Sex hormones and functional gastrointestinal disorders in menopausal women.

Although basic research and some clinical studies have confirmed that HRT has a positive protective effect on the GI tract as a whole, there remains considerable controversy regarding whether E and P replacement therapy positively influences GI tract function in menopausal women. Nonetheless, limited literature reports also discuss the effects of HRT or E replacement therapy on various aspects of GI function, including GERD ( 145 ) and functional gastroparesis ( 21 ), to varying degrees, as well as organic lesions within the GI tract. However, there are relatively few research reports focusing solely on FGIDs. Therefore, when referencing the GI dysfunction associated with HRT reported in such literature to elucidate its impact on FGIDs in this article, it is essential to clarify two conceptual distinctions between GERD and DGBI. According to the classification principles outlined in Rome IV for FGIDs/DGBI, these disorders are currently more accurately defined as a group of disorders classified by GI symptoms related to any combination of motility disturbances, visceral hypersensitivity, altered mucosal and immune function, gut microbiota, and/or CNS processing ( 8 ). Therefore, it cannot be traditionally understood as a functional disorder of non- organic changes in the GI tract. According to the Rome IV criteria, the FGIDs/DGBI that may be related to GERD is mainly reflected in aspects of esophageal dysfunction (FGIDs/DGBI-ED) with reflux symptoms ( 3 , 8 ). The esophageal DGBI comprises functional esophageal chest pain, functional heartburn, functional dysphagia, and the newly introduced reflux hypersensitivity. They are characterized by the presence of chronic symptoms attributed to the esophagus without evidence of esophageal structural, inflammatory, or motility abnormalities. Also, Rome IV suggests for the first time the possibility that functional heartburn or reflux hypersensitivity might overlap with GERD ( 146 ). Accordingly, many diagnostic tests with endoscopy and biopsies, esophageal pH ± impedance monitoring, and high-resolution esophageal manometry are necessary to establish esophageal DGBI diagnoses. Therefore, in the absence of a preliminary determination of whether it is FGIDs/DGBI-ED, it is crucial to clarify whether it is GERD. Therefore, in the Lyon Consensus 2.0 objective GERD criteria ( 147 – 150 ) and the Rome IV-DGBI: ED diagnostic principles ( 3 ), the use of esophageal acid exposure time (AET), DeMeester score ( 151 ), esophagogastroduodenoscopy (EGD) results for the Los Angeles (LA) grade, as well as other diagnostic tests such as esophageal pH ± impedance monitoring and proton pump inhibitor (PPI) testing, can help differentiate and clarify the diagnosis of disease types. In addition, in endoscopic examination, GERD can be ruled out by monitoring reflux in patients without higher level (LA-A or B) reflux esophagitis and without pathological acid exposure (AET < 4.0%) in dynamic reflux monitoring under normal endoscopy. Although GERD and FGIDs/DGBI-ED are two different categories of diseases, there is an overlap between FGIDs and GERD ( 152 ), especially between functional heartburn and reflux hypersensitivity in GERD patients ( 151 ). For example, overlap of functional heartburn with proven GERD is diagnosed according to Rome IV criteria when heartburn persists despite maximal PPI therapy in patients with a history of proven GERD, and pH ± impedance testing on PPI therapy demonstrates physiologic acid exposure without reflux-symptom association ( 151 ). In addition, reflux monitoring is offered in patients without higher grades (LA-A or B) of reflux esophagitis on endoscopy, and the absence of pathologic acid exposure on ambulatory reflux monitoring (AET < 4.0%) with a normal endoscopy, rules out GERD. Erosive esophagitis of LA-B or higher and/or AET ≥ 6.0% constitutes conclusive GERD evidence. Patients with LA-A esophagitis and/or AET ≥4.0% but otherwise not meeting criteria for conclusive GERD are considered to have borderline GERD ( 151 ). The specific clinical diagnostic process and criteria for FGIDs/DGBI-ED and GERD are fully displayed in Table 5 and Figure 10 , named as the Rome IV criteria for FGIDs/DGBI-ED and the Lyon II criteria for GERD. Rome IV criteria for FGIDsDGBI-ED and Lyon criteria for GERD. Rome IV diagnostic algorithms for chest pain, dysphagia, and heartburn. Part (a) depicts the diagnostic algorithm for chest pain, ruling out chest pain from cardiac causes, GERD, NERD, and major motor disorders to arrive at a diagnosis of functional chest pain. Part (b) starts with the symptom of dysphagia, and guides the physician through decision actions that rule out oropharyngeal abnormalities, NERD, and major motor disorders to arrive at a diagnosis of FD. Part (c) patients with heartburn and negative endoscopy and biopsies may include two groups: those with previously unproven GERD and those with previously proven GERD. In the first group, esophageal pH monitoring with/without impedance off PPI is recommended to establish a diagnosis of functional heartburn, reflux hypersensitivity or NERD. In patients with proven GERD, pH/impedance monitoring on PPI is recommended to diagnose functional heartburn or reflux hypersensitivity overlapping with GERD, or GERD that has not been well controlled with