Elsevier

Maturitas

Volume 57, Issue 4, 20 August 2007, Pages 405-414
Maturitas

Clinical trial paper
Black cohosh with or without St. John's wort for symptom-specific climacteric treatment—Results of a large-scale, controlled, observational study

https://doi.org/10.1016/j.maturitas.2007.04.008Get rights and content

Abstract

Objectives

To evaluate usage pattern, effectiveness and safety of Black cohosh alone or in fixed combination with St. John's wort on menopausal symptoms in general clinical practice.

Method

Prospective, controlled open-label observational study of 6141 women at 1287 outpatient gynecologists in Germany. Subjects were treated with recommended doses of study therapies, with treatment chosen by the participating physicians. Patients were followed up for 6 months, optionally 12 months. The primary effectiveness variable was Menopause Rating Scale (MRS) subscore PSYCHE at Month 3 evaluated by ANCOVA.

Results

The treatment groups were comparable at baseline, excepting the main MRS score and the PSYCHE score (monotherapy: 0.31 ± 0.22; combination therapy: 0.42 ± 0.23). Reductions from baseline were seen with both regimens for all variables. The changes in the primary variable remained significantly different between groups (p < 0.001) when adjusted for differences at baseline with the combination therapy being superior: from 0.37 (adjusted) to 0.25 (95% CI: 0.24–0.25) and 0.23 (95% CI: 0.22–0.23) at Month 3 in the monotherapy and combination-therapy groups, respectively. The improvement by both therapies was maintained at 6 and 12 months. The rate of possibly treatment-related adverse events was 0.16%, all non-serious.

Conclusion

The results support the effectiveness and tolerability profiles of two Black cohosh-based therapies for menopausal symptoms in general practice. They were used differentially: the monotherapy for neurovegetative symptoms, the combination for patients with more pronounced mood complaints. The fixed combination of Black cohosh and St. John's wort was superior to Black cohosh alone in alleviating climacteric mood symptoms.

Introduction

The menopausal transition is very frequently accompanied by hot flushes, sleep disturbances or mood changes [1], [2], [3], [4]. A recent estimate puts the percentages of women experiencing such symptoms during menopause at 85% [5]. In addition, a large proportion of women resort to self-medications with over-the-counter (OTC) medications or complementary and alternative medications (CAM) [6].

After the Women's Health Initiative Study (WHI) shed doubt on the value of hormone replacement therapy (HRT) [7] the interest in alternative therapies has increased. Among herbal remedies to alleviate menopausal complaints, the most common are preparations based on Black cohosh (Actaea racemosa, formerly called Cimicifuga racemosa). The effects of Black cohosh are commonly attributed to the two main constituent groups, i.e. triterpene glycosides (actein, 27-deoxyactein, cimicifugoside) and cinnamic acid esters [8], [9]. The research on Black cohosh is recognized also by the American Herbal Pharmacopoeia [10], World Health Organization and others. Most of the data available on the efficacy and safety have been obtained with the commercially available preparation Remifemin® (Remifemin; Schaper & Brümmer GmbH & Co. KG, Salzgitter, Germany) based on 2.5 mg native isopropanolic Black cohosh extract (isopropanolic C. racemosa = iCR), corresponding to approximately 20 mg herbal rootstock matter per tablet.

Each tablet of the combination preparation Remifemin® plus contains 3.75 mg iCR extract and 70 mg of an ethanolic extract from 245 to 350 mg St. John's wort (Hypericum perforatum), a dosage recommended by the German Commission E. The efficacy of St. John's wort for the treatment of mild depression has been demonstrated in numerous clinical studies [11]. Guidelines from the American College of Physicians–American Society of Internal Medicine state that St. John's wort may be considered for short-term treatment of mild acute depression [12].

Both Black cohosh-based preparations have been shown to be effective and well-tolerated in placebo-controlled randomized clinical trials using standardized efficacy assessment methods [13], [14]. Osmers et al. showed daily administration of the Remifemin monotherapy preparation to improve Menopause Rating Scale (MRS) [15] score by 0.03 to 0.05 units compared with placebo over a period of 12 weeks in 304 subjects; a similar effect to those with hormone replacement therapy. In a study by Uebelhack et al. of the combination preparation with H. perforatum in 301 subjects with pronounced psychological symptoms, both MRS score and the summary score on the Hamilton Depression Rating Scale improved with active treatment compared with placebo over 16 weeks of treatment. In both these randomized trials, there were no relevant group differences in adverse events, laboratory findings, or tolerability.

