoroughfare vessel and the conception vessel. The women with advanced-age infertility are generally accompanied with irregular menstrual cycles and scanty menstrual flow. During menstruation, the tenderness commonly appears near to the acupoints of Sanyinjiao (SP6) and Diji (SP8), manifested by soreness, distention and dull pain. During the period of non-menstruation stage, the tenderness points are generally not detected on spleen meridian, while there is a feeling of indentation with a distinct sense of emptiness, which aligns with the main pathogenesis of kidney deficiency [18].

In summary, the disease location of advanced-age infertility lies in the baogong, governed by the dysfunction of the kidney, liver and spleen, and closely associated with the thoroughfare vessel, the conception vessel and the foot-taiyin spleen meridian. The disorders of zangfu and meridians are consequently manifested as the abundance and deficiency of gi and blood.

1.2. Identifying time: correlation of the physiological and pathological rhythms of menstruation, IVF-ET and day and night

The thoroughfare vessel and the conception vessel exhibit a physiological lunar rhythm. The abundant gi and blood of these two meridians supplies the full nourishment to baogong, the overflow of blood results in the onset of menstruation, which is referred as "fullness/excess", representing the menstrual phase. After menstruation, qi and blood of these two meridians is gradually declined, the meridian circulation is retarded, which is referred as "consumption/deficiency", representing the postmenstrual phase or follicular phase. Zangfu transforms blood, and the thoroughfare vessel and the conception vessel turn to be full, the meridian circulation becomes smoother, which is referred as "filling-up", representing the premenstrual phase, or the luteal phase [19].

Women undergoing the IVF-ET cycle will experience processes including ovulation stimulation, egg retrieval, and embryo transfer, in which their body will also have corresponding pathological rhythmic changes. In the IVF-ET cycle, during the controlled ovarian stimulation, doctors monitor hormone levels and adjust the dosage of exogenous gonadotropins as needed [20]. At this stage, the thoroughfare vessel and the conception vessel, as well as the sea of blood are in a state of "deficiency", additionally, the direct effect of exogenous substances on the "kidney-tiangui (menstruation, sexual function)-chongren (thoroughfare vessel and conception vessel)-baogong axis" easily leads to the imbalance of gi and blood of these two meridians. Meanwhile, the use of exogenous drugs promotes the development and ovulation of multiple follicles, leading to the consumption of kidney essence and the deficiency of gi and blood of these two meridians. Oocyte pickup is an invasive process, Which easily damages qi and blood of the baogong, the thoroughfare vessel and the conception vessel, resulting in gi and blood stagnation. In addition, egg retrieval causes the loss of numerous granular follicles, further increasing the likelihood of kidney deficiency in women during this phase compared to a natural cycle [21]. Before embryo transfer, the thoroughfare vessel and the conception vessel, as well as the sea of blood gradually fills; and after embryo transfer, the thoroughfare vessel and the conception vessel, as well as the sea of blood are in full state.

2. Acupuncture-moxibustion treatment strategy for advanced-aged infertility women during IVF-ET cycle

According to the change of physiological and pathological rhythm, acupuncture treatment for advanced-age infertility should adopt the staged regimens on the basis of a basic prescription. At the beginning of IVF-ET, the tonic regimen is applied by replenishing the kidney, with a combination of acupuncture and moxibustion, for a treatment period of at least three menstrual cycles or more. Before ovulation stimulation and egg retrieval, the treatment focuses on replenishing the kidney, combined with promoting blood and qi circulation, incorporating electroacupuncture. After egg retrieval and before embryo transfer, the treatment is emphasized on replenishing the kidney and regulating the thoroughfare vessel and the conception vessel, and the acupoints at the lumbosacral region are added to strengthen the therapeutic effect. After embryo transfer, the regimen is modified to replenish the kidney, strengthen the spleen and calm the mind, with the addition of auricular acupressure. It is noteworthy that "regulating the mind" is crucial throughout the entire process of treatment.

