Pii: s0378-5122(02)00314-6

A pilot study comparing the clinical effects of Jia-Wey Shiau- Yau San, a traditional Chinese herbal prescription, and a continuous combined hormone replacement therapy in postmenopausal women with climacteric symptoms Lih-Chi Chen Yun-Tson Tsao c, Kun-Ying Yen b, Yu-Fang Chen a, Mei- a Department of Pharmacy, Veterans General Hospital-Taipei, No.201, Sec.2, Shih-pai Road, Taipei 112, Taiwan, ROC b Department of Pharmacognosy, Graduate Institute of Pharmaceutical Sciences, Taipei Medical College, Taipei 110, Taiwan, ROC c Department of Chinese Medicine, Taipei Municipal Chung-Hsin Hospital, Taipei 103, Taiwan, ROC Received 30 October 2001; received in revised form 5 September 2002; accepted 17 October 2002 Objectives: Interest in use of alternative remedies for managing menopausal symptoms is increasing exponentially during these years. Jia-Wey Shiau-Yau San (JWSYS), one of the traditional Chinese herbal prescriptions, is a famousherbal remedy used for the management of various menopausal-related symptoms. A randomized, controlled pilotstudy was performed to evaluate the clinical effects of JWSYS compared with those of a continuous combined hormonereplacement therapy, Premelle†, on quality of life in non-hysterectomized postmenopausal women. Methods: Thepresent trial compared the effect of a l6-week treatment with JWSYS or HRT (Premelle†) in postmenopausal womenwith climacteric symptoms. The Greene Climacteric Scale was used to assess the clinical effects at baseline and after 16weeks’ treatment with either JWSYS or Premelle†. The physiological parameters, such as follicle-stimulating hormoneand estradiol levels, were also recorded at the same time points. Results: The results showed that JWSYS had arelatively lower discontinuation rate due to adverse effects, in particular the bleeding and breast tenderness. BothJWSYS and Premelle† effectively alleviated most of the menopausal symptoms with no significant differences betweentreatment groups, whereas the beneficial effects of JWSYS were not mediated by hormone replacement-like effects.
Moreover, JWSYS showed a good compliance and safety without estrogenic effects and metabolic alterations.
Conclusions: It was suggested that JWSYS was a safe and efficacious therapy and might be an alternative choice forrelief of climacteric symptoms in postmenopausal women. However, the exact efficacy and clinical roles of JWSYS havenot been convincingly demonstrated in this study because of the blinding approach and some statistical concerns, andonly the possibility of its efficacy has been raised. Therefore, a blinding trial with more patient numbers to evaluate theefficacy of JWSYS deserves further study.
# 2002 Elsevier Science Ireland Ltd. All rights reserved.
* Corresponding author. Tel: '/886-2-28757369; fax: '/886-2-28757706E-mail address: (L.-C. Chen).
0378-5122/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 3 7 8 - 5 1 2 2 ( 0 2 ) 0 0 3 1 4 - 6 L.-C. Chen et al. / Maturitas 44 (2003) 55 Á/62 Keywords: Jia-Wey Shiau-Yau San; Hormone replacement therapy; Menopause; Chinese medicines a controlled, randomized trial by means of astandardized questionnaire.
Most women in their postmenopausal years may experience a variety of physical symptoms, such ashot flashes, vaginal dryness and menstrual irregu- larities, which are associated with menopause .
Management of menopause has received increased attention in recent years, as a consequence both ofthe growing interest in women’s health and of the Non-hysterectomized postmenopausal women, greater number of women entering the menopau- aged between 45 and 65 years old, with complaints sal years. Although the current trend is to treat of climacteric symptoms were included. The wo- climacteric women with various form of hormone men included in this study were recruited from the replacement therapy (HRT), many women prefer outpatients who were attending our hospital. All not to or cannot take HRT Instead, some may the women had their last menstruation at least 6 take alternative medicines, including herbal drugs or traditional Chinese medicines (TCMs), to within the last 6-month period. Subjects with severe metabolic, endocrine, or gastrointestinal Use of alternative medicines or unconventional disease, concomitant heart disease, uncontrolled medicines is on the rise worldwide In the US, the national surveys demonstrated that alternative metriosis, undiagnosed vaginal bleeding and psy- medicine has a substantial presence in the US chiatric illness were excluded. Other exclusion criteria were women with surgically induced me- surveys performed outside the US also suggested nopause, previous or current estrogen-dependent that alternative medicine is popular throughout tumors, other current malignant or life-threatening the industrialized world and its use is widespread disease, and previous or concomitant serious or ÁTherefore, interest in use of alternativeremedies for managing menopausal symptoms isincreasing exponentially during these years .
