Menopause: Evidence-Based Supplement Guide

No one in Avelor currently holds a supplement saved for menopause. This guide is written anyway. Menopause is the condition where the most people take the most things on the least information. Three of its compounds are also subject to a live ruling in this product, which this guide is the right place to answer. **The treatments with the strongest evidence are prescribed, and the guide says so first.** Two current position statements cover hormone therapy and non-hormone therapy separately (PMID 35797481, 37252752). A 2025 clinical practice guideline covers evaluation and management (PMID 41082911), and a systematic review appraises the guidelines against each other (PMID 38336466). An umbrella review of menopausal hormone therapy concludes it has a complex balance of benefits and harms across outcomes, and that the quality of available evidence is only moderate to poor (PMID 34339416). Newer non-hormonal medicines have randomised evidence: fezolinetant reduced moderate to severe vasomotor symptoms (PMID 36734148), and a systematic review compared it with elinzanetant (PMID 39746208). The plant-derived supplements have more evidence than their reputation and less than their marketing. A systematic review and meta-analysis of plant-derived dietary supplements reported significant improvements while describing the underlying evidence as of generally suboptimal quality and heterogeneous (PMID 38189863). Soy and isoflavones have the largest literature. A meta-analysis of phytoestrogens reported reduced hot flush frequency without serious side effects (PMID 25263312). A systematic review of isoflavone supplements found it difficult to reach a conclusion, because of variability in dose, outcome and duration (PMID 31689947). A further systematic review examined their effects on measures of estrogenicity (PMID 39433088). A meta-analysis reported an inverse association between isoflavone intake and breast cancer occurrence, which matters because the opposite is widely assumed (PMID 35241506). Bone and mood are the parts most often left out. A meta-analysis reported that combined calcium and vitamin D supplementation could prevent hip fracture in postmenopausal women (PMID 33237064). A 2025 meta-analysis reported an effect on bone mineral density **without** a reduction in clinical fracture risk in women who already have osteoporosis (PMID 41063100). Those two are not contradictory and they are not the same claim, and the difference is the population. A meta-analysis of mind-body exercise reported benefits across bone density, sleep, anxiety, depression and fatigue (PMID 38669625), and a systematic review found elevated depression risk in perimenopause specifically (PMID 38642901).

1. **Start with the guidelines, because they cover the treatments that work best** (PMID 35797481, 37252752, 41082911). 2. **Ask about non-hormonal prescription options if hormone therapy is not for you**, rather than going straight to a supplement (PMID 37252752, 36734148). 3. **Ask about bone and mood, not only about hot flushes** (PMID 33237064, 38642901). 4. **Treat mind-body exercise as an intervention with evidence**, not as a consolation (PMID 38669625). 5. **If you take a plant-derived supplement, tell whoever manages your care**, particularly if you have or have had a hormone-sensitive cancer.

Where the research supports a timeframe, the red clover analysis found its clearest signal at around **twelve weeks** (PMID 33920485), and the saffron trial ran for **six weeks** (PMID 29332222). The calcium and vitamin D fracture outcomes are measured over **years**, which is the timescale bone works on (PMID 33237064, 41063100). Hormone therapy duration is an individual clinical decision covered by the position statement rather than a number this guide can give (PMID 35797481).

- **The supplement evidence is graded as generally suboptimal quality by its own review** (PMID 38189863). The effects are real in the pooled numbers and the trials underneath are not strong. - **The isoflavone literature cannot reach a conclusion because of variability in dose, outcome and duration** (PMID 31689947). Two products labelled the same are not the same intervention. - **The red clover meta-analysis reported high heterogeneity and called for better studies** (PMID 33920485). - **The saffron evidence is one randomised trial in a small group** (PMID 29332222), and its primary framing was depression associated with hot flushes rather than hot flushes alone. - **The calcium and vitamin D results differ by population** (PMID 33237064, 41063100). Preventing a first fracture and reducing fracture risk in established osteoporosis are different questions with different answers. - **Even hormone therapy's evidence base is rated moderate to poor by its umbrella review** (PMID 34339416), which is worth knowing before treating any supplement comparison as unfair.

