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Siberian rhubarb root
Rheum rhaponticum (ERr 731®) dry root extract
Action
- Oestrogen receptor beta (ERβ) agonist
Clinical Applications
- Reduces eight common symptoms of menopause:
- Vasomotor symptoms (VMS); hot flushes and night sweats
- Irritability and mood swings
- Sleep disturbances and insomnia
- Fatigue and weakness
- Low libido
- Sexual dysfunction
- Vaginal dryness
- Muscular aches and mild joint pain
- Supports general health and emotional wellbeing in perimenopause
Introduction
Perimenopause typically occurs between the ages of 45 to 55 and bridges the transition from reproductive years to menopause. During this time ovarian function declines, triggering compensatory hormonal fluctuations and ultimately the cessation of ovarian hormone synthesis and output. The resulting menopausal symptoms are mainly related to the systemic loss of ovarian oestrogen.[2–4]
Up to 80% of Australian women report characteristic hot flushes, or vasomotor symptoms (VMS), alongside a constellation of menopause-associated symptoms that commonly impact their health, wellbeing and quality of life.[2,5] Furthermore, over 85% of women experiencing symptoms remain medically untreated, often due to contraindications or aversion to hormonal therapies.[6]
The standardised extract ERr 731®, sourced from the root of Rheum rhaponticum (Siberian rhubarb), is a non-hormonal compound that acts selectively on oestrogen receptors to enable menopausal symptom relief without elevating oestrogen levels.[7] ERr 731® has been used throughout Europe since the 1950s and internationally recognised since 2010 for its ability to provide relief of menopausal symptoms.[8,9] Scientific clinical trials have confirmed that ERr 731® significantly and safely relieves eight core menopausal symptoms.[7,10–15] A recent meta-analysis and systematic review elevates the evidence for its efficacy, safety and tolerability in reducing the severity of menopausal symptoms compared to placebo.[9]
Figure 1: Menopausal symptoms shown to be relieved by 4 mg/day ERr 731® within 12 weeks.[9]
Background Information
Up to 25% of Australian women transition perimenopause with scarcely a sign, yet the remaining 75% experience widespread and potentially debilitating symptoms.[6] The most common symptoms women seek treatment for are VMS, being hot flushes and/or night sweats. These present as episodes of unexpected sensations of heat, sweating, flushing, anxiety and chills, lasting for up to five minutes. Flushing gradually increases in frequency and severity to peak approximately one year after the final menstrual period. These VMS may persist for around six months, yet up to 40% of women may report flushing for over a decade.[5,16] Although multiple mechanisms contribute to this abnormal vasodilatory response to minor elevations of core body temperature, oestrogen deficiency plays a cardinal role.[16]
The oestrogen deficiency of menopause has widespread effects, also being linked with sleep disturbances, anxiety and the genitourinary syndrome of menopause (GSM), which features vaginal dryness, dyspareunia (painful intercourse) and low libido.[16,17] Moreover, the perimenopausal fluctuations in oestrogen and progesterone play a pivotal role in musculoskeletal pain and joint stiffness.[18]
Actions
Oestrogen Receptor Beta (ERβ) Agonist
Oestrogen is a master regulator throughout the body, functioning through a network of
nuclear oestrogen receptors (ER) alpha (ERα) and beta (ERβ) to initiate complex and
interrelated functions throughout the reproductive, cardiovascular, musculoskeletal, and
nervous systems.[19] Whilst these receptors occur together, ERα mediates classic oestrogen activity, including developmental growth and pregnancy, especially influencing the uterus and breast. ERβ, however, modulates oestrogen signalling and can regulate ERα activity.[20,21]
Excessive hormonal activation of ERα can cause safety concerns related to inflammatory
and proliferative activity in oestrogen-sensitive tissues such as the breast and uterus.
