Woman on the beach thinking about life after menopause

Menopause & Perimenopause

Menopause & Perimenopause

Last Section Update: 06/2023

Contributor(s): Maureen Williams, ND; Shayna Sandhaus, PhD; Stephen Tapanes, PhD; Scott Fogle, ND; Franco Melis; Shanti Albani, ND

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

The symptoms of menopause shown as a cartoon chart 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 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

Menopause Series: Siberian Rhubarb with Dr. Michael A. Smith MD

Siberian rhubarb extract. A standardized extract from the root of Siberian rhubarb (Rheum rhaponticum), known as Err 731, 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 Err 731 daily for 12 weeks compared with a 3-point decrease in those taking placebo.35 Two similar trials, each including 109 perimenopausal women, found 4 mg Err 731 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 Err 731 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 Err 731 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 Err 731 can safely and effectively improve symptoms in perimenopausal women.39,40

A safety review examined adverse events reported by women using ERr 731 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

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

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

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 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

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

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

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.

  1. Peacock K, Ketvertis KM, Doerr C. Menopause (Nursing). StatPearls. StatPearls Publishing Copyright © 2022, StatPearls Publishing LLC.; 2023.
  2. 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. Oct 2019;26(10):1213-1227. doi:10.1097/GME.0000000000001424.  https://www.ncbi.nlm.nih.gov/pubmed/31568098
  3. Davis SR, Baber RJ. Treating menopause - MHT and beyond. Nature reviews Endocrinology. Aug 2022;18(8):490-502. doi:10.1038/s41574-022-00685-4. https://www.ncbi.nlm.nih.gov/pubmed/35624141
  4. Casper R F, Barbieri R L (ed.), Crowley W F (ed.), Martin K A (ed.). Clinical manifestations and diagnosis of menopause. UpToDate. Updated Feb. 28, 2023. Accessed Apr. 18, 2023, https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-menopause?search=menopause&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
  5. Williams M, Richard-Davis G, Williams PL, Christensen L, Ward E, Schrager S. A review of African American women's experiences in menopause. Menopause. Nov 1 2022;29(11):1331-1337. doi:10.1097/GME.0000000000002060. https://www.ncbi.nlm.nih.gov/pubmed/36126249
  6. Nappi RE, Chedraui P, Lambrinoudaki I, Simoncini T. Menopause: a cardiometabolic transition. Lancet Diabetes Endocrinol. Jun 2022;10(6):442-456. doi:10.1016/S2213-8587(22)00076-6. https://www.ncbi.nlm.nih.gov/pubmed/35525259
  7. Lobo RA, Gompel A. Management of menopause: a view towards prevention. Lancet Diabetes Endocrinol. Jun 2022;10(6):457-470. doi:10.1016/S2213-8587(21)00269-2. https://www.ncbi.nlm.nih.gov/pubmed/35526556
  8. Buckinx F, Aubertin-Leheudre M. Sarcopenia in Menopausal Women: Current Perspectives. International journal of women's health. 2022;14:805-819. doi:10.2147/IJWH.S340537. https://www.ncbi.nlm.nih.gov/pubmed/35769543
  9. Jett S, Schelbaum E, Jang G, et al. Ovarian steroid hormones: A long overlooked but critical contributor to brain aging and Alzheimer's disease. Front Aging Neurosci. 2022;14:948219. doi:10.3389/fnagi.2022.948219. https://www.ncbi.nlm.nih.gov/pubmed/35928995
  10. Martin KA, Barbieri RL, Crowley WF (ed.), Mulder JE (ed.). Treatment of menopausal symptoms with hormone therapy. UpToDate. Accessed Feb. 2, 2023, https://www.uptodate.com/contents/treatment-of-menopausal-symptoms-with-hormone-therapy?search=menopausal%20hormone%20therapy&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H21
  11. Pinkerton JV. Concerns About Compounded Bioidentical Menopausal Hormone Therapy. The Cancer Journal. 2022;28(3)https://journals.lww.com/journalppo/Fulltext/2022/05000/Concerns_About_Compounded_Bioidentical_Menopausal.11.aspx
  12. Nappi RE, Martini E, Cucinella L, et al. Addressing Vulvovaginal Atrophy (VVA)/Genitourinary Syndrome of Menopause (GSM) for Healthy Aging in Women. Front Endocrinol (Lausanne). 2019;10:561. doi:10.3389/fendo.2019.00561. https://www.ncbi.nlm.nih.gov/pubmed/31496993
  13. Brady PH, Gin GT, Rosenblum E, Wilkinson LD. Female Pelvic Conditions: Genitourinary Syndrome of Menopause. FP essentials. Apr 2022;515:32-42. https://www.ncbi.nlm.nih.gov/pubmed/35420405
  14. Peters KJ. What Is Genitourinary Syndrome of Menopause and Why Should We Care? Perm J. May 2021;25doi:10.7812/TPP/20.248. https://www.ncbi.nlm.nih.gov/pubmed/33970091
  15. Thurston RC. Vasomotor symptoms: natural history, physiology, and links with cardiovascular health. Climacteric : the journal of the International Menopause Society. Apr 2018;21(2):96-100. doi:10.1080/13697137.2018.1430131. https://www.ncbi.nlm.nih.gov/pubmed/29390899
  16. Kodoth V, Scaccia S, Aggarwal B. Adverse Changes in Body Composition During the Menopausal Transition and Relation to Cardiovascular Risk: A Contemporary Review. Womens Health Rep (New Rochelle). 2022;3(1):573-581. doi:10.1089/whr.2021.0119. https://www.ncbi.nlm.nih.gov/pubmed/35814604
  17. Santoro N. Perimenopause: From Research to Practice. Journal of women's health (2002). Apr 2016;25(4):332-9. doi:10.1089/jwh.2015.5556. https://www.ncbi.nlm.nih.gov/pubmed/26653408
  18. Bromberger JT, Kravitz HM, Chang Y, et al. Does risk for anxiety increase during the menopausal transition? Study of women's health across the nation. Menopause. May 2013;20(5):488-95. doi:10.1097/GME.0b013e3182730599. https://www.ncbi.nlm.nih.gov/pubmed/23615639
  19. Bromberger JT, Schott LL, Kravitz HM, et al. Longitudinal change in reproductive hormones and depressive symptoms across the menopausal transition: results from the Study of Women's Health Across the Nation (SWAN). Archives of general psychiatry. Jun 2010;67(6):598-607. doi:10.1001/archgenpsychiatry.2010.55. https://www.ncbi.nlm.nih.gov/pubmed/20530009
  20. Maki PM, Henderson VW. Cognition and the menopause transition. Menopause. Jul 2016;23(7):803-5. doi:10.1097/GME.0000000000000681. https://www.ncbi.nlm.nih.gov/pubmed/27272226
  21. Mosconi L, Berti V, Dyke J, et al. Menopause impacts human brain structure, connectivity, energy metabolism, and amyloid-beta deposition. Sci Rep. Jun 9 2021;11(1):10867. doi:10.1038/s41598-021-90084-y. https://www.ncbi.nlm.nih.gov/pubmed/34108509
  22. Taylor-Swanson L, Wong AE, Pincus D, et al. The dynamics of stress and fatigue across menopause: attractors, coupling, and resilience. Menopause. Apr 2018;25(4):380-390. doi:10.1097/GME.0000000000001025. https://www.ncbi.nlm.nih.gov/pubmed/29189603
  23. Kamp E, Ashraf M, Musbahi E, DeGiovanni C. Menopause, skin and common dermatoses. Part 1: hair disorders. Clin Exp Dermatol. Dec 2022;47(12):2110-2116. doi:10.1111/ced.15327. https://www.ncbi.nlm.nih.gov/pubmed/35796569
  24. Carpenter JS, Sheng Y, Elomba CD, et al. A Systematic Review of Palpitations Prevalence by Menopausal Status. Current Obstetrics and Gynecology Reports. 2021/03/01 2021;10(1):7-13. doi:10.1007/s13669-020-00302-z. https://doi.org/10.1007/s13669-020-00302-z https://link.springer.com/content/pdf/10.1007/s13669-020-00302-z.pdf
  25. Watt FE. Musculoskeletal pain and menopause. Post Reprod Health. Mar 2018;24(1):34-43. doi:10.1177/2053369118757537. https://www.ncbi.nlm.nih.gov/pubmed/29412042
  26. Rowe IJ, Baber RJ. The effects of phytoestrogens on postmenopausal health. Climacteric : the journal of the International Menopause Society. Feb 2021;24(1):57-63. doi:10.1080/13697137.2020.1863356. https://www.ncbi.nlm.nih.gov/pubmed/33395316
  27. Wang X, Ha D, Yoshitake R, Chan YS, Sadava D, Chen S. Exploring the Biological Activity and Mechanism of Xenoestrogens and Phytoestrogens in Cancers: Emerging Methods and Concepts. Int J Mol Sci. Aug 16 2021;22(16)doi:10.3390/ijms22168798. https://www.ncbi.nlm.nih.gov/pubmed/34445499
  28. Farkas S, Szabo A, Hegyi AE, et al. Estradiol and Estrogen-like Alternative Therapies in Use: The Importance of the Selective and Non-Classical Actions. Biomedicines. Apr 6 2022;10(4)doi:10.3390/biomedicines10040861. https://www.ncbi.nlm.nih.gov/pubmed/35453610
  29. Petrine JCP, Del Bianco-Borges B. The influence of phytoestrogens on different physiological and pathological processes: An overview. Phytother Res. Jan 2021;35(1):180-197. doi:10.1002/ptr.6816. https://www.ncbi.nlm.nih.gov/pubmed/32780464
  30. Domínguez-López I, Yago-Aragón M, Salas-Huetos A, Tresserra-Rimbau A, Hurtado-Barroso S. Effects of Dietary Phytoestrogens on Hormones throughout a Human Lifespan: A Review. Nutrients. Aug 15 2020;12(8)doi:10.3390/nu12082456.
  31. Abdi F, Rahnemaei FA, Roozbeh N, Pakzad R. Impact of phytoestrogens on treatment of urogenital menopause symptoms: A systematic review of randomized clinical trials. European journal of obstetrics, gynecology, and reproductive biology. Jun 2021;261:222-235. doi:10.1016/j.ejogrb.2021.03.039. https://www.ncbi.nlm.nih.gov/pubmed/33962824
  32. Chang JL, Montalto MB, Heger PW, Thiemann E, Rettenberger R, Wacker J. Rheum rhaponticum Extract (ERr 731): Postmarketing Data on Safety Surveillance and Consumer Complaints. Integr Med (Encinitas). Jun 2016;15(3):34-9. https://www.ncbi.nlm.nih.gov/pubmed/27547165
  33. Wober J, Moller F, Richter T, et al. Activation of estrogen receptor-beta by a special extract of Rheum rhaponticum (ERr 731), its aglycones and structurally related compounds. J Steroid Biochem Mol Biol. Nov-Dec 2007;107(3-5):191-201. doi:10.1016/j.jsbmb.2007.04.002. https://www.ncbi.nlm.nih.gov/pubmed/17692514
  34. Moller F, Zierau O, Jandausch A, Rettenberger R, Kaszkin-Bettag M, Vollmer G. Subtype-specific activation of estrogen receptors by a special extract of Rheum rhaponticum (ERr 731), its aglycones and structurally related compounds in U2OS human osteosarcoma cells. Phytomedicine. Nov 2007;14(11):716-26. doi:10.1016/j.phymed.2007.09.001. https://www.ncbi.nlm.nih.gov/pubmed/17935960
  35. Kaszkin-Bettag M, Ventskovskiy BM, Solskyy S, et al. Confirmation of the efficacy of ERr 731 in perimenopausal women with menopausal symptoms. Altern Ther Health Med. Jan-Feb 2009;15(1):24-34. https://www.ncbi.nlm.nih.gov/pubmed/19161045
  36. Heger M, Ventskovskiy BM, Borzenko I, et al. Efficacy and safety of a special extract of Rheum rhaponticum (ERr 731) in perimenopausal women with climacteric complaints: a 12-week randomized, double-blind, placebo-controlled trial. Menopause. Sep-Oct 2006;13(5):744-59. doi:10.1097/01.gme.0000240632.08182.e4. https://www.ncbi.nlm.nih.gov/pubmed/16894335
  37. Kaszkin-Bettag M, Ventskovskiy BM, Kravchenko A, et al. The special extract ERr 731 of the roots of Rheum rhaponticum decreases anxiety and improves health state and general well-being in perimenopausal women. Menopause. Mar-Apr 2007;14(2):270-83. doi:10.1097/01.gme.0000251932.48426.35. https://www.ncbi.nlm.nih.gov/pubmed/17213754
