This trial is sponsored and financially supported by the National Key Technology R&D Program during the Twelfth Five-year Plan Period of China. The study reported in this article is only one part of this program, which is an international multicenter systematic evaluation of clinical effectiveness of acupuncture. The purposes of this international collaborative program are to prove the therapeutic effects and safety of acupuncture and to establish guidelines for clinical practice. The result of this trial is expected to provide convincing evidence that acupuncture is effective for patients with perimenopausal syndrome.
Previous RCTs show acupuncture in the treatment of symptoms of both perimenopausal and postmenopausal females has no advantage, compared with placebo needles [16–19]. Compared with no medical treatment (for example, self-caring, waiting), however, acupuncture is able to relieve symptoms quite well [16, 17, 29]. In view of controversial results, some researchers asserted that the placebo needles might have similar effects to verum acupuncture , and this view may underestimate the total effectiveness of verum acupuncture. We are therefore conducting a pragmatic trial that requires a positive drug as the control group to clarify an acupuncture therapeutic effect rather than a placebo needle. Moreover, we use a non-inferiority method to estimate the sample size, and only include perimenopausal patients. What we expect is to prove the therapeutic effects of acupuncture on perimenopausal syndrome, and provide another alternative treatment for perimenopausal women.
HRT has been in use for more than half a century and is regarded as a gold standard treatment for vasomotor, urogenital symptoms and their potential consequences such as sleep problems, and mood disorders [31–33]. HRT can improve the health-related quality of life through the alleviation of these symptoms. Meanwhile, HRT is beneficial to prevent aging women from osteoporosis, metabolic syndrome, and cardiovascular problems . HRT is thus an ideal treatment for females with perimenopausal syndrome. Given all patients in this trial have an intact uterus, we choose estrogen plus progestin therapy to negate the risk of endometrial cancer rather than using estrogen alone, and 12-week treatment for women aged 40 to 55 should be safe according to the statement of the North American Menopause Society . Furthermore, studies have shown that sequential estradiol valerate and cyroterone acetate combinations: relieve climacteric complaints via increasing serum estrogen, and provide a good menstrual cycle inducing a physiological secretory transformation of the endometrium without side effects ; exert a positive effect on body fat mass and distribution ; and may have protective effects for postmenopausal bone loss . We therefore chose Climen® as a positive drug control.
We chose the MRS as the primary outcome, which was initially developed to measure the severity of aging symptoms and their impact on health-related quality of life in the 1990s . Three different dimensions of symptoms (psychological, somato-vegetative, and urogenital symptoms) are measured by 11 items, which can be easily completed by women themselves rather than physicians [37, 38]. The total scores of MRS vary between 0 (no symptom) and 44 (highest degree of symptoms) based on the severity of symptoms; the higher scores patients obtain, the more serious symptoms they have. Since 1992 the MRS has been developed and proven to be reliable and valid for decades [39, 40]. This self-assessment scale has the following objectives: to enable comparisons of the symptoms of aging between groups of women under different conditions; to compare severity of symptoms over time; and to measure changes before and after treatment [36–38]. Since the English version was published , 24 different languages versions are now available on the website . Due to its reliability and validity, we chose the MRS as the primary outcome of this trial to assess perimenopausal syndrome. We chose Menopause-Specific Quality of Life as one of the secondary outcomes to assess the severity of these symptoms affecting patients’ life quality. To measure the severity and frequency of hot flashes and sweats, participates will be required to fill hot-flash dairies for 1 week before each measurement point. The average hot-flash score during 24 hours is the 7-day total score of severity (0, none; 1, mild; 2, moderate; 3, severe)/7.
One recent RCT found that traditional acupuncture continued relieving the vasomotor symptoms throughout the 3-month treatment period, while the sham acupuncture was tending towards stability after the first month . A longer duration of treatment was hypothesized to be a superior effect between traditional and sham acupuncture. Accordingly, in order to observe a significant effectiveness of acupuncture, participants in our study will receive 3 months of treatment. Another study indicated that the effectiveness of acupuncture on perimenopausal syndrome was superior to HRT during the 6-month follow-up period . Therefore, it is necessary to conduct a longer period of follow-up to obverse the continuous effects of acupuncture compared with positive drug, and also to assess the safety after treatment. Before this trial we conducted a questionnaire survey of 156 women with perimenopausal syndrome in the First Affiliated Hospital of Chengdu University of TCM to obtain the public’s acceptance and understanding of acupuncture treatment for perimenopausal problems (the detail of this survey will be available soon). According to the results of the survey, previous RCTs and the opinions of experts, we designed this protocol for better treatment and follow-up arrangements.
Our study still has limitations. Firstly, the whole research period of this study is 37 weeks (1 week baseline, 12 weeks of treatment and 24 weeks of follow-up) and may increase the rate of patient drop-out. We therefore reduce the treatment demand after the first month of treatment and keep close contact with our patients via telephone calls, short messages, emails, and so forth, during the follow-up period, to decrease the drop-out rate. Secondly, the three centers of this study are in Chengdu, which is a capital city located in the southwest of China, and the patients we will include in this trial are mostly local residents. The population may therefore not represent the advantages of a multicenter study. Thirdly, participants assigned to the acupuncture group may have more opportunities for contact with their acupuncturists and build a good doctor–patient relationship rather than those of the control group, which may improve the therapeutic effect . We will therefore keep close contact with patients in the control group by telephone, Internet, and so on, to decrease this potential bias. Meanwhile, it is difficult to blind patients after randomization due to the specificity of acupuncture. We therefore strictly conduct central randomization and appoint different people to perform therapy, measurement and statistical analysis.
Owing to a lack of solid evidence for effectiveness of acupuncture treatment on perimenopausal syndrome, this trial aims to clarify this issue by means of a multicenter randomized controlled large-scale trial.
In conclusion, the results of this trial are expected to confirm whether acupuncture is effective in relieving perimenopausal syndrome.