2.1. Developing basic acupuncture-moxibustion prescription based on the integration of disease and syndrome differentiation

2.1.1. Determining main acupoints based on disease differentiation, taking the acupoints of the conception vessel, spleen meridian and kidney meridian, as well as the back-shu points of liver, spleen and kidney as the priority

The core pathogenesis of advanced-age infertility is kidney qi deficiency and dysfunction of the thoroughfare vessel and the conception vessel. Therefore, throughout the entire IVF-ET cycle, the major principle of treatment should focus on tonifying kidney qi and regulating the thoroughfare vessel and the conception vessel. The main acupoints are composed of the acupoints of the conception vessel, foot-taiyin spleen meridian and foot-shaoyin kidney meridian, back-shu points, which include Qihai (CV6), Guanyuan (CV4), Zhongji (CV3), Huangshu (KI16), Sanyinjiao (SP6) and Taixi (KI3).

CV6, CV4 and CV3 are located in the lower abdominal region, nourishing the gi and blood of the thoroughfare vessel and the conception vessel, cultivating the primary yin and yang. Of these three points, CV6 is specialized on regulating and promoting д! movement, CV4 is on replenishing kidney and warming the lower jiao, and CV3 is on activating blood circulation and resolving stasis. When needling these three acupoints, the needle tip is inserted downward to conduct meridian qi to baogong. KI16 is the site where the congenital qi gather. When puncturing this acupoint, the needle is inserted toward Shenque (CV8), to cultivate the congenital qi, and regulate gi and blood of chongmai and renmai. SP6 is the key point for regulating menstruation, regarded as "the sage point of gynecology", working on nourishing qi, tonifying the liver and kidney, regulating the circulation of gi and blood and stabilizing emotions. From the previous discussion, it is known that SP6 often shows tenderness or other positive reactions during the menstrual period, showing its dynamic changes. Therefore, before acupuncture operated, it is advisable to press along the spleen meridian over the area around SP6 to locate the most sensitive reactive site; and acupuncture should then be performed at this site, with the needle inserted obliquely upward, to conduct the meridian gi to baogong. In clinical practice, tenderness may also be found around the Sanyinjiao area, extending approximately 3 to 5 cm along the running course of spleen meridian, and acupuncture can target SP6 and two or three other points along this area, applying the technique of "dispersing needle method." KI3 works on replenishing kidney qi, the reinforcing technique should be operated at this point. Hold the needle handle firmly and rotate the needle in small amplitude with the thumb moved clockwise forcefully and rapidly. Deqi is obtained when the needle handle bounces up and down. Besides, moxibustion can be applied with a moxa box placed directly on the lower abdominal region to achieve a warming yang effect.

2.1.2. Determining the supplementary points according to syndrome differentiation and symptoms

Acupoint selection by syndrome differentiation: in advancedaged infertility, kidney deficiency is often accompanied by other syndrome, including the deficiency of gi and blood, blood stagnation and liver gi stagnation. (1) For kidney yang deficiency predominated, Mingmen (GV4) and Yaoyangguan (GV3) are added to tonify the kidney, cultivate the primordial gi and warm kidney yang. For kidney yin deficiency predominated, Rangu (KI2) and Fuliu (KI7) are added to nourish yin and clear heat. For severe kidney deficiency, Yongquan (KI1) is added and stimulated with fine needle and punctured superficially to activate qi of kidney meridian. (2) When accompanied by gi and blood deficiency, Zusanli (ST36) and Zhongwan (CV12) are added to tonify gi and blood. (3) When accompanied by spleen deficiency, Taibai (SP3), Pishu (BL20) and Daheng (SP15) are added to strengthen the spleen and boost up qi. (4) When accompanied by blood stagnation, Zhaohai (KI6), Lieque (LU7), Xuehai (SP10) and Geshu (BL17) are added. (5) When accompanied by liver gi stagnation, Taichong (LR3), Hegu (14), Waiguan (TE5) and Ganshu (BL18) are added to smooth liver qi.

Supplementary points selected according to symptoms: for irregular menstruation, Shuifen (CV9), Shuidao (ST28), Guilai (ST29), LU7 and KI6 are added to regulate gi and blood of chongmai and renmai. For polycystic ovarian syndrome, Daimai (GB26), Yinlingquan (SP9), Fenglong (ST40), Tianshu (ST25) and CV12 are added to strengthen the spleen, resolve phlegm and remove dampness. For adenomyosis, KI6, SP8, Shiqizhui (EX-B8), LR3 and LI4 are added to active blood circulation and resolve stasis. For the organic disease such as pelvic inflammation, Zigong (EX-CA1), reproductive area of scalp acupuncture, Ligou (LR5), Xingjian (LR2) and Xiaxi (GB43) are added to clear heat and remove dampness.