  38. Hasper I, Ventskovskiy BM, Rettenberger R, Heger PW, Riley DS, Kaszkin-Bettag M. Long-term efficacy and safety of the special extract ERr 731 of Rheum rhaponticum in perimenopausal women with menopausal symptoms. Menopause. Jan-Feb 2009;16(1):117-31. doi:10.1097/GME.0b013e3181806446. https://www.ncbi.nlm.nih.gov/pubmed/18978638
  39. Shah J, Chandanani S, Reddy J, et al. Evaluation of the Efficacy and Safety of Rheum rhaponticum Root Extract (ERr 731) for Menopausal Symptoms in Perimenopausal Indian Women: An Interim Analysis. Journal of mid-life health. Apr-Jun 2021;12(2):108-115. doi:10.4103/jmh.jmh_86_21. https://www.ncbi.nlm.nih.gov/pubmed/34526744
  40. Kaszkin-Bettag M, Beck S, Richardson A, Heger PW, Beer AM. Efficacy of the special extract ERr 731 from rhapontic rhubarb for menopausal complaints: a 6-month open observational study. Altern Ther Health Med. Nov-Dec 2008;14(6):32-8. https://www.ncbi.nlm.nih.gov/pubmed/19043936
  41. Guida M, Raffone A, Travaglino A, et al. Cimicifuga racemosa isopropanolic extract for menopausal symptoms: an observational prospective case-control study. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. Dec 2021;37(12):1132-1137. doi:10.1080/09513590.2021.1974381. https://www.ncbi.nlm.nih.gov/pubmed/34477029
  42. Castelo-Branco C, Navarro C, Beltran E, Losa F, Camacho M, on the behalf of the Natural Products Study Group of the Spanish Menopause S. Black cohosh efficacy and safety for menopausal symptoms. The Spanish Menopause Society statement. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. May 2022;38(5):379-384. doi:10.1080/09513590.2022.2056591. https://www.ncbi.nlm.nih.gov/pubmed/35403534
  43. Castelo-Branco C, Gambacciani M, Cano A, et al. Review & meta-analysis: isopropanolic black cohosh extract iCR for menopausal symptoms - an update on the evidence. Climacteric : the journal of the International Menopause Society. Apr 2021;24(2):109-119. doi:10.1080/13697137.2020.1820477. https://www.ncbi.nlm.nih.gov/pubmed/33021111
  44. Fernandes ES, Celani MFS, Fistarol M, Geber S. Effectiveness of the short-term use of Cimicifuga racemosa in the endothelial function of postmenopausal women: a double-blind, randomized, controlled trial. Climacteric : the journal of the International Menopause Society. Jun 2020;23(3):245-251. doi:10.1080/13697137.2019.1682542. https://www.ncbi.nlm.nih.gov/pubmed/31691621
  45. Gorach NV. Effects of cimicifuga racemosa on the hemodynamics parameters and quality of life in perimenopausal women with arterial hypertension. Wiadomosci lekarskie (Warsaw, Poland : 1960). 2018;71(5):1010-1014. https://www.ncbi.nlm.nih.gov/pubmed/30176632
  46. Mohapatra S, Iqubal A, Ansari MJ, et al. Benefits of Black Cohosh (Cimicifuga racemosa) for Women Health: An Up-Close and In-Depth Review. Pharmaceuticals (Basel). Feb 23 2022;15(3)doi:10.3390/ph15030278. https://www.ncbi.nlm.nih.gov/pubmed/35337076
  47. Pkhaladze L, Davidova N, Khomasuridze A, Shengelia R, Panossian AG. Actaea racemosa L. Is More Effective in Combination with Rhodiola rosea L. for Relief of Menopausal Symptoms: A Randomized, Double-Blind, Placebo-Controlled Study. Pharmaceuticals (Basel). May 21 2020;13(5)doi:10.3390/ph13050102. https://www.ncbi.nlm.nih.gov/pubmed/32455817
  48. Rattanatantikul T, Maiprasert M, Sugkraroek P, Bumrungpert A. Efficacy and Safety of Nutraceutical on Menopausal Symptoms in Post-Menopausal Women: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. J Diet Suppl. 2022;19(2):168-183. doi:10.1080/19390211.2020.1853648. https://www.ncbi.nlm.nih.gov/pubmed/33331798
  49. Shayan A, Masoumi SZ, Kazemi F, Oshvandi K. Effect of Combined Herbal Capsule Menohelp on Hot Flashes and Night Sweats in Postmenopausal Women: A Single-Blind Randomized Controlled Trial. Journal of menopausal medicine. Aug 2020;26(2):135-142. doi:10.6118/jmm.20002. https://www.ncbi.nlm.nih.gov/pubmed/32893515
  50. Rotem C, Kaplan B. Phyto-Female Complex for the relief of hot flushes, night sweats and quality of sleep: randomized, controlled, double-blind pilot study. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. Feb 2007;23(2):117-22. doi:10.1080/09513590701200900.
  51. Henneicke-von Zepelin HH. 60 years of Cimicifuga racemosa medicinal products : Clinical research milestones, current study findings and current development. Wien Med Wochenschr. May 2017;167(7-8):147-159. 60 Jahre Arzneimittel aus Cimicifuga racemosa : Meilensteine klinischer Forschung, aktuelle Studienergebnisse und derzeitige Entwicklung. doi:10.1007/s10354-016-0537-z. https://www.ncbi.nlm.nih.gov/pubmed/28155126
  52. Ruan X, Mueck AO, Beer AM, Naser B, Pickartz S. Benefit-risk profile of black cohosh (isopropanolic Cimicifuga racemosa extract) with and without St John's wort in breast cancer patients. Climacteric : the journal of the International Menopause Society. Aug 2019;22(4):339-347. doi:10.1080/13697137.2018.1551346. https://www.ncbi.nlm.nih.gov/pubmed/30626212
  53. Chen LR, Chen KH. Utilization of Isoflavones in Soybeans for Women with Menopausal Syndrome: An Overview. Int J Mol Sci. Mar 22 2021;22(6)doi:10.3390/ijms22063212. https://www.ncbi.nlm.nih.gov/pubmed/33809928 https://mdpi-res.com/d_attachment/ijms/ijms-22-03212/article_deploy/ijms-22-03212.pdf?version=1616405994
  54. Daily JW, Ko BS, Ryuk J, Liu M, Zhang W, Park S. Equol Decreases Hot Flashes in Postmenopausal Women: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. J Med Food. Feb 2019;22(2):127-139. doi:10.1089/jmf.2018.4265. https://www.ncbi.nlm.nih.gov/pubmed/30592686
  55. Crisafulli A, Marini H, Bitto A, et al. Effects of genistein on hot flushes in early postmenopausal women: a randomized, double-blind EPT- and placebo-controlled study. Menopause. Jul-Aug 2004;11(4):400-4. doi:10.1097/01.gme.0000109314.11228.e5. https://www.ncbi.nlm.nih.gov/pubmed/15243277
  56. D'Anna R, Cannata ML, Marini H, et al. Effects of the phytoestrogen genistein on hot flushes, endometrium, and vaginal epithelium in postmenopausal women: a 2-year randomized, double-blind, placebo-controlled study. Menopause. Mar-Apr 2009;16(2):301-6. doi:10.1097/gme.0b013e318186d7e2. https://www.ncbi.nlm.nih.gov/pubmed/19034051
  57. Fang K, Dong H, Wang D, Gong J, Huang W, Lu F. Soy isoflavones and glucose metabolism in menopausal women: A systematic review and meta-analysis of randomized controlled trials. Mol Nutr Food Res. Jul 2016;60(7):1602-14. doi:10.1002/mnfr.201501024. https://www.ncbi.nlm.nih.gov/pubmed/27004555
  58. Baranska A, Blaszczuk A, Kanadys W, et al. Effects of Soy Protein Containing of Isoflavones and Isoflavones Extract on Plasma Lipid Profile in Postmenopausal Women as a Potential Prevention Factor in Cardiovascular Diseases: Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrients. Jul 24 2021;13(8)doi:10.3390/nu13082531. https://www.ncbi.nlm.nih.gov/pubmed/34444691
  59. Sathyapalan T, Aye M, Rigby AS, et al. Soy isoflavones improve cardiovascular disease risk markers in women during the early menopause. Nutr Metab Cardiovasc Dis. Jul 2018;28(7):691-697. doi:10.1016/j.numecd.2018.03.007. https://www.ncbi.nlm.nih.gov/pubmed/29739677
  60. Boutas I, Kontogeorgi A, Dimitrakakis C, Kalantaridou SN. Soy Isoflavones and Breast Cancer Risk: A Meta-analysis. In Vivo. Mar-Apr 2022;36(2):556-562. doi:10.21873/invivo.12737. https://www.ncbi.nlm.nih.gov/pubmed/35241506
  61. Touillaud M, Gelot A, Mesrine S, et al. Use of dietary supplements containing soy isoflavones and breast cancer risk among women aged >50 y: a prospective study. Am J Clin Nutr. Mar 1 2019;109(3):597-605. doi:10.1093/ajcn/nqy313. https://www.ncbi.nlm.nih.gov/pubmed/30831601
  62. Leonard LM, Choi MS, Cross TL. Maximizing the Estrogenic Potential of Soy Isoflavones through the Gut Microbiome: Implication for Cardiometabolic Health in Postmenopausal Women. Nutrients. Jan 27 2022;14(3)doi:10.3390/nu14030553. https://www.ncbi.nlm.nih.gov/pubmed/35276910
  63. Mayo B, Vazquez L, Florez AB. Equol: A Bacterial Metabolite from The Daidzein Isoflavone and Its Presumed Beneficial Health Effects. Nutrients. Sep 16 2019;11(9)doi:10.3390/nu11092231. https://www.ncbi.nlm.nih.gov/pubmed/31527435
  64. Sekikawa A, Ihara M, Lopez O, et al. Effect of S-equol and Soy Isoflavones on Heart and Brain. Curr Cardiol Rev. 2019;15(2):114-135. doi:10.2174/1573403X15666181205104717. https://www.ncbi.nlm.nih.gov/pubmed/30516108
  65. Franke AA, Lai JF, Halm BM, et al. Equol production changes over time in postmenopausal women. J Nutr Biochem. Jun 2012;23(6):573-9. doi:10.1016/j.jnutbio.2011.03.002. https://www.ncbi.nlm.nih.gov/pubmed/21775122
  66. Setchell KD, Cole SJ. Method of defining equol-producer status and its frequency among vegetarians. J Nutr. Aug 2006;136(8):2188-93. doi:10.1093/jn/136.8.2188. https://www.ncbi.nlm.nih.gov/pubmed/16857839
  67. Iino C, Shimoyama T, Iino K, et al. Daidzein Intake Is Associated with Equol Producing Status through an Increase in the Intestinal Bacteria Responsible for Equol Production. Nutrients. Feb 19 2019;11(2)doi:10.3390/nu11020433. https://www.ncbi.nlm.nih.gov/pubmed/30791484
  68. Nakatsu CH, Armstrong A, Clavijo AP, Martin BR, Barnes S, Weaver CM. Fecal bacterial community changes associated with isoflavone metabolites in postmenopausal women after soy bar consumption. PLoS One. 2014;9(10):e108924. doi:10.1371/journal.pone.0108924. https://www.ncbi.nlm.nih.gov/pubmed/25271941
  69. Ko TF, Tsai HS, Lin SM, Liu CD, Learn SP, Chiou RY. GC-MS determined distribution of urinary equol producers as affected by age, gender, and repeated ingestions of soymilk. J Food Sci. Nov-Dec 2010;75(9):H306-10. doi:10.1111/j.1750-3841.2010.01860.x. https://www.ncbi.nlm.nih.gov/pubmed/21535605
  70. Tanaka M, Fujimoto K, Chihara Y, et al. Isoflavone supplements stimulated the production of serum equol and decreased the serum dihydrotestosterone levels in healthy male volunteers. Prostate Cancer Prostatic Dis. 2009;12(3):247-52. doi:10.1038/pcan.2009.10. https://www.ncbi.nlm.nih.gov/pubmed/19597532
  71. Nettleton JA, Greany KA, Thomas W, Wangen KE, Adlercreutz H, Kurzer MS. Plasma phytoestrogens are not altered by probiotic consumption in postmenopausal women with and without a history of breast cancer. J Nutr. Aug 2004;134(8):1998-2003. doi:10.1093/jn/134.8.1998. https://www.ncbi.nlm.nih.gov/pubmed/15284389
  72. Bonorden MJ, Greany KA, Wangen KE, et al. Consumption of Lactobacillus acidophilus and Bifidobacterium longum do not alter urinary equol excretion and plasma reproductive hormones in premenopausal women. Eur J Clin Nutr. Dec 2004;58(12):1635-42. doi:10.1038/sj.ejcn.1602020. https://www.ncbi.nlm.nih.gov/pubmed/15213709
  73. Teas J, Hurley TG, Hebert JR, Franke AA, Sepkovic DW, Kurzer MS. Dietary seaweed modifies estrogen and phytoestrogen metabolism in healthy postmenopausal women. J Nutr. May 2009;139(5):939-44. doi:10.3945/jn.108.100834. https://www.ncbi.nlm.nih.gov/pubmed/19321575
  74. Rowland IR, Wiseman H, Sanders TA, Adlercreutz H, Bowey EA. Interindividual variation in metabolism of soy isoflavones and lignans: influence of habitual diet on equol production by the gut microflora. Nutr Cancer. 2000;36(1):27-32. doi:10.1207/S15327914NC3601_5. https://www.ncbi.nlm.nih.gov/pubmed/10798213
