Clinical Efficacy of Acupuncture on the Liver Meridian in Women With Diminished Ovarian Reserve

Ovarian Reserve Clinical Trial

— GJZLLCCBGNXJ  

Official title:

Clinical Study of Liver Meridian in the Treatment of Male Impotence and Female Premature Ovarian Failure

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05743218
• Other study ID #: 2019YFC1709104-1
• Status: Recruiting
• Phase: N/A
• Start date: January 25, 2023
• Est. completion date: December 31, 2023

Study information

• Verified date: February 2023
• Source: The First Affiliated Hospital of Hunan University of Traditional Chinese Medicine
• Contact: Wei Zhang, Doctor
• Phone: +86 135 4863 9198
• Email: 507395550[@]qq.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Diminished ovarian reserve (DOR) refers to a decrease in the number and quality of oocytes in the ovary, which results in impaired ovarian function and decreased fertility. Meanwhile, levels of the anti-Müllerian hormone (AMH), antral follicle count (AFC), and Follicle-Stimulating Hormone (FSH) also decrease in patients with DOR. In general, there is a decline in fertility and premature menopause. Some patients will have low menstrual volume, oligomenorrhea or even amenorrhea, abnormal uterine bleeding, ovulation disorders, infertility and perimenopausal performance before the age of 40, and eventually develop into premature ovarian failure. In recent years, with the changes of social culture, living environment, work pressure and other factors, the incidence of this disease has increased year by year, which has a great impact on women's fertility, mental health, quality of life, family relations and other aspects.

As a green and safe complementary and alternative therapy, acupuncture has been proved to be effective. According to the statistics, 904 (33.54%) of the 2695 syndromes indicated by acupoints of the liver meridian recorded in 93 ancient medical books are reproductive disorders, ranking first in the diseases indicated by the liver meridian and the 14 meridians. The body surface course of the liver meridian is closely related to the genitals, and there is a close relationship between the liver meridian and the genitals in physiology and pathology. According to the theory of the relationship between meridians and zangfu organs, the study aims to verify the efficacy and safety of acupuncture of the liver meridian and provide high-level research evidence for meridian syndrome differentiation of reproductive system diseases via "treatment from the liver."

Description:

This is an exploratory multicenter randomized controlled trial involving four clinical research centers, including the First Affiliated Hospital of Hunan University of Traditional Chinese Medicine, Hubei Hospital of Traditional Chinese Medicine, Shaanxi Hospital of Traditional Chinese Medicine, and Guizhou Hospital of Traditional Chinese Medicine. Each clinical research center strictly screened cases according to the diagnostic criteria, inclusion criteria and exclusion criteria. After confirmation of enrollment, random numbers were obtained according to the application for random coding process until the total number of observation was completed. According to the sample size, a total of 198 patients with DOR need to be enrolled. The 29-week study period consists of a 4-week screening period, 1-week baseline period, 12-week treatment period, 12-week follow-up period, and assessments at baseline. He patients were randomly divided into three groups: the liver meridian, stomach meridian, and non-acupoint acupuncture groups. Due to the particularity of acupuncture research, it is impossible to blind acupuncture operators. Blinded evaluation will be adopted in the trial, and the third party who does not know the grouping will evaluate the efficacy. Blind statistical analysis was used in the data summary stage, and the researchers, operators and statisticians were separated. In the experimental group (liver meridian group), EA was applied to Taichong, Li gou, Ququan and Jimai. In the control group 1 (gastric meridian group), EA was applied to Chongyang, Fenglong, Zusanli and Biguan. In the control group 2 (the non-meridian non-acupoint group), 4 non-meridian non-acupoints were selected from the lateral thigh, the lateral calf and the lateral calcaneus, respectively (see the treatment methods of the non-meridian non-acupoint group for details) and stimulated with EA.

