Premature Ovarian Insufficiency (POI) is a series of clinical syndromes (elevated gonadotropins and low estradiol levels) caused by ovarian dysfunction (less than 40 years of age), resulting in an altered or disturbed menstrual period (amenorrhea or oligomenorrhea).[1,2] A decline in women's quality of life is also directly related to the disease. POI brings severe psychological pressures on women in reproductive age as well as long-term sequelae such as menopausal symptoms (hot flushes, night sweats, sexual dysfunctions, and insomnia), bone loss, low energy, impaired memory, labile mood, and related heart diseases. Therefore, early diagnosis, integrated, and individualized patient treatment plans are of utmost importance to a woman's quality of life, especially in childbearing age.
Unfortunately, it is a complicated etiology disease and lack of effective clinical treatment. POIs are usually associated with autoimmunity, iatrogenicity, genetics, environmental factors, and poor lifestyle. It has been determined that at least 20% to 25% of women with POI have a genetic basis, including chromosomal abnormalities and gene mutation.[5–7] In China, however, the frequency of pathogenic gene mutations in POI patients is generally <2%, although clinical diagnostic reports concerning these values are limited. Common iatrogenic factors include surgery, radiotherapy, and chemotherapy. Besides, Some POI patients have autoimmune diseases, and it is most related to autoimmune thyroid disease.
POI, generally affects approximately 1% of women before the age of 40, although its prevalence remains uncertain. Hormone replacement therapy (HRT), if there are no contraindications, however, should be given all POI patients, as HRT not only relieves symptoms of low estrogen but also prevents cardiovascular diseases and osteoporosis.[1,12,13] The use of HRT may, however, increase the risk of venous thromboembolism, although, depending on the dose and timing of initiation. In developed countries, there is a growing public interest in and use of therapies outside the traditional (customary) western medical practice. In the UK and other European countries as well as Australia, complementary and alternative medicines are now mainstream, as the use of herbal medicines is widely accepted.[16–19]
Presently, women with POI also seek out complementary and alternative therapies, such as excise, acupuncture, Chinese herbal medicine, acupressure, breathing, hypnotherapy, massage, and meditation. Zhang and colleagues through a randomized controlled trial and found that “Tiaoren Tongdu acupuncture” is beneficial to POI of kidney deficiency. Also, treatments using Chinese herbal formulas carried out by a group of Chinese researchers proved useful in improving symptoms and regulating hormonal levels as compared to placebo in women with POI.[21,22] However, most alternative and complementary therapies lack safety data and limited sufficient evidence. Notwithstanding, nonhormonal alternatives such as lifestyle changes, psychosomatic techniques, diet management and supplementation, prescription therapy, and other strategies are, however, still available and useful. These are nonhormonal alternatives. Many complementary and alternative therapies lack sufficient, high-quality evidence to support their prevention and treatment under different conditions.
The objectives of this study are to assess the conventional applications of alternative and complementary treatments available for POI patients and to summarize the potential benefits. A network meta-analysis (NMA) was applied in this research although similar studies were not available.
2 Materials and methods
2.1 Study registration
The protocol is conducted based on the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines to conduct this study. This NMA has been registered in the International Prospective Systematic Registration Review (PROSPERO) and the registration number is CRD42020163873.
2.2 Inclusion criteria
All relevant complementary and alternative randomized controlled trials (therapies) for POI were factored in.
2.2.1 Types of patients
The type of patients was selected on the basis of the European Society of Human Reproduction and Embryology (ESHRE) POI diagnostic criteria, which included vthe following:
- 1. Age less than 40 years;
- 2. oligo/amenorrhea for at least 4 months;
- 3. an elevated FSH level 25 IU/l on 2 occasions 4 weeks apart.
The treatment group will receive alternative and complementary therapies, such as moxibustion, acupuncture, Chinese herbal drugs, and topical heat. Besides, combined interventions with other treatments will be included. The control group will include placebo, no treatment, sham acupuncture, HRT, and western medicine.
The main outcome indicators are:
- 1. Clinical total effective rate;
- 2. Decrease rate of symptom integral;
- 3. Improvement of menstrual symptoms;
- 4. Comparison of serum FSH, LH, and E2 levels between day 2 to day 5 of the menstrual cycle.
Secondary outcome indicators are
- 1. Anti Mullerian Hormone (AMH) levels;
- 2. Antral follicle count between day 2 to day 5 of the menstrual cycle (assessed by transvaginal ultrasound);
- 3. Endometrial thickness;
- 4. Adverse events.
