Transfer of preclinical study data on the influence of cimicifuga racemosaon functional changes in the hippocampus during menopause.

Menopausal transition in women involves complex neurobiochemical changes linked to ovarian dysfunction, resulting in symptoms like vasomotor symptoms (VMS), sleep disturbances, anxiety, and cognitive impairments. Hormone replacement therapy is the first-line treatment. However, many women are reluctant to use HRT or have contraindications toward HRT and seek for alternatives. Non-hormonal therapies with extracts of Cimicifuga racemosa rhizomes like the isopropanolic extract (iCR, black cohosh) offer a promising alternative. A preclinical pilot study exploring iCR's effects on gene expression in the hippocampus and hypothalamus of ovarectomized (OVX) rats mimicking menopausal conditions identified important signaling pathways and CNS-based contributions to the multitargeted modes of action of iCR. Especially in the hippocampus, iCR compensated effects of OVX on gene expression profiles. These changes are reflected by the genes AVPR1A, GAL, CALCA, HCRT, PNOC, ESR1, ESR2 and TAC3 contributing to the formation of hot flushes or thermoregulation as well as to secondary effects such as blood pressure, metabolism, hormonal regulation, homeostasis, mood regulation, neuroendocrine modulation, regulation of sleep and arousal, and in learning, memory and cognition. To understand the mechanisms in the brain of estrogen-depressed animals (OVX) and subsequent iCR treatment we combined the results of the pilot study with those of up-to-date literature and tried to transfer the current knowledge to humans during menopausal transition and adaptation. Focus was laid on changes in the hippocampal function, that is disturbed by hormonal fluctuations, but can also be brought back into balance by iCR.

Machine Learning-Based Analysis Reveals Triterpene Saponins and Their Aglycones in Cimicifuga racemosa as Critical Mediators of AMPK Activation.

Cimicifuga racemosa (CR) extracts contain diverse constituents such as saponins. These saponins, which act as a defense against herbivores and pathogens also show promise in treating human conditions such as heart failure, pain, hypercholesterolemia, cancer, and inflammation. Some of these effects are mediated by activating AMP-dependent protein kinase (AMPK). Therefore, comprehensive screening for activating constituents in a CR extract is highly desirable. Employing machine learning (ML) techniques such as Deep Neural Networks (DNN), Logistic Regression Classification (LRC), and Random Forest Classification (RFC) with molecular fingerprint MACCS descriptors, 95 CR constituents were classified. Calibration involved 50 randomly chosen positive and negative controls. LRC achieved the highest overall test accuracy (90.2%), but DNN and RFC surpassed it in precision, sensitivity, specificity, and ROC AUC. All CR constituents were predicted as activators, except for three non-triterpene compounds. The validity of these classifications was supported by good calibration, with misclassifications ranging from 3% to 17% across the various models. High sensitivity (84.5-87.2%) and specificity (84.1-91.4%) suggest suitability for screening. The results demonstrate the potential of triterpene saponins and aglycones in activating AMP-dependent protein kinase (AMPK), providing the rationale for further clinical exploration of CR extracts in metabolic pathway-related conditions.

AMPK Activation by Cimicifuga racemosa Extract Ze 450 Is Associated with Metabolic Effects and Cellular Resilience against Age-Related Pathologies in Different Tissue Cell Types.

Cimicifuga racemosa extracts (CREs) have gained well-established use for the treatment of menopausal symptoms such as hot flushes and excessive sweating, and weight gain. While the clinical effects of CREs have been well documented, the mechanisms underlying these effects are largely unknown. More recently, the metabolic effects of the CRE Ze 450 were demonstrated in cultured cells in vitro and in mouse models of obesity in vivo. At the molecular level, metabolic regulation, enhanced insulin sensitivity, and increased glucose uptake were linked to the activation of AMP-activated protein kinase (AMPK). Therefore, we tested the effects of Ze 450 on AMPK phosphorylation and thus activation in cells from different tissues, i.e., murine C2C12 myoblast cells, human HEPG2 liver cells, mouse HT22 neuronal cells, and in murine 3T3L1 adipocytes. Using a FRET-based HTRF-assay, we found that Ze 450 induced AMPK phosphorylation and the activation of this key enzyme of metabolic regulation in cells from various different tissues including C2C12 (muscle), HEPG2 (liver), HT22 (hippocampal), and 3T3-L1 (adipocyte) cells. In C2C12 muscle cells, enhanced AMPK activation was accompanied by reduced mitochondrial respiration and enhanced glucose uptake. Further, Ze 450 enhanced the resilience of the cells against oxidative death induced by ferroptosis inducers erastin or RSL3. Our findings suggest a general effect of Cimicifuga racemosa on AMPK activation in different tissues and across species. This may have a significant impact on expanded therapeutic applications of Ze 450, since AMPK activation and the related metabolic effects have been previously associated with anti-aging effects and the prevention of the metabolic syndrome.

