Globally, Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is one of the major presentations and causes of chronic liver disease associated with significant public health burden and increased incidence of comorbidity events such as dyslipidemia and obesity [1]. Singeap et al. report that MASLD accounts for over 30% of all hepatic disorders, surpassing the prevalence of other liver conditions such as viral hepatitis and alcoholic liver disease [2]. The most common etiology of MASLD involves dysregulated lipid metabolism in the liver, resulting in lipid accumulation, inflammation, hepatocellular injury, and fibrosis in individuals without a history of significant alcohol use [3,4].  However, the pathogenesis of MASLD has been described as a multifactorial phenomenon involving numerous parallel facets, including metabolic, immunological, and genetic imbalances, leading to the development of steatosis and non-alcoholic steatohepatitis [5].

Currently, the prevalence rates of MASLD have been on an upward spiral, primarily driven by changing in lifestyle and dietary patterns [6]. A recent meta-analysis from a pooled estimate of 1,030,160 individuals estimates the overall global incidence of MASLD at 46.9 per 1000 person-years, with the highest prevalence observed in males [7]. Furthermore, Riazi et al. put the male-to-female ratio at 70.8 cases per 1,000 person-years compared to 26.9 cases per 1,000 person-years [7]. 

Current developments in gastroenterology have proposed a change in nomenclature geared towards better reflecting the multifactorial pathogenesis of the disease [8,9]. MASLD has been strongly associated with the incidence and comorbidity of obesity, diabetes mellitus, hyperlipidemia, and metabolic syndrome [10,11]. Additionally, recent studies have shown an association between MASLD and several endocrinopathies, including polycystic ovarian syndrome, hypopituitarism, growth hormone deficiencies, hypothyroidism, hypercortisolism, and hypogonadism [12].

Leonardo et al. define hypogonadism as a genetic or acquired medical condition characterized by a significant decrease in reproductive functions in both males and females, regardless of the cause [13]. Hypogonadism is classified as either primary/hypergonadotropic or secondary /hypogonadotropic hypogonadism [14]. Hypergonadotropic hypogonadism refers to the decreased sex hormone expression with an elevation in gonadotropin levels such as LH and FSH. Hypogonadotropic hypogonadism is described as the inability of the hypothalamus or the pituitary to produce sufficient levels of LH or FSH, resulting in an overall concentration of sex hormones [14].

Autoimmune disorders, genetics, infections, hepatic and kidney diseases, and cancer treatment modalities such as radiation, surgery, and trauma are identified as some of the critical causes of primary hypogonadism [14]. Meanwhile, pituitary gland injury or hemorrhages, anorexia nervosa, radiation, opiates, glucocorticoids, excess body ion concentrations, surgery, tumors, and trauma are documented causes of secondary hypogonadism [14]. Hypogonadism presents in both male and female populations with a bidirectional association between MASLD reported in global studies [15-17].

Multiple studies and case reports have underscored the association between MASLD and hypogonadism [15-17]. This association, as detailed by Winters et al., is complex, multifactorial and bidirectional distinguished by the progression of healthy livers through lipogenesis to MASLD [18]. Several studies have established the relationship between metabolic disorders and an elevated prevalence of hypogonadism [19,20]. However, to date, no actual prevalence of hypogonadism in MASLD patients has been established. Therefore, we aimed to systematically review available studies investigating the association between MASLD and hypogonadism in male patients.

Study Design

This study was conducted in complete adherence to the Preferred Reporting Item for Systematic Reviews and Meta-Analysis (PRISMA).

