A Review of the Benefits and Risks of Black Cohosh

(Cimicifuga racemosa syn Actaea racemosa)

in the Treatment of Vasomotor Irregularities

Resulting from Menopause

by Noelani Fox

for Issues in Nutrition and Healthat The University of Texas at Austin

November 22, 2011

Introduction• Menopause and Hot Flashes• Associated Risks• Evaluation Scales• Traditional and Alternative Treatments• Black Cohosh

Methods• Literature Search• Inclusion / Exclusion• Outcome Measures

Results• Efficacy• Safety

Discussion• Effectiveness and Safety• Concurrence and Disagreement• Conflict• Strengths / Weaknesses• Conclusion

References

Introduction

Menopause: a fact of life

Hot flashesNight sweatsProfuse sweatingHeadachesDepressionIrritabilitySleep disordersVaginal drynessHeart discomfortAnxietySexual dysfunctionBladder problemsJoint painMuscular discomfort

◦12 months of amenorrhea

◦Many, varied symptoms

◦2/3 of women between 40 and 60

◦80% severe

◦Vasomotor symptoms are the most common

Menopause: a fact of life

Hot flashesNight sweatsProfuse sweatingHeadachesDepressionIrritabilitySleep disordersVaginal drynessHeart discomfortAnxietySexual dysfunctionBladder problemsJoint painMuscular discomfort

◦12 months of amenorrhea

◦Many, varied symptoms

◦2/3 of women between 40 and 60

◦80% severe

◦Vasomotor symptoms are the most common

Risks Associated with Hot Flashes

Longer history of hot flashes correlated with:

◦Greater aortic calcification

◦Coronary artery calcification

◦Higher cholesterol levels

◦Higher blood pressure

◦Increased BMI

◦Reduced dilation of right brachial artery

Risks Associated with Hot Flashes

Longer history of hot flashes correlated with:

◦Greater aortic calcification

◦Coronary artery calcification

◦Higher cholesterol levels

◦Higher blood pressure

◦Increased BMI

◦Reduced dilation of right brachial artery

Evaluation Scales

Kupperman Index◦Developed 1953◦Eleven symptoms

Scale of 0 (none) to 3 (severe)

• Menopause Rating Scale• Developed 1990’s• Eleven symptoms

• Three subscales• Scale of 0 (none) to

4 (severe)

Kupperman Index

Symptoms Factor Severity Numerical conversion (factor × severity)

Vasomotor

Paraesthesia

Insomnia

Nervousness

Melancholia

Vertigo

Weakness (fatigue)

Arthralgia and myalgia

Headaches

Palpitations

Formication

Menopausal index (sum)0 (none)=0, S (slight)=1, M (moderate)=2, and + (severe)=3

Menopause Rating Scale

 

Symptoms 

Somatic

1 Hot flushes, night sweats (episodes of sweating)          

2 Heart discomfort (unusual awareness of heart beat, heart skipping, heart racing, tightness)

         

3 Sleep problems (difficulty in falling asleep, difficulty in sleeping through, waking up early)

         

Psychological

4 Depressive mood (feeling down, sad, on the verge of tears, lack of drive, mood swings)

         

5 Irritability (feeling nervous, inner tension, feeling aggressive)          

6 Anxiety (inner restlessness, feeling panicky)          

7 Physical and mental exhaustion (general decrease in performance, impaired memory, decrease in concentration, forgetfulness)

         

Urogenital

8 Sexual problems (change in sexual desire, in sexual activity and satisfaction)

         

9 Bladder problems ((difficulty in urinating, increased need to urinate, bladder incontinence)

         

10 Dryness of vagina (sensation of dryness or burning in the vagina, difficulty with sexual intercourse)

         

Som

11 Joint and muscular discomfort (pain in the joints, rheumatoid complaints)

         

Traditional Therapy (HRT)

◦ Hormone Replacement Therapy• Estrogen and progestin

◦ Women’s Health Initiative• 16,608 women• Terminated 3 years early

◦ Breast cancer◦ Stroke◦ Pulmonary embolism

Alternatives to Hormone Replacement

Multibotanicals

Over 80 trials reviewed

20 alternative treatments

Botanical Extracts

Pharmaceuticals

Black Cohosh

Used in US for over 100 years

◦ Coughs and colds◦ Constipation◦ Fatigue◦ Rheumatism

Menstrual maladies since 1950’s

History

Black Cohosh

Estrogen-receptor mediation unlikely

Thermogenesis regulated by serotonergic receptors

◦ Nω-methylserotonin Binds to receptors Induces cAMP activity Prevents serotonin reuptake