  75. Vázquez L, Flórez AB, Verbruggen S, et al. Modulation of equol production via different dietary regimens in an artificial model of the human colon. Journal of Functional Foods. 2020/03/01/ 2020;66:103819. doi:10.1016/j.jff.2020.103819. https://www.sciencedirect.com/science/article/pii/S1756464620300438
  76. Setchell KD, Brown NM, Summer S, et al. Dietary factors influence production of the soy isoflavone metabolite s-(-)equol in healthy adults. J Nutr. Dec 2013;143(12):1950-8. doi:10.3945/jn.113.179564. https://www.ncbi.nlm.nih.gov/pubmed/24089421
  77. Mohsen A, Fatemeh K, Leila N, Mona P, Mohammad Z, Mozafar K. Pharmacological and therapeutic properties of the Red Clover (Trifolium pratense L.): an overview of the new finding. J Tradit Chin Med. Aug 2021;41(4):642-649. doi:10.19852/j.cnki.jtcm.20210324.001. https://www.ncbi.nlm.nih.gov/pubmed/34392659
  78. Kanadys W, Baranska A, Blaszczuk A, et al. Evaluation of Clinical Meaningfulness of Red Clover (Trifolium pratense L.) Extract to Relieve Hot Flushes and Menopausal Symptoms in Peri- and Post-Menopausal Women: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrients. Apr 11 2021;13(4)doi:10.3390/nu13041258. https://www.ncbi.nlm.nih.gov/pubmed/33920485
  79. Myers SP, Vigar V. Effects of a standardised extract of Trifolium pratense (Promensil) at a dosage of 80mg in the treatment of menopausal hot flushes: A systematic review and meta-analysis. Phytomedicine. Jan 15 2017;24:141-147. doi:10.1016/j.phymed.2016.12.003. https://www.ncbi.nlm.nih.gov/pubmed/28160855
  80. Blaszczuk A, Baranska A, Kanadys W, et al. Role of Phytoestrogen-Rich Bioactive Substances (Linum usitatissimum L., Glycine max L., Trifolium pratense L.) in Cardiovascular Disease Prevention in Postmenopausal Women: A Systematic Review and Meta-Analysis. Nutrients. Jun 14 2022;14(12)doi:10.3390/nu14122467. https://www.ncbi.nlm.nih.gov/pubmed/35745197
  81. Kanadys W, Baranska A, Jedrych M, Religioni U, Janiszewska M. Effects of red clover (Trifolium pratense) isoflavones on the lipid profile of perimenopausal and postmenopausal women-A systematic review and meta-analysis. Maturitas. Feb 2020;132:7-16. doi:10.1016/j.maturitas.2019.11.001. https://www.ncbi.nlm.nih.gov/pubmed/31883666
  82. Wickham KA, Norregaard LB, Oxfeldt M, et al. Short-Term Supplementation With Fermented Red Clover Extract Reduces Vascular Inflammation in Early Post-menopausal Women. Front Cardiovasc Med. 2022;9:826959. doi:10.3389/fcvm.2022.826959. https://www.ncbi.nlm.nih.gov/pubmed/35224058
  83. Bolton JL, Dunlap TL, Hajirahimkhan A, et al. The Multiple Biological Targets of Hops and Bioactive Compounds. Chemical research in toxicology. Feb 18 2019;32(2):222-233. doi:10.1021/acs.chemrestox.8b00345. https://www.ncbi.nlm.nih.gov/pubmed/30608650
  84. Stulikova K, Karabin M, Nespor J, Dostalek P. Therapeutic Perspectives of 8-Prenylnaringenin, a Potent Phytoestrogen from Hops. Molecules. Mar 15 2018;23(3)doi:10.3390/molecules23030660. https://www.ncbi.nlm.nih.gov/pubmed/29543713
  85. van Hunsel F, van de Koppel S, van Puijenbroek E. Post-Menopausal Vaginal Hemorrhage Related to the Use of a Hop-Containing Phytotherapeutic Product. Drug Saf Case Rep. Dec 2015;2(1):14. doi:10.1007/s40800-015-0016-2. https://www.ncbi.nlm.nih.gov/pubmed/27747726
  86. Keiler AM, Zierau O, Kretzschmar G. Hop extracts and hop substances in treatment of menopausal complaints. Planta Med. May 2013;79(7):576-9. doi:10.1055/s-0032-1328330.
  87. Aghamiri V, Mirghafourvand M, Mohammad-Alizadeh-Charandabi S, Nazemiyeh H. The effect of Hop (Humulus lupulus L.) on early menopausal symptoms and hot flashes: A randomized placebo-controlled trial. Complement Ther Clin Pract. May 2016;23:130-5. doi:10.1016/j.ctcp.2015.05.001. https://www.ncbi.nlm.nih.gov/pubmed/25982391
  88. Heyerick A, Vervarcke S, Depypere H, Bracke M, De Keukeleire D. A first prospective, randomized, double-blind, placebo-controlled study on the use of a standardized hop extract to alleviate menopausal discomforts. Maturitas. May 20 2006;54(2):164-75. doi:10.1016/j.maturitas.2005.10.005. https://www.ncbi.nlm.nih.gov/pubmed/16321485
  89. Erkkola R, Vervarcke S, Vansteelandt S, Rompotti P, De Keukeleire D, Heyerick A. A randomized, double-blind, placebo-controlled, cross-over pilot study on the use of a standardized hop extract to alleviate menopausal discomforts. Phytomedicine. May 2010;17(6):389-96. doi:10.1016/j.phymed.2010.01.007.
  90. Kim HI, Kim MK, Lee I, Yun J, Kim EH, Seo SK. Efficacy and Safety of a Standardized Soy and Hop Extract on Menopausal Symptoms: A 12-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Trial. J Altern Complement Med. Nov 2021;27(11):959-967. doi:10.1089/acm.2021.0027. https://www.ncbi.nlm.nih.gov/pubmed/34399063
  91. Morali G, Polatti F, Metelitsa EN, Mascarucci P, Magnani P, Marre GB. Open, non-controlled clinical studies to assess the efficacy and safety of a medical device in form of gel topically and intravaginally used in postmenopausal women with genital atrophy. Arzneimittelforschung. 2006;56(3):230-8. doi:10.1055/s-0031-1296715. https://www.ncbi.nlm.nih.gov/pubmed/16618016
  92. Sun W, Shahrajabian MH, Cheng Q. Fenugreek Cultivation with Emphasis on Historical Aspects and its uses in Traditional Medicine and Modern Pharmaceutical Science. Mini Rev Med Chem. 2021;21(6):724-730. doi:10.2174/1389557520666201127104907. https://www.ncbi.nlm.nih.gov/pubmed/33245271
  93. Chen Y, Tang YM, Yu SL, et al. Advances in the pharmacological activities and mechanisms of diosgenin. Chinese journal of natural medicines. Aug 2015;13(8):578-87. doi:10.1016/S1875-5364(15)30053-4. https://www.ncbi.nlm.nih.gov/pubmed/26253490
  94. Semwal P, Painuli S, Abu-Izneid T, et al. Diosgenin: An Updated Pharmacological Review and Therapeutic Perspectives. Oxid Med Cell Longev. 2022;2022:1035441. doi:10.1155/2022/1035441. https://www.ncbi.nlm.nih.gov/pubmed/35677108
  95. Khanna A, John F, Das S, et al. Efficacy of a novel extract of fenugreek seeds in alleviating vasomotor symptoms and depression in perimenopausal women: A randomized, double-blinded, placebo-controlled study. J Food Biochem. Dec 2020;44(12):e13507. doi:10.1111/jfbc.13507. https://www.ncbi.nlm.nih.gov/pubmed/33025616
  96. Shamshad Begum S, Jayalakshmi HK, Vidyavathi HG, et al. A Novel Extract of Fenugreek Husk (FenuSMART) Alleviates Postmenopausal Symptoms and Helps to Establish the Hormonal Balance: A Randomized, Double-Blind, Placebo-Controlled Study. Phytother Res. Nov 2016;30(11):1775-1784. doi:10.1002/ptr.5680. https://www.ncbi.nlm.nih.gov/pubmed/27406028
  97. Steels E, Steele ML, Harold M, Coulson S. Efficacy of a Proprietary Trigonella foenum-graecum L. De-Husked Seed Extract in Reducing Menopausal Symptoms in Otherwise Healthy Women: A Double-Blind, Randomized, Placebo-Controlled Study. Phytother Res. Sep 2017;31(9):1316-1322. doi:10.1002/ptr.5856. https://www.ncbi.nlm.nih.gov/pubmed/28707431
  98. Mazalzadeh F, Hekmat K, Namjouyan F, Saki A. Effect of Trigonella foenum (fenugreek) vaginal cream on vaginal atrophy in postmenopausal women. J Family Med Prim Care. Jun 2020;9(6):2714-2719. doi:10.4103/jfmpc.jfmpc_1220_19. https://www.ncbi.nlm.nih.gov/pubmed/32984113
  99. Safary M, Hakimi S, Mobaraki-Asl N, Amiri P, Tvassoli H, Delazar A. Comparison of the Effects of Fenugreek Vaginal Cream and Ultra Low- Dose Estrogen on Atrophic Vaginitis. Curr Drug Deliv. 2020;17(9):815-822. doi:10.2174/1567201817666200708112655. https://www.ncbi.nlm.nih.gov/pubmed/32640956
  100. Wahab S, Annadurai S, Abullais SS, et al. Glycyrrhiza glabra (Licorice): A Comprehensive Review on Its Phytochemistry, Biological Activities, Clinical Evidence and Toxicology. Plants (Basel). Dec 14 2021;10(12)doi:10.3390/plants10122751. https://www.ncbi.nlm.nih.gov/pubmed/34961221
  101. Minnetti M, De Alcubierre D, Bonaventura I, et al. Effects of licorice on sex hormones and the reproductive system. Nutrition. Nov-Dec 2022;103-104:111727. doi:10.1016/j.nut.2022.111727. https://www.ncbi.nlm.nih.gov/pubmed/35872407
  102. Markina YV, Kirichenko TV, Markin AM, et al. Atheroprotective Effects of Glycyrrhiza glabra L. Molecules. Jul 22 2022;27(15)doi:10.3390/molecules27154697. https://www.ncbi.nlm.nih.gov/pubmed/35897875
  103. Azizsoltani A, Piri K, Behzad S, et al. Ethyl Acetate Extract of Licorice Root (Glycyrrhiza glabra) Enhances Proliferation and Osteogenic Differentiation of Human Bone Marrow Mesenchymal Stem Cells. Iran J Pharm Res. Summer 2018;17(3):1057-1067. https://www.ncbi.nlm.nih.gov/pubmed/30127828
  104. Boonmuen N, Gong P, Ali Z, et al. Licorice root components in dietary supplements are selective estrogen receptor modulators with a spectrum of estrogenic and anti-estrogenic activities. Steroids. Jan 2016;105:42-9. doi:10.1016/j.steroids.2015.11.006. https://www.ncbi.nlm.nih.gov/pubmed/26631549
  105. Hajirahimkhan A, Simmler C, Yuan Y, et al. Evaluation of estrogenic activity of licorice species in comparison with hops used in botanicals for menopausal symptoms. PLoS One. 2013;8(7):e67947. doi:10.1371/journal.pone.0067947. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3709979/pdf/pone.0067947.pdf
  106. Mersereau JE, Levy N, Staub RE, et al. Liquiritigenin is a plant-derived highly selective estrogen receptor beta agonist. Mol Cell Endocrinol. Feb 13 2008;283(1-2):49-57. doi:10.1016/j.mce.2007.11.020. https://www.ncbi.nlm.nih.gov/pubmed/18177995
  107. Nahidi F, Zare E, Mojab F, Alavi-Majd H. Effects of licorice on relief and recurrence of menopausal hot flashes. Iran J Pharm Res. Spring 2012;11(2):541-8. https://www.ncbi.nlm.nih.gov/pubmed/24250477
  108. Menati L, Khaleghinezhad K, Tadayon M, Siahpoosh A. Evaluation of contextual and demographic factors on licorice effects on reducing hot flashes in postmenopause women. Health Care Women Int. Jan 2014;35(1):87-99. doi:10.1080/07399332.2013.770001. https://www.ncbi.nlm.nih.gov/pubmed/23663094
  109. Sadeghi M, Namjouyan F, Cheraghian B, Abbaspoor Z. Impact of Glycyrrhiza glabra (licorice) vaginal cream on vaginal signs and symptoms of vaginal atrophy in postmenopausal women: A randomized double blind controlled trial. Journal of traditional and complementary medicine. Mar 2020;10(2):110-115. doi:10.1016/j.jtcme.2019.02.005. https://www.ncbi.nlm.nih.gov/pubmed/32257873
  110. Kwon YJ, Son DH, Chung TH, Lee YJ. A Review of the Pharmacological Efficacy and Safety of Licorice Root from Corroborative Clinical Trial Findings. J Med Food. Jan 2020;23(1):12-20. doi:10.1089/jmf.2019.4459.
  111. McHugh J, Nagabathula R, Kyithar MP. A life-threatening case of pseudo-aldosteronism secondary to excessive liquorice ingestion. BMC endocrine disorders. Aug 6 2021;21(1):158. doi:10.1186/s12902-021-00816-4. https://www.ncbi.nlm.nih.gov/pubmed/34362360
  112. Deutch MR, Grimm D, Wehland M, Infanger M, Kruger M. Bioactive Candy: Effects of Licorice on the Cardiovascular System. Foods. Oct 14 2019;8(10)doi:10.3390/foods8100495. https://www.ncbi.nlm.nih.gov/pubmed/31615045
  113. Yang HM, Liao MF, Zhu SY, Liao MN, Rohdewald P. A randomised, double-blind, placebo-controlled trial on the effect of Pycnogenol on the climacteric syndrome in peri-menopausal women. Acta obstetricia et gynecologica Scandinavica. 2007;86(8):978-85. doi:10.1080/00016340701446108. https://www.ncbi.nlm.nih.gov/pubmed/17653885
