Health disorders in menopausal women: microbiome alterations, associated problems, and possible treatments

Abstract

Perimenopause marks a critical transition in women’s lives, characterized by declining estrogen levels that trigger profound physiological and psychological changes, impacting quality of life and increasing susceptibility to age-related degenerative diseases. This review systematically examines the intricate relationships among menopause, disease associations, microbiome alterations, and intervention strategies. Estrogen fluctuations disrupt the microbial balance in the vagina, intestine, urethra, and oral cavity, contributing to microecological imbalance and heightened disease risk. Menopause is closely linked to a spectrum of health issues, including reproductive system disorders (e.g., uterine fibroids, ovarian cancer microbiota changes), metabolic syndromes (obesity, type 2 diabetes), cardiovascular diseases (influenced by gut microbiota and dietary patterns), osteoporosis, and mental health disturbances. Current interventions—ranging from dietary modifications (cocoa polyphenols, dietary fiber, soy isoflavones) and menopausal hormone therapy (MHT) to probiotic supplementation, plant extracts (soybean, black cohosh, red clover), and traditional therapies—exhibit distinct advantages and limitations. Technological advancements in microbiome analysis, tissue processing, and cell isolation have revolutionized diagnostic and therapeutic approaches, while immune function, socioeconomic factors, and lifestyle choices significantly modulate health outcomes. Future research should prioritize exploring synergistic intervention strategies, developing personalized health management programs, and unraveling the mechanistic links between the microbiome and menopause-related diseases. This comprehensive synthesis aims to advance evidence-based strategies for improving the health and quality of life of menopausal women.

Introduction

Perimenopause, a crucial phase in a woman’s life cycle, indicates the waning of reproductive function from its peak state [1]. During this period, estrogen levels in women's bodies drop significantly, triggering changes in the menstrual cycle, physiology and psychology [2]. Physical manifestations like hot flashes and sweating, sleep disorders, urinary and reproductive tract infections, joint muscle pain, as well as psychological problems such as anxiety and depression, seriously reduce women's quality of life [3]. More importantly, perimenopause is also the embryonic stage of senile degenerative diseases like osteoporosis, cardiovascular disease, and Alzheimer's disease have a significant influence on the health-related lifespan of women. With the acceleration of the global population aging process, the health problems of menopausal women have attracted increasing attention [4]. The large population of the elderly means that many women are in or about to experience perimenopause, and their health needs need to be met urgently [5]. Scientific and effective intervention for perimenopause can not only improve the quality of life of this group, but also reduce the risk of degenerative diseases in the elderly. Reasonable control of medical expenses has important social and economic significance [6].

Currently, menopausal hormone therapy (MHT) remains the most common treatment for perimenopausal women, demonstrating efficacy in alleviating menopausal symptoms and preventing age-related diseases through estrogen supplementation [7]. However, potential risks of MHT—such as breast lesions and thrombosis—have raised safety concerns. Despite international advancements in understanding MHT safety and optimizing treatment protocols (e.g., the impact of early MHT initiation on cardiovascular health and rational progestogen selection to mitigate breast cancer risk), significant knowledge gaps persist [8].

The female vaginal microecosystem is intimately linked to estrogen levels, with estrogen fluctuations altering vaginal microbiota and compromising vaginal health. During perimenopause, declining estrogen induces vaginal epithelial atrophy, reduced glycogen content, and Lactobacillus depletion—pathophysiological changes that contribute to genitourinary syndrome of menopause (GSM) and elevate the risk of urinary/reproductive tract infections. Estrogen also modulates microbiomes in the intestines, urethra, and oral cavity, where microbial dysbiosis correlates with various diseases [9, 10]. Notably, systematic investigations into vaginal microecological changes and associated immune regulation under estrogen insufficiency or hormone replacement therapy remain limited.

In terms of the relationship between menopause and disease, numerous research findings have indicated that menopause has a close connection with diseases in multiple fields such as reproductive system diseases, metabolic diseases, cardiovascular diseases, bone health, mental health, etc. Menopause may reduce the risk of uterine fibroids, but it is related to changes within the cervical and vaginal microbiota of ovarian cancer patients [11, 12]; changes in body metabolism after menopause increase the occurrence rate of metabolic disorders like obesity and type 2 diabetes; changes in cardiovascular disease risk after menopause are closely associated with alterations in the intestinal microbiota and dietary patterns; estrogen deficiency caused by menopause accelerates bone mass loss and heightens the likelihood of osteoporosis and fractures; changes in hormone levels before and after menopause affect neurotransmitter balance and are closely related to the appearance of psychiatric symptoms [13]. In addition, menopause also has an impact on oral health, sleep quality, and the immune system.

To enhance the health condition of menopausal women, a variety of interventions have been widely studied. In terms of dietary intervention, nutrients such as cocoa polyphenols, dietary fiber, soy isoflavones in chocolate, and bioactive ingredients in fermented soy products have positive effects on the cardiovascular health, intestinal function, bone health and menopausal symptom relief of menopausal women. Hormone therapy needs to pay attention to its potential cancer risk while alleviating menopausal symptoms and maintaining bone health. It is essential to choose a reasonable treatment plan. Probiotic intervention can regulate the vaginal and intestinal microbial community structure of postmenopausal women, improve immune function, and relieve menopausal symptoms [14, 15]. It also has certain benefits in metabolic health and bone health. Plant extracts such as soybean extract, black cohosh extract, and red clover extract, as well as traditional therapies such as acupuncture and moxibustion, provide more options for the health management of menopausal women [16, 17]. They play a unique role in relieving menopausal symptoms, regulating endocrine and nervous system functions, and enhancing immunity.

Additionally, technologies like microbiome analysis, tissue processing, and cell isolation play a vital role in diagnosing and treating menopause-related diseases [18]. High-throughput 16S rRNA sequencing of the microbiome aids disease diagnosis and guides probiotic therapy. Tissue processing technology helps understand bone tissue pathology in osteoporosis, while cell isolation technology enables genetic and protein analysis of cancer cells for precise breast cancer diagnosis and treatment. Moreover, the immune system, socioeconomic factors, and lifestyle significantly impact menopausal women’s health. Strong immune function, high socioeconomic status, and a healthy lifestyle help maintain their physical and mental well-being. This review comprehensively examines the research on menopausal women's health, exploring the links between menopause and diseases, microbiome changes, intervention effects, and other related progress. It identifies research gaps and challenges through a thorough analysis, and proposes future research directions to promote menopausal women's health and provide more scientific health management strategies.