2.1.3. Determining the supplementary points based on the lunar rhythm of the thoroughfare vessel and the conception vessel, and combining both reinforcing and reducing methods

Based on the lunar rhythm of the thoroughfare vessel and the conception vessel, the staging-based treatment is determined in compliance with the different pathological characteristics in menstrual cycle [22]. During menstrual phase, the sea of blood is full and spilled over, the blood chamber is open, the transition from yang to yin occurs, yang begins to transform into yin when its energy reaches the peak, yang is getting weaker, and yin starts becoming dominant, and the thoroughfare vessel and the conception vessel are gradually depleting. At this stage, SP10, KI6, LR3 and LI4 are added to activate blood circulation, nourish blood and regulate menstrual flow. When needling LR3, the needle tip is penetrated toward KI1 to mutually smooth liver gi and replenish the kidney. After menstruation, these two meridians gradually replenish, CV9, ST25 and ST36 are added to strengthen the spleen, replenish the kidney, nourish gi and blood; and SP10 and CV4 are added to nourish yin and cultivate yang. At intermenstrual stage (ovulation phase), the transition from yin to yang occurs, yin begins to transform into yang when its energy reaches the peak, yin is getting weaker, and yang starts becoming dominant, KI6 and SP8 are added to replenish the kidney, activate blood circulation and promote regular ovulation. At premenstrual stage, the thoroughfare vessel and the conception vessel reach fullness, ST28, ST29, BL23 and GV3 are added to warm and strengthen kidney yang, nourish kidney yin and balance yin and yang of the kidney.

2.2. Staging-based treatment associated with different time points of IVF-ET

2.2.1. Ovulation stimulation and egg retrieval

During controlled ovarian hyperstimulation, the body is in a state of imbalance of chongmai and renmai, as well as the depletion of kidney essence. In addition to the main acupoints in treatment, moxibustion is greatly considered to warm and tonify gi and blood. Besides, the use of ovulation induction drugs may easily cause ovarian hyperstimulation syndrome [23], manifested as abdominal distention. Gongsun (SP4), PC6 and CV12 are added to regulate gi and harmonize the stomach. SP4 and PC6 are a pair of confluent points, linked with the thoroughfare vessel and yin-heel vessel. This pair of points can regulate and control gi and blood of the thoroughfare vessel and the conception vessel, and strengthen the spleen, harmonize the stomach and regulate qi. Animal experiment has shown that acupuncture at PC6 can inhibit the transmission of y-aminobutyric acid, and reduce the inhibition of vagus motor nerve fibers, thus promoting gastrointestinal peristalsis [24].

2.2.2. Before embryo transfer

The treatment before embryo transfer should focus on replenishing the kidney, filling up the essence, warming the kidney, strengthening yang, benefiting gi and invigorating blood and promoting pregnancy. Based on the main acupoints, the acupoints of the governor vessel and foot-taiyang bladder meridian in the lumbosacral region should be added, such as BL23, GV4, GV3, EX-B8 and Ciliao (BL32).

During acupuncture, a stronger sensation is desired, with the ideal response being a local feeling of numbness and radiation. In association with the anatomy of modern medicine, the pelvic visceral nerves innervating the internal genitals are from the 2nd to 4th sacral segments of the spinal cord [25] and are distributed under the acupoints of lumbosacral region. Therefore, acupuncture at these acupoints can directly stimulate the illness location and regulate the nerves of reproductive system. BL23 is the site where kidney qi infuses. The needle is punctured penetrating toward the governor vessel, to regulate the governor vessel and foottaiyang bladder meridian simultaneously. GV4 and GV3 are the acupoints with most abundant yang qi along the governor vessel, acting on replenishing kidney yang, warming the uterus and eliminating cold. The V lumbar nerve is distributed under ЕХ-В8, this nerve and the ipsilateral pelvic visceral nerve composes of the pelvic plexus together and are distributed in the cervix and vaginal fornix. Acupuncture at this point can directly regulate the function of the pelvic organs [26]. BL32 is punctured deeply to conduct the needling sensation to the lower abdominal region. The above mentioned two sets of acupoints (one set in the front, and another set on the back) are combined to regulate yin, yang, gi and blood through the conception vessel and the governor vessel and replenish kidney and benefit gi through spleen and kidney meridians; and regulate the pelvic nerves in association with the acupoints at the lumbosacral region. The author's research team found that on the day of embryo transfer, acupuncture before transfer resulted in a clinical pregnancy rate of 55.2%, which was higher than the 40.0% in the control group without acupuncture intervention [27].

