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Cimicifuga racemosaWomen’s health is an imminent concern worldwide, but it remains an ignored segment of research in most developing countries, and is yet to take the center stage in even developed nations. Some exclusive female health concerns revolve around both pathological and physiological aspects. These gender-specific maladies include breast, cervical, and ovarian cancers, and physiological concerns such as menopause and osteoporosis, which are often coexistent. Recently, women’s health issues, including postmenopausal syndrome, have attracted the attention of researchers and practitioners alike, opening newer pharmaceutical research and clinical avenues. Although not counted as a disease, postmenopausal syndrome (PMS) is a female health phenomenon underpinned by hormonal depletion. Enhanced life expectancy in women has added to their suffering, and pharmacological interventions are needed. Amongst the available treatment modalities, the use of numerous botanicals has emerged as an efficient health management tool for women. Cimicifuga racemosa (CR or Black Cohosh) is a plant/herb which has been traditionally exploited and extensively used by women. CRThis review is native to eastern and central North America, and corresponds to the family Ranunculaceae. It is also distributed in Canada and China, and cultivated in Europe. It is often called black cohosh, bugbane, rattle weed, snakeroot, squaw root, or rheumatism weedan attempt to compile and provide a summary of the importance of CR in complementary and alternative therapies for the improvement of various disorders related to women, such as menopausal syndrome, mammary cancer, and osteoporosis. It aims to systematically highlight the bioactive constituents, pharmacology, pharmacokinetics, therapeutic potentials, quality control processes, chromatographic techniques, and possible mechanisms of action of clinically effective phytomedicine for women’s health. Various clinical trials and patents relating to CR and women’s health have been collated. Furthermore, the plant and its related products have been considered from a regulatory perspective to reveal its commercial feasibility. The present review summarizes the existing data on CR focusing on women’s health, which can help to introduce this traditional phytomedicine to the world and provide some reference for future drug development.
- menopause
- postmenopausal syndrome
- women health
- black cohosh
1. Introduction
Menopause is a natural health concern among women all over the world, and can be better understood as a natural transition period in reproductive females. It is characterized by dramatic hormonal changes, and frequently includes social changes. It also likely changes the physical and mental needs of an adult female. Low estrogen levels as a result of ovarian dysfunction are an important characteristic feature found in postmenopausal women. This variation in hormones may lead to a diverse range of indications, collectively called postmenopausal syndrome (PMS) [1]. It is expected in all fertile women in the later stages of life, and accompanies much hardship. According to a study, there will be 1.2 billion menopausal and postmenopausal women by the year 2030, with an additional 47 million new entrants per year [2]. It has been testified that, in the developing world, maternal mortality rate is decreasing, and the life expectancy of women is increasing continuously. Therefore, attention needs to paid to women’s health in order to improve quality of life (QoL) after menopause [3]. Hormonal replacement therapy (HRT), commonly known as menopausal hormone therapy (MHT), is an extensively used treatment for postmenopausal syndrome, but its associated risks outweigh the benefits in long-term use, and it can be contraindicated in situations where women suffer from many restrictions in continuous use [4,5]. Another therapy comprises low-dose anti-depressants, serotonin, and norepinephrine reuptake inhibitors, such as Gabapentin, but none come without the burden of side effects and other pharmaco-technical limitations [6]. The detrimental effects of HRT have forced many postmenopausal women to search for a natural alternative (non-hormonal phytoconstituent) for this multifaceted problem.
Phytomedicine has been used in traditional medicine for centuries. Parts such as the flower, fruit, seed, root, rhizome, leaf, and bark are used for this purpose. Indigenous communities (such as Native Americans and Africans) used herbs in their rituals for healing. Ancient Chinese and Egyptians also used medicinal plants as early as 3000 BC. Ayurveda is a medical system primarily practiced in India that has been known for using botanicals for nearly 5000 years. Unani medicine is another known system of traditional medicine that has helped mankind for centuries by alleviating diseases using drugs derived from plant origin. Nowadays, with herbalism becoming more mainstream, there is continuous upgrading/improvements in analysis and quality control along with advances in clinical research, which add value to the botanicals in treating and preventing disease. The categories are drugs (e.g., Ayurveda and Unani), complementary and alternative medicines (CAM), dietary supplements, and novel foods. There is a range of botanicals that are extensively used for several health problems, with either curative or supportive potential, that add a quantity of referenced data related to global consumption and trade. One such botanical is Cimicifuga racemosa/Actea racemosa (CR) which is extensively used to treat women’s health-related issues, and also carries a lot of traditional uses [7]. CR has been used for over 40 years in Europe for the treatment of menstrual pain.