  114. Errichi S, Bottari A, Belcaro G, et al. Supplementation with Pycnogenol(R) improves signs and symptoms of menopausal transition. Panminerva Med. Sep 2011;53(3 Suppl 1):65-70. https://www.ncbi.nlm.nih.gov/pubmed/22108479
  115. Kohama T, Negami M. Effect of low-dose French maritime pine bark extract on climacteric syndrome in 170 perimenopausal women: a randomized, double-blind, placebo-controlled trial. J Reprod Med. Jan-Feb 2013;58(1-2):39-46. https://www.ncbi.nlm.nih.gov/pubmed/23447917
  116. Luzzi R, Belcaro G, Hosoi M, et al. Normalization of cardiovascular risk factors in peri-menopausal women with Pycnogenol(R). Minerva ginecologica. Feb 2017;69(1):29-34. doi:10.23736/S0026-4784.16.03913-7. https://www.ncbi.nlm.nih.gov/pubmed/28116886
  117. Majidi Z, Ansari M, Maghbooli Z, et al. Oligopin(R) Supplementation Mitigates Oxidative Stress in Postmenopausal Women with Osteopenia: A Randomized, Double-blind, Placebo-Controlled Trial. Phytomedicine. Jan 2021;81:153417. doi:10.1016/j.phymed.2020.153417. https://www.ncbi.nlm.nih.gov/pubmed/33250314
  118. Cesarone MR, Belcaro G, Scipione C, et al. Prevention of vaginal dryness in perimenopausal women. Supplementation with Lady Prelox(R). Minerva ginecologica. Dec 2019;71(6):434-441. doi:10.23736/S0026-4784.19.04466-6. https://www.ncbi.nlm.nih.gov/pubmed/32064827
  119. Marini A, Grether-Beck S, Jaenicke T, et al. Pycnogenol(R) effects on skin elasticity and hydration coincide with increased gene expressions of collagen type I and hyaluronic acid synthase in women. Skin Pharmacol Physiol. 2012;25(2):86-92. doi:10.1159/000335261. https://www.ncbi.nlm.nih.gov/pubmed/22270036
  120. Rani A, Sharma A. The genus Vitex: A review. Pharmacognosy reviews. Jul 2013;7(14):188-98. doi:10.4103/0973-7847.120522.
  121. Daniele C, Thompson Coon J, Pittler MH, Ernst E. Vitex agnus castus: a systematic review of adverse events. Drug safety. 2005;28(4):319-32. doi:10.2165/00002018-200528040-00004. https://www.ncbi.nlm.nih.gov/pubmed/15783241
  122. Chopin Lucks B. Vitex agnus castus essential oil and menopausal balance: a research update [Complementary Therapies in Nursing and Midwifery 8 (2003) 148-154]. Complement Ther Nurs Midwifery. Aug 2003;9(3):157-60. doi:10.1016/S1353-6117(03)00020-9. https://www.ncbi.nlm.nih.gov/pubmed/12852933
  123. Lucks BC, Sorensen J, Veal L. Vitexagnus-castus essential oil and menopausal balance: a self-care survey. Complement Ther Nurs Midwifery. Aug 2002;8(3):148-54. doi:10.1054/ctnm.2002.0634. https://www.ncbi.nlm.nih.gov/pubmed/12353616
  124. van Die MD, Burger HG, Teede HJ, Bone KM. Vitex agnus-castus extracts for female reproductive disorders: a systematic review of clinical trials. Planta Med. May 2013;79(7):562-75. doi:10.1055/s-0032-1327831. https://www.ncbi.nlm.nih.gov/pubmed/23136064
  125. Dericks-Tan JS, Schwinn P, Hildt C. Dose-dependent stimulation of melatonin secretion after administration of Agnus castus. Exp Clin Endocrinol Diabetes. Feb 2003;111(1):44-6. doi:10.1055/s-2003-37500. https://www.ncbi.nlm.nih.gov/pubmed/12605350
  126. Naseri R, Farnia V, Yazdchi K, Alikhani M, Basanj B, Salemi S. Comparison of Vitex agnus-castus Extracts with Placebo in Reducing Menopausal Symptoms: A Randomized Double-Blind Study. Korean J Fam Med. Nov 2019;40(6):362-367. doi:10.4082/kjfm.18.0067. https://www.ncbi.nlm.nih.gov/pubmed/31067851
  127. Maffei S, Franchini M, Fortunato L, Guiducci L. Long-term effects of a combination of isoflavones, agnus castus and magnolia extracts on climacteric symptoms and cardiometabolic risk profile in postmenopausal women. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. Apr 2022;38(4):339-344. doi:10.1080/09513590.2022.2047171. https://www.ncbi.nlm.nih.gov/pubmed/35257639
  128. De Franciscis P, Grauso F, Luisi A, Schettino MT, Torella M, Colacurci N. Adding Agnus Castus and Magnolia to Soy Isoflavones Relieves Sleep Disturbances Besides Postmenopausal Vasomotor Symptoms-Long Term Safety and Effectiveness. Nutrients. Feb 13 2017;9(2)doi:10.3390/nu9020129.
  129. Molaie M, Darvishi B, Jafari Azar Z, Shirazi M, Amin G, Afshar S. Effects of a combination of Nigella sativa and Vitex agnus-castus with citalopram on healthy menopausal women with hot flashes: results from a subpopulation analysis. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. Jan 2019;35(1):58-61. doi:10.1080/09513590.2018.1499086. https://www.ncbi.nlm.nih.gov/pubmed/30129806
  130. Ahmad S, Campos MG, Fratini F, Altaye SZ, Li J. New Insights into the Biological and Pharmaceutical Properties of Royal Jelly. Int J Mol Sci. Jan 8 2020;21(2)doi:10.3390/ijms21020382. https://www.ncbi.nlm.nih.gov/pubmed/31936187
  131. Pasupuleti VR, Sammugam L, Ramesh N, Gan SH. Honey, Propolis, and Royal Jelly: A Comprehensive Review of Their Biological Actions and Health Benefits. Oxid Med Cell Longev. 2017;2017:1259510. doi:10.1155/2017/1259510. https://www.ncbi.nlm.nih.gov/pubmed/28814983
  132. Balan A, Moga MA, Dima L, Toma S, Elena Neculau A, Anastasiu CV. Royal Jelly-A Traditional and Natural Remedy for Postmenopausal Symptoms and Aging-Related Pathologies. Molecules. Jul 20 2020;25(14)doi:10.3390/molecules25143291. https://www.ncbi.nlm.nih.gov/pubmed/32698461
  133. Sharif SN, Darsareh F. Effect of royal jelly on menopausal symptoms: A randomized placebo-controlled clinical trial. Complement Ther Clin Pract. Nov 2019;37:47-50. doi:10.1016/j.ctcp.2019.08.006. https://www.ncbi.nlm.nih.gov/pubmed/31470366
  134. Asama T, Matsuzaki H, Fukushima S, Tatefuji T, Hashimoto K, Takeda T. Royal Jelly Supplementation Improves Menopausal Symptoms Such as Backache, Low Back Pain, and Anxiety in Postmenopausal Japanese Women. Evid Based Complement Alternat Med. 2018;2018:4868412. doi:10.1155/2018/4868412. https://www.ncbi.nlm.nih.gov/pubmed/29853955
  135. Seyyedi F, Rafiean-Kopaei M, Miraj S. Comparison of the Effects of Vaginal Royal Jelly and Vaginal Estrogen on Quality of Life, Sexual and Urinary Function in Postmenopausal Women. J Clin Diagn Res. May 2016;10(5):QC01-5. doi:10.7860/JCDR/2016/17844.7715. https://www.ncbi.nlm.nih.gov/pubmed/27437306
  136. Peterson B, Nguyen H. St. John's Wort. StatPearls. 2023.
  137. Eatemadnia A, Ansari S, Abedi P, Najar S. The effect of Hypericum perforatum on postmenopausal symptoms and depression: A randomized controlled trial. Complement Ther Med. Aug 2019;45:109-113. doi:10.1016/j.ctim.2019.05.028. https://www.ncbi.nlm.nih.gov/pubmed/31331546
  138. Abdali K, Khajehei M, Tabatabaee HR. Effect of St John's wort on severity, frequency, and duration of hot flashes in premenopausal, perimenopausal and postmenopausal women: a randomized, double-blind, placebo-controlled study. Menopause. Mar 2010;17(2):326-31. doi:10.1097/gme.0b013e3181b8e02d. https://www.ncbi.nlm.nih.gov/pubmed/20216274
  139. Liu YR, Jiang YL, Huang RQ, Yang JY, Xiao BK, Dong JX. Hypericum perforatum L. preparations for menopause: a meta-analysis of efficacy and safety. Climacteric : the journal of the International Menopause Society. Aug 2014;17(4):325-35. doi:10.3109/13697137.2013.861814. https://www.ncbi.nlm.nih.gov/pubmed/24188229
  140. Al-Akoum M, Maunsell E, Verreault R, Provencher L, Otis H, Dodin S. Effects of Hypericum perforatum (St. John's wort) on hot flashes and quality of life in perimenopausal women: a randomized pilot trial. Menopause. Mar-Apr 2009;16(2):307-14. doi:10.1097/gme.0b013e31818572a0. https://www.ncbi.nlm.nih.gov/pubmed/19194342
  141. van Die MD, Burger HG, Bone KM, Cohen MM, Teede HJ. Hypericum perforatum with Vitex agnus-castus in menopausal symptoms: a randomized, controlled trial. Menopause. Jan-Feb 2009;16(1):156-63. doi:10.1097/gme.0b013e31817fa9e0. https://www.ncbi.nlm.nih.gov/pubmed/18791483
  142. van Die MD, Bone KM, Burger HG, Reece JE, Teede HJ. Effects of a combination of Hypericum perforatum and Vitex agnus-castus on PMS-like symptoms in late-perimenopausal women: findings from a subpopulation analysis. J Altern Complement Med. Sep 2009;15(9):1045-8. doi:10.1089/acm.2008.0539. https://www.ncbi.nlm.nih.gov/pubmed/19757982
  143. Briese V, Stammwitz U, Friede M, Henneicke-von Zepelin HH. Black cohosh with or without St. John's wort for symptom-specific climacteric treatment--results of a large-scale, controlled, observational study. Maturitas. Aug 20 2007;57(4):405-14. doi:10.1016/j.maturitas.2007.04.008. https://www.ncbi.nlm.nih.gov/pubmed/17590291
  144. Mahboubi M. Evening Primrose (Oenothera biennis) Oil in Management of Female Ailments. Journal of menopausal medicine. Aug 2019;25(2):74-82. doi:10.6118/jmm.18190. https://www.ncbi.nlm.nih.gov/pubmed/31497576
  145. Safdari F, Motaghi Dastenaei B, Kheiri S, Karimiankakolaki Z. Effect of Evening Primrose Oil on Postmenopausal Psychological Symptoms: A Triple-Blind Randomized Clinical Trial. Journal of menopausal medicine. Aug 2021;27(2):58-65. doi:10.6118/jmm.21010. https://www.ncbi.nlm.nih.gov/pubmed/34463069
  146. Sharif SN, Darsareh F. Impact of evening primrose oil consumption on psychological symptoms of postmenopausal women: a randomized double-blinded placebo-controlled clinical trial. Menopause. Feb 2020;27(2):194-198. doi:10.1097/GME.0000000000001434. https://www.ncbi.nlm.nih.gov/pubmed/31738736
  147. Farzaneh F, Fatehi S, Sohrabi MR, Alizadeh K. The effect of oral evening primrose oil on menopausal hot flashes: a randomized clinical trial. Archives of gynecology and obstetrics. Nov 2013;288(5):1075-9. doi:10.1007/s00404-013-2852-6. https://www.ncbi.nlm.nih.gov/pubmed/23625331
  148. Kazemi F, Masoumi SZ, Shayan A, Oshvandi K. The Effect of Evening Primrose Oil Capsule on Hot Flashes and Night Sweats in Postmenopausal Women: A Single-Blind Randomized Controlled Trial. Journal of menopausal medicine. Apr 2021;27(1):8-14. doi:10.6118/jmm.20033. https://www.ncbi.nlm.nih.gov/pubmed/33942584
  149. Chenoy R, Hussain S, Tayob Y, O'Brien PM, Moss MY, Morse PF. Effect of oral gamolenic acid from evening primrose oil on menopausal flushing. BMJ. Feb 19 1994;308(6927):501-3. doi:10.1136/bmj.308.6927.501. https://www.ncbi.nlm.nih.gov/pubmed/8136666
  150. Jenabi E, Shobeiri F, Hazavehei SMM, Roshanaei G. The effect of Valerian on the severity and frequency of hot flashes: A triple-blind randomized clinical trial. Women Health. Mar 2018;58(3):297-304. doi:10.1080/03630242.2017.1296058. https://www.ncbi.nlm.nih.gov/pubmed/28278010
  151. Mirabi P, Mojab F. The effects of valerian root on hot flashes in menopausal women. Iran J Pharm Res. Winter 2013;12(1):217-22. https://www.ncbi.nlm.nih.gov/pubmed/24250592
  152. Taavoni S, Ekbatani N, Kashaniyan M, Haghani H. Effect of valerian on sleep quality in postmenopausal women: a randomized placebo-controlled clinical trial. Menopause. Sep 2011;18(9):951-5. doi:10.1097/gme.0b013e31820e9acf. https://www.ncbi.nlm.nih.gov/pubmed/21775910
  153. Lee MS, Shin BC, Yang EJ, Lim HJ, Ernst E. Maca (Lepidium meyenii) for treatment of menopausal symptoms: A systematic review. Maturitas. Nov 2011;70(3):227-33. doi:10.1016/j.maturitas.2011.07.017. https://www.ncbi.nlm.nih.gov/pubmed/21840656
  154. Meissner HO, Kapczynski W, Mscisz A, Lutomski J. Use of gelatinized maca (lepidium peruvianum) in early postmenopausal women. International journal of biomedical science : IJBS. Jun 2005;1(1):33-45. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3614576/pdf/IJBS-1-33.pdf