2.2.3. After embryo transfer

After embryo transfer, the treatment should focus on strengthening the spleen, replenishing the kidney and protecting the fetus. Besides the regular acupuncture with filiform needle, auricular acupressure with ear seeds is recommended, particularly for patients experiencing severe anxiety and poor sleep quality. Before auricular acupressure applied, a cotton swab is used to locate the tender points (positive reaction), and the ear seeds are being pressed onto positive response points. This method is safe, noninvasive, and provides persistent stimulation to achieve a sedative effect. The auricle is innervated by several nerves, including the auricular branch of vagus nerve, with the auricular concha being the most densely innervated region. Vagus nerve, the longest cranial nerve in the body, is an important part of the parasympathetic nervous system, which governs the function of the internal organs of the chest, abdominal cavity and maintains the internal balance of the body [28]. Study has shown that stimulating the auricular vagus nerve can activate the brainstem solitary bundle nucleus, affect the locus coeruleus, and regulate the secretion of neurotransmitters, thus promote sleep [29].

2.3. Regulating the physical and mental state simultaneously throughout the whole treatment

Women with advanced-age infertility are prone to experiencing negative emotions such as anxiety, tension or depression due to prolonged infertility. From the perspective of ancient philosophy of TCM, this results from the mutual influence between the "body shape" and "heart mind".

From the perspective of modern medicine, circadian rhythm disturbance results from the dysfunction of the hypothalamus, which leads to an imbalance of body mechanism such as hypothalamic-pituitary-gonadal axis, indicating a close relationship with the brain. As discussed in previous sections, the heart (brain)-kidney-uterine reproduction axis of TCM corresponds to the hypothalamic-pituitary-gonadal axis of modern medicine. It can be considered that the circadian rhythm disorder is associated with the dysfunction of heart mind of TCM. TCM believes that the "body shape" and "heart mind" mutually affect each other [30]. Therefore, while the "body shape disorder" is treated, the treatment of "mind disorder" should be equally emphasized. In other words, the shape and the mind should be regulated simultaneously, and the mind regulation may exert therapeutic effect on body shape disorder. In acupuncture-moxibustion regimen, the acupoints on the head are used to regulate the brain mind, and the acupoints of the heart and pericardium meridians, as well as the back-shu point of heart are selected to regulate the heart mind, the acupoints of the liver meridian and the back-shu point of liver are used to regulate liver mind.

3. Summary

Multiple domestic and international studies have shown that fertilization rate, embryo implantation rate, clinical pregnancy rate in assisted reproductive technology decline with age for advancedage infertility women [31,32]. Acupuncture can promote ovulation, adjust hormone levels, improve the quantity and quality of dominant follicles, advance the endometrial blood supply and receptivity, and effectively increase the pregnancy rate [33]. For advancedage women with infertility, during menstrual and IVF-ET cycles, qi and blood of the thoroughfare vessel, the conception vessel and baogong exhibit corresponding rhythmic changes. Hence, the staging-based treatment of acupuncture-moxibustion is crucial. On the basic principle for replenishing the kidney and regulating menstruation, the treatment should focus on activating blood circulation and nourishing blood during menstruation, strengthening the spleen and replenishing the kidney at the post-menstrual stage, promoting blood circulation and regulating gi at ovulation stage, and tonifying yin and yang at premenstrual stage. During ovarian stimulation and egg retrieval, kidney gi nourishment is important. Before embryo transfer, the anterior and posterior acupoints are selected and combined to harmonize gi and blood. After embryo transfer, the treatment focuses on replenishing the kidney, strengthening the spleen and calming down the mind. At each stage, the different therapeutic methods and the techniques of acupuncture and moxibustion are adopted correspondingly, which embodies the theoretic basis of TCM of "treatment determined according to the variability of individual and time".

