Menopause is a physiological milestone that signifies the cessation of menstrual cycles and the end of reproductive capacity in women [1]. It typically occurs between the ages of 45 and 55 and is primarily caused by decreased production of estrogen and progesterone hormones [1]. This is a major period in terms of women’s health with effects that extend far beyond reproductive function [1, 2]. Vasomotor symptoms 80% and vulvovaginal symptoms demonstrate a 34% prevalence among postmenopausal women [3]. The steep decline in estrogen levels has many multi-systemic consequences that can also lead to alterations in metabolic syndrome (MetS) components, such as lipid profiles and insulin resistance, as well as deteriorations in bone metabolism [1, 2].

MetS is a well described but incompletely understood condition that presents a cluster of risk factors, including insulin resistance, abdominal obesity, dyslipidemia, and hypertension [4]. It may also underlie cardiovascular diseases and type 2 diabetes [5, 6]. The metabolic alterations that occur during menopause seem to increase the likelihood of developing MetS [7, 8]. Additionally, menopause is associated with a shift in fat distribution toward the abdomen and an increase in fat mass [9]. Yet it is still unclear if the aging process or hormonal fluctuations are to blame for these alterations. These hormonal changes not only influence metabolic and skeletal health but also contribute to the onset and progression of various menopausal symptoms, including vasomotor and urogenital complaints.

Recent studies have increasingly focused on the intricate relationships between menopause, MetS, and bone health. Estrogen deficiency plays a critical role in this complex relationship, contributing to endothelial dysfunction, increased adiposity, altered lipid metabolism, and reduced osteoblastic activity [10, 11]. These hormonal changes may not only worsen the metabolic profile but also accelerate bone resorption, thereby increasing the risk of osteoporosis and cardiovascular comorbidities [12, 13]. Furthermore, the inflammatory environment associated with MetS, characterized by elevated cytokines such as tumor necrosis factor-$\alpha$ (TNF-$\alpha$) and interleukin (IL)-6, may further aggravate both bone loss and menopausal symptom severity [12].

Despite growing evidence suggesting a relationship between menopausal symptoms, MetS, and bone mineral density (BMD) loss, the exact nature of these associations remains poorly defined. The research landscape presents a complex picture, with some investigations demonstrating clear associations between severe somatic symptoms and both MetS and low BMD [14, 15, 16], while other well-designed study has found no significant relationships [17]. This inconsistency in findings likely stems from the inherent complexity of menopause itself, as well as the diverse populations studied. Factors such as ethnic background, lifestyle patterns, nutritional habits, and individual genetic makeup may all influence how these conditions interact within different women. Moreover, it is still debated whether menopausal symptoms can serve as early clinical indicators of underlying metabolic or bone health problems.

Arising from these questions, we proposed the specific hypothesis that postmenopausal women exhibiting both low BMD and MetS would report greater severity of menopausal symptoms compared to those with either condition alone or neither. Recognizing the critical gaps in our understanding and the urgent clinical need to identify postmenopausal women at heightened risk for metabolic and bone health complications, we conducted this study to investigate the potential interrelationship among BMD, MetS, and menopause-related symptoms, aiming to enhance insight into the shared pathophysiological pathways and inform potential screening strategies in this population

During the study period, 326 postmenopausal women were examined for eligibility and 193 women who met the inclusion criteria were analyzed.

The current study was designed to assess menopausal symptoms, MetS and BMD findings in our postmenopausal cohort and to identify possible relationships between the severity of menopausal symptoms and MetS and/or low BMD. Our study revealed that approximately 40% of our patients had MetS, 50% had low BMD, and 21% had co-existence of MetS and low BMD. Despite the expected links between MetS and menopausal symptoms due to metabolic dysregulation, our findings did not confirm this relationship. The presence of only MetS was not associated with increased total, somatic, psychological, or urogenital MRS scores in postmenopausal women. However, the presence of low BMD and the co-existence of low BMD and MetS were found to be associated with worse urogenital symptoms.

MetS is a complex condition that emerges in relation with many underlying properties and causes risks for cardiovascular disease and diabetes, often manifesting as insulin resistance, high blood pressure, elevated triglyceride levels, low levels of high-density lipoprotein cholesterol, and obesity (especially central obesity) [4]. The reported prevalence of MetS varies, with estimates ranging from 20% to 55% among postmenopausal women. In the current study, we found the frequency of MetS in naturally menopausal women to be approximately 40%, which aligns with previously reported rates in this population. Our results indicated a positive association between MetS and high pregnancy rates and the time elapsed since menopause onset, while regular exercise appeared to be protective against MetS. Notably, we did not find a significant correlation between MetS and menopause symptom severity, which contradicts several previous reports.

A previous study has suggested a decline in quality of life in postmenopausal women with MetS [15]. While estrogen deficiency is linked to MetS [10, 11]. The inconsistent effects of Hormone Replacement Therapy (HRT) suggest other factors may be involved [23, 24, 25]. Furthermore, the role of exercise in metabolic regulation has been widely documented, and the findings of the recent studies reinforce its protective effects against MetS [26]. Nevertheless, our study did not observe significant associations between MetS and menopause symptom scores. One study has demonstrated increased MRS scores, particularly somatic and vasomotor symptoms, in patients with MetS [26]. Others have identified significant positive correlations between abdominal obesity, TG, blood pressure, and MRS scores [15]. While many studies support a link between MetS and menopausal symptoms [16, 27], there is a conflicting study that reports no significant relationship [17], which may suggest that lifestyle, genetic predisposition or aging alone may influence this association. Although hormonal changes and lipid alterations have been proposed as potential mechanisms linking MetS and menopause, the cross-sectional nature of our study limits our ability to infer causality.