Effects of Cimicifuga racemosa (L.) Nutt on sexual function in women receiving tamoxifen for breast cancer.

To assess the effects of Cimicifuga racemosa (L.) Nutt on climacteric symptoms and sexual function in women receiving tamoxifen after breast cancer treatment. A prospective study of women treated at the Mastology Outpatient Clinic of the Department of Obstetrics and Gynecology of the Santa Casa de Sao Paulo School of Medical Science of the hospital was conducted between 2018 and 2021. Patients diagnosed with breast cancer that underwent surgical, radiotherapy and chemotherapy treatment more than one year prior, receiving tamoxifen, exhibited climacteric symptoms and were sexually active were selected. Total of 34 women were recruited and during outpatient visits completed sociodemographic questionnaire, Blatt-Kupperman Index (KI) and Female Sexual Function Index (FSFI). The group showed improvements in climacteric symptoms (p<.001) and sexual function (p=.011) after the 6-month follow-up. Cimicifuga racemosa (L.) Nutt promoted improvements in climacteric symptoms and sexual function in women surgically treated for breast cancer. Clinical Trials.gov ID: NCT02467686.Impact StatementWhat is already known on this subject? The medications used for the treatment of breast cancer can lead to important complaints of vasomotor manifestations with a negative impact on the success of their treatment, and cases have been described until their interruption. Cimicifuga racemosa (L.) Nutt. is described in several works as a therapy to alleviate these symptoms. Numerous works in the literature present climatic symptoms and sexual function with a selective approach to the themes.What do the results of this study add? Our study evaluated a group of women who were treated for breast cancer after menopause taking into account the following aspects: climacteric symptoms and sexual function. When we reviewed the literature, we did not find, so far, work similar to ours.What are the implications of these findings for clinical practice and/or further research? In clinical practice, assessing vasomotor symptoms and sexual response of breast cancer patients can contribute towards improving the lives of this patient group. Prescribing Cimicifuga racemosa (L.) Nutt in cases with climacteric complaints and poor sexual response can relieve distress and promote better health and life status for these women. Although the present investigation has generated important data on female breast cancer survivors, there are limitations regarding the number of participants. We recommend further clinical research with expansion of the sample studied and the results presented.

Cimicifuga racemosa (L.) Nutt. en el tratamiento de los síntomas vasomotores de la menopausia: revisión / Cimicifuga racemosa (L.) Nutt. in the treatment of vasomotor symptoms of menopause: a review

Introducción: Diversos estudios han puesto de manifiesto que los preparados a base de los rizomas y raíces de cimicífuga (Cimicifuga racemosa (L.) Nutt.) pueden ser útiles para aliviar los síntomas menopáusicos. El objetivo de este trabajo es realizar una revisión de la eficacia y seguridad de estos preparados en el tratamiento de los síntomas vasomotores de la menopausia. Método: Se realizó una búsqueda de los artículos publicados desde enero de 2005 a marzo de 2021 en el buscador de recursos de la Universidad de La Laguna, “el Punto Q”. Se seleccionaron los ensayos clínicos aleatorizados y controlados, que tuvieran las palabras claves en el resumen, texto o título, tanto en inglés como en español.Resultados:Se identificaron 13 ensayos clínicos que incluían los criterios de selección establecidos. Se encontró que los preparados de cimicífuga (principalmente extractos comerciales estandarizados en su contenido en principios activos) produjeron en la mayoría de los estudios una reducción significativa comparada con el placebo de los síntomas vegetativos (sofocos y sudores nocturnos) y psicológicos de la menopausia, así como una mejoría de la calidad de vida. No se observaron efectos adversos serios a las dosis utilizadas. Conclusiones: Los extractos de cimicífuga pueden ser eficaces y seguros para el tratamiento de los síntomas vegetativos y psicológicos de la menopausia, siendo bien tolerados. No obstante, son necesarios más ensayos clínicos con mayor número de pacientes, más extensos, uso de preparaciones estandarizadas, así como con criterios similares de inclusión y valoración de los síntomas, para obtener datos más concluyentes.(AU)

