CLIMACTERIC 2015;18:11–28
Effects of herbal preparations on symptom clusters during the menopausal transition R. Ismail∗,†, L. Taylor-Swanson∗, A. Thomas∗, J. G. Schnall‡, L. Cray∗∗, E. S. Mitchell†† and N. F. Woods‡‡ ∗School of Nursing, University of Washington, USA; †Ministry of Health, Republic of Indonesia; ‡Health Sciences Library,
University of Washington, USA; **College of Nursing, Seattle University, USA; ††Family and Child Nursing, School of r University of Washington, USA; ‡‡Biobehavioral Nursing & Health Systems, School of Nursing, University of Washington, USA
Climacteric Downloaded from informahealthcare.com by Kainan University on 04/18/15 For personal use only.
Key words: MENOPAUSE, HERBAL THERAPIES, HOT FLUSHES, SLEEP, COGNITIVE, MOOD, PAIN
ABSTRACT Aims To determine the effects of herbal therapies on hot flushes and at least one other symptom including, sleep, mood, cognition, and pain that women experience during the menopausal transition and early postmenopause. Methods An extensive search of PubMed/Medline, CINAHL Plus, PsycInfo, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Web of Science, EMBASE, AMED, and Alt-Health Watch for randomized, controlled trials reported in English between January 2004 and July was conducted by an experienced reference librarian. There were 1193 abstracts identified but only 58 trials examined effectiveness of therapies for hot flushes and at least one additional co-occurring symptom. Results Seventeen studies used herbal preparation including seven studies of black cohosh, two studies of black cohosh mixed with other herbals, and eight studies of other herbals. Of these, one study of black cohosh, two studies of black cohosh mixed with other herbals, and four other herbal studies had significant effects on hot flushes and at least one additional co-occurring symptom. The adverse events of herbal therapies were various, ranging from mild to moderate and women were generally tolerant of the preparations. Conclusions Black cohosh mixed with other herbals, Rheum rhaponticum, and French maritime pine bark had significant effects on hot flushes and at least one other symptom. These herbal therapies may be a promising alternative treatment to hormonal treatment. Future studies should classify women based on their menopausal stages, report each symptom separately, have adequate sample size, focus on multiple co-occurring symptoms, and target symptom management of menopausal symptoms.
INTRODUCTION The hot flush is one of the most common symptoms that women face during the menopausal transition and early postmenopause1,2. An estimated 14–51% of premenopausal women, 35–50% of perimenopausal women, and 30–80% of postmenopausal women experienced vasomotor r including hot flushes and night sweat3. Furthermore, hot flushes and other symptoms may persist for years after menopause4. Hormonal changes during these periods have been associated with hot flushes and other menopause-related symptoms5. Cray and colleagues revealed that women who participated in the Seattle Midlife Women’s Health study experienced multiple co-occurring symptoms during the menopausal transition and
early postmenopause, including hot flushes, awakening in the night, depressed mood, forgetfulness and difficulty concentrating, and pain symptoms6. Although these symptoms are not life-threatening, they could affect women’s quality of life7,8. Hormonal therapy has been used to manage hot flushes, but results of the co Health Initiative study raised concern about the effects of hormone therapy on the risk of breast cancer and cardiovascular disease9. As a result, many women and health-care providers have searched for alternative treatments that could alleviate their symptoms. A population-based survey among women aged 45–65 years old in Washington, USA showed that 76.1% of women used at least one alternative therapy for menopause symptoms. This study also revealed that 22.1% of women
Correspondence: Dr R. Ismail, School of Nursing University of Washington, Biobehavioral Nursing & Health Systems, Health Science Building 1959 NE Pacific Street, Seattle, WA 98195, USA; E-mail:
[email protected] REVIEW © 2015 International Menopause Society DOI: 10.3109/13697137.2014.900746
Received 03-02-2014 Accepted 01-03-2014
Climacteric Downloaded from informahealthcare.com by Kainan University on 04/18/15 For personal use only.
Effects of herbal preparations on symptom clusters used at least one type of preparation to manage their menopausal symptoms such as herbal therapy10. Black cohosh is one of the herbal therapies that has been used to alleviate menopause-related symptoms11. A recently reported study of postmenopausal women showed that the subscores of the Menopause Rating Scale (MRS), particularly hot flushes, decreased significantly more in early menopausal women who received black cohosh than those in the placebo group12. Zheng and colleagues also reported that vasomotor and physical subscores of the Menopause-Specific Quality of Life (MENQOL) decreased significantly in early postmenopausal women after consuming black cohosh for 3 months13. However, recent systematic reviews showed opposite results. A Cochrane review demonstrated that black cohosh did not have significant effects in reducing the frequency of hot flushes compared to placebo14. Another systematic review by Laakmann and colleagues indicated similar results that most black cohosh studies did not show a i decrease in menopause-related symptoms, particularly hot flushes, compared to placebo15. Inconsistent results of the effects of black cohosh in alleviating menopause-related symptoms were also found in a systematic review by Borrelli and Ernst16. Despite the increasing number of women who prefer alternative therapies for menopause-related symptoms, limited information is available about the efficacy of herbal therapy on co-occurring symptoms during the menopausal transition and early postmenopause. Most clinical trials have focused on hot flushes even though studies showed that hot flushes are commonly associated with other symptoms. Cray and colleagues have demonstrated that women experience clusters of symptoms, including hot flushes, sleep, pain, o and cognition symptoms17. Other studies have focused on the co-occurrence of hot flushes and sleep symptoms as well as hot flushes and depressed mood18,19. Therefore, the purpose of this systematic review was to determine the effects of herbal therapies on hot flushes and at least one other symptom including sleep, mood, cognition, and pain, that women experience during the menopausal transition and early postmenopause.
METHODS This systemic review included published reports of controlled clinical trials that studied multiple co-occurring symptoms as treatment outcomes, including primary and secondary outcomes. Co-occurring symptoms means that hot flushes and at least one of other symptom groups were measured as outcomes in the same study. The four other symptom groups included sleep disturbances (awakening during the night, difficulty getting to sleep, early morning awakening, and sleep disorders), mood disturbances (depressed mood, mood changes, crying, irritability, anxiety, melancholia), cognitive disturbances (problem concentrating, forgetfulness, poor memory), and pain symptoms (joint aches or pains, backache or pain, headache, arthralgias)6,17. An extensive search of PubMed/MEDLINE (National Library of Medicine), CINAHL Plus (Cumulative Index n
12
Ismail et al. Nursing and Allied Health Literature EBSCO), PsycInfo (EBSCO), Cochrane Database of Systematic Reviews (Wiley), Cochrane Central Register of Controlled Trials (Wiley), Web of Science (Thomson Reuters), Embase (Elsevier), AMED (Allied and Complementary Medicine Database-EBSCO), and Alt HealthWatch (EBSCO) for randomized, controlled trials reported in English between January 2004 and July 6, 2011 was conducted by an experienced reference librarian, Janet G. Schnall. There were 1193 abstracts identified but only 58 trials studied met the inclusion and exclusion criteria. Of these, 17 focused on herbal preparations, 17 on soy/ isoflavones/amino acids, 14 on traditional Chinese medicine, and ten reports of eight trials of mind–body interventions. A complete c of the electronic search methods, including the PubMed search strategy, has been published previously20.
RESULTS This review included 17 studies that used herbal preparations in managing hot flushes and at least one of the following symptoms: sleep, mood, cognitive, and pain symptoms. Of these, seven studies used only black cohosh21–27; two studies used black cohosh mixed with other herbs including PhytoFemale Complex28 or St. John’s Wort29; and eight studies used other herbals including Pueraria mirifica30, Rheum rhaponticum31,32, consultation and herbal medicines33, French maritime pine bark34, Diascorea alata35, H. perforatum L (St. John’s Wort) and V. agnus-castus (Chaste tree/berry)36 and Femal37. The summary of efficacy of the intervention for hot flushes and the four symptom groups, including significant differences between the treatment and control groups or multiple treatment groups, is described in Tables 1 and 2. Multiple measurements were used to measure hot flushes including ambulatory sternal skin conductance monitoring24, the Greene Climacterium Scale (GCS)21,23,25,30,33,35,36, the Kupperman Menopause Index (KMI)22,23,26, the Menopause Rating Scale (MRS)26,27,29,31,32,37, the Women’s Health Questionnaire (WHQ)31,34, the Menopause-Specific Quality of Life (MENQOL)31, and diaries7,23–25,27,31,32,36. Other symptoms, including sleep, mood, cognitive, and pain, were also evaluated using a variety of instruments including the Hamilton Anxiety Rating scale (HAM-A)21,29,36, the Beck Anxiety Inventory (BAI)21, the Psychological General Wellness Being Index (PGWBI)21, the Pittsburgh Sleep Quality Index (PSQI)23, the Symptom Rating test25, the Positive and the Negative Affect Schedule23,24, the California Learning Test (CVLT-modified)24, the Primary Mental Abilities vocabulary test24, the Memory Functioning Questionnaire (MFQ)24, the Logical memory subtest of the Wechsler Memory Scale-Revised24, the Benton Visual Retention Test24, the Modified Card Rotations test24, the Letter Fluency24, the Digit Span Forward and Backward24, the Brief Test of Attention-Modified24, the EuroQol Visual Analogue Scale24, SF-3626, the Utian Quality of Life t and diaries23 (see Appendix). Studies were conducted in 12 countries, including the United States21,23,24, China22, the Czech Republic27, Italy25,
Climacteric
Climacteric isoflavones); 0.625 mg CEE/2.5 mg MPA
placebo (n ⫽ 22); phase
80 completed (88 included
in analysis).
Mood and cognitive:
aerial parts of RC (398
(n ⫽ 17)
placebo. Modified Card
Placebo 52.25.
64.82, RC 63.22, CEE 73.82,
forgetting on MFQ from baseline to
decrease in objective HF. test; MFQ; Positive and Negative Affect
group consumed 2 capsules/evening Control: Placebo
Mood: NR
(Continued)
12 months compared to BC and CEE/MPA
Placebo groups reported less seriousness in
group showed a significant
Scale
from baseline to 12 months in all groups.
0% in placebo. Only CEE/MPA CEE/MPA (0.625 mg/2.5
Abilities vocabulary
Finding As test; daidzein);
Hot flush frequency/week: BC
Primary Mental
intervention compared to baseline. Seriousness of forgetting on MFQ decreased significantly* was 17% in BC, 33% in RC, and
of Attention-Modified;
1.6 mg genistein, 0.9 mg
45.40, Placebo 35.04;
mg). Participants in each
free recall decreased significantly at end of HF from baseline to 12 months
Backward; Brief Test
W group: Irrespective of group, CVLT short-delay Magnitude of change in objective
Forward and
Months since last period: BC
56.6 mg formononetin,
(12 months)
group than placebo. Mood: NR
57.5 mg biochanin A,
Fluency; Digit Span
aglycones, specifically
clinical trial
in CEE group than placebo. Performance in digit spam decreased significantly* in CEE
including vasomotor symptom in the model; Verbal fluency improved significantly* more
CEE/MPA group compared to placebo after
and RC groups compared with placebo. Verbal learning decreased significantly* more in
B group: No impact in verbal memory in BC
reported
Data for joint pain, and, mood changes not
reported.