Mechanism of Action

Black Cohosh

Hepatic perfusion and liver function◦ No change in blood flow◦ No negative change in liver enzymes

Lipid and glucose profiles◦ No effect on glucose or insulin◦ No effect on lipids or fibrinogen

Safety

Methods

Literature Search

• 47,873Menopause

• 1,659Hot flash

• 104Black cohosh

• 99English language

• 70Currency

(post 2005)

Criteria for Consideration

Inclusion Exclusion

Original study Reviews

Monopreparation of Black Cohosh

Meta-analyses

Hot flashes as primary or secondary outcome measure

Related to breast cancer survivors

Assessment of safety or risk factors

Published previous to 2005

Outcome Measures

Efficacy

◦Self assessment

Kupperman Index

Menopause Rating Scale

Frequency of hot flashes

Severity of hot flashes

Safety

◦Adverse events

◦Liver function

◦Lipid profiles

◦Endometrial changes

Results

ResultsEfficacy Measures

1 2 3

Aaa

Bbb

Ccc

Ddd

Zzz

Kupperman Index

Fluoxetine Tibolone

05

1015202530

25.1 25.2

13

18.5

Baseline12 Weeks

Blac

k Coh

osh

Tibo

lone

05

1015202530

24.7 24.7

11.2 11.27.7 7.5

Baseline4 weeks12 weeks

Kupperman Index

Fluoxetine Tibolone

Blac

k Coh

osh

Fluo

xetin

e05

1015202530

25.1 25.2

13

18.5

Baseline12 Weeks

05

1015202530

24.7 24.7

11.2 11.27.7 7.5

Baseline4 weeks12 weeks

Menopause Rating Scale

Placebo Combination Therapy

Difference in treatment in favor of Black Cohosh (p=0.027)

◦ Covariates eliminated (p=0.02)

◦ Confounders considered (p<0.001)

Monotherapy Combination Therapy

Base- line

Mo 3 Mo 6 Base-line

Mo 3 Mo 6

Hot Flashes

0.52 ± 0.21

0.33 ± 0.19

0.25 ± 0.16

0.56 ± 0.21

0.34 ± 0.19

0.25 ± 0.16

Psyche

0.31 ± 0.22

0.21 ± 0.18

0.16 ± 0.14

0.42 ± 0.23

0.26 ± 0.18

0.19 ± 0.15

Total MRS Score

0.30 ± 0.17

0.20 ± 0.14

0.16 ± 0.11

0.36 ± 0.17

0.24 ± 0.14

0.18 ± 0.12

Menopause Rating Scale

Placebo Combination Therapy

Difference in treatment in favor of Black Cohosh (p=0.027)

◦ Covariates eliminated (p=0.02)

◦ Confounders considered (p<0.001)

Monotherapy Combination Therapy

Base- line

Mo 3 Mo 6 Base-line

Mo 3 Mo 6

Hot Flashes

0.52 ± 0.21

0.33 ± 0.19

0.25 ± 0.16

0.56 ± 0.21

0.34 ± 0.19

0.25 ± 0.16

Psyche

0.31 ± 0.22

0.21 ± 0.18

0.16 ± 0.14

0.42 ± 0.23

0.26 ± 0.18

0.19 ± 0.15

Total MRS Score

0.30 ± 0.17

0.20 ± 0.14

0.16 ± 0.11

0.36 ± 0.17

0.24 ± 0.14

0.18 ± 0.12

Menopause Rating Scale

Placebo Combination Therapy

Difference in treatment in favor of Black Cohosh (p=0.027)

◦ Covariates eliminated (p=0.02)

◦ Confounders considered (p<0.001)