Introduction: Several studies have shown that preparations based on the rhizomes and roots of black cohosh (Cimicifuga racemosa (L.) Nutt.) can be useful in alleviating the menopausal symptoms. The aim of this study is to perform an update bibliographic review of the efficacy and safety of black cohosh in the treatment of the vasomotor symptoms of menopause. Method: A review of published articles from January 2005 to March 2021 in the resource search engine of the University of La Laguna, el punto Q”. Randomized and controlled clinical trials, which had the key words in the abstract, text or title, in both English and Spanish, were selected.Results:We found 13 trials which met the selection criteria. The studies reviewed showed that the black cohosh preparations (mainly commercial extracts standardized in their content of active ingredients) produced in most of the studies a significant reduction compared to placebo in the vegetative (hot flashes and night sweats) and psychological symptoms of menopause, as well as an improvement in the quality of life. No serious adverse effects were reported at the dose administered. Conclusions: Cimicifuga racemosa extracts can be effective and safe for the treatment of vegetative and psychological symptoms of menopause, being well tolerated. However, more clinical trials with a larger number of patients, more extensive, the use of standardized preparations, as well as similar criteria for inclusion and assessment of symptoms, are necessary to obtain more conclusive data.(AU)

Physiological Concentrations of Cimicifuga racemosa Extract Do Not Affect Expression of Genes Involved in Estrogen Biosynthesis and Action in Endometrial and Ovarian Cell Lines.

In postmenopausal women, estrogen levels exclusively depend on local formation from the steroid precursors dehydroepiandrosterone sulfate and estrone sulfate (E1-S). Reduced estrogen levels are associated with menopausal symptoms. To mitigate these symptoms, more women nowadays choose medicine of natural origin, e.g., Cimicifuga racemosa (CR), instead of hormone replacement therapy, which is associated with an increased risk of breast cancer, stroke, and pulmonary embolism. Although CR treatment is considered safe, little is known about its effects on healthy endometrial and ovarian tissue and hormone-dependent malignancies, e.g., endometrial and ovarian cancers that arise during menopause. The aim of our study was to examine the effects of CR on the expression of genes encoding E1-S transporters and estrogen-related enzymes in control and cancerous endometrial and ovarian cell lines. CR affected the expression of genes encoding E1-S transporters and estrogen-related enzymes only at very high concentrations, whereas no changes were observed at physiological concentrations of CR. This suggests that CR does not exert estrogenic effects in endometrial and ovarian tissues and probably does not affect postmenopausal women's risks of endometrial or ovarian cancer or the outcomes of endometrial and ovarian cancer patients.

Black cohosh efficacy and safety for menopausal symptoms. The Spanish Menopause Society statement.

OBJECTIVE: The increasing interest in Western countries regarding phytotherapy use to treat menopause-related symptoms has led the Spanish Menopause Society (AEEM) to update its position statement performed in 2009 on the role of black cohosh (Cimicifuga racemosa) for the treatment of menopausal symptoms. MATERIAL AND METHODS: A panel of experts from both clinical and research backgrounds were assembled to investigate the best available evidence. Selected studies were obtained by an electronic search, including the Internet search engines MEDLINE-Pubmed (1997-December 2021) and the Cochrane Controlled Trials Register. RESULTS: Most of the well-designed studies published in recent years have been conducted with the isopropanolic extract of black cohosh/C. racemosa. The most common dose is 40 mg/day capable of achieving a significant reduction in hot flushes (particularly in women with intense hot flushes) and an improvement in mood. Used at the recommended doses, C. racemose produces no significant adverse reactions. CONCLUSION: Black cohosh is an effective and safe treatment option for the relieving of vasomotor symptoms. Finally, further clinical trials with sufficient patient enrollment and longer study follow-up are needed.

Treat more than heat-New therapeutic implications of Cimicifuga racemosa through AMPK-dependent metabolic effects.

