Evaluating theclinical efficacy of Thunder-Firemoxibustion combined with ovulation monitoring in thetreatment of adenomyosiscombined with infertility

Hua Wang,Yan Chen,Yong Yin,Chun-Hua Cao,Sai-Li Wang,Qin Wang*,De-Xi Peng,Chun-Jian Zhu,Lin-Wei Chen*

1Taizhou Hospital of Traditional Chinese Medicine,Affiliated to Nanjing University of Traditional Chinese Medicine,Taizhou,China.

Background

Adenomyosis(AM)is the benign invasion of endometrial tissue into the myometrium,with the characteristics of growth of ectopic,non-neoplastic,endometrial glands,and local or diffuse lesions of stroma within adjacent hypertrophic and hyperplastic myometrial tissue[1,2].The clinical manifestations are progressive dysmenorrhea,an enlarged uterus,and increased and prolonged menstrual flow.The incidence of AM has increased along with the increase in the number of women delaying childbearing to an older age.It is not clear whether AM is common in subfertile women or that it is a cause of infertility[3].It is estimated that 30%-50%of AM patients are infertile and that infertile women are 6-8 times more likely than healthy fertile women to develop AM[4-6].Although AM is a benign disease,its biological behaviors include infiltration, tissue destruction, and recurrence, which are also the characteristics of malignancy.The 2 year recurrence rate of AM is more than 30%,the cure rate is low,and AM can severely affect the health and quality of life of women of childbearing age [7 - 9]. The definitive treatment for AM is hysterectomy.However,it is less benifical to patients who wish to preserve their fertility [10].Currently,improving the chance of pregnancy in AM-associated infertility ischallenging.

Thunder-Fire moxibustion, a kind of special moxibustion therapy,stemmed from the Taoism magic arts before the Yuan Dynasty of China(1271 A.D.-1368 A.D.)and took shape in the middle of the Ming Dynasty of China(1368 A.D.-1644 A.D.).Thunder-Fire moxibustion was first recorded in the Bencaogangmu,a book published in 1578 A.D.and described as Thunder-Fire god needle.Today,it is still developing and applying by many doctors.The pathology of AM is considered as cold stagnation and blood stasis in traditional Chinese medicine (TCM).Thunder-Fire moxibustion has the effects of warming channel,activating the blood and relieving pain[11-13].Modern medical research find it can alleviate the symptoms of AM,including cold pain in the lower abdomen,cold extremities,and dark purple menstrual color.It also increases sperm-egg compatibility resulting in fertility[14-15].

Thunder-Fire moxibustion has been used to treat various gynecological diseases[16,17],infertility[18],dysmenorrhea [19],pelvic inflammation [20] and endometriosis [21]. In this study, Thunder-Fire moxibustion was used in combination with ovulation monitoring to treat AM-associated infertility and explore the characteristic treatment of TCM to lay the foundation for further study of the mechanism of action.

Material and Methods

Patients

A total of 120 patients admitted to the Department of Gynecology of Taizhou Hospital of TCM between January 2013 and June 2017 were diagnosed with uterine AM and infertility and were evaluated for study inclusion.They were randomly divided into treatment group and control group with 60 casesin each group.

The study was approved by the institutional ethics committee(no.2017001).All subjects gave their written informed consent before enrolling in the study.The study was performed in accordancewith the ethical standardsof the1964 Declaration of Helsinki.

Diagnostic criteria

The Western medicine criteria described in the 2015 guide to Diagnosis and Treatment of Endometriosis[22]and National Higher Medical Textbook Construction Research Society Twelfth Five-Year Planning Materials:Obstetricsand Gynecology Eight Years,Third Edition[23]were adopted to diagnose AM.The Western criteria included:(a)progressive aggravation of secondary dysmenorrhea possibly accompanied by menorrhagia or prolonged menstruation;(b)an enlarged,abnormally spherical appearance with a hard texture,limited deformability,and possible tenderness were seen on gynecological examination;(c) ultrasound revealed uterine enlargement, diffuse thickening of the myometrium,uneven echo or localized hyperechoic areas,and lesions with an unclear muscle layer boundary;the endometrial transition line may be either thickened or unchanged.(d)Cancer antigen 125(CA-125)can be mildly or moderately elevated.