CR is native to eastern and central North America, and corresponds to the family Ranunculaceae. It is also distributed in Canada and China, and cultivated in Europe. It is often called black cohosh, bugbane, rattle weed, snakeroot, squaw root, or rheumatism weed [8]. Furthermore, various synonyms of CR, according to the International Plant Name Index, are listed as Actaea racemosa L., Actaea monogyna Walter, Actaea gyrostachya Wender, Botrophis pumila Raf, Botrophis serpentaria Raf, Botrophis actaeoides Raf. ex Fisch. and C.A. Mey, Cimicifuga americana Muhl, Cimicifuga serpentaria Raf, and Thalictrodes racemosa (L.) Kuntze [9]. The root and rhizome of CR have traditionally been used in the management of ailments such as rheumatism, malaria, sore throats, colds, and complications associated with childbirth [10]. It has been used for centuries by Europeans for treating menopausal symptoms, and a recent clinical study also supports the safety and efficacy of CR [11,12]. In contemporary Western herbal medicine, the use of CR is usually restricted to the management of menopausal symptoms and other difficulties related to the reproductive system in women [13]. Currently, CR is widely used to mitigate menopausal symptoms such as hot flashes, night sweats, sleep disturbances, vertigo, nervousness, mood swings, and vaginal dryness associated with postmenopausal females [14]. CR was listed among the ten bestselling OTC (over-the-counter) herbal remedies in America in the year 2018 [15,16,17]. Currently, CR-containing preparations are marketed in huge quantities in the United States and Europe under various brand names, such as Remifemin, Cimicifuga-Oligoplex and Cimicifuga Pentakran. Some of the products available on the US market have been listed in Table 1 [18].
Table 1. Available commercial products of CR on the US market.
| Sl. No | Products | Serving Size | Amount (mg) of CR Extract/1 Serving Size | Amount of Triterpenes/1 Serving Size (mg) |
|---|---|---|---|---|
| 1 | Remifemin | 1 tablet | - | 40 |
| 2 | Enzymatic Therapy Remifemin | 1 tablet | - | 20 |
| 3 | XYMOGEN MenoFem | 1.0 Capsule(s) | 50 | - |
| 4 | Vitanica Women’s Passage | 1.0 Capsule(s) | 40 | - |
| 5 | Estroven Extra Strength Estroven | 2.0 Caplet(s) | 40 | - |
| 6 | Irwin Naturals EstroPause | 4.0 Liquid Softgel(s) | 80 | - |
This herbaceous perennial plant has a long history of treating varieties of ailments with global demand. Nowadays, it is an internationally admired herbal remedy for the treatment of menopausal symptoms. In Germany, CR extract has been marketed since 1956, and the technical data on this herbal product has been included in several monographs, including American herbal Pharmacopoeia 2002, British Herbal Compendium 1992, British Herbal Pharmacopoeia 1996, British Pharmaceutical Codex 1934, Complete German Commission E (equivalent to US FDA), Martindale 32nd edition, Mills and bone, WHO volume 1 (1999), and PDR of herbal medicines 2nd edition [19,20]. According to the European medicines agency (EMEA) and the committee of the herbal medicinal product (CHMP), the rhizome of CR is a well-known herbal alternative for human consumption and has a therapeutic indication for alleviating minor neuro vegetative complaints associated with menopause, such as hot flashes, sweating, etc. [21]. In Canada, CR rhizome is legally recognized as an active ingredient of registered natural health products intended for oral use [22]. Therapeutic uses include pain associated with menstruation, relief of premenstrual symptoms, and relief of symptoms associated with menopause and muscle and joint pain associated with the rheumatoid condition. It is included in the category of herbal remedies or dietary supplements [23]. Many clinical, preclinical, in silico and in vitro studies confirm that the aqueous or ethanolic CR extract does not contain an estrogenic compound, rather it has neurotransmitter-like activities which positively influence postmenopausal syndrome.