CEE/MPA group. Other groups were not
42.62, RC 49.92, CEE/MPA
significantly in all groups from baseline to 12 months**.
Rotations test; Letter
120 mg isoflavone
randomized
Placebo 29.64;
W group: Subjective HF decreased
CEE/MPA group compared to Visual Retention Test;
mg/day standardized to
30.82, CEE/MPA 25.85,
Asian; BMI: BC 28.89, RC
44% white; 2% Hispanic; 1%
and HF
reduced significantly more in Scale-Revised; Benton symptoms diary
ethanolic extract of
and placebo
Mean age 53.13 years; 53% AA; Phase II
subjective and objective HF
subtest of the Wechsler Memory
measures of vasomotor
area. mg triterpene glycosides);
placebo but not significant. The number** and intensity* of
day standardized to 7.27
Logical memory
BC and RC groups compared to
B group: Objective HF decreased in
MPA (n ⫽ 17),
monitor; diary
CVLT-modified;
(n ⫽ 14), CEE/
ground parts (128 mg/
(n ⫽ 18), RC
to women residing in Chicago
skin conductance
Ambulatory sternal
group, and 63% in placebo group
34% in BC group, 57% in RC
groups, 94% in CEE/MPA group,
and NS) reduced significantly in all
W group: Vasomotor symptoms (HF
89 enrolled, 66 completed.
extract of BC below
groups: BC
boards and targeted mailings
Randomized to 4
Recruited from internet, bulletin
Chicago24
KI, GCS
with placebo. but not different over time
(3, 6, 9, 12)
last menstrual period
3.5 years
on overall quality of sleep when compared compared to placebo at 3 months
12 months
use hormone 43.8%; mean
W group: Sleep improved significantly more in
None of groups had significant improvement significantly more in BC
every 3 months for
Pacific Islander 1.1%; past
compared with placebo at 3, 12 months.
significantly only in CEE/MPA group when
Greene vasomotor score increased
Intervention: ethanolic
at 6 and 9 months Vasomotor symptoms on KI score &
12 months
(moderate), 3
1 (mild), 2
The impact of HF on sleep (PSQI) improved
compared to placebo at 12 months
measured. However, the Greene anxiety score decreased significantly* only in RC group
groups compared to placebo at any time
changes did not decreased significantly in all
B group: Insomnia, joint pain, sleep, mood
(severe); evaluated
12 months
group compared to placebo
placebo. Vasomotor intensity increased significantly* in BC
CEE/MPA group compared to
and throughout
before randomized
Diaries minimal 2 weeks
Affect Schedule; KI
HF decreased in all groups but decreased significantly*** only in
B group: Intensity and number of
intensity scored
randomization and
Positive and Negative
and pain. GCS; PSQI;
43.3%, Hispanic 4.3%,
28.7; race AA 44%, white
Mean age 53 years; mean BMI
Control: Placebo
12 months; HF
standardized to 120 mg
MPA (n ⫽ 23),
II randomized;
throughout
RC (398 mg/day
(n ⫽ 22), CEE/
(n ⫽ 88);
before
mg triterpene glycosides);
(n ⫽ 22), RC
for at least 2 weeks
postmenopausal women
1452 screened, 89 randomized,
placebo group W group: NR
significantly different between BC and
0.62, p ⫽ 0.163)
2, 4, 8, 12 W group: NR
p ⫽ 0.063). Anxiety and depression scores not
subscale (-0.87; 95% CI -2.09 to
screen, baseline, weeks
Diaries for HF and NS Sleep, mood, cognitive,
day standardized to 7.27
Intervention: BC (128 mg/
groups: BC
Randomized 4
healthy perimenopausal and
Outpatients of Medical Center;
years
years; white 71.43/61.54
Mean age BC/placebo 56.7/50.8
significant (-2.68; 95% CI -5.51 to -0.15;
groups on GCS vasomotor
measured after the
12 weeks
(15/13), 20 completed.
Control: Placebo (rice flour)
BC group than placebo group but not
mg BC) by week 4
(n ⫽ 13);
34 enrolled; 28 randomized
significant difference between
95% CI -8.59 to -3.12); no
Treatment-emergent
weeks 2, 4, 8, 12)
max 4 capsules/day (128
placebo
examination. adverse effect profile;
decrease on GCS psychological subscale in
favoring placebo group (-4.45;
BAI; PGWBI;
screen, baseline,
& gradually increased to
(n ⫽ 15) and
placebo group in HAM-A score; a modest
B group: No significant difference in BC and
Results: other symptoms
normal gynecologic
B group: Total GCS score decreased significantly* more in BC group
Results: hot flushes
(64 mg BC) for 2 weeks
and pain. HAM-A,
Sleep, mood, cognitive,
symptoms
Outcome measures: other
groups, BC
outcome) (after the
GCS (secondary
hot flushes
Outcome measures:
postmenopausal women with
Maki, 2009,
Illinois23
Geller, 2009,
Philadelphia21
Amsterdam, 2009, Amenorrhea perimenopausal &
Randomized into 2 Intervention: 2 capsules/day
comparison/control
Black cohosh
Main intervention and
followed)
study location
Study design
(screened, enrolled, completed,
Study population, sample size
Trials of herbal therapies for hot flushes and associated symptoms: study population, design, interventions, outcomes, and results
Author, year,
Table 1
Climacteric Downloaded from informahealthcare.com by Kainan University on 04/18/15 For personal use only.
Effects of herbal preparations on symptom clusters Ismail et al.
13
14 group at 12 weeks when compared with
sweating after 4 and 8 weeks in BC group but p value was not
sweating and sleep disturbances
severe (1.0); daily diary of sweating episodes
20 mg herbal drug; 2 capsules of 0.3 mg CE/day
(n ⫽ 20); 12 weeks
mean height (cm)
164.20/167/164; MRS
2.73/2.83/3.23 Control: Placebo
impaired performance memory, disorders of sexuality) decreased significantly only* in BC
to placebo.
pain ⫽ MRS Daily diary: number of
(0.7–0.9), very
extract corresponding to
placebo
weight (kg) 67.0/67.86/65.15;
but not significantly different compared to placebo.
decreased 80% in BC, 55% in CE, and 41% in placebo
baseline, at baseline, after 4, 8, and 12 weeks
were not reported
complaints, and somatic complaints
periods, mental score, major climacteric
W group: Data for number of nightly wake -up
compared to placebo
12* weeks) and in CE group*( at 12* weeks)
Somatic complaints (HF and joint/muscle pain) decreased significantly in BC (at 8* and
significantly only in BC group compared to placebo at 8* and 12* weeks
moods, joint/muscle pain) decreased
Major climacteric complaints (HF, depressive
placebo. Mental score decreased in CE group HF/sweating episode/day
Data collected 2 weeks prior to
Mental score (depressive mood, nervousness,
provided. After 12 weeks,
W group: Clear reduction of daily
significantly only in BC compared to placebo at 8* and 12* weeks significantly different compared memory, joint/muscle
(0.4–0.6), severe
1.66–2.86 mg of native
(n ⫽ 22),
52.25/52.32/54.05; mean
CE group also decreased but not
of night with early awakenings decreased
Impaired performance
capsule contained
(n ⫽ 20), CE (0.1–0.3), moderate
12 weeks. HF/daily sweating in
nervousness/irritability,
none (0), mild
A. racemosa. Each
BC/CE/placebo mean age
compared to placebo after 12 weeks. Ratio BC group than placebo after
depressive moods,
symptoms 1–10:
BNO 1055 of rhizome of
B group: Number of nightly wake-up periods decreased significantly more in BC* and CE*
extract of BC
B group: HF/daily sweating decreased significantly* more in
ethanolic
pain; sleep disorders;
Sleep, mood, cognitive,
randomized, 62 completed.
menopausal
MRS Severity scale of
and outpatient clinics; 97
of dried aqueous extract
Intervention: 2 capsule/day
groups after 12 weeks compared to baseline
and vertigo reduced significantly in both
depressive mood swings), sleep disturbances,
Republic27
groups:
Randomized to 3
at baseline. W group: Psychological symptoms (nervousness,
at 4 and 12 weeks intervention
assessment of efficacy at week 12
was significant different in both groups
more in iCR and tibolone group
3; subject’s global
significantly different; Insomnia item score
decreased in iCR and tibolone group but not
time-point
visit; (CGI 2 at visits 2 W group: HF decreased significantly
pain, headache, and palpitation score in KMI
not significantly different at each
and 3; CGI 3 at visit
mood, vertigo, weakness and fatigue, joint
in iCR and tibolone group but
rate; CGI 1 at each
private gynecological practices
Postmenopausal women from 13
Results: other symptoms
B group: HF score in KMI decreased B group: Insomnia, nervousness, depressive
Results: hot flushes
KMI; KMI responder
Sleep, mood, and pain.
symptoms
Outcome measures: other
Czech
Wuttke, 2006,
China22
hot flushes
Outcome measures:
Intervention: Isopropanolic KMI; KMI responder Randomized to Recruited from 5 centers of 3 cities in China; rate; CGI Item 1 extract of iCR rootstock two groups: 40–60-year-old women with (severity of (0.018–0.026 ml liquid iCR group menopausal complaints for at climacteric extract iCR (n ⫽ 122) and least 4 weeks; No syndrome) at each rootstock ⫽ 2.5 mg dry tibolone group hysterectomy, cancer. visit; CGI Item 2 extract and 20 mg herbal (n ⫽ 122); 12 316 screened, 244 enrolled and (global drug/twice daily) weeks. randomized (122/group), improvement of Control: 2.5 mg tibolone Double dummy 218 completed. climacteric design, iCR FAS (n ⫽ 238): isopropanolic complaints) at group had two extract of Actaea visits 2 and 3; iCR tablets ( ⫽ Cimicifuga) racemosa CGI Item 3 (1-0-1) and one (iCr)/tibolone Mean age (therapeutic effect) tibolone51.8/51.5; BMI 23.2/23.5; at visit 3; subject’s matching number of HF episodes/week global assessment placebo per at screening 30.0/30.1; former of efficacy at day); and HRT use 37.3%/40.0%. week 12 tibolone group PP set (n ⫽ 213). iCR//tibolone had two iCR mean age 51.6/51.6; BMI -matching 23.1/23.6; number of HF episodes/week at screening placebo and one 29.9/29.8; former HRT use tibolone- tablet/ 39.3%/42% day; 12 weeks
comparison/control
Bai, 2007,
Main intervention and Study design
followed)
study location
Study population, sample size
(screened, enrolled, completed,
(Continued)
Author, year,
Table 1
Climacteric Downloaded from informahealthcare.com by Kainan University on 04/18/15 For personal use only.