The TCM diagnostic criteria of dysmenorrhea,endometriosis,and AM followed the TCM Diagnosis and Treatment Plan developed by the key specialist collaboration group of the State Administration of TCM[24].Syndrome of cold coagulation and blood stasis:(a)main symptoms include premenstrual or menstrual lower abdomen cold pain that improved with application of heat,and cold extremities;(b)secondary symptoms include dark purple menstrual fluid with blockage,vomiting and diarrheaduring menstruation,leucorrheawith whitecolor,purple tongue with ecchymosis or white coating,and stringy or tight pulse.

The World Health Organization defines infertility as follows:The definition of infertility is a woman of reproductive age has not conceived after regular unprotected sexual intercourse for 1 year in the absence of known reproductive pathology.Primary infertility is infertility in a couple who have never had a child.Secondary infertility is failure to conceive following a previous pregnancy.

Inclusion criteria

(a)Patients were diagnosed with AM;(b)TCM syndrome differentiation was cold coagulation and blood stasis;(c)patients met the Western medicine infertility criteria;(d)age ranged from 20 to 40 years of age;(e)patients had a CA-125 level≤85 IU/mL;(f)patients agreed to the study treatment,and follow-up evaluations were eligible for inclusion.

Exclusion criteria

(a)Patientsdid not meet the inclusion criteria;(b)women with the combination of bilateral oviduct obstruction that both sides were blocked after recanalization;(c)patients had infertility complicated by ovulatory or immunity factors;(d)patients had severe diseases associated with important organ systems,acute pelvic inflammatory disease,or other reproductive system tumors;(e)infertility caused by uterine hypoplasia or malformation,congenitally physiological defect,and so on;(f)combination of male infertility factors;(g)couples had abnormally sexual life;(h)severeallergic woman.

Treatment

Treatment group.The patients in the treatment group was treated with both the general treatment and Thunder-Fire moxibustion treatment. (a) General treatment:follicular development and ovulation were monitored by ultrasound on the tenth day of the menstrual cycle.According to the monitoring results,the husband and wife were counselled together.(b)Thunder-Fire moxibustion abdominal array treatment:in the supine position,a Thunder-Fire moxibustion box array was placed at the Qihai(CV 6),1.5 inches below the navel,and the Guanyuan(CV 4)at the anterior midline of the lower abdomen 3 inches below the navel(Figure 1),and treated with moxibustion,a form of heat therapy,for 20 minutes.(c)The time and course of treatment:treatment with the Thunder-Fire moxibustion pendulum array began the day after mature ovarian follicles were released until the first day of the next menstrual period.One course of treatment continued for three menstrual cycles.Patients were treated with two courses,which included six menstrual cycles.

Control group.The control group was only treated with general treatment.

Outcomes

Main observation index.The primary outcome was pregnancy in the six menstrual cycles(cumulative pregnancy rate%=total number of pregnancies/overall number of people× 100%)during which the patients were treated.If pregnancy occurred,the following indicators don’t need to be measured after the first treatment course or the second treatment course;otherwise,thefollowing indicatorsneed to bemeasured.

Secondary observation index.The degree of dysmenorrhea was assessed by the digital pain score(NRS).0-10 represented varying degrees of pain.0 indicated painless,and 10 indicated unbearable pain.1-3 indicated mild pain,4-6 indicated moderate pain,and 7-10 indicated severe pain.Before treatment as well as after one and two courses of treatment,the number that best represented the degree of pain was chosen by the each patient.

The points of TCM symptoms.Before treatment as well as after one and two courses of treatment,TCM symptoms were evaluated separately,the specific scoring rules of TCM symptoms were shown in Table 1.

The changes of serum CA-125.Serum CA-125 concentration was assayed by an immunoradiometric assay in samples of serum from venous blood collected from the two study groups before treatment as well as after one and two courses of treatment.The assay results were read by an FJ2008 type gamma counter.

B-mode ultrasonography.The average diameter of uterus in two groups before treatment as well as after one and two courses of treatment,were evaluated by B-mode ultrasonography.