2. Phytochemicals Constituent of CR
Phytochemicals, otherwise known as secondary metabolites, have significant biological activity and are also responsible for the color and odor of plants. Many secondary metabolites such as alkaloids, flavonoids, sterols, triterpenes, etc., play major roles in nutrition, physiology, and the management of various ailments [24,25]. They represent some of the most distinctive classes of compounds in higher plants, and may be classified based on chemical structure, composition, or solubility in various solvents or pathways by which they are synthesized. Components of plants explored for phytochemical constituents comprise of the underground (roots and rhizomes) as well as aerial parts (stems, leaves, flowers and fruits). Phytochemicals in CR rhizomes have been well studied, and the key constituents are triterpene glycosides, phenols, flavonoids and alkaloids, etc. CR also contains aromatic acid (ferulic acid, iso ferulic acid, caffeic acid and caffeic acid methyl esters), cinnamic acid esters (cimicifugic acid, cimicifugic acid A–F, cimiracemates A–D, fukiic acid, piscidic acid and fukinolic acid), resin, phytosterol, fatty acid, starch, and sugar as minor compounds [26,27]. It contains some alkaloids such as quinoline and quinolizidine types, anagyrine, baptifoline, magnoflorine, methyl cystine, methyl serotonin, etc. Some of the alkaloids are also undefined, which are present in minor quantities. Other constituents include citrullol, gum, resin, tannins, phosphoric acid, starch, phytosterol, cholines, and Betaine.2.1. Triterpenoids
Triterpene glycosides are a large, structurally distinct group of chemicals obtained from the metabolites of isopentenyl pyrophosphate oligomers, and signify the largest group of phytochemicals. Triterpene glycoside conjugates accrue in plants and produce saponins. Triterpenes and saponins have been shown to possess a range of biological actions such as anti-inflammatory and anti-cancer effects, and can promote or induce apoptosis [24,28]. These are the main class of compounds found in CR extract. CR triterpenes have a five-ring structure, the same as that of the four-ring structure of steroids. The majority of triterpene glycosides have 9, 19-cycloartane triterpene skeletons with different substitutions. The position and varieties of chemical substitution are responsible for different stereochemical configurations. Moreover, 23-epi-26-deoxyactein (previously known as 27-deoxyactein), actein, and cimiracemoside A are commercially available triterpenes, and are commonly used for the standardized CR extract.
As with many botanicals, CR is complicated to study due to the absence of standardization of the extract to one or more active ingredients. Certainly, in CR, the active components are ambiguous; nonetheless, the triterpenes of CR are thought to be responsible for its biological action, and hence are used for the relief of PMS [29,30].
Furthermore, the majority of investigations on efficacy have been carried out on whole extracts or standardized extracts of CR with respect to triterpenes. Although many components are found in the extract, which components are actually necessary for the symptomatic relief of menopause is still unknown.
Triterpenes are one of the most important constituents present in hydroalcoholic extracts of CR. Primarily, the bioactive constituents of CR extract are supposed to be found in the triterpene glycoside fraction. So far, more than 40 types of triterpenes have been isolated from CR extract [31,32]. To distinguish triterpenes from each other is a major challenge because of their complexity and structural similarities. Actein and 23-epi-26-deoxyactein are the highly abundant triterpenes found in the root and rhizome of the CR, and are frequently used as standardization markers for CR formulations [33,34]. Quantization of the triterpene glycosides is generally difficult because they do not have a chromophore that absorbs light above 200 nm, thus limiting their sensitivity and the ability for UV analysis. Thus, HPLC-evaporative light scattering detection (HPLC-ELSD) has become the most accepted technique used for the quantitation of the triterpene glycosides in CR [34], but ELSD has some limitations such as poor sensitivity, highly non-linear calibration curves, and poor reproducibility. Table 2 enumerates various chromatographic techniques for the evaluation of CR triterpenes.
Table 2. Different chromatographic techniques for the evaluation of CR triterpenes.