Another significant health challenge faced by postmenopausal women is osteoporosis. Menopausal symptoms, particularly vasomotor and urogenital complaints, tend to fluctuate over time. A meta-analysis including 35,445 women reported that hot flashes typically persist for around 4 years, peaking around 1 year prior to the final menstrual period and gradually decreasing thereafter [28]. In contrast, vulvovaginal symptoms often increase postmenopause, reaching a plateau prevalence of over 84% by the sixth year [29]. Estrogen loss is a key driver of these symptoms and is also known to increase osteoclastic activity while reducing osteoblastic function, thereby contributing to bone loss [12, 13]. The pathophysiological connection between menopausal symptoms and BMD can be explained through several mechanisms, including decline in estrogen, increased inflammation and oxidation, changes in calcium and vitamin D levels, co-existence of hormonal dysregulation and the aging processes, which can come together to create a general deceleration in the renewal of bone tissue [12, 13]. In the present study, patients with low BMD were older, had been in menopause for longer, and had lower BMI. Our findings align with previously established risk factors for osteoporosis. Interestingly, a higher proportion of women in the low BMD group engaged in regular exercise, which may reflect a proactive approach to osteoporosis prevention rather than a causal relationship. Women with low BMD exhibited higher MRS urogenital scores, but other symptom scores remained unaffected. Those with co-existing low BMD and MetS were older, had been menopausal longer, and also reported higher MRS urogenital scores. Previous studies investigating the relationship between menopausal symptoms, BMD, and MetS have yielded conflicting results. While some found associations between severe somatic symptoms and both MetS and low BMD [15, 16], others reported fewer vasomotor symptoms in women with MetS [15]. Vaginal dryness has also been linked to greater bone loss in certain studies [30, 31]. Prior research has linked decreased BMD with severe vasomotor symptoms such as hot flashes and night sweats [32, 33, 34]. However, our study did not observe a direct relationship between vasomotor symptoms and BMD. Instead, we identified a significant association between BMD loss and urogenital symptoms. This matches the findings from the AGATA study, which reported genitourinary syndrome in 79.1% of women and an increasing prevalence over time after menopause [35]. These findings suggest that postmenopausal urogenital symptoms could serve as an early indicator of declining BMD, warranting further investigation into potential shared pathophysiological pathways.

The current study demonstrated a correlation between severe urogenital symptoms in postmenopausal women and a decline in BMD. If confirmed in future studies, this association could contribute to improved screening strategies. Severe urogenital symptoms can be used as an indicator to identify women at risk of low BMD and osteoporosis. Taking measures to protect bone health and implementing pharmacological interventions, when necessary, may be vital for preventing fractures in this particular patient group.

Due to the single-center design and the potential adverse impacts of analyzing a homogenous population, our findings may not be generalizable to broader postmenopausal populations. The cross-sectional design of the study may limit the possibility to establish long-term causal links between BMD and MetS in postmenopausal women. Since the primary aim of the study was to investigate the effects of MetS and low BMD on postmenopausal symptoms, only postmenopausal women were included. However, excluding premenopausal women compromises the evaluation of the impact of non-menopausal factors on MetS and BMD. Additionally, selection bias may be present, as our cohort consisted of women presenting for routine check-ups, potentially representing a health-conscious population. Although the MRS urogenital subscale provided a standardized measure, future studies might benefit from supplementing it with condition-specific tools (e.g., Female Sexual Function Index for sexual health) to capture nuanced symptom profiles. Furthermore, the subgroup with both MetS and low BMD included only 40 individuals, which may be considered small. Although expanding this group would improve statistical power, strict inclusion and exclusion criteria were necessary to minimize confounding effects, especially in older women with multiple comorbidities. This limited the number of eligible participants. Future prospective, long-term cohort studies with broader recruitment criteria may help to better clarify these associations.

The present study demonstrated that while MetS did not correlate with menopausal symptom severity, low BMD was significantly associated with worse urogenital symptoms. This relationship remained significant in women with both low BMD and MetS, suggesting that urogenital symptoms may be a potential marker of osteoporosis risk in postmenopausal women. Although the observational design limits causal interpretations, our findings emphasize the need for further large-scale investigations into the relationship between BMD loss and urogenital symptoms.

BMD, bone mineral density; MetS, metabolic syndrome; BMI, body mass index; FSH, follicle-stimulating hormone; WHO, World Health Organization; STEPS, STEPwise approach to Surveillance; WHR, waist-to-hip ratio; TG, triglycerides; HDL-C, high density lipoprotein cholesterol; MRS, Menopause Rating Scale; HRT, Hormone Replacement Therapy; NCEP-ATP III, National Cholesterol Education Program-Adult Treatment Panel III; TNF-$\alpha$, tumor necrosis factor-$\alpha$; IL, interleukin; DXA, dual-energy X-ray absorptiometry; ANOVA, analysis of variance; Q-Q, quantile-quantile.

The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request.

AAM and SC designed the study. AAM and SC analyzed the data and performed the statistical analysis. AAM collected data. SC interpreted of data of the work. Both authors contributed to editorial changes in the manuscript. Both authors read and approved the final manuscript. Both authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The study was initiated after obtaining the approval of the ethics committee at Istanbul Istinye University (Decision date: 21 December 2022, decision no: 3/2022.K-95) and conducted in compliance with the relevant ethical guidelines and the Declaration of Helsinki. Written informed consent was obtained from all participants.

This research received no external funding.

The authors declare no conflict of interest.

During the preparation of this work, the authors used ChatGPT to check spelling and grammar. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.