Effects of herbal preparations on symptom clusters during the menopausal transition.

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


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


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;


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


B group: HF score in KMI decreased B group: Insomnia, nervousness, depressive


KMI; KMI responder

Sleep, mood, and pain.

symptoms


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



(Continued)

Author, year,

Table 1



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


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


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,



15

16

Taiwan35

Hsu, 2011,

GCS at baseline,


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,


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 ⫹


decreased significantly 53.4% in

perforatum) extracts

and placebo

climacteric complaints with a

16 weeks)

and pain. HDRS sum


symptoms


(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,


followed)

study location



(Continued)

Author, year,

Table 1



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


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



17

18 Intervention: 100 mg FMPB

Randomized to 2

UK33

Green, 2007,

Taiwan34 twice daily for 6 months

GCS; MYMOP2


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/


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


compared to start of treatment in

Intervention: Course of

and pain: WHQ


symptoms


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,


followed)

study location



Author, year,

Table 1 (Continued)



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,



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

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.


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


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


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

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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


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.

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Effects of herbal preparations on symptom clusters Endometrial thickness also did not change after women who received herbal therapies completed the studies25,28,35.


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

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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


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

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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

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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)


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


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



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Effects of traditional Chinese medicine on symptom clusters during the menopausal transition.

Symptom severity of bipolar disorder during the menopausal transition.

Endocrine biomarkers and symptom clusters during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women's Health Study.

Follicular depletion during the menopausal transition.

Ovarian adrenal interactions during the menopausal transition.

Re: Endocrine biomarkers and symptom clusters during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women's Health Study.

Progression of Metabolic Syndrome Severity During the Menopausal Transition.

Positive well-being during the menopausal transition: a systematic review.

Migraine and the menopausal transition.

Fungal contaminations of herbal face mask preparations.

Letter: Herbal hepatotoxicity--an update on traditional Chinese medicine preparations.

Bladder Symptoms in the Early Menopausal Transition.

Reliability and validity of the Menopausal Symptom Scale.

The effects of herbal medicine on epilepsy.

Presence of young children at home may moderate development of hot flashes during the menopausal transition.

Herbal preparations for the menopause: beyond isoflavones and black cohosh.

Female Sexual Function During the Menopausal Transition in a Group of Iranian Women.

ethnic differences.

The Relationship between Cortisol Activity during Cognitive Task and Posttraumatic Stress Symptom Clusters.

Characterizing the trajectories of vasomotor symptoms across the menopausal transition.

Hot flush severity during the menopausal transition and early postmenopause: beyond hormones.

Menopause, symptom clusters, and the complexity of women's lives.

Reducing depression during the menopausal transition: study protocol for a randomised controlled trial.

Factors associated with seeking treatment for urinary incontinence during the menopausal transition.