| Title of the Manuscript | System and Detector | Plate or Column Used | Solvent System/Mobile Phase | Advantage | Reference |
|---|---|---|---|---|---|
| “Actaea racemosa (root and rhizome)” | HPTLC-anisaldehyde reagent | TLC plate having coating of Silica gel 60, F254 | Toluen:ethyl formate:formic acid (5:3:2, v/v/v) | Simple method | [35] |
| “Fast analysis of Triterpene glycosides in CR using Agilent 1290 Infinity LC system and Agilent Poroshell 120 SB c-18 2.7 µm” | 1290 infinity LC system ELSD |
Poroshell 120 SB C-18 2.7 µm column. Agilent 385 ELSD, Model-G4 261 A. |
A Solvent: 1% formic acid in water B Solvent: Acetonitrile |
This is a revised method for the established USP method of analysis of CR triterpenes. A more efficient approach than USP condition in terms of time and solvent consumption. Here, all the conditions (mobile phase, detector setting and column temp) are the same except for column | [36] |
| 11 black cohosh products were analyzed for triterpene glycosides and other constituents by using HPLC-PDA and a newly selected ion monitoring LC-MS method. The study concluded that the product contained Asian Actaea as a replacement for black cohosh | |||||
| [ | |||||
| 45 | |||||
| ] | |||||
| “Chemical profiling of Actaea species and commercial products using UPLC-QTof-MS” | |||||
| UPLC-QTof-MS | Acquity UPLC HSS T3 2.1 × 100 mm,1.8 μm 40 °C | Gradient elution with Solvent A: 0.1% formic acid in water | Solvent B: acetonitrile |
Helps to recognize useful marker compounds such as cimifugin derivatives, triterpenes, and alkaloids that distinguish between Actaea species based on exact mass precursor ion, theoretical isotopic distribution, and high-energy fragment ion data | [46] |
| “The value of plant collections in ethnopharmacology: a case study of 85-year-old black cohosh (Actaea racemosa L.) sample” | HPLC- PDA- LCMS | C18 column (3.9 mm × 150 mm, 5 m) | Solvent A: water Solvent B: acetonitrile | A comparative study to confirm stability between the ingredients of the 85-year-old plant sample with that of a new collection of Actaea racemosa by quantitative study. Both plant samples have comparable quantities of the 4 major triterpene glycosides, thus concluding the similarity of both samples and confirming the stability of the older sample | [47] |
| “Species Identification of Black Cohosh by LC-MS for Quality Control” | Reversed-phase liquid chromatography with positive atmospheric pressure chemical ionization mass spectrometry (LC/(+)APCIMS | A fast and accurate method for analyzing the 4 triterpene: actein, 27-deoxyactein, cimicifugoside M and cimicifugoside from CR for quality control purposes | [48] |
2.2. Phenolic Constituents
The main phenolic components of CR are caffeic acid, hydroxycinnamic acids, ferulic acid, and isoferulic acid. Other phenolic constituents separated from the extract of the CR roots and rhizomes include rotocatechuic acid, fukinolic acid, protocatechualdehyde, methyl caffeate, p-coumaric acid, ferulate-1-methyl ester, 1-isoferuloyl-β-d-glucopyranoside, and cimicifugic acids A, B, and D–F [49]. It has been found that both triterpenes and phenols are stable for many years under controlled environmental conditions, and do not undergo considerable changes [47,50]. Furthermore, it has been found that triterpenes can maintain their stability at a variety of temperatures and humidity conditions; polyphenols, on the other hand, are only stable at room temperature and low humidity conditions. The characteristics of CR not only enhance its utility in industry, but are also very useful in clinical research.
2.3. Flavonoids
Many findings have found that flavonoids, such as the isoflavone formononetin, can be isolated from CR [14,33,51,52]. The presence of formononetin in the CR extract was first discovered by Jarry et al. [53] following the analysis of the extract by various analytical methods. It was believed that the pharmacological action of the plant was due to the presence of formononetine which helps to alleviate menopausal distress in adult women by its estrogenic activity. The presence of formononetine from the methanolic extract of rhizomes and roots of CR was confirmed by using TLC fluorometry [54]. The research, however, was unable to identify the compound in raw plant materials or extracts. Struck et al. [51] were unable to identify the compound in the ethanolic and isopropanolic extract of the CR. Li et al. also failed to identify formononetine from the methanolic extract by using an HPLC–photodiode array detector (HPLC-PDA) and an HPLC-ELSD [27]. Later on, Kennelly et al. and Jiang et al. [45,55] also failed in identifying the presence of formononetine in the commercial CR products and rhizomes by using various analytical techniques in separate experiments.