[11,22,23] On the other hand, activation of ERβ promotes anti-inflammatory processes
and down-regulates ERα expression to balance these effects.[24]
ERr 731® is a standardised extract of Rheum rhaponticum root, containing active
constituents including rhaponticin, which has a high affinity for ERβ, without ERα activation(Figure 2).[9] ERr 731® is shown to be up to 30 times more selective for ERβ activation than the soy isoflavone, genestien.[21] This heightened affinity for ERβ helps alleviate menopausal symptoms throughout the body, whilst down-regulating ERα activity to protect oestrogen-sensitive tissues from inflammation and hyperplasia.[21]
Figure 2: Oestrogen binds to both ERα and ERβ, whereas ERr 731® selectively binds to ERβ, which is shown to alleviate menopausal symptoms and protect oestrogen sensitive tissues.[21]
Clinical Applications
Reduces Eight Common Symptoms of Menopause
In a randomised, double-blind, placebo-controlled trial, 109 symptomatic perimenopausal women were assigned either a daily dose of 4 mg ERr 731® or placebo for 12 weeks.[7] Within four weeks, the number and severity of hot flushes had significantly reduced (p<0.0001) in the treatment group. By 12 weeks ERr 731® had significantly decreased hot flushes, sleep disturbances, irritability, joint and muscle complaints, low libido, vaginal dryness and fatigue, compared to placebo (p<0.0001;Figure 3).
Figure 3: ERr 731® significantly reduced menopause symptoms in 12 weeks.[7]
Supports Emotional Wellbeing in Perimenopause
Retrospectively, analysis of the previous study investigated the correlation between hot
flushes and mood, specifically anxiety.[13] At baseline, moderate to severe symptoms of
anxiety were evident in most of the 109 participants, as scored on the Hamilton Anxiety
Scale (HAM-A). Within just four weeks, those taking ERr 731® significantly decreased
anxiety symptoms, (p<0.0001) which continued to improve over the course of the 12 weeks. Overall HAM-A scores reduced in the ERr 731® group from 27.5 to 9.4 compared with no change in the placebo group (Figure 4).
Figure 4: ERr 731® effectively reduced anxiety scores.[4]
Furthermore, reduced anxiety correlated with a mean reduction of VSM from (mean) 16.7 hot flushes daily to 3.3 episodes daily after 12 weeks. These benefits notably improved women’s quality of life and wellbeing.[12]
Figure 5: ERr 731® significantly reduced anxiety and hot flushes in 12 weeks.[12]
An ongoing observational study has confirmed the benefits of continuous ERr 731® dosing up to two years.[9] Following on from the previous twelve-week trial, 80 women, from either the placebo or ERr 731® study groups, entered an observational study (OS) taking 4 mg/day of ERr 731® for a further 48 weeks (OS I). Then, after assessment, 51 women went on to complete a further 48 weeks of supplementation in OS II. (Figure 6)
All participants experienced continuous and sustained symptom reduction. By the end of the study, hot flushes had reduced to (mean) 1.4 mild episodes daily alongside an overall 83% reduction of symptoms, as measured on the Menopausal Rating Scale II (MRS II). What's more, these women manifested no adverse changes in gynaecological health, such as endometrial hyperplasia or breast tissue abnormalities. These results find that ERr 731® is efficacious, safe and well-tolerated for longer term support for perimenopausal women.
Figure 6: Clinically proven to deliver sustained relief for up to 2 years with no change in safety parameters.[9]
In 2023, Metagenics independently conducted an online Patient Satisfaction Survey after women had supplemented with Rheum rhaponticum root (ERr 731®) for Menopause Symptom Relief for 12 weeks.[24] Results from 424 respondents reflected similar outcomes from scientific clinical trials, with 91% of women reporting improved hot flushing, 70% with less sleep disruption and 95% noticing mood improvements upon adding ERr 731® to their daily routine.
Safety Established for ERr 731® to Manage Menopausal Symptoms
The use of ERr 731® is well-tolerated in clinical trials over 12 weeks to two years.[6,8–10,13,22] Published post-marketing surveillance data over 20 years, from 153 million doses sold since 1993, suggests ERr 731® is generally well tolerated and safe.[7] Furthermore, a six-month observational trial reported efficacy, safety, and tolerability with high patient satisfaction, as 90% of participants wished to continue with ERr 731®.[11]
Safety Information
Disclaimer: In the interest of supporting health Practitioners, all safety information provided at the time of publishing (Jan 2025) is in accordance with Natural Medicine Database (NATMED PRO), renowned for its professional monographs which include a thorough assessment of safety, warnings, and adverse effects. For further information on specific interactions with health conditions and medications, refer to clinical support at 1800 777 648, or via email, anz_clinicalsupport@metagenics.com.