2.2.4 Exclusion criteria
Patients who do not conform to the above diagnostic criteria or are without diagnostic criteria.
2.3 Search strategy
The following electronic bibliographic database were searched: VIP database, Web of Science, Wanfang database, Chinese National Knowledge Infrastructure (CNKI), PubMed, The Cochrane Library, and EMBASE since inception till 31 December 2019. Searches in World Health Organization (WHO) International Clinical Trials Registry Platform will also be done. The MeSH terms and free words will be used to construct the retrieval formula. The selection will not be limited to the publication status, year of publication, country or date. Taken as example, the following (Table 1) is the specific search process for PubMed.
2.4 Study selection and data collection
2.4.1 Note Express 3.2.0 software will be used for document management
Firstly, duplicate pieces of literature will be checked by software and manually. Then, abstracts and keywords will be read to eliminate inconsistent literature. Finally, after eliminating the inconsistent literature, what is available will be downloaded and reevaluated.
2.4.2 Data collection
Two independent researchers will extract the literature and establish a database of Excel, which will mainly include: the title, author, publish time, number of patients, the patients’ essential characteristics, ways of intervention, observe outcome indicators, and results. A third researcher would be invited to discuss and resolve disagreements were differences in opinion exists.
2.5 Literature quality evaluation
Two independent reviewers will assess risk of bias among studies with Cochrane Collaboration's tool. The following 7 domain categories will be applied in this exercise: blinding of personnel and participants (performance bias); and other bias; blinding of outcome assessment (detection bias); incomplete outcome data (attrition bias); selective outcome reporting (reporting bias); random sequence generation (selection bias); allocation concealment (selection bias). In case of disagreements, a third reviewer will called upon.
2.6 Statistical analysis
First, the network evidence graph was drawn and consistently tested by Stata15.0 software. Then, direct comparisons’ meta-analysis will be performed by Rev Man5.3 software, and NMA will be performed by ADDIS 1.16.8 software. Odds ratios and 95% credibility intervals (CrI) will be used to be reported, and a ranking table will be conducted for each intervention. P value <.05 and 95%CrI will be used as the criteria for statistical differences. ADDIS software mainly uses the potential scale reduction factor to evaluate the convergence of the results. It indicates that the results have good convergence performance and the analysis is reliable when potential scale reduction factor is close to or equal to 1.
2.7 Subgroup analysis
If I2 > 50%, heterogeneity sources will be determined through a subgroup analysis. A detailed subgroup analysis will be listed.
- 1. Patient characteristics: age and course of the disease.
- 2. Interventions: acupuncture; traditional Chinese medicine; psychosomatic techniques; exercise and other treatments.
2.8 Sensitivity analysis
As a commonly used method, sensitivity analysis will be applied to check the certainty of results and evaluate the effect of each study with a high risk of bias.
2.9 Grading the quality of evidence
GRADE Pro V3 software will be utilized to check the quality of the GRADE handbook evidence. The evaluation process will be assessed from the standpoints of limitations, publication bias inconsistency, imprecision, and indirectness. The results of the evidence would then be categorized in four quality grades: shallow, low, moderate, and high quality.
Recently, as the number of people with POI increases in China, these group of women now tend to seek complementary and alternative therapies. To the best of our knowledge, although there are many researches on the effectiveness of traditional Chinese medicine and acupuncture in POI management, the evaluation and comparison of various treatment methods are insufficient. This study aims to provide more convincing and detailed information on complementary and alternative therapies to improve symptoms of POI. We searched databases for systematic reviews and NMA; however, data were lacking. NMA will demonstrate an effective treatment for POI, providing clinicians with evidence-based resources and the confidence to use them.
Some restrictions may affect the conclusions drawn in this research protocol. Though there are several complementary and alternative therapies, however, the subgroup analysis set up in this program were mainly Chinese medicine, acupuncture, exercise therapy, psychosomatic techniques, and other therapies. They may be heterogeneous. Finally, due to the language barrier of the researchers, they decided to consult only English and Chinese literature, which may, however, have potentially lead to a few missing essential pieces of literature.
Conceptualization: Lei Zhang, Jianwei Zhang.
Data curation: Lei Zhang, Honglin Li, Xinliang Kong, Jianwei Zhang.
Methodology: Lei Zhang, Jianwei Zhang, Honglin Li, Zhijuan Wu.
Project administration: Zhijuan Wu.
Search strategy: Lei Zhang, Xinliang Kong, Zhijuan Wu, Jianwei Zhang.