  155. Meissner HO, Reich-Bilinska H, Mscisz A, Kedzia B. Therapeutic Effects of Pre-Gelatinized Maca (Lepidium Peruvianum Chacon) used as a Non-Hormonal Alternative to HRT in Perimenopausal Women - Clinical Pilot Study. International journal of biomedical science : IJBS. Jun 2006;2(2):143-59.
  156. Meissner HO, Mscisz A, Reich-Bilinska H, et al. Hormone-Balancing Effect of Pre-Gelatinized Organic Maca (Lepidium peruvianum Chacon): (II) Physiological and Symptomatic Responses of Early-Postmenopausal Women to Standardized doses of Maca in Double Blind, Randomized, Placebo-Controlled, Multi-Centre Clinical Study. International journal of biomedical science : IJBS. Dec 2006;2(4):360-74. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3614647/pdf/IJBS-2-360.pdf
  157. Meissner HO, Mscisz A, Reich-Bilinska H, et al. Hormone-Balancing Effect of Pre-Gelatinized Organic Maca (Lepidium peruvianum Chacon): (III) Clinical responses of early-postmenopausal women to Maca in double blind, randomized, Placebo-controlled, crossover configuration, outpatient study. International journal of biomedical science : IJBS. Dec 2006;2(4):375-94. https://www.ncbi.nlm.nih.gov/pubmed/23675006
  158. Brooks NA, Wilcox G, Walker KZ, Ashton JF, Cox MB, Stojanovska L. Beneficial effects of Lepidium meyenii (Maca) on psychological symptoms and measures of sexual dysfunction in postmenopausal women are not related to estrogen or androgen content. Menopause. Nov-Dec 2008;15(6):1157-62. doi:10.1097/gme.0b013e3181732953.
  159. Stojanovska L, Law C, Lai B, et al. Maca reduces blood pressure and depression, in a pilot study in postmenopausal women. Climacteric : the journal of the International Menopause Society. Feb 2015;18(1):69-78. doi:10.3109/13697137.2014.929649. https://www.ncbi.nlm.nih.gov/pubmed/24931003
  160. Lin HQ, Gong AG, Wang HY, et al. Danggui Buxue Tang (Astragali Radix and Angelicae Sinensis Radix) for menopausal symptoms: A review. J Ethnopharmacol. Mar 6 2017;199:205-210. doi:10.1016/j.jep.2017.01.044. https://www.ncbi.nlm.nih.gov/pubmed/28163116
  161. Hook IL. Danggui to Angelica sinensis root: are potential benefits to European women lost in translation? A review. J Ethnopharmacol. Feb 27 2014;152(1):1-13. doi:10.1016/j.jep.2013.12.018. https://www.ncbi.nlm.nih.gov/pubmed/24365638
  162. Zhang WL, Zheng KY, Zhu KY, et al. Chemical and biological assessment of Angelica herbal decoction: comparison of different preparations during historical applications. Phytomedicine. Aug 15 2012;19(11):1042-8. doi:10.1016/j.phymed.2012.07.009. https://www.ncbi.nlm.nih.gov/pubmed/22902230
  163. Circosta C, Pasquale RD, Palumbo DR, Samperi S, Occhiuto F. Estrogenic activity of standardized extract of Angelica sinensis. Phytother Res. Aug 2006;20(8):665-9. doi:10.1002/ptr.1928. https://www.ncbi.nlm.nih.gov/pubmed/16691630
  164. Haines CJ, Lam PM, Chung TK, Cheng KF, Leung PC. A randomized, double-blind, placebo-controlled study of the effect of a Chinese herbal medicine preparation (Dang Gui Buxue Tang) on menopausal symptoms in Hong Kong Chinese women. Climacteric : the journal of the International Menopause Society. Jun 2008;11(3):244-51. doi:10.1080/13697130802073029. https://www.ncbi.nlm.nih.gov/pubmed/18568789
  165. Kupfersztain C, Rotem C, Fagot R, Kaplan B. The immediate effect of natural plant extract, Angelica sinensis and Matricaria chamomilla (Climex) for the treatment of hot flushes during menopause. A preliminary report. Clinical and experimental obstetrics & gynecology. 2003;30(4):203-6.
  166. Hirata JD, Swiersz LM, Zell B, Small R, Ettinger B. Does dong quai have estrogenic effects in postmenopausal women? A double-blind, placebo-controlled trial. Fertility and sterility. Dec 1997;68(6):981-6. doi:10.1016/s0015-0282(97)00397-x. https://www.ncbi.nlm.nih.gov/pubmed/9418683
  167. Tober C, Schoop R. Modulation of neurological pathways by Salvia officinalis and its dependence on manufacturing process and plant parts used. BMC Complement Altern Med. Jun 13 2019;19(1):128. doi:10.1186/s12906-019-2549-x. https://www.ncbi.nlm.nih.gov/pubmed/31196061
  168. Margetts G, Kleidonas S, Zaibi NS, Zaibi MS, Edwards KD. Evidence for anti-inflammatory effects and modulation of neurotransmitter metabolism by Salvia officinalis L. BMC Complement Med Ther. May 12 2022;22(1):131. doi:10.1186/s12906-022-03605-1. https://www.ncbi.nlm.nih.gov/pubmed/35550086
  169. Elgayed SH, Afify EA, Amin HA, Abdellatif AAH. Estrogenic Effect of Salvia officinalis Extract on Reproductive Function of Female Mice and Identification of Its Phenolic Content. Combinatorial chemistry & high throughput screening. 2021;24(10):1654-1663. doi:10.2174/1386207323666200811095527. https://www.ncbi.nlm.nih.gov/pubmed/32781955
  170. Koubaa-Ghorbel F, Chaabane M, Jdidi H, Turki M, Makni-Ayadi F, El Feki A. Salvia officinalis mitigates uterus and liver damages induced by an estrogen deficiency in ovariectomized rats. J Food Biochem. May 2021;45(5):e13542. doi:10.1111/jfbc.13542. https://www.ncbi.nlm.nih.gov/pubmed/33124046
  171. Sabry MM, Abdel-Rahman RF, El-Shenawy SM, Hassan AM, El-Gayed SH. Estrogenic activity of Sage (Salvia officinalis L.) aerial parts and its isolated ferulic acid in immature ovariectomized female rats. J Ethnopharmacol. Jan 10 2022;282:114579. doi:10.1016/j.jep.2021.114579. https://www.ncbi.nlm.nih.gov/pubmed/34499963
  172. Ghorbani A, Esmaeilizadeh M. Pharmacological properties of Salvia officinalis and its components. Journal of traditional and complementary medicine. Oct 2017;7(4):433-440. doi:10.1016/j.jtcme.2016.12.014. https://ac.els-cdn.com/S2225411017300056/1-s2.0-S2225411017300056-main.pdf?_tid=8b38b819-0c78-49d2-a7a3-95b0daba9b3d&acdnat=1539608269_e4e328fa40eaf4204ed9573911ef703d
  173. Dadfar F, Bamdad K. The effect of Saliva officinalis extract on the menopausal symptoms in postmenopausal women: An RCT. Int J Reprod Biomed. Apr 2019;17(4):287-92. doi:10.18502/ijrm.v17i4.4555. https://www.ncbi.nlm.nih.gov/pubmed/31435607
  174. Bommer S, Klein P, Suter A. First time proof of sage's tolerability and efficacy in menopausal women with hot flushes. Adv Ther. Jun 2011;28(6):490-500. doi:10.1007/s12325-011-0027-z. https://www.ncbi.nlm.nih.gov/pubmed/21630133
  175. Das S. Natural therapeutics for urinary tract infections-a review. Futur J Pharm Sci. 2020;6(1):64. doi:10.1186/s43094-020-00086-2. https://www.ncbi.nlm.nih.gov/pubmed/33215041
  176. Schoendorfer N, Sharp N, Seipel T, Schauss AG, Ahuja KDK. Urox containing concentrated extracts of Crataeva nurvala stem bark, Equisetum arvense stem and Lindera aggregata root, in the treatment of symptoms of overactive bladder and urinary incontinence: a phase 2, randomised, double-blind placebo controlled trial. BMC Complement Altern Med. Jan 31 2018;18(1):42. doi:10.1186/s12906-018-2101-4. https://www.ncbi.nlm.nih.gov/pubmed/29385990
  177. Zapala L, Juszczak K, Adamczyk P, et al. New Kid on the Block: The Efficacy of Phytomedicine Extracts Urox((R)) in Reducing Overactive Bladder Symptoms in Rats. Frontiers in molecular biosciences. 2022;9:896624. doi:10.3389/fmolb.2022.896624. https://www.ncbi.nlm.nih.gov/pubmed/35801157
  178. Mehta J, Kling JM, Manson JE. Risks, Benefits, and Treatment Modalities of Menopausal Hormone Therapy: Current Concepts. Front Endocrinol (Lausanne). 2021;12:564781. doi:10.3389/fendo.2021.564781. https://www.ncbi.nlm.nih.gov/pubmed/33841322
  179. The Hormone Therapy Position Statement of The North American Menopause Society" Advisory P. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. Jul 1 2022;29(7):767-794. doi:10.1097/GME.0000000000002028. https://www.ncbi.nlm.nih.gov/pubmed/35797481
  180. Crandall CJ, Mehta JM, Manson JE. Management of Menopausal Symptoms: A Review. JAMA. Feb 7 2023;329(5):405-420. doi:10.1001/jama.2022.24140. https://www.ncbi.nlm.nih.gov/pubmed/36749328
  181. Coughlan GT, Betthauser TJ, Boyle R, et al. Association of Age at Menopause and Hormone Therapy Use With Tau and beta-Amyloid Positron Emission Tomography. JAMA Neurol. Apr 3 2023;doi:10.1001/jamaneurol.2023.0455. https://www.ncbi.nlm.nih.gov/pubmed/37010830
  182. Tremollieres FA, Chabbert-Buffet N, Plu-Bureau G, et al. Management of postmenopausal women: College National des Gynecologues et Obstetriciens Francais (CNGOF) and Groupe d'Etude sur la Menopause et le Vieillissement (GEMVi) Clinical Practice Guidelines. Maturitas. Sep 2022;163:62-81. doi:10.1016/j.maturitas.2022.05.008. https://www.ncbi.nlm.nih.gov/pubmed/35717745
  183. Ali ES, Mangold C, Peiris AN. Estriol: emerging clinical benefits. Menopause. Sep 2017;24(9):1081-1085. doi:10.1097/GME.0000000000000855. https://www.ncbi.nlm.nih.gov/pubmed/28375935
  184. The National Academies of Science E, and Medicine. The Clinical Utility of Compounded Bioidentical Hormone Therapy: A Review of Safety, Effectiveness, and Use. NASEM. Accessed Oct. 14, 2022, https://nap.nationalacademies.org/download/25791
  185. Hill DA, Crider M, Hill SR. Hormone Therapy and Other Treatments for Symptoms of Menopause. Am Fam Physician. Dec 1 2016;94(11):884-889. https://www.ncbi.nlm.nih.gov/pubmed/27929271
  186. Benini V, Ruffolo AF, Casiraghi A, et al. New Innovations for the Treatment of Vulvovaginal Atrophy: An Up-to-Date Review. Medicina (Kaunas). Jun 6 2022;58(6)doi:10.3390/medicina58060770. https://www.ncbi.nlm.nih.gov/pubmed/35744033
  187. Zhang GQ, Chen JL, Luo Y, et al. Menopausal hormone therapy and women's health: An umbrella review. PLoS Med. Aug 2021;18(8):e1003731. doi:10.1371/journal.pmed.1003731. https://www.ncbi.nlm.nih.gov/pubmed/34339416
  188. Keck C, Taylor M. Emerging Research on the Implications of Hormone Replacement Therapy on Coronary Heart Disease. Curr Atheroscler Rep. Oct 22 2018;20(12):57. doi:10.1007/s11883-018-0758-2. https://www.ncbi.nlm.nih.gov/pubmed/30350133
  189. Anagnostis P, Lambrinoudaki I, Stevenson JC, Goulis DG. Menopause-associated risk of cardiovascular disease. Endocr Connect. Apr 22 2022;11(4)doi:10.1530/EC-21-0537. https://www.ncbi.nlm.nih.gov/pubmed/35258483
  190. Cui J, Shen Y, Li R. Estrogen synthesis and signaling pathways during aging: from periphery to brain. Trends Mol Med. Mar 2013;19(3):197-209. doi:10.1016/j.molmed.2012.12.007.
  191. Perkins MS, Louw-du Toit R, Africander D. A comparative characterization of estrogens used in hormone therapy via estrogen receptor (ER)-alpha and -beta. J Steroid Biochem Mol Biol. Nov 2017;174:27-39. doi:10.1016/j.jsbmb.2017.07.022. https://www.ncbi.nlm.nih.gov/pubmed/28743541
  192. Perkins MS, Louw-du Toit R, Africander D. Hormone Therapy and Breast Cancer: Emerging Steroid Receptor Mechanisms. J Mol Endocrinol. Oct 16 2018;61(4):R133-R160. doi:10.1530/JME-18-0094. https://www.ncbi.nlm.nih.gov/pubmed/29899079
  193. Hamoda H, Panay N, Pedder H, Arya R, Savvas M. The British Menopause Society & Women's Health Concern 2020 recommendations on hormone replacement therapy in menopausal women. Post Reprod Health. Dec 2020;26(4):181-209. doi:10.1177/2053369120957514. https://www.ncbi.nlm.nih.gov/pubmed/33045914