Analysis of the connection between menopause and disorders

Reproductive system diseases

Menopause, a crucial stage in women's physiological process, is closely linked to reproductive system diseases. During this period, women’s hormone levels change significantly, impacting reproductive organs and altering the risk of related diseases. Adebamowo et al. [19] found that menopausal status was inversely associated with uterine fibroids, i.e. menopause may diminish the likelihood of getting uterine fibroids as well as other factors that pose risks to the reproductive system such as number of children, history of miscarriage, etc., were also identified in association with uterine fibroids. Morikawa et al. [20] focused on premenopausal ovarian cancer patients, noting that the cervical and vaginal microbiota of ovarian cancer patients is altered, similar to that of healthy mail carriersopausal subjects, with diverse characteristics. Heutz et al. [21] found that postmenopausal women have an increased risk of developing anti-citrullinated protein antibody-negative inflammatory arthritis (IA) compared with premenopausal women. Additionally, early menopause, reduced reproductive years, and reduced ovulatory years all increase the risk of ACPA-negative IA.

These studies show that the female reproductive system changes dynamically around menopause. Menopause impacts the risk of uterine fibroids and correlates with changes in the cervical and vaginal microbiota of ovarian cancer patients. This provides a key basis for studying the link between menopause and reproductive system diseases, and aids in disease prevention, diagnosis, and treatment.

Metabolic disease

Menopause, a crucial physiological turning point for women, is closely tied to metabolic diseases. Post-menopause, the sharp decline in estrogen levels triggers metabolic changes, greatly raising the risk of conditions like obesity and type 2 diabetes. Ako et al. [22] discovered that there was a significant connection between gallbladder disease and type 2 diabetes, with a higher risk associated with central obesity, suggesting that changes in body metabolism after menopause increase the risk of metabolic disease. Choi et al. [23] compared the gut microbial community of mice suffering from obesity induced by ovariectomy and obesity induced by diet and found that the gut microbiome changed after menopause, and there were bacteria specifically associated with menopause, suggesting that menopause may be involved in the development of obesity by affecting the gut microbiome. Frankenfeld et al. [24] found that obesity is associated with the ability of gut microbes to metabolize soy isoflavones to produce O-demethylangolan (ODMA). Obese individuals are more likely to become non-producers of ODMA, and this association exists in pre- and post-menopausal women, suggesting that gut microbial metabolic function has a connection with metabolic diseases such as obesity after menopause. Miller et al. [25] further confirmed that in premenopausal women, obesity was associated with the ability of gut microbes to metabolize soy isoflavones, and that the phenotype of non-production in ODMA was notably related to obesity, re-emphasizing the significant function of gut microbes within the link between menopause and metabolic maladies. Kim et al. [26] found that compared with women who experienced menopause at 50 years old or above, women with premature menopause had a significantly increased risk of developing metabolic-dysfunction-associated fatty liver disease. These literatures show that menopause affects metabolism via multiple pathways and is closely linked to metabolic disorders such as obesity and type 2 diabetes, offering a key basis for understanding the pathogenesis and prevention of postmenopausal metabolic diseases.

Cardiovascular disease

Postmenopausal women undergo physiological changes like hormonal fluctuations, metabolic shifts, and gut microbiome alterations. These interconnected changes impact cardiovascular health, raising the risk of cardiovascular diseases. Leite et al. [27] focused on alterations in the duodenal microbiome of postmenopausal females, it was found that postmenopausal women who did not receive hormone therapy (HT⁻) experienced a rise in Proteobacteria levels and a decline in Bacteroidetes levels in the duodenal microbiome. This alteration was linked to elevated fasting blood glucose levels, reduced duodenal microbial diversity, and decreased testosterone levels, which in turn affected cardiovascular disease risk; while women who received hormone therapy (HT⁺) had higher estrogen and progesterone levels, lower fasting blood glucose, the relative abundance of Prevotella was elevated, while that of Escherichia, Klebsiella, and Lactobacillus was reduced. These changes were related to lower cardiovascular disease risk, suggesting that hormone therapy may have an impact on cardiovascular health in postmenopausal women by modulating the duodenal microbiome. Cabre et al. [28] conducted the research on dietary patterns and postmenopausal women's cardiovascular disease risk shows that diets like Mediterranean, despite limited data, can improve biomarkers, reducing cholesterol, oxidative stress, and inflammation, and enhancing endothelial function. Bernier et al. [29] reported that cardiovascular disease is the leading cause of death among women in the United States. Physiological changes during perimenopause and menopause increase women's risk of CVD.

According to these literatures, postmenopausal women's cardiovascular disease risk changes are closely linked to gut microbiome and dietary habit alterations, offering multi-dimensional directions for research and intervention in preventing and managing such diseases.

Bone health

After menopause, women experience a significant drop in estrogen levels. Estrogen protects bones by inhibiting osteoclast activity, reducing bone resorption, and preserving bone mass. With lower estrogen, osteoclasts become more active, leading to increased bone resorption over formation. This speeds up bone loss and makes postmenopausal women more prone to bone issues like osteoporosis. Stepan et al. [30] pointed out that postmenopausal women, due to a lack of estrogen, experience increased osteoclast activity and accelerated bone resorption occurs, which causes swift bone loss and notably heightens the likelihood of osteoporosis as well as fractures, highlighting the key physiological mechanisms by which menopause affects bone health. Lecomte et al. [31] further confirmed this conclusion, it was also found that 8-prenylnaringenin-standardized hop extract can improve bone density in postmenopausal women with osteoporosis by regulating hormone levels and bone metabolism-related factors, offering a new approach for postmenopausal bone health interventions. Moreover, Wallimann et al. [32] discovered that certain probiotics can regulate gut microbiota balance, enhance gut calcium absorption, modulate bone metabolism signaling pathways, thus influencing bone metabolism, highlighting the gut microbiome's crucial role in post-menopausal bone health. In summary, menopause significantly affects bone health through hormone regulation, plant extract intervention, and gut microbiome modulation, offering theoretical and practical guidance for preventing and treating menopausal bone issues.