However, randomized controlled clinical trials represent an artificial situation that does not necessarily correspond to that encountered by individuals taking medications in daily life. The efficacy and safety of drugs depend on a variety of factors and patients’ treatment patterns are seldom as standardized as in closely monitored randomized trials, which are based on highly selected study populations, specified outcomes and restricted use of other therapies. The enormous number of women affected by menopausal symptoms results in huge variation within the patient population that would be difficult to capture in randomized studies. Thus, there is a need for data on the usage patterns (the prescribing behavior under conditions of everyday medical practice) and on the effectiveness of both products in such settings. The primary objective of this study was to prove superiority of Remifemin® plus versus Remifemin® on psychological symptoms after 3 months of treatment. The choice of primary variable was governed by the main difference between the two preparations used in the study, i.e., the presence of St. John's Wort in Remifemin® plus. For this purpose, a large-scale, non-randomized, observational design was chosen.

Section snippets

Study design

This was a prospective, non-randomized, open-label observational study conducted between March 2002 and March 2004 in 1287 outpatient gynecologists’ practices from all parts of Germany. The study design and conduct was in accordance with the German federal recommendations for the conduct of observational trials [16]. Included were women with any menopausal symptoms. Exclusion criteria were treatment with any study medication during the previous 6 months and hormone replacement therapy (HRT) in

Patient disposition and demographics

A total of 6141 women were enrolled in 1287 practices. They received at least one dose of study medication and effectiveness data was reported at least once, thus qualifying for inclusion in the ITT population. Of the enrolled subjects, 3027 (49%) received the monotherapy, mostly as tablets (n = 2798; 46%) but in a few cases (n = 229; 4%) as solution. The combination preparation was administered to 3114 subjects (51%). During the course of the study, 244 subjects (4%) changed treatment from

Discussion

The risks associated with hormone replacement therapy (HRT) demonstrated by the Women's Health Initiative Study in 2002 [7] highlighted the need for a differentiated approach to the management of menopausal symptoms [21]. The data presented here, from a large-scale observational study, provide information on prescription patterns, long-term effectiveness and tolerability of two herbal preparations based on Black cohosh (C. racemosa) across a wide range of menopausal patient types in everyday

Acknowledgment

Financial support for this study was provided by Schaper and Brümmer GmbH & Co. KG, Salzgitter, Germany.

References (30)

  • J.E. Roussow

    Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial

    JAMA

    (2002)
  • K. He et al.

    Direct analysis and identification of triterpene glycosides by LC/MS in black cohosh, Cimicifuga racemosa, and in several commercially available black cohosh products

    Planta Med

    (2000)
  • K. Hostanska et al.

    Cimicifuga racemosa extract inhibits proliferation of estrogen receptor-positive and negative human breast carcinoma cell lines by induction of apoptosis

    Breast Cancer Res Treat

    (2004)
  • Upton R, editor. American herbal pharmacopoeia and therapeutic compendium: Black Cohosh rhizome. Santa Cruz (CA): AHP;...
  • K. Linde et al.

    St. John's wort for depression

    Cochrane Database Syst Rev

    (2000)
  • Cited by (45)

    • The effect of probiotics on mood and sleep quality in postmenopausal women: A triple-blind randomized controlled trial

      2022, Clinical Nutrition ESPEN
      Citation Excerpt :

      Symptoms such as irritability, anger and depression also increase during menopause [11]. About 85% of postmenopausal women suffer from sleep disorders, mood swings (anxiety and depression), and hot flashes [12]. Insomnia is a common complaint and a significant change in menopausal women [13], and sleep problems in postmenopausal women may be due to vasomotor symptoms, reduced estrogen levels, and psychological factors [14].

    • Antidepressant-like effects of the extract from Cimicifuga foetida L.

      2012, Journal of Ethnopharmacology
      Citation Excerpt :

      In the last decade, there is a growing interest in the therapeutic effects of botanical agents on the menopausal symptoms including hot flushes, sleep disruption, depression and anxiety, etc. It is notable that some botanical agents such as Black cohosh (Cimicifuga racemosa, Remifemin®) (Lieberman, 1998; Osmers et al., 2005) and St John’s Wort herb (Hyperricum perforatum) (Briese et al., 2007; Grube et al., 1999; Uebelhack et al., 2006) have exerted antidepressant-like effects in the perimenopausal women. Cimicifuga foetida L., a well-known medicinal plant widely distributed in China, is a species of Cimicifuga genus (the same genus as C. racemosa).

    • Herb induced liver injury presumably caused by black cohosh: A survey of initially purported cases and herbal quality specifications

      2011, Annals of Hepatology
      Citation Excerpt :

      This review summarizes present key issues of supposed HILI cases in association with assumed BC use and related quality specifications of BC as an herbal product. In none of the numerous clinical trials using BC drugs was there any suspicion of adverse reactions related to liver injury.16,19 In particular, lack of hepatotoxicity by BC was confirmed in a recent metaanalysis of randomized, double blind controlled clinical trials.16

    View all citing articles on Scopus
    View full text