  194. Gallez A, Dias Da Silva I, Wuidar V, Foidart JM, Pequeux C. Estetrol and Mammary Gland: Friends or Foes? Journal of mammary gland biology and neoplasia. Sep 2021;26(3):297-308. doi:10.1007/s10911-021-09497-0. https://www.ncbi.nlm.nih.gov/pubmed/34463898
  195. Gerard C, Arnal JF, Jost M, et al. Profile of estetrol, a promising native estrogen for oral contraception and the relief of climacteric symptoms of menopause. Expert review of clinical pharmacology. Feb 2022;15(2):121-137. doi:10.1080/17512433.2022.2054413. https://www.ncbi.nlm.nih.gov/pubmed/35306927
  196. Lee A, Syed YY. Estetrol/Drospirenone: A Review in Oral Contraception. Drugs. Jul 2022;82(10):1117-1125. doi:10.1007/s40265-022-01738-8. https://www.ncbi.nlm.nih.gov/pubmed/35781795
  197. Estetra. A Randomized Double-blind Placebo Controlled Phase 3 Trial to Evaluate the Efficacy and Safety of Estetrol for the Treatment of Moderate to Severe Vasomotor Symptoms in Postmenopausal Women (E4Comfort Study I). NCT04209543. Accessed Oct. 13, 2022, https://beta.clinicaltrials.gov/study/NCT04209543?distance=50&term=NCT04209543&rank=1
  198. Valdes A, Bajaj T. Estrogen Therapy. StatPearls. 2022.
  199. Garzon S, Apostolopoulos V, Stojanovska L, Ferrari F, Mathyk BA, Lagana AS. Non-oestrogenic modalities to reverse urogenital aging. Prz Menopauzalny. Sep 2021;20(3):140-147. doi:10.5114/pm.2021.109772. https://www.ncbi.nlm.nih.gov/pubmed/34703415
  200. Cobin RH, Goodman NF. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT ON MENOPAUSE-2017 UPDATE. Endocr Pract. Jul 2017;23(7):869-880. doi:10.4158/ep171828.ps. http://journals.aace.com/doi/pdf/10.4158/EP171828.PS
  201. Stevenson JC, Rozenberg S, Maffei S, Egarter C, Stute P, Römer T. Progestogens as a component of menopausal hormone therapy: the right molecule makes the difference. Drugs Context. 2020;9doi:10.7573/dic.2020-10-1.
  202. Kolatorova L, Vitku J, Suchopar J, Hill M, Parizek A. Progesterone: A Steroid with Wide Range of Effects in Physiology as Well as Human Medicine. Int J Mol Sci. Jul 20 2022;23(14)doi:10.3390/ijms23147989. https://www.ncbi.nlm.nih.gov/pubmed/35887338
  203. Prior JC. Progesterone for treatment of symptomatic menopausal women. Climacteric : the journal of the International Menopause Society. Aug 2018;21(4):358-365. doi:10.1080/13697137.2018.1472567. https://www.ncbi.nlm.nih.gov/pubmed/29962247
  204. Goletiani NV, Keith DR, Gorsky SJ. Progesterone: review of safety for clinical studies. Experimental and clinical psychopharmacology. Oct 2007;15(5):427-44. doi:10.1037/1064-1297.15.5.427. https://www.ncbi.nlm.nih.gov/pubmed/17924777
  205. Gartlehner G, Patel SV, Reddy S, Rains C, Schwimmer M, Kahwati L. Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Persons: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. Nov 1 2022;328(17):1747-1765. doi:10.1001/jama.2022.18324. https://www.ncbi.nlm.nih.gov/pubmed/36318128
  206. Rozenberg S, Di Pietrantonio V, Vandromme J, Gilles C. Menopausal hormone therapy and breast cancer risk. Best Pract Res Clin Endocrinol Metab. Dec 2021;35(6):101577. doi:10.1016/j.beem.2021.101577. https://www.ncbi.nlm.nih.gov/pubmed/34535397
  207. Wooten AL. The Panel Put Policy-Making Before Patient Need. Alliance for Pharmacy Compounding. Accessed Feb. 3, 2023, https://compounding.com/flaws-in-the-fdas-research
  208. Constantine GD, Archer DF, Graham S, Bernick BA, Mirkin S. Prescribing of FDA-approved and compounded hormone therapy differs by specialty. Menopause. Oct 2016;23(10):1075-82. doi:10.1097/GME.0000000000000683. https://www.ncbi.nlm.nih.gov/pubmed/27648594
  209. The FDA Group. THE IMPORTANCE OF CGMP TO THE SAFETY OF COMPOUNDED DRUGS. Accessed Mar. 23, 2023, https://www.thefdagroup.com/the-importance-of-cgmp-to-the-safety-of-compounded-drugs
  210. FDA. FDA Continues Collaboration with Drug Compounders as Second Anniversary of Compounding Quality Center of Excellence Approaches. FDA. Accessed Mar. 23, 2023, https://www.fda.gov/news-events/fda-voices/fda-continues-collaboration-drug-compounders-second-anniversary-compounding-quality-center
  211. Barentsen R, van de Weijer PH, Schram JH. Continuous low dose estradiol released from a vaginal ring versus estriol vaginal cream for urogenital atrophy. European journal of obstetrics, gynecology, and reproductive biology. Jan 1997;71(1):73-80. doi:10.1016/s0301-2115(96)02612-7. https://www.ncbi.nlm.nih.gov/pubmed/9031963
  212. Henriksson L, Stjernquist M, Boquist L, Alander U, Selinus I. A comparative multicenter study of the effects of continuous low-dose estradiol released from a new vaginal ring versus estriol vaginal pessaries in postmenopausal women with symptoms and signs of urogenital atrophy. Am J Obstet Gynecol. Sep 1994;171(3):624-32. doi:10.1016/0002-9378(94)90074-4. https://www.ajog.org/article/0002-9378(94)90074-4/pdf
  213. Liu Y, Yuan Y, Day AJ, et al. Safety and efficacy of compounded bioidentical hormone therapy (cBHT) in perimenopausal and postmenopausal women: a systematic review and meta-analysis of randomized controlled trials. Menopause. Feb 14 2022;29(4):465-482. doi:10.1097/GME.0000000000001937. https://www.ncbi.nlm.nih.gov/pubmed/35357369
  214. Jiang X, Bossert A, Parthasarathy KN, et al. Safety assessment of compounded non-FDA-approved hormonal therapy versus FDA-approved hormonal therapy in treating postmenopausal women. Menopause. May 10 2021;28(8):867-874. doi:10.1097/gme.0000000000001782.
  215. Dama A, Baggio C, Boscaro C, Albiero M, Cignarella A. Estrogen Receptor Functions and Pathways at the Vascular Immune Interface. Int J Mol Sci. Apr 20 2021;22(8)doi:10.3390/ijms22084254. https://www.ncbi.nlm.nih.gov/pubmed/33923905
  216. Paterni I, Granchi C, Katzenellenbogen JA, Minutolo F. Estrogen receptors alpha (ERalpha) and beta (ERbeta): subtype-selective ligands and clinical potential. Steroids. Nov 2014;90:13-29. doi:10.1016/j.steroids.2014.06.012. https://www.ncbi.nlm.nih.gov/pubmed/24971815
  217. Jia M, Dahlman-Wright K, Gustafsson JA. Estrogen receptor alpha and beta in health and disease. Best Pract Res Clin Endocrinol Metab. Aug 2015;29(4):557-68. doi:10.1016/j.beem.2015.04.008. https://www.ncbi.nlm.nih.gov/pubmed/26303083
  218. McCarthy M, Raval AP. The peri-menopause in a woman's life: a systemic inflammatory phase that enables later neurodegenerative disease. J Neuroinflammation. Oct 23 2020;17(1):317. doi:10.1186/s12974-020-01998-9. https://www.ncbi.nlm.nih.gov/pubmed/33097048
  219. da Silva JS, Montagnoli TL, Rocha BS, Tacco M, Marinho SCP, Zapata-Sudo G. Estrogen Receptors: Therapeutic Perspectives for the Treatment of Cardiac Dysfunction after Myocardial Infarction. Int J Mol Sci. Jan 7 2021;22(2)doi:10.3390/ijms22020525. https://www.ncbi.nlm.nih.gov/pubmed/33430254
  220. Vargas KG, Milic J, Zaciragic A, et al. The functions of estrogen receptor beta in the female brain: A systematic review. Maturitas. Nov 2016;93:41-57. doi:10.1016/j.maturitas.2016.05.014.
  221. Pinkerton JV, Conner EA. Beyond estrogen: advances in tissue selective estrogen complexes and selective estrogen receptor modulators. Climacteric : the journal of the International Menopause Society. Apr 2019;22(2):140-147. doi:10.1080/13697137.2019.1568403. https://www.ncbi.nlm.nih.gov/pubmed/30895900
  222. Pinkerton JV. Tissue-selective Estrogen Complex for Menopausal Hormone Therapy. Clin Obstet Gynecol. Sep 2018;61(3):463-469. doi:10.1097/GRF.0000000000000386. https://www.ncbi.nlm.nih.gov/pubmed/29851863
  223. Bianchi VE, Bresciani E, Meanti R, Rizzi L, Omeljaniuk RJ, Torsello A. The role of androgens in women's health and wellbeing. Pharmacol Res. Sep 2021;171:105758. doi:10.1016/j.phrs.2021.105758. https://www.ncbi.nlm.nih.gov/pubmed/34242799
  224. Uloko M, Rahman F, Puri LI, Rubin RS. The clinical management of testosterone replacement therapy in postmenopausal women with hypoactive sexual desire disorder: a review. Int J Impot Res. Nov 2022;34(7):635-641. doi:10.1038/s41443-022-00613-0. https://www.ncbi.nlm.nih.gov/pubmed/36198811
  225. Kingsberg SA, Faubion SS. Clinical management of hypoactive sexual desire disorder in postmenopausal women. Menopause. Sep 1 2022;29(9):1083-1085. doi:10.1097/GME.0000000000002049. https://www.ncbi.nlm.nih.gov/pubmed/36040433
  226. Shifren JL, Monz BU, Russo PA, Segreti A, Johannes CB. Sexual problems and distress in United States women: prevalence and correlates. Obstet Gynecol. Nov 2008;112(5):970-8. doi:10.1097/AOG.0b013e3181898cdb.
  227. Achilli C, Pundir J, Ramanathan P, Sabatini L, Hamoda H, Panay N. Efficacy and safety of transdermal testosterone in postmenopausal women with hypoactive sexual desire disorder: a systematic review and meta-analysis. Fertility and sterility. Feb 2017;107(2):475-482.e15. doi:10.1016/j.fertnstert.2016.10.028.
  228. Parish SJ, Simon JA, Davis SR, et al. International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women. The journal of sexual medicine. May 2021;18(5):849-867. doi:10.1016/j.jsxm.2020.10.009. https://www.ncbi.nlm.nih.gov/pubmed/33814355
  229. Tang J, Chen LR, Chen KH. The Utilization of Dehydroepiandrosterone as a Sexual Hormone Precursor in Premenopausal and Postmenopausal Women: An Overview. Pharmaceuticals (Basel). Dec 29 2021;15(1)doi:10.3390/ph15010046. https://www.ncbi.nlm.nih.gov/pubmed/35056103
  230. Marina L, Sojat AS, Maseroli E, Spaggiari G, Pandurevic S, Santi D. Hormonal profile of menopausal women receiving androgen replacement therapy: a meta-analysis. J Endocrinol Invest. Jun 2020;43(6):717-735. doi:10.1007/s40618-020-01192-x. https://www.ncbi.nlm.nih.gov/pubmed/32016915
  231. U.S. Food & Drug Administration. FDA approves Intrarosa for postmenopausal women experiencing pain during sex. Updated Nov. 17, 2016. Accessed Feb. 14, 2023, https://www.fda.gov/news-events/press-announcements/fda-approves-intrarosa-postmenopausal-women-experiencing-pain-during-sex
  232. Shim S, Park KM, Chung YJ, Kim MR. Updates on Therapeutic Alternatives for Genitourinary Syndrome of Menopause: Hormonal and Non-Hormonal Managements. Journal of menopausal medicine. Apr 2021;27(1):1-7. doi:10.6118/jmm.20034. https://www.ncbi.nlm.nih.gov/pubmed/33942583
  233. Stomati M, Monteleone P, Casarosa E, et al. Six-month oral dehydroepiandrosterone supplementation in early and late postmenopause. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. Oct 2000;14(5):342-63. doi:10.3109/09513590009167703. https://www.ncbi.nlm.nih.gov/pubmed/11109974
  234. Rabijewski M, Papierska L, Binkowska M, et al. Supplementation of dehydroepiandrosterone (DHEA) in pre- and postmenopausal women - position statement of expert panel of Polish Menopause and Andropause Society. Ginekologia polska. 2020;91(9):554-562. doi:10.5603/GP.2020.0091. https://www.ncbi.nlm.nih.gov/pubmed/33030737
  235. Zhang S, Zhou J, Li L, et al. Effect of dehydroepiandrosterone on atherosclerosis in postmenopausal women. Bioscience trends. Jan 23 2022;15(6):353-364. doi:10.5582/bst.2021.01320. https://www.ncbi.nlm.nih.gov/pubmed/34759119
  236. Chatterton RT. Functions of dehydroepiandrosterone in relation to breast cancer. Steroids. Mar 2022;179:108970. doi:10.1016/j.steroids.2022.108970. https://www.ncbi.nlm.nih.gov/pubmed/35122788