Table 1 Grading table of cold coagulation and blood stasis syndrome

Figure 1 Location of thunder-fire moxibustion array

Statistical analysis

SPSS,version 18.0 software(SSPS Inc.Chicago,IL,USA)was used to analyze the data.The results were expressed as mean±SD and t-testswere used to compare differences in mean values.Counting data were expressed as utilization rate and compared with the chi squared test results.P-values<0.05 wereconsidered statistically.

Results

Patient baselinedata

As shown in Table 2,the mean age of the 60 patients in the treatment group was 30.37±3.55 years and the range was 25-37 years.The mean duration of infertility was 2.27±1.19 years;the range was 1-6 years.There were 38 cases of secondary infertility and 22 cases of primary infertility.The mean age of the 60 patients in the control group was 29.83±3.61 years,and the range was 26-36 years.The mean duration of infertility was 2.27±1.19 years,the range was 1-5 years.There were 42 cases of secondary infertility and 18 cases of primary infertility.Age(P=0.187),duration of infertility(P=0.131),dysmenorrhea(P=0.104),TCM symptom(P=0.072)scores,the average diameter of the uterus(P=0.143),and serum CA-125 levels(P=0.159)in the two study groupswere not statistically different.

Comparison of main observation indexes

As shown in Table 3,30 of the 60 patients in the treatment group(50%)became pregnant,12 in the first course of treatment(20%).Fourteen of the 60 patients in the control group(23.3%)became pregnant,four(6.7%)after the first treatment course.Treatment effectiveness was significantly better in the Thunder-Fire moxibustion group than in the control group after both the first(P=0.039)and thesecond(P=0.021)courseof treatment.

Table 2 Comparison of baseline data

Table 2 Comparison of baseline data

CA-125,Cancer antigen 125.

Thelevel of serum CA-125(IU/ml)Treatment group 60 30.37±3.55 2.27±1.19 5.70±1.63 10.47±3.20 68.63±7.07 60.45±16.97 Control group 60 29.83±3.61 2.82±1.41 5.33±1.28 9.80±2.51 67.83±7.61 59.37±13.72 Thevalueof P 0.187 0.131 0.104 0.072 0.143 0.159 Age(years)Duration of infertility(years)Thescores of dysmenorrhea Thescoresof TCM symptoms Average diameter of uterus(mm)

Table 3 Comparison of pregnant rate

Comparison of secondary observation indexes after a courseof treatment

Dysmenorrhea and TCM syndrome scores,uterus diameter,and serum CA-125 after one course of treatment are shown in Table 4.The dysmenorrhea and TCM syndrome scores significantly decreased in the treatment group and were significantly lower than the control group scores.The dysmenorrhea scores were 4.58±1.46 vs.5.46±0.99,P=0.005 and the TCM syndrome scores were 8.08±3.06 vs.9.93±2.12,P=0.009,respectively,in the treatment vs.control groups.Serum CA-125 levels were decreased in the treatment group but were not significantly different from the control group concentrations(57.52±15.29 IU/mL vs.61.96±12.24 IU/mL).The average diameter of the uterus in the treatment group(67.33±7.52 cm)was not significantly different from that in thecontrol group(69.43±6.67 cm).

Comparison of secondary observation indexes after two coursesof treatment

Dysmenorrhea and TCM syndrome scores,uterus diameter,and serum CA-125 levels after two courses of treatment are shown in Table 5.The dysmenorrhea and TCM syndrome scores and serum CA-125 levels in the treatment group significantly decreased, and the differences were significant compared with the control group.The dysmenorrhea scores were 3.87±2.03 vs.5.70±1.01,P=0.002,the TCM syndrome scores were 7.33±4.11 vs.10.52±2.33,P=0.006,and the serum CA-125 levels was 55.45±14.65 IU/mL vs.63.34±11.41 IU/mL(P=0.031).The uterine diameters in the control(69.89±5.30 cm)and the experimental(67.13±7.59)groupswerenot statistically different(P=0.137).

Table 4 Comparison after a course of treatment

Table 4 Comparison after a course of treatment

TCM,Traditional Chinesemedicine;CA-125,Cancer antigen 125.