Mental health

Some women may experience anxiety, depression, and mood swings before and after menopause, making the relationship between menopause and mental health a key area of research and concern. Through a survey of a large number of menopausal women, Abdoli et al. [33] found that hormonal changes during menopause, like fluctuations and drops in estrogen levels, can disrupt neurotransmitter balance, triggering mood swings, anxiety, and depression. This shows a strong link between menopause and women's mental health. Ramin et al. [34] focused on the impact of socio-psychological factors on the mental health of postmenopausal women, highlighting that life stress, social role changes, and perceptions of aging interact with the physiological changes associated with menopause, further exacerbating the mental burden and affecting their psychological well-being. Kedare et al. [35] found that women's mental health is influenced by multi-dimensional factors such as biological, sociocultural factors, and varies according to life stages such as adolescence, perinatal period, and menopause. It is even more particular in the Indian context, so targeted safeguard measures and policy recommendations need to be put forward. Martin-Key et al.[36] confirmed based on the Health Belief Model that the intention of menopausal women to use mental health apps is mainly influenced by cues to action and perceived barriers. These studies show the intricate link between menopause and mental health, involving hormonal changes and social-psychological impacts, offering key theoretical groundwork and research directions for enhancing postmenopausal women’s mental well-being.

Other health issues

Menopause is closely linked to various aspects of women's health. Auriemma et al. [37] indicated that postmenopausal women's oral health deteriorates as lower estrogen weakens gum tissue’s anti-inflammatory resistance, raising the risk of periodontal disease. Muhleisen et al. [38] found that menopause affects sleep quality; hormonal fluctuations cause hot flushes and night sweats, disrupting sleep and increasing sleep disorder rates, which impacts overall well-being. Wang et al. [39] showed that menopause alters the immune system, changing immune cell activity and factor secretion, reducing the body's resistance and increasing disease and autoimmune disorder risks. In conclusion, these studies demonstrate menopause's multi-faceted impact on women’s health, emphasizing the need to address menopausal women's diverse health issues (Table 1).

Table 1.

The relationship between menopause and disease

Disease type	Disease-related manifestations	Brief description of the impact mechanism	Research significance	References
Reproductive system diseases	Menopause–uterine fibroids correlation and microbiome changes in ovarian cancer patients	Menopausal hormonal impacts on uterine/ovarian aspects and microbial communities	Basis for reproductive disease prevention/diagnosis and personalized health management	[19–21, 40]
Metabolic disease	Relationships among menopausal gallbladder disease, type 2 diabetes, central obesity, gut microbiome, and soy isoflavone metabolism	Menopausal hormonal impacts on metabolism (including fat, gallbladder, blood sugar, intestinal microecology, and soy isoflavone metabolism)	Multi-D approach for MCMDs prevention/treatment and precision microbial-based intervention research	[22–26, 41]
Cardiovascular disease	Mail carriers' menopause-related gut–diet–heart link and hormone therapy effects	Menopause gut microbiome changes, diet and therapy impacts on cardiovascular factors	Dietary/therapeutic interventions for CVD prevention in postmenopausal women and multidisciplinary prevention	[27–29, 42]
Bone health	Hormonal, herbal, and probiotic impacts on bone health	Estrogen, hops extract, and probiotics in bone health (covering deficiency effects, regulatory roles in hormones, metabolism, and absorption)	Provide directions for post-menopausal bone health prevention/treatment and explore intervention synergy	[30–32, 43, 44]
Mental health	Menopausal hormonal and psychosocial impacts on mental state	Estrogen, social-psychological factors affecting menopausal mental health	Comprehensive intervention ideas for menopausal women's mental health (physiological–psychological synergy focus)	[33–36]
Other health issues	Menopausal oral health, sleep quality, and immune system issues (focusing on increased risks like periodontal disease, sleep disorders, infections, and autoimmune diseases)	Estrogen-related impacts on gums, sleep, and immune function post-menopause	Providing basis for menopausal women's health attention and intervention	[37–39]

Relationship between the microbiome and menopause

Vaginal

In the process of female growth, Chen et al. [45] pointed out that estrogen levels rise during puberty. The vaginal microbiome is gradually dominated by Lactobacillus. By the reproductive period, Das et al. [46] showed that Lactobacillus maintains the stability of the vaginal microecology and ensures vaginal health. During pregnancy, according to Foschi et al. [47], the vaginal microbiome also adjusts accordingly due to adaptive changes in hormones and the immune system. And generally maintains a relative balance. However, after entering menopause, ovarian function declines and estrogen levels drop significantly. Muhleisen et al. [38] clearly pointed out that this resulted in a thinning of the vaginal epithelium, a sharp decrease in glycogen content, limited growth of Lactobacillus, and an increase in vaginal pH. The homeostasis of the microbiome originally dominated by Lactobacillus was broken. It gradually transitioned to aerobic bacteria and facultative anaerobic bacteria. The stability of the vaginal micro-ecological environment experienced a notable decline.

The alteration within the vaginal microbiome exerts a substantial influence on the health of women. On the one hand, it increases the risk of various vaginal diseases. Research by Kaur et al. [48] showed that the decrease in lactobacillus and the growth of anaerobic bacteria result in bacterial vaginosis. Mitchell et al. [49] shows that after the vaginal microbiome is unbalanced. It is more susceptible to trichomoniasis, which causes trichomoniasis vaginitis; research by Morikawa et al. [20] points out that the vaginal microecological imbalance creates conditions for the proliferation of Candida vulvovaginalis, resulting in vulvovaginal Candida disease; Murphy et al. [50]. Emphasize that estrogen deficiency and microbiome changes work together to cause atrophic vaginitis. On the other hand, the study by Auriemma et al. [37] shows that changes in the vaginal microbiome reduce local immune function, making the vagina more susceptible to infections, which in turn increases the incidence of diseases such as urethritis. Not only that, Pino et al. [51] also found that changes in the vaginal microbiome after menopause may be potentially linked to systemic diseases such as cardiovascular disease and osteoporosis by affecting local inflammation and immune status.

