# Menopause & Perimenopause # Menopause & Perimenopause [Share via Facebook](/content/protocols/female-reproductive/menopause-perimenopause/index.html) [Share via Twitter](/content/protocols/female-reproductive/menopause-perimenopause/index.html) [Share via Pinterest](/content/protocols/female-reproductive/menopause-perimenopause/index.html) [Share via Messenger](/content/protocols/female-reproductive/menopause-perimenopause/index.html) [Share via LinkedIn](/content/protocols/female-reproductive/menopause-perimenopause/index.html) [Print](/content/protocols/female-reproductive/menopause-perimenopause/index.html) [Download PDF](/content/protocols/female-reproductive/menopause-perimenopause/index.html) [Share via Email](mailto:?body=I%20want%20to%20recommend%20Lifeextension.com%0A%0AMenopause%20is%20normal,%20but%20it%20can%20cause%20tough%20symptoms.%20Effective%20treatments%20include%20hormonal%20and%20non-hormonal%20options,%20as%20well%20as%20nutrients%20like%20Siberian%20rhubarb%20extract,%20soy%20isoflavones,%20and%20hops%20extract.%0A%0ALearn%20more%3A%20https://www.lifeextension.com/protocols/female-reproductive/menopause-perimenopause&subject=I%20want%20to%20recommend%20Lifeextension.com) [Last Section Update:](/content/protocols/female-reproductive/menopause-perimenopause#history/index.html) 04/2024 **Contributor(s)**: [Maureen Williams](/content/about/scientific-expert-reviewers#contributors/index.html), ND; [Shayna Sandhaus](/content/about/scientific-expert-reviewers/index.html), PhD; [Stephen Tapanes](/content/about/scientific-expert-reviewers/index.html), PhD; [Scott Fogle](/content/about/scientific-expert-reviewers/index.html), ND; [Franco Melis](/content/about/scientific-expert-reviewers#contributors/index.html); [Shanti Albani](/content/about/scientific-expert-reviewers/index.html), ND **Table of Contents** 01. [What is Menopause?](/content/protocols/female-reproductive/menopause-perimenopause#SectionWhatisMenopause/index.html) 02. [Signs & Symptoms](/content/protocols/female-reproductive/menopause-perimenopause#SectionSignsSymptoms/index.html) 03. [Causes of Menopause](/content/protocols/female-reproductive/menopause-perimenopause#SectionCausesofMenopause/index.html) 04. [Treatment for Symptoms of Menopause](/content/protocols/female-reproductive/menopause-perimenopause#SectionTreatmentforSymptomsofMenopause/index.html) 05. [Diet & Menopause: What to Eat & What to Avoid](/content/protocols/female-reproductive/menopause-perimenopause#SectionDietMenopauseWhattoEatWhattoAvoid/index.html) 06. [Lifestyle Changes](/content/protocols/female-reproductive/menopause-perimenopause#SectionLifestyleChanges/index.html) 07. [Nutrients](/content/protocols/female-reproductive/menopause-perimenopause#SectionNutrients/index.html) 08. [Menopause & Perimenopause: Myths & Facts](/content/protocols/female-reproductive/menopause-perimenopause#SectionMenopausePerimenopauseMythsFacts/index.html) 09. [Frequently Asked Questions About Menopause & Perimenopause](/content/protocols/female-reproductive/menopause-perimenopause#SectionFrequentlyAskedQuestionsAboutMenopausePerimenopause/index.html) 10. [Update History](/content/protocols/female-reproductive/menopause-perimenopause#SectionUpdateHistory/index.html) 11. [References](/content/protocols/female-reproductive/menopause-perimenopause#SectionReferences/index.html) ## 1 What is Menopause? A woman is said to have entered **menopause** 12 months after her last menstrual period. This marks the time at which ovarian hormone cycling has come to an end.1 Menopause is a normal part of aging, and represents a major health milestone in a woman’s life. It heralds fundamental biological, psychological, behavioral, and social changes that affect all aspects of a woman’s health and life.1,2 Natural menopause typically occurs between ages 46 and 52 years, varies with ethnicity and geography, and is considered normal any time after age 45.1,3-5 The time leading up to menopause, during which changes in the hormone cycle are evident, is known as the **menopausal transition** or **perimenopause**, and the years following menopause are called **postmenopause**.1 Many women experience a variety of symptoms during perimenopause and menopause. Some of the more common and troublesome manifestations of menopause include **hot flashes**, **sleep problems**, **brain fog**, **mood swings**, and general **fatigue**. Importantly, while menopause is not a disease, it is associated with long-term changes in health and chronic disease risk, including: - Increased risk of cardiovascular disease6 - Alterations in glucose and lipid metabolism, leading to increased risk of overweight, obesity, and type 2 diabetes7 - Bone loss and increased risk of osteoporosis7 - Declining muscle mass and strength, and increased risk of sarcopenia8 - Brain changes, cognitive impairment, and increased risk of dementia7,9 The good news is that there are evidence-based treatment options available that can help. For instance, supplementation with **nutrients** such as Siberian rhubarb extract, black cohosh, soy isoflavones, and red clover may help ease menopause symptoms for some women. **Eating healthy**, minimally processed foods, **exercising**, **limiting alcohol** intake, and proactively taking steps to **manage stress** may all help relieve some menopausal symptoms as well. Moreover, **menopausal hormone therapy**, particularly emphasizing **bioidentical hormone formulations**, can help relieve menopause symptoms and carries minimal risk for most women under age 60 or within 10 years of menopause.10,11 ### Stages of Reproductive Aging The Stages of Reproductive Aging Workshop (STRAW) in 2011 developed a staging system that divides the female reproductive life into three categories, based mainly on menstrual cycle characteristics1: - **The reproductive stage** of a woman’s life is characterized by regular monthly menstrual cycles, with slight variability in cycle length and heaviness of flow. Around middle age, variability in cycle length increases and the menopause transition becomes imminent.2 - **Perimenopause** is characterized by increasing variability in menstrual cycle length. Persistent seven-day or longer differences in menstrual cycle length from one month to the next indicate early perimenopause (or the early stage of the menopause transition), and when 60 days or more pass without a period, a woman is considered to have moved into late perimenopause (or the late stage of the menopause transition).2 Late perimenopause typically lasts one to three years, and ends one year after the last menstrual period. Symptoms such as hot flashes are especially common during late perimenopause.1 - **Postmenopause** begins after 12 months with no menstrual period. Hot flashes and other symptoms of hormonal fluctuation are common during the early postmenopausal years. After three to six years, FSH levels stabilize, marking the onset of late postmenopause.1 The most common symptoms in late postmenopausal women are vaginal dryness, vulvovaginal atrophy, and urinary problems.12 ## 2 Signs & Symptoms _Figure 1: Symptoms of menopause. Credit: Natty\_Blissful, Shutterstock_ Most women begin experiencing symptoms of perimenopause years before their final menstrual period, often beginning with changes to their menstrual cycle. In general, the menstrual cycle begins increasing in length more than seven years prior to the last menstrual period and becomes variable in length during the last two years, coinciding with an increasing percentage of cycles without ovulation. While menstrual cycle changes resolve with the onset of menopause, other symptoms can persist long after menopause.2 The symptoms of perimenopause and menopause vary tremendously among individual women. Common symptoms, some of which are interrelated, include those listed in this section. ## Genitourinary Syndrome of Menopause Genitourinary syndrome of menopause encompasses the vaginal, vulvar, sexual, and urinary symptoms that result from estrogen deficiency.12 It affects an estimated 65% of women in the first year after menopause and 84% of women within six years after menopause.13 Vaginal dryness and vulvovaginal atrophy (thinning and weakening) are the most common symptoms reported by postmenopausal women and is the main feature of genitourinary syndrome of menopause. Other symptoms include those listed below, which generally begin around the time of menopause, worsen after menopause, persist throughout older age, and can have a significant negative effect on quality of life.12,14 - vaginal itching, burning, and irritation - pain with intercourse and sexual dysfunction - urinary frequency, urgency, pain, and incontinence - recurring vaginal and urinary tract infections ## Hot Flashes and Night Sweats (Vasomotor Symptoms) About 80% of women report experiencing vasomotor menopause symptoms, usually beginning years before and persisting for years after their last menstrual period. In fact, the average duration of frequent or moderate-to-severe hot flashes is seven to 10 years, and mild hot flashes may continue for much longer.2,15 ## Weight Gain Approximately 60–70% of women experience weight gain as a symptom of menopause. On average, women gain about 1.5 pounds per year between ages 50 and 60 years. Changes in body composition occur throughout the menopause transition, with increasing fat mass and decreasing muscle mass. These changes are associated with increased cardiovascular and metabolic disease risk.16 ## Sleep Problems Sleep difficulties, including trouble falling asleep, wakefulness, and waking earlier than planned, increase through the menopausal transition and may persist after menopause, whether or not vasomotor symptoms are present.2 ## Anxiety and Depressed Mood Women are more likely to experience manifestations of anxiety (eg, irritability, nervousness or tension, fear for no reason, and pounding heartbeat) and depressed mood (eg, sadness and crying, restless sleep, feeling lonely) during peri- and postmenopause than before menopause.17-19 ## Cognitive Changes Many women report cognitive problems like forgetfulness, brain fog, and difficulty concentrating during the menopausal transition.20 Researchers have noted differences in brain structure, nerve connectedness, and brain cell energy use during the menopausal transition that stabilize after menopause. It is thought these brain changes may contribute to cognitive symptoms around menopause, as well as hot flashes, sleep difficulties, and mood problems.21 ## Physical and Mental Exhaustion More women report physical and mental exhaustion during perimenopause than in the premenopausal stage, and the percentage increases after menopause, even when stress levels are low.22 ## Hair Loss Female hormones are important regulators of hair follicle cycles. Female pattern hair loss (alopecia)—characterized by thinning of hair with no change in hairline—and a type of alopecia with frontal hair loss have been associated with peri- and postmenopause.23 ## Heart Discomfort Although the exact nature of the relationship is unclear, evidence suggests heart palpitations, experienced as missed, exaggerated, or irregular heartbeats, are more common in perimenopause and after menopause than in the premenopausal stage.24 ## Joint and Muscle Pain Some women experience the onset of musculoskeletal and joint pain around menopause. However, whether menopausal hormone changes are a contributing cause is still uncertain.25 ## 3 Causes of Menopause As women age, the ovaries’ ability to produce estrogen and inhibin (a signaling protein secreted by the ovaries) diminishes. This interrupts negative feedback signaling in the pituitary gland of the brain, resulting in increased release of the ovary-activating hormones, follicle stimulating hormone (FSH) and luteinizing hormone (LH).1 Ovulation becomes less likely, and progesterone production falls.308 Historically, a natural menopausal transition has been recognized as a life stage marked by gradually decreasing levels of estradiol (E2, the predominant ovarian estrogen) and progesterone accompanied by increasing levels of FSH and LH, beginning in earnest about two years before and stabilizing about two years after the last menstrual period.2 However, it is now apparent that hormone levels fluctuate widely during perimenopause and the pattern of hormonal change over the years prior to menopause varies substantially between individuals.2,309 For example, one study that followed-up on 3,302 middle-aged women from across the United States for about 20 years found that, in more than 30% of participants, E2 levels were elevated during perimenopause and did not decline until less than one year before their final period.2 Estrogen receptors are found on cells throughout the body, and fluctuating or low estrogen levels are thought to cause the symptoms that characterize peri- and postmenopause by affecting temperature regulation, mood, skin, bones, and urogenital tissues, as well as cardiovascular, cognitive, and metabolic function.310,311 A research review noted that women who suffered from PMS during their reproductive years had a greater chance of having hot flashes during their peri- and postmenopausal years. High perceived stress level, anxiety symptoms, and depressive symptoms have also been associated with increased risk of menopausal hot flashes.287 Surgical menopause occurs in reproductive-aged women who have had both ovaries surgically removed. Menopause can also be induced by therapies that are toxic to the ovaries, such as radiation therapy and some chemotherapies, or by