Literature search strategy

The review undertook an extensive internet-based literature search for peer-reviewed published literature pertinent to the incidence of hypogonadism and NAFLD/MASLD in February 2024. To achieve this objective, a modified search string comprises relevant keyword combinations and Medical Subject headings (MeSH) terms paired with Boolean operators, truncations, and field tags. The National Institute of Health (NIH) library and the Cochrane Library were the primary data sources, with further extensive research conducted in the Web of Science, MEDLINE, and Scopus journal databases. Additional manual scouring of references and citations from identified potential studies was included. The following search query was used to search for appropriate article and adjusted accordingly for each database:

(("non-alcoholic fatty liver disease"[MeSH Terms] OR ("non-alcoholic"[All Fields] AND "fatty"[All Fields] AND "liver"[All Fields] AND "disease"[All Fields]) OR "non-alcoholic fatty liver disease"[All Fields] OR "nafld"[All Fields]) OR MAFLD[All Fields]) AND (("hypogonadism"[MeSH Terms] OR "hypogonadism"[All Fields]) OR (low[All Fields] AND ("testosterone"[MeSH Terms] OR "testosterone"[All Fields]))) AND ("male"[MeSH Terms] OR "male"[All Fields] OR "males"[All Fields])

Eligibility Criteria

An elaborate screening process governed the literature search process to ensure conclusive identification and extraction of pertinent data.

Inclusion criteria

We included eligible studies if they met the following conditions:

• Primary studies with patients diagnosed with MASLD/NAFLD, i.e., patients with evidence of steatosis identified through imaging and patients with no other causes of hepatic fat accumulation, such as alcohol consumption.
• Only studies assessing the prevalence and association between MASLD/NAFLD and hypogonadism in males.
• Studies reporting statistical outcomes based on empirical analysis in the form of continuous outcomes (Means, median, SDs, variance, standard errors, etc.), dichotomous, Odd Ratios, Relative Risks, and Hazard Ratios.

• Studies with participants older than 18 years.
• Studies in English.
• Studies classify the non- MASLD/NAFLD group as a reference group.

On the other hand, we excluded non-full-text articles and studies that did not meet the above conditions. We also excluded in-vitro studies. There was no restriction on the publication date.

Study Selection and Data Collection

The review employed two additional reviewers (SYC, PW) to assist in the data collection and study selection processes to optimize the data collection process and avoid bias. A comprehensive assessment of corresponding titles was initially conducted by running the above search string in the identified digital journal databases and libraries. Potentially relevant studies identified following this step were subjected to abstract analysis, with studies meeting the eligibility criteria moved to full-text analyses. This step was carried out in an MS EXCEL spreadsheet with references collected in the ZOTERO reference manager software. Any ensuing disagreements in the process were forwarded to the third review (NP), and experts in the field were also consulted, intending to ensure the highest quality data collection process.   

Data Analysis and Quality Appraisal

The Cochrane tool for systematic reviews and Meta-Analysis and the REVMAN 5.4 statistical software packages were the primary meta-analytical software analyses of the empirical data derived from the studies. Corresponding heterogeneity was calculated using the Chi-square statistic, with a 95% confidence interval (CI) corresponding to a statistical significance of P>0.05. Furthermore, the Dersimonian random effects model was applied based on the anticipated significant heterogeneity between the studies. Following extensive literature scouring, the most common study design realized from most studies was the cross-sectional study design. Thus, the review adopted the AXIS quality appraisal tool for cross-sectional studies by two reviewers (SYC, PW). The third reviewer (NP) resolved any disagreements (Appendix 1).

Appendix 1: Axis Checklist.

Literature Search

Literature scouring in PubMed and PubMed Central (PMC) journal databases, the Cochrane Library for Clinical Trials, Web of Science, and the Scopus databases revealed 938 possible citations for inclusion in the systematic review and meta-analysis. Five hundred records were identified in the PubMed Central database, 250 from PubMed, 100 from the Web of Science, 48 from the Cochrane Library, and 40 from the Scopus Library.