In response to the above problems, Wang et al. [52] explored the intervention method, through the local use of estrogen, is capable of facilitating the proliferation as well as the differentiation of vaginal epithelium, increase glycogen secretion, facilitate the growth of lactobacillus, and reshape the vaginal microecological balance; the application of probiotic preparations can regulate the microbiome composition, restrain the growth of noxious bacteria, decrease inflammation, and lower the risk of associated diseases. Bar et al. [53] provides complementary research ideas for understanding the relationship between menopause and the vaginal microbiome, as well as the impact on vaginal health.

Gut

There is a close and complex two-way relationship between menopause and the gut microbiome, and this relationship is synergistically influenced by various factors such as diet, exercise, and drugs. After menopause, women's estrogen levels drop sharply, becoming a key trigger for remodeling the gut microbiome. Baker et al. [54] and Barrea et al. [55] found that the decrease in estrogen levels significantly alters the richness and diversity of gut microbes, resulting in an imbalance in the ratio of Firmicutes to Bacteroides. Furthermore, Chen et al. [56] and Chen et al. [57] point out that the metabolic activity of the intestinal microbiome is also deeply affected, and the production of key metabolites such as short URL fatty acids is greatly reduced. As an important energy source for intestinal epithelial cells, the reduction of short URL fatty acids not only impairs the intestinal barrier function and hinders the normal absorption of nutrients, but also interferes with immune regulation, which greatly compromises the defense and regulation ability of the intestine. Although the existing literature does not clearly explain how changes in the gut microbiome affect the health of postmenopausal women, it is reasonable to speculate that the imbalance of the intestinal microbiome will have adverse effects on the overall health status of postmenopausal women through changes in intestinal immunity and metabolites.

The state of the gut microbiome after menopause is regulated by many factors. In terms of diet, Peters et al.'s research shows that [58, 59], a diet rich in dietary fiber can provide sufficient nutrients for beneficial bacteria such as bifidobacteria, promote their proliferation, and optimize the intestinal microecology. On the contrary, a diet high in sugar and fat will break the original balance of intestinal microorganisms and aggravate the disorder of the intestinal microbiome after menopause. From the perspective of exercise, Peters et al. [60] pointed out that regular exercise can effectively promote intestinal peristalsis, accelerate intestinal blood circulation, create a suitable living environment for beneficial bacteria, and maintain the stability of intestinal microecology. In terms of drugs, Shen et al. [61] and Soliman et al. [62] found that antibiotics can cause serious damage to the living environment of beneficial bacteria while killing harmful bacteria; although hormone replacement therapy can relieve some menopausal symptoms such as hot flashes, it may interfere with the composition and function of intestinal microorganisms and break the balance of intestinal microecology. It is worth mentioning that Wang et al. [63] and Wei et al. [64] proposed that supplementation of probiotics and prebiotics is able to boost the quantity of beneficial bacteria, stimulate the growth and metabolism of beneficial bacteria, effectively regulate the mail carriersopausal disordered intestinal microbiome, and help restore the balance of intestinal microecology.

Urethral

After women enter menopause, they can cause changes within the makeup of the microbial community within the urethra. By analyzing the microbial samples of the urethra of premenopausal women [65, 66], it was found that the estrogen level in postmenopausal women dropped sharply, the urethral mucosa became thinner, and the pH value increased, which created the conditions for the change of the urethral microbiome. The number of Lactobacillus that originally dominated was greatly reduced, while the aerobic bacteria such as Enterobacteriaceae and Staphylococcus and facultative anaerobic bacteria proliferated, resulting in substantial alterations in the diversity and composition of urethral microbiota. At the same time, Kim et al. [67] pointed out that this change in the microbiome weakens the local defense mechanism of the urethra, making the urethra less resistant to pathogens. Studies [68, 69] show that the imbalance of the urinary tract microbiome after menopause significantly increases the risk of urinary tract infection. A significant quantity of harmful bacteria penetrate the urinary tract's defense barrier, triggering an inflammatory response, resulting in frequent urination, urgency, urinary pain and other symptoms, which seriously affect the quality of life of postmenopausal women. In addition, Saenz et al. [70] found through long-term follow-up studies that repeated urinary tract microbiome imbalance and urinary tract infection may also lead to more serious urinary system diseases, such as cystitis, pyelonephritis, etc., which pose a potential threat to kidney function.

Interventions targeting urinary microbiome alterations have also been reported. Some studies [71, 72] explored a series of interventions to improve the imbalance of urinary microbiome after menopause. Topical use of estrogen can promote the proliferation and differentiation of urinary mucosal epithelial cells, restore the acidic environment of the urethra, and favor the growth of lactobacillus, thereby reshaping the microecological balance of the urethra. In addition, supplementation of probiotic preparations can also regulate the urinary microbiome to a certain extent, inhibit the growth of harmful bacteria and reduce the incidence of urinary tract infections through competitive inhibition. This provides new ideas and methods to maintain the health of the urinary tract in postmenopausal women.

Oral

Menopause has a wide range of effects on women’s physiology. Among them, the oral microbiome is affected by it, and it undergoes significant changes, which in turn causes a series of chain reactions on oral and systemic health. Hosgood et al. [73] have found that the level of estrogen in postmenopausal women decreases sharply, resulting in the deterioration of the oral microenvironment. The amount of saliva secreted decreases, the pH value rises, and the oral mucosa is more easily damaged due to thinning, providing a new environment for the survival and reproduction of microorganisms. The composition and diversity of the oral microbiome are disrupted, and periodontitis-related pathogens such as Fusobacterium nucleatum and Porphyromonas gingivalis multiply, while the number of beneficial bacteria gradually decreases. The impact of these changes is not limited to the oral cavity. According to Tramice et al.’s report [74], the inflammatory response triggered by pathogens leads to damage to periodontal tissue, causing symptoms of periodontitis such as red, swollen gums, bleeding, loose teeth, and in severe cases, alveolar bone absorption, resulting in tooth loss. Not only that, Yakar et al. [75] indicated that the oral cavity serves as a crucial conduit for the interaction between the human body and the external environment, and an unbalanced oral microbiome can spread to the whole body through blood circulation and immune response. Oral pathogens and their metabolites enter the bloodstream, which may cause systemic inflammation, increase the risk of cardiovascular diseases such as atherosclerosis, and interfere with insulin sensitivity, aggravate glucose metabolism disorders, and increase the risk of diabetes. Although existing studies do not provide intervention strategies, combined with the research results, enhancing the oral well-being of postmenopausal women and regulating the equilibrium of the oral microbiome are of great significance for the prevention of both oral and systemic disorders. This also points the way for follow-up research and promotes the development of more control strategies (Table 2).