treatment with anti-estrogenic drugs, such as those used to treat endometriosis or breast cancer.1 Surgical and medical menopause are sudden events and cause abrupt onset of symptoms of estrogen deficiency that can be more severe than symptoms of natural menopause.312 ### Premature Ovarian Insufficiency or “Premature Menopause” About 5% of women experience early menopause, between the ages of 40 and 45 years, and about 1% experience premature ovarian insufficiency (also called premature menopause) prior to age 40.1 The cause of premature ovarian insufficiency is often undetermined, but suspected causes include genetics, autoimmune and metabolic conditions, infections, environmental factors, and medical interventions.313 Infertility can be a serious complication of premature ovarian insufficiency. In addition, women with premature ovarian insufficiency may experience more severe menopausal symptoms and have higher risks of diseases related to estrogen depletion, including genitourinary syndrome, osteoporosis, heart disease, and dementia, than those whose menopause transition occurs after age 45.9,314-316 Hormone therapy using estrogen and progesterone is an important intervention for staving off the long-term effects of early loss of female sex hormones. The American College of Obstetricians and Gynecologists recommends women who experience premature ovarian insufficiency begin hormone therapy as soon as possible and continue at least until the normal age of natural menopause (average age 46–52 years), except when contraindicated.315,317,318 Transdermal estradiol plus vaginal or oral micronized progesterone may be more beneficial and safer than other forms of hormone therapy in women with premature ovarian insufficiency.315 ## 4 Treatment for Symptoms of Menopause Menopause is a normal physiologic process and does not require reversal. Nevertheless, symptoms common during peri- and postmenopause can significantly disturb physical and mental health. Treatment is appropriate when used to alleviate menopausal symptoms, improve quality of life, and prevent complications of long-term estrogen depletion, such as vulvovaginal atrophy and osteoporosis.1 Although menopause is a normal life stage and not a disease, it is associated with increased risks of chronic cardiovascular, metabolic, neurological, and musculoskeletal disorders. More detailed information about preventing and treating these conditions can be found in their independent protocols, such as Atherosclerosis and Cardiovascular Disease, Diabetes and Glucose Control, Weight Management, Sarcopenia, and Osteoporosis. In general, a woman’s symptom severity, health history, and personal preferences can be used to guide the initial approach to menopausal symptom relief. A three-month trial of dietary and lifestyle changes, as well as targeted nutrient supplementation, is a reasonable initial approach. Several nutrients discussed in this Protocol contain phytoestrogens, which exert a low-potency estrogen-like effect and may relieve menopausal symptoms for some women. If symptoms are distressing or persistent after a three-month trial of dietary and lifestyle changes, an alternative approach using hormone replacement therapy with bioidentical hormones may be a good choice. ### Menopause Series: Selecting the Right Menopause Doctor with Dr. Scott Fogle Menopause Series: Selecting the Right Menopause Doctor - YouTube Tap to unmute [Menopause Series: Selecting the Right Menopause Doctor](https://www.youtube.com/watch?v=j4kz81J556s) [Life Extension Wellness](https://www.youtube.com/channel/UCMCxYAb6EFMlPp99yeIkYlQ) Life Extension Wellness9.93K subscribers ## Hormone Therapies Hormone therapies are effective for all types of menopausal symptoms, including vaginal dryness and other aspects of genitourinary syndrome of menopause; hot flashes, and mood and sleep problems; and may be used to prevent (but not treat) osteoporosis.1,178,179 The goal of menopausal hormone therapy is to relieve symptoms, and the dosage of hormones should be adjusted based on the symptomatic response.179,180 In general, guidelines, such as those issued by the North American Menopause Society, state that women under age 60 or within 10 years of menopause may be candidates for initiation of menopausal hormone therapy. Women with a uterus should receive estrogen plus a progestogen (eg, bioidentical estradiol and micronized bioidentical progesterone) to protect against endometrial hyperplasia. Women who do not have a uterus because they have undergone a hysterectomy should receive bioidentical estrogen and can elect to receive a progestogen as well, if they choose, for symptom relief. The duration of use of hormone therapy after initiation depends on each woman’s clinical situation. Hormone therapy may continue beyond age 60 if it continues to provide symptomatic relief and quality of life improvement. Women on hormone replacement therapy should consult their prescribing physician at least annually to assess whether continued hormone therapy is appropriate.179 Current clinical guidelines,such as those endorsed by the North American Menopause Society, recommend initiating hormone therapy within 10 years of menopause (and not doing so later) for women under age 60 years on the basis of several studies that showed better risk-benefit profiles with this approach than with later initiation.178,179 Some evidence also suggests earlier initiation of hormone replacement therapy (within five years of menopause) may be preferred over later initiation (between five and 10 years after menopause) in terms of cognitive function.178 For example, a cross-sectional study published in 2023 found that, compared with non-users of hormone replacement therapy, initiation of hormone replacement therapy five or more years after menopause was associated with increased tau protein accumulation apparent on brain PET scans, whereas initiation within five years of menopause was not. Women who initiated hormone therapy five or more years after menopause also had slightly lower performance on a standardized cognitive assessment than those who initiated therapy within five years of menopause.181 **Bioidentical** hormone formulations (identical to human hormones) are preferred over non-bioidentical formulations. Bioidentical menopausal hormone replacement formulations are available in FDA-approved and compounded preparations.10 As of early 2023, available evidence generally lends support to a preferred approach to menopausal hormone therapy beginning within 10 years of menopause and comprising transdermal estradiol along with oral micronized progesterone for the management of vasomotor symptoms. Vaginally applied estradiol or estriol is effective for genitourinary symptoms specifically, though estriol is not available as an FDA-approved product but is approved by regulatory agencies in other countries.10,182 Also, estriol is often incorporated into compounded preparations used for hormone replacement in the United States. Whereas these preparations are not approved by the FDA, there is evidence that estriol can help relieve menopausal symptoms.183 Although no rigorous randomized controlled trials have shown estriol to be safer or more effective than estradiol,184 some physicians experienced in prescribing compounded hormones prefer transdermal formulations comprising primarily estriol (eg, Bi-Est). Similarly, some physicians prefer transdermal progesterone rather than oral progesterone. In the context of treatment of menopausal symptoms, relief of symptoms and improvement in quality of life is the primary metric for monitoring hormone therapy. However, various hormone testing methods are available and may be used in conjunction with monitoring symptomatic responses in some cases. Hormone levels can be assessed via blood, saliva, and urine. The available evidence does not unequivocally support the superiority of one method of hormone testing over another for all women. Each method has its advantages and disadvantages. Clinicians differ in their preferred approach to hormone testing, often based on their clinical experience. If the desired results of hormone therapy are not being achieved, hormone testing may be useful. Speak with your clinician about whether hormone testing may be helpful in your situation. In addition to the summary here, readers are encouraged to refer to Life Extension’s Female Hormone Restoration Protocol for a more comprehensive overview of the approaches to, and risks and benefits of, hormone therapy. **Estrogens.** Estrogen therapy is the most effective treatment for hot flashes; furthermore, low-dose intravaginal estrogens are the gold standard for treating genitourinary syndrome of menopause that cannot be sufficiently treated with non-hormonal therapies.185,186 Estrogen therapy is recommended by several prominent medical organizations to treat menopausal symptoms and prevent osteoporosis.179,187,188 Moreover, a growing body of evidence suggests estrogen therapy before age 60 and during the first 10 years after menopause may reduce cardiovascular risk by improving blood glucose regulation and lipid levels.178,189 There are multiple types of estrogen in the body, all made primarily by the ovaries and in smaller amounts by other cells. The three main forms of human estrogen are190: - estrone (E1), which can be synthesized by fat cells and plays a larger physiological role after menopause - estradiol (E2), which is the “strongest” estrogen and predominates in the reproductive years - estriol (E3), which is sometimes described as a “weak” estrogen, and circulates at low levels during the reproductive life stage, except during pregnancy when the placenta produces large amounts Over the last few decades, there has been some debate regarding the relative “strength” of E1, E2, and E3, particularly as it relates to their inclusion in compounded systemic hormone replacement therapy formulations. Some physicians experienced in the use of compounded hormone replacement therapy claim that estriol exerts “weaker” estrogenic effects and is thereby safer. There is evidence that oral estriol and low-dose vaginally applied estriol are effective for the management of menopausal symptoms, particularly urogenital symptoms.183 However, preclinical research regarding the relative strength of estriol in terms of estrogen receptor activity and stimulation of breast cancer cells is ongoing and not all studies agree that estriol exerts weaker effects in this regard.11,191,192 As of early 2023, no randomized controlled trials have compared estriol and estradiol in terms of long-term safety and efficacy in the treatment of menopausal symptoms. There is no FDA-approved systemic estriol formulation for the treatment of menopausal symptoms. Oral products made with conjugated or esterified estrogens contain multiple estrogens, including E1 and E2, that are derived from horses (Premarin and Menest) or are synthetic and are not bioidentical. Oral E2 (Estrace), vaginal preparations (eg, Femring), and transdermal patches, gels, and sprays are all formulations of bioidentical E2.185 Estrogen taken orally undergoes transformation in the liver prior to reaching the systemic bloodstream, a phenomenon known as “first pass.” The by-products of estrogen metabolism in the liver have more negative side effects, particularly cardiovascular effects, than estrogen. **For this reason, bioidentical transdermal formulations (for systemic** **symptoms) and vaginal formulations (for genitourinary symptoms) are** **generally the first choice for estrogen therapy.** 182,193 ### Estetrol Estetrol, or E4, is an estrogen made exclusively by the fetal liver during pregnancy. Because of its tissue-dependent effects on estrogen receptors, E4 is currently under investigation as a treatment for menopausal symptoms.194,195 Early clinical evidence suggests E4 may slow bone loss and relieve menopausal hot flashes, genitourinary symptoms, and cognitive changes without increasing risks of blood clots, and may have a neutral effect on breast cancer risk. E4 stimulates endometrial thickening, and treatment with E4 should be balanced with progesterone in non-hysterectomized women.194,195 Nextstellis (E4 combined with drospirenone \[a synthetic progestogen\]) is approved as an oral contraceptive in the United States and Europe.196 As of early 2023, a late-stage (phase 3) clinical trial was underway to assess the effectiveness of E4 alone and in combination with progesterone in the treatment of vasomotor symptoms in postmenopausal women.197 Potential adverse side effects of estrogen therapy include breast tenderness, bloating, nausea, headaches, leg cramps, and vaginal or breakthrough bleeding.198 Additionally, the following issues should be considered prior to starting hormone therapy: - The lining of the uterus thickens in response to estrogen, and progesterone counters this effect. Therefore, hormone therapy with estrogen without a progestogen (ie, unopposed estrogen) causes **thickening (hyperplasia) of the uterine lining** (endometrium). Over time, this increases the risk of uterine cancer. To reduce this risk, estrogen is generally prescribed in combination with a progestogen (progesterone or a synthetic progestogen) except in women who have had a hysterectomy.178 Progesterone is not necessary for vaginal estrogen treatment using low-dose or ultra-low-dose estrogen.178,199 - **_Oral_** estrogen, with or without a progestogen, increases the risk of **blood clots**. **_Transdermal_** (topical) and low-dose **_intravaginal_** estrogen, which is not conjugated by the liver before entering circulation, has not been linked to blood clots and is therefore generally the preferred approach.178,200 - While transdermal estrogen alone appears to be safe for, and may even protect, **breast cells,** some estrogen plus progestin combinations have been found to increase the risk of breast cancer when used for more than three to five years. This risk seems to be attributable to progestins (synthetic progestogens), as opposed to natural progesterone. In fact, some studies have reported observing a decreased risk of breast cancer in those taking estrogen plus oral micronized progesterone compared with estrogen plus synthetic progestogens.178,185 Of note, the progestin dydrogesterone, a stereoisomer of progesterone (meaning its molecular formula is the same as progesterone but the spatial orientation of the molecule is different) has also not been linked to an increased risk of breast cancer.201 **Progestogens (Progesterone & Progestins).