Jing-Yu Xu,Yi-Hua Fan,Jun-Ze Geng,Na Gao,Feng-Hua Yu,Tian Xia＊

1First Teaching Hospital of Tianjin University of Traditional Chinese Medicine,Tianjin 300193,China.2National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion,Tianjin 300193,China.3Tianjin University of Traditional Chinese Medicine,Tianjin301617,China.

Abstract The decline of ovarian reserve is an important cause of female infertility.More and more older women want to be pregnant again,especially because of the liberal birth policy.But the main reason for limiting fertility in older women is the decline of ovarian reserve.At the same time,due to the change of social environment,the incidence of ovarian function decline has a trend of youth.Therefore,in the infertile women,ovarian dysfunction was found to account for a higher proportion.Finding ways to improve ovarian function is especially important for improving female fertility.Modern medicine has no clear treatment for the disease,only some health products such as coenzyme Q10,dehydroepiandrosterone are used to maintain the ovaries.As a simple and convenient non-drug therapy,acupuncture has been widely used in improving the ovarian function of infertile women in recent years,and its effect has been explored by many researchers.Therefore,this article will start from the human body research and the animal experiment two aspects,discusses the acupuncture improvement ovary function.

Keywords:Acupuncture,Ovarian hypofunction,Infertility,Application

Background

Now the times progress,material development,people’s rhythm of life is gradually accelerated,life style is also gradually diversified.This has been accompanied by a growing number of problems,of which reproductive difficulties are of particular concern[1].Changes in lifestyle cause a lot of health problems,such as endocrine disorders,often leading to hormonal abnormalities in women,especially reproductive hormones[2];and as society becomes more demanding of women,in the new era,the mental pressure on women is increasing,which often leads women to neglect the issue of reproductive health.Studies have shown that the proportion of female infertility is growing in recent years[3].For example,staying up late drinking and eating,etc.,is the most common cause of damage to female ovarian function[4].On the other hand,infertile women with decreased ovarian function experience greater reproductive stress,and even have irregular or amenorrhea,severe anxiety and depression[5,6].This will also seriously affect the quality of life of patients and couples.

Adding to the frustration,there is no clear drug that can restore ovarian function in women.The clinical use of dehydroepiandrosterone,Fertile One PC600,coenzyme Q10 and other health products to alleviate ovarian aging,improve ovarian function,but the effect varies.Therefore,it is very important to find a therapy to improve the ovarian function of women.Acupuncture is a widely used therapeutic method in clinical practice and has been found to have good therapeutic effect in female infertility recently[7].More and more clinical doctors choose to use acupuncture to improve women’s ovarian function,thereby improving women’s fertility[8].At the same time,many interested researchers have emerged to explore the mechanism and specific therapeutic effect of acupuncture on improving ovarian function.Acupuncture is easy to operate in clinic,and reduces the adverse drug reactions[9],which has a higher application value.Therefore,this article will discuss the therapeutic effect of acupuncture from two aspects of human research and animal experiment,in order to summarize and analyze the application progress of acupuncture in ovarian hypofunction.

Research object embodying the effect of acupuncture on improving ovarian function

Patients

Every study used women with ovarian dysfunction as subjects,and the diagnostic criteria for ovarian dysfunction were based on“ESHRE Guideline:management of women with premature ovarian insufficiency”[10],designated by the European Society of Human Reproduction and Embryology in 2016.Reproductive hormones(follicle-stimulating hormone(FSH),luteinizing hormone(LH),estradiol(E2)),anti-Müllerian hormones and the number of ovarian antral follicle under B ultrasound were the main indexes to evaluate ovarian function in the world.

Laboratory animals

Models of decreased ovarian function are often used for research.Because the ovarian volume in animals is very small,specific pathogen free healthy female Sprague-Dawley rats are often used for experimental modeling under the condition of ensuring accuracy[11].