2.4. Alkaloid
Alkaloids are important constituents of natural products that have established biological action, principally as CNS agents. There are more than a hundred nitrogenous compounds in CR extract [56]. It contains isoquinoline, indole, and guanidine-type alkaloids. The presence of guanidine-type alkaloids in the extract is one of the distinctive characteristics of the CR metabolome. Phenolic acids present in the extract may possibly behave as counter ions to positively charged alkaloids and create strong ion pairs that are responsible for the biological activity of the extract. Nω-methylserotonin (indole alkylamine) is a compound that is found in CR extract, and it has the active serotonergic principle [57,58]. It binds to the serotonin transporter, and hence may be considered as a selective serotonin reuptake inhibitor, which may contribute to the biological activity of CR extract in menopause. The preceding fact suggests that alkaloids are most likely the active components accountable for the perceived CNS action of CR.
Most of the research work focuses only on triterpenes as the active ingredient in CR extract, which are believe to be responsible for pharmacological action. Table 3 describes the pharmacologically active constituents of CR from the roots and rhizome of the plant. However, other types of CR ingredients may be explored for their pharmacological activity. It is also important to investigate the other part of the plant apart from the root and rhizome to find out the most active ingredients.
Table 3. Pharmacologically active constituents of CR.
| Source | Compound Class and Name | Part of the Plant | Reference | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Cimicifuga racemosa | Cimigenol-3-O-β-D-xyloside (Cimigenoside) |
Rhizome | [59] | ||||||||
| 25-O-Acetylcimigenol-3-O-β-Dxyloside (25-O-Acetylcimigenol xyloside |
Rhizome | [60] | |||||||||
| “Determination of Triterpene Glycosides in Cimicifuga racemosa (Black Cohosh) by HPLC-CAD” | HPLC-CAD | C18 HPLC column, 4.6 × 150 mm, 2.7 μm particle size | A Solvent: 0.1% formic acid in water | ||||||||
| Cimiracemoside A | B Solvent: Acetonitrile | Here, the calibration curves and signal-to-noise ratios for ELSD and charged aerosol detection of the triterpene glycoside (27-deoxyactein) in a black cohosh extract are compared. It can be concluded that the Thermo Scientific Dionex Corona™ CAD™ Charged Aerosol detector has ↑ sensitivity, calibration linearity, and reproducibility over ELSD | Rhizome | [37] | |||||||
| [ | 44 | ,61] | “Detection of Actaea racemosa Adulteration by Thin-Layer Chromatography and Combined Thin-Layer Chromatography-Bioluminescence” | HPTLC and HPTLC Bioluminescence | |||||||
| (24S)-24-O-Acetylhydroshengmanol- 3-O-β-D-xyl-Δ16,17-enol ether | (For identification of adulterants)—5% H2SO4–anisaldehyde reagent, Vibrio fischeri culture |
Bioluminex silica gel 60 F254 HPTLC plates | Toluene:ethyl formate:formic acid (5 + 3 + 2, v/v/v). | An efficient, economical, and effective technique that helps to identify common adulterants in black cohosh. Unknown contaminants that were not identified by standard identification techniques were easily identified by this | [38] | ||||||
| Root and rhizome | [ | 62] | “The HPLC Analysis of CR Using an INA Method” | HPLC-ELSD | Phenomenex Prodigy ODS-3, 5 μm, 250 × 4.6 mm | A Solvent:0.1% formic acid B Solvent: Acetonitrile |
|||||
| 23-epi-26-Deoxyactei | Root and rhizome | --- | [ | [63] | 39] | ||||||
| “Isolation, structure elucidation, and absolute configuration of 26-deoxyactein from Cimicifuga racemosa and clarification of nomenclature associated with 27-deoxyactein” | HPLC-ELSD | YMC ODS-AQ RP-18 column (5 μm, 120 Å, 4.6 × 250 mm) | Solvent A: water containing 0.05% TFA, Solvent B: acetonitrile, Solvent C: water |
Helps to isolate 3 triterpenes from the roots/rhizomes of CR | [40] | ||||||
| 26-Deoxyactein (=27-Deoxyactein) | Root and rhizome | [40] | 7 | Lydia E. 8Pinkham Herbal Liquid Supplement with Vitamins C and E | 1.0 Tablespoon(s) | - | - | ||||