** The term “progestogen” refers to natural progesterone as well as synthetic progesterone-like compounds called progestins. Progesterone is made by the ovaries and in small amounts by the adrenal gland, fat cells, and other tissues. In addition to helping regulate reproductive function, progesterone has been found to have important effects on cardiovascular and neurological function.201,202 Micronized progesterone (Prometrium) is a bioidentical form of progesterone, while dydrogesterone (Duphaston), medroxyprogesterone (Provera), norethindrone (Aygestin), and levonorgestrel (used in the combination product Climara) are among the synthetic progestins used in combination hormone therapy after menopause.185 While the main conventional use of progesterone and other progestogens is to mitigate the effect of estrogen therapy on the endometrium,201 progesterone therapy alone has also been found to reduce menopausal symptoms, particularly hot flashes and sleep problems.203 Progesterone alone is also used to treat abnormal endometrial thickening and uterine bleeding in perimenopausal women, which is thought to be caused by a hormone imbalance favoring estrogen.202 Synthetic progestins have been associated with side effects such as fatigue, low mood, and water retention (swelling).185,204 Importantly, the inclusion of some progestins in postmenopausal hormone therapy has been linked to increased breast cancer risk and may reverse the cardioprotective benefits of estrogen therapy.205 Natural progesterone, and particularly micronized natural progesterone, have fewer adverse side effects than synthetic progestins.185,204 Micronized progesterone and dydrogesterone (which is very similar to progesterone in structure and chemical composition) are safer than other progestogens with regard to breast cancer and cardiovascular disease risks.189,201,206 Oral and vaginal preparations of micronized progesterone are known to be effective at preventing endometrial overstimulation by estrogen.201 Because of their safety and effectiveness, the first choice for progesterone in combination hormone therapy after menopause is generally either oral micronized progesterone or dydrogesterone.182,193 Transdermal progesterone is sometimes used for menopausal symptom relief as well. ### Compounded Bioidentical Hormone Replacement Therapy (HRT) versus FDA-Approved Bioidentical Hormone Replacement Therapy Formulations A woman considering HRT for her menopausal symptoms may quickly find herself overwhelmed by conflicting information about whether she should consider FDA-approved HRT or custom-compounded bioidentical hormone preparations. Here we will try to clear up some of the confusion to help women have more informed discussions with their physicians about which approach is best for their unique situation. In decades past, most FDA-approved hormone therapies comprised synthetic progestogens, called progestins, along with horse-derived (equine) estrogens. Although these preparations have been studied in randomized clinical trials in which they were shown to be effective for relief of some menopausal symptoms, many women may find the nature of these products unappealing. Moreover, these preparations were not without side effects. As a result, many doctors and researchers who specialize in HRT began exploring options that would be safer and more tolerable. These research efforts led to the rising popularity of bioidentical HRT. The term “bioidentical” generally refers to hormone replacement preparations that contain exogenous hormones that are identical to those produced naturally by women’s bodies. In contrast, synthetic progestins and equine estrogens are similar, but not identical, to the hormones women’s bodies produce. More recently, as demand for bioidentical HRT grew, pharmaceutical companies entered the market with bioidentical hormone products. Today, there are many FDA-approved hormone preparations available that contain bioidentical estrogen and progesterone. Despite the availability of FDA-approved bioidentical hormones, the debate continues within the medical community regarding the potential superiority of custom-compounded hormone preparations over FDA-approved bioidentical products. Generally, proponents of compounded hormone therapy report that compounding allows for better formulation and dosage customization to meet the needs of each patient.207,208 Unfortunately, there is not enough evidence available to justify sweeping conclusions about the superiority of one approach over the other. However, available facts can help inform choices. **Fact #1**: Transdermal estrogen is generally preferred over oral estrogen due to its better safety profile. Transdermal bioidentical estrogen is available in compounded as well as FDA-approved preparations. **Fact #2**: Bioidentical progesterone is preferred over synthetic progestins due to its better safety profile. Bioidentical progesterone is available in compounded as well as FDA-approved oral and vaginal preparations. Transdermal progesterone is available in compounded formulations. **Fact #3**: The only form of bioidentical estrogen available in FDA-approved products is estradiol (E2). Compounded formulations can contain estriol (E3) and estrone (E1) as well as estradiol (E2). **Fact #4:** FDA-approved bioidentical hormone products will deliver consistent dosages, whereas compounded bioidentical hormone preparations may be more prone to dosage inconsistencies.184 It is important to ensure your compounded hormone preparations are produced in a facility that adheres to current good manufacturing practices (cGMP). Compounding pharmacies are designated as either 503A or 503B facilities. Pharmacies with 503B designations are federally regulated and required to fully comply with cGMP as defined in federal statutes; those with 503A designations are regulated at the state level and are not required to adhere to cGMP by federal regulators, though many do so voluntarily. Check with your doctor to make sure he or she has a relationship with a cGMP-adherent pharmacy to fill the prescriptions for compounded bioidentical hormones prescribed to you.209,210 **Fact #5**: There is not enough available evidence to determine whether compounded HRT is safer or more effective than FDA-approved bioidentical HRT.179,180,184 - While advocates of compounded HRT contend that the inclusion of estriol in compounded formulations may result in a better efficacy and/or safety profile than estradiol-only FDA-approved products, there is not enough evidence from rigorous controlled trials to support this conclusion. In fact, the few studies that have compared the efficacy of estriol and estradiol for menopausal symptoms have concluded that the two hormones are similarly efficacious.184,211,212 Very few trials have directly compared compounded hormones with FDA-approved hormone products in general. Those that have were short-term and generally showed similar adverse effect profiles and withdrawal rates between the compounded and FDA-approved formulations.213 Nevertheless, because some, but not all, preclinical and observational evidence supports a biological plausibility argument that estriol may be safer, this debate will likely continue until a definitive long-term clinical trial is undertaken and published. **Fact #6**: There is not enough evidence available to determine whether compounded HRT or FDA-approved HRT is more cost-effective in terms of out-of-pocket costs over the long term. The National Academies of Science, Engineering, and Medicine (NASEM) reported that available evidence suggests compounded HRT may entail more out-of-pocket expenses in some cases.184 On the other hand, the Alliance for Pharmacy Compounding rebutted the cost analysis undertaken by the NASEM.207 Debate continues surrounding cost advantages and disadvantages of compounded hormone therapy and FDA-approved hormone therapy. **Fact #7**: Some forms of compounded bioidentical HRT, such as implantable subcutaneous pellets, may result in excessively high (supraphysiological) hormone levels and should be used with caution and only done by an experienced practitioner who is also carefully monitoring hormone levels.214 In conclusion, each woman must have an informed discussion with her physician to determine whether to initiate hormone therapy with compounded bioidentical hormones or FDA-approved bioidentical hormones. There are pros and cons with each approach. Understanding the facts described above can help you choose the approach that best meets your needs. **Selective estrogen receptor modulation.** Estrogens exert their actions by interacting with estrogen receptors (ERs) on cells. Two classic ER subtypes, ER-alpha and ER-beta, are known to directly affect nuclear gene expression and elicit different cell responses.215 Although both ER-alpha and ER-beta are important for ovarian development and function and cardiovascular protection, ER-alpha is the more prominent mediator of estrogen’s effects on metabolism and the breasts, uterus, and bones, whereas ER-beta is more involved in mediating nervous system and immune effects of estrogen, and counteracts pro-proliferation signaling by ER-alpha in the breasts and uterus.216,217 Another type of estrogen-responsive receptor, known as G protein-coupled estrogen receptor 1 (GPER-1), acts indirectly by activating secondary messenger molecules inside cells.215 Preclinical evidence suggests ER-beta activation stimulates anti-inflammatory processes and may help protect blood vessel and neurological health after menopause without promoting cell proliferation in breast or endometrial tissues.218-220 One advantage of most plant compounds with estrogen-like effects, including isoflavones from soybeans and red clover, is that they activate ER-beta receptors much more strongly than ER-alpha receptors.26,27 GPER-1 also appears to have an important role in reducing inflammatory immune activity and mediating estrogen’s positive effects on cardiovascular and cognitive health.215,218,219 **Selective estrogen receptor modulators (SERMs)** are chemicals that have different effects on different estrogen receptor types and different tissue types. For example, a SERM might act as a partial estrogen receptor activator in bone tissue, but an inhibitor of estrogen receptor activity in breast cells. The independent and interdependent actions of different estrogen receptor types in different body tissues is complex, and the therapeutic implications of SERM use in menopause is an emerging field of research.28 There are several SERMs currently in use for conditions related to estrogen depletion28,221: - Raloxifene (Evista) and bazedoxifene (in combination with non-bioidentical conjugated estrogens \[Duavee\]) are used to prevent osteoporosis. - Bazedoxifene plus non-bioidentical conjugated estrogens and another SERM, ospemifene (Osphena), are used to treat genitourinary syndrome of menopause. - Bazedoxifene plus non-bioidentical conjugated estrogens is approved for treatment of moderate-to-severe menopausal hot flashes. These medications do not cause adverse uterine and breast tissue effects, but are associated with an increased risk of blood clots.215,222 **Testosterone.