BACKGROUND: Cimicifuga racemosa extracts (CRE) have obtained a "well-established use status" in the treatment of postmenopausal (i.e., climacteric) complaints, which predominantly include vasomotor symptoms such as hot flushes and sweating, as well as nervousness, irritability, and metabolic changes. Although characteristic postmenopausal complaints are known for a very long time and the beneficial effects of CRE on climacteric symptoms are well accepted, both the pathophysiology of postmenopausal symptoms and the mechanism of action of CREs are not yet fully understood. In particular, current hypotheses suggest that changes in the α-adrenergic and serotonergic signaling pathways secondary to estrogen depletion are responsible for the development of hot flushes. PURPOSE: Some of the symptoms associated with menopause cannot be explained by these hypotheses. Therefore, we attempted to extend our classic understanding of menopause by integrating of partly age-related metabolic impairments. METHODS: A comprehensive literature survey was performed using the PubMed database for articles published through September 2021. The following search terms were used: (cimicifuga OR AMPK) AND (hot flush* OR hot flash* OR menopaus* OR osteoporos* OR cancer OR antioxida* OR cardiovasc*). No limits were set with respect to language, and the references cited in the articles retrieved were used to identify additional publications. RESULTS: We found that menopause is a manifestation of the general aging process, with specific metabolic changes that aggravate menopausal symptoms, which are accelerated by estrogen depletion and associated neurotransmitter dysregulation. Cimicifuga extracts with their metabolic effects mitigate climacteric symptoms but may also modulate the aging process itself. Central to these effects are effects of CRE on the metabolic key regulator, the AMP-activated protein kinase (AMPK). CONCLUSIONS: As an extension of this effect dimension, other off-label indications may appear attractive in the sense of repurposing of this herbal treatment.

Systematic Review of Black Cohosh (Cimicifuga racemosa) for Management of Polycystic Ovary Syndrome-Related Infertility.

Polycystic ovary syndrome (PCOS) is a common cause of female infertility. To conduct a systematic review assessing the efficacy and safety of black cohosh for ovulation-induction through hormone regulation and increased endometrial thickness to improve pregnancy rates in women with PCOS-related infertility. Preferred Reporting Items for Systematic Reviews and Meta-Analyses was used. A search of Medline, Embase, International Pharmaceutical Abstracts, Science Direct, and Cumulative Index of Nursing and Allied Health Literature spanning origin to December 19, 2020 was conducted using keywords and permutations of "black cohosh" and "PCOS." A search for "PCOS" in the National Clinical Trials database and International Clinical Trials Registry Platform was conducted in December 2020 to identify additional records. Eligibility criteria included reported efficacy or safety outcomes; studies in women with PCOS; English language; and primary literature. Eligible records were evaluated using applicable risk-of-bias tools. A total of 181 records were screened after deduplication from 207 results. Two randomized controlled trials (RCT) met inclusion criteria. Review of 1386 records from clinical trial registries and subsequent scoping searches resulted in identification of 4 additional records (3 published). Improvement in hormone regulation and endometrial thickness were found for black cohosh groups compared to clomiphene citrate (CC). Three RCTs reported improved pregnancy rates using black cohosh plus CC. There were no differences in adverse events. Studies demonstrated several risk-of-bias concerns. There is a lack of high-quality evidence supporting the effectiveness of black cohosh for improving pregnancy rates in PCOS-related infertility. Short-term use of black cohosh appears to be safe.

Weight gain in menopause: systematic review of adverse events in women treated with black cohosh.

Weight gain is a frequent problem in perimenopausal and postmenopausal women. Cimicifuga racemosa (CR) is a popular treatment option for menopausal symptoms. The aim of this review was to investigate whether there is scientific evidence that CR causes weight gain. We searched our database for medically confirmed, spontaneous adverse events regarding weight gain, literature for case reports and randomized controlled trials. Thirty cases in total were spontaneously reported in 15 years. The causality was not considered certain/likely in any of the cases. A nurse (consumer) assessed the causality as possible. Only one case was published in the literature. However, no change in body fat composition was reported, and the causality seems unlikely. Of the 31 identified studies, 17 were double-blind placebo-controlled, five were double-blind reference-controlled and nine were open reference-controlled. In total, 1839 women were treated with CR for up to 12 months. Two studies reported weight gain as an adverse event; however, no significant differences in weight changes were observed between the groups. One case of weight gain (about 2 kg) was reported, but the authors did not specify in which treatment group. In conclusion, this study provides no scientific evidence that the use of Cimicifuga racemosa causes weight gain in menopausal women.

Gene expression analyses on multi-target mode of action of black cohosh in menopausal complaints - a pilot study in rodents.