Human body study on the improvement of ovarian function by acupuncture-evaluation of therapeutic effect

Li X et al.[12]showed in a randomized controlled trial that the patients’blood FSH and FSH/LH levels decreased and E2 and antral follicle levels increased after acupuncture treatment and at follow-up compared with those before treatment;and the clinical pregnancy rate after treatment was as high as 15%,suggesting that acupuncture has some effect in promoting pregnancy by improving ovarian function.A prospective study by Wang F et al.[13]also confirmed that acupuncture significantly increased serum E2 levels in patients with ovarian hypofunction.A prospective study by Jie S[14]showed that compared with the pre-needling period,FSH and LH decreased and E2 and anti-Müllerian hormones increased in patients after treatment,while antral follicle did not change significantly;this indicates that acupuncture is more likely to improve ovarian function by regulating reproductive endocrine levels.In the present analysis,it was found that patients with sporadic menstruation due to ovarian hypofunction showed a more significant improvement in pregnancy rate after acupuncture treatment than those with amenorrhea,suggesting that acupuncture can improve menstrual infertility due to ovarian hypofunction to a certain extent.

Animal study on the improvement of ovarian function by acupuncture-mechanism

Structural improvements

A study by Lu G et al.[15]showed that compared with the model group of rats with ovarian atrophy,the ovaries of the group of rats treated with acupuncture after ovarian atrophy showed larger sinus follicles under light microscopy,more granulosa cell layer than the model group,better luteal development,fewer atretic follicles,and less inflammatory infiltration.The study by Fang CC et al.[16]also confirmed that acupuncture could improve the number of follicles in the ovary and reduce atretic follicles;it also showed that acupuncture could reduce Bax mRNA expression levels and increase Bcl-2 mRNA expression levels,thus improving ovarian tissue structure.Wang S et al.[17]showed that acupuncture can upregulate the PI3K/Akt signaling pathway by regulating hormone(FSH,E2)levels in hypovulatory rats,resulting in increased phosphatidylinositol 3-kinase(PI3K),protein kinase B(Also known as Akt),B-cell lymphoma-2(Bcl-2)gene and protein expression levels increase,Bax expression levels decrease,and p-Akt protein expression levels increase,thereby reducing granulosa cell apoptosis and activating follicle development to improve ovarian function.

Functional improvements

In a study by Wang H[18],acupuncture was shown to increase the release of hypothalamic inhibitory neurotransmitters such as dopamine,γ-aminobutyric acid,and β-endorphin and decrease the release of excitatory neurotransmitters such as glutamate and aspartate in de-ovulatory rats,resulting in a hyper-release of hypothalamic gonadotropin-releasing hormone.This reduces the release of hypothalamic gonadotropin-releasing hormone,thereby reducing serum FSH levels,and in this way improves the overall reproductive hormone levels in women through feedback regulation of the hypothalamic-pituitary-ovarian axis.And this study found that the acupuncture effect could also improve the blood supply to the ovaries directly through the sympathetic nerves associated with the ovaries to the supraspinal reflex center,thus regulating the local microenvironment of the ovaries for better follicle development and maturation.

Cheng K et al.[19]observed the effects of acupuncture on the hypothalamic-pituitary-ovarian axis in de-ovulatory rats by acupuncture at“Guan Yuan(RN4)”and“San Yin Jiao(SP6)”points,and the results showed that acupuncture could effectively improve low estrogen and reduce serum hypogonadotropic hormone in rats;this suggests that acupuncture can improve abnormal reproductive hormone levels by regulating the hypothalamic-pituitary-ovarian axis in de-ovulatory rats.

Li Y et al.[20]observed the effect of electroacupuncture on natural perimenopausal rats:compared with the model group,the level of E2 in the electroacupuncture group was significantly higher,and the levels of FSH,LH,and GnRH were all decreased to different degrees.Zhang J et al.[21]showed by systematically evaluating the efficacy of acupuncture on diminished ovarian reserve that acupuncture reduced serum FSH and LH levels more dramatically compared to hormone replacement therapy(Table 1).

