Original Article

Volume 000, Number 000, June 2025, pages 000-000

Clinical Significance of Serum Total Testosterone Concentration in Japanese Elderly Women With Pre-Heart Failure With Preserved Ejection Fraction

In recent years, the prevalence of heart failure (HF) has been steadily increasing not only among Westerners but also among Asians, driven by the increased life expectancy and other factors. Consequently, the growing number of older patients with HF in clinical settings has led to the condition being described as a “heart failure pandemic” [1, 2]. Furthermore, the prognosis of heart failure with preserved ejection fraction (HFpEF) was found to be as poor as that for HF with reduced ejection fraction in several studies [3, 4]. According to recent clinical research, sodium glucose cotransporter 2 (SGLT2) inhibitor intervention improves HFpEF [5-7]. However, residual risks remain even with SGLT2 inhibitor, and therefore, additional treatment strategies need to be considered to enhance the prognosis of patients with HFpEF. Additionally, it has been observed that the prognosis is poor following stage C of the HF stage classification, when HF symptoms begin to develop [8, 9]. Therefore, early intervention is considered necessary for managing HF at an earlier stage. From this perspective, it is clinically important to explore novel treatment strategies for HFpEF during stages in which patients do not yet exhibit subjective symptoms of HF.

Although few studies have examined the relationship between testosterone levels and HFpEF, several reports indicate a significant relationship between HFpEF development or prognosis and low blood testosterone concentration in men [10, 11]. However, only one study has examined the association between serum total testosterone concentration (T-T) and the incidence of HFpEF in women in the United States, and it found no statistically significant relationship [11]. In addition, no studies to date have examined the relationship between T-T and HFpEF in Asian women. In this cross-sectional study, the author examined the clinical significance of T-T in Japanese elderly women with pre-HFpEF, which occurs prior to the onset of HF.

Among the outpatients of elderly women aged 65 years and older who visited the Hitsumoto Medical Clinic from March 2023 to February 2025, 232 consecutive pre-HFpEF patients with all clinical parameters, including T-T, were enrolled. T-T was evaluated employing a commercial kit (ARCHITECT Estradiol II, Chicago, IL, USA), and the correlation between T-T and other clinical parameters was analyzed. In this study, pre-HFpEF was defined as a left ventricular ejection fraction of 50% or more, an E/e' ratio ≥ 9 on echocardiography as a marker of diastolic dysfunction, absence of HF symptoms, and no history of HF-related hospitalization. The cutoff value of 9 for the E/e' ratio in this study was determined by consulting previous studies; this cutoff value and the score using this cutoff value were found to be related to the prognosis of HF [12-14].

This study was conducted in accordance with the Declaration of Helsinki and the ethical standards of institutions responsible for human research. Informed consent was obtained from all patients participating in this study, and the study protocol was approved by the Institutional Review Board of Hitsumoto Medical Clinic (date of approval: February 17, 2023; approval number: HMC-2023-2R-1).

Various clinical parameters were evaluated, including conventional cardiovascular risk factors, presence of coronary artery disease (CAD) and atrial fibrillation, echocardiography outcomes, kidney function, blood concentrations of brain natriuretic peptide (BNP) and serum high-sensitivity cardiac troponin T (hs-cTnT), as well as markers of inflammation and oxidative stress. Classic risk factors for cardiovascular disease were defined in accordance with previous reports [15]. In this study, CAD was defined as the presence of angina pectoris and/or myocardial infarction managed either with coronary revascularization or oral medication alone. Paroxysmal and chronic atrial fibrillation were considered as types of atrial fibrillation. Echocardiography was performed utilizing standard procedures, and left ventricular wall thickness, left ventricular extended period diameter, left ventricular ejection fraction, left atrial dimension, and E/e' ratio were measured. Fasting blood samples were collected from peripheral veins following a routine protocol, and blood glucose-related indicators, lipid-related indices, kidney function indicators, BNP, hs-cTnT, as well as inflammatory and oxidative stress indices were evaluated. The estimated glomerular filtration rate (eGFR), a marker of kidney function, was calculated using Japanese criteria [16]. A commercial kit was used for assessing BNP (SHIONOSPOT Reader; Shionogi & Co., Osaka, Japan) and hs-cTnT (Roche Diagnostics, Switzerland) levels. Serum high-sensitivity C-reactive protein (hs-CRP) concentration, a marker of inflammation, was measured using the latex nephelometry technique. The derivatives-reactive oxygen metabolites (d-ROMs) test, an oxidative stress marker, was ascertained using a commercial kit (Diacron, Grosseto, Italy) [17]. Use of oral medications, such as renin-angiotensin system (RAS) inhibitors (renin-angiotensin inhibitors or angiotensin receptor blockers), β-blockers, statins, and SGLT2 inhibitors, was also documented. However, no patients in the study were receiving mineralocorticoid receptor antagonists and diuretics.