Effects of herbal preparations on symptom clusters Ismail et al.
Climacteric
Climacteric daily
(n ⫽ 136)
Israel28
Rotem, 2007,
Sleep quality score in placebo group decreased 21% at end of study (lower end of study (80% vs. 35%) W group: HF decreased significantly over time of intervention (73%) in PFC group while HF in placebo group decreased 8% and 38%. 22% women in placebo group experienced aggravation of symptoms and 19% reported alleviation of HF. None of women in PFC group reported aggregation of symptoms and 81% experienced amelioration of symptoms on HF. 47% HF stopped on PFC and 19% on
intensity and sleep quality: subjectively assessed on a scale of 1 to 5
symptoms (HF and NS from 1 week before throughout the 3 months
(2.5 mg triterpen glycoside, 2.5%); dong quai (Angelica sinensis) root extract, 75 mg (7.5 mg ligustilides, 1%); milk thistle herb extract, 75 mg (60 mg silymarin, 80%); red clover flower extract, 50 mg (4 mg isoflavone, 8%); American ginseng root extract, 50 mg (12.5 mg ginsenosides, 25%); chaste-tree berry fruit extract, 50 mg (2.5 mg vitexin, 5%)
12 weeks
55.3/59.0; years in menopause
6.88/8.95; weight (kg)
65.80/70.58
PFC formula/placebo mean age
Control: Placebo
and 70% at week 12) compared to baseline. PFC group than placebo group at
symptoms; symptom
menopausal
BC root extract, 100 mg
(n ⫽ 25);
(19/16).
vs. 38%). Intensity of HF decreased significantly** more in
due to vasomotor
intensity of
Each capsule contains
placebo
postmenopausal women
50 randomized, 35 completed
placebo
since second week (25%) and
(Continued)
score ⫽ higher quality of sleep)
significantly in PFC group (52% at week 8
compared to placebo group (73% W group: Sleep quality score decreased
awakenings at night
frequency and
twice daily for 3 months.
(n ⫽ 25) and
Services; healthy pre- and
more in PFC group than placebo group.
B group: Sleep quality improved significantly***
formula PFC prescribed
on number of
and sleep disorder were not reported
groups: PFC
Randomized 2
‘hot flushes’ W group: Data for psyche score, soma score,
clinics of General Health
5 community gynecological
12 weeks
questionnaire on
of data were
3 months 20%/19%
Intervention: Oral herbal
implausibilities
HF/week 28/28; HRT in last cleaned;
cardiac complaints) Data for sleep were included in MRS subscore
all relevant
iCR/placebo mean age 54/55;
33%/39%; median number of
No relevant effects of iCR on MRS subscore
compared to placebo group
impaired performance, and memory) in MRS decreased significantly** more in iCR group
soma (joint and muscle symptoms,
B group: Number of HF decreased significantly* more in PFC group
W group: NR
than placebo group
B group: Psyche score (depressive mood, B group: HF decreased nervousness, nervous irritability, generally significantly** more in iCR group
analysis after
Sleep: daily questionnaire
Form 36
Outcomes Study Short
and Medical
and pain. MRS, KI,
at 3 months compared to baseline
statistical
Structured
Short Form 36
Outcomes Study
decreased significantly in BC and
W group: Anxiety and depression significantly*** decreased in BC and TTSE2
both groups but not significantly different.
B group: Anxiety and depression decreased in
BMI 25.5/24.9; hysterectomy
268 completed
Control: Placebo
of root stock), twice
placebo
postmenopausal women Unblinding for
corresponding to 20 mg
(n ⫽ 136) and
private practices;
309 enrolled, 304 randomized,
tablet (2.5 mg iCR
Intervention: Remifemin
2 groups: iCR
or gynecologically experienced
Recruited from 24 gynecologic
estradiol treatment Sleep, mood, cognitive,
12 days of 3-month
12 weeks
menopause 9.0/9.1 months, MRS; KI; the Medical
10 mg/day for last
(n ⫽ 32);
CR/TTSE2 mean age 50.5/50.9,
Randomized to
treatment
dihydrogesterone
31), TTSE2
64 enrolled and 63 completed
BMI 22.9/22.0
TTSE2 from the first month of
3 months plus
of CR (n ⫽
W group: Number of HF*** and vasomotor symptoms***
25 μg every 7 days for
aqueous extract
postmenopausal women
different
Greene scale
and Greene scale
Modena, Italy;
Control: low-dose TTSE2
isopropanolic
TTSE2 but not significantly
B group: HF decreased in CR and
and depression and
Mood: SRT for anxiety
number of HF/day
HF diaries recording
of Universities of Pavia and
CR
Intervention: 40 mg/day of
2 groups:
Randomized to
of Obstetrics and Gynecology
Conducted at Departments
Black cohosh mixed with other herbal therapies
Germany26
Osmers, 2005,
Italy25
Nappi, 2005,
Climacteric Downloaded from informahealthcare.com by Kainan University on 04/18/15 For personal use only.
Effects of herbal preparations on symptom clusters Ismail et al.
15
16
Taiwan35
Hsu, 2011,
GCS at baseline,
Sleep, mood, cognitive,
W group: Compared to baseline, HF
group (12.7%)
standardized to 0.25 mg total hypericine
2.6/2.6
from menopause (years)
mean BMI 23.4/24.2; interval
DA/placebo mean age 51.9/53.1;
completed.
significantly different
12 months
12 months in both groups
W group: Vasomotor symptoms
concealed;
12 months
decreased significantly at 6 and
placebo (n ⫽ 25) Control: placebo
ingredients; no breast cancer; randomized;
(12 mg/sachet)
(n ⫽ 25) and
hypersensitivity to product
70 screened; 50 randomized; 50
of DA extracts
Intervention: 2 sachets daily
groups, DA
postmenopausal women; no
Volunteers; 2 medical centers; all
Control: Placebo
245–350 mg herb)
native extract and
decreased in both groups but not
BC ⫹ SJW group (41.8%) than in placebo
and SJW extract
4.3/4.0 years
B group: Vasomotor symptoms
HDRS score decreased significantly more in
to 41.25 mg rootstock)
depressive moods
and pain: GCS
group (13.7%) since week 8. At 16 weeks
native extract and 22.5
years; mean duration of
6 months and
BC ⫹ SJW group (30%) compared to placebo
on average to 3.75 mg
mean duration of HF 4.4/3.8
(corresponding to 70 mg
group between 2nd and 3rd examinations but
glycosides (corresponding
others 25/9/49 vs. 21/14/59;
DA group at 12 months compared to baseline
Musculoskeletal pain decreased significantly in
DA group at 12 months compared to baseline
had a marked improvement (significantly) in
Insomnia, feeling tense or nervous, and excitable
compared to baseline
W group: Psychological scores decreased significantly** in DA group at 12 months
12 months compared to placebo
improved significantly more in DA group at
group Insomnia** and musculoskeletal pain* score
group at 12 months compared to placebo
B group: Psychological score especially anxiety**, feeling tense and nervous**, and excitable* decreased significantly more in DA
to baseline vs. 12.7% in placebo group
⫹ SJW group (41.8%) at 16 weeks compared
HDRS score decreased significantly more in BC
SJW group and 27.9% in placebo group)
groups at 2nd examination (39.5% in BC ⫹
Soma factor decreased significantly in both
with post comparison)
and placebo group (20.0%) (pre compared
W group: Psyche factor improved significantly*** in BC ⫹ SJW group (56.4%)
slightly increased in placebo group HDRS score decreased significantly*** more in
factors score kept decreasing in BC ⫹ SJW
1 mg triterpene
unilateral oophorectomy/
SJW group compared to placebo group at 2nd examination (39.5% vs. 27.9%); Soma
placebo group
extract standardized to
52.4/51.9; BMI 25.2/24.7;
number of hysterectomy/
morning and in evening.
nervousness, impaired memory, joint/muscle pain) decreased significantly*** more in BC⫹
Soma factor (sleep disorder, depressive moods,
(week 8) and 3rd examinations
group compared to placebo group at 2nd
nervousness, impaired performance memories) improved significantly*** more in BC ⫹ SJW
B group: Psyche factor (depressive mood,
Results: other symptoms
Each tablet contained BC
BC ⫹ SJW/placebo mean age
completed but 294 analyzed
Randomized to 2
day (weeks 1–8) and
weeks
component
to placebo group
examination (week 8) compared
SJW group since second
BC ⫹ SJW group and 25.4% in
2 tablets orally twice/day
(n ⫽ 150);16
pronounced psychological
score and MRS
B group: HF decreased significantly*** more in BC ⫹
Results: hot flushes
decreased significantly 53.4% in
perforatum) extracts
and placebo
climacteric complaints with a
16 weeks)
and pain. HDRS sum
Sleep, mood, cognitive,
symptoms
Outcome measures: other
(weeks 9–16), in
and SJW (Hypericum
SJW (n ⫽ 151)
pharmacies, women with
after 8 weeks; after
MRS (at baseline,
hot flushes
Outcome measures:
1 tablet orally twice/day
(Cimicifuga racemosa)
Intervention: BC
groups: BC ⫹
Randomized to 2
announcements, practices and
372 screened, 301 included, 287
Other herbal therapies
Germany29
Recruited from newspaper
comparison/control
Uebelhack, 2006,
Main intervention and Study design
followed)
study location
Study population, sample size
(screened, enrolled, completed,
(Continued)
Author, year,
Table 1
Climacteric Downloaded from informahealthcare.com by Kainan University on 04/18/15 For personal use only.
Effects of herbal preparations on symptom clusters Ismail et al.