The initial citation assessment led to the exclusion of thirty-two duplicate articles, leading to the screening of 906 potential articles. Following this screening, 839 studies were excluded based on the title and abstract and were termed irrelevant to the objective of this study. The exclusion led to only 67 articles proceeding to full-text retrieval; thirty-seven studies could not be retrieved despite communication with the principal authors and publishing partners. The remaining thirty studies were rigorously analyzed based on the eligibility criteria, and 15 were excluded. From the excluded studies, five studies generalized gender (male and female), nine did not clearly define hypogonadism and MASLD, and one study was non-full text. The systematic review and meta-analysis included thirteen high-quality cross-sectional, cohort, and retrospective studies. A PRISMA flow diagram showing the literature search process is shown in Figure 1.

Figure 1: A PRISMA flow chart illustrating articles sourced from databases.

This figure summarizes the systematic literature search process for the systematic review and meta-analysis. Initially, 938 citations were identified across multiple databases. After excluding duplicates and screening titles and abstracts, 67 articles proceeded to full-text retrieval. Ultimately, thirteen high-quality studies were included in the systematic review and meta-analysis. See text for details.

Study Characteristics

Fifteen high-quality studies were included in the systematic review and meta-analysis (Table 1). Ten of the studies adopted cross-sectional study designs [15,21–29]. Two studies, Sarkar et al.30 and Zhang et al. were cohort studies, while Shin et al [31]. was a retrospective analysis with Wang et al. a retrospective case control study. Most studies were restricted to Asia (Korea, Taiwan and China)[21–23,23,24,26,28,31–33], while two were European (Italy15 and the Netherlands34) and the two other in the United States [25,29]. A sample total of eleven thousand nine hundred and sixty-two male patients were randomized with either MASLD diagnosis or non-MASLD. All studies stratified this population as either MASLD patients or normal patients with the mean ages, mean testosterone, and mean BMI described in the studies. Among the most common comorbidities associated with MASLD were diabetes and smoking. Interestingly, the majority of the MASLD population were currently smoking. The overall mean age of the participant was estimated as 46.39 ± 10.44 years, while the mean BMI was 25.31 ± 2.9 Kg/m2. The overall number of patients diagnosed with diabetes was 1646, while the number of current smokers was 1689, with the individual matrix significantly.

Table 1: Study Characteristics.

MASLD – Metabolic Dysfunction-Associated Liver Disease; BMI- Basal Metabolic Index; Data presented as Mean ± SD; N/A-Not Applicable/Not Reported; RCS- Retrospective Cross-sectional.; CS- Cross Sectional; RS-Retrospective CH-Cohort Studies; LU- Liver Ultrasonography; LB-Liver Biopsy; RCC-Retrospective Case Control; IHH-Idiopathic Hypogonadotropic Hypogonadism; PC-Prospective Cohort.

NOTE: For conversion of Confidence Intervals to SD we adopted the Cochrane Handbook for Systematic Review of Interventions [35].

Association Between NAFLD And Hypogonadism

Low serum testosterone levels primarily characterize hypogonadism in males. A pooled analysis of continuous outcomes assessing the association between the MASLD, and total testosterone levels compared to males without MASLD was conducted on 15 studies using a random-effects model. A standardized Mean Difference (SMD) with a 95% Confidence Interval (CI) was utilized in the meta-analysis. The pooled analysis from fifteen studies showed a robustly significant deficit in testosterone levels among male MASLD patients compared to normal patients (without MASLD): SMD of -0.33 (95% CI -0.50, -0.15); P=0.0002 (Figure.2). The I2 value of 93% (p<0.00001) (fig. 2) indicates a significantly high level of heterogeneity from the studies. The high heterogeneity might be attributed to variations in study populations and methodologies.

Figure 2: Forest showing pooled Standardized Mean Differences for the total testosterone levels between the MASLD and normal males.

This figure presents the results of a meta-analysis assessing the association between MASLD and total testosterone levels in males. A pooled analysis of fifteen studies using a random-effects model revealed a significant deficit in testosterone levels among MASLD patients compared to those without MASLD: Standardized Mean Difference (SMD) of -0.33 (95% CI -0.50, -0.15); P=0.0002. The high level of heterogeneity (I2=93%, p<0.00001) suggests variability in study populations. See text for details.