The commercialized software Stat View-J version 5.0 (HULINKS Inc., Tokyo, Japan) and MedCalc for Windows (MedCalc Software, Ostend, Belgium) were employed for performing statistical analysis. Continuous variables are expressed in terms of mean and standard deviation or median (interquartile range). Simple regression analysis was performed using the Spearman rank correlation, and multivariate analysis was performed using multiple regression analysis. Multiple regression analysis was performed for T-T as a dependent variable. Eight explanatory variables, age, CAD, E/e' ratio, eGFR, BNP, hs-cTnT, hs-CRP, and d-ROMs test, were selected based on their significant correlations with T-T in univariate analysis. A P-value < 0.05 was considered statistically significant.

The patient characteristics are presented in Table 1. The mean age of the participants was 75 years. The lowest T-T value was 7.7 ng/dL, the highest was 69.0 ng/dL, and the median was 26.2 ng/dL. There were 53 (23%) CAD patients. The median value of the E/e' ratio was 14.5. Among those receiving oral medications, SGLT2 inhibitor use was noted in 16 patients (7%).

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Table 1. Baseline Characteristics of the Study Population

Figure 1 depicts the correlation between T-T and E/e' ratio. A significant negative correlation was observed between T-T and E/e' ratio (r = -0.24, P < 0.001).

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Figure 1. Correlation between T-T and E/e' ratio. T-T: blood total testosterone concentration.

Table 2 illustrates the correlation between T-T and various clinical parameters. T-T exhibited significantly negative correlations with age, presence of CAD, BNP, hs-cTnT, hs-CRP, and d-ROMs tests. However, T-T demonstrated a significantly positive correlation with eGFR. There was no significant association between SGLT2 inhibitor use and T-T.

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Table 2. Correlation Between T-T and Various Clinical Characteristics

The results of the multiple regression analysis are illustrated in Table 3. Among the eight explanatory factors, five (i.e., d-ROMs test, BNP, hs-cTnT, E/e' ratio, and CAD) were selected as independent variables, with T-T serving as the dependent variable.

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Table 3. Multivariate Analysis for T-T

This study aimed to clarify the clinical significance of T-T in Japanese elderly women with pre-HFpEF. T-T exhibited a significantly negative correlation with the E/e' ratio, a marker of left ventricular diastolic function. Furthermore, an increase in the E/e' ratio was identified as an independent predictor of low T-T levels. Cardiac biomarkers such as BNP and hs-cTnT were also independently associated with low T-T, and an independent correlation was noted between CAD and low T-T. However, the d-ROMs test, an oxidative stress marker, was identified as the strongest predictor for low T-T.

Several researchers have emphasized the relevance of left ventricular diastolic dysfunction in HFpEF pathogenesis [18-20]. In this study, the E/e' ratio, an index of diastolic function, was also employed as a diagnostic criterion for pre-HFpEF. In addition, several clinical reports have indicated that low blood testosterone concentrations are significantly associated with left ventricular diastolic dysfunction in men, as assessed by echocardiography [21-23]. However, although a relatively weak negative correlation between T-T and the E/e' ratio was detected in this study, it was statistically significant, and an independent relationship between the two markers was observed. Therefore, it is considered that low blood testosterone concentration is associated with left ventricular diastolic dysfunction even in elderly women with pre-HFpEF. To clarify the direct effects of testosterone on left ventricular diastolic function, it is desirable to screen elderly women with pre-HFpEF who have low T-T and investigate whether testosterone replacement therapy contributes to the improvement of the E/e' ratio or other left ventricular diastolic function marker and ultimately prevents the onset of HF in these patients.

BNP increases when there is left ventricular overload. In addition, several researchers have indicated that BNP can be a prognostic indicator for HFpEF, similar to HF-related rehospitalization [24-26]. Furthermore, previous studies have also reported that BNP can be employed as an index for predicting initial HF-related hospitalization [27, 28]. Therefore, the independent relationship between BNP and T-T in the study results indicates that T-T may be a predictor for the HF onset through increased left ventricular load in elderly women with pre-HFpEF. Multiple studies have indicated the importance of arterial dysfunction in the pathogenesis of HFpEF [29-31]. In addition, there are reports demonstrating a significant association between low T-T and arterial dysfunction in postmenopausal women [32-34]. In this study, the evaluation of arterial function was not conducted; however, arterial dysfunction associated with decreased testosterone levels may lead to an increase in BNP due to left ventricular overload caused by increased afterload. Future research focusing on the relationship between testosterone and arterial function is required.

Hs-cTnT is used clinically as a biomarker to ascertain the degree of myocardial injury. In addition, numerous studies have demonstrated the prognostic significance of hs-cTnT in patients with HFpEF [35, 36]. Basic research has identified several mechanisms by which testosterone induces myocardial damage [37, 38]. Chung et al revealed that testosterone inhibits myofibroblast differentiation induced by transforming growth factor-β1, as well as cardiac fibroblast migration and proliferation [37]. Tsang et al demonstrated that testosterone stimulates α(1)-adrenergic receptors to protect the heart of rats exposed to ischemia [38]. Thus, the results of these basic studies and this cross-sectional study can be interpreted as indicating that low testosterone levels affect the progression of myocardial damage in elderly women with pre-HFpEF. To confirm this hypothesis, further prospective study is required to confirm prognosis of elderly women with HFpEF using T-T and hs-cTnT.