PPIs due to lack of combined anti- emotional and behavioral therapy. Rome IV criteria for FGIDs/DGBI-ED and lyon consensus 2.0 criteria for GERD Research has indicated that there are no significant differences in the effects of female sex steroids on gastric emptying, small intestine transport, and colon transport among healthy menopausal subjects, particularly following the administration of micronized P, which does not appear to influence intestinal transport function ( 153 ). This smooth muscle cell relaxant decreases the tone of both the lower esophageal sphincter and esophageal body, potentially predisposing patients to GERD ( 56 ). Clinicians prescribing E-only HRT to menopausal women should be acutely aware of the potential increased risk for GERD and its associated complications. When appropriate, healthcare providers should consider alternative HRT options such as P-only therapy for patients already experiencing reflux-related symptoms due to its reduced risk for GERD ( 153 ). Pre- menopausal healthy women who take oral contraceptives (OC), whether single-phase or three-phase preparations, supplementing hormones usually leads to an increase in GI symptoms during menstruation ( 154 ). Conversely, women with IBD who utilize OCs containing both E and P tend to report fewer abdominal symptoms compared to IBS sufferers who do not use OCs ( 16 , 50 , 155 ). Nevertheless, studies have also indicated that oral contraceptive therapies may elevate the incidence of IBD ( 156 ) and increase the risk of gastroparesis ( 21 ). Overall, introducing exogenous hormones into an endogenous environment may disrupt the normal balance between hormones and gut microbiota. The diversity of these complications could be attributed to various types of combined oral contraceptives (COCs) their specific compositions, as well as changes within study populations ( 157 ). Recent systematic reviews and meta-analyses have identified a significant direct association between E use and GERD (aOR = 1.41, 95% CI = 1.16–1.66, I ² = 97.6%). Similarly, P use has also been linked to GERD in two studies (aOR = 1.39, 95% CI = 1.15–1.64, I ² = 0.0%). Furthermore, the utilization of combined HRT was associated with an increased risk of developing GERD (aOR = 1.16, 95% CI = 1.00–1.33, I ² = 87.9%). Overall, HRT usage correlated with a statistically significant increase in the odds of developing GERD by approximately 29% (aOR = 1.29, 95% CI = 1.17–1.42, I ² = 94.8%) ( 155 ). However, the substantial number of pooled participants, along with variations in study design, geographical location, patient characteristics, and outcome assessments contributed to considerable heterogeneity among the findings ( 157 ). The biological effects of E and P are well documented, demonstrating both synergistic and antagonistic interactions that often depend on their dosage ratio. This phenomenon is particularly evident within the reproductive system across various physiological stages. Furthermore, this relationship can be indirectly supported by observations in women suffering from IBD, where differing doses and ratios of E/P result in varying degrees of FGIDs/DGBI ( 155 ). Research has also established a dose-dependent regulatory effect of P on gastric emptying function through animal studies ( 96 ).

Functional gastrointestinal disorders (FGIDs) encompass a diverse array of chronic conditions characterized by recurrent gastrointestinal (GI) symptoms in the absence of structural or biochemical abnormalities ( 1 , 2 ). The pathophysiology of FGIDs is complex but involves bidirectional regulation of disorders of gut–brain interaction (DGBI) ( 2 ). At present, many studies have found that FGIDs/DGBI involve many regulatory mechanisms, such as gut microbial dysbiosis ( 3 ), inflammatory immune response (IMS) ( 4 ), metabolic disorders ( 5 ), and abnormal neurotransmitter secretion ( 6 ). In fact, various functional GI symptoms are highly prevalent among menopausal women, but many of these women lack an organic explanation for their symptoms ( 7 ). These conditions affect up to 40% of people at any one point in time, and two-thirds of these people will have chronic, fluctuating symptoms, at least one FGID/DGBI, such as more common esophageal dysfunction (ED) and functional dyspepsia (FD) ( 8 , 9 ), especially for menopausal women with a higher incidence rate ( 10 ). Menopausal women with underlying GI diseases may have more severe clinical symptoms of FGIDs/DGBI ( 11 , 12 ). The symptoms of FGIDs in menopausal women also tend to worsen significantly, which is strong evidence of ovarian function- related FGIDs ( 13 , 14 ). In other words, although the symptoms related to postmenopausal GI dysfunction have not been included in the scope of CS ( 15 ), FGIDs that manifest after menopause may represent a clinical manifestation of the progression of climacteric syndrome (CS) ( 5 , 14 ). This is particularly relevant as menopausal women exhibit a heightened susceptibility to developing FGIDs, such as irritable bowel syndrome (IBS) ( 11 , 13 ). Furthermore, they are 2.9 times more likely to experience abnormal GI symptoms, which include functional heartburn and reflux hypersensitivity, visceral hypersensitivity, and irregular GI motility, among others ( 10 , 14 , 16 ). Recent clinical research and literature reports support the regulatory actions of sex hormones exerted at different