Climacteric
Climacteric (2 tablets/day) for 16-week treatment phase
and placebo (n ⫽ 46)
follow-up
2 ovaries retained 8/7;
Ukraine31
Heger, 2006,
women
Ukraine32 day); 12 weeks
(n ⫽ 56);
& surgeries (%) 38/41
previous gynecology disease
Control); BMI 26.2/25.7;
Mean age 59.3/48.6 (Rr/
in ITT analysis)
82 completed (109 included trial; 12 weeks
Phase III clinical
placebo (n ⫽ 55)
(n ⫽ 54) and
902 screened, 110 randomized,
for 12 weeks Control: Placebo
groups: ERr
Intervention: 4 mg ERr 731
with climacterium complaints
Randomized to 2
observational)
(52 weeks
Trial; 12 weeks
Phase III Control
Control: Placebo
731 (n ⫽ 56) and placebo
extract 731 (1 tablet/
groups: ERr
departments, perimenopausal
Outpatients at 9 gynecological
49.4/49.6; BMI 25.7/26.4
ERr 731/placebo mean age
analysis; 105 PP analysis)
107 completed (112 ITT
171 screened; 112 randomized;
outpatient); perimenopausal
2009,
Multicenter (gynecology
9.42/9.65
flushing episodes per day Intervention: 4 mg ERr dry
(week 24) Control: Placebo
plus 8 weeks
26.2/26.8; hysterectomy 9/8;
Randomized to 2
post-treatment follow-up
intervention,
mean age 52.5/51.9; BMI
Herbal combination/placebo
16-week
and analyzed, 93 completed
761 eligible, 100 randomized
MRS II; diary; WHQ
HFWWS
severity of HF);
(number and
84 days); diary
increased from 2.5 to 2.6 (p value not provided)
to 1.5 in ERr 731 group while placebo group
Joint and muscular discomfort decreased from 2.8
in placebo group
ERr 731 group and from 2.7 to 2.3
group. Anxiety decreased from 2.7 to 1.1 in
ERr 731 group and from 2.9 to 2.2 in placebo
group. Irritability decreased from 2.7 to 1.1 in
731 group and from 2.7 to 2.1 in placebo
Depressive mood decreased from 2.5 to 0.8 in ERr
placebo group
1.0 in ERr group and from 2.4 to 2.1 in
W group: Sleep problems decreased from 2.5 to
placebo group.
Joint and muscular discomfort decreased significantly*** more in ERr 731 group than
placebo group
Depressive mood, irritability, and anxiety decreased significantly*** more in ERr 731 group over
group than placebo group
B group: Based on ITT analysis, sleep problem decreased significantly*** more in ERr 731
(Continued)
B group: The number and severity of B group: Sleep disturbance, mood (depression HF decreased significantly*** mood, irritability, anxiety), pain (joint and and pain: MRS II; more in ERr 731 group than muscle complaints) decreased significantly*** MENQOL; EuroQol placebo after 4 weeks. more in ERr 731 group compared Visual Analogue Scale; W group: The number and severity to placebo group. Hamilton Anxiety of HF decreased significantly*** W group: Sleep disturbance, mood, pain Scale, WHQ in ERr 731 group since week 4 decreased significantly in ERr 731 group Vasomotor score in MENQOL after 12 weeks. Placebo group no change decreased significantly in both groups but greater in ERr 731 group Sleep, mood, cognitive,
and pain: MRS
B group: HF decreased significantly*** more in ERr 731 group compared to day 84. HFWWS decreased significantly*** more in ERr 731 group compared to placebo W group: HF decreased significantly in ERr 731 group at day 84 compared to baseline. HFWWS decreased significantly in ERr 731 group from day 1 to day 84
B group: HF and GCS scores B group: Psychological, anxiety, depression, decreased in H. perforatum L and somatic score decreased in both groups but V. agnus-castus L group and not significantly different. The HDI score scores (completed at placebo group but not decreased at week 16 in both groups but not 4-week intervals significantly different. significantly different. throughout treatment Sleep improved in both groups but not period and at 8-week W group: Significant improvement for HF in H. perforatum L and V. significantly different follow-up), Utian agnus-castus L group** and W group: Psychological, anxiety, depression, Quality of Life Scale placebo groups*** at end of sleep, somatic score in GCS scale and scores (at baseline and study compared to baseline; daily depression (HDI-17) score improved week 16) weighted HF decreased 43.5% in significantly*** in both groups after H. perforatum L and V. 16 weeks compared to baseline agnus-castus L group and 45.6% in placebo group at week 16 compared to baseline.
and pain. GCS, HDI
Sleep, mood, cognitive,
MRS (on 0, 28, 56, & Sleep, mood, cognitive,
L (500 mg of fry fruit)
berry) (n ⫽ 47)
experienced at least 5 HF/
Kaszkin-Bettag,
GCS
day) and V. agnus-castus
(Chaste tree/
late-perimenopausal women
and 1 week during
moderate, severe);
perforatum (3 tablets/
agnus-castus
postmenopausal or
Parallel trial,
of HF as mild,
mg Hypericum
SJW and Vitex.
community clinics;
sweating episode/day
(number & severity
Daily symptom diaries
of 2 herbal extracts, 300
web sites, and fliers at
Australia36
Intervention: Combination
groups: extracts
Newspapers, radio interview,
van Die, 2009,
Randomized to 2
Climacteric Downloaded from informahealthcare.com by Kainan University on 04/18/15 For personal use only.
Effects of herbal preparations on symptom clusters Ismail et al.
17
18 Intervention: 100 mg FMPB
Randomized to 2
UK33
Green, 2007,
Taiwan34 twice daily for 6 months
GCS; MYMOP2
Sleep, mood, cognitive,
placebo group compared to start point
nutrition, lifestyle and individualized herbal prescription) & consumed herbal
control (offered waiting after 4 months) (n ⫽ 30)
invited by letter. Experienced
menopausal problem for at
least 3 months
Control: Waiting list control group offered treatment after waiting 4 months
randomized, waiting list controlled pilot study; 5 months
52.67/52.82; took HRT in
past 21%/23%; Hysterectomy
7%/3%; past purchase of
herbal product for any
43%/70%
reduce menopausal symptoms
expectation treatment will
condition 50%/83%;
Intervention/control mean age
pragmatic,
45 randomized, 34 completed
medicines for 24 weeks.
to baseline
5 months (discussion of
(n ⫽ 15) and
owner-occupied houses;
Prospective,
the end of study compared
six consultations over
practitioners
education, mostly living in
252 eligible, 161 replied letter,
both groups but not significantly different control group.
practitioners; Treatment:
herbal
employment, income &
to baseline
and somatic decreased by week 24 compared
W group: psychological (anxiety & depression)
group; somatic (physical change) decreased in intervention group compared to
MYMOP2
from one of three herbal
treatment from
W group: Vasomotor scale (HF & NS) decreased significantly** at
intervention group compared to control
and MYMOP2 (HF & NS) decreased significantly** more in
and pain: GCS;
individualized treatment
2 groups:
significantly (but not depression) more in
B group: Scores anxiety in GCS decreased
women with high levels of
B group: Vasomotor score in GCS
for poor memory questions Only poor memory improved significantly* in
group did not show significant change except
compared to start of treatment while placebo
improved significantly in FMPB extract group
concentration, anxiety, and sleep problem
practice (5000 patients);
Randomized to
treatment: Somatic symptoms (tiredness and
significant change
Recruited from 1 urban GP
in FMPB extract group compared to start of
C group did not show any
headache), depressed mood, memory/
W group: All symptoms improved significantly
than placebo group
(headache, back pain) improved significantly*** more in FMPB extract group
than placebo group. Somatic problems
concentration, and sleep decreased significantly*** more in FMPB extract group
B group: Mood (depressed, anxiety), memory/
Results: other symptoms
FMPB extract group while
W group: Vasomotor symptoms improved significantly***
to placebo group
in FMPB extract group compared
B group: Vasomotor symptoms improved significantly*** more
Results: hot flushes
compared to start of treatment in
Intervention: Course of
and pain: WHQ
Sleep, mood, cognitive,
symptoms
Outcome measures: other
24.12/24.06
6 months
WHQ
hot flushes
Outcome measures:
46.73/47.02; BMI
FMPB extract/placebo mean age
Control: Placebo
and placebo
completed
(n ⫽ 75);
(Pycnogenol®) capsules
extract (n ⫽ 80)
sometimes of HF
200 enrolled, 155 patients
bark extract
groups: FMPB
complained frequently or
Perimenopausal women
comparison/control
Yang, 2007,
Main intervention and Study design
followed)
study location
Study population, sample size
(screened, enrolled, completed,
Author, year,
Table 1 (Continued)
Climacteric Downloaded from informahealthcare.com by Kainan University on 04/18/15 For personal use only.
Effects of herbal preparations on symptom clusters Ismail et al.
Climacteric
Climacteric Sleep, mood, cognitive,
Femal & placebo
hysterectomy 2/0; number of
HF/day 6.1/4.7 3 months
3 months
matching of
51.2/51.6; BMI 26.9/26.4;
group after 3 months compared to baseline
Mood improved significantly** only in Femal
months compared to baseline
in Femal group particularly at 1 and 3
group compared to placebo W group: Dizziness decreased significantly* only
were not significantly different in Femal
Sleep disturbance, depression, and joint pain
statistically significant
(4.1%)in placebo group but not
intervention compared to baseline.
not change significantly after 3 months
Sleep disturbance, joint pains and depression did
significantly only at 2 months in Femal group
In contrast, HF tended to increase Headache, irritability, & sensitiveness changed
(22%) compared to start point.
significantly in Femal group at 2 months* (23%) and 3 months*
W Group: Number of HF decreased
group than placebo group
tablets/morning for
(run-in period),
Femal/placebo mean age Control: Placebo
Based on diary, HF reduced significantly** more in Femal
14 mg amino acids. Two
groups but not significantly different between Femal and placebo groups
B group: Dizziness and mood decreased in both
group and from 2.16 to 0.4 in CEE ⫹ MPA ⫺ group
Insomnia decreased from 1.53 to 0.26 in PM
after 6 months intervention.
neglected, excitable) decreased in both groups
Mood (mood instability, nervous, feeling
decreased in PM group and CEE ⫹ MPA ⫺ group compared to baseline
(headache, back pain, and muscle pain)
compared to placebo (38%) from 2* months to end of study*.
pistil extract (PI 82) plus
54 completed.
64 recruited; 64 randomized;
significantly different W group: (p values were not provided). Pain
more in Femal group (65%)
B Group: HF decreased significantly
treatment
episodes)
(GC Fem) and 120 mg
and placebo
for at least 6 months
and pain: MRS
First month no
of HF & sweating
40 mg pollen extracts
groups: Femal
with menopausal symptoms
Local newspaper ads; women
smoker.
participant was a cigarette
Randomized to 2
but not significantly different
24 weeks
Insomnia decreased in both groups but not
CEE ⫹ MPA (p values were not ⫺ provided)
Phase III study;
drinking alcohol; only one
neglected, excitable) decreased in both groups
group and from 2.1 to 0.3 in
non-blind trial.