Table 2.

Association between the microbiome and menopause

Microbiome site	Changes in the microbiome before and after menopause	Health effects	Intervention measures and principles	References
Vaginal	Microbial shift in vaginal flora pre- and post-menopause	Increased risks of vaginal, urethral, and systemic diseases	Topical estrogen and probiotic use for vaginal microecology regulation	[20, 37, 38, 45–53]
Gut	Menopause-related changes in intestinal microbiome (including estrogen-induced shifts in richness, diversity, Firmicutes–Bacteroides ratio, and short-chain fatty acid production)	Impairs intestinal function, absorption, and immune regulation in menopausal women	Ways to optimize intestinal microecology (including fiber-rich diet, exercise, avoiding antibiotics, and supplementing probiotics/prebiotics)	[54–64]
Urethral	Urethral microbiome changes from pre- to post-menopause	Increased UTI risk, symptoms, and potential for serious urinary diseases	Topical estrogen for urethral microecology and probiotics for UTI prevention	[65–70] [71, 72]
Oral	Oral microbiome changes from pre- to post-menopause	Periodontitis symptoms, oral microbiome imbalance and systemic health risks	Improving oral health, microbiome balance (through cleaning and proper diet)	[73–75]
Duodenal	Postmenopausal women (non-hormone therapy users) have more Proteobacteria and less Bacteroidetes. Helicobacter pylori infection raises Haemophilus, Neisseria, and Streptococcus levels. High-cholesterol diets and aging change flora composition	Associated with increased cardiovascular disease risk via intestinal barrier dysfunction, chronic inflammation, and metabolic disruption	Hormone therapy to restore beneficial flora; duodenal-jejunal bypass devices for metabolic regulation; dietary supplements to modulate flora and reduce inflammation	[27, 76–81]

Duodenal

Hormonal changes in postmenopausal women can affect the duodenal microbiome, such as a decrease in beneficial bacteria and an increase in harmful bacteria. These changes may increase the risk of cardiovascular diseases through pathways such as affecting intestinal barrier function, triggering chronic inflammation, and participating in metabolic regulation. Leite et al. [27] first discovered an association between the duodenal microbiome in postmenopausal women and cardiovascular diseases. The study compared postmenopausal women who did not receive (HT-) and those who received hormone therapy (HT +), as well as premenopausal women. The result indicates that hormone therapy may improve the cardiovascular health of postmenopausal women by regulating the duodenal flora.

Hormonal changes in postmenopausal women can affect the duodenal microbiome, such as a decrease in beneficial bacteria and an increase in harmful bacteria. Busch et al. [76] pointed out in their study on metabolic syndrome (MetSyn) that gut microbiota participate in lipid metabolism and inflammation regulation by influencing metabolites such as short-chain fatty acids (SCFAs). As a key site for nutrient absorption, the imbalance of the duodenal flora may exacerbate atherosclerosis by promoting the entry of endotoxin into the blood or interfering with bile acid metabolism. In addition, Liu et al. [77] found in a quail model that a high-cholesterol diet could lead to an increase in Escherichia and Enterobacteriaceae in the duodenal flora, accompanied by an increase in the level of low-density lipoprotein (LDL), further supporting the association between the duodenal flora and lipid metabolism.

Helicobacter pylori infection can disrupt the original balance of the duodenal flora, leading to changes in the composition and function of the flora. Suarez-Jaramillo et al. [78] compared the duodenal flora of Helicobacter pylori-infected and non-infected individuals and found that the abundances of Haemophilus, Neisseria, and Streptococcus in the infected group increased significantly, and the flora diversity also increased.

The exploration of the duodenal flora as a therapeutic target is to study how to prevent, treat diseases, or improve health by regulating the duodenal flora. Glaysher et al. [79], tested the efficacy of the duodenal–jejunal bypass sleeve device (EndoBarrier) in patients with type 2 diabetes mellitus (T2DM) and found that this device could improve blood glucose control and cardiovascular risk factors by isolating the duodenal mucosa from chyme. In addition, Yang et al. [80] found in a broiler chicken model that the supplementation of modified palygorskite (Mpal) and essential oil complex could regulate the duodenal flora (increase Bacteroidetes and decrease Proteobacteria), and at the same time reduce the levels of serum lipopolysaccharide (LPS) and inflammatory factors, providing an intervention idea for improving metabolism and cardiovascular health by regulating the duodenal flora.

Study how age and drugs change the composition and function of the duodenal flora. Tsujimoto et al. [81] found that the use of proton pump inhibitors (PPI) could increase the abundance of Lactobacillales in the duodenum of aspirin users, which may indirectly affect cardiovascular health by regulating gastric acid secretion and intestinal barrier function. Schutte et al. [82] pointed out in their study on healthy aging that the composition of the gut microbiota changes significantly with age, but did not specifically focus on the duodenum. Combining with the data of postmenopausal women in Leite et al. [27], it is suggested that age and hormonal status may affect the risk of cardiovascular diseases by jointly regulating the duodenal flora.

By comparing the similarities and differences in metabolic pathways among different species, the commonalities and differences in life activities are revealed, providing a theoretical basis and innovative ideas for fields such as disease treatment and drug development. Liu et al. [77] found in a quail model that the duodenal flora of the anti-atherosclerotic genotype (RES) had a higher abundance of genes related to vitamin B6 and linoleic acid metabolism, and a lower abundance of Escherichia, providing cross-species evidence for analyzing how the duodenal flora affects cardiovascular health through metabolic pathways.

Existing studies have revealed the association between the duodenal microbiome and cardiovascular diseases, especially the regulatory effect of hormone therapy on the flora in postmenopausal women. In the future, it is necessary to explore the effects of flora metabolites, infection mechanisms, and precise intervention strategies to provide new targets for the cardiovascular health management of specific populations.