Acknowledgments

The authors thank all the reviewers who have provided their valuable comments in the revision of our manuscript: Shu-han QU, PhD; Xiao-lin SONG, PhD; Sha-sha YI; Chu-feng WANG.

CRediT authorship contribution statement

Shu Bee CHEN: conceptualization, writing-original draft

Jing LIU: writing-original draft

Xue-si HOU: writing-review & editing

Li-kun YANG: data curation

Yi-ni SUN: data curation

Shu-qi MI: supervision

Ji-ping ZHAO: conceptualization, supervision, writing-review & editing

Role of the funder/sponsor

The sponsor is Dongzhimen Hospital, affiliated to Beijing University of Chinese Medicine. The study sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data sharing statement

You can contact the corresponding author for the data.

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ARTICLE INFO

Article history:

Received 6 December 2023

Revised 15 October 2024

Accepted 4 March 2025

Available online 9 March 2025

References

References

[1] Chen ZJ, Liu JY, Huang HF, Qiao J, Zhou CQ, Huang GN, et al. Guidelines for the diagnosis of infertility. Chin J Obstet Gynecol 2019;54(8):505-11 .

[2] Devesa-Peiro A, Sebastian-Leon P, Parraga-Leo A, Pellicer A, Diaz-Gimeno P. Breaking the ageing paradigm in endometrium: endometrial gene expression related to cilia and ageing hallmarks in women over 35 years. Hum Reprod 2022;37(4):762-76 .

[3] Loh SF, Agarwal R, Chan JK, Chia SJ, Yu SL. Academy of medicine-ministry of health clinical practice guidelines: assessment and management of infertility at primary healthcare level. Singap Med J 2014;55(2):58 .

[4] Medicine Chinese Society of Reproductive. Clinical practice guidelines for assisted reproduction in elderly infertile women in China. Chin J Evid Based Med 2019;19(3):253-70 .

[5] Pfeifer S, Goldberg J, Lobo R, Thomas M, Widra E, Licht M, et al. Definitions of infertility and recurrent pregnancy loss: a committee opinion Fertil Steril. Offic J Am Fertil Soc, Pacific Coast Fertil Soc, Cndn Fertil Androl Soc 2020;113(3):533-5 .

[6] Pathare ADS, Loid M, Saare M, Gidlöf SB, Zamani Esteki M, Acharya G, et al. Endometrial receptivity in women of advanced age: an underrated factor in infertility. Hum Reprod Update 2023;29(6):773-93 .

[7] Zegers-Hochschild F, Adamson GD, Jd Mouzon, Ishihara O, Mansour R, Nygren K, et al. The International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary on ART terminology, 2009. Hum Reprod 2009;24(11):2683-7 .

[8] Carson SA, Kallen AN. Diagnosis and management of infertility: a review. JAMA 2021;326(1):65-76 .

[9] Chen HL, Guo CJ, Li RQ, Wang HZ, Wang BZ, Cao LY, et al. Clinical insights into the time rhythm of Jin Gui Yao Lue from the perspective of chronomedicine. Chin J Tradit Chin Med 2023;38(04):1465-8 .

[10] Rosbash M. Circadian rhythms and the transcriptional feedback loop (Nobel lecture). Angew Chem Int Ed Engl 2021;60(16):8650-66 .

[11] Zhao MJ, Zong ZQ, Wang XC, Tang Y. Research progress on circadian rhythm disorders and infertility. Pract Prev Med 2023;30(12):1545-50 .

[12] Zhou X, He FJ, Li N, Li XN, Bai J, Zhu HL. Distribution of Traditional Chinese Medicine syndrome types on trigger day in 230 advanced age women undergoing in vitro fertilization-embryo transfer and its relation to pregnancy outcomes. Chin J Info Trad Chin Med 2022;29(08):107-11 .

[13] Tian HF, Chen YX, Zhou QC, Wang L, Wen ZH, Tang J, et al. On "differentiating disease location" as the first step in acupuncture syndrome differentiation and treatment. Chin J Trad Chin Med 2015;30(11):3807-10 .

[14] Reproductive Medicine Branch of Chinese Medical Association. Guidelines for diagnosis and treatment of infertility in women in advanced age. Chin J Reprod Contracept 2017;37(2):87-100 .