Quality of The Studies

The AXIS quality assessment checklist was employed as the primary data appraisal tool for studies included in the systematic review and meta-analysis. The tool contains twenty parameters stratified into two categories to assess the quality of the study. Studies were documented as high-quality studies meeting almost all parameters (more than 18) of the Axis checklist as shown in Appendix 1.

Publication Bias

We utilized a funnel plot to examine the potential publication bias among the included studies (Figure 3). There was a symmetrical distribution of studies on both sides of the standardized mean difference, indicating absence of bias among the studies.

Figure 3: Funnel plot of studies assessing publication bias among the studies evaluating the association between MASLD and Hypogonadism.

This figure displays a funnel plot used to assess publication bias among the included studies. The symmetrical distribution of studies around the standardized mean difference suggests the absence of bias. See text for details.

The primary objective of this systematic review and meta-analysis was to establish the association between hypogonadism and non-fatty liver disease. Several studies have purposed to establish an association between low testosterone levels and adverse clinical outcomes associated with liver disease [36-38] Notably, we recognize the impact of the meta-analysis conducted by Jaruvongvanich et al. assessing the association of testosterone, sex-hormone-binding globulin, and MASLD [39].

Our investigation established a statistically significant (P=0.0002) association between the MASLD male group and low testosterone levels (indicating the correlation between MASLD and hypogonadism) compared to males without MASLD. Moreover, a negative standardized mean difference score of -0.33 (95% CI -0.50, -0.15) indicated low testosterone levels in the MASLD group compared to the normal group. This observation collaborates with the cross-sectional studies conducted by Volzke et al. and Shin et al. on the association of MASLD indices with the lowered production of sex hormones in male patients [22,40]. Notably, these two studies showed a positive association between testosterone deficiency and MASLD without comorbidities such as diabetes, obesity, insulin resistance, and dyslipidemia. On the other hand, a significant association between low serum testosterone levels and MASLD in the presence of diabetes was established by Shin et al. and Polyzos et al [5,31]. However, in the case of these two studies, contrasting conclusions on the influence of MASLD on testosterone production in type-II diabetes mellitus patients were realized [8,31].

Longitudinal investigations by Hyodo et al. established a significant correlation between decreased testosterone levels and fatty liver in patients treated with MASLD in their childhood and adult years. However, this study was significantly impaired by its significantly low sample size and the fact that the sample population was composed of cancer survivors, thus subject to various identified and hidden risk factors based on the immune compromise [41].

Generally, the number of studies investigating the association between MASLD and hypogonadism has been on the rise, with the most notable contribution in the field articulated by Elsheikh et al [42]; Bruno et al [43]; McKenzie et al [44]; Charlton et al [45]; El-Mansoury et al [46]; Koulouri et al [47]; Gutierrez et al [48]; Haider et al [49]; Sumida et al [50]; Koga et al [51]; Koehler et al.; Tokushinge et al [52]; Yang et al [53]; Hanew et al [54]; Klair et al [17]; Wang et al [24]; Jaruvongvanich et al [39]; Gild et al [16]; and  Polyzos et al [5]. This caseload is composed of cross-sectional studies [5,16,17,46–48,50,51,53–55], a retrospective analysis [53], a prospective study[42], a cohort study [52], two RCTs [43,44], and a meta-analysis [39]. This observation ascertains the overall limitation of longitudinal randomized control studies investigating the association between MASLD and hypogonadism.

Per the specified parameters expressed in this paper, our primary focus was mainly on the male population diagnosed with MASLD and exhibiting low serum testosterone levels. This criterion was based on the significant prevalence and overall global burden of MASLD and hypogonadism in males, which is significantly more effective in the male population compared to females. This observation collaborates with Brand et al.’s association of testosterone with metabolic syndrome, with the highest correlation observed in the male cohorts [56]. Moreover, a meta-analysis by Ding et al. observed a significant association between elevated testosterone levels and a heightened risk of diabetes in women, while higher testosterone levels in males were associated with a lower risk of diabetes [57].

