ABSTRACT OBJECTIVES The present study aimed to investigate the relationship between male hormones and metabolic dysfunction-associated fatty liver disease (MAFLD) in males. METHODS Data from

the Fangchenggang Area Male Health and Examination Survey (FAMHES) were used to analyze the male hormone levels between MAFLD patients and controls. Univariate and multivariate logistic

regression analyses were performed to identify risk factors for MAFLD. Receiver operating characteristic curve analysis was used to assess the diagnostic performance of male hormones for

MAFLD. RESULT A total of 1578 individuals were included, with 482 individuals (30.54%) of MAFLD, including 293 (18.57%) with mild disease and 189 (11.98%) with moderate-to-severe disease.

MAFLD. FSH showed an excellent diagnostic value, with an AUC of 0.992 alone and 0.996 after adjusting age. CONCLUSIONS Our findings indicate that FSH may be a potential diagnostic and

predictive biomarker for MAFLD. SIMILAR CONTENT BEING VIEWED BY OTHERS CORRELATION ANALYSIS OF THE TRIGLYCERIDE–GLUCOSE INDEX AND RELATED PARAMETERS IN METABOLIC DYSFUNCTION-ASSOCIATED FATTY

LIVER DISEASE Article Open access 02 January 2025 A SCREENING STUDY OF HIGH-RISK GROUPS FOR LIVER FIBROSIS IN PATIENTS WITH METABOLIC DYSFUNCTION-ASSOCIATED FATTY LIVER DISEASE Article Open

access 10 October 2024 COMPARISON OF CARDIOMETABOLIC RISK FACTORS BETWEEN OBESE AND NON-OBESE PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE Article Open access 04 September 2023

INTRODUCTION Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is the most common cause of chronic liver disease

worldwide and can progress to liver fibrosis, cirrhosis, and even hepatocellular carcinoma [1,2,3,4]. Therefore, MAFLD is a major public health issue. A meta-analysis conducted in 2016

revealed that the prevalence of MAFLD in the general population is 25.24%, with the highest prevalence in the Middle East (31.79%) and South America (30.45%), and the lowest in Africa

(13.48%) [5]. Another meta-analysis conducted in 2019 reported that the pooled prevalence of MAFLD in China is 29.2%, and it has been increasing rapidly, from 25.4% in 2008–2010 to 32.3% in

2015–2018 [6]. With the rising incidence of obesity worldwide, the prevalence of MAFLD is also growing rapidly [3, 7]. Currently, a liver biopsy is regarded as the gold standard for

clinically diagnosing and staging MAFLD [7, 8]. However, its invasive nature makes it challenging to perform in routine clinical practice. Therefore, the identification of novel biomarkers

associated with MAFLD has become crucial for the early detection and assessment of MAFLD severity [9]. MAFLD is clinically highly associated with metabolic syndrome [10]. Besides causing

significant pathological changes in the liver, MAFLD also affects the function of other organs and systems, especially the endocrine system [11, 12]. MAFLD is a sex-dimorphic disease, with a

generally greater prevalence in men [13, 14]. Gender and sex hormones have a significant impact on various factors associated with MAFLD, such as genetic variants, cytokines, stress, and

environmental factors, which can modify the risk profiles and phenotypes of MAFLD in individuals [14, 15]. Testosterone is the major male hormone and is responsible for regulating many

metabolic processes, such as fat metabolism, insulin sensitization, and suppression of lipogenesis, besides maintaining normal sexual function and reproductive ability [16]. Several studies

have investigated the relationship between testosterone levels and MAFLD, but the results are inconsistent. Some studies have reported that a lower total testosterone (TT) level is

associated with a high prevalence of MAFLD and adverse clinical outcomes [17,18,19], while other studies have shown that there is no significant association between the testosterone level

and MAFLD [20, 21]. Luteinizing hormone (LH) and sex hormone-binding globulin (SHBG) are two key regulatory factors that regulate testosterone levels [22,23,24]. LH can promote testosterone

secretion by Leydig cells in the testis [24], while SHBG can bind to testosterone and affect its bioavailability in the body [22, 23]. A recent meta-analysis has shown that although a lower

testosterone level is associated with the severity of MAFLD, the relationship between SHBG and the severity of MAFLD remains controversial [22]. For example, a higher SHBG level was

associated with the severity of MAFLD in men with a body mass index >27 kg/m2, while a lower SHBG level was associated with the severity of MAFLD in men older than 50 years old [22]. Two

other studies found that SHBG was negatively correlated with MAFLD in men [25, 26]. Cao and collaborators showed that there was no association between LH and MAFLD in men, whereas women with

MAFLD had significantly lower levels of LH than those without MAFLD [25]. Furthermore, follicle-stimulating hormone (FSH) is an important hormone regulating the proliferation and maturation

of germ cells [24]. FSH is reported to be associated with MAFLD in postmenopausal women [27,28,29]; however, studies regarding the relationship between FSH and MAFLD in men are limited.