The main evaluation index will be Anti-Müllerian hormone(AMH), The secondary evaluation index include serum sex hormones (bFSH, bE2, bLH, bFSH/bLH), antral follicle count(AFC),, menstrual status, the modified Kupperman Index(KI), perimenopausal quality of life score (MENQOL) ,Self-Rating Anxiety Scale( SAS ), self-rating depression scale(SDS), Menstrual conditions. The patients were evaluated at different time points during the baseline period, treatment period and follow-up period, and the incidence of adverse events will be recorded. Double data entry will be used in this trial to ensure the accuracy of data entry. A three-level quality control system (self-inspection by each center, supervision by project management team, and third-party audit) was implemented to ensure that the implementation, recording and reporting of clinical trials were in accordance with the trial protocol, standard operating procedures, and relevant laws and regulations. The statistical analysis plan was developed by the statistical analysis principal and the principal investigators in accordance with the protocol and was finalized before the database was locked. The tables for the statistical analysis were developed. Statistical analysis will be calculated by SPSS25.0 statistical analysis software, P<0.05 (i.e., =0.05) will be considered statistically significant, in order to clarify the efficacy and safety of acupuncture on DOR.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 198
• Est. completion date: December 31, 2023
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 40 Years

Eligibility

Inclusion Criteria:

• The inclusion criteria are as follows:

1. patients with the detection indicators within 3 months before enrollment met the diagnostic criteria of DOR.

2. patients aged between 18 and 40 years old.

3. patients who have received no other treatment in the 2 months before enrollment. (4) patients who voluntarily participate in this study and can actively cooperate with the study process.

(5) patients who have signed an informed consent form. Patients who meet all five criteria will be eligible for this study.

Exclusion Criteria:

• (1) Patients with polycystic ovarian syndrome, hyperprolactinemia, pituitary or hypothalamic amenorrhea, thyroid dysfunction, congenital malformations, and organic lesions in the reproductive organs.

(2) Patients with a history of local ovarian surgery, such as oophorectomy and ovarian tumor surgery.

(3) Patients with a history of chemotherapy or pelvic radiotherapy and a history of therapy with immunosuppressive agents.

(4) Patients with comorbidities in the cardiovascular system, liver, kidney, hematopoietic system, nervous and mental system, diabetes, hypertension, and other diseases.

(5) Patients being administered estrogen, progesterone, or dehydroepiandrosterone (DHEA) within 2 months before enrollment.

(6) Patients who cannot tolerate blood or ultrasound testing. (vii) Patients who are also participating in other clinical trials.

(7) Patients who refuse to sign the informed consent form. Patients who meet any of the above criteria will be excluded.

Related Conditions & MeSH terms

• Acupuncture Therapy
• Meridian
• Ovarian Reserve

Intervention

Other:
• electropuncture
Electroacupuncture (EA) is a method of treating diseases by inserting a needle (usually a filiform needle) into the skin or tissue of a patient at a certain Angle, and then passing through the needle (sensing) micro-current waves of human bioelectricity to stimulate specific parts of the human body (acupoints). Disposable sterile acupuncture filiform needle (0.16mm×13mm, 0.30mm×25mm, 0.30mm× 40mm), Guizhou Andi Medical Equipment Co, LTD, Guizhou Food and Drug Supervision and Equipment Production Xu 20170011. Electroacupuncture apparatus: SDZ-? electroacupuncture apparatus of Huatuo brand, Suzhou Medical Supplies Factory Co., LTD., Registration No. : 20172270675.

Locations

Country	Name	City	State
China	The First Affiliated Hospital of Hunan University of Chinese Medicine	Changsha	Hunan

Sponsors (1)

Lead Sponsor	Collaborator
The First Affiliated Hospital of Hunan University of Traditional Chinese Medicine

Country where clinical trial is conducted

China, 

References & Publications (18)

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Brinkhaus B, Hummelsberger J, Kohnen R, Seufert J, Hempen CH, Leonhardy H, Nogel R, Joos S, Hahn E, Schuppan D. Acupuncture and Chinese herbal medicine in the treatment of patients with seasonal allergic rhinitis: a randomized-controlled clinical trial. Allergy. 2004 Sep;59(9):953-60. doi: 10.1111/j.1398-9995.2004.00540.x. — View Citation

Bunnewell SJ, Honess ER, Karia AM, Keay SD, Al Wattar BH, Quenby S. Diminished ovarian reserve in recurrent pregnancy loss: a systematic review and meta-analysis. Fertil Steril. 2020 Apr;113(4):818-827.e3. doi: 10.1016/j.fertnstert.2019.11.014. Epub 2020 Mar 4. — View Citation