PURPOSE: This study aimed at assessing gene expression profiles in hippocampus and hypothalamus of ovariectomized (OVX) rats with or without treatment with an isopropanolic extract of Cimicifuga racemosa rhizomes (iCR) in comparison to intact rats. METHODS: Exploration of hippocampal (Hi) and hypothalamic (Hy) tissue from Sprague Dawley rats: without OVX (NHi = NHy = 4), tissues 3 months after OVX (NHi = 4, NHy = 3), or tissues of rats after their treatment with iCR for 3 months after OVX (NHi = NHy = 2). Gene expression profiles in these tissues were investigated by RNA-microarray-analysis and subsequent verification by qPCR. RESULTS: 4812 genes were differentially regulated when comparing the three groups in hippocampus and hypothalamus. iCR compensated the effects of OVX in 518 genes. This compensatory effect was most prominent in hippocampal signalling pathways, thereof genes (GAL, CALCA, HCRT, AVPR1A, PNOC, etc.) involved in thermoregulation, regulation of sleep and arousal, blood pressure regulation, metabolism, nociception, hormonal regulation, homeostasis, learning and cognition, mood regulation, neuroendocrine modulation, etc.. In the hypothalamus, iCR compensated OVX-effects at TAC3 and OPRM1 but not at KISS1. These genes are involved in the pathophysiology of hot flashes. CONCLUSIONS: Our pilot study findings support a multifaceted mode of action of iCR in menopausal complaints on a tissue-specific brain gene expression level.

Cimicifuga racemosa Extract Ze 450 Re-Balances Energy Metabolism and Promotes Longevity.

Recently, we reported that the Cimicifuga racemosa extract Ze 450 mediated protection from oxidative cell damage through a metabolic shift from oxidative phosphorylation to glycolysis. Here, we investigated the molecular mechanisms underlying the effects of Ze 450 against ferroptosis in neuronal cells, with a particular focus on mitochondria. The effects of Ze 450 on respiratory complex activity and hallmarks of ferroptosis were studied in isolated mitochondria and in cultured neuronal cells, respectively. In addition, Caenorhabditis elegans served as a model organism to study mitochondrial damage and longevity in vivo. We found that Ze 450 directly inhibited complex I activity in mitochondria and enhanced the metabolic shift towards glycolysis via cMyc and HIF1α regulation. The protective effects against ferroptosis were mediated independently of estrogen receptor activation and were distinct from effects exerted by metformin. In vivo, Ze 450 protected C. elegans from the mitochondrial toxin paraquat and promoted longevity in a dose-dependent manner. In conclusion, Ze 450 mediated a metabolic shift to glycolysis via direct effects on mitochondria and altered cell signaling, thereby promoting sustained cellular resilience to oxidative stress in vitro and in vivo.

Ethnobotany, Phytochemistry, Traditional and Modern Uses of Actaea racemosa L. (Black cohosh): A Review.

Actaea racemosa (AR) also known as Cimicifuga racemosa, is a perennial plant from Ranunculaceae family which was used as traditional remedies in treatment of various condition like rheumatoid muscular pain, headache, inflammation and dysmenorrhea. Actaea racemosa was basically native to Canada and the Eastern United State. This chapter proposed the ethnopharmacological uses of Actaea racemosa, and its phytochemical properties. Specifically, in this article we focused on use of Actaea racemose for menopausal and post-menopausal symptoms management. Electronic databases including PubMed and Scopus were searched for studies on Actaea racemose and its administration in management of menopausal symptoms. Chem Office software was also used in order to find chemical structures. The key words used as search terms were Cimicifuga racemose, Actaea racemose, Ranunculaceae, Black cohosh, Menopausal symptoms. We have included all relevant animal and human studies up to the date of publication. The analysis on Actaea racemose showed various indications for different plant's extracts. Approximately 131 chemical compounds have been isolated and identified from Actaea racemosa. According to recently studies, the most important chemicals known of the Actaea racemosa are phenolic compounds, chromones, triterpenoids, nitrogen-containing constituents. In addition, in vivo and in vitro studies reported wide range of pharmacological activities for Black cohosh like attenuating menopausal symptoms. Mechanism of action for some ethnomedicinal indications were made clear while some of its activities are not confirmed by pharmacological studies yet. Further investigations on its pharmacological properties are necessary to expand its clinical effective use. Also, additional large clinical trials are recommended for clarifying the effect of Black cohosh.

GnRH-a-Induced Perimenopausal Rat Modeling and Black Cohosh Preparations' Effect on Rat's Reproductive Endocrine.