Therefore, the present study aimed to investigate the relationship between male hormones (LH, SHBG, FSH, and testosterone) and MAFLD in males, hoping to provide novel biomarkers for the

early identification of MAFLD severity and prognosis in patients with MAFLD. MATERIALS AND METHODS PARTICIPANTS This study was conducted using the data from the Fangchenggang Area Male

Health and Examination Survey (FAMHES), which is a population-based survey conducted from September 2009 to December 2009 among noninstitutionalized Chinese males aged 17–88 years old in

Guangxi, China, and has been used in many previous studies [30,31,32,33,34]. The aim of FAMHES was to investigate the impact of environmental and genetic factors, as well as their

interactions, on the development of age-related chronic diseases. A comprehensive population and health questionnaire was provided to 4303 male participants at the Medical Center of the

First People’s Hospital of Fangchenggang, and extensive physical examinations were conducted. Written informed consent was obtained from all participants. This human data is in accordance

with the Declaration of Helsinki. and the study was approved by the Guangxi ethics committee. All participants were requested for follow-up, which included another health questionnaire and

biochemical analysis of a fasting blood sample collected in the morning. A trained expert measured the height and weight of the participants using standard procedures. Participants were

excluded from this study if any of the following conditions were met: (I) currently diagnosed with diabetes, coronary heart disease, stroke, hyperthyroidism, rheumatoid arthritis,

inflammatory disease of the reproductive system, urinary diseases (infection, stone, hematuria, or hematospermia), prostatitis or history of any cancers; (II) taking any medication; (III)

with impaired liver function (alanine aminotransferase >2.0 times the upper limit of normal); (IV) with a history of excessive alcohol consumption (>40 mL/d); or (V) with impaired

kidney function (serum creatinine >178 mmol/L). After excluding participants who did not undergo complete clinical and laboratory tests or ultrasound examinations, a total of 1951

participants were available for analysis. It was found that 310 participants were positive for hepatitis B virus (determined by hepatitis B surface antigen detection), 45 participants were

excessive alcohol drinkers (>40 mL/d), 11 participants had at least one potential cause of chronic liver disease, and seven participants were taking medications known to cause fatty liver

imaging. After excluding these participants, 1578 males were finally included in this study (Fig. 1). ULTRASOUND EXAMINATION Two experienced ultrasound doctors [Cohen’s kappa of 0.621 (95%

CI 0.352–0.876)] performed abdominal ultrasound examinations on all patients using a portable ultrasound device (GE, LOGIQ, 5.0 MHz transducer, USA). The size, contour, echogenicity,

structure, and posterior attenuation of the liver were assessed for each participant. The ultrasound criteria for diagnosing a fatty liver included increased liver echogenicity (bright),

liver parenchymal echogenicity greater than that of the renal parenchyma, and blurring and narrowing of the hepatic vein lumen [35, 36]. According to the criteria described by Saadeh et al.

[36], all participants were divided into two groups (mild and moderate-to-severe). LABORATORY TESTS In the laboratory tests of FAMHES, all participants were required to fast overnight.

Samples containing approximately 10 mL of venous blood were collected from 8 am to 11 am the next day, frozen (~2 h), and sent to the testing center of the First Affiliated Hospital of

Guangxi Medical University in Nanning. The samples were centrifuged within 15–25 min and then stored at −80 °C until analysis. The serum samples were thawed at room temperature for 1 h and

then analyzed by inverting the test tube ten times. All analyses were performed by the same operator using the same batch of reagents. The blood lipid parameters were measured on an

automated analyzer (Dade Behring, USA) in the laboratory at the Fangchenggang. The FSH, LH, SHBG, estradiol (E2), and testosterone levels were determined using the COBAS 6000 system E601

(Elecsys module) and an immunoassay analyzer (Roche Diagnostics GmbH, Mannheim, Germany). The inter-assay coefficients of variation were 3.6% for E2, 4.4% for SHBG, 4.3% for FSH, and 3.6%

for LH. The lower limit of detection for the assay was 0.05 pg/mL. Hormones were measured in nonfasting blood samples that were collected within 4 h after waking up, thus balancing the

diurnal variation of hormone levels. All measurements were performed according to the manufacturer’s instructions. STATISTICAL ANALYSIS Statistical analysis was performed using SPSS 20.0.

Data distribution was analyzed by the Kolmogorov–Smirnov and Shapiro–Wilk tests. Continuous data with a normal distribution were expressed as the mean ± standard derivation, while continuous

data with a non-abnormal distribution were expressed as the median (range). Univariate logistic regression analysis was performed to identify risk factors for MAFLD or moderate-to-severe

MAFLD in all collected factors. Parameters with a _P_ value less than 0.1 in univariate analysis entered multivariate logistic regression analysis to identify independent risk factors for