| “Stability Evaluation of Selected Polyphenols and Triterpene Glycosides in CR” | HPLC-PDA | 125 × 4.0 mm i.d. Hypersil ODS column-quantitative 250 × 4.6 mm i.d., 5 μm Aqua C18 column-qualitative |
A Solvent: 5% (v/v) acetonitrile B Solvent: Water |
Evaluates the stability of the triterpene glycosides present in CR (plant material, extracts, and encapsulated commercial extract). With an HPLC-PDA method, 3 triterpene glycosides in CR were quantitatively measured for a specific period and were found stable at the tested conditions | [41 | 8 | Gaia Herbs Single Herbs Black Cohosh | 1.0 Capsule(s) | 400 | 2 | |
| ] | |||||||||||
| “Quantitative determination of triterpenoids and formononetin in rhizomes of black cohosh (Actaea racemosa) and dietary supplements by using UPLC-UV/ELS detection and identification by UPLC-MS” | UPLC-UV/ELS | UPLC BEH C18 column (100 mm × 2.1 mm i.d., 1.7 μm | Gradient elution with water and acetonitrile: methanol (7:3) at a constant flow rate of 0.3 mL/min n, 55% A/45% B; in the next 7 min, 35% A/65% B using a slightly concave gradient profile |
Successfully used to examine the various commercial product of CR along with differentiating between 2 other Actaea species. It has been concluded that there was significant inconsistency in the quantities of the selected triterpenes for different products of black cohosh | [33] | 9 | Oregon’s Wild Harvest Black Cohosh | 1.0 Capsule(s) | 300 | - | |
| “Direct analysis and identification of triterpene glycosides by LC/MS in black cohosh, Cimicifuga racemosa, and in several commercially available black cohosh products” | 10 | Natrol Black Cohosh Extract 80 mg | 2.0 Capsule(s)) | 160 | |||||||
| Actein | Root and rhizome | [40,63] | |||||||||
| Caffeic acid | Root and rhizome | [64] | |||||||||
| Cimiracemate A | Rhizome | 4 | |||||||||
| 11 | Major Black Cohosh 40 mg | 1.0 Capsule(s) | - | 40 | |||||||
| HPLC-PDA | Hypersil ODS column-(5 μm, 4ID × 125 mm | A Solvent: water B Solvent: acetonitrile | Used to differentiate CR products from different plant species for quality control reasons | [ | 42] | ||||||
| [ | 60 | ] | “HPLC Analysis of Triterpene Glycosides in Black Cohosh Formulations using the PL-ELS 2100” | PL-ELS 2100 (neb = 30 °C, evap = 50 °C, gas = 1.4 SLM) UV-Vis @ 230 nm | Inertsil C18 5 µm, 150 × 4.6 mm | A Solvent: 0.1% Formic Acid in Water B Solvent: Acetonitrile | To certify the potency of commercially available black cohosh tablets | [43] | |||
| Cimiracemate B | Rhizome | [65] | “Phytochemical Fingerprinting to Thwart Black Cohosh Adulteration: a 15 Actaea Species Analysis” | HPLC-PDA-LCMS | Triterpene glycosides were performed with a 125 × 4.0 mm i.d. Hypersil ODS column (Agilent, Santa Clara, CA, USA | Step gradient starting with 5% (v/v) acetonitrile (A) in water (B) and ↑ to 100% acetonitrile over 60 min | A practical, reliable method for authenticating black cohosh and differentiating it from adulterants | [44] | 12 | Bluebonnet Standardized Black Cohosh Root Extract | 1.0 Capsule(s) |
| “Evaluation of the Botanical Authenticity and Phytochemical Profile of Black Cohosh Products by High-Performance Liquid Chromatography with Selected Ion Monitoring Liquid Chromatography−Mass Spectrometry” | HPLC-PDA -LCMS (APCI) | 250 | 6.25 | ||||||||
| 150 mm × 3.9 mm i.d., 5 µm, Waters C18 column | Step gradient starting with 5% ( | v | /v) acetonitrile (solvent A) in water (Solvent B) | 13 | Gaia Herbs SystemSupport Women’s Balance | 1.0 Capsule(s) | 200 | 1 | |||
| 14 | Nature’s Way Black Cohosh Root | 3.0 Capsule(s) | 540 | - | |||||||
| 15 | Oregon’s Wild Harvest Black Cohosh | 1.0 mL | 500 | - | |||||||
| 16 | NOW Red Clover/Black Cohosh 225 mg/40 mg | Serving size: 1.0 Vcap(s)(R) | 40 | - | |||||||
| 17 | Vitamin World Extra Strength Black Cohosh 40 mg | 1.0 Softgel(s) | 40 | 1 | |||||||
| 18 | Terry Naturally Menopause Relief plus | 2 capsule(s) | - | - | |||||||
| 19 | Botanic Choice Black Cohosh Root | 1.0 mL | 35 | - |