  237. Nounu A, Kar SP, Relton CL, Richmond RC. Sex steroid hormones and risk of breast cancer: a two-sample Mendelian randomization study. Breast Cancer Res. Oct 8 2022;24(1):66. doi:10.1186/s13058-022-01553-9. https://www.ncbi.nlm.nih.gov/pubmed/36209141
  238. Endogenous H, Breast Cancer Collaborative G, Key TJ, et al. Sex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies. Lancet Oncol. Sep 2013;14(10):1009-19. doi:10.1016/S1470-2045(13)70301-2. https://www.ncbi.nlm.nih.gov/pubmed/23890780
  239. Helzlsouer KJ, Gordon GB, Alberg AJ, Bush TL, Comstock GW. Relationship of prediagnostic serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate to the risk of developing premenopausal breast cancer. Cancer Res. Jan 1 1992;52(1):1-4. https://www.ncbi.nlm.nih.gov/pubmed/1530765
  240. Gomes P, Cassanas G, Halberg F, et al. [Blood levels of dehydroepiandrosterone sulfate (DHEA-S) and the risk of breast cancer]. C R Acad Sci III. 1988;306(7):261-4. Taux sanguin du sulfate de la dehydroepiandrosterone (DHEA-S) et risque de cancer du sein. https://www.ncbi.nlm.nih.gov/pubmed/2967730
  241. Zeleniuch-Jacquotte A, Bruning PF, Bonfrer JM, et al. Relation of serum levels of testosterone and dehydroepiandrosterone sulfate to risk of breast cancer in postmenopausal women. Am J Epidemiol. Jun 1 1997;145(11):1030-8. doi:10.1093/oxfordjournals.aje.a009059. https://www.ncbi.nlm.nih.gov/pubmed/9169912
  242. Barrett-Connor E, Friedlander NJ, Khaw KT. Dehydroepiandrosterone sulfate and breast cancer risk. Cancer Res. Oct 15 1990;50(20):6571-4. https://www.ncbi.nlm.nih.gov/pubmed/2145063
  243. Jones DL, James VH. Determination of dehydroepiandrosterone and dehydroepiandrosterone sulphate in blood and tissue. Studies of normal women and women with breast or endometrial cancer. J Steroid Biochem. Jan 1987;26(1):151-9. doi:10.1016/0022-4731(87)90044-6. https://www.ncbi.nlm.nih.gov/pubmed/2950279
  244. Zhang X, Tworoger SS, Eliassen AH, Hankinson SE. Postmenopausal plasma sex hormone levels and breast cancer risk over 20 years of follow-up. Breast Cancer Res Treat. Feb 2013;137(3):883-92. doi:10.1007/s10549-012-2391-z. https://link.springer.com/article/10.1007/s10549-012-2391-z
  245. Cagnacci A, Barattini DF, Casolati E, Pecoroni A, Mangrella M, Patrascu LC. Polycarbophil vaginal moisturizing gel versus hyaluronic acid gel in women affected by vaginal dryness in late menopausal transition: A prospective randomized trial. European journal of obstetrics, gynecology, and reproductive biology. Mar 2022;270:239-245. doi:10.1016/j.ejogrb.2022.01.021. https://www.ncbi.nlm.nih.gov/pubmed/35131532
  246. Buzzaccarini G, Marin L, Noventa M, et al. Hyaluronic acid in vulvar and vaginal administration: evidence from a literature systematic review. Climacteric : the journal of the International Menopause Society. Dec 2021;24(6):560-571. doi:10.1080/13697137.2021.1898580. https://www.ncbi.nlm.nih.gov/pubmed/33759670
  247. Shin JJ, Kim SK, Lee JR, Suh CS. Ospemifene: A Novel Option for the Treatment of Vulvovaginal Atrophy. Journal of menopausal medicine. Aug 2017;23(2):79-84. doi:10.6118/jmm.2017.23.2.79. https://www.ncbi.nlm.nih.gov/pubmed/28951854
  248. Fabian CJ, Nye L, Powers KR, et al. Effect of Bazedoxifene and Conjugated Estrogen (Duavee) on Breast Cancer Risk Biomarkers in High-Risk Women: A Pilot Study. Cancer Prev Res (Phila). Oct 2019;12(10):711-720. doi:10.1158/1940-6207.CAPR-19-0315. https://www.ncbi.nlm.nih.gov/pubmed/31420361
  249. Marlatt KL, Lovre D, Beyl RA, et al. Effect of conjugated estrogens and bazedoxifene on glucose, energy and lipid metabolism in obese postmenopausal women. Eur J Endocrinol. Oct 2020;183(4):439-452. doi:10.1530/EJE-20-0619. https://www.ncbi.nlm.nih.gov/pubmed/32698159
  250. Sarmento ACA, Lirio JF, Medeiros KS, et al. Physical methods for the treatment of genitourinary syndrome of menopause: A systematic review. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. May 2021;153(2):200-219. doi:10.1002/ijgo.13561. https://www.ncbi.nlm.nih.gov/pubmed/33354773
  251. Juhasz MLW, Korta DZ, Mesinkovska NA. Vaginal Rejuvenation: A Retrospective Review of Lasers and Radiofrequency Devices. Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al]. Apr 1 2021;47(4):489-494. doi:10.1097/DSS.0000000000002845. https://www.ncbi.nlm.nih.gov/pubmed/33165070
  252. Astellas Pharma US I. VEOZAH (fezolinetant) tablets, for oral use. FDA. Accessed 05/18/2023,
  253. Lederman S, Ottery FD, Cano A, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. The Lancet. 2023;401(10382):1091-1102. doi:10.1016/S0140-6736(23)00085-5. https://doi.org/10.1016/S0140-6736(23)00085-5
  254. FDA. FDA Approves Novel Drug to Treat Moderate to Severe Hot Flashes Caused by Menopause. 05/12/2023. Accessed 05/18/2023. https://www.fda.gov/news-events/press-announcements/fda-approves-novel-drug-treat-moderate-severe-hot-flashes-caused-menopause?utm_medium=email&utm_source=govdelivery
  255. Johnson KA, Martin N, Nappi RE, et al. Efficacy and Safety of Fezolinetant in Moderate to Severe Vasomotor Symptoms Associated With Menopause: A Phase 3 RCT. The Journal of Clinical Endocrinology & Metabolism. 2023;doi:10.1210/clinem/dgad058. https://doi.org/10.1210/clinem/dgad058
  256. Sahni S, Lobo-Romero A, Smith T. Contemporary Non-hormonal Therapies for the Management of Vasomotor Symptoms Associated with Menopause: A Literature Review. touchREV Endocrinol. Nov 2021;17(2):133-137. doi:10.17925/EE.2021.17.2.133. https://www.ncbi.nlm.nih.gov/pubmed/35118459
  257. Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. Jama. Jun 4 2003;289(21):2827-34. doi:10.1001/jama.289.21.2827.
  258. Henssler J, Heinz A, Brandt L, Bschor T. Antidepressant Withdrawal and Rebound Phenomena. Dtsch Arztebl Int. May 17 2019;116(20):355-361. doi:10.3238/arztebl.2019.0355.
  259. Yoon SH, Lee JY, Lee C, Lee H, Kim SN. Gabapentin for the treatment of hot flushes in menopause: a meta-analysis. Menopause. Apr 2020;27(4):485-493. doi:10.1097/GME.0000000000001491. https://www.ncbi.nlm.nih.gov/pubmed/32049930
  260. MC. Mayo Clinic. Cognitive Behavioral Therapy: Overview. Available at https://www.mayoclinic.org/tests-procedures/cognitive-behavioral-therapy/about/pac-20384610 Published 03/16/2019. Accessed 08/21/2022. 2019;
  261. van Driel CM, Stuursma A, Schroevers MJ, Mourits MJ, de Bock GH. Mindfulness, cognitive behavioural and behaviour-based therapy for natural and treatment-induced menopausal symptoms: a systematic review and meta-analysis. BJOG : an international journal of obstetrics and gynaecology. Feb 2019;126(3):330-339. doi:10.1111/1471-0528.15153. https://www.ncbi.nlm.nih.gov/pubmed/29542222
  262. Ye M, Shou M, Zhang J, et al. Efficacy of cognitive therapy and behavior therapy for menopausal symptoms: a systematic review and meta-analysis. Psychol Med. Feb 2022;52(3):433-445. doi:10.1017/S0033291721005407. https://www.ncbi.nlm.nih.gov/pubmed/35199638
  263. Diem SJ, LaCroix AZ, Reed SD, et al. Effects of pharmacologic and nonpharmacologic interventions on menopause-related quality of life: a pooled analysis of individual participant data from four MsFLASH trials. Menopause. Oct 2020;27(10):1126-1136. doi:10.1097/GME.0000000000001597. https://www.ncbi.nlm.nih.gov/pubmed/32701665
  264. Lam CM, Hernandez-Galan L, Mbuagbaw L, Ewusie JE, Thabane L, Shea AK. Behavioral interventions for improving sleep outcomes in menopausal women: a systematic review and meta-analysis. Menopause. Oct 1 2022;29(10):1210-1221. doi:10.1097/GME.0000000000002051. https://www.ncbi.nlm.nih.gov/pubmed/36067398
  265. Samami E, Shahhosseini Z, Elyasi F. The effects of psychological interventions on menopausal hot flashes: A systematic review. Int J Reprod Biomed. Apr 2022;20(4):255-272. doi:10.18502/ijrm.v20i4.10898. https://www.ncbi.nlm.nih.gov/pubmed/35822187
  266. Dunneram Y, Greenwood DC, Cade JE. Diet, menopause and the risk of ovarian, endometrial and breast cancer. The Proceedings of the Nutrition Society. Aug 2019;78(3):438-448. doi:10.1017/S0029665118002884. https://www.ncbi.nlm.nih.gov/pubmed/30706844
  267. Martiniakova M, Babikova M, Mondockova V, Blahova J, Kovacova V, Omelka R. The Role of Macronutrients, Micronutrients and Flavonoid Polyphenols in the Prevention and Treatment of Osteoporosis. Nutrients. Jan 25 2022;14(3)doi:10.3390/nu14030523. https://www.ncbi.nlm.nih.gov/pubmed/35276879
  268. Noll P, Campos CAS, Leone C, et al. Dietary intake and menopausal symptoms in postmenopausal women: a systematic review. Climacteric : the journal of the International Menopause Society. Apr 2021;24(2):128-138. doi:10.1080/13697137.2020.1828854. https://www.ncbi.nlm.nih.gov/pubmed/33112163
  269. Cano A, Marshall S, Zolfaroli I, et al. The Mediterranean diet and menopausal health: An EMAS position statement. Maturitas. Sep 2020;139:90-97. doi:10.1016/j.maturitas.2020.07.001. https://www.ncbi.nlm.nih.gov/pubmed/32682573
  270. Pugliese GD, Barrea LD, Laudisio DD, et al. Mediterranean diet as tool to manage obesity in menopause: A narrative review. Nutrition. Nov-Dec 2020;79-80:110991. doi:10.1016/j.nut.2020.110991. https://www.ncbi.nlm.nih.gov/pubmed/32979767
  271. Beezhold B, Radnitz C, McGrath RE, Feldman A. Vegans report less bothersome vasomotor and physical menopausal symptoms than omnivores. Maturitas. Jun 2018;112:12-17. doi:10.1016/j.maturitas.2018.03.009. https://www.ncbi.nlm.nih.gov/pubmed/29704911
  272. Barnard ND, Kahleova H, Holtz DN, et al. The Women's Study for the Alleviation of Vasomotor Symptoms (WAVS): a randomized, controlled trial of a plant-based diet and whole soybeans for postmenopausal women. Menopause. Jul 12 2021;28(10):1150-1156. doi:10.1097/GME.0000000000001812. https://www.ncbi.nlm.nih.gov/pubmed/34260478
  273. Barnard ND, Kahleova H, Holtz DN, et al. A dietary intervention for vasomotor symptoms of menopause: a randomized, controlled trial. Menopause. Jan 1 2023;30(1):80-87. doi:10.1097/GME.0000000000002080. https://www.ncbi.nlm.nih.gov/pubmed/36253903
  274. Karavasiloglou N, Selinger E, Gojda J, Rohrmann S, Kuhn T. Differences in Bone Mineral Density between Adult Vegetarians and Nonvegetarians Become Marginal when Accounting for Differences in Anthropometric Factors. J Nutr. May 1 2020;150(5):1266-1271. doi:10.1093/jn/nxaa018. https://www.ncbi.nlm.nih.gov/pubmed/32055831
  275. Noll P, Noll M, Zangirolami-Raimundo J, et al. Life habits of postmenopausal women: Association of menopause symptom intensity and food consumption by degree of food processing. Maturitas. Feb 2022;156:1-11. doi:10.1016/j.maturitas.2021.10.015. https://www.ncbi.nlm.nih.gov/pubmed/35033227
  276. Herber-Gast GC, Mishra GD. Fruit, Mediterranean-style, and high-fat and -sugar diets are associated with the risk of night sweats and hot flushes in midlife: results from a prospective cohort study. Am J Clin Nutr. May 2013;97(5):1092-9. doi:10.3945/ajcn.112.049965. https://www.ncbi.nlm.nih.gov/pubmed/23553160
  277. Kroenke CH, Caan BJ, Stefanick ML, et al. Effects of a dietary intervention and weight change on vasomotor symptoms in the Women's Health Initiative. Menopause. Sep 2012;19(9):980-8. doi:10.1097/gme.0b013e31824f606e. https://www.ncbi.nlm.nih.gov/pubmed/22781782
  278. Flor-Alemany M, Marin-Jimenez N, Coll-Risco I, Aranda P, Aparicio VA. Influence of dietary habits and Mediterranean diet adherence on menopausal symptoms. The FLAMENCO project. Menopause. Sep 2020;27(9):1015-1021. doi:10.1097/GME.0000000000001574. https://www.ncbi.nlm.nih.gov/pubmed/32852453