Cohen J, Chabbert-Buffet N, Darai E. Diminished ovarian reserve, premature ovarian failure, poor ovarian responder--a plea for universal definitions. J Assist Reprod Genet. 2015 Dec;32(12):1709-12. doi: 10.1007/s10815-015-0595-y. Epub 2015 Oct 13. — View Citation

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Hilditch JR, Lewis J, Peter A, van Maris B, Ross A, Franssen E, Guyatt GH, Norton PG, Dunn E. A menopause-specific quality of life questionnaire: development and psychometric properties. Maturitas. 1996 Jul;24(3):161-75. doi: 10.1016/s0378-5122(96)82006-8. Erratum In: Maturitas 1996 Nov;25(3):231. — View Citation

Hong L, Peng S, Li Y, Fang Y, Wang Q, Klausen C, Yin C, Wang S, Leung PCK, Yang X. miR-106a Increases Granulosa Cell Viability and Is Downregulated in Women With Diminished Ovarian Reserve. J Clin Endocrinol Metab. 2018 Jun 1;103(6):2157-2166. doi: 10.1210/jc.2017-02344. — View Citation

Liu CZ, Xie JP, Wang LP, Liu YQ, Song JS, Chen YY, Shi GX, Zhou W, Gao SZ, Li SL, Xing JM, Ma LX, Wang YX, Zhu J, Liu JP. A randomized controlled trial of single point acupuncture in primary dysmenorrhea. Pain Med. 2014 Jun;15(6):910-20. doi: 10.1111/pme.12392. Epub 2014 Mar 17. — View Citation

Liu L, Pang R, Sun W, Wu M, Qu P, Lu C, Wang L. Functional social support, psychological capital, and depressive and anxiety symptoms among people living with HIV/AIDS employed full-time. BMC Psychiatry. 2013 Dec 1;13:324. doi: 10.1186/1471-244X-13-324. — View Citation

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Practice Committee of the American Society for Reproductive Medicine. Electronic address: asrm@asrm.org; Practice Committee of the American Society for Reproductive Medicine. Testing and interpreting measures of ovarian reserve: a committee opinion. Fertil Steril. 2020 Dec;114(6):1151-1157. doi: 10.1016/j.fertnstert.2020.09.134. — View Citation

Steiner AZ, Pritchard D, Stanczyk FZ, Kesner JS, Meadows JW, Herring AH, Baird DD. Association Between Biomarkers of Ovarian Reserve and Infertility Among Older Women of Reproductive Age. JAMA. 2017 Oct 10;318(14):1367-1376. doi: 10.1001/jama.2017.14588. — View Citation

Sun W, Stegmann BJ, Henne M, Catherino WH, Segars JH. A new approach to ovarian reserve testing. Fertil Steril. 2008 Dec;90(6):2196-202. doi: 10.1016/j.fertnstert.2007.10.080. Epub 2008 Apr 22. — View Citation

Sun XY, Lan YZ, Liu S, Long XP, Mao XG, Liu L. Relationship Between Anti-Mullerian Hormone and In Vitro Fertilization-Embryo Transfer in Clinical Pregnancy. Front Endocrinol (Lausanne). 2020 Dec 4;11:595448. doi: 10.3389/fendo.2020.595448. eCollection 2020. — View Citation

Wang Y, Li Y, Chen R, Cui X, Yu J, Liu Z. Electroacupuncture for reproductive hormone levels in patients with diminished ovarian reserve: a prospective observational study. Acupunct Med. 2016 Oct;34(5):386-391. doi: 10.1136/acupmed-2015-011014. Epub 2016 May 13. — View Citation