PM/CEE ⫹ MPA mean age ⫺ 48.2/48.5; no one in habit of
Intervention: Femal contains MRS; Diary (number
to PM group
significantly in CEE ⫹ MPA group compared ⫺
significantly different. Joint pain decreased
pain) decreased in both groups but not
B group: Pain (headache, back pain, and muscle
decreased from 2.1 to 0.53 in PM Mood (mood, instability, nervous, feeling
W group: At end of study, HF
different
in PM group and CEE ⫹ MPA ⫺ group but not significantly
B group: HF decreased in all points
71 enrolled; 60 completed.
score ⫽ severe)
6 months (higher
monthly for
modified GCS
Sleep, mood, and pain;
St. John’s Wort; SRT, Symptom Rating Scale; W-group, within group; WHQ, Women’s Health Questionnaire; MENQOL, Menopause Quality of Life Questionnaire; TTSE2, transdermal estradiol
n, number of participants; NS: night sweats; NR, not reported; PFC, Phyto-Female Complex; PGWBI, Psychological General Wellness Being Index; PM, Pueraria mirifica; PP, per protocol; PSQI, Pittsburgh Sleep Quality Index; RC, Red clover; SJW,
intention to treat; KI, Kupperman Index; KMI, Kupperman Menopause Index; MFQ, Memory Functioning Questionnaire; MPA, medroxyprogesterone acetate; MRS, Menopause Rating Scale; MYMOP2, Measure Yourself Medical Outcome Profile;
Scale; HDI, Hamilton Depression Inventory; HDRS, Hamilton Depression Rating Scale; HF, hot flushes; HFWWS, Hot Flush Weekly Weighted Score; HRT, hormone replacement therapy; iCR, isopropanolic extract of Cimicifuga racemosa; ITT,
Cimicifuga racemosa; CVLT, California Verbal Learning Test; DA, Diascorea alata; ERr, enteric coated Rheum rhaponticum; FAS, full analysis set; FMPB, French maritime pine bark; GCS, Greene Climacteric Scale; HAM-A, Hamilton Anxiety Rating
*, p ⬍ 0.05; **, p ⬍ 0.01; ***, p ⬍ 0.001 ⫺ ⫺ ⫺ AA, African American; BAI, Beck Anxiety Inventory; BC, Black cohosh; B-group, between group; BMI, body mass index; CE, conjugated estrogen; CEE, conjugated equine estrogen; CGI, Clinical Global Impression; CI, confidence interval; CR,
Sweden37
Winther, 2005;
plus 2.5 mg MPA daily
and CEE ⫹ ⫺ MPA (n ⫽ 30);
symptoms without HRT and
chronic illness
daily or CEE 0.625 mg
(n ⫽ 30)
experienced vasomotor
baseline and
Control: CEE 0.625 mg
groups; PM
Thailand30
Modified GCS;
Intervention: PM 50 mg
Randomized to 2
clinic; perimenopausal women
Recruited from menopausal
2007,
Chandeying,
Climacteric Downloaded from informahealthcare.com by Kainan University on 04/18/15 For personal use only.
Effects of herbal preparations on symptom clusters Ismail et al.
19
20 ⫹ NR ⫹ NS ⫹ ⫹ ⫹ NR NS
⫹ ⫹ NS ⫹ NR ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ↓ ⫹
⫹ NS NS ⫹ ⫹ ⫹ NS NS ⫹ ⫹ ⫹ ⫹ NS ⫹
Chandeying30 (Pueraria mirifica 50 mg)
Winther37 (Femal formula)
NS NS ⫹
⫹ ⫹ ⫹
NS NS ⫹
NS
↓
⫹ ⫹ ⫹ ⫹ ⫹ NR
⫹ NR
NR NR NR NR
NM NM NM ⫹
NR NR ⫹
NR
W group
Sleep
NS
NS
⫹ NS ⫹ ⫹ ⫹ ⫹
NM ⫹
NR NR NS NR
NR NR NR NS
NS ⫹ NS
NS
B group
⫹
↓
⫹ ⫹ ⫹ ⫹ ⫹ ↓
NM ⫹
NR NR + NR
NR NR NR ⫹
NR NR NR
NR
W group
Mood
NR
NR
NR NR NR NR ⫹ NR
NM NR
NR NR NR NR
NS NS ⫺ NM
NR NR NR
NR
B group
NR
NR
NR NR NR NR ⫹ NR
NM NR
NR NR NR NR
⫺ ⫺ ⫺ NM
NR NR NR
NR
W group
Cognitive
NS
NS
⫹ NR ⫹ ⫹ ⫹ NR
NM NR
NR NR NR NS
NM NM NM NS
NS NS NS
NR
B group
⫹
↓
⫹ NR ⫹ ⫹ ⫹ NR
NM NR
NR NR NR NR
NM NM NM ⫹
NR NR NR
NR
W group
Pain
NS, not significant; NR, not reported; NM, not measured; ↓, decreased (p value not provided); ⫹, significant positive treatment effect; -, significant negative treatment effect; Obj, objective measurements; Subj, subjective measurements; BC, Black cohosh; RC, red clover; CEE, conjugated equine estrogen; CE, conjugated estrogens; PFC, Phyto-Female Complex; SJC, St. John’s Wort; FMPB, French maritime pine bark
NS
⫹ ⫹ NR NR
NM NM NM NS
NR
NR
Subj ⫹ ⫹ ⫹
B group
NS
Obj NS NS ⫹
W group
NS NS ⫹ NS
B group
Black cohosh Amsterdam21 (64 mg) Geller23 (128 mg) BC RC CEE Maki24 (128 mg) BC RC CEE Bai22 (40 mg) Wuttke27 (40 mg) BC CE Nappi25 (40 mg) Osmers26 (40 mg) Black cohosh mixed with other herbals Rotem28 (PFC) Uebelhack29 (BC ⫹ SJC) Other herbals Hsu35 (Diascorea alata 12 mg) van Die36 (H. perforatum L 300 mg⫹V. agnus-castus L 500 mg) Kaszkin-Bettag32 (Rheum rhaponticum 4 mg) Heger31 (Rheum rhaponticum 4 mg) Yang34 (FMPB extract 100 mg) Green33 (Consultations & herbal medicines)
Type of intervention/study
Hot flushes
Table 2 Summary of treatment outcomes (between-group (B Group) and within-group (W group) differences for treatments vs. controls or comparisons) for hot flushes and co-occurring symptoms for herbal therapies
Climacteric Downloaded from informahealthcare.com by Kainan University on 04/18/15 For personal use only.
Effects of herbal preparations on symptom clusters Ismail et al.
Climacteric
Effects of herbal preparations on symptom clusters Germany26,29, Israel28, Taiwan34,35, Australia36, Ukraine31,32, the United Kingdom33, Thailand30, and Sweden37. The study durations ranged from 12 weeks to 12 months and the majority (nine studies) were conducted in 12 weeks. Participants were recruited using various methods including advertisements on the internet24, bulletin boards24, newspapers29,36,37, radio36, fliers at community clinics36, and mailings24. The numbers of women who participated in the studies ranged from 34 to 309 with a mean age of 46.7–59.3 years. Perimenopausal and postmenopausal women from multiple ethnic backgrounds were involved in the studies.
Climacteric Downloaded from informahealthcare.com by Kainan University on 04/18/15 For personal use only.
Black cohosh Among the seven studies of black cohosh, only two studies showed that women in the intervention groups experienced a significantly greater decrease in hot flushes than those in the control groups. Both studies used 40 mg of black cohosh for 12 weeks and measured hot flushes using the MRS26,27. Of these two studies, only one study showed that hot flushes and at least one of the other symptoms improved more than in comparison groups. Wuttke and colleagues found that hot flushes and sleep symptoms improved more significantly in the intervention groups than in the control groups27. The Osmers study showed that hot flushes decreased significantly greater in the intervention group than in the control groups; however, pain symptoms did not show significant differences between the two groups. Other symptoms in the Osmers study, including sleep, mood, and cognitive, were not reported26. In addition, two 12-month studies comparing black cohosh, red clover, and conjugated equine estrogen (CEE) with placebo demonstrated that the magnitude of hot flushes decreased significantly only for the CEE group compared with the placebo group23,24. Black cohosh had a variety of effects on other symptoms. Among the six studies that included sleep symptoms21–23,25–27, only one study indicated that sleep quality improved more in the black cohosh group than in the control group27. Wuttke and colleagues used 40 mg of black cohosh for 12 weeks and measured sleep disturbances including the frequency of awakening up per night and night with early awakening, using diaries and the MRS27. Two studies that used either used 40 mg or 128 mg of black cohosh did not show a significant result on sleep symptoms in the intervention groups compared to control groups22,23. Three other studies that included sleep symptoms did not report sleep symptoms separately but included them in other subscales such as hot flushes subscales in the MRS21,25,26. Of seven trials that measured mood symptoms, four black cohosh studies did not produce a significant result for mood symptoms21–23,25. Three other studies either did not report mood symptoms or included mood symptoms in heterogeneous subscale scores such as the mental score in the MRS24,26,27. A study conducted over 12 months comparing 128 mg of black cohosh, 398 mg of red clover, 0.625 of CEE plus 2.5 mg of medroxyprogesterone acetate (MPA) and placebo revealed
Climacteric
Ismail et al. that only women in the red clover group experienced a significant improvement in mood symptoms compared with the placebo group23 (Table 1). Among the six studies that assessed cognitive symptoms, one study showed no significant effect of black cohosh greater than the effect of placebo24. The other five studies did not report the results of black cohosh in cognitive symptoms separately21,23,25–27. The Osmers and the Wuttke studies included cognitive symptoms in the psyche and mental subscale of the MRS scale26,27, while the Geller, Amsterdam, and Nappi studies did not provide specific information on treatment effects on cognitive symptoms21,23,25. Interestingly, Maki and colleagues using black cohosh, red clover, CEE, and placebo found that women who received CEE had worse verbal learning after adjusting for vasomotor symptoms compared to those in the placebo group. In contrast, women who received black cohosh and red clover did not show any significant improvement in cognitive symptoms compared to those in placebo groups24. Regarding pain symptoms, six trials included these symptoms21–23,25–27. Three studies did not show significant results in improving pain symptoms when compared to the control groups22,23,26. The three other studies that used the GCS or the MRS scale did not provide the results on pain symptoms separately but measured them in other heterogeneous subscales such as the major climacteric and the somatic complaint subscales21,25,27. The adverse effects of black cohosh are various, ranging from mild to moderate. Women in the black cohosh group experienced vertigo, headache, hypertension, bronchitis, rhinitis, arthralgia, edema, musculoskeletal and connective tissue disorders, infections and infestations, abdominal pain, leukorrhea, vaginal bleeding, and breast pain/enlargement21,22,26,27. These conditions resulted in some women from the intervention group discontinuing their participation in the study21,22. However, the study results indicated no difference in adverse effects between black cohosh and control groups21,22. Bai and colleagues revealed that the number of adverse effects in the black cohosh group was significantly lower compared to the hormonal group22. Safety analyses indicated no significant differences between the black cohosh and placebo groups, such as breast and endometrial safety or liver enzymes and lipid profiles23. In addition, endometrial thickness did not change after 12 weeks of interventions with black cohosh compared to baseline25. Lastly, hematology, blood chemistry, and urinary test results showed no difference between the black cohosh and control groups22. Overall, women were generally tolerant of black cohosh.
Black cohosh mixed with other herbals Two trials mixed black cohosh with one of the two herbal preparations: Phyto-Female Complex (black cohosh mixed with other herbals including dong quai, milk thistle, red clover, American ginseng, and chaste-tree berry) or St. John’s Wort. Both trials revealed that hot flushes and at least one of
21
Climacteric Downloaded from informahealthcare.com by Kainan University on 04/18/15 For personal use only.