Monotherapy Combination Therapy

Base- line

Mo 3 Mo 6 Base-line

Mo 3 Mo 6

Hot Flashes

0.52 ± 0.21

0.33 ± 0.19

0.25 ± 0.16

0.56 ± 0.21

0.34 ± 0.19

0.25 ± 0.16

Psyche

0.31 ± 0.22

0.21 ± 0.18

0.16 ± 0.14

0.42 ± 0.23

0.26 ± 0.18

0.19 ± 0.15

Total MRS Score

0.30 ± 0.17

0.20 ± 0.14

0.16 ± 0.11

0.36 ± 0.17

0.24 ± 0.14

0.18 ± 0.12

Symptom Diary

Low-dose estradiol Placebo

Basal

Mon

th 1

Mon

th 2

Mon

th 3

02468

101214

TTSE2Black Cohosh

0-24

25-4

9

40-7

4

75-1

00

>10

00

2

4

6

8

10

12

14

16

18

Placebo

Black Cohosh

Symptom Diary

Low-dose estradiol Placebo

Basa

l

Mon

th 1

Mon

th 2

Mon

th 3

02468

101214

TTSE2Black Cohosh

0-24

25-4

9

40-7

4

75-1

00

>10

00

2

4

6

8

10

12

14

16

18

Placebo

Black Cohosh

ResultsSafety

Adverse Events

Gastrointestinal distress

Allergic skin reactions

Infections

Sleep disturbances

Gynecological

Headaches

Adverse Events

Black

Coh

osh

Fluo

xetin

e0

20

40

60

TotalAdverse Events

Black

Coh

osh

Tibo

lone

0

50

100

150

TotalAdverse Events

Black

Coh

osh

Plac

ebo

0

50

100

150

200

TotalAdverse Events

Black Cohosh

0

1700

3400

5100

6800

Total

Adverse Events

Laboratory Measures

Liver function◦AST, ALT ◦γ-glutamyl transpeptidase◦GOT, GPT

Heart rate, blood pressure, weight

Total cholesterol◦HDL, LDL

Endometrial Change

No change in estradiol study

Clinically irrelevant change in tibolone study

◦Both peri- and postmenopausal women on tibolone

◦Only perimenopausal women on black cohosh

Discussion

Overview of Efficacy and Safety

Five of six studies found reductive effect ◦Equivalent to HRT◦More effective than SSRI, placebo◦Effective as monopreparation or combination

Good tolerability and safety◦Low rate of adverse events

Less common than HRT, comparable to placebo None serious

◦No adverse effect on liver, cardiovascular function

Concurrence and Disagreement

Cumulative findings consistent with literature

One of six studies found no significant benefit to Black Cohosh vs placebo

◦Only study with crossover design◦Shortest treatment period◦Enhanced placebo effect?

Conflict of Interest

Hans-Heinrich Henneicke-von Zepelin◦Co-author of three studies

Ute Stammwitz◦Co-author of one study

Schaper and Brümmer, Salzgitter, Germany◦Manufacturer of Remifemin®

Strengths and Weaknesses

Strengths

◦Current studies◦Peer reviewed ◦Reputable journals◦Monopreparation as

one treatment◦Range of locations/

populations (US, China, Turkey, Germany and Italy)

Weaknesses

◦Reliance on self reporting of symptoms

◦Short term treatment◦All studies not same

formulation◦Limited to six studies◦English language only◦PubMed only

database searched

Conclusion

Effective alternative

◦Reduce health risk

Long history of hot flashes Hormone replacement therapy

◦Maintain higher quality of life

Conclusion

Safe for short term use

◦Additional trials needed

Recommend Black Cohosh as valid alternative for management of vasomotor irregularities in menopausal women

Review Articles

1. Oktem M, Eroglu D, Karahan HB, Taskintuna N, Kuscu E, Zeyneloglu HB, Black cohosh and fluoxetine in the treatment of postmenopausal symptoms: A prospective, randomized trial, Adv Ther, 2007; 24: 1055-1068

2. Bai W, Henneicke-von Zepelin HH, Wang S, Zheng S, Liu J, Zhang Z, Geng L, Hu L, Jiao C, Liske E, 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

3. Pockaj BA, Gallagher JG, Loprinzi CL, Stella PJ, Barton DL, Sloan JA, Lavasseur BI, Rao RM, Fitch TR, Rowland KM, Novotny PJ, Flynn PJ, Richelson E, Fauq AH, Phase III double-blind, randomized, placebo-controlled crossover trial of black cohosh in the management of hot flashes: NCCTG Trial N01CC, J Clin Oncol, 2006; 24: 2836-2841

4. 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: 1074-1083

5. Nappi R, 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(1): 30-35

6. Briese V, Stammwitz U, Friede M, Henneicke-von Zepelin HH, Black cohosh with or without St. John’s wort for symptom specific climacteric treatment- Results of a large-scale, controlled, observational study, Maturitas, 2007; 57: 405-414

References

A. Rossouw J, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SAA, Howard BV, Johnson KC, Kotchen JM, Ockene J, 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(3): 321-333

