Review & meta-analysis: isopropanolic black cohosh extract iCR for menopausal symptoms – an update on the evidence

Figures & data

Table 1. Characteristics of the double-blind RCTs comparing iCR with placebo for neurovegetative and psychological menopausal symptoms, used as the basis for the meta-analysis.

First author, year of publication	Number of patients; indication; ethnicity	Daily dose; duration of application	Inclusion criteria	Exclusion criteria	Main efficacy results; standardized difference in means [95% CI]	Impact on evidence; remarks; RoB
Stoll, 1987	30 iCR, 20 placebo; ms; Caucasian	2 × 2 tab. = 8 mg extractum siccum; 3 months	46–58 years old, perimenopausal and postmenopausal patients suffering from neurovegetative, psychological, and somatic menopausal symptoms	Patients after bilateral OVX or pelvic radiation. Contraindication for HT. Other causes for symptoms than menopause. Osteoporosis. Intake of HT ≤4 weeks before study entry. Intake of antihypertensives	Significant improvement of the KMI and HAMA scores under iCR compared to placebo. Symptom intensity decreasing from moderate to mild; −1.020 [−1.586, −0.454]	⊕⊕ Well-conducted RCT; low RoB
Jacobson, 2001	42 iCR, 43 placebo; iatrogenic ms due to Tam (breast cancer); mainly Caucasian (African-American, Asian)	2 × 1 tab. ≙ 40 mg drug; 2 months	Breast cancer patients >18 years old with daily hot flushes. Completion of primary therapy including chemotherapy and radiation ≥2 months before entering study	Use of HT. Pregnancy. Major psychiatric illness. Known recurrent or metastatic breast cancer	Comparable reduction of hot flush frequency and intensity in both groups and significantly stronger reduction of sweating under iCR compared to placebo; −0.187 [−0.659, 0.285]	⊕ Study duration rather short to show efficacy; some concerns on RoB
Osmers, 2005	153 iCR, 151 placebo; ms; Caucasian	2 × 1 tab. ≙ 40 mg drug; 3 months	Postmenopausal patients ≥ 45 years old (≥12 months of amenorrhea or ≥6 months of amenorrhea with FSH ≥50 IU/l). Climacteric symptoms of ≥0.4 in ≥3 MRS items	BMI ≥28 kg/m^2. Cancer or other diseases with interference potential. Drug abuse. Participation in other trial ≤180 days before study entry. Use of HT during or ≤4 weeks before study entry. Use of non-hormonal climacteric drugs, including supplements and homeopathics. Use of anti-epileptics, psycholeptics, or psychoanaleptics, including phytotherapeutics	Significant improvement of the MRS total score vs. placebo. Strongest effect in vasomotor complaints (hot flushes, sweating, sleep disorders) and higher superiority during menopausal transition; −0.394 [−0.626, −0.162]	⊕⊕ Well-conducted RCT; low RoB
Uebelhack, 2006	151 iCR+HP 150 placebo; ms; Caucasian	Week 1–8, 2 × 2 tab. ≙ 128 mg drug, Week 9–16, 2 × 1 tab. ≙ 64 mg drug; 4 months	45–60 years old, perimenopausal and postmenopausal patients with climacteric complaints with pronounced psychological component for ≥3 months, untreated for ≥2 months. MRS of ≥0.4 in ≥3 items. HAMD scale items of ≥1 of 2 points	Use of HT, non-hormonal climacteric drugs or other treatment for climacteric symptoms ≤12 weeks before study entry. Use of synthetic or herbal anti-epileptics, psycholeptics, or psychoanaleptics ≤12 weeks before study entry. Psychological or psychiatric therapy. Bilateral OVX. Severe diseases. Abnormal TSH. Treatment with interference potential. Suicidality or attempted suicide in the past year	Significant superiority vs. placebo in the improvement of the MRS and HAMD scores; −0.999 [−1.225, −0.773]	⊕⊕ Well-conducted RCT; low RoB
Li Y, 2011	45 iCR, 32 placebo; ms; Asian	2 × 1 tab. ≙ 40 mg drug; 3 months	45–55 years old, perimenopausal patients with spontaneous menopausal status for ≥3 months with E2 ≤ 20 pg/ml and FSH ≥40 IU/l. KMI ≥17	History of diabetes, serious or unstable physical illness. Use of estrogen, antidepressants, or antipsychotics. Use of supplements for perimenopausal symptoms ≤3 months before study entry. Unexplained uterine bleeding, abnormal cervical smear, endometrial thickness ≥0.5 cm	Significant improvement of the KMI score and hot flushes compared to placebo; −0.792 [−1.246, −0.338]	⊕ Low quality of reporting, which may imply a high RoB
Jiang, 2015	24 iCR, 24 placebo; ms; Asian	2 × 1 tab. ≙ 40 mg drug; 6 months	45–60 years old, postmenopausal patients, STRAW +1b, +1c. BMI ≤30 kg/m^2. FSH ≥30 IU/l	Bilateral OVX, hysterectomy. Termination of ovarian function by chemotherapy or radiation therapy. Poorly controlled clinical diseases. Historic or present psychiatric disorders. Sleep-related respiratory or movement disorders. Use of opioids, anti-epileptics, anxiolytics, hypnotics, sedatives, antidepressants, or antihistamines ≤3 months before study entry. Use of HT or other therapy against menopausal symptoms ≤3 months before study entry. Participation in other study ≤3 months before study entry. Intake of ≥7 alcoholic drinks/week. History of drug/substance abuse	Significantly increased sleep efficiency and decreased WASO duration under iCR compared to placebo. Significantly better improvement of vasomotor and physical domains of Men-QoL by iCR; −0.836 [−1.442, −0.230]	⊕⊕ Well-conducted RCT; some concerns on RoB

BMI, body mass index; CI, confidence interval; E2, estradiol; FSH, follicle stimulating hormone; HAMA, Hamilton Rating Scale for Anxiety; HAMD, Hamilton Rating Scale for Depression; HT, hormone therapy; iCR, isopropanolic Cimicifuga racemosa extract; iCR+HP, fixed combination of isopropanolic Cimicifuga racemosa extract plus St. John’s wort (Hypericum perforatum) extract; IU, international units; KMI, Kupperman Menopause Index; ms, menopausal symptoms; Men-QoL, Menopause-specific Quality of Life Questionnaire; MRS, Menopause Rating Scale; OVX, ovariectomy; RCT, randomized, controlled trial; RoB, risk of bias; STRAW, Stages of Reproductive Aging Workshop; Tam, tamoxifen; TSH, thyroid-stimulating hormone; WASO, wake after sleep onset; ≙: corresponding to; ⊕: exploratory evidence; ⊕⊕: confirmatory evidence.

Figure 1. Risk of bias assessment of the placebo-controlled randomized controlled trials (RCTs).

Figure 2. Forest plot of isopropanolic Cimicifuga racemosa extract (iCR) versus placebo in neurovegetative and psychological menopausal symptoms.

CI, confidence interval; Fixed, summary of the respective group of studies under the fixed-effect size model; HP, Hypericum perforatum (St. John’s wort); ms, menopausal symptoms; n, number of patients; Std diff, standardized mean difference; SE, standard error of the standardized difference.