Research on the influence of intervention strategies on the health of menopausal women

Dietary intervention

Certain foods may help relieve osteoporosis, a common problem in postmenopausal women, by providing sufficient calcium and vitamin D and other nutrients to enhance bone strength. Or some foods may be beneficial to the cardiovascular health of postmenopausal women and minimize the likelihood of heart disease. Some foods may help regulate hormone levels in postmenopausal women and alleviate menopausal manifestations like hot flushes and nocturnal sweating. Abdoli et al. [33] focused on the effects of chocolate on postmenopausal women, studies have shown that cocoa polyphenols and other ingredients contained in chocolate possess antioxidant and anti-inflammatory characteristics, are capable of modulating vascular endothelial function, and to some degree, decrease the risk of cardiovascular disease among postmenopausal women. At the same time, some of the ingredients it contains can also act on the nervous system, improve the emotional state of postmenopausal women, and relieve anxiety, depression and other bad emotions. Positive effects of dietary fiber and soy-related foods. Ramin et al. [34] pointed out that adequate dietary fiber intake can effectively improve intestinal function in menopausal women, promote intestinal peristalsis, prevent constipation, and help regulate lipid metabolism, reduce cholesterol levels, and play a positive protective role in cardiovascular health. Some literature [57, 83–85] focused on dietary ingredients such as soy isoflavones, and find that soy isoflavones, as a phytoestrogen, can bind to human estrogen receptors, exert estrogen-like and anti-estrogen effects, alleviate menopausal manifestations like hot flushes and nocturnal sweats. Additionally, it is capable of enhancing bone density and diminishing the likelihood of osteoporosis.

Some other studies [86, 87] on fermented soy products have shown that fermented soy products produce unique bioactive ingredients during fermentation, which not only retain the benefits of soy isoflavones, but also produce beneficial substances such as probiotics and short URL fatty acids due to the action of microorganisms, which further enhance the regulation of intestinal microecology and improve immunity. The above research confirms from multiple dimensions that through reasonable dietary intervention, choosing foods rich in specific nutrients can improve the health status of menopausal women from physical and psychological aspects. These findings provide a theoretical basis for developing a scientific diet plan for menopausal women, and future research can further explore the synergies between different foods, as well as the development of personalized diet plans, to help menopausal women better maintain their health and improve their quality of life through diet.

Treatment strategies that utilize hormones

Many studies have focused on the impact of menopausal hormone therapy (MHT) on the health of menopausal women, and have systematically revealed the role and impact of MHT in the health management of menopausal women from the dimensions of menopausal symptoms, bone health, microbiome and cancer risk. Barrea et al. [55] showed that MHT is capable of markedly alleviating vasomotor as well as neuropsychiatric manifestations like hot flushes, night sweats, and sleeplessness among menopausal females. By supplementing estrogen and progesterone, it regulates the hypothalamic thermoregulation center, stabilizes neurotransmitter levels, and greatly improves the quality of life of menopausal women. In terms of bone health, Stepan et al. [30] states that the deficiency of estrogen is the primary factor leading to post-menopausal osteoporosis. MHT builds a strong defense for bone health in postmenopausal women by inhibiting osteoclast activity, reducing bone resorption, promoting osteoblast function, boosting bone density and lessening the likelihood of fracture. The gut microbiome has a significant part to play in human well-being. Leite et al. [27] studies have found that MHT regulates the gut microbial composition of postmenopausal women. Women undergoing MHT experience a rise in the relative prevalence of beneficial gut bacteria. These beneficial bacteria participate in a variety of metabolic processes, enhance the function of the gut barrier, regulate immunity, and reduce inflammatory responses, which have a positive impact on overall health.

However, the safety of MHT is also a focus of research. Jovani et al. [88] suggested that long-term use of MHT may increase the risk of breast cancer and endometrial cancer. This may be related to hormone stimulation of cell proliferation. However, the risk is not absolute. Reasonable selection of MHT regimen and control of use time can reduce the risk of cancer. Diet also plays an auxiliary role in the process of MHT. Peters et al. [58] showed that a diet rich in dietary fiber, calcium and other nutrients, combined with MHT, can enhance the therapeutic effect, like facilitating the growth of advantageous bacteria within the intestines, improving calcium absorption, and promoting bone health. These studies provide a scientific basis for clinicians to develop MHT regimens, guiding menopausal women to consider their own conditions, weigh the advantages and disadvantages, and choose appropriate treatment methods to improve health while reducing latent risks.

Probiotic intervention

There are literatures on the positive impact of probiotics on the health of menopausal women, which comprehensively and deeply reveal the value of probiotics in the field of health management of menopausal women from multiple dimensions such as microbiome regulation and menopausal symptom relief. Barrea et al. [55] reported that clinical research has indicated that postmenopausal women undergo notable alterations in the microbiomes of both the vagina and the intestines due to a significant decrease in estrogen levels, resulting in reduced local immunity. After supplementing with specific probiotics, the microbial community structure of the vagina and intestines can be remodeled. The increase in the number of beneficial bacteria dominated by Lactobacillus not only maintains the acidic milieu within the vagina functions to effectively impede the proliferation of detrimental bacteria, but also enhances the intestinal barrier function and enhances the overall immunity. In relieving menopausal symptoms, Bisanz et al. [89] pointed out that probiotics can improve the emotional state of menopausal women by regulating the synthesis and metabolism of neurotransmitters, relieve negative emotions such as anxiety and depression, and improve sleep quality. This regulatory mechanism plays an important role in helping menopausal women cope with physical and psychological changes. Koradia et al. [90] have found that probiotics also perform well in bone health maintenance. Bone loss in postmenopausal women accelerates, while probiotics can regulate the absorption and utilization of calcium in the intestines, activate osteoblast activity, and inhibit osteoclast function, thereby increasing the density of bones and the lessening of the risk of osteoporosis.

At the same time, Mezzasalma et al. [91] directed attention to the effect of probiotics on the metabolic health status of postmenopausal women. It can regulate lipid metabolism, reduce blood lipid levels, improve insulin resistance, and has positive significance for the prevention and control of metabolic syndrome. Yun et al. [92] evaluated the safety and stability of probiotics, indicating that under the premise of rational use, probiotics can not only effectively improve the health status of postmenopausal women, but also have high safety and will not cause serious adverse reactions. These research results provide a scientific basis for postmenopausal women to improve their health status by supplementing probiotics, and also point out the direction for the subsequent development of targeted probiotic preparations to promote their wide application in the field of health management of postmenopausal women.