Effects of herbal preparations on symptom clusters the other symptoms improved significantly more in the intervention groups than in women in the control groups28,29. Phyto-Female Complex formula improved hot flushes and sleep symptoms significantly in the Rotem study28 while black cohosh mixed with St. John’s Wort improved hot flushes and mood symptoms in the Uebelhack study29. The study by Rotem and Kaplan with 50 healthy pre- and postmenopausal women indicated that the intensity of hot flush symptoms decreased by 80% in the Phyto-Female Complex group compared to 35% in the control group28. These two studies measured hot flushes using the MRS28,29. Sleep symptoms were addressed in both studies. However, only women in the Phyto-Female Complex group reported positive effects on sleep symptoms greater than the women in the control group28. At the end of this 12-week trial, using the KMI, the quality of sleep scores decreased by 70% in the intervention group and by 21% in the placebo group, where lower scores indicated higher quality of sleep28. Instead of reporting sleep symptoms individually, Uebelhack and colleagues included sleep disorders as part of the soma factors scale that consisted of other symptoms such as depressive moods and joint pain. Therefore, it is difficult to evaluate the effects of black cohosh mixed with St. John’s Wort in sleep symptoms alone29. Mood symptoms were measured and reported only in the study that used black cohosh with St. John’s Wort29. Women in the intervention group experienced a significantly greater improvement in their mood symptoms than those in the control group. The Hamilton Depression Rating Scale score decreased significantly by 30% in the first 8 weeks in women in the intervention group and by 41.8% in 16 weeks compared to their initial levels29. Regarding cognitive and pain symptoms, only the Uebelhack study included these symptoms29. However, Uebelhack and colleagues did not report these symptoms separately. The cognitive symptoms were included in the psyche and soma subscales, while pain symptoms were classified in the soma subscale of the MRS29. Therefore, it is not possible to evaluate the effects of this herbal preparation on cognitive and pain symptoms separately. The two studies using a mixture of black cohosh with other herbals indicated no differences in adverse effects between the intervention group and the placebo group28,29. Uebelhack and colleagues revealed that infections and infestations were one of the most frequent adverse events in both the intervention and placebo groups. One participant in the intervention group and two participants in the placebo group dropped out from the study because of lack of efficacy in the women who received black cohosh mixed with St. John’s Wort; adverse events seemed unlikely to be related to herbal therapy29. Rotem and Kaplan revealed that there were no endometrial thickness changes in women using the Phyto-Female Complex formula28. These studies suggest that black cohosh mixed with other herbals may be well tolerated by women.
22
Ismail et al.
Other herbals Of the eight trials that focused on hot flushes, four studies that used either Rheum rhaponticum dry extract, French maritime pine bark extract, or consultations and herbal medicines showed a significantly greater improvement in hot flushes and at least one of the other symptoms compared to the control groups31–34. One study using French maritime pine bark had a remarkable result on hot flushes and all other symptoms34. The two studies using 4 mg of Rheum rhaponticum for 12 weeks improved hot flushes, sleep, mood, and pain symptoms31,32. Lastly, Green and colleagues found that hot flushes and mood symptoms improved significantly greater in the intervention group than in the control group33. In addition, these studies used a variety of instruments to measure hot flushes, including the MRS, the HFWWS, the WHQ, the GCS, and diaries. Of five studies, three studies were conducted over 3 months31,32,37; others were conducted for 6 months33,34. One study using Femal formula (which contains a pure pollen extract-GC Fem and a combined pollen and pistil extract-PI 82) only improved hot flushes but not any of the other symptoms37. Studies that used either Diascorea alata, H. perforatum L with V. agnus-castus L, or Pueraria mirifica did not show significant effects on hot flushes compared to control groups30,35,36. Regarding other symptoms, all studies included sleep symptoms, but only four studies that used either Diascorea alata, Rheum rhaponticum, or French maritime pine bark showed positive results for sleep symptoms compared to control groups31,32,34,35. Women who used H. perforatum L with V. agnus-castus L, Pueraria mirifica, or Femal did not have a significant difference in sleep symptoms compared to women in the control groups30,36. The Green study using consultations and herbal medicines measured sleep symptoms; however, they reported them as part of the psychological subscale of the GCS33. All studies also included mood symptoms but only five preparations significantly improved mood symptoms including those that treated women with Diascorea alata, Rheum rhaponticum, consultations and herbal medicines, or French maritime pine bark compared to the control group31–35. The three other trials that used either H perforatum L and V agnus castus, Pueraria mirifica, or Femal formula reported no improvements in mood symptoms compared to control groups30,36,37. All trials measured cognitive symptoms; however, only one study improved cognitive symptoms significantly compared to control groups34. Yang and colleagues reported that women who received 100 mg of French maritime pine bark twice daily over a period of 6 months showed greater improvement in memory/concentration than women in the control group34. The WHQ was used to evaluate cognitive symptoms in this study. This instrument has 36 questions including three items about memory/concentration34. Seven other studies did not report cognitive symptoms30–33,35–37.
Climacteric
Climacteric Downloaded from informahealthcare.com by Kainan University on 04/18/15 For personal use only.
Effects of herbal preparations on symptom clusters Of the eight trials of other herbal preparations that measured pain symptoms, only women in the Diascorea alata, Rheum rhaponticum, and French maritime pine bark extract group reported a significant decrease in the number of pain symptoms compared to the control groups31,32,34,35. Pain symptoms in women who received 50 mg of Puerari mirifica30 or Femal formula did not improve significantly compared to the control groups37. Similar to the black cohosh studies, adverse effects of other herbal remedies vary widely, ranging from mild to moderate. Flatulence with soft stools, nausea, vaginal discharge/ spotting, vertigo, asthenia, headache, viral infection of the upper respiratory tract, duodenal ulcer, cardiomyopathy, intercostal neuralgia, cervical dysplasia, dizziness, back pain, mastodynia, and worsening of pre-existing insomnia are some of the adverse events that women experienced in the intervention groups30–37. However, three studies indicated that these adverse events found in the intervention groups were not significantly different compared to placebo groups31,35,36. Adverse events that are related to reproductive hormones (estradiol, follicle stimulating hormone) either did not differ significantly between the intervention and control groups or resulted in a positive result for the intervention group. Hsu and colleagues revealed that increasing endometrium thickness was not found among women who received Diascorea alata for 12 months. Furthermore, the number and size of breast cysts and uterine myomas in the intervention group were similar to those in the placebo group35. None of the women who received 4 mg of Rheum rhaponticum over the 12-week period experienced adverse events related to gynecological organs or tissues31,32. Liver function tests, enzyme serum levels, and laboratory parameters resulted in no abnormal results31,32,36,37. The results of these studies indicate that other herbal therapies are also well tolerated when used safely in specified time frames.
DISCUSSION This review indicated that only eight of the 17 herbal preparations produced significant effects on hot flushes and at least one of the other symptoms compared to other groups such as placebo and hormonal treatment26–29,31–34. Black cohosh, black cohosh mixed with other herbs, Rheum rhaponticum, French maritime pine bark, and consultations with herbal therapies improved hot flushes and at least one other symptom significantly more than other herbal preparations26–29,31–34. However, in the within-group analyses, hot flushes decreased significantly from baseline to post-intervention in 13 trials that used either black cohosh, black cohosh mixed with Phyto-Female Complex or St. John’s Wort, Rheum rhaponticum, consultation with herbal medicines, French maritime pine bark, Diacorea alata, H. perforatum L, and Femal formula22,23,25,27–29,31–37. Similar results were found in a large study comparing black cohosh, multibotanical with black cohosh plus nine other ingredients, multibotanical and soy counseling, and hormonal therapy with placebo. None of the
Climacteric
Ismail et al. herbal preparations showed significant improvement in hot flushes38. Among 16 studies that included sleep symptoms, six studies showed significant improvement in symptoms that including those treated with black cohosh; a combination of black cohosh mixed with Phyto-Female Complex formula; Diascorea alata; Rheum rhaponticum, and French maritime pine bark27,28,31,32,34,35. Women who received 40 mg of black cohosh or 300 mg of H. perforatum L with 500 mg of V. agnus-castus reported a significant within-group improvement in sleep problems at the end of a 12-week intervention compared to the start point,although it was not significantly different from those treated in the control group22,36. Of the 16 studies that included mood symptoms, seven studies that used red clover, black cohosh with St. John’s Wort, Diascorea alata, Rheum rhaponticum, French maritime pine bark, and consultation with herbal medicines, improved mood symptoms significantly more than comparison groups23,29,31–35. Women in the intervention groups using either 40 mg of black cohosh, H. perforatum L with V. agnuscastus, or Femal formula showed a significant within-group improvement in mood symptoms at the end of intervention compared to baseline22,25,36,37. Of 15 trials that measured cognitive symptoms, only one study revealed a significant result with a herbal preparation compared to control groups34. One study did not show any difference between the intervention and control groups24, and 13 studies did not provide data12,21,23,25,27,29–33,35–37. Women who received French maritime pine bark extract for 6 months showed significant improvement in cognitive symptoms compared to those in the control group34. In contrast, the Maki study indicated that women who received CEE reported worse cognitive symptoms, particularly verbal learning, compared to women receiving placebo24. Among 16 studies that included pain, four studies using either Diascorea alata, Rheum rhaponticum, or French maritime pine bark extract demonstrated significantly greater decreases in pain problems than in comparison groups31,32,34,35. Of 17 trials, more preparations (41%) used black cohosh than any other treatments. Black cohosh has been used to treat gynecologic complaints by Native Americans for years and to alleviate menopausal symptoms in many countries such as Germany39,40. Although there is no clear explanation how black cohosh reduces menopause-related symptoms, an in vitro study indicated that black cohosh consists of estrogen compounds41. Other studies suggest that black cohosh has estrogenic effects on vaginal cytology and bone markers42. In contrast, some studies showed that black cohosh did not have estrogenic activity43 or act on estrogen receptors44. Despite controversial findings about estrogen compounds in black cohosh, other trials showed that black cohosh has antidepressant activity45 and binds serotonin and dopamine receptors44. Therefore, black cohosh may affect emotional and anxiety behaviors26. This review identified only one of seven black cohosh studies that had positive effects on hot flushes and other symptoms27. Longer duration of study and higher doses of black
23
Climacteric Downloaded from informahealthcare.com by Kainan University on 04/18/15 For personal use only.