Table 1 Summary of acupuncture treatment of ovarian dysfunction

Safety of acupuncture

Acupuncture as a treatment method in clinical application for a long time,its safety is obvious.But this does not mean that acupuncture does not cause harm at all,acupuncture as a means of treating disease,there are still its attention.The performer should have a good knowledge of anatomy and master the method of acupunctur to prevent the organs from being stabbed due to improper angle and depth.

At the same time the use of acupuncture therapy for patients with certain requirements.Patients with weak constitution,high mental stress and coagulopathy are not suitable for acupuncture.Adverse reactions have been reported in the following areas:syncope,stuck needle,subcutaneous hematoma,skin allergy,infection.So on,even if the occurrence rate is extremely low,it is necessary to be cautious in the operation.

Summary and outlook

Acupuncture therapy can be used to treat a variety of diseases.In improving the ovarian function of infertile women,acupuncture also has its unique efficacy.First of all,acupuncture has the flexibility and convenience in clinical practice.Flexibility is based on patients with different symptoms to choose different acupuncture points and techniques,simple that is easy to operate,just a few needles can achieve the treatment goal.And the adverse reaction of the medicine is avoided.Second,acupuncture has been found to regulate the body’s endocrine system,in infertile women,acupuncture can regulate the secretion of female reproductive hormones,thereby improving women’s ovarian function.This role has a holistic nature,and can make the female reproductive axis(i.e.hypothalamus-pituitary-ovary axis)in a balance,which is conducive to women’s reproductive health.

The root cause of female ovarian hypofunction is the generation of large amounts of reactive oxygen species due to oxidative stress in the ovary,which mediates the inflammatory response and activates the apoptotic system;acupuncture can activate the transcription and translation of the anti-apoptotic member Bcl-2 by upregulating the PI3K/Akt signaling pathway,stimulate the expression of anti-inflammatory genes Nrf2 and HO-1 in ovarian cells,thereby reducing the damage to ovarian tissue caused by inflammation and regulating follicular cell proliferation and development.This can reduce ovarian tissue damage caused by inflammation,regulate follicle cell proliferation and development,and improve ovarian function.In a basic study,it was found that the number of sinus follicles and the number of granulosa cells in the ovaries of rats with ovarian atrophy increased after acupuncture treatment.

At the same time,clinical study confirmed that after acupuncture treatment,FSH,LH significantly decreased,and E2 significantly increased in the bodies of women with decreased ovarian function,which reflects the ovarian secretion function has been restored,and it’s conducive to the normal development of follicles;at the same time,anti-Müllerian hormones increased and antral follicle increased under B ultrasound,which indicated the improvement of ovarian reserve function.Acupuncture not only helps women conceive naturally,but also helps women who use assisted reproductive technology to help them conceive,since quality eggs are essential for pregnancy.

As a non-pharmacological treatment,acupuncture has fewer side effects than drugs and is quicker and easier to use than surgical methods.However,as a medical treatment,acupuncture requires professional training,and even if it is easy to perform,it must be done carefully.Although acupuncture is widely used in clinical practice and its efficacy is evident,the occurrence of adverse events such as stagnant needles,dizziness,hematoma,and infection still warrants clinicians’vigilance.The sterilization process should be strictly controlled during the use of needling,the appropriate depth of needling should be mastered,and the patient's status should be asked before treatment is administered.

Current evidence points to the role of acupuncture in improving ovarian function,not only by improving ovarian function,but also by regulating the whole endocrine system of the female body,thereby improving female fertility,increase the pregnancy rate.But future exploration of acupuncture’s effects will go far beyond that.Acupuncture therapy has the characteristic of individualization.The choice and compatibility of acupuncture points,the angle and direction of acupuncture vary from person to person.Therefore,the future needs more rigorous,larger samples of clinical research to explore the most effective way of acupuncture treatment of ovarian dysfunction.At the same time,more basic research is needed to explore the mechanism of acupuncture to improve ovarian function,which is also conducive to the development of more treatments to improve ovarian function.In a word,acupuncture has a good application value in improving women’s ovarian function,which is worth popularizing and applying in clinic.