TCMs, one of the popular alternative medicines, Composition of the herbal preparation JWSYS have been practiced in China for more than 2000years. These therapies, including specific dietary and exercises, acupuncture, and medicinal herbs, are usually used for the treatment of menopause in Angelicae Radix (Angelica dehurica Benth.) Shiau-Yau San (JWSYS), one of the traditional Chinese herbal prescriptions, is a famous herbal Paeoniae Radix (Paeonia lactiflora Pallas) remedy used for the management of various Glycyrrhizae Radix (Glycyrrhiza uralensis the wide use in clinical application, the scientific literature on efficacy and safety of JWSYS for the Moutan Bark (Paeonia suffruticosa Andrews) Gardeniae Fructus (Gardenia jasminoides Ellis) 2.5 treatment of menopause is not available. The aim Zingiberis Rhizoma (Zingiber officinale Ros- of this study, therefore, was to compare the effects of JWSYS and HRT on quality of life in post- menopausal women with climacteric symptoms in L.-C. Chen et al. / Maturitas 44 (2003) 55 Á/62 chronic medical conditions. Subjects taking con- JWSYS (Sun Ten Pharmaceutical Co., Taipei, comitant medication such as tranquilizers or Taiwan) or Premelle† (Wyeth Medica, New- bridge, Co. Kildare, Ireland). The JWSYS iscomposed of 10 herbal drugs which (total 33 g) were extracted with hot water, filteredand lyophilized to 7 g of extract. The extract was The aim of this study, a randomized, active- controlled, parallel comparative trial, was to compare the effect of a l6-week treatment with administered orally at a dose of 4 g three times a JWSYS or HRT in postmenopausal women with day. Each Premelle† tablet consists of conjugated climacteric symptoms. After a 2-week run-in estrogen 0.625 mg and medroxyprogesterone ace- period without treatment, the women were ran- tate 2.5 mg, to be taken once daily. The study was domly allocated to receive either powder of conducted according to good clinical practice and L.-C. Chen et al. / Maturitas 44 (2003) 55 Á/62 the protocol was approved by the regional Phar- macy and Therapeutics Committee. All partici- Baseline demographic and clinical characteristics pants gave their written informed consent prior to Before inclusion in the trial, a general medical and gynecologic examination was performed, in- cluding weight, height, heart rate, systolic and diastolic blood pressure. At the randomization visit, laboratory measures were taken including hematology, blood chemistry, follicle-stimulating hormone (FSH) and estradiol (E2) levels and urine analysis. For the women who completed the study, done at the end of the study. The frequency, Data are presented as the Mean9/S.D.
duration, and intensity of any uterine bleedingwere recorded throughout the study on diary cardsand recorded by the gynecologist. Any events orside effects reported by the patient during the symptoms 1 Á/11, 12 Á/18 and 19 Á/20, respectively.
study were graded according to severity (mild, The psychological scale can be further subdivided to give measures of anxiety (a sum of symptoms1 Á/6) and depression (a sum of symptoms 7 Á/11). Inaddition, symptom 21 is a probe for sexual dysfunction. The scale was completed by thewomen by the start of the run-in period, at the Quality of life was assessed using the Greene initiation and after 8 and 16 weeks of treatment.