** Testosterone in women, although present in lesser amounts than in men, plays a vital role in maintaining reproductive, cardiovascular, bone, muscle, and neurological health.223 It supports genitourinary structures, including the pelvic floor, bladder, vulvovaginal tissues, and urethra, and is needed for sexual motivation and responsiveness, as well as vaginal lubrication. The ovaries produce about 25% of the testosterone in the female body, and a drop in testosterone levels that accompanies the onset of menopause is believed to contribute to hypoactive sexual desire disorder in postmenopausal women. Hypoactive sexual desire disorder is defined as absence of sexual fantasies, absence of sexual desire or receptivity, or both, causing personal distress or relationship difficulties lasting six months or longer.224 It is estimated to affect roughly 14% of middle-aged women.225,226 A meta-analysis of seven randomized controlled trials with a combined total of 3,035 participants found testosterone therapy increased the frequency of sexually satisfying episodes and improved other measures of sexual function in postmenopausal women with hypoactive sexual desire disorder.227 As a result of positive research findings, a Global Consensus Position Statement on the Use of Testosterone Therapy for Women was released in 2019, which endorsed the use of testosterone in postmenopausal women with hypoactive sexual desire disorder. Furthermore, the International Society for the Study of Women’s Sexual Health published the first clinical practice guidelines on the use of testosterone therapy for this purpose in 2021. Despite the evidence, postmenopausal hypoactive sexual desire disorder is not an FDA-approved indication for testosterone therapy.228 According to published guidelines, only transdermal testosterone is recommended for treating hypoactive sexual desire disorder in postmenopausal women, and an appropriate female dosage is approximately one-tenth of the male dosage. Specifically, either a testosterone patch providing 300 mcg of testosterone per day or a cream or gel providing 5 mg of testosterone per day is generally effective at restoring free testosterone levels to the normal premenopausal range. Although the guidance only applies to postmenopausal women, there is limited evidence that testosterone therapy may also benefit perimenopausal women with hypoactive sexual desire disorder.228 Importantly, total testosterone levels should be measured before initiating testosterone therapy. Female sexual dysfunction is complex, and not every case is related to low testosterone production.224,228 Side effects of testosterone therapy in women include hirsutism (facial hair growth), acne, deepening of the voice, and weight gain, but are less common with lower doses.223 Another concern with transdermal preparations is the possible transfer of testosterone to others, such as children, other females, and pets, through skin-to-skin contact. This risk can be mitigated by careful placement of topicals and diligent handwashing after application.224 **Dehydroepiandrosterone.** Dehydroepiandrosterone (DHEA), a hormone made primarily in the adrenal glands and ovaries in women, is transported in the blood mainly as DHEA-sulfate (DHEA-s). DHEA has important metabolic, immune-modulating, and neuroprotective effects and is also a precursor for testosterone and estrogens.229 In postmenopausal women, DHEA supplementation has been found to raise circulating levels of E1, E2, and testosterone.230 Levels of DHEA and DHEA-s diminish with age.229 DHEA formulated as a once-daily vaginal insert is approved by the FDA for the treatment of pain during sexual intercourse. The approved product provides 6.5 mg of DHEA.231 Intravaginal DHEA has been found to normalize vaginal pH, thicken the vaginal lining, and reduce pain with sexual intercourse in postmenopausal women with vulvovaginal atrophy.229 Clinical trials in postmenopausal women have found a 0.5% vaginal DHEA preparation providing 6.5 mg of DHEA per day or 50 mg of oral DHEA effectively reduced symptoms of genitourinary syndrome of menopause without stimulating the endometrium, and may reduce hot flashes and menopausal symptoms.232,233 In general, local, vaginally applied, DHEA has been shown to be safe and effective for the treatment of genitourinary symptoms of menopause.179 Although the evidence is inconclusive, some research suggests oral systemic DHEA may improve cognitive function, mood, and sexual function in healthy older individuals, and may help mitigate bone loss, loss of muscle mass and strength, and the increase in abdominal fat that occurs in aging women.229,234 Higher DHEA and DHEA-s levels have also been correlated with lower cardiovascular risk.235 The link between long-term systemic DHEA therapy and breast cancer is more complex and uncertain. In general, prospective randomized controlled trials have not assessed the effects of long-term systemic DHEA supplementation on breast cancer risk.213 Some observational evidence has linked higher DHEA and DHEA-s levels with increased breast cancer risk.232,236 A Mendelian randomization study published in 2022 also found an association between higher DHEA-s levels and breast cancer risk.237 However, in some of the observational studies, the associations may have been confounded by body mass index (BMI) and other variables.238 On the other hand, some observational research has found the inverse: higher DHEA levels were associated with lower breast cancer risk.239,240 Other studies have found no association.241-243 Also, in some studies, levels of DHEA or DHEA-s were measured many years before breast cancer diagnosis.244 Overall, the evidence on the association between DHEA and/or DHEA-s levels with breast cancer is mixed. Women with or at high risk of breast cancer should consult with a physician before initiating systemic DHEA therapy. DHEA therapy has been reported to be associated with adverse side effects such as growth of body and facial hair (hirsutism), acne, greasy or itchy skin, vaginal discharge, and increased sweating and sweat odor.234 However, these side effects are often dose dependent, meaning more likely with higher dosages. Some women are also genetically prone to preferentially convert DHEA into testosterone and dihydrotestosterone (DHT), which can cause these side effects. Those women will need to use more care with DHEA and typically need lower DHEA dosages or a different form of DHEA, such as 7-keto DHEA, that does not convert into sex hormones like testosterone or estrogen. ## Other Therapies ### Menopause Series: Ask The Doctor About the Latest Treatments with Dr. Stephen Tapanes Menopause Series: Ask the Doctor About the Latest Treatments! - YouTube Tap to unmute [Menopause Series: Ask the Doctor About the Latest Treatments!](https://www.youtube.com/watch?v=31twhorsbn0) [Life Extension Wellness](https://www.youtube.com/channel/UCMCxYAb6EFMlPp99yeIkYlQ) Life Extension Wellness9.93K subscribers **Vaginal lubricants and moisturizers** are first-line therapies for vaginal dryness and related irritation, discomfort, or sexual dysfunction. Lubricants provide temporary relief of dryness and can facilitate sexual intercourse. They may be water-, silicone-, or oil-based, and should have an acidic pH of around 4.5 and be sufficiently dilute to reduce the risk of triggering vaginal dysbiosis (imbalance of the normal bacteria).232 Moisturizers, such as gels with hyaluronic acid or polycarbophil, improve tissue hydration and may provide a longer duration of relief from vulvovaginal irritation.232,245,246 However, these treatment options do not reverse chronic, progressive, age-related atrophy of the genitourinary tissues and are generally only to provide relief from dryness.186 In cases not sufficiently treated with lubricants and moisturizers, oral **ospemifene** is approved as an alternative to estrogen therapy for treating vaginal dryness and pain with intercourse.186 It is a SERM, with roughly equal likelihood of binding ER-alpha and ER-beta. Ospemifene has demonstrated both pro-estrogenic and anti-estrogenic effects, depending on the tissue. For example, it has demonstrated pro-estrogenic effects on bone and anti-estrogenic effects on breast tissue, although its safety in women with breast cancer has not yet been confirmed.247 Ospemifene does not stimulate the endometrium, but may worsen hot flashes and increase blood clot risk.186,232 **Bazedoxifene** is another SERM that is being investigated for its potential to improve genitourinary syndrome of menopause. Combined with conjugated estrogens into one drug, bazedoxifene appears to reduce negative effects of estrogen on the endometrium and breast tissue while promoting vulvovaginal and bone health and relieving hot flashes and menopausal symptoms in general222,248; however, it may have an adverse effect on liver fat metabolism and increased blood clot risk.222,249 **Physical modalities** involving the use of laser and radiofrequency treatments have shown promising effects on vaginal atrophy and urinary incontinence in postmenopausal women.250,251 **Fezolinetant (Veozah)** is a non-hormonal neurokinin 3 receptor (NK3R) antagonist indicated for the treatment of moderate-to-severe vasomotor symptoms (VMS), or hot flashes, due to menopause.252,253 It was FDA-approved for this indication in May 2023. The NK3R plays a role in the brain’s regulation of body temperature.254 Some women who experience hot flashes and have a history of vaginal bleeding, stroke, heart attack, blood clots or liver disease, cannot take hormone therapies. Fezolinetant is not a hormone.254 It is the second non-hormonal drug approved for the treatment of menopausal vasomotor symptoms, the other being the selective serotonin reuptake inhibitor (SSRI) paroxetine (Bridselle). Fezolinetant was initially for treatment of hot flashes in menopause. In each of the two pivotal phase 3 trials, women aged 40 to 65 years with confirmed menopausal vasomotor symptoms (average seven moderate-to-severe VMS/day) took 30 or 45 mg fezolinetant per day.253-255 The studies consisted of a 12-week period where placebo controls were used, followed by a 40-week extension phase during which the durability of the effects was evaluated. In the SKYLIGHT 1 trial, which included 522 women, fezolinetant demonstrated efficacy in reducing hot flashes in menopausal and perimenopausal women, with a 58% and 61% decrease at a dosage of 30 mg and 45 mg, respectively, after 12 weeks of treatment. And in the SKYLIGHT 2 trial, which included 500 women, a 57% and 62% reduction in hot flashes was observed at dosages of 30 mg and 45 mg, respectively, after 12 weeks of treatment.253,255 Common side effects of fezolinetant include abdominal pain, diarrhea, insomnia, back pain, and elevated liver enzymes.252,254 In the phase 3 trials, headache was the most common treatment-emergent adverse event.253 Serious treatment-emergent adverse effects were infrequent. There were no serious drug-related adverse events in SKYLIGHT 2, and only two (increased transaminases and abnormal liver function test) in SKYLIGHT 1. Adverse events leading to discontinuation were reported by fewer than 6% of participants in both trials.253,255 Several other **neurologically active** **non-hormonal medications** have been found to be helpful for reducing hot flashes. They include: - **Selective serotonin reuptake inhibitors.** Paroxetine and escitalopram (Lexapro) are antidepressants in the SSRI class. Paroxetine is the only antidepressant approved for use in treating postmenopausal hot flashes, but escitalopram has demonstrated similar benefits.256 Paroxetine has been shown to reduce hot flash frequency by an average of about three hot flashes per day.257 It has also been found to reduce hot flash severity and improve sleep. SSRIs can cause adverse side effects such as headache, nausea, dizziness, fatigue, dry mouth, digestive problems, weight changes, and, rarely, suicidal thoughts.256 Paroxetine has also been linked to a prolonged withdrawal syndrome after discontinuation.258 - **Serotonin-norepinephrine reuptake inhibitors.** Venlafaxine (Effexor) and desvenlafaxine (Pristiq), antidepressants in the serotonin-norepinephrine reuptake inhibitor (SNRI) class, are also sometimes used to treat menopausal hot flashes. Venlafaxine and desvenlafaxine have been found to reduce the frequency and severity of hot flashes; venlafaxine has also been found to improve sleep. Possible adverse side effects of SNRIs include nausea, constipation, mood symptoms, tremor, high blood pressure, and, rarely, suicidal thoughts.256 Venlafaxine has also been associated with a prolonged withdrawal syndrome following discontinuation.258 - **Gabapentin.** Gabapentin (Neurontin) is a drug used to treat nerve pain and seizures, and some evidence shows it can modestly reduce the frequency of menopausal hot flashes.259 Dizziness is a common adverse side effect of gabapentin.185,259 Other possible side effects include drowsiness, fatigue, weight gain, headache, and unstableness, as well as suicidal thoughts in rare cases.256 - **Clonidine.** Clonidine (Catapres), a medication used to lower high blood pressure, has been shown to be helpful in cases of mild menopausal symptoms (eg, hot flashes and night sweats). It has been linked to adverse side effects such as low blood pressure, light-headedness, dizziness, dry mouth, headache, constipation, and rebound high blood pressure upon discontinuation.256 **Behavioral therapy.