Pregnancy: Unsuitable during pregnancy. Safety has not been conclusively established.
Breastfeeding: Unsuitable during breastfeeding. Safety has not been conclusively established.
Cautions:
- Digoxin - Theoretically, overuse of rhubarb might increase the risk of adverse effects when taken with digoxin.
- Hepatotoxic drugs - Theoretically, concomitant use of rhubarb with potentially hepatotoxic drugs might increase the risk of developing liver damage.
- Nephrotoxic drugs - Theoretically, long-term use of anthraquinones from rhubarb might increase the risk of nephrotoxicity when used with nephrotoxic drugs.
- Warfarin - Theoretically, excessive use of rhubarb might increase the risk of bleeding when taken with warfarin.[1]
Contraindications:
- Hepatic - Orally, chronic use of anthraquinone-containing products, such as rhubarb, has been associated with hepatotoxicity.
- Renal - Orally, chronic use or abuse of rhubarb can cause electrolyte loss (especially potassium), albuminuria, hematuria, dehydration, and nephropathies.
References:
[1] Database NM. Estrovera by Metagenics. Published 2025. https://naturalmedicines.therapeuticresearch.com/databases/commercial-products/commercial-product.aspx?cpid=26851
[2] Santoro N, Roeca C, Peters BA, Neal-Perry G. The menopause transition: signs, symptoms, and management options. J Clin Endocrinol Metab. 2020;106(1):1-15. doi:10.1210/clinem/dgaa764
[3] Talaulikar V. Menopause transition: physiology and symptoms. Best Pr Res Clin Obstet Gynaecol. 2022;81:3-7. doi:10.1016/j.bpobgyn.2022.03.003
[4] Monteleone P, Mascagni G, Giannini A, Genazzani AR, Simoncini T. Symptoms of menopause — global prevalence, physiology and implications. Nat Rev Endocrinol. 2018;14(4):199-215. doi:10.1038/nrendo.2017.180
[5] Gartoulla P, Worsley R, Bell RJ, Davis SR. Moderate to severe vasomotor and sexual symptoms remain problematic for women aged 60 to 65 years. Menopause. 2018;25(11):1331-1338. doi:10.1097/gme.0000000000001237
[6] Davis SR, Magraith K. Advancing menopause care in Australia: barriers and opportunities. Méd J Aust. 2023;218(11):500-502. doi:10.5694/mja2.51981
[7] Heger M, Ventskovskiy BM, Borzenko I, Kneis KC, Rettenberger R, Kaszkin-Bettag M, et al. Efficacy and safety of a special extract of Rheum rhaponticum (ERr 731) in perimenopausal women with climacteric complaints. Menopause. 2006;13(5):744-759. doi:10.1097/01.gme.0000240632.08182.e4
[8] Chang JL, Montalto MB, Heger PW, Thiemann E, Rettenberger R, Wacker J. Rheum rhaponticum extract (ERr 731): postmarketing data on safety surveillance and consumer complaints. Integr Medicine Encinitas Calif. 2016;15(3):34-39. Accessed 13th December 2024. Available at: Rheum rhaponticum Extract (ERr 731): Postmarketing Data on Safety Surveillance and Consumer Complaints - PubMed
[9] Dubey VP, Sureja VP, Kheni DB. Efficacy evaluation of standardized Rheum rhaponticum root extract (ERr 731®) on symptoms of menopause: A systematic review and meta-analysis study. J Biomed Res. 2024;38(3):278-286. doi:10.7555/jbr.37.20230219
[10] Hasper I, Ventskovskiy BM, Rettenberger R, Heger PW, Riley DS, Kaszkin-Bettag M. Long-term efficacy and safety of the special extract ERr 731 of Rheum rhaponticum in perimenopausal women with menopausal symptoms. Menopause. 2009;16(1):117-131. doi:10.1097/gme.0b013e3181806446
[11] Kaszkin-Bettag M, Ventskovskiy BM, Solskyy S, Beck S, Hasper I, Kravchenko A, et al. Confirmation of the efficacy of ERr 731 in perimenopausal women with menopausal symptoms. Altern Ther Health M. 2009;15(1):24-34. Accessed 13th December 2024. Available at: Confirmation of the efficacy of ERr 731 in perimenopausal women with menopausal symptoms - PubMed