Results were analyzed from women who had a pendently measures psychological, somatic and complete set of Greene Scale recordings for all vasomotor symptoms; each symptom is rated by visits. An additional questionnaire was completed the subject according to its severity using a four- on the last visit at the end of the study, to assess point rating scale. The psychological, somatic and the patients’ general satisfaction related to the vasomotor scales are a sum of Greene Scale Student’s t -test was used to assess baseline demographic comparability. Primary outcomevariable, improvement in symptom relief, ex- pressed as the changes of the mean overall scores of the Greene Climacteric Scale, were analyzed using paired Student’s t -test for comparisons within the treatment group. Unpaired Student’s t -test for independent samples was used to analyze the differences between the groups. The contin- uous secondary outcome variables (FSH and E2 levels) and the related clinical parameters (BUN,creatinine, ALT, fasting blood sugar, cholesterol, triglyceride) were also studied using the paired t - L.-C. Chen et al. / Maturitas 44 (2003) 55 Á/62 Table 5Quality of life as assessed by the Greene Climacteric Scale before and after 16-weeks’ treatment with JWSYS or Premelle† Data are presented as the Mean values (S.D.). NS: not significant.
* P B/0.01 (paired t -test for the evolution within the treatment group).
test for the evolution within the treatment group n 0/ 24 ; Premelle† n 0/ 14). The rate of disconti- and Student’s t -test for independent samples was nuing treatment were 35.14% (13/37) and 44% (11/ used for the comparison between groups.
25) for JWSYS and Premelle†, respectively ( No statistically significant differences between the groups were present for any of the baselinedata, including age, duration since menopause, weight, height, blood pressure and heart rate.
participate in the trial, 62 initial recruits satisfied Also, no differences were detected at baseline all inclusion and exclusion criteria (JWSYS n 0 between the treatment groups with respect to the Premelle† n 0/ 25). Finally, a total of 38 subjects which completed the trial in all stages were Both JWSYS and Premelle† induced a signifi- available for the analysis of efficacy (JWSYS cant reduction of prevalence and severity of Table 6Clinical parameters before and after 16-weeks’ treatment with JWSYS or Premelle† Data are presented as the Mean values (S.D.).
* P B/0.05 (paired t -test for the evolution within the treatment group).
L.-C. Chen et al. / Maturitas 44 (2003) 55 Á/62 Adverse events related to treatments during the study period Despite widespread use of alternative treat- ments, scientific evidence supporting the efficacy and safety of most complementary treatments for relief of menopausal symptoms is sparse. There- fore, randomized controlled trials demonstrating the short- and long-term effects of these treatments are needed. The present study is the first controlled trial to compare the clinical effects of the tradi- tional Chinese herbal prescription, JWSYS, and anestrogen Á/progestogen combined HRT, Premelle†, on climacteric symptoms in non-hysterectomizedpostmenopausal women. This pilot study indicatedthat JWSYS and Premelle† both effectively alle-viate menopausal symptoms. Moreover, JWSYS menopausal symptoms. The mean total scores and caused less unusual vaginal bleeding or spotting the mean scores of primary endpoints, psycholo- episodes and absence of breast tenderness during gical and somatic, decreased markedly with both treatments. The significant changes of mean scores Many postmenopausal women do not accept the in vasomotor symptoms and sexual dysfunction withdrawal bleeding which is associated with were found with the treatment of JWSYS and cyclical oestrogen Á/progestogen mixtures, prefer- Premelle†, respectively. In general, no statistically ring regimens, which do not induce bleeding .
significant differences between treatments were The present results showed that there was a observed in most of menopausal symptoms, except tendency towards fewer discontinuations with JWSYS as compared to Premelle†. Although the With comparisons of principal clinical para- overall discontinuation rate was not significantly meters, no significant changes were observed for different between the two groups, JWSYS had a the levels of FSH, E2, BUN, creatinine, ALT, relatively lower discontinuation rate due to ad- fasting blood sugar, cholesterol and triglyceride verse effects, in particular the bleeding and breast within the groups (before and after the treatment) tenderness. These findings may be of clinical during the 16-week study period and in the relevance with respect to compliance with long- between-group comparisons. Except that the sig- term treatment. Generally, treatment with either nificant changes of mean scores in FSH and E2 JWSYS or Premelle† appeared to be safe, and were found with the treatment of Premelle† ( serious adverse experiences were not related to treatment. The low frequency of breast tenderness Nine patients reported adverse events (five with JWSYS compared with oestrogen-containing patients in the JWSYS group, four patients in HRT suggests that women complaining of breast the Premelle† group). Five adverse events were tenderness while on conventional HRT might be Premelle† group. The adverse events reported in In this study, both JWSYS and Premelle† JWSYS group were bloated abdomen (8.33%), showed significant improvements in overall symp- unusual vaginal bleeding (4.17%), nausea (4.17%) tomatic relief of the primary endpoint (total score and cough (4.17%). Whereas the adverse events of the Greene Climacteric Scale). Moreover, the reported in Premelle† group were unusual vaginal significant reductions of psychological (anxiety, bleeding (14.29%), breast tenderness (14.29%), depression) and somatic symptom scores on the headache (7.14%), nausea (7.14%) and abdominal Although the exploratory analyses of sexual dys- L.-C. Chen et al. / Maturitas 44 (2003) 55 Á/62 function showed a statistically significant differ- cular disease may be reduced by up to 50%. The ence in favor of Premelle† compared with JWSYS, data mainly refer to the use of unopposed con- both preparations effectively alleviate most of jugated equine estrogens in women in the US .