** Psychological interventions, including mindfulness training, cognitive behavioral therapy (CBT, a type of psychotherapy that involves identifying and changing unhelpful behavioral and thought patterns), and other behavioral therapies have been found to reduce menopausal symptoms in multiple clinical trials, probably in part by reducing stress.260,261 A meta-analysis of 14 randomized controlled trials with a total of 1,618 participants found CBT can modestly reduce menopause-related hot flashes, night sweats, depression, anxiety, and fatigue, and improve quality of life.262 Another meta-analysis that included data from 12 randomized controlled trials found mindfulness and behavioral therapies reduced hot flash symptoms and menopausal symptoms generally.261 A form of CBT targeting insomnia has also been found to improve sleep and quality of life in postmenopausal women.263 In fact, interventions based on mindfulness and relaxation, CBT, and exercise were found to improve sleep difficulties in peri- and postmenopausal women in a meta-analysis that included 16 randomized controlled trials.264 In addition, a comprehensive research review found the evidence generally supports the use of hypnotherapy and applied relaxation, as well as mindfulness and CBT, as non-hormonal interventions for menopausal hot flashes.265 ## 5 Diet & Menopause: What to Eat & What to Avoid ## Eat A **well-balanced nutrient-dense diet**, high in **plant foods** and **fiber** and supplying adequate vitamins, minerals, polyunsaturated fatty acids, protein, and phytonutrients, may help mitigate both the short- and long-term consequences of menopause.266-268 A **Mediterranean diet** in particular has been shown to lower risks of diseases common in postmenopausal women, such as cardiovascular disease, overweight and obesity, type 2 diabetes, and breast cancer, and may also slow bone loss and cognitive decline while supporting healthy mood.269,270 A **vegan diet** has also been linked to reduced menopausal symptoms in observational and clinical research.271,272 In one randomized controlled trial, 84 postmenopausal women experiencing at least two moderate-to-severe hot flashes daily were assigned to eat a low-fat vegan diet (that included cooked soybeans) or make no dietary change; after 12 weeks, the frequency of moderate-to-severe hot flashes were reduced by 88% in the vegan diet group compared with 34% in the control group. Half of those in the intervention group reported no moderate-to-severe hot flashes at week 12 while the control group remained unchanged.273 Despite concerns about osteoporosis risk in women who eat a plant-based diet, the lower bone mineral density observed in vegan and vegetarian women has been found to be almost entirely related to their lower BMI and waist circumference.274 **Vegetables**, **whole grains**, and **unprocessed foods** have been associated with lower intensity of menopausal hot flashes and genitourinary, mood, and sleep symptoms.268,275 An observational study that included 6,040 women who experienced natural menopause found that, after following them for nine years, those who ate diets high in **fruit** and those whose diets closely reflected a Mediterranean diet were about 19% and 20%, respectively, less likely to report hot flashes, while those who consumed a high-sugar/high-fat diet were about 23% more likely to report hot flashes.276 Another study in more than 17,000 postmenopausal women not using hormone therapy found those who lost at least 10 pounds or 10% of their baseline body weight after one year were more likely to report resolution of their hot flashes than those whose weight was unchanged. And even without weight loss, a healthy diet program was associated with a higher likelihood of symptom elimination, albeit to a lesser degree than when it was accompanied by weight loss.277 **Soy** intake has been correlated with reduced menopausal symptoms, including hot flashes.63 An observational study in 172 women found soy milk and vegetable consumption were correlated with fewer hot flashes and other menopausal symptoms, while skimmed dairy products and poultry consumption were associated with more symptoms.278 In addition, soy consumption has been linked to lower risks of cardiovascular disease; type 2 diabetes; obesity; high blood pressure; lipid dysregulation; osteoporosis; neurologic diseases; and breast, colon, and prostate cancers.63,279 The positive health effects of soy foods are partly due to their isoflavones (a type of phytoestrogens). The two major isoflavones in soy are genistein and daidzein. _Refer to_ “Soy Isoflavones” _in the_ “Nutrients” _section for more details on soy and its phytoestrogens._ **Lignans**, another type of phytoestrogens, are found in virtually all plant foods but are particularly concentrated in **flax** and **sesame** seeds.280 Although the results of clinical trials have been mixed, some evidence suggests ground flaxseed consumption can reduce menopausal symptoms and improve quality of life.281 In addition, eating ground flaxseed appears to modulate the gut microbiome composition and has been found to decrease blood pressure, improve blood glucose control in type 2 diabetics, lower cardiovascular disease risk, and reduce the risk of breast and other cancers.280,281 Flaxseeds are also high in a heat-sensitive polyunsaturated omega-3 fatty acid called alpha-linolenic acid (ALA). Flaxseeds have been shown to tolerate temperatures up to 350°F/178°C for two hours without undergoing structural change of their ALA; therefore, using flaxseeds in baked goods like breads or muffins is a reasonable way to increase consumption.281 ## Avoid **Highly processed foods**, **saturated fats**, and **sugars** have been linked to increased menopausal symptoms.268,275 An observational study in 288 postmenopausal women found higher consumption of **ultra-processed foods** was correlated with increased severity of hot flashes and other menopausal symptoms.275 Ultra-processed foods are made with ingredients extracted from foods, like added fats, sugars, starches, and hydrogenated oils, and often have non-nutrient ingredients like artificial colors, flavors, preservatives, and emulsifiers and stabilizers (eg, guar gum and xanthan gum).282,283 Examples include frozen meals, soft drinks, hot dogs and other processed meats, fast foods, and packaged cookies, pastries, chips, and other snack foods.283 Diets high in **meat**, **poultry**, and **skimmed dairy products** have been correlated with more hot flashes and other menopausal symptoms in observational research.271,278 **Alcohol** intake has been correlated with an increased risk of bothersome early-onset hot flashes,284 and some research suggests increased **caffeine** consumption may be associated with a small increase in menopausal hot flash scores.285 Foods stored and heated in plastic containers can become contaminated with endocrine disrupting chemicals called **phthalates**. Increased exposure to phthalates, as determined by urine phthalate levels, has been associated with increased menopausal symptoms and may contribute to earlier onset of menopause and premature ovarian insufficiency (premature menopause).286 ## 6 Lifestyle Changes In addition to eating a balanced nutritious diet, several lifestyle practices may help reduce menopausal symptoms. ## Not Smoking Smoking is a strong predictor of menopausal hot flashes.287,288 Even passive smokers (those exposed to second-hand smoke) have been found to have higher likelihood and severity of menopausal hot flashes compared with non-smokers.286 Conversely, quitting smoking has a positive impact: one study found women who quit smoking more than five years before menopause were less likely to have hot flashes and experienced fewer and less intense hot flashes than those who continued smoking.289 Cigarette smoke contains thousands of chemicals, many of which have known toxicity.286 It reduces estrogen bioavailability, which can accelerate estrogen depletion and possibly trigger early menopause, as well as aggravate menopausal symptoms.186,290 In addition to increasing the risk of premature ovarian insufficiency, observational evidence suggests women who smoke begin experiencing menopausal symptoms one to two years earlier than non-smokers.286 Smoking also contributes to increased risks of cardiovascular and metabolic disorders, osteoporosis, and cancer after menopause.6 ## Maintaining a Healthy Weight Overweight and obesity have been linked to higher risk of hot flashes, especially in early menopause.287,288 Obesity also appears to decrease genitourinary blood flow and may thereby contribute to vulvovaginal atrophy.186 Weight control is increasingly difficult as women age; nevertheless, an open uncontrolled clinical trial in 17,473 postmenopausal women who participated in a one-year dietary intervention that involved decreasing fat intake and increasing intake of fruits, vegetables, and whole grains found those who lost at least 10% of their baseline body weight were more likely to experience a reduction in their menopausal symptoms than those who did not lose weight.277 On the other hand, being underweight can contribute to earlier onset of menopause and premature ovarian insufficiency, and increases the risk of osteoporosis.290,291 ## Exercising Physical activity reduces the risk of chronic disease and is well established as a critical part of healthy aging. Among other effects, aerobic exercise and strength training can help mitigate estrogen deficiency-related loss of muscle mass, strength, and function.292 Exercise is a key part of combatting metabolic changes that begin in perimenopause and lead to decreased fat burning, weight gain, muscle loss, and increased abdominal fat accumulation.293-295 Observational evidence has linked exercise to better psychological and social health around menopause.296 Water-based exercise has been shown to have similar benefits to land-based exercise on muscle strength and flexibility, bone density, and aerobic fitness.297 _Refer to the_ Exercise Enhancement _protocol for more detailed information about how to implement an exercise regimen for optimal health._ In a controlled trial that included 112 middle-aged women, those who participated in a 16-week multi-component exercise program for 60 minutes three times per week had greater improvement in menopausal hot flashes and other symptoms than those who received counseling instead.298 This is consistent with current exercise guidelines for adults, which recommend a minimum of 150 minutes of moderate-intensity exercise per week.299 Yoga is a type of mind-body exercise that has been found in multiple clinical trials to improve well-being and reduce symptoms in peri- and postmenopausal women.300-302 Observational evidence suggests peri- and postmenopausal women who are long-term yoga practitioners may also have better cardiovascular and metabolic health and higher quality of life than those who engage in other forms of physical activity.303-305 ## Managing Stress Postmenopausal women who report high ability to manage stress have been found to be less likely to experience sexual dysfunction.306 In one controlled trial that included 61 peri- and postmenopausal women, participation in an eight-week stress management training program reduced menopausal symptoms and had positive effects on sleep, mood, self-esteem, and sense of control over health. Another trial that enrolled 104 women in the menopause transition found an eight-week mindfulness-based stress reduction course led to improvements in depressive symptoms as well as anxiety, perceived stress, resilience, and sleep.307 ## 7 Nutrients ## Phytoestrogens Symptoms of menopause are often well managed through the use of nutritional interventions. Many of these therapies contain **phytoestrogens**, non-steroidal plant compounds that weakly activate estrogen receptors, usually with a preference for ER-beta over ER-alpha.26,27 Refer to the section of this Protocol titled “Selective estrogen receptor modulation” for further discussion of the differences between ER-alpha and ER-beta. During the reproductive years when E2 levels are high, phytoestrogens may compete with E2 for receptor sites and thereby have an anti-estrogenic effect, whereas in menopause, when E2 levels are low, phytoestrogens may have a pro-estrogenic effects through their ability to stimulate estrogen receptors (to a lesser degree than endogenous estrogens).28 In other words, phytoestrogens are partial agonists of estrogen receptors. Some phytoestrogens also have antioxidant, anti-inflammatory, anti-proliferative, and epigenetic actions that may contribute to their health-promoting effects.29,30 In general, phytoestrogens reduce menopausal symptoms, including hot flashes and urogenital symptoms, and protect metabolism, bones, and cardiovascular tissue from the negative effects of estrogen depletion, without increasing (and possibly decreasing) endometrial or breast cancer risks.26,30,31 **Siberian rhubarb extract.** A standardized extract from the root of Siberian rhubarb ( _Rheum rhaponticum_) has been used for decades to treat menopausal symptoms. Phytoestrogens from Siberian rhubarb have been shown to preferentially activate ER-beta, with a significantly weaker effect on ER-alpha, indicating its probable safety in breast and endometrial tissues.32-34 In a randomized placebo-controlled trial that included 112 symptomatic perimenopausal women, menopausal symptom scores as rated by the 44-point menopause rating scale (MRS) decreased by 14.6 points in those taking one 4 mg tablet of a standardized Siberian rhubarb daily for 12 weeks compared with a 3-point decrease in those taking placebo.35 Two similar trials, each including 109 perimenopausal women, found that 4 mg of Siberian rhubarb extract daily reduced hot flashes, anxiety symptoms, and total menopausal symptom scores, and improved overall health and well-being more effectively than placebo after 12 weeks.36,37 In two of the aforementioned trials, researchers reported changes in each of the 11 symptoms on the MRS: women taking the Siberian rhubarb extract in these trials experienced significant reductions in all 11 items on the MRS after 12 weeks compared with those taking placebo.35,36 In a follow-up study, 80 of the initial 109 participants were given the same dose of the extract for 48 weeks of observation, and 51 continued treatment for an additional 48 weeks; participants reported additional decreases in menopausal symptoms during both phases of follow up.38 Findings from uncontrolled trials further indicate Siberian rhubarb extract can safely and effectively improve symptoms in perimenopausal women.39,40 A systematic review and meta-analysis published in mid-2024 confirmed the benefits of supplementation with Siberian rhubarb extract for the relief of menopausal symptoms. This analysis included data from four high-quality studies that enrolled 390 participants in total. The meta-analysis showed that Siberian rhubarb extract significantly reduced the Menopause Rating Scale score compared with control treatment.324 A safety review examined adverse events reported by women using the Siberian rhubarb extract between 1993 and 2014, during which time approximately 140 million daily doses were sold. The review found that adverse events were relatively uncommon; most were allergic reactions or digestive symptoms. Only two serious events had been reported, including one case of endometrial cancer (no cases of breast cancer were reported); it was unclear whether these serious events were related to the use of Siberian rhubarb.32 **Black cohosh.