[12] Kaszkin-Bettag M, Beck S, Richardson A, Heger PW, Beer AM. Efficacy of the special extract ERr 731 from rhapontic rhubarb for menopausal complaints: a 6-month open observational study. Altern Ther Health M. 2008;14(6):32-38. Accessed 13th December 2024. Available at: Efficacy of the special extract ERr 731 from rhapontic rhubarb for menopausal complaints: a 6-month open observational study - PubMed
[13] Kaszkin-Bettag M, Ventskovskiy BM, Kravchenko A, Rettenberger R, Richardson A, Heger PW, et al. The special extract ERr 731 of the roots of Rheum rhaponticum decreases anxiety and improves health state and general well-being in perimenopausal women. Menopause. 2007;14(2):270-283. doi:10.1097/01.gme.0000251932.48426.35
[14] Keiler AM, Papke A, Kretzschmar G, Zierau O, Vollmer G. Long-term effects of the rhapontic rhubarb extract ERr 731® on estrogen-regulated targets in the uterus and on the bone in ovariectomized rats. J Steroid Biochem Mol Biology. 2012;128(1-2):62-68. doi:10.1016/j.jsbmb.2011.08.016
[15] Shah J, Chandanani S, Reddy J, Kirubamani H, Boruah AM, Jain A, et al. Evaluation of the efficacy and safety of Rheum rhaponticum root extract (ERr 731) for menopausal symptoms in perimenopausal Indian women: an interim analysis. J Mid-life Heal. 2021;12(2):108-115. doi:10.4103/jmh.jmh_86_21
[16]Bansal R, Aggarwal N. Menopausal hot flashes: a concise review. J Mid-Life Heal. 2019;10(1):6-13. doi:10.4103/jmh.jmh_7_19
[17] Paschou SA, Athanasiadou KI, Hafford-Letchfield T, Hinchliff S, Mauskar M, Rees M, et al. Sexual health and wellbeing and the menopause: an EMAS clinical guide. Maturitas. 2024;189:108055. doi:10.1016/j.maturitas.2024.108055
[18] Strand NH, D’Souza RS, Gomez DA, Whitney MA, Attanti S, Anderson MA, et al. Pain during menopause. Maturitas. 2025;191:108135. doi:10.1016/j.maturitas.2024.108135
[19] McCarthy M, Raval AP. The peri-menopause in a woman’s life: a systemic inflammatory phase that enables later neurodegenerative disease. J Neuroinflamm. 2020;17(1):317. doi:10.1186/s12974-020-01998-9
[20] Chen P, Li B, Ou-Yang L. Role of estrogen receptors in health and disease. Front Endocrinol. 2022;13:839005. doi:10.3389/fendo.2022.839005
[21] Wober J, Möller F, Richter T, Unger C, Weigt C, Jandausch A, et al. Activation of estrogen receptor-β by a special extract of Rheum rhaponticum (ERr 731®), its aglycones and structurally related compounds. J Steroid Biochem Mol Biology. 2007;107(3-5):191-201. doi:10.1016/j.jsbmb.2007.04.002
[22] Zahr T, Boda VK, Ge J, Yu L, Wu Z, Que J, et al. Small molecule conjugates with selective estrogen receptor β agonism promote anti-aging benefits in metabolism and skin recovery. Acta Pharm Sin B. 2024;14(5):2137-2152. doi:10.1016/j.apsb.2024.01.014
[23] Wilson M, Konda V, Heidt K, Rathinasabapathy T, Desai A, Komarnytsky S. Rheum rhaponticum root extract improves vasomotor menopausal symptoms and estrogen-regulated targets in ovariectomised rat model. Int J Mol Sci. 2021;22(3):1032. doi:10.3390/ijms22031032
[24] Jia M, Dahlman-Wright K, Gustafsson JÅ. Estrogen receptor alpha and beta in health and disease. Best Pract Res Cl En. 2015;29(4):557-568. doi:10.1016/j.beem.2015.04.008
[25] Desai N, Blake M, Desai A. Investigating the effectiveness of Estrovera: Insights from a patient satisfaction survey on menopausal symptom relief. 2023 Menopause Society. 2023.