menopausal symptoms with no significant differ- In this study, both treatments did not significantly alter the total cholesterol and triglyceride levels.
However, in this study JWSYS was given in However, data are not available on whether long- powder form and Premelle† in tablet form. The term treatment with JWSYS has a similarly question arises as to whether the women receiving protective effect on the risk of cardiovascular JWSYS were aware that they were taking an disease. The clinical significance underlying the established traditional Chinese herbal remedy.
effects of JWSYS on the cardiovascular disease Since the trial was not a blind one and the should be interpreted in the further studies.
improvement in the symptoms of these women In general, substances of herbal origin are could be due to an expectancy/placebo effect, considered to exhibit the mild and progressive given the cultural milieu. The further blinding action as well as a good safety profile. This makes study to evaluate the efficacy should be consid- them particularly appealing, as they can be used for preventive purposes and for long-term applica- On the other hand, it should be noted that the tion. In this trial, treatment with either JWSYS or Premelle† group had lower scores on psychologi- Premelle† appeared to be safe. No serious adverse cal, anxiety and vasomotor symptoms, albeit not events were reported with the treatment of JWSYS significantly. However, these women have less during the study period of 16 weeks, which capacity for improvement, since scores cannot indicated that JWSYS is well tolerated.
fall below zero. That is, it is noteworthy that thereis a ‘floor’ effect on these measures in thePremelle† group. Besides, in regard to statistical concerns, the Premelle† group showed a greaterpercentage improvement in all symptom measures.
In conclusion, the present study is the first Although there were no significant differences, it is controlled trial to compare the clinical effects of suggested that if the Premelle† group had con- tained the same number of subjects as the JWSYS JWSYS, and an estrogen Á/progestogen combined group, statistically significant differences between HRT on climacteric symptoms in non-hysterecto- the groups would have emerged. The discrepancy mized postmenopausal women. The results ob- between the numbers in each group was mainly tained in this pilot study suggested that JWSYS due to the randomization of the small patient might offer effective relief in climacteric symp- numbers and the various rates of discontinuing toms, whereas the beneficial effects might not be mediated by hormone replacement-like effects, as In addition, the present study provides preli- the FSH and E2 levels were not affected by the minary evidence for the safety of JWSYS. The results of the physiological investigations indicated compliance and safety without estrogenic effects that the improvements in climacteric symptoms of and metabolic alterations. Generally, the prelimin- JWSYS were not mediated by estrogenic effects ary results suggested that JWSYS was a safe and because no changes were seen in the E2 and FSH efficacious therapy and might be an alternative levels. This is consistent with the finding that choice for relief of climacteric symptoms in post- breast tenderness was less frequent with JWSYS menopausal women who refuse or have contra- than with Premelle†, which might be related to the indications for HRT. However, the exact efficacy relatively high E2 levels with the latter.
and clinical roles of JWSYS have not been convin- It is widely accepted that estrogens protect cingly demonstrated in this study because of the against cardiovascular disease, and meta-analyses blinding approach and some statistical concerns, have indicated that the relative risk of cardiovas- and only the possibility of its efficacy has been L.-C. Chen et al. / Maturitas 44 (2003) 55 Á/62 raised. Therefore, a blinding trial with more patient numbers to evaluate the efficacy of JWSYS [7] Millar WJ. Use of alternative health care practitioners by Canadians. Can J Public Health 1997;88:154 Á/8.
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