B. Dog TL, Menopause: A review of botanical dietary supplements, Am J Med, 2005; 118: 98S-108SC. Shams T, Setia MS, Hemmings R, McCusker J, Sewitch M, Ciampi A, Efficacy of black cohosh-containing preparations on

menopausal symptoms, Altern Ther Health Med, 2010; 16(1): 36-44D. Nasr A, Nafeh H, Influence of black cohosh (Cimicifuga racemosa) use by postmenopausal women on total hepatic

perfusion and liver function, Fertil Steril, 2009; 92(5):1780-1782E. Powell SL, Godecke T, Nikolic D, Chen SN, Ahn S, Dietz B, Farnsworth NR, van Breemen RB, Lankin DC, Pauli GF, Bolton JL,

In vitro serotonergic activity of black cohosh and identification of Nω-methylserotonin as a potential active constituent, J

Agric Food Chem, 2008; 56:11718-11726F. Thurston RC, Kuller LH, Edmundowicz D, Matthews KA, History of hot flashes and aortic calcification among

postmenopausal women, Menopause, 2010;17(2):256-261 G. Gast GCM, Grobbee DE, Pop VJM, Keyzer JJ, Wijnands-van Gent CJM, Samsioe GN, Nilsson PM, van der Schouw YT,

Menopausal complaints are associated with cardiovascular risk factors, Hypertension, 2008; 51:1492-1498H. Thurston RC, Sutton-Tyrrell K, Everson-Rose SA, Hess R, Matthews KA, Hot flashes and subclinical cardiovascular disease,

Circulation, 2008; 118: 1234-1240I. Mahady GB, Fabricant D, Chadwick LR, Dietz B, Black cohosh: An alternative therapy for menopause? Nutr Clin Care, 2002;

5: 283-289J. Cheema D, Coomarasamy A, El-Toukhy T, Non-hormonal therapy of post-menopausal vasomotor symptoms, Arch Gynecol

Obstet, 2007; 276: 463-469K. Rotem C, Kaplan B, Phyto-Female Complex for the relief of hot flushes, night sweats and quality of sleep, Gynecol

Endocrinol, 2007; 23(2): 117-122

References

A. Uebelhack R, Blohmer JU, Graubaum HJ, Busch R, Gruenwald J, Wernecke KD, Black cohosh and St. John’s wort for climacteric complaints: A randomized trial, Obstet Gynecol, 2006; 107: 247-255

B. Chung DJ, Kim HY, Park KH, Jeong KA, Lee SK, Lee YI, Hur SE, Cho MS, Lee BS, Bai SW, Kim CM, Cho SH, Hwang JY, Park JH, Black cohosh and St. John’s wort (GYNO-Plus®) for climacteric symptoms, Yonsei Med J, 2007; 48(2): 289-294

C. Reed SD, Newton KM, LaCroix AZ, Grothaus LC, Grieco VS, Ehrlich K, Vaginal, endometrial, and reproductive hormone findings: Randomized, placebo-controlled trial of black cohosh, multibotanical herbs, and dietary soy for vasomotor symptoms: The Herbal Alternatives for Menopause (HALT) Study, Menopause, 2008; 15(1): 51-58

D. Sammartino A, Tommaselli GA, Gargano V, di Carlo C, Attianese W, Nappi C, Short-term effects of a combination of isoflavones, lignans and Cimicifuga racemosa on climacteric-related symptoms in postmenopausal women: A double-blind, randomized, placebo-controlled trial, Gynecol Endocrinol, 2006; 22(11): 646-650

E. Spangler L, Newton KM, Grothaus LC, Reed SD, Ehrlich K, LaCroix AZ, The effects of black cohosh therapies on lipids, fibrinogen, glucose and insulin, Maturitas, 2007; 57: 195-204

F. 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: 869-879

G. Heinemann LAJ, DoMinh T, Strelow F, Gerbsch S, Schnitker J, Schneider HPG, The Menopause Rating Scale (MRS) as outcome measure for hormone treatment? A validation study, Health Qual Life Outcomes, 2004; 2: 67

H. Metintas S, Arýkan I, Kalyoncu C, Ozalp S, Menopause Rating Scale as a screening tool in rural Turkey, Rural Remote Health, 2010;1230 (Accessed 11/4/2011)

I. ZEG Berlin. MRS - Menopause Rating Scale. (Online) no date, http://www.menopause-rating-scale.info/ (Accessed 11/4/2011).

J. Heinemann K, Ruebig A, Potthoff P, Schneider HPG, Strelow F, Heinemann LAJ, Thai DM, The Menopause Rating Scale (MRS) scale: A methodological review, Health Qual Life Outcomes, 2004; 2:45, http://www.hqlo.com/content/2/1/45 (Accessed 11/4/2011).

K. Alder E, The Blatt-Kupperman menopausal index: a critique, Maturitas, 1998; 29:1:19-24

Questions?