MAFLD or moderate-to-severe MAFLD. The variance inflation factor was calculated to analyze the multicollinearity and variables with multicollinearity were excluded from the multivariate

logistic regression. The receiver operating characteristic (ROC) curve was plotted, and the area under the curve (AUC) with 95% confidence interval (CI) was used to assess the diagnostic

performance of male hormones for MAFLD. A _P_ value less than 0.05 was considered statistically significant. RESULTS BASELINE CHARACTERISTICS OF THE INCLUDED INDIVIDUALS Of the included 1578

subjects, 482 individuals (30.54%) were diagnosed with MAFLD, with 293 (18.57%) having mild disease and 189 (11.98%) having moderate-to-severe disease (Table 1). Therefore, these

participants were divided into three groups: control (1096 cases), mild MAFLD (293 cases), and moderate-to-severe MAFLD (189 cases). The MAFLD patients was significantly older than those

without MAFLD (_P_ < 0.001), and the patients with moderate-to-severe MAFLD were older than those with mild MAFLD (_P_ < 0.05). The LH, FSH, and SHBG were significantly greater in the

MAFLD patients compared to the control group (_P_ < 0.001). In addition, the LH, and FSH levels were greater in the patients with moderate-to-severe MAFLD compared to those with mild

MAFLD (_P_ < 0.05), while there was no significant difference in the SHBG levels between the patients with moderate-to-severe MAFLD and those with mild MAFLD (Table 1). Moreover, the

levels of LH, FSH, and SHBG were all significantly greater in the MAFLD patients than in the control group among different age groups and increased in an age-dependent manner (_P_ < 0.05,

Table 2). Since age was a confounder for MAFLD, the parameters with a _p_ value less than 0.05 in Table 1 was further analyzed using age as a covariate. After adjusting age, LH, FSH, and

SHBG remained significantly higher in the MAFLD patients compared to the control group (Table 1). LOGISTIC REGRESSION ANALYSIS FOR THE RISK FACTORS OF MAFLD Univariate logistic regression

analysis showed that age, waist–hip ratio (WHR), systolic blood pressure (SBP), diastolic blood pressure (DBP), blood glucose (GLU), cholesterol (CHOL), high-density lipoprotein (HDL),

low-density lipoprotein (LDL), FSH, LH, SHBG, and E2 were all risk factors for the occurrence of MAFLD (all _P_ < 0.05) (Table 3). Multivariate logistic regression analysis identified

that only FSH was an independent risk factor for MAFLD (_P_ < 0.001) (Table 3). According to the univariate regression analysis comparing the severe MAFLD patients with the mild MAFLD

patients, age, FSH, and LH were found to be risk factors for severe MAFLD (all _P_ < 0.05). Compared to the patients aged >45 years old, those aged <35 years old (OR = 0.341, 95%

CI: 0.197–0.589) or 35–45 years old (OR = 0.598, 95% CI: 0.398–0.898) had a reduced risk of moderate-to-severe MAFLD (_P_ < 0.05) (Table 4). Further multivariate regression analysis

revealed that only FSH was an independent risk factor for moderate-to-severe MAFLD (_P_ < 0.001) (Table 4). DIAGNOSTIC VALUE OF MALE HORMONES FOR MAFLD We also analyzed the diagnostic

values of LH, FSH, TT, SHBG, and E2 for MAFLD. As shown in Fig. 2A, FSH showed an excellent diagnostic value, with an AUC of 0.992 (95% CI: 0.985–0.999); LH had an AUC of 0.710 (95% CI:

0.682–0.738); while TT, SHBG, and E2 only had AUC values of 0.446–0.597. After adjusting the age confounder, AUCs of all hormones were increased, with FSH presenting an AUC of 0.996 (95% CI:

0.991–1.000) and LH presenting an AUC of 0.788 (0.764–0.811) (Fig. 2B). DISCUSSION In the present study, we found that age, WHR, SBP, DBP, GLU, CHOL, HDL, LDL, FSH, LH, SHBG, and E2 were

all risk factors for MAFLD (all _P_ < 0.05). Moreover, the severity of MAFLD was correlated with age, FT, LH, and SHBG. Multivariate regression analysis revealed that FSH was an

independent risk factor for MAFLD as well as moderate-to-severe MAFLD. FSH showed an excellent diagnostic value, with an AUC value of 0.992. Age-adjusted FSH presents an AUC value of 0.996.

Univariate logistic regression analysis determined that LH and SHBG, but not TT affected the occurrence of MAFLD. Many studies have shown that serum testosterone concentrations decrease with

age, which is partly due to a decrease in the number and function of interstitial cells in the testes and a decrease in the pulsatile secretion of LH that stimulates interstitial cells

[37]. SHBG is a sex hormone-binding globulin synthesized by liver cells that protects sex hormones from adhesion as well as biological and chemical degradation [38]. The SHBG level in adult

males gradually increases with age, leading to more testosterone binding to SHBG [38]. Several previous studies have demonstrated that a lower TT level is associated with a high prevalence

of MAFLD [17,18,19], while other studies have found no significant association between the testosterone level and MAFLD [20, 21]. Moreover, in this study, multivariate regression analysis

revealed that only FSH was an independent risk factor. Many previous studies only compared the parameters between the MAFLD and control groups but did not adjust for confounders [17,18,19],

which may explain the controversial results. In the current study, we found that