Several clinical studies have reported that the presence of CAD is a poor prognostic factor for patients with HFpEF [39, 40]. However, the relationship between CAD and testosterone levels in women remains controversial. Das et al reported that high T-T levels were significantly associated with the development of CAD [41]. In contrast, Kaczmarek et al reported that decreased testosterone levels are significantly linked to CAD [42]. In this study, T-T was significantly lower in patients with CAD than in non-CAD patients. Furthermore, an independent association was observed between CAD and low T-T levels. Thus, the results of this study are consistent with the report of Kaczmarek et al and indicate that low T-T also adversely influences the prognosis of elderly women with pre-HFpEF from the perspective of coronary artery atherosclerosis. Researchers highlight the importance of inflammation brought on by low testosterone as a contributing factor to the finding that male patients with low testosterone levels are also at risk of developing CAD [43, 44]. Although this cross-sectional study did not directly evaluate inflammatory markers, the findings suggest that inflammation may contribute to the significant association between low T-T and CAD in the study population. In the future, it is hoped that the relationship between T-T and inflammation in elderly women with pre-HFpEF will be clarified, and further prospective examination will be conducted to ascertain the benefits of interventions such as testosterone replacement therapy and lifestyle modifications.

Research has highlighted that oxidative stress is closely linked to HFpEF pathogenesis [9, 45, 46]. In addition, several reports have reported relationships between d-ROMs tests, which are oxidative stress markers, and HF [27, 47, 48]. Hirata et al examined the association between the d-ROMs test and hospitalized HFpEF patients and reported that patients with elevated d-ROMs test parameters experienced significantly more cardiovascular events and HF-related readmissions than those with lower parameters and a poor prognosis [47]. In addition, the independent relationship between low T-T and d-ROMs test in the results of this cross-sectional study indicates that elderly women with pre-HFpEF and low blood testosterone concentration are at an increased risk of developing cardiovascular disease, including the initial onset of HF, not just progression to HFpEF after hospitalization. Zhang et al reported that low testosterone contributed to increased oxidative stress in cardiomyocytes [49]. Therefore, testosterone replacement may be effective for elderly women with pre-HFpEF for lowering oxidative stress. However, in this cross-sectional study, the mechanism by which oxidative stress is involved in the decrease of T-T may also be considered. Therefore, it is desirable to investigate whether antioxidant therapy can promote an increase in T-T and subsequently aid in preventing cardiovascular disease, including the onset of HF.

The limitations of this study are described below. First, this study did not evaluate other relevant sex hormones such as dehydroepiandrosterone sulfate, sex hormone binding globulin, and estradiol. According to previous research, dehydroepiandrosterone sulfate in particular plays a major role in the development of HFpEF in postmenopausal females [11]. In the multivariate analysis conducted in this study, including these hormone values as analysis factors may have eliminated the relationship between T-T and various HF-related indicators. In the future, it would be desirable to include the evaluation of related hormones, such as dehydroepiandrosterone sulfate, in further investigations. Second, this study used the E/e' ratio for clinical simplicity. However, there are multiple indicators for left ventricular diastolic function, such as HFA-PEFF scores, left atrial volume index, tricuspid regurgitation velocity, and global longitudinal strain. In the future, it is hoped that the relationship between these indicators and T-T will be explored to elucidate the association between left ventricular diastolic function and T-T. Third, in this study, a decrease in T-T was associated with various indicators related to HFpEF in elderly women with pre-HFpEF. However, since this study is a cross-sectional analysis, it is necessary to verify through future prospective studies how cases of low T-T progress over time, how they develop HF, and what their severity is. Furthermore, it is necessary to conduct risk stratification based on T-T using a large number of cases and investigate whether interventions such as testosterone replacement therapy and lifestyle improvements for elderly women with low T-T can improve the prognosis of pre-HFpEF.

This cross-sectional study indicated that low T-T levels reflect unfavorable pathophysiological conditions in Japanese elderly women with pre-HFpEF. To clarify the relevance of T-T as a predictive indicator for the onset of cardiovascular diseases, including HF incidence in elderly women with pre-HFpEF, future prospective studies, including interventional treatments, should be conducted.

Acknowledgments

None to declare.

Financial Disclosure

None to declare.

Conflict of Interest

None to declare.

Informed Consent

Informed consent was obtained from all patients who participated in this study.

Author Contributions

Takashi Hitsumoto contributed to the research planning, data acquisition and analysis, and manuscript writing and editing.

Data Availability

The author declares that data supporting the findings of this study are available within the article.

Abbreviations

BNP: brain natriuretic peptide; CAD: coronary artery disease; d-ROMs: derivatives-reactive oxygen metabolites; eGFR: estimated glomerular filtration rate; HFpEF: heart failure with preserved ejection fraction; hs-CRP: high-sensitivity C-reactive protein; hs-cTnT: high-sensitivity cardiac troponin T; RAS: renin-angiotensin system; SGLT2: sodium glucose cotransporter 2; T-T: total testosterone concentration

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