Effects of herbal preparations on symptom clusters cohosh did not show a better result for managing hot flushes and other symptoms. The Wuttke study that showed improvement in hot flushes and at least one of the other symptoms was shown in 12 weeks27 while 12-month studies did not show any difference from the comparison groups23,24. Similar to the duration of study, higher doses of black cohosh did not alleviate hot flushes better than lower doses. The study reported significant improvement of hot flushes and at least one of the other symptoms using 40 mg of black cohosh27 while the other studies that used 64 mg and 128 mg of black cohosh did not have significant impacts on hot flushes or other symptoms21,23,24. A study using a higher dose of black cohosh and conducted over a longer time, 160 mg/day for 12 months, among late menopausal transition and postmenopausal women demonstrated that the number of hot flushes in the intervention group was not different from that in the placebo group38. The possible reasons for differences in study results may be because the effects of herbal therapies such as black cohosh could be sensitive to dose, extraction method, plant time, and co-administration of other herbals38. In addition, mixing black cohosh with other herbal preparations yielded a positive result in hot flushes and other symptoms particularly in sleep and mood28,29. St. John’s Wort has been used for years to treat psychological complaints. Studies have demonstrated that St. John’s Wort has a positive effect on a milder form of depression46,47, possibly accounting for the different results seen when black cohosh is combined with St. John’s Wort. For those reasons, this review showed that a mixture of black cohosh with St. John’s Wort had a better result than black cohosh alone to alleviate hot flushes and other symptoms, particularly mood. French maritime pine bark extract is another herbal preparation that has powerful effects on hot flushes and all other symptoms. This herbal might act as a phytoestrogen and decrease blood pressure34. Studies indicated that French maritime pine bark extract increased plasma oxygen radical absorbance capacity48, decreased systolic blood pressure49, and was also effective in reducing edema and pain50. Improved cognitive performance may be related to restoration of adequate sleep and effects on mood in women who received French maritime pine bark extract. Rheum rhaponticum also demonstrated positive treatment effects on hot flushes and sleep, mood, and pain symptoms (cognitive symptoms were not reported). Rheum rhaponticum consists of estrogen receptor-β-positive that can reduce anxiety23. French maritime pine bark and Rheum rhaponticum may share mechanisms affecting estrogens. These two preparations demonstrated positive results on hot flushes and other symptoms; however, it is too early to conclude on the effects of these two herbal preparations on hot flushes and other symptoms since the number of studies of these preparations is very limited. Although Diascorea alata only showed positive effects on hot flushes based on within-group analysis, this herb had significant between-group results in alleviating sleep, mood, and pain symptoms. A study among healthy postmenopausal women who replace their staple food with 390 g of yam or
24
Ismail et al. Dioscorea alata in two of three meals per day for 30 days showed a significant increase in serum concentration of estrone (26%), sex hormone binding globulin (9.5%) and a nearly significant increase in estradiol (27%)51. The mechanism of action of Diascorea alata might be related to its effects on estrogen. Several limitations are identified in this review. Most studies of herbal preparations used different doses for varying duration. For example, of seven studies using black cohosh, four studies used 40 mg for 3 months22,25–27, one study used 64 mg for 3 months21, and two studies used 128 mg for 12 months23,24. Instrumentation is another issue in this review. Different kinds of questionnaires such as the GCS, the KMI, the HAM-A, and the BAI were used in each trial to measure hot flushes and other symptoms. Therefore, it is not possible to compare the study results that used different doses, durations of study, and instruments. Another issue that is found in this review is that some studies used heterogeneous subscale scores to measure symptoms and did not provide specific information for each symptom. Most of these studies focused on and reported hot flushes despite evidence from recent studies showing that hot flushes co-occur with other symptoms such as sleep and pain52,53. For example, several studies included cognitive symptoms in mental or somatic subscales. Furthermore, some studies reported only the comparison results between herbal preparations and control groups but did not provide information about symptoms before and after intervention in each herbal preparation. Sample size was also identified as an issue in this review. The number of women who completed studies in this review ranged between 18 and 287. Some studies had fewer than 20 participants in one herbal preparation group and 71% of these studies had fewer than 100 participants completing the studies. Inadequate sample size can result in inadequate power to assess effects of herbal preparations for all symptoms. In addition, women who participated in the studies were in varying stages of menopausal transition or postmenopause and each study used different inclusion criteria for health. Therefore, different stages of reproductive aging and health definitions could affect the number and severity of hot flushes and women’s response to herbal therapies. Compared to placebo, most herbal preparations had significant effects on hot flushes and other symptoms. Of 13 studies comparing placebo and herbal therapies, nine studies revealed that the effects of herbal therapies on hot flushes and most of the other symptoms that were measured were superior to placebo26–29,31–34,37. Of three studies comparing herbal therapies and hormonal preparations, none showed significantly greater effects on hot flushes and other symptoms. However, these study results also indicated that herbal therapies, particularly 40 mg of black cohosh and 50 mg of Pueraria mirifica, had similar effects in reducing hot flushes and other symptoms in menopausal women22,25,30. Furthermore, women were generally tolerant of herbal therapies. Breast and endometrial safety or liver enzymes and lipid profiles were not different or did not show more abnormal results in women in the intervention groups than those in the placebo or control groups23,31,32,36,37.
Climacteric
Effects of herbal preparations on symptom clusters Endometrial thickness also did not change after women who received herbal therapies completed the studies25,28,35.
Climacteric Downloaded from informahealthcare.com by Kainan University on 04/18/15 For personal use only.
CONCLUSION In conclusion, this review indicated that herbal preparations, particularly black cohosh mixed with Phyto-Female Complex or St. John’s Wort, Rheum rhaponticum, and French maritime pine bark had positive effects on hot flushes and other symptoms and may be a promising alternatives to hormonal treatment. The adverse events of herbal therapies were various, ranging from mild to moderate. However, the safety profile of herbal therapies was good and even superior compared to hormonal therapies. Overall, herbal therapies were well tolerated by women, particularly when they were used safely in specified time frames. For future study, it is important to classify women based on their menopausal stages including early or late menopausal transition or postmenopause. This will clarify our understanding of the period during which herbal therapies
Ismail et al. are effective in reducing hot flushes and others symptoms. Reporting each symptom separately and providing comparison data between baseline and post-intervention in each group will also help clarify effects that can guide treatment for multiple co-occurring symptoms. More studies with adequate sample size are needed to provide adequate statistical power to estimate the effectiveness of therapies on hot flushes and other symptoms. Conflict of interest The authors report no confl ict of interest. The authors alone are responsible for the content and writing of this paper. Source of funding This work was supported by grants from the National Institute of Nursing Research (NINR 1R21NR012218-01 Menopause Symptom Clusters: Refocusing Therapeutics; NR 04141 - Menopausal Transition: Biobehavioral Dimensions; P30 NR 04001, P50NR02323 – Center for Women’s Health and Gender Research).
References 1. Woods NF, Mitchell ES. Symptoms during the perimenopause: prevalence, severity, trajectory, and significance in women’s lives. Am J Med 2005;118(Suppl 12B):14–24 2. Gold EB, Colvin A, Avis N, et al. Longitudinal analysis of the association between vasomotor symptoms and race/ethnicity across the menopausal transition: Study of Women’s Health Across the Nation. Am J Public Health 2006;96:1226–35 3. NIH State-of-the-Science Conference Statement on management of menopause-related symptoms. NIH Consens State Sci Statements 2005;22:21–3 4. Nelson HD, Haney E, Humphrey L, et al. Management of menopause-related symptoms. Evidence Report/Technology Assessment No. 120. Rockville, MD: Agency for Healthcare Research and Quality, 2005. Available from: http://archive.ahrq. gov/downloads/pub/evidence/pdf/menopause/menopaus.pdf 5. Freeman EW, Sammel MD, Lin H, Gracia CR, Kapoor S, Ferdousi T. The role of anxiety and hormonal changes in menopausal hot flashes. Menopause 2005;12:258–66 6. Cray LA, Woods NF, Herting JR, Mitchell ES. Symptom clusters during the late reproductive stage through the early postmenopause: observations from the Seattle Midlife Women’s Health Study. Menopause 2012;19:864–9 7. Blumel JE, Castelo-Branco C, Binfa L, et al. Quality of life after the menopause: a population study. Maturitas 2000;34:17–23 8. Williams RE, Levine KB, Kalilani L, Lewis J, Clark RV. Menopause-specific questionnaire assessment in US populationbased study shows negative impact on health-related quality of life. Maturitas 2009;62:153–9 9. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–33 10. Newton KM, Buist DS, Keenan NL, Anderson LA, LaCroix AZ. Use of alternative therapies for menopause symptoms: results of a population-based survey. Obstet Gynecol 2002;100:18–25
Climacteric
11. Viereck V, Emons G, Wuttke W. Black cohosh: just another phytoestrogen? Trends Endocrinol Metab 2005;16:214–21 12. Ross SM. Menopause: a standardized isopropanolic black cohosh extract (remifemin) is found to be safe and effective for menopausal symptoms. Holist Nurs Pract 2012;26:58–61 13. Zheng TP, Sun AJ, Xue W, et al. Efficacy and safety of Cimicifuga foetida extract on menopausal syndrome in Chinese women. Chin Med J (Engl) 2013;126:2034–8 14. Leach MJ, Moore V. Black cohosh (Cimicifuga spp.) for menopausal symptoms. Cochrane Database Syst Rev 2012;9: CD007244:i–99 15. Laakmann E, Grajecki D, Doege K, zu Eulenburg C, Buhling KJ. Efficacy of Cimicifuga racemosa, Hypericum perforatum and Agnus castus in the treatment of climacteric complaints: a systematic review. Gynecol Endocrinol 2012;28:703–9 16. Borrelli F, Ernst E. Black cohosh (Cimicifuga racemosa) for menopausal symptoms: a systematic review of its efficacy. Pharmacol Res 2008;58:8–14 17. Cray L, Woods NF, Mitchell ES. Symptom clusters during the late menopausal transition stage: observations from the Seattle Midlife Women’s Health Study. Menopause 2010;17:972–7 18. Freeman EW, Sammel MD, Lin H. Temporal associations of hot flashes and depression in the transition to menopause. Menopause 2009;16:728–34 19. Ensrud KE, Stone KL, Blackwell TL, et al. Frequency and severity of hot flashes and sleep disturbance in postmenopausal women with hot flashes. Menopause 2009;16:286–92 20. Woods NF, Mitchell ES, Schnall JG, et al. Effects of mind-body therapies on symptom clusters during the menopausal transition. Climacteric 2014;17:10–22 21. Amsterdam JD, Yao Y, Mao JJ, Soeller I, Rockwell K, Shults J. Randomized, double-blind, placebo-controlled trial of Cimicifuga racemosa (black cohosh) in women with anxiety disorder due to menopause. J Clin Psychopharmacol 2009;29: 478–83
25
Climacteric Downloaded from informahealthcare.com by Kainan University on 04/18/15 For personal use only.