Background: Endometriosis (EMS) is an estrogen-dependent disease, which easily recurs after operation. Gonadotropin-releasing hormone agonist (GnRH-a), an estrogen-inhibiting drug, can effectively inhibit the secretion of gonadotropin by pituitary gland, so as to significantly decrease the ovarian hormone level and facilitate the atrophy of ectopic endometrium, playing a positive role in preventing postoperative recurrence. The application of GnRH-a can lead to the secondary low estrogen symptoms, namely the perimenopausal symptoms, and is a main reason for patients to give up further treatment. The add-back therapy based on sex hormones can well address the perimenopausal symptoms, but long-term use of hormones may cause the recurrence of EMS, as well as liver function damage, venous embolism, breast cancer and other risks, which has long been a heated topic in the industry. Therefore, it is necessary to find effective and safe anti-additive drugs soon. Studies at home and abroad show that, as a plant extract, isopropanolic extract of cimicifuga racemosa (ICR) can well relieve the perimenopausal symptoms caused by natural menopause. Some studies have preliminarily confirmed that black cohosh preparations can antagonize perimenopausal symptoms of EMS patients treated with GnRH-a after operation. Objective: To establish a rat model of perimenopausal symptoms induced by GnRH-a injection, for the purposes of laying a foundation for further research and preliminarily exploring the effect of black cohosh preparations on reproductive endocrine of the rat model. Method: The rat model of perimenopausal symptoms was established by GnRH-a injection, and normal saline (NS injection) was used as the control. The rats were randomly divided into four groups according to different modeling methods and drug intervention schemes. GnRH-a injection + normal saline intervention group (GnRH-a + NS), normal saline injection control + normal saline intervention group (NS + NS), GnRH-a injection + estradiol intervention group (GnRH-a + E2), and GnRH-a injection + black cohosh preparations intervention group (GnRH-a + ICR). After modelling was assessed to be successful with the vaginal smear method, the corresponding drugs were given for intervention for 28d. In the process of rat modeling and drug intervention, the skin temperature and anus temperature of the rat tails were measured every other day, the body weights of the rats were measured every other day, and the dosage was adjusted according to the body weight. After the intervention was over, the serum sex hormone level, the uterine weight, the uterine index, and the endometrial histomorphology changes, as well as the ovarian weight, the ovarian index, and the morphological changes of ovarian tissues of each group were measured. Results: (1) The vaginal cell smears of the control group (NS + NS) showed estrous cycle changes, while other model rats had no estrous cycle of vaginal cells. (2) The body weight gains of the GnRH-a + NS, GnRH-a + E2 and GnRH-a + ICR groups were significantly higher than that of the NS + NS control group. The intervention with E2 and ICR could delay the weight gain trend of rats induced by GnRH-A. (3) After GnRH-a injection, the temperature of the tail and anus of rats showed an overall upward trend, and the intervention with E2 and ICR could effectively improve such temperature change. (4) The E2, FSH, and LH levels in the GnRH-a + NS, GnRH-a + E2, and GnRH-a + ICR groups were significantly lower than those in the NS + NS group (P < 0.01). The E2 level was significantly higher and the LH level was significantly lower in the GnRH-a + E2 group than those in the GnRH-a + NS and GnRH-a + ICR groups (P < 0.05). Compared with those of the GnRH-a + NS and GnRH-a + ICR groups, the FSH level of the GnRH-a + E2 group showed a slight downward trend, but the difference was not statistically significant (P > 0.05). There was no significant difference in the levels of sex hormones between the GnRH-a + NS group and GnRH-a + ICR group (P > 0.05). (5) Compared with those of the NS + NS group, the uterine weight and uterine index of the GnRH-a + NS, GnRH-a + E2 and GnRH-a + ICR groups significantly decreased (P < 0.01). In a comparison between the groups, the uterine weight and uterine index in the GnRH-a + NS and GnRH-a + ICR groups were significantly lower than those in the GnRH-a + E2 group (P < 0.01). There was a statistical difference in the uterine weight and uterine index between the GnRH-a + NS group and GnRH-a + ICR group (P > 0.05). (6) Compared with those of the NS + NS group, the ovarian weight and ovarian index of the GnRH-a + NS, GnRH-a + E2 and GnRH-a + ICR groups significantly decreased (P < 0.01). There was no statistical difference in the ovarian weight and ovarian index among the GnRH-a + E2, GnRH-a + NS and GnRH-a + ICR groups (P > 0.05). (7) Compared with those in the NS + NS group, the number of primordial follicles increased significantly, while the number of growing follicles and mature follicles decreased significantly in the GnRH-a + NS, GnRH-a + E2, and GnRH-a + ICR groups (P < 0.01), but there was a statistical difference in the total number of follicles among the four groups (P > 0.05). Conclusions: The GnRH-a injection could achieve the desired effect. The animal model successfully achieved a significant decrease in the E2, FSH, and LH levels in rats, and could cause the rats to have rising body surface temperature similar to hot flashes in the perimenopausal period. The intervention with E2 and ICR could effectively relieve such "perimenopausal symptoms", and ICR had no obvious effect on the serum sex hormone level in rats.