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* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	White blood cell (WBC)	Normal value (unit): 3.5-9.5 (109/L). Assessment with reference to the normal range. 1- Normal (Within the reference range) 2- Abnormal (Outside the reference range). The purpose is to evaluate whether acupuncture has an effect on WBC, which is a safety assessment.	Baseline period(1 week before enrollment), enrollment 12 weeks (Change from Baseline at 12weeks).
Other	Red blood cell (RBC)	Normal value (unit): 3.8-5.1(1012/L). Assessment with reference to the normal range. 1- Normal (Within the reference range) 2- Abnormal (Outside the reference range). The purpose is to evaluate whether acupuncture has an effect on RBC, which is a safety assessment.	Baseline period(1 week before enrollment), enrollment 12 weeks (Change from Baseline at 12weeks)
Other	Blood platelet	Normal value (unit): 125-350(109/L). Assessment with reference to the normal range. 1- Normal (Within the reference range) 2- Abnormal (Outside the reference range). The purpose is to evaluate whether acupuncture has an effect on Blood platelet, which is a safety assessment.	Baseline period(1 week before enrollment), enrollment 12 weeks (Change from Baseline at 12weeks)
Other	Hemoglobin	Normal value (unit): 115-150 (g/L). Assessment with reference to the normal range. 1- Normal (Within the reference range) 2- Abnormal (Outside the reference range). The purpose is to evaluate whether acupuncture has an effect on Hemoglobin, which is a safety assessment.	Baseline period(1 week before enrollment), enrollment 12 weeks (Change from Baseline at 12weeks)
Other	Alanine aminotransferase(ALT)	Normal value (unit): 0-33(IU/L). Assessment with reference to the normal range. 1- Normal (Within the reference range) 2- Abnormal (Outside the reference range). The purpose is to evaluate whether acupuncture has an effect on ALT, which is a safety assessment.	Baseline period(1 week before enrollment), enrollment 12 weeks (Change from Baseline at 12weeks)
Other	Aspartate aminotransferase (AST)	Normal value (unit): 0-32(IU/L). Assessment with reference to the normal range. 1- Normal (Within the reference range) 2- Abnormal (Outside the reference range). The purpose is to evaluate whether acupuncture has an effect on AST, which is a safety assessment.	Baseline period(1 week before enrollment), enrollment 12 weeks (Change from Baseline at 12weeks)
Other	Blood - urea nitrogen (UREA)	Normal value (unit): 2.14-7.14 (umol/L). Assessment with reference to the normal range. 1- Normal (Within the reference range) 2- Abnormal (Outside the reference range). The purpose is to evaluate whether acupuncture has an effect on UREA, which is a safety assessment.	Baseline period(1 week before enrollment), enrollment 12 weeks (Change from Baseline at 12weeks)
Other	Creatinine (CREA)	Normal value (unit): 45-84 (umol/L). Assessment with reference to the normal range. 1- Normal (Within the reference range) 2- Abnormal (Outside the reference range). The purpose is to evaluate whether acupuncture has an effect on CREA, which is a safety assessment.	Baseline period(1 week before enrollment), enrollment 12 weeks (Change from Baseline at 12weeks)
Other	Prothrombin time (PT)	Normal value (unit): 11-14(s). Assessment with reference to the normal range. 1- Normal (Within the reference range) 2- Abnormal (Outside the reference range). The purpose is to evaluate whether acupuncture has an effect on PT, which is a safety assessment.	Baseline period(1 week before enrollment), enrollment 12 weeks (Change from Baseline at 12weeks)
Other	Activated partial thromboplastin time(ATPP)	10.Activated partial thromboplastin time(ATPP)	Baseline period(1 week before enrollment), enrollment 12 weeks (Change from Baseline at 12weeks)
Other	Thrombin time(TT)	Normal value (unit): 20 (s). Assessment with reference to the normal range. 1- Normal (Within the reference range) 2- Abnormal (Outside the reference range). The purpose is to evaluate whether acupuncture has an effect on TT, which is a safety assessment.	Baseline period(1 week before enrollment), enrollment 12 weeks (Change from Baseline at 12weeks)
Other	Fibrinogen concentration(FBI)	Assessment with reference to the normal range. 1- Normal (Within the reference range) 2- Abnormal (Outside the reference range). The purpose is to evaluate whether acupuncture has an effect on FBI, which is a safety assessment.	Baseline period(1 week before enrollment), enrollment 12 weeks (Change from Baseline at 12weeks)