Other interventions

As people’s attention to health has increased, research on the health management of menopausal women has become more and more in-depth. The influence of plant extracts on the health status of menopausal women has been probed. At the same time, some studies have also involved traditional therapies such as acupuncture, providing solutions for the health of menopausal women from multiple dimensions. Heo et al. [93] focuses on soy extract, which is rich in soy isoflavones as phytoestrogens, which can bind to human estrogen receptors. By simulating the estrogen effect, it can effectively relieve the symptoms of vasomotor manifestations like hot flushes and nocturnal sweating in menopausal females, while regulating bone metabolism, stimulating osteoblast activity, inhibiting osteoclast overabsorption, as a result, it enhances bone density and diminishes the likelihood of osteoporosis. Hong et al. [94] studied black cohosh extract, and the results showed that the extract can act on the central nervous system, regulate neurotransmitter levels, significantly improve negative emotions such as anxiety and depression in menopausal women, improve sleep quality, and help menopausal women maintain a good mental state. Wallimann et al. [32] focuses on red clover extract, which not only relieves menopausal-related symptoms, but also has antioxidant properties, can scavenge free radicals in the body, alleviate oxidative stress-induced harm, safeguard the cardiovascular system, and decrease the likelihood of cardiovascular disease.

In addition to plant extracts, traditional therapies such as acupuncture have gradually become a research hotspot. Acupuncture regulates the flow of qi and blood in the meridians of the human body by stimulating specific acupoints, balancing yin and yang. For menopausal women, it can regulate the endocrine system, promote the secretion and regulation of estrogen, relieve symptoms such as hot flashes and insomnia. In addition, acupuncture can also regulate the function of the nervous system, improve emotional state, and enhance the body’s immunity. Although multiple studies have not given specific numbers, they have confirmed the unique advantages of traditional therapies in the health management of menopausal women. Compared with drug treatment, traditional therapies such as acupuncture have fewer side effects and are safer. These studies provide more options for health interventions for menopausal women, and follow-up studies can further explore the synergies between plant extracts and traditional therapies to develop more comprehensive and personalized health management plans (Table 3).

Table 3.

Study on the impact of interventions on the health of postmenopausal women

Intervention measures	Specific role	Mechanism of action	Application suggestion	Reference
Dietary intervention	Benefits of substances in food (polyphenols in chocolate, fiber, soy isoflavones, fermented soy products)	Cocoa and soy components' functions (including polyphenols, fiber, isoflavones, and fermented products)	Rationally match foods by health and preference to boost nutrient-rich intake	[33, 34, 57, 83–87]
Hormone therapy	Menopause-related impacts, benefits, risks and dietary aids	Hormonal regulation and associated effects (including thermoregulation, bone, gut, and cancer risk)	Doctor-guided cautious hormone treatment with health assessment and diet cooperation	[27, 30, 55, 58, 88]
Probiotic intervention	Regulate microbiota for immunity, relieve menopause, improve mood/sleep, maintain bone health, prevent metabolic syndrome, with high safety	Probiotic-mediated multi-functional regulation (including for vaginal flora, intestinal function, neurotransmitters, calcium metabolism, and lipid/insulin regulation)	Select, dose, store and cycle probiotic prep	[55, 89–92]
Other interventions (plant extracts and traditional remedies)	Soybean, black cohosh, red clover extracts and acupuncture for menopausal relief and health benefits	Soybean isoflavones' estrogen-like effect, black cohosh's neurotransmitter-regulating action, red clover's antioxidant and cardiovascular-protecting function, and acupuncture's meridian-regulating role	Choose plant extracts, traditional therapies (like acupuncture by pros) per situation	[32, 93, 94]

Other studies related to menopause

Diagnosis and treatment methods

Multiple research techniques for diagnosing and treating diseases associated with menopause, such as disease diagnosis and treatment through microbiome analysis, tissue processing and cell isolation technology. The menopause represents a crucial phase within the life journey of women, and the incidence of menopausal-related diseases has also increased along with significant changes in physiological functions. Many studies on the diagnosis and treatment of menopausal-related diseases have provided new ideas and new means for addressing these diseases through microbiome analysis, tissue processing and cell isolation technologies. Some studies also involve 16S rRNA high-throughput sequencing technology has significantly advanced the profound research on diseases. Brunner et al. [95] utilized high-throughput sequencing of 16S rRNA to conduct research on the vaginal and gut microbiomes of postmenopausal women. Diagnostically, analyzing the microbial gene sequences clearly depicts alterations in the makeup and quantity of microbial communities within healthy conditions and diseased states of postmenopausal women. For example, if a postmenopausal woman has bacterial vaginosis, sequencing results demonstrate a notable decline in the levels of Lactobacillus and a considerable rise in harmful bacteria like Gardnerella. This technique not only identifies specific microorganisms, but also precisely analyzes their relative abundances, providing reliable microbiological evidence for disease diagnosis. In treatment, based on sequencing results, doctors can use probiotics to target and regulate the microbiome. Supplementing with formulations rich in Lactobacillus helps restore vaginal microecological balance, achieving the goal of treating bacterial vaginosis.

Moreover, Duong et al. [96] used tissue processing technology to study the bone tissue of mail carriersopausal osteoporosis patients. The researchers first fixed the bone tissue samples obtained to ensure the stability of tissue morphology and structure. Subsequently, through decalcification treatment, the calcium salt in the bone tissue is removed, so that the tissue can be easily sliced. After the resulting slices are stained, the microstructure of the bone tissue, such as the number, morphology and distribution of trabeculae, is clearly observed under the microscope. This technology helps researchers gain a deeper understanding of the pathological changes in bone tissue caused by osteoporosis, providing a key morphological foundation for the advancement of novel therapeutic medications and approaches. For example, based on the observation results, the development of drugs to promote trabecular growth and enhance bone density, or the use of physical therapy to improve the microstructure of bone tissue to relieve osteoporosis symptoms. Zhao et al. [97] used cell separation techniques to isolate cancer cells from tumor tissues of postmenopausal breast cancer patients. By employing methods such as density gradient centrifugation and flow cytometry, they effectively separated cancer cells from normal cells. During diagnosis, genetic testing and protein analysis of the isolated cancer cells were conducted to obtain molecular characteristics of the cancer cells, which aids in more accurately determining the subtype and stage of breast cancer, providing a basis for personalized treatment plans. In terms of treatment, targeted therapy drugs were developed based on the characteristics of the isolated cancer cells, precisely targeting specific molecular targets of cancer cells to inhibit their growth while minimizing damage to normal cells.