Multimodal Care for Headaches, Lumbopelvic Pain, and Dysmenorrhea in a Woman With Endometriosis: A Case Report.

Objective: The purpose of this case report is to describe the conservative management of a patient with headaches, lumbopelvic pain, and dysmenorrhea. Clinical Features: A 36-year-old woman presented with intense pelvic and daily lumbar pain. She had difficulty sleeping and focusing and had 3 to 4 headaches per week. Before, during, or after her menses, she would have migraine headaches. During her menses, she experienced severe lumbopelvic pain and dysmenorrhea with moderate bloating, constipation, nausea, and diarrhea. When she was 32 years old, her gynecologist diagnosed endometriosis and prescribed nonsteroidal anti-inflammatory drugs and hormonal oral contraceptives, which failed to alleviate her symptoms. She sought an alternative approach to help control her symptoms. Intervention and Outcome: A multimodal approach was selected for this patient, which consisted of acupuncture combined with supplements of magnesium citrate, B-100 complex and botanicals turmeric (Curcuma longa/root extract), bromelain (Ananas comosus [pineapple stem]) and black cohosh (Cimicifuga racemosa). After an initial trial of care, her daily lumbopelvic pain was reduced, and she was sleeping better and feeling more focused and less fatigued. She rarely had tension headaches during the week or migraine headaches or dysmenorrhea before, during, or after menses. Her lumbopelvic pain and gastrointestinal symptoms were reduced. Conclusion: A patient who was experiencing headaches, lumbopelvic pain, and dysmenorrhea responded favorably to a course of care that included a combination of botanicals, supplements, and acupuncture.

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

A systematic literature search revealed 35 clinical studies and one meta-analysis comprising 43,759 women, of which 13,096 were treated with isopropanolic Cimicifuga racemosa extract (iCR). Compared to placebo, iCR was significantly superior for treating neurovegetative and psychological menopausal symptoms, with a standardized mean difference of -0.694 in favor of iCR (p < 0.0001). Effect sizes were larger when higher dosages of iCR as monotherapy or in combination with St. John's wort (Hypericum perforatum [HP]) were given (-1.020 and -0.999, respectively), suggesting a dose-dependency. For psychological symptoms, the iCR+HP combination was superior to iCR monotherapy. Efficacy of iCR was comparable to low-dose transdermal estradiol or tibolone. Yet, due to its better tolerability, iCR had a significantly better benefit-risk profile than tibolone. Treatment with iCR/iCR+HP was well tolerated with few minor adverse events, with a frequency comparable to placebo. The clinical data did not reveal any evidence of hepatotoxicity. Hormone levels remained unchanged and estrogen-sensitive tissues (e.g. breast, endometrium) were unaffected by iCR treatment. As benefits clearly outweigh risks, iCR/iCR+HP should be recommended as an evidence-based treatment option for natural climacteric symptoms. With its good safety profile in general and at estrogen-sensitive organs, iCR as a non-hormonal herbal therapy can also be used in patients with hormone-dependent diseases who suffer from iatrogenic climacteric symptoms.

Structure-Guided Identification of Black Cohosh (Actaea racemosa) Triterpenoids with In Vitro Activity against Multiple Myeloma.

Black cohosh is a well-established medicinal plant and preparations of its rootstock are used for the treatment of mild climacteric complaints. The compounds considered responsible for the therapeutic effect are triterpene glycosides, characterized by a cycloartane scaffold and a pentose moiety. Because some of these triterpenoids were found to exhibit relevant cytotoxic effects against human breast cancer cells, we decided to investigate their activity on multiple myeloma cell lines NCI-H929, OPM-2, and U266. In a systematic approach, we initially tested three known cytotoxic compounds of three different triterpenoid types, revealing the cimigenol-type triterpenoid as the most active constituent. In a second round, seven naturally occurring cimigenol derivatives were compared with respect to their sugar moiety and their substitution pattern at position C-25, leading to 25-O-methylcimigenol-3-O-α-L-arabinopyranoside as the most potent candidate. Interestingly, not only the methyl group at position C-25 increased the cytotoxic effect but also the arabinose moiety at position C-3 had an impact on the activity. The variety of cimigenol derivatives, moreover, allowed a detailed discussion of their structure-activity relationships, not only for their effect on multiple myeloma cells but also with regard to previous studies on the cytotoxicity of black cohosh triterpenoids.