Primary	The value of anti-mullerian hormone(AMH)	This index is used to measure ovarian hormone secretion function and assess ovarian reserve function. Instrument:Beckman Coulter Access automatic immune analyzer.; Method: Venous blood will be collected on an empty stomach at 3-5mL in the morning on the 2nd to 4th day of menstruation, centrifuged at 5000r/min for 3min with a high-speed centrifuge, and the upper serum is taken and stored in a -80? refrigerator for test.; Unit: ng/mL.	3 checkpoints. Baseline period(1 week before enrollment), enrollment 12 weeks (Change from Baseline at 12weeks) and enrollment 24 weeks(Changes at 12 weeks of treatment and 12 weeks of follow-up).
Secondary	The number of antral follicle count (AFC)	The number of antral follicles was detected by three-dimensional B-ultrasound to evaluate ovarian reserve function. The smaller the number, the more severe the symptoms.	3 checkpoints. Baseline period(1 week before enrollment), enrollment 12 weeks (Change from Baseline at 12weeks) and enrollment 24 weeks(Changes at 12 weeks of treatment and 12 weeks of follow-up).
Secondary	Sex hormone: follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2)	Use Chemiluminescence immunoassay to detected the ovarian hormone secretion. On the 2nd to 4th day of menstruation, 5 ml of venous blood will be collected from subjects in the morning under the condition of fasting for 8 h and put into the test tube without anticoagulant. The collected samples will be centrifuged to separate the upper serum and stored in the refrigerator at -70? for examination. Unit: FSH(mLU/mL), LH(mLU/mL), E2( pg/mL).	3 checkpoints. Baseline period(1 week before enrollment), enrollment 12 weeks (Change from Baseline at 12weeks) and enrollment 24 weeks(Changes at 12 weeks of treatment and 12 weeks of follow-up).
Secondary	The total score of the modified Kupperman scale	To evaluate the severity of perimenopausal syndrome symptoms.Each item has a different basic and severity score, the severity score is calculated according to 0-3 points, and the symptom score is calculated as follows:Symptom score=basic score×severity score.The sum of each symptom score is the total score; the higher the total score, the more severe the disease. Patients with a normal score have <6 points. This with mild, moderate, and severe disease have 6-15, 16-30, and >30 points, respectively.	3 checkpoints. Baseline period(1 week before enrollment), enrollment 12 weeks (Change from Baseline at 12weeks) and enrollment 24 weeks(Changes at 12 weeks of treatment and 12 weeks of follow-up).
Secondary	The total score of the perimenopausal quality of life score	29 items, divided into Vasomotor symptoms, psychosocial function, physical function, sexual life, each item scored 1-7 points.; Dimension score = Total score of item questions in each dimension ? Number of questions Total score = Sum of four dimensions scores	3 checkpoints. Baseline period(1 week before enrollment), enrollment 12 weeks (Change from Baseline at 12weeks) and enrollment 24 weeks(Changes at 12 weeks of treatment and 12 weeks of follow-up).
Secondary	The total score of the self-rating anxiety Scale	Reflect anxiety level. 20 items, each item 1-4 points, total score and standard score (total score ×1.25), the higher the score, the more severe symptoms.	3 checkpoints. Baseline period(1 week before enrollment), enrollment 12 weeks (Change from Baseline at 12weeks) and enrollment 24 weeks(Changes at 12 weeks of treatment and 12 weeks of follow-up).
Secondary	The total score of the self-rating Depression Scale	Reflect the degree of depression. 20 items, each item 1-4 points, total score and standard score (total score ×1.25), the higher the score, the more severe symptoms.	3 checkpoints. Baseline period(1 week before enrollment), enrollment 12 weeks (Change from Baseline at 12weeks) and enrollment 24 weeks(Changes at 12 weeks of treatment and 12 weeks of follow-up).
Secondary	Menstrual assessment	Menstruation was assessed throughout the study period (a total of 7 times). The evaluation consists of 6 items, each item is scored (0 to 4 points), and the total score is calculated for each time. The lower the total score is, the better the menstrual condition is.	Enrollment 1?4?8?12?16?20?24 weeks.

External Links

•   30.Hong-yan Y, Fang-Ping C, Xiao-Yun W, Ze-huai W, Chun-ling Z. Clinical application and evaluation of the Chinese version of the Menopausal quality of life scale. Chin J Epidemiol. 2005;01:50-3
•   30.Hong-yan Y, Fang-Ping C, Xiao-Yun W, Ze-huai W, Chun-ling Z. Clinical application and evaluation of the Chinese version of the Menopausal quality of life scale. Chin J Epidemiol. 2005;01:50-3
•   33.Chun-fang W, Ze-huan CAI, Qing XU. The Self-Rating Depression Scale (SDS) was used to evaluate 1340 normal subjects. Chin J NeurolPSYCHIATRIC Disorders;1986