levels of the gut–brain axis in IBS ( 17 – 19 ). Sex hormones, especially estrogen (E), may influence peripheral and central regulatory mechanisms contributing to the alterations in visceral sensitivity, GI motility, stress and fear, anxiety and depression, permeability, and immune activation of intestinal mucosa ( 20 ). After menopause, the levels of E and progesterone (P) decrease significantly, decreasing the protective effect of GI function ( 13 ). However, in many menopausal women who take HRT and/or E, their GI functions show different clinical effects. In the former, real-world association studies suggest an increased risk of gastroparesis in menopausal women indicated with HRT ( 21 ). And in the latter, single E supplementation may promote gastric emptying. A study has found that 17 β-estradiol (E 2 ) supplementation can restore rapid gastric emptying by restoring the damaged Nrf2 and nNOS functions in ovariectomized mice with obesity- induced diabetes ( 22 ). Obviously, the regulatory influence of sex hormones on GI function is well established. However, in addition to their direct biological effects on the GI tract, these hormones exert their regulatory impact through various indirect mechanisms. These include modulating the composition of gut microbiota ( 17 , 18 , 20 ), influencing energy balance within the central nervous system (CNS) ( 23 , 24 ), affecting IMS and immune system networks ( 20 ), as well as interacting with other endocrine axes originating from non-gonadal sources ( 25 , 26 ). All available evidence, both direct and indirect, supports the existence of interactions and physiological–pathological mechanisms linking sex hormones with FGIDs in menopausal women. In this study, we conducted a comprehensive narrow review and analysis of the effects and possible regulatory mechanisms of different sex hormones on GI function in menopausal women. Our aim was to elucidate the pathophysiological mechanisms associated with sex hormones in FGIDs among this population, thereby paving the way for novel therapeutic approaches in the fields of FGIDs in menopausal women.

A comprehensive literature search was conducted using PubMed, EMBASE, and Google Scholar databases. Articles published between January 2000 and June 2025 were screened using keywords such as “sex hormones [GnRH, E, P], “ “mechanism, “ “FGIDs [GI motility, IBS, FD, ED], “ “DGBI [gut microbiota, gut–brain axis], “ “menopausal women, “ “CS [anxiety, depression, insomnia], “ and “[HRT, GERD, GI symptom, IBD].” Relevant clinical trials, case reports, meta-analyses, and expert guidelines were prioritized to ensure an evidence-based and up-to-date overview. We used the “Classification-Gradual Recycling” method to screen English literature from the past 25 years (to expand the search time range only when the required relevant research content cannot be obtained within the specified time period), and the specific inclusion and exclusion criteria are shown in Supplementary Table 1 . All figures were drawn using Graph Pad Prism 9.0 and PowerPoint software equipped with a biological mapping plugin package.

FGIDs and DGBI are highly prevalent GI conditions associated with menopause, characterized by persistent and recurrent GI symptoms in menopausal women. Menopause-induced elevation of GnRH stimulates LH secretion via GnRH receptors in the hypothalamic-pituitary axis. In the GI tract, LH exerts detrimental effects, including enteric neuropathy, GI epithelial cell apoptosis, and enteric neurodegeneration, through its cognate receptors expressed on enteric neurons and GI mucosal cells. In addition, menopause-associated declines in estrogen and progesterone levels exert complex, context-dependent modulatory effects on GI function via their nuclear and membrane-bound receptors distributed across multiple interconnected systems: the local GI tract, the CNS, the enteroinsular axis, and the thyroid-gut axis. Within the local GI tract, estrogen and progesterone regulate smooth muscle contractility primarily through classical genomic signaling pathways; however, their depletion compromises mucosal barrier integrity and disrupts intestinal microbial homeostasis, thereby contributing to epithelial barrier dysfunction and dysbiosis. In the CNS, 17β-estradiol maintains brain energy homeostasis and activates the oxytocinergic pathway in the hypothalamic paraventricular nucleus, thereby regulating food intake, body weight, cognitive function, and motor coordination. Under hypoestrogenic conditions, this dysregulation may collectively promote weight gain. In the enteroinsular axis, estrogen and progesterone modulate insulin synthesis and secretion from pancreatic β cells, influencing glucagon-like peptide-1 (GLP-1) release and downstream appetite regulation. In the thyroid-gut axis, estrogen deficiency downregulates cytochrome P450 expression, impairing local estrogen biosynthesis and altering small intestinal microbiota composition. Collectively, these interrelated disruptions across the sex hormone–gut-brain axis represent key pathophysiological mechanisms underlying the onset and progression of FGIDs/DGBIs in menopausal women. Importantly, climacteric syndrome, insomnia, and anxiety or depression, common neuropsychiatric manifestations of menopause, further exacerbate GI symptom burden and disease severity through bidirectional gut–brain communication.