Effects of herbal preparations on symptom clusters 22. Bai W, Henneicke-von Zepelin HH, Wang S, et al. Efficacy and tolerability of a medicinal product containing an isopropanolic black cohosh extract in Chinese women with menopausal symptoms: a randomized, double blind, parallel-controlled study versus tibolone. Maturitas 2007;58:31–41 23. Geller SE, Shulman LP, van Breemen RB, et al. Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms: a randomized controlled trial. Menopause 2009; 16:1156–66 24. Maki PM, Rubin LH, Fornelli D, et al. Effects of botanicals and combined hormone therapy on cognition in postmenopausal women. Menopause 2009;16:1167–77 25. Nappi RE, Malavasi B, Brundu B, Facchinetti F. Efficacy of Cimicifuga racemosa on climacteric complaints: a randomized study versus low-dose transdermal estradiol. Gynecol Endocrinol 2005;20:30–5 26. Osmers R, Friede M, Liske E, Schnitker J, Freudenstein J, Henneicke-von Zepelin HH. Efficacy and safety of isopropanolic black cohosh extract for climacteric symptoms. Obstet Gynecol 2005;105:1074–83 27. Wuttke W, Rauš K, Gorkow C. Efficacy and tolerability of the Black cohosh (Actaea racemosa) ethanolic extract BNO 1055 on climacteric complaints: a double-blind, placebo- and conjugated estrogens-controlled study. Maturitas 2006;55(Suppl 1):S83–91 28. Rotem C, Kaplan B. Phyto-Female Complex for the relief of hot flushes, night sweats and quality of sleep: randomized, controlled, double-blind pilot study. Gynecol Endocrinol 2007;23:117–22 29. Uebelhack R, Blohmer JU, Graubaum HJ, Busch R, Gruenwald J, Wernecke KD. Black cohosh and St. John’s wort for climacteric complaints. Obstet Gynecol 2006;107:247–55 30. Chandeying V, Sangthawan M. Efficacy comparison of Pueraria mirifica (PM) against conjugated equine estrogen (CEE) with/ without medroxyprogesterone acetate (MPA) in the treatment of climacteric symptoms in perimenopausal women: phase III study. J Med Assoc Thai 2007;90:1720–6 31. Heger M, Ventskovskiy BM, Borzenko I, et al. Efficacy and safety of a special extract of Rheum rhaponticum (ERr 731) in perimenopausal women with climacteric complaints: a 12-week randomized, double-blind, placebo-controlled trial. Menopause 2006;13:744–59 32. Kaszkin-Bettag M, Ventskovskiy BM, Solskyy S, et al. Confirmation of the efficacy of ERr 731 in perimenopausal women with menopausal symptoms. Altern Ther Health Med 2009;15:24–34 33. Green J, Denham A, Ingram J, Hawkey S, Greenwood R. Treatment of menopausal symptoms by qualified herbal practitioners: a prospective, randomized controlled trial. Fam Pract 2007;24:468–74 34. Yang HM, Liao MF, Zhu SY, Liao MN, Rohdewald P. A randomised, double-blind, placebo-controlled trial on the effect of Pycnogenol on the climacteric syndrome in peri-menopausal women. Acta Obstet Gynecol Scand 2007;86:978–85 35. Hsu CC, Kuo HC, Chang SY, Wu TC, Huang KE. The assessment of efficacy of Diascorea alata for menopausal symptom treatment in Taiwanese women. Climacteric 2011;14:132–9 36. van Die MD, Bone KM, Burger HG, Reece JE, Teede HJ. Effects of a combination of Hypericum perforatum and Vitex agnus-castus on PMS-like symptoms in late-perimenopausal
26
Ismail et al.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50. 51.
52.
53.
women: findings from a subpopulation analysis. J Altern Complement Med 2009;15:1045–8 Winther K, Rein E, Hedman C. Femal, a herbal remedy made from pollen extracts, reduces hot flushes and improves quality of life in menopausal women: a randomized, placebo-controlled, parallel study. Climacteric 2005;8:162–70 Newton KM, Reed SD, LaCroix AZ, Grothaus LC, Ehrlich K, Guiltinan J. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: a randomized trial. Ann Intern Med 2006;145:869–79 Foster S, Tyler VE. Tyler’s Honest Herbal: A Sensible Guide to the Use of Herbs and Related Remedies. Binghamton, NY: Haworth Herbal Press, 1999 Borrelli F, Ernst E. Black cohosh (Cimicifuga racemosa): a systematic review of adverse events. Am J Obstet Gynecol 2008; 199:455–66 Jarry H, Metten M, Spengler B, Christoffel V, Wuttke W. In vitro effects of the Cimicifuga racemosa extract BNO 1055. Maturitas 2003;44(Suppl 1):S31–8 Wuttke W, Seidlová-Wuttke D, Gorkow C. The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebo-controlled study: effects on menopause symptoms and bone markers. Maturitas 2003;44(Suppl 1):S67–77 Liu J, Burdette JE, Xu H, et al. Evaluation of estrogenic activity of plant extracts for the potential treatment of menopausal symptoms. J Agric Food Chem 2001;49:2472–9 Burdette JE, Liu J, Chen SN, et al. Black cohosh acts as a mixed competitive ligand and partial agonist of the serotonin receptor. J Agric Food Chem 2003;51:5661–70 Winterhoff H, Spengler B, Christoffel V, Butterweck V, Lohning A. Cimicifuga extract BNO 1055: reduction of hot flushes and hints on antidepressant activity. Maturitas 2003;44(Suppl 1):S51–8 Fava M, Alpert J, Nierenberg AA, et al. A double-blind, randomized trial of St John’s wort, fluoxetine, and placebo in major depressive disorder. J Clin Psychopharmacol 2005;25:441–7 Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St John’s wort) in major depressive disorder: a randomized controlled trial. JAMA 2002;287:1807–14 Devaraj S, Vega-López S, Kaul N, Schönlau F, Rohdewald P, Jialal L. Supplementation with a pine bark extract rich in polyphenols increases plasma antioxidant capacity and alters the plasma lipoprotein profile. Lipids 2002;37:931–4 Hosseini S, Lee J, Sepulveda RT, Rohdewald P, Watson RR. A randomized, double-blind, placebo-controlled, prospective, 16 week crossover study to determine the role of Pycnogenol in modifying blood pressure in mildly hypertensive patients. Nutr Res 2001;21:1251–60 Arcangeli P. Pycnogenol in chronic venous insufficiency. Fitoterapia 2000;7:236–44 Wu WH, Liu LY, Chung CJ, Jou HJ, Wang TA. Estrogenic effect of yam ingestion in healthy postmenopausal women. J Am Coll Nutr 2005;24:235–43 Woods NF, Mitchell ES. Sleep symptoms during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women’s Health Study. Sleep 2010;33:539–49 Mitchell ES, Woods NF. Pain symptoms during the menopausal transition and early postmenopause. Climacteric 2010;13:467–78
Climacteric
Vasomotor symptoms Vasomotor hot flushes, night sweats Hot flushes and night sweats Vasomotor hot flushes Hot flushes
Cannot use total; vasomotor Hot flushes Sternal skin-attached hot flush recorder Hot flushes NA
NA NA
NA
NA
Greene Climacteric Scale21,23,25,30,33,35,36
Climacteric
Women’s Health Questionnaire31,34
MENQOL31 Subscale name, symptoms we accept Menopause Rating Scale26,27,29,31,32,37
Kupperman Menopause Index22,23,26 Total scale, symptoms we accept
Hot Flush Weekly Weighted Score32 Ambulatory sternal skin conductance monitor24 Diary23–25,27,31,32,36,37 Psychological General Wellness Being Index21
Beck Depression Index Total scale21 Hamilton Anxiety Rating Scale21,29,36
Pittsburgh Sleep Quality Index23
Positive and Negative Affect Schedule23,24
Sleep quality, sleep latency, causes of trouble sleeping, habitual sleep efficiency, sleep meditation, day time dysfunction NA
Positive and negative emotions
NA Depressed, nervousness, sad feelings Depression Anxious mood, depressed mood, tension NA
NA NA
NA Insomnia
NA NA
NA
NA (combined with cognitive) Depressive mood, irritability, anxiety (combined with psyche score)
Depressed mood, depressed, crying spells, irritability Depressed, anxiety
Mood disturbances
NA NA
Cannot use total; insomnia
NA (combined with pain) Sleep problem (combined with major climacteric complaints )
Sleep problems
NA (combined with mood & cognitive)
Sleep disturbances
Measurement subscales and symptoms defined as appropriate measures for each symptom group of interest
Scales, subscales and symptoms used
Appendix Cognitive disturbances
NA
NA
NA Concentration, poor memory
NA NA
NA NA
NA (combined with mood) Impaired memory, decrease in concentration, forgetfulness (combined with psyche scores) NA
Memory/concentration
NA (combined with mood & sleep)
Climacteric Downloaded from informahealthcare.com by Kainan University on 04/18/15 For personal use only.
NA
NA
(Continued)
NA Somatic (muscular)
NA NA
Cannot use total; arthralgia/myalgia, headache NA NA
Somatic problems (headache, back pain) NA (combined with sleep) Joint and muscular discomfort (combined with somatic scores
Somatic, headache, muscle/joint pain
Pain symptoms
Effects of herbal preparations on symptom clusters Ismail et al.
27
28 NA
NA
NA NA NA
NA NA NA NA NA
Memory Functioning Questionnaire (MFQ)24 Symptom Rating Test for anxiety25 Utian Quality of Life Scale scores36
The EuroQol Visual Analogue Scale31
The Medical Outcomes Study Short Form 3626 Subscale name, symptoms we accept
Mental health, depressed, down in the dumps
Depression, anxiety Depressed mood, anxiety Anxiety/depression
NA
NA NA NA
NA NA
NA
NA
NA
NA
Mood disturbances
NA
NA
NA NA
Verbal fluency Attention and working memory Auditory attention Visuoperceptual speed Acculturation improves the diagnostic accuracy of neuropsychological Memory
Verbal learning and short- and long-delay verbal recall Immediate and delayed recall of a short story Short-term figural memory Visuospatial ability
Cognitive disturbances
Bodily pain, pain
Pain/discomfort
NA NA
NA
NA NA NA
NA NA
NA
NA
NA
NA
Pain symptoms
NA, not applicable, e.g. no subscale appropriately matching symptom group. Where scale or subscale and symptoms are noted, the symptoms listed met our criteria as indicators of the symptom groups in the review. Names of subscales and symptoms are those used in the scale
NA
NA
NA NA NA
NA NA
NA NA NA NA NA
NA
NA
Brief Test of Attention-Modified24 Finding As test24 Primary Mental Abilities vocabulary test24
Modified Card Rotations test; Letter Fluency24 Letter Fluency24 Digit Span Forward and Backward24
NA
NA
Logical memory subtest of the Wechsler Memory Scale-Revised24 Benton Visual Retention Test24
NA
NA
California Verbal Learning Test-modified24
Sleep disturbances
Vasomotor symptoms
(Continued)
Scales, subscales and symptoms used
Appendix
Climacteric Downloaded from informahealthcare.com by Kainan University on 04/18/15 For personal use only.
Effects of herbal preparations on symptom clusters Ismail et al.
Climacteric