These studies employ various techniques such as microbiome analysis, tissue processing, and cell separation to provide diverse strategies for diagnosing and treating menopause-related diseases. High-throughput sequencing of 16S rRNA has played a crucial role in microbiome research, significantly enhancing the accuracy of disease diagnosis and the effectiveness of treatment, offering new hope for improving the health of postmenopausal women.

Comprehensive study of health-related factors

At present, there are many comprehensive studies on the impact of various factors related to the health of menopausal women, including the immune system, socioeconomic factors, and lifestyle on the health of menopausal women. Menopause represents a crucial phase in the life course of women, and women’s physical and mental health will face many challenges along with the drastic changes in hormone levels in the body. The literature comprehensively explores the factors affecting the health of menopausal women from multiple dimensions such as immune system, socioeconomic factors, and lifestyle, providing a comprehensive theoretical basis for improving the health status of this group. Brettle et al. [98] discovered that the estrogen levels in postmenopausal women drop substantially, which greatly affects their immune system. Estrogen regulates the proliferation, differentiation, and plays a role in immune cells and participates in modulating immune responses. The lack of estrogen after menopause leads to an imbalance in immune cell function, reducing immune surveillance and increasing the risk of infections and tumors. Further research by Özdemir et al. [99] revealed that with aging and menopause, the aging of immune cells accelerates, immune memory weakens, and vaccine responses diminish, lowering postmenopausal women's resistance to infectious diseases.

Furthermore, research [100, 101] has indicated that socioeconomic factors are of vital significance in the health management of postmenopausal women. Women with better economic conditions can access higher quality medical resources, undergo regular health check-ups, and promptly address potential health issues. In contrast, low-income groups often forego necessary medical examinations and treatments due to financial pressure, leading to delayed intervention for diseases. Additionally, educational level is closely related to the health of postmenopausal women. Highly educated women are more focused on learning about health knowledge and adopting healthy lifestyles, exhibiting stronger self-care awareness, while women with lower education levels may neglect their health problems due to a lack of health knowledge.

In addition, there are literature reports on lifestyle studies [102–104], finding that a healthy lifestyle is essential for the health of menopausal women. Regular physical exercise can enhance the muscle strength of menopausal women, enhance bone density and decrease the likelihood of osteoporosis, while improving cardiovascular function, reducing menopausal symptoms such as hot flashes. A reasonable diet structure, such as increasing the intake of vegetables, fruits, consuming whole grains and cutting down on the consumption of saturated fat and sugar are beneficial for weight management. Moreover, they can also lower the likelihood of developing cardiovascular diseases and diabetes. In addition, quitting smoking and limiting alcohol can reduce the damage of harmful substances to the body and improve physical immunity. Good sleep quality and psychological state are also indispensable. Adequate sleep helps the body recover and balance hormones, while a positive mindset can reduce stress, reduce the incidence of anxiety and depression, and promote physical and mental health [105, 106].

The comprehensive study of these literatures reveals that the well-being of menopausal women stems from the combined influence of a multitude of factors. In the future, comprehensive intervention measures need to be taken, from improving the level of medical security, popularizing health knowledge, and guiding menopausal women to develop a healthy lifestyle.

Summary and outlook

The perimenopausal period is a crucial transition in a woman's life. The decline of ovarian function and estrogen levels triggers physical and mental changes, affecting the quality of life. It is also associated with various geriatric degenerative diseases, involving multiple systems such as reproductive, metabolic, cardiovascular, skeletal, and mental health, including uterine fibroids, metabolic diseases, osteoporosis, etc. At the same time, it affects oral, sleep, and immune functions. Changes in estrogen can alter the microbiome in multiple parts of the body. The imbalance of the related microbiome after menopause increases the risk of diseases.

Currently, there are various intervention measures for the health problems of postmenopausal women. The nutrients in dietary interventions are beneficial to cardiovascular, intestinal, and bone health and can also relieve menopausal symptoms. Hormone therapy can relieve symptoms and maintain bone health, but there is a risk of cancer. Probiotic interventions can regulate the microbial community and improve immunity, etc. Plant extracts and traditional therapies play a role in regulating the functions of the endocrine and nervous systems and enhancing immunity. Technologies such as microbiome analysis contribute to precision medicine. Factors such as the immune system, socioeconomic status, and lifestyle also have a significant impact on the health of postmenopausal women.

Future research should focus on the following directions: first, explore the synergistic effects of different intervention measures to optimize the health management plan. Second, conduct personalized intervention research to meet individual health needs. Third, analyze the correlation mechanism among the microbiome, menopause, and diseases to innovate diagnostic and treatment methods. Fourth, reveal the mechanism of action of traditional therapies to better utilize their advantages. Fifth, pay attention to the impact of psychosocial factors on postmenopausal women and strengthen psychological interventions. Through these studies, it is expected to provide more scientific, comprehensive, and personalized health management strategies for postmenopausal women, promote the development of the female health field, and contribute to solving the female health problems under global aging.

Abbreviations

MHT

Menopausal hormone therapy

GSM

Genitourinary syndrome of menopause

MCMDS

Menopause-related Chronic Metabolic Diseases

UTI

Urinary tract infection

CVD

Cardiovascular disease

ODMA

O-Demethylangolan

HT-

No hormone therapy received

HT + 

Receiving hormone therapy

Author contributions

All authors contributed to the study conception and design. Feiyun Lin performed the data curation and formal analysis. Feiyun Lin and Lin Ma performed the methodology and data analysis. Zhumei Sheng read and approved the final manuscript.

Funding

Zhejiang Provincial Medical and Health Science and Technology Project: “Research on the Impact of Hormone Therapy for Menopause on the Vaginal Microbiota of Perimenopausal Women Based on 16S rRNA High-throughput Gene Sequencing Technology, 2022KY275, 2022KY275, 2022KY275

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.