[15] Zhao JP. Meridians and acupoint diagnosis: an important method to improve clinical diagnosis and treatment of acupuncture. Chin Acupunct Moxibust 2018;38(10):1119 .

[16] Tang XR, Zhou HF, Zhong QX, Feng H. The treatment of hyperprolactinemic infertility based on the "heart (brain)-kidney-uterus reproductive axis" theory by master of Chinese Medicine Xia Guicheng. Trad Chin Med Info 2021;38(12):62-5 .

[17] Wang GQ, Zhang JJ, Du SH, Xie XL, Du SH, Han GX, et al. Application of meridian and acupoint diagnosis of the three yin meridians in acupuncture treatment of gynecological diseases. Chin Acupunct Moxibust 2023;43(05):565-8 .

[18] Tan C, Zhang C, Zhang JJ, Wang J. Professor Zhao Jiping's experience in treating primary dysmenorrhea using meridian diagnosis. Chin Acupunct Moxibust 2016;36(03):303-6 .

[19] Meng X, Zhao JP, Cheng L, Mi SQ, Zhang XD. Application of Trad Chin Med time rhythm in acupuncture clinical practice. J Tradit Chin Med 2020;61(4):311-14 .

[20] Qiao J, Ma CH, Liu JY, Ma X, Li SW, Yang YZ, et al. Expert consensus on ovarian stimulation for assisted reproductive technology. Reprod Contracept 2015;35(4):211-23 .

[21] Tan Y. Application and reflection of integrative Chinese and western medicine methods in in vitro fertilization-embryo transfer. Chin J Integr Med 2021;41(02):167-71 .

[22] Hou XS, Zhou QC, Wang L, Cheng L, Zhao JP. Acupuncture diagnosis and treatment approach for secondary dysmenorrhea in uterine adenomyosis based on disease location and mechanism. Chin Acupunct Moxibust 2017;37(10):1108-12 .

[23] Wang ZY, Zhang YZ. Research progress on prevention and treatment of ovarian hyperstimulation syndrome. Pharm Guide 2016;35(01):62-6 .

[24] Lu M, Chen C, Li W, Yu Z, Xu B. EA at PC6 promotes gastric motility: role of brainstem vagovagal neurocircuits. Evid Based Complement Alternat Med 2019;2019:7457485 .

[25] Jiang GH, Wang HF, Si YC, Li XH, Wang YF, Luo YF. Local anatomy. Beijing: China Traditional Chinese Medicine Press; 2016 .

[26] Zhao JF, Han JL. A brief discussion on the clinical application of the 17 vertebral acupoints. Asia Pacific Trad Med 2016;12(24):73-4 .

[27] Wang YR, Wang SZ, Kiltz R, Zhao JP. The effect of acupuncture intervention at different time points on pregnancy rates following frozen-thawed embryo transfer. Chin Acupunct Moxibust 2022;42(09):987-90 .

[28] Butt MF, Albusoda A, Farmer AD, Aziz Q. The anatomical basis for transcutaneous auricular vagus nerve stimulation. J Anat 2020;236(4):588-611 .

[29] Yakunina N, Kim SS, Nam EC. Optimization of transcutaneous vagus nerve stimulation using functional MRI. Neuromodulation 2017;20(3):290-300 .

[30] Wang SZ, Yang C, Tian HF, Du SH, Fu WB, Zhao JP. From the concept of body- mind unity to psychosomatic medicine: theory and practice in acupuncture clinical practice. Chin Acupunct Moxibust 2023;43(04):390-4 .

[31] MD H. State of the ART: assisted reproductive technologies in the United States. Reprod Sci 2016;23(12):1630-3 .

[32] Zhang XD, Deng CY, Huang XF, Liu P, Zhou CQ, Feng Y, et al. Chinese society of reproductive medicine: 2019 report on assisted reproductive technology data. Reprod Med 2022;31(8):1015-21 .

[33] Sun KF, He MR, Ou YF, Li XX, Kong DM, Zhang CF, et al. Clinical research progress on acupuncture treatment of ovulation disorders. Chin Med Herald 2020;17(16):49-53 .

Footnote

* Supported by Beijing University of Chinese Medicine First Class Discipline Construction:90010961020079

* Corresponding author.

E-mail address: [email protected] (J.-p. ZHAO).

* Theses authors contributed equally to this work.