Despite the bulk of investigation and research into the correlation between MASLD and hypogonadism, the mechanism of association between testosterone and MASLD is still generally unclear. Cohen and Rao et al. explain this mechanism in terms of the hypogonadal-obesity-adipocytokine hypothesis in males [58,59]. In MASLD, visceral adiposity is a proven indicator for both MASLD and insulin resistance [60].

An increase in visceral adipose tissue significantly correlates with an elevation in aromatase enzyme activity, which converts testosterone to estrogen, resulting in an overall decrease in testosterone levels. This low testosterone level has been associated with an increase in lipoprotein lipase activity, increasing the triglyceride uptake into the adipocytes, improving visceral adiposity [39]. These processes have been associated with an exacerbation of the insulin resistance mechanism, resulting in a vicious cycle which further diminishes the testosterone levels. Van der Poll et al. additionally highlight the role of pro-inflammatory adipocytokines, such as the interleukin-1&6, responsible for the adipose tissue, lowering testosterone levels [61].

The analysis further showed several risk factors associated with hypogonadism and MASLD males with mean BMI, diabetes incidence, and smoking status shown in Table 1. However, based on the restrictions stated by the research objective, our parameters were restricted to the levels of testosterone solely. The overall mean BMI and diabetes incidence were high in the MASLD group compared to the reference group. Interestingly, the number of current smokers was higher in the normal group compared with the MASLD group; however, the number of smokers who may have stopped smoking on diagnosis with MASLD may further elucidate the status of smoking as a risk factor in MASLD and hypogonadism.

Limitations

As with all research, this systematic review and meta-analysis was plagued by several limitations. Firstly, the significantly high heterogeneity observed in the analysis, I2 =98%, Chi2 =525.86, and a Tau2 =0.30 with a statistically significant P-value (P<0.0001), was a major challenge in reporting conclusive findings by the paper. This heterogeneity was mainly attributed to the differences in study designs and overall divergent study methodologies observed by the review. Secondly, since this meta-analysis is largely based on observational studies and can only demonstrate an association, not causality, we cannot make conclusive remarks on the association between MASLD and hypogonadism in the male population.

In conclusion, the comprehensive review of MASLD in males underscores its significance as a burgeoning public health crisis with profound implications for global healthcare systems. The meta-analysis examining the association between MASLD, and testosterone levels provides valuable insights into the intricate interplay between metabolic disorders and endocrine dysfunction in males. The findings of the meta-analysis, demonstrating a relatively strong significant association between MASLD and total testosterone levels, underscore the multifaceted nature of MASLD’s impact beyond hepatic manifestations. This association suggests a potential bidirectional relationship, wherein MASLD may contribute to testosterone deficiency, while low testosterone levels could exacerbate metabolic dysfunction and MASLD progression in males.

Furthermore, the review highlights the sex disparities in the prevalence and severity of MASLD, with males exhibiting a higher likelihood of disease progression to advanced fibrosis, cirrhosis, and hepatocellular carcinoma. Despite recent recognition of MASLD as a global health challenge affecting both sexes, males remain disproportionately affected, emphasizing the need for targeted interventions and tailored healthcare approaches. Moving forward, addressing the complex interplay between MASLD, testosterone deficiency, and associated metabolic disturbances requires a multidisciplinary approach integrating hepatology, endocrinology, and preventive medicine. Efforts aimed at early detection, risk stratification, lifestyle modifications, and targeted therapeutic interventions hold promise in mitigating the burden of MASLD and its systemic consequences in males.

Acknowledgements

The authors wish to thank the staffs from Texas Tech University Health Science Center, Lubbock, TX, USA.

Acknowledgement of Grant Support

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of Interest

All authors declare no conflicts of interest.

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