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description
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
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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,
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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
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Questions?