Software: Lei Zhang, Jianwei Zhang, Honglin Li, Xinliang Kong, Zhijuan Wu.
Statistical analysis: Lei Zhang, Honglin Li, Xinliang Kong.
Writing – original draft: Lei Zhang.
Writing – review & editing: Lei Zhang.
. Webber L, Davies M, Anderson R, et al. European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI. ESHRE Guideline: management of women with premature ovarian insufficiency
. Hum Reprod 2016;31:926–37.
. Michala L, Stefanaki K, Loutradis D. Premature ovarian insufficiency
in adolescence: a chance for early diagnosis? Hormones (Athens) 2019;1–7.
. Hamoda H, British Menopause S, Women's Health C. The British Menopause Society and Women's Health Concern recommendations on the management of women with premature ovarian insufficiency
. Post Reprod Health 2017;23:22–35.
. Sullivan SD, Sarrel PM, Nelson LM. Hormone replacement therapy in young women with primary ovarian insufficiency and early menopause. Fertil Steril 2016;106:1588–99.
. Qin Y, Jiao X, Simpson JL, et al. Genetics of primary ovarian insufficiency: new developments and opportunities. Hum Reprod Update 2015;21:787–808.
. Jiao X, Qin C, Li J, et al. Cytogenetic analysis of 531 Chinese women with premature ovarian failure. Hum Reprod 2012;27:2201–7.
. Tucker EJ, Grover SR, Bachelot A, et al. Premature ovarian insufficiency
: new perspectives on genetic cause and phenotypic spectrum. Endocr Rev 2016;37:609–35.
. Jiao X, Zhang H, Ke H, et al. Premature ovarian insufficiency
: phenotypic characterization within different etiologies. J Clin Endocrinol Metab 2017;102:2281–90.
. De Vos M, Devroey P, Fauser BC. Primary ovarian insufficiency. Lancet 2010;376:911–21.
. Dragojevic-Dikic S, Marisavljevic D, Mitrovic A, et al. An immunological insight into premature ovarian failure (POF). Autoimmun Rev 2010;9:771–4.
. Coulam CB, Adamson SC, Annegers JF. Incidence of premature ovarian failure. Obstet Gynecol 1986;67:604–6.
. Baber RJ, Panay N, Fenton A. Group IMSW. 2016 IMS recommendations on women's midlife health and menopause hormone therapy. Climacteric 2016;19:109–50.
. Dragojevic Dikic S, Vasiljevic M, Jovanovic A, et al. Premature ovarian insufficiency
- novel hormonal approaches in optimizing fertility. Gynecol Endocrinol 2020;36:162–5.
. Machura P, Grymowicz M, Rudnicka E, et al. Premature ovarian insufficiency
- hormone replacement therapy and management of long-term consequences. Prz Menopauzalny 2018;17:135–8.
. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey. JAMA 1998;280:1569–75.
. Ekor M. The growing use of herbal medicines: issues relating to adverse reactions and challenges in monitoring safety. Front Pharmacol 2014;4:1–6.
. Calapai G. European legislation on herbal medicines: a look into the future. Drug Saf 2008;31:428–31.
. Braun LA, Tiralongo E, Wilkinson JM, et al. Perceptions, use and attitudes of pharmacy customers on complementary medicines and pharmacy practice. BMC Complement Altern Med 2010;10:1–7.
. Anquez-Traxler C. The legal and regulatory framework of herbal medicinal products in the European Union: a focus on the traditional herbal medicines category. Drug Inf J 2011;45:15–23.
. Zhang JW, Liu YS, Deng R, et al. [Observation on therapeutic effect of “Tiaoren Tongdu acupuncture” on premature ovarian insufficiency
of kidney deficiency]. Zhongguo Zhen Jiu 2019;39:579–82.
. Ma K, Yuan Y, Zhang HX. Clinical efficacy of Bushen Culuan Decoction in treating infertility due to premature ovarian insufficiency
. Zhongguo Zhong Yao Za Zhi 2019;44:1075–9.
. Cao XJ, Huang X, Liu J, et al. A randomized, double-blind, placebo-controlled trial of Chinese herbal medicine capsules for the treatment of premature ovarian insufficiency
. Menopause 2018;25:918–26.
. Rada G, Capurro D, Pantoja T, et al. Non-hormonal interventions for hot flushes in women with a history of breast cancer. Cochrane Database Syst Rev 2010;CD004923.
. Nappi RE, Cucinella L, Martini E, et al. Sexuality in premature ovarian insufficiency
. Climacteric 2019;22:289–95.
. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med 2009;151:W65–94.