- **Black cohosh has caused liver injury.** A case of cholestatic drug-induced liver injury resolved after stopping it (PMID 33962922), and hepatotoxicity risk has been identified in part of the plant (PMID 35164202). Anyone with liver disease, or taking a medicine processed by the liver, should raise it with **a clinician**. Jaundice, dark urine or unexplained itching means stopping and contacting **a doctor**. - **If you have or have had a hormone-sensitive cancer, every plant oestrogen on this page is a question for your oncology team**, not a decision to make from a label. The isoflavone and breast cancer meta-analysis is reassuring at a population level (PMID 35241506) and that is not the same as advice for one person with a diagnosis. - **Tell your prescriber before adding anything if you take hormone therapy**, because several of these compounds act on the same receptors the treatment does. - **Bleeding after menopause is never normal and always needs assessment by a doctor**, regardless of what you are taking. - **Persistently low mood in perimenopause deserves treatment rather than management** (PMID 38642901). It is common, it is documented, and it is not something to supplement through.

Resolves **and** has a catalogue key, so it can be interaction-checked: - `avelor:sup:black-cohosh` - `avelor:sup:soy-isoflavones` - `avelor:sup:dong-quai` Resolves but has **no catalogue key**: - `avelor:sup:magnesium-l-threonate` No supplement entity, and none is invented here: **red clover**, **saffron**, **calcium**, **vitamin D**, **evening primrose** and **maca**. Black cohosh is the one compound in this guide with a documented liver-injury signal, and it is also one of only three here that both resolves and carries a catalogue key. That is the opposite of what happened in inflammation, where curcumin's liver signal was unreachable, and in hair, where biotin's four major rows were unreachable. Across twenty guides the pattern is now clear enough to state as a finding rather than an observation. Coverage is uncorrelated with importance in both directions: black cohosh and folic acid are covered, curcumin and biotin and iron and vitamin A are not, and no principle separates the two groups. The entity list was not derived from anything, so it is neither good nor bad. It is arbitrary, and arbitrary is the thing to fix. Red clover and saffron both meet the reinstatement test above and neither can be resolved. So even if the hold were lifted tomorrow, the product could not represent two of the three compounds it would be reinstating.

| PMID | Title | | --- | --- | | 35797481 | "The 2022 hormone therapy position statement of The North American Menopause Society" | | 37252752 | "The 2023 nonhormone therapy position statement of The North American Menopause Society" | | 41082911 | "European society of endocrinology clinical practice guideline for evaluation and management of menopause and the perimenopause" | | 38336466 | "A systematic review and critical appraisal of menopause guidelines" | | 34339416 | "Menopausal hormone therapy and women's health: An umbrella review" | | 36734148 | "Efficacy and Safety of Fezolinetant in Moderate to Severe Vasomotor Symptoms Associated With Menopause: A Phase 3 RCT" | | 39746208 | "Fezolinetant and Elinzanetant Therapy for Menopausal Women Experiencing Vasomotor Symptoms: A Systematic Review and Meta-analysis" | | 38189863 | "Efficacy of plant-derived dietary supplements in improving overall menopausal symptoms in women: An updated systematic review and meta-analysis" | | 37192826 | "Black cohosh extracts in women with menopausal symptoms: an updated pairwise meta-analysis" | | 33962922 | "Case of cholestatic drug-induced liver injury (DILI) associated with black cohosh" | | 35164202 | "Fibrous Roots of Cimicifuga Are at Risk of Hepatotoxicity" | | 33920485 | "Evaluation of Clinical Meaningfulness of Red Clover (" | | 29332222 | "Efficacy of Crocus sativus (saffron) in treatment of major depressive disorder associated with post-menopausal hot flashes: a double-blind, randomized, placebo-controlled trial" | | 25263312 | "Efficacy of phytoestrogens for menopausal symptoms: a meta-analysis and systematic review" | | 31689947 | "Isoflavone Supplements for Menopausal Women: A Systematic Review" | | 39433088 | "Effect of Soy Isoflavones on Measures of Estrogenicity: A Systematic Review and Meta-Analysis of Randomized Controlled Trials" | | 35241506 | "Soy Isoflavones and Breast Cancer Risk: A Meta-analysis" | | 33237064 | "Effects of combined calcium and vitamin D supplementation on osteoporosis in postmenopausal women: a systematic review and meta-analysis of randomized controlled trials" | | 41063100 | "The effects of combined calcium and vitamin D supplementation on bone mineral density and fracture risk in postmenopausal women with osteoporosis: a systematic review and meta-analysis of randomized controlled trials" | | 38669625 | "Effects of mind-body exercise on perimenopausal and postmenopausal women: a systematic review and meta-analysis" | | 38642901 | "The risk of depression in the menopausal stages: A systematic review and meta-analysis" |