Effect of CIMicifuga racemosa on metaBOLIC parameters in women with menopausal symptoms: a retrospective observational study (CIMBOLIC).

PURPOSE: To compare the influence of Cimicifuga racemosa extract (CR, Ze 450) and menopausal hormone therapy (MHT) on metabolic parameters and body weight in symptomatic menopausal women. METHODS: In this monocentric retrospective cohort study, women over 40 years old with a first consultation between 2009 and 2016 were screened. Included in the final analysis were women treated with either MHT or CR and having at least one follow-up consultation. Metabolic serum parameters (lipids, glucose, insulin, and HOMA-IR), body weight, and menopausal symptoms [Menopause Rating Scale (MRS)-II] were the main outcome measures. Statistical analysis by uni- and multi-variable linear mixed-effects regression models assuming a linear effect of time. RESULTS: 174 women were included in the final analysis (CR n = 32, MHT n = 142). There was no difference between the groups regarding baseline characteristics (age, BMI, serum metabolic parameters, hormones, and blood pressure) and total MRS-II score, while reproductive stage differed significantly with more postmenopausal women treated with CR (83%) than MHT (55%) (p = 0.038). Median follow-up time was 12 months. In both groups, metabolic serum parameters and body weight did not change over the follow-up period, while total and MRS-II subscores improved. CONCLUSION: Menopausal symptoms improved significantly in both groups (MHT and CR), while serum metabolic parameters and body weight did not change in MHT- or CR-treated women.

Effectiveness of the short-term use of Cimicifuga racemosa in the endothelial function of postmenopausal women: a double-blind, randomized, controlled trial.

Objective: This study aimed to assess the effects of daily use of Cimicifuga racemosa on endothelial function through flow-mediated dilation of the brachial artery, when used for 28 days by healthy postmenopausal women.Methods: The double-blind, randomized, placebo-controlled study included two groups of postmenopausal women (n = 31 each). The subjects were clinically assessed and flow-mediated dilation of the brachial artery was measured before and after 28 days of treatment. Patients received dry extract corresponding to 160 mg C. racemosa (extract with 4 mg of triterpene glycosides) or placebo.Results: Mean age, time since menopause, and body mass index in the two groups were similar. The measurements of flow-mediated dilation of the brachial artery, pre and post treatment, respectively, showed a significant increase in patients who used C. racemosa (p = 0.006), unlike patients who used placebo, who did not present changes in the outcome of flow-mediated dilation of the brachial artery after 28 days of use (p ≥ 0.05). When comparing the number of women in both groups who showed an increase in flow-mediated dilation, a significant difference was found in the measurements of the treated group after the use of the medication (p = 0.018).Conclusions: Daily use of 160 mg C. racemosa extract by postmenopausal women for 28 days beneficially influences endothelial function by promoting elasticity of the brachial artery.

Effect of cimicifuga racemosa on menopausal syndrome caused by LHRH-a in breast cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: Cimicifuga racemose is previously proved effective on nature menopausal syndrome (MPS). However, its clinical value in treating with MPS induced by luteinizing-hormone releasing hormone analogue (LHRH-a) therapy of pre-/peri-menopausal breast cancer patients is still unknown. AIM OF STUDY: This perspective randomised-design study is to investigate the effect and safety of cimicifuga racemosa on MPS induced by LHRH-a in breast cancer (clinical trial registered: NCT03339882). MATERIALS AND METHODS: Breast cancer patients planning for LHRH-a treatment were randomly divided into 2 groups. The control group which was being treated with the standard treatment of LHRH-a. The other group was being treated with Remifemin, the commercialized product of cimicifuga racemose extract, combined with LHRH-a, called Remifemin group. Our main endpoint was Kupperman menopause index (KMI). Hormone levels in peripheral blood and gynecological complications were also evaluated. RESULTS: Totally, 85 patients (42 in Remifemin group and 43 in control group) were enrolled in Zhejiang Cancer Hospital. At the 4th, 8th and 12th week after using LHRH-a, the KMI were all significantly lower in Remifemin group than in control group (P < 0.01), while the hormone levels, including estradiol (E2), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were similar in the two groups. In addition, the incidence of cervical cyst in Remifemin group was higher than that in control group (P = 0.02), and there was no significant difference in the other gynecological complications, including endometrial thickening, ovarian cyst or uterine fibroid (P > 0.05). CONCLUSIONS: Cimicifuga racemose is effective, oncological safe and reliable for treatment of MPS caused by LHRH-a in breast cancer.