  279. Kim IS. Current Perspectives on the Beneficial Effects of Soybean Isoflavones and Their Metabolites for Humans. Antioxidants (Basel). Jun 30 2021;10(7)doi:10.3390/antiox10071064. https://www.ncbi.nlm.nih.gov/pubmed/34209224
  280. Rodriguez-Garcia C, Sanchez-Quesada C, Toledo E, Delgado-Rodriguez M, Gaforio JJ. Naturally Lignan-Rich Foods: A Dietary Tool for Health Promotion? Molecules. Mar 6 2019;24(5)doi:10.3390/molecules24050917. https://www.ncbi.nlm.nih.gov/pubmed/30845651
  281. Parikh M, Maddaford TG, Austria JA, Aliani M, Netticadan T, Pierce GN. Dietary Flaxseed as a Strategy for Improving Human Health. Nutrients. May 25 2019;11(5)doi:10.3390/nu11051171. https://www.ncbi.nlm.nih.gov/pubmed/31130604
  282. O’Connor A. Washington Post: What are ultra-processed foods? What should I eat instead? Available at https://www.washingtonpost.com/wellness/2022/09/27/ultraprocessed-foods/  Published 09/27/2022. Accessed 11/08/2022. 2022;
  283. McManus KD. Harvard Health. What Are Ultra-Processed Foods and Are The Bad For Our Health? Available at https://www.health.harvard.edu/blog/what-are-ultra-processed-foods-and-are-they-bad-for-our-health-2020010918605  Published 01/09/2020. Accessed 11/08/2022. 2020;
  284. Kwon R, Chang Y, Kim Y, et al. Alcohol Consumption Patterns and Risk of Early-Onset Vasomotor Symptoms in Premenopausal Women. Nutrients. May 29 2022;14(11)doi:10.3390/nu14112276. https://www.ncbi.nlm.nih.gov/pubmed/35684078
  285. Faubion SS, Sood R, Thielen JM, Shuster LT. Caffeine and menopausal symptoms: what is the association? Menopause. Feb 2015;22(2):155-8. doi:10.1097/GME.0000000000000301. https://www.ncbi.nlm.nih.gov/pubmed/25051286
  286. Neff AM, Laws MJ, Warner GR, Flaws JA. The Effects of Environmental Contaminant Exposure on Reproductive Aging and the Menopause Transition. Current environmental health reports. Mar 2022;9(1):53-79. doi:10.1007/s40572-022-00334-y. https://www.ncbi.nlm.nih.gov/pubmed/35103957
  287. Avis NE, Crawford SL, Green R. Vasomotor Symptoms Across the Menopause Transition: Differences Among Women. Obstetrics and gynecology clinics of North America. Dec 2018;45(4):629-640. doi:10.1016/j.ogc.2018.07.005. https://www.ncbi.nlm.nih.gov/pubmed/30401547
  288. Costanian C, Zangiabadi S, Bahous SA, Deonandan R, Tamim H. Reviewing the evidence on vasomotor symptoms: the role of traditional and non-traditional factors. Climacteric : the journal of the International Menopause Society. Jun 2020;23(3):213-223. doi:10.1080/13697137.2019.1711051. https://www.ncbi.nlm.nih.gov/pubmed/31975617
  289. Smith RL, Flaws JA, Gallicchio L. Does quitting smoking decrease the risk of midlife hot flashes? A longitudinal analysis. Maturitas. Sep 2015;82(1):123-7. doi:10.1016/j.maturitas.2015.06.029. https://www.ncbi.nlm.nih.gov/pubmed/26149340
  290. Mishra GD, Chung HF, Cano A, et al. EMAS position statement: Predictors of premature and early natural menopause. Maturitas. May 2019;123:82-88. doi:10.1016/j.maturitas.2019.03.008. https://www.ncbi.nlm.nih.gov/pubmed/31027683
  291. Management of Osteoporosis in Postmenopausal Women: The Position Statement of The North American Menopause Society'' Editorial P. Management of osteoporosis in postmenopausal women: the 2021 position statement of The North American Menopause Society. Menopause. Sep 1 2021;28(9):973-997. doi:10.1097/GME.0000000000001831. https://www.ncbi.nlm.nih.gov/pubmed/34448749
  292. Cho EJ, Choi Y, Jung SJ, Kwak HB. Role of exercise in estrogen deficiency-induced sarcopenia. J Exerc Rehabil. Feb 2022;18(1):2-9. doi:10.12965/jer.2244004.002. https://www.ncbi.nlm.nih.gov/pubmed/35356136
  293. Gould LM, Gordon AN, Cabre HE, et al. Metabolic effects of menopause: a cross-sectional characterization of body composition and exercise metabolism. Menopause. Feb 28 2022;29(4):377-389. doi:10.1097/GME.0000000000001932. https://www.ncbi.nlm.nih.gov/pubmed/35231009
  294. Murawska-Cialowicz E, Kaczmarek A, Kalwa M, Oniszczuk A. Influence of Training and Single Exercise on Leptin Level and Metabolism in Obese Overweight and Normal-Weight Women of Different Age. Int J Environ Res Public Health. Sep 26 2022;19(19)doi:10.3390/ijerph191912168. https://www.ncbi.nlm.nih.gov/pubmed/36231470
  295. Chopra S, Sharma KA, Ranjan P, Malhotra A, Vikram NK, Kumari A. Weight Management Module for Perimenopausal Women: A Practical Guide for Gynecologists. Journal of mid-life health. Oct-Dec 2019;10(4):165-172. doi:10.4103/jmh.JMH_155_19. https://www.ncbi.nlm.nih.gov/pubmed/31942151
  296. Hybholt M. Psychological and social health outcomes of physical activity around menopause: A scoping review of research. Maturitas. Oct 2022;164:88-97. doi:10.1016/j.maturitas.2022.07.014. https://www.ncbi.nlm.nih.gov/pubmed/35964395
  297. Saquetto MB, Dos Santos MR, Alves IGN, Queiroz RS, Machado RM, Neto MG. Effects of water-based exercises on functioning of postmenopausal women: A systematic review with meta-analysis. Exp Gerontol. Sep 2022;166:111875. doi:10.1016/j.exger.2022.111875. https://www.ncbi.nlm.nih.gov/pubmed/35764204
  298. Baena-Garcia L, Flor-Alemany M, Marin-Jimenez N, Aranda P, Aparicio VA. A 16-week multicomponent exercise training program improves menopause-related symptoms in middle-aged women. The FLAMENCO project randomized control trial. Menopause. May 1 2022;29(5):537-544. doi:10.1097/GME.0000000000001947. https://www.ncbi.nlm.nih.gov/pubmed/35102099
  299. CDC. Centers for Disease Control and Prevention. How Much Physical Activity do Adults Need? Available at https://www.cdc.gov/physicalactivity/basics/adults/index.htm Last Updated 06/02/2022. Accessed 03/07/2023. 2022;
  300. Susanti HD, Sonko I, Chang PC, Chuang YH, Chung MH. Effects of yoga on menopausal symptoms and sleep quality across menopause statuses: A randomized controlled trial. Nurs Health Sci. Jun 2022;24(2):368-379. doi:10.1111/nhs.12931. https://www.ncbi.nlm.nih.gov/pubmed/35191141
  301. Swain D, Nanda P, Das H. Impact of yoga intervention on menopausal symptoms-specific quality of life and changes in hormonal level among menopausal women. J Obstet Gynaecol Res. Oct 2021;47(10):3669-3676. doi:10.1111/jog.14939. https://www.ncbi.nlm.nih.gov/pubmed/34254406
  302. Shepherd-Banigan M, Goldstein KM, Coeytaux RR, et al. Improving vasomotor symptoms; psychological symptoms; and health-related quality of life in peri- or post-menopausal women through yoga: An umbrella systematic review and meta-analysis. Complement Ther Med. Oct 2017;34:156-164. doi:10.1016/j.ctim.2017.08.011. https://www.ncbi.nlm.nih.gov/pubmed/28917368
  303. Souza L, Lima AA. Anthropometric, biochemical and clinical parameters in climacteric yoga practitioners. Climacteric : the journal of the International Menopause Society. Jun 2022;25(3):293-299. doi:10.1080/13697137.2021.1965115. https://www.ncbi.nlm.nih.gov/pubmed/34423699
  304. Souza L, Reis IA, Lima AA. Climacteric symptoms and quality of life in yoga practitioners. Explore (NY). Jan-Feb 2022;18(1):70-75. doi:10.1016/j.explore.2020.09.005. https://www.ncbi.nlm.nih.gov/pubmed/33036931
  305. Sharifi N, Afshari F, Bahri N. The effects of yoga on quality of life among postmenopausal women: A systematic review study. Post Reprod Health. Dec 2021;27(4):215-221. doi:10.1177/20533691211046152. https://www.ncbi.nlm.nih.gov/pubmed/34779291
  306. Rahnavardi M, Khalesi ZB, Rezaie-Chamani S. Effects of lifestyle on sexual function among postmenopausal women. Afr Health Sci. Dec 2021;21(4):1823-1829. doi:10.4314/ahs.v21i4.40. https://www.ncbi.nlm.nih.gov/pubmed/35283965
  307. Gordon JL, Halleran M, Beshai S, Eisenlohr-Moul TA, Frederick J, Campbell TS. Endocrine and psychosocial moderators of mindfulness-based stress reduction for the prevention of perimenopausal depressive symptoms: A randomized controlled trial. Psychoneuroendocrinology. Aug 2021;130:105277. doi:10.1016/j.psyneuen.2021.105277. https://www.ncbi.nlm.nih.gov/pubmed/34058560
  308. O'Connor KA, Ferrell R, Brindle E, et al. Progesterone and ovulation across stages of the transition to menopause. Menopause. Nov-Dec 2009;16(6):1178-87. doi:10.1097/gme.0b013e3181aa192d.
  309. Grub J, Suss H, Willi J, Ehlert U. Steroid Hormone Secretion Over the Course of the Perimenopause: Findings From the Swiss Perimenopause Study. Front Glob Womens Health. 2021;2:774308. doi:10.3389/fgwh.2021.774308. https://www.ncbi.nlm.nih.gov/pubmed/34970652
  310. Koothirezhi R, Ranganathan S. Postmenopausal Syndrome. StatPearls. StatPearls Publishing Copyright © 2022, StatPearls Publishing LLC.; 2023.
  311. Monteleone P, Mascagni G, Giannini A, Genazzani AR, Simoncini T. Symptoms of menopause - global prevalence, physiology and implications. Nature reviews Endocrinology. Apr 2018;14(4):199-215. doi:10.1038/nrendo.2017.180. https://www.ncbi.nlm.nih.gov/pubmed/29393299
  312. Secosan C, Balint O, Pirtea L, Grigoras D, Balulescu L, Ilina R. Surgically Induced Menopause-A Practical Review of Literature. Medicina (Kaunas). Aug 14 2019;55(8)doi:10.3390/medicina55080482. https://www.ncbi.nlm.nih.gov/pubmed/31416275
  313. Chon SJ, Umair Z, Yoon MS. Premature Ovarian Insufficiency: Past, Present, and Future. Frontiers in cell and developmental biology. 2021;9:672890. doi:10.3389/fcell.2021.672890. https://www.ncbi.nlm.nih.gov/pubmed/34041247
  314. Nash Z, Al-Wattar BH, Davies M. Bone and heart health in menopause. Best practice & research Clinical obstetrics & gynaecology. May 2022;81:61-68. doi:10.1016/j.bpobgyn.2022.03.002. https://www.ncbi.nlm.nih.gov/pubmed/35400590
  315. Machura P, Grymowicz M, Rudnicka E, et al. Premature ovarian insufficiency - hormone replacement therapy and management of long-term consequences. Prz Menopauzalny. Sep 2018;17(3):135-138. doi:10.5114/pm.2018.78559. https://www.ncbi.nlm.nih.gov/pubmed/30357030
  316. Huang Y, Qi T, Ma L, et al. Menopausal symptoms in women with premature ovarian insufficiency: prevalence, severity, and associated factors. Menopause. Jan 15 2021;28(5):529-537. doi:10.1097/GME.0000000000001733. https://www.ncbi.nlm.nih.gov/pubmed/33470756
  317. Naftolin F, Friedenthal J, Nachtigall R, Nachtigall L. Cardiovascular health and the menopausal woman: the role of estrogen and when to begin and end hormone treatment. F1000Res. 2019;8doi:10.12688/f1000research.15548.1. https://www.ncbi.nlm.nih.gov/pubmed/31543950
  318. ACOG. American College of Obstetrics and Gynecology. Committee Opinion: Hormone Therapy in Primary Ovarian Insufficiency. Available at https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2017/05/hormone-therapy-in-primary-ovarian-insufficiency Published 05/2017. Accessed 10/31/2022. 2017;
  319. Voedisch AJ, Ariel D. Perimenopausal contraception. Curr Opin Obstet Gynecol. Dec 2020;32(6):399-407. doi:10.1097/GCO.0000000000000667. https://www.ncbi.nlm.nih.gov/pubmed/33002952
  320. Song Y, Xu W, Chatooah ND, et al. Comparison of low dose versus ultra-low dose hormone therapy in menopausal symptoms and quality of life in perimenopause women. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. Mar 2020;36(3):252-256. doi:10.1080/09513590.2019.1666815. https://www.ncbi.nlm.nih.gov/pubmed/31538509