The level of serum CA-125(IU/ml)Treatment group 48 4.58±1.46 8.08±3.06 67.33±7.52 57.52±15.29 Control group 56 5.46±0.99 9.93±2.12 69.43±6.67 61.96±12.24 Thevalueof P 0.005 0.009 0.113 0.178 The scores of dysmenorrhea The scores of TCM symptoms Average diameter of uterus(mm)

Table5 Comparison after two coursesof treatment

Table5 Comparison after two coursesof treatment

TCM,Traditional Chinesemedicine;CA-125,Cancer antigen 125.

Thelevel of serum CA-125 Treatment group 30 3.87±2.03 7.33±4.11 67.13±7.59 55.45±14.65 Control group 46 5.70±1.01 10.52±2.33 69.89±5.30 63.34±11.41 Thevalueof P The scores of dysmenorrhea Thescoresof TCM symptoms Average diameter of uterus(mm)0.002 0.006 0.137 0.031

Discussion

AM isan estrogen-dependent disease.The pathogenesisof the AM effects on fertility are not clear,but may involve abnormal peristalsis of the uterine endometrial and muscle layer boundary,abnormal endocrine immune responses,and related cytokine changes[26].In TCM theory,the pathology is thought to be cold stagnation and blood stasis.The primary clinical manifestations of the diffuse or localized lesions produced in AM are dysmenorrhea and infertility [25]. Other clinical manifestations of AM are similar to those of dysmenorrhea and infertility in TCM theory,including cold,painful menstruation,pain relief with application of heat,dark purple menstrual fluid with blockage,cold limbs,vomiting,and diarrheaoccur.

There is currently no standard treatment for AM with infertility.Individualized treatment can be chosen based on theseverity of the disease,clinical symptoms,age,and fertility requirements[27,28].Conservative treatment with antiestrogen drugs and gonadotropin-releasing hormone receptor agonists improves symptoms,but only temporarily.Hysterectomy is currently the only definitive treatment,but many women want to keep their reproductive organs [7].In addition,postoperative adhesions cannot be completely avoided.Conservative surgical intervention has not been widely applied in the management of infertile patients with AM,because it is difficult to completely clear lesions without removing the uterus.In TCM treatments,at the Guanyuan(CV 4)and Qihai(CV 6)with the Thunder-Fire moxibustion abdominal array,"warmschannelsand activatesblood".It has been widely used to treat diverse gynecological diseaseswith good therapeutic effect[29-30].

In this study,Thunder-Fire moxibustion combined with ovulation monitoring was effective in the treatment of AM-associated infertility.It increased the pregnancy rate of patients with AM,relieved dysmenorrhea and the related TCM syndromes,and elevated serum CA-125 levels compared with the control group after two courses of treatment.Thunder-Fire moxibustion was based on the theory of TCM meridians.It used the heat generated by the burning of drugs,infrared radiation and chemical factors,physical factors to pass through the veins and acupoints to achieve the meridian and meridians,regulate the body functions to treat diseases.Guanyuan(CV 4)and Qihai(CV 6)were the health points of the human body.Acupuncturing Guanyuan(CV 4)and Qihai(CV 6)could regulate endocrine,so as to achieve the purpose of treating reproductive system diseases[31-32].Relevant studies have proved that Guanyuan(CV 4)can overlap and project into the spinal ganglion of L3-L5,which provides a possible theoretical basis for the treatment of gynecological diseasesby moxibustion on Guanyuan(CV 4)[33].Modern medical research showed that there was no fat tissue under the umbilicus,the barrier effect was poor,and it was rich in blood vessels and had strong permeability [34]. Thunder-Fire moxibustion with Guanyuan(CV 4)and Qihai(CV 6)could exert the effect of warming and dredging medicine and heat,produce heat effect on human body through heat transfer of meridians and nerves,inhibit uterine smooth muscle and vasoconstriction, improve local microcirculation,ultimately improve the symptoms of adenomyosis and increasethepregnancy rateof patients.

Conclusion

Thunder-Fire moxibustion combined with ovulation monitoring improved the pregnancy rate of patients with AM,and relieved dysmenorrhea and related TCM syndromes.It was an effective treatment of AM complicated with infertility,and warrants further study of itsmechanism.

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