** Black cohosh ( _Cimicifuga racemosa_) is a North American plant with a long history of use in treating menopausal symptoms and other women’s health issues. Compared with no treatment, treatment with black cohosh extract, at a dose of 20 mg twice per day, for three months improved hot flashes, sleep, and irritability in a controlled study that included 163 women with menopausal symptoms.41 A review of clinical evidence concluded that 40 mg daily of a standardized isopropyl alcohol extract of black cohosh (Remifemin) was safe and effective for reducing hot flashes and improving mood during the menopause transition.42 Another review that examined 35 clinical trials with a total of 43,759 participants (including over 13,000 who were treated with black cohosh extract) found black cohosh extract worked similarly to low-dose transdermal E2 therapy for treating menopausal symptoms, and its benefits on mood symptoms were enhanced by combining it with St. John’s wort, a plant frequently used to treat depressive symptoms. Four of the six randomized controlled trials included in the analysis used dosages of 40 mg per day, while one used 8 mg per day, and another used 64–128 mg per day. The composition of the specific extract varied across the trials.43 Black cohosh may also have positive effects on blood vessel and bone health.44-46 Black cohosh is often combined with other herbal ingredients or nutrients that may add to its beneficial effects. For example, a trial in 220 symptomatic menopausal women over 12 weeks found a combination of black cohosh (13 mg daily) and rhodiola ( _Rhodiola rosea_; 400 mg daily) was more effective than black cohosh alone (both 13 mg and high dose of 1,000 mg daily) or placebo for alleviating menopausal symptoms, particularly mood symptoms, and increasing quality of life.47 A randomized placebo-controlled trial with 101 menopausal participants found a combination of 520 mg black cohosh, 400 mg chaste tree, 100 mg soy isoflavones, and 500 mg evening primrose oil, taken once daily for 12 weeks, improved hot flashes and sweating, sleep problems, mood, and irritability, as well as levels of C-reactive protein (CRP) (a marker of inflammation), LDL-cholesterol, and triglycerides.48 In another randomized placebo-controlled trial with 170 participants, a combination that included black cohosh, chaste tree, soy, burdock ( _Arctium lappa_), and wild yam ( _Dioscorea villosa_), taken at a dose of 550 mg twice daily for eight weeks, reduced the frequency and intensity of menopausal night sweats (but not hot flashes).49 A three-month, randomized, controlled trial in 50 peri- and postmenopausal women reported a combination of black cohosh, vitex, red clover, dong quai, American ginseng ( _Panax quinquefolius_), and milk thistle ( _Silybum marianum_) led to a 73% reduction in hot flashes and 69% reduction in night sweats; 47% of women treated with the herbal combination were hot flash-free at the end of the trial versus only 19% of those given placebo.50 Some studies of black cohosh have reported finding phytoestrogenic compounds, but these compounds have not been consistently found in all extracts. Other black cohosh constituents have been shown to act on serotonin and other neurotransmitter receptors, which could contribute to black cohosh’s ability to relieve menopausal hot flashes, reduce anxiety, and improve cognition.46,51 Compounds with oxidative stress-reducing and anti-inflammatory actions present in black cohosh extracts are also thought to contribute to bone mass preservation.46 The safety of black cohosh has been established in multiple clinical trials showing it does not have mutagenic effects in breast or endometrial tissue, does not impede treatment effects of tamoxifen (Soltamox) (a selective estrogen receptor modulator \[SERM\]) in breast cancer patients, and does not have liver toxicity; furthermore, some evidence suggests black cohosh may improve disease-free survival in breast cancer patients.51,52 **Soy isoflavones.** Soy is rich in phytoestrogenic compounds called isoflavones. The main soy isoflavones are genistein and daidzein. In some individuals, daidzein is metabolized by specific gut bacteria into equol, another phytoestrogen. The estrogenic potency of daidzein is approximately 1/10,000th that of E2, while genistein and equol are closer to 1/1,000th as potent as E2. Another important feature of isoflavones is their preference for ER-beta (found mainly in bone, urogenital tissue, and the cardiovascular system) over ER-alpha (found mainly in breast and uterine tissues).53 Evidence suggests soy isoflavones can reduce menopausal hot flashes.53 One meta-analysis evaluated the results from five randomized controlled trials that used equol in peri- and postmenopausal women or soy isoflavones in women confirmed to be equol producers. The analysis found women who received 10–20 mg equol or up to 200 mg isoflavones (equol producers only) experienced reductions in menopausal hot flashes.54 Other randomized controlled trials have found genistein, at a dose of 54 mg daily for 12 months, effectively reduced hot flashes without triggering endometrial thickening.55,56 Soy isoflavones have demonstrated other beneficial effects in postmenopausal women, such as slowing bone loss,57 improving lipid levels58 and glucose metabolism,57 and decreasing heart disease risk.59 Although multiple clinical trials have indicated high dietary soy isoflavone intake decreases the overall risk of breast cancer,60 the possible protective effect of isoflavone supplements on breast cancer risk may be limited to estrogen receptor-expressing (ER+) tumors and women in perimenopause or early postmenopasue.61 ### Equol Equol is an isoflavone metabolite made from daidzein by gut bacteria.62 Equol is more stable, more readily absorbed, has greater bioavailability, and stronger phytoestrogenic activity than daidzein.62-64 It is also the most potent antioxidant among isoflavone-derived compounds.63,64 It is thought the ability to produce equol may be related to a combination of genetic factors and gut microbiome composition.63 In Asian populations, 50–70% of people are equol producers, while only 20–30% of Westerners have been found to produce equol.64 This low prevalence of equol-producers among Western populations has been proposed as one reason researchers have not been able to consistently link soy food consumption to cardiovascular and other health benefits.62,64 Whether or not equol nonproducers can become equol producers is a topic of emerging research. A study that followed 350 postmenopausal women for 2.5 years found the capacity to produce equol can change over time, but the circumstances leading to conversion were uncertain.65 In one study in 41 healthy American adults given 500 mL daily of a soy milk drink for three consecutive days, vegetarians were more than twice as likely to be equol producers as non-vegetarians (59% vs. 25%, respectively), leading to speculation that dietary intake might be a determining factor in equol producer status.66 This notion was further supported by the finding that, among 1,044 adult Japanese subjects, equol producers had higher dietary intake of the soy isoflavone daidzein than nonproducers.67 A clinical trial in 17 postmenopausal women reported significant changes in the gut microbiome after just one week of adding a soy bar with 160 mg of isoflavones to their daily diet.68 In an uncontrolled trial, drinking 1,000 mL soymilk weekly for 16 weeks led to conversion from equol-nonproducer to equol-producer status in eight (40%) of 20 subjects.69 In another uncontrolled trial, two of 10 healthy equol nonproducing men became equol producers after three months of supplementing with 60 mg soy isoflavones daily.70 Ordinary probiotics, however, have not shown promise with regard to equol production: in two randomized controlled trials, probiotic supplements were not able to promote equol production in female equol-nonproducers.71,72 More research examining the effects of dietary changes and nutritional supplements on equol producer status is needed. Dietary habits beyond soy consumption appear to affect how much equol is produced. A small clinical trial found supplementing the diet with 5 grams of seaweed powder daily for seven weeks increased equol production in five subjects who were equol producers, and the addition of soy protein isolate (2 mg soy isoflavones per kg of body weight) during the seventh week further increased their production of equol.73 Another study in 24 healthy adult equol producers found those whose habitual diets were high in fat were more likely to be low equol producers, while those whose habitual diets were low in fat and high in carbohydrates were more likely to be high equol producers.74 In a study performed using a model of the human intestine inoculated with bacteria from equol-producing women and supported by a soy isoflavone-fortified standardized diet, equol production doubled with a high-carbohydrate diet and dropped sharply with a high-protein diet.75 However, an observational study in 159 healthy adults from the United States and Australia found no differences in protein, carbohydrate, fat, saturated fat, or fiber intakes between equol producers and non-producers, although diets of equol producers were higher in polyunsaturated fats, maltose (a type of sugar found in grains, fruits, and honey), and vitamins A and E, and lower in cholesterol.76 **Red clover.** Red clover ( _Trifolium pratense_) is a common plant that grows around the world and is a source of isoflavone phytoestrogens such as biochanin A, genistein, and daidzein. Red clover has been studied for its potential benefits in treating menopausal symptoms and has been shown to have anti-inflammatory and oxidative stress-reducing properties.77 A meta-analysis of eight placebo-controlled trials found red clover can effectively reduce the incidence of hot flashes. The best effects were seen in trials that included women experiencing five or more hot flashes per day, those that used 80 mg or more of red clover isoflavones per day, those reporting higher concentrations of the isoflavone biochanin A, and those trials lasting 12 weeks or longer.78 Another meta-analysis that included three trials using a standardized red clover isoflavone extract (Promensil) at a dose of 80 mg per day found a significant hot flash-reducing effect.79 Red clover may also improve cardiovascular health by improving lipid profiles and reducing vascular inflammation.80-82 **Hops.** Hops ( _Humulus lupulus_) may be best known for their contribution to the distinctive taste of beer, but are also used traditionally as a sedative and a treatment for menopausal symptoms. The main active constituents of hops are prenylated flavonoids.83,84 8-prenylnaringenin in particular has demonstrated relatively potent phytoestrogenic activity by interacting more strongly with ER-alpha than ER-beta. On the other hand, 8-prenylnaringenin has also been found to inhibit aromatase, an enzyme involved in estrogen synthesis, in the laboratory—an effect that could potentially lower E2 levels. Laboratory research also shows extracts from hops can improve metabolism, promote normal cell death, reduce inflammatory signaling, enhance detoxification, and increase antioxidant capacity.83 Although animal research suggests hops do not strongly trigger proliferation in endometrial and breast tissues, there have been reports of endometrial thickening and bleeding in postmenopausal women using hops, and its long-term safety in women with a history or high risk of breast cancer is uncertain.84-86 In a randomized placebo-controlled trial with 120 participants in perimenopause or early postmenopause, daily treatment with 500 mg hops, providing 100 mcg of phytoestrogens, for 12 weeks reduced the number of hot flashes and overall symptom scores.84,87 Another trial with 67 participants found a hops extract standardized to supply 100 mcg of 8-prenylnaringenin per day reduced hot flashes more than placebo after six weeks, but the difference between hops and placebo disappeared after 12 weeks.88 A 16-week crossover trial in 36 women did not show any differences between hops (providing 100 mcg of 8-prenylnaringenin per day) and placebo in reducing menopausal symptoms after the first eight-week phase, but women assigned to placebo in the first phase and hops in the second phase had greater symptom relief at week 16 than those assigned to hops followed by placebo, indicating a strong placebo effect and a possible benefit from hops.84,89 Hops may be combined with other nutrients for enhanced effectiveness. In a randomized placebo-controlled trial in 78 women with moderate-to-severe menopausal symptoms, 190 mg per day of combined hops and soy extracts for 12 weeks resulted in a 20.16-point reduction in menopausal symptom scores, compared with a 14.80-point reduction in the placebo groups, and no changes in endometrial thickness or hormone profiles were detected.90 A vaginal gel made with hops extract combined with hyaluronic acid (a connective tissue component) and vitamin E, applied in the amount of 2.5 grams nightly for one week followed by twice weekly for 11 weeks, relieved vaginal dryness and improved all vaginal symptoms in an uncontrolled trial in 100 postmenopausal women.91 **Fenugreek.** Fenugreek ( _Trigonella foenum-graecum_) seed is used traditionally to treat a range of conditions including high cholesterol levels, high glucose levels, and digestive problems, as well as promote breast milk production, relieve symptoms of premenstrual syndrome (PMS), and reduce menopausal symptoms.92 Fenugreek contains the phytoestrogen diosgenin, which may contribute to cardioprotective, neuroprotective, and immune-modulating effects.93,94 In a randomized placebo-controlled trial that included 48 perimenopausal women, 250 mg fenugreek extract twice daily for 42 days reduced symptoms, especially hot flashes, night sweats, depression, and insomnia, and improved hormone balance by increasing E2, progesterone, and testosterone levels and decreasing levels of FSH and sex hormone binding globulin (SHBG) (a protein that binds estrogen and testosterone, making them unavailable).95 Another randomized controlled trial that included 88 participants with moderate-to-severe menopausal symptoms found 1,000 mg fenugreek extract daily for 90 days improved hot flashes and other symptoms, as well as quality of life, and increased E2 levels compared with placebo.96 A trial in which 115 participants received 600 mg fenugreek extract or placebo daily for 12 weeks found fenugreek reduced hot flashes, night sweats, and psychosocial, physical, and sexual symptoms as well as overall menopausal symptom scores, without affecting E2 levels.97 Clinical evidence shows vaginal preparations with fenugreek may help treat menopause-related vaginal symptoms. In one trial, 60 postmenopausal women with vaginal atrophy were given a vaginal cream with 5% fenugreek extract or placebo; after eight weeks, atrophy was improved and symptoms were diminished in those using the fenugreek cream.98 In another trial with 60 participants, 0.5 grams of 5% fenugreek vaginal cream twice weekly for 12 weeks resulted in improvement in vaginal atrophy and its symptoms, but was not as effective as low-dose conjugated estrogen vaginal cream.99 **Licorice.** Licorice root ( _Glycyrrhiza glabra_ and other species) has a long history of use in Chinese and Ayurvedic herbal medicine traditions.100 Licorice extracts contain phytoestrogenic compounds and a number of other biologically active substances. Licorice-derived compounds have been shown to have a variety of effects in preclinical research, including anti-inflammatory, immune-modulating, antimicrobial, anti-ulcer, anti-clotting, liver-protective, and bone growth-promoting actions.100-103 Laboratory research has shown licorice phytoestrogens bind estrogen receptor sites with no more than 1/1,000th the affinity of E2 and with a preference for ER-beta, while other licorice compounds have anti-estrogenic effects; the overall effect appears to depend largely on the cell type.104 In particular, licorice’s main phytoestrogen, liquiritigenin, has demonstrated a substantially stronger binding affinity for ER-beta than ER-alpha105,106; in one study, liquiritigenin’s affinity for ER-beta was reported to be 13-times stronger than its affinity for ER-alpha.104 In a placebo-controlled trial that included 90 women with menopausal hot flashes, taking 330 mg licorice extract three times daily for eight weeks reduced hot flash frequency and intensity, and the effect did not diminish until two weeks after stopping treatment.107 A randomized clinical trial with 60 participants compared 1,140 mg per day of licorice to standard hormone replacement therapy (HRT) with 0.312 mg conjugated estrogens plus 2.5 mg medroxyprogesterone per day, taken for 90 days, on menopausal hot flashes. Licorice and hormone therapy were similarly effective for reducing hot flash number and duration, but hormone therapy was more effective for reducing hot flash intensity.108 In a trial in 70 women with vaginal atrophy, eight weeks of treatment with a vaginal cream containing 2% licorice was more effective than placebo for improving vaginal cell health and symptoms of vaginal atrophy.109 It is important to note that long-term, high-dosage use of licorice can cause sodium and water retention as well as potassium loss that may lead to increased blood pressure and edema.110,111 The compound responsible for these actions is called glycyrrhizin. The European Scientific Committee on Food recommends daily intake should be limited to less than 100 mg of glycyrrhizin, equivalent to approximately 60–70 grams of crude licorice. Although typically used doses of licorice are considered safe for most people, those with existing hypertension, kidney disease, or heart disease should use licorice with caution, unless it is deglycyrrhizinated (typically referred to as “DGL”).112 ## French Maritime Pine Bark French maritime pine bark extract, known widely under the trade name Pycnogenol, is rich in free radical-scavenging flavonoids called proanthocyanidins. In a randomized placebo-controlled trial with 200 perimenopausal participants, those given 200 mg Pycnogenol daily for six months had improvements in all menopausal symptoms, as well as lipid profile and antioxidant status.113 A controlled trial that included 38 women with menopausal symptoms given 100 mg Pycnogenol daily and 33 similar women given no treatment for eight weeks found those given Pycnogenol had reduced symptom scores for a subset of six common symptoms: hot flashes, night sweats, mood swings, sleep difficulty, low libido, vaginal dryness, and irregular menstrual periods.114 In a randomized placebo-controlled trial, 170 perimenopausal women were assigned to receive 30 mg Pycnogenol twice daily or placebo. After 12 weeks, menopausal symptom scores decreased by 56% in the Pycnogenol group compared with 39% in the placebo group, and hot flashes and sleep difficulties were particularly improved.115 Pine bark extract may have health benefits beyond relief of menopausal symptoms. Eight weeks of treatment with 100 mg Pycnogenol per day not only reduced menopausal symptoms but also improved cardiovascular risk profiles by lowering high blood pressure as well as cholesterol, triglyceride, blood glucose, homocysteine, CRP, and free radical levels in 35 postmenopausal women, while no such changes were seen in 35 matched controls.116 A randomized controlled trial in 43 postmenopausal women with osteopenia found 150 mg daily of a different French maritime pine bark extract improved markers of bone turnover and antioxidant status compared with placebo after 12 weeks.117 A combination of Pycnogenol plus two amino acids (L-arginine and L-citrulline) and rose hip extract was reported to improve vaginal symptoms and sexual function in peri- and postmenopausal women.118 Pycnogenol was also reported to improve skin elasticity and hydration after 12 weeks in 20 postmenopausal women participating in an uncontrolled trial.119 ## Vitex Vitex (or chaste tree, _Vitex agnus castus_) is widely used in the treatment of women’s health problems including menstrual disorders, PMS, breast pain, infertility, and menopausal symptoms.120,121 Although extracts from the berries are most often used, essential oil from vitex leaf has also been examined for its effects on menopausal symptoms, and has been reported to be potentially beneficial.122,123 Vitex extracts have demonstrated the ability to activate dopamine pathways in the nervous system, thereby inhibiting prolactin release and potentially normalizing hormonal cycles. Vitex has also been found to increase melatonin secretion without altering the normal circadian pattern, which may contribute to improved sleep in postmenopausal women.124,125 In a randomized placebo-controlled trial in 52 participants with menopausal symptoms, 30 mg vitex extract twice daily for eight weeks reduced hot flashes, anxiety, and total menopausal symptom scores.126 Vitex is often used in herbal combinations to treat menopausal symptoms. For example, clinical trials (described above) that tested vitex in combination with black cohosh, soy isoflavones, and evening primrose oil, or black cohosh, soy isoflavones, burdock, and wild yam have described beneficial effects in menopausal women.48,49 In an open uncontrolled trial, a combination of vitex plus soy isoflavones and magnolia ( _Magnolia officinalis_) for 12 months reduced hot flashes and mood and sleep symptoms in 71 healthy postmenopausal women. In addition, treatment reduced blood pressure, heart rate, homocysteine levels, and blood glucose levels, and improved markers of insulin resistance and inflammation.127 Another clinical trial with 180 participants compared a combination of vitex (40 mg), soy isoflavones (60 mg), magnolia (50 mg), _Lactobacillus sporogenes_ (109 spores \[the\ dormant form of this bacterium\]), and vitamin D (35 mcg or 1,400 IUs) to soy isoflavones alone for 12 months and found the combination formula was more effective for reducing frequency and intensity of hot flashes, and improving sleep and psychological wellness; and neither therapy caused changes in endometrial or breast tissue.128 Vitex may also enhance the effectiveness of antidepressant therapy in postmenopausal women. In an eight-week, randomized, placebo-controlled trial that included 46 menopausal women being treated with citalopram (Celexa), the addition of vitex (equivalent of 1,000 mg dried vitex berry daily) plus black cumin ( _Nigella sativa_, 500 mg ground seeds daily) to treatment resulted in greater improvements in hot flashes and physical and psychosocial functioning compared with placebo.129 ## Royal Jelly Royal jelly is a nutrient-dense substance produced by nurse bees and fed to queen bees throughout their lives and to worker bees in the early larval stage.130 Unlike honey, which is high in sugar and used as a sweetener, royal jelly is high in protein and is not generally consumed as food by humans.131 Royal jelly has demonstrated anti-inflammatory, free radical-quenching, antimicrobial, and immune-modulating effects, and may promote cardiovascular, metabolic, and neurological health. In addition, royal jelly has been found to affect female reproductive hormone activity by influencing estrogen receptor function and triggering epigenetic changes, giving it potential therapeutic effects in peri- and postmenopausal women.130,132 In a randomized controlled trial in 200 postmenopausal women, 1 gram of royal jelly, taken daily for eight weeks, led to greater reductions in menopausal symptom scores than placebo.133 Another placebo-controlled trial in 42 postmenopausal women found 800 mg of enzyme-treated royal jelly per day for 12 weeks significantly reduced anxiety and back pain, but not other menopausal symptoms.134 A trial that included 90 postmenopausal women with genitourinary symptoms compared treatment using a 15% royal jelly vaginal cream with vaginal estrogen therapy (conjugated equine estrogens) or a lubricant. After three months, those receiving royal jelly had greater improvement in sexual and urinary function and quality of life than those receiving estrogen or lubricant, although laboratory testing showed estrogen therapy was the most effective for reversing vaginal atrophy.135 ## St. John’s wort St. John’s wort ( _Hypericum perforatum_) is a plant best known for its use in the context of mood disorders, particularly depression.136 Randomized controlled trials in postmenopausal women have found treatment with St. John’s wort resulted in reduced intensity and severity of hot flashes as well as severity of depressive symptoms.137-139 In one trial, 47 symptomatic perimenopausal women given 900 mg St. John’s wort extract three times daily for 12 weeks had better quality of life and fewer sleep problems than those given placebo.140 Combinations of St. John’s wort and other herbs have also been investigated for their effects on menopausal symptoms. In a randomized placebo-controlled trial that included 100 peri- and postmenopausal women, treatment with St. John’s wort (900 mg daily) plus chaste tree extract (1,000 mg daily) for 16 weeks was not effective for reducing menopausal symptoms141; however, in a subgroup of 14 late-perimenopausal women with PMS-like symptoms, this herbal combination reduced these symptoms.142 In an observational study that monitored 6,141 menopausal women taking either a combination of St. John’s wort plus black cohosh or black cohosh alone for six months, St. John’s wort plus black cohosh was associated with greater improvement in mood symptoms.143 ## Evening Primrose Oil Evening primrose oil, known for its relatively high content of the anti-inflammatory omega-6 fatty acid gamma-linoleic acid (GLA), is often recommended for women’s health concerns, such as PMS, breast pain, gestational diabetes, and menopausal symptoms.144 In a four-week, randomized, placebo-controlled trial in 100 women with menopausal symptoms, psychological symptom scores decreased by 73% in those receiving 1,000 mg evening primrose oil (standardized to provide 70–140 mg of GLA) twice daily but were unchanged in those given placebo.145 An eight-week trial in which 189 women were given either 1,000 mg evening primrose oil daily or placebo also reported improvement in psychological symptoms related to menopause in those who received evening primrose oil.146 In a randomized controlled trial with 56 participants, taking 500 mg evening primrose oil twice daily for six weeks reduced menopausal hot flash severity, but not frequency or duration, more than placebo.147 A trial completed by 163 postmenopausal women found 1,000 mg evening primrose oil twice daily for eight weeks reduced the frequency and severity of night sweats compared with placebo. However, women in both groups experienced hot flashes to a similar extent.148 In addition, a small trial completed by 35 women found evening primrose oil at a dose of 2,000 mg, in addition to 40 mg natural vitamin E, twice daily for six months did not relieve hot flashes more than placebo.149 ## Valerian Valerian ( _Valeriana officinalis_) is a plant best known for its beneficial effects on sleep. In a randomized placebo-controlled trial in 60 women with menopause symptoms, 530 mg valerian extract twice daily for two months led to reductions in hot flash frequency and severity.150 In another trial in 68 women with menopausal hot flashes, 255 mg valerian extract three times daily for eight weeks was more effective than placebo at decreasing hot flash frequency and intensity.151 A trial that included 100 postmenopausal women experiencing insomnia found 530 mg valerian extract twice daily for four weeks improved sleep quality better than placebo.152 ## Maca Maca ( _Lepidium meyenii_) is a South American plant in the Brassica family used historically to treat infertility and other women’s hormonal health problems.153 Although clinical research is limited, one research group has conducted several randomized controlled trials and found maca has beneficial effects in peri- and postmenopausal women. In their first pilot trial, 20 early-postmenopausal women were given 1 gram of gelatinized maca powder tablets twice daily or placebo for two months, and eight participants received maca or placebo for eight months. Those who received maca had increases in E2, progesterone, and LH, and decreases in FSH levels relative to placebo, as well as reductions in stress and discomfort related to menopause; however, they did note a strong placebo effect.154 The same researchers conducted a four-month crossover trial with 20 perimenopausal women (each participant receiving two months of maca, at a dose of 1 gram twice daily, and two months of placebo, in random order) and found menopausal symptoms, such as hot flashes, night sweats, sleep problems, nervousness, depression, and heart palpitations, and improved parameters of metabolism were reduced during maca treatment.155 In a randomized placebo-controlled trial with 124 participants in early-postmenopause, 1 gram of gelatinized maca twice daily for three or four months increased E2 and lowered FSH levels, and decreased menopausal symptoms, especially hot flashes and night sweats.156 A follow-up study involving 12 of these participants found maca use was associated with increased levels of markers of bone density and improved symptoms of hot flashes, night sweats, and markers of the stress response.157 In a crossover trial performed by a different research group, scores on tests of psychological and mood symptoms, as well as sexual function, improved after six weeks of treatment with 3.5 grams of powdered maca per day relative to placebo in 14 postmenopausal women.158 A separate 12-week crossover study in 29 postmenopausal women randomized to receive 3.3 grams daily of maca or placebo, each for six weeks, found maca reduced symptoms of depression relative to placebo.159 ## Dong Quai Dong quai ( _Angelica sinensis_) has been used in traditional Chinese medicine, most often with astragalus ( _Astragalus membranaceus_, also referred to as huang qi), for centuries to treat menopausal symptoms and other women’s reproductive health problems.160,161 Preclinical evidence suggests don quai has phytoestrogenic effects and, with astragalus, may promote bone growth.162,163 In a randomized placebo-controlled trial in 100 women with menopausal symptoms, treatment with a traditional formulation of dong quai plus astragalus for six months led to a significant reduction in mild hot flashes, but no other improvements in menopausal symptoms, relative to placebo.164 A trial that included 55 symptomatic postmenopausal women found a combination of dong quai plus chamomile ( _Matricaria_ _chamomilla_) for 12 weeks reduced the number and intensity of hot flashes, sleep disturbance, and fatigue more than placebo.165 However, in a study with 71 participants, 1.5 grams of dong quai extract three times daily had no effect on hot flashes or other menopausal symptoms compared with placebo after 24 weeks.166 ## Sage Sage ( _Salvia officinalis_) is a common culinary herb that has been traditionally used for women’s hormone-related health concerns. Sage has been found to modulate neurotransmitter signaling, and studies in animals show sage has phytoestrogenic effects.167-171 It has also demonstrated anti-inflammatory, pain-relieving, free radical-scavenging, antimicrobial, memory-enhancing, and blood glucose- and cholesterol-lowering effects.172 In an uncontrolled trial in 30 symptomatic postmenopausal women, taking 100 mg sage extract daily for four weeks reduced the severity of hot flashes, night sweats, panic, and fatigue, and improved concentration.173 In another uncontrolled trial, 69 postmenopausal women experiencing at least five hot flashes per day were treated with 280 mg sage extract once daily. After eight weeks, their hot flashes decreased in frequency and intensity, and scores on tests of physical functioning, psychological functioning, and urogenital symptoms improved.174 ## Horsetail, Three-leaf Caper, and Lindera Horsetail ( _Equisetum arvense_), three-leaf caper ( _Crataeva_ _nurvala_), and lindera ( _Lindera aggregata_) have a safe history of use to support urinary tract health and may help support urinary regularity.175,176 A preclinical study using a rat model of overactive bladder found that bladder function was improved following administration of a combination of horsetail, three-leaf caper, and lindera extracts.177 The same combination was evaluated in a clinical study that included 88 women (average 62 years old) given 840 mg of the herbal blend or placebo once daily for eight weeks. Urinary frequency was normalized in those given the herbal extracts. Recipients of the herbal blend also reported improved quality of life and significant reductions in urinary urgency, nighttime urination, and incontinence.176 ## 8 Menopause & Perimenopause: Myths & Facts ## Myth \#1: The transition to menopause involves steadily declining hormone levels. **Fact:** Researchers now know estrogen levels, in particular, can be all over the map during perimenopause. That means some women will have symptoms related to high estrogen levels, like heavy, painful periods and symptoms of PMS, until just before menopause.2 ## Myth \#2: A woman cannot become pregnant during perimenopause. **Fact:** Although fertility decreases around the age of natural menopause, there is still a small chance of becoming pregnant during perimenopause. Most doctors recommend using contraception until a full 12 months pass without a period—in other words, until you reach menopause.319 ## Myth \#3: Hot flashes usually last for a year or two after menopause. **Fact:** The average duration of frequent or moderate-to-severe menopausal hot flashes is 7–10 years! And many women have mild hot flashes even longer.15 ## Myth \#4: A woman’s sex life ends at menopause. **Fact:** Although vaginal atrophy and its accompanying symptoms, such as dryness, irritation, and pain with sexual intercourse, are commonly experienced by postmenopausal women, there are numerous safe and effective therapies for relieving symptoms and improving sexual function after menopause. They include non-hormonal therapies like lubricants and vaginally applied nutrient therapies, as well as low- and ultra-low-dose vaginal preparations that supply estrogen directly to the vaginal tissue.12 ## Myth \#5: Hormone therapy is dangerous and should only be used in severe cases. **Fact:** Hormone therapy has come a long way over the past few decades. Low-dose and ultra-low-dose options with a high degree of safety are now available.320 What’s more, using hormone therapy during the first 10 years after menopause may actually reduce your risk of heart attack, stroke, and type 2 diabetes, as well as slow bone loss, restore vaginal tissue health, and relieve symptoms of menopause.178 Women also have a variety of delivery methods and hormone forms to choose from. Working with your doctor to select the optimal delivery and hormone combination can also enhance safety. ## Myth \#6: Phytoestrogens cause breast cancer. **Fact:** Phytoestrogens have a weaker ability to activate estrogen receptors (ERs) compared with estrogen and generally have an even weaker ability to bind to the type of ERs that predominate on breast cells. Phytoestrogens tend also to have preferential binding affinity for ER-beta, which may be more protective of breast tissue. In fact, phytoestrogens have complex actions that may include acting as anti-inflammatory, anti-proliferative, and free radical-scavenging agents that may protect against breast cancer.30 ## 9 Frequently Asked Questions About Menopause & Perimenopause ## How do you know if you are menopausal? In women over 45 years old, menopause is detected based on the clinical picture: variability, lengthening, and cessation of the menstrual cycle can be accurately presumed to indicate perimenopause or postmenopause. In women whose menstrual cycles cease before age 45, other causes need to be considered. Pregnancy is the most common cause of amenorrhea (lack of menstrual cycles) in women under 45 and should be investigated first. Other possible causes include obstruction due to scarring or anatomical reasons; dysfunction of the hypothalamic-pituitary-gonadal axis, such as due to polycystic ovary syndrome, hyperprolactinemia, pituitary tumor, obesity, anorexia nervosa, some cancers, and other problems affecting the ovaries, pituitary gland, or hypothalamus; and, endocrine disorders such as thyroid or adrenal disease.1 ### Menopause Series: Q&A With Dr. Crystal Gossard Menopause Series: Q&A with Dr. Crystal Gossard - YouTube Tap to unmute [Menopause Series: Q&A with Dr. Crystal Gossard](https://www.youtube.com/watch?v=qxDRFXFjj04) [Life Extension Wellness](https://www.youtube.com/channel/UCMCxYAb6EFMlPp99yeIkYlQ) Life Extension Wellness9.93K subscribers ## What is perimenopause and when does it start? Perimenopause is a symptomatic time before menstrual cycles stop completely (menopause). It begins when the lengths of menstrual cycles consistently differ by seven days or more, which may be three or more years before menopause.2 ## What is menopause and when does it start? Menopause is the time in a woman’s life when menstrual cycles cease. It is defined as 12 months after the last menstrual period. The average age of menopause is around 46–52 years depending on ethnicity and geography.1,5 ## How is menopause different than perimenopause? Perimenopause is the symptomatic time before and around menopause and can last several years.2 Menopause is a point in time 12 months after a woman’s last menstrual period. The postmenopausal stage continues for the rest of a woman’s life.1 ## What are common perimenopause symptoms? Women in perimenopause experience menstrual irregularity and may have hot flashes, sleep difficulty, depressed mood or anxiety, and vaginal dryness, especially in late perimenopause.17 ## What supplements may help during perimenopause? Herbs with compounds called phytoestrogens have been shown to relieve symptoms of perimenopause and may help prevent long-term consequences of estrogen depletion.26 Examples include Siberian rhubarb, black cohosh, and soy isoflavones. Other plants and plant-derived compounds that may help include lignans, licorice, dong quai, and chaste tree. ## What are the stages of menopause? Perimenopause, marked by increasing irregularity and lengthening of menstrual cycles, and postmenopause, which begins 12 months after the last menstrual period.1 ## What are the top symptoms of menopause? A year with no menstrual periods and menopause symptoms such as: - hot flashes2 - vaginal dryness2 - sleep problems2 - anxious or depressed mood2 - weight gain16 - difficulty concentrating20 - fatigue22 - heart discomfort24 - joint and muscle pain25 ## What nutrients do you need during menopause? A well-balanced nutrient-dense diet, high in plant foods and fiber and supplying adequate vitamins, minerals, polyunsaturated fatty acids, protein, and phytonutrients, may protect health and quality of life through the menopause transition and into later life.266-269 Eating foods high in phytoestrogens, such as soy foods and flaxseeds, may also help reduce menopausal symptoms and protect long-term health.63,280 ### Update History ### 2024 - **Apr**: Updated sections on hormone therapies and other therapies in Treatment for Symptoms of Menopause ### 2023 - **Jun**: Initial publication ### _Disclaimer and Safety Information_ _This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein._ _The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature._ ### References 001. Peacock K, Ketvertis KM, Doerr C. Menopause (Nursing). _StatPearls_. StatPearls Publishing Copyright © 2022, StatPearls Publishing LLC.; 2023. 002. El Khoudary SR, Greendale G, Crawford SL, et al. The menopause transition and women's health at midlife: a progress report from the Study of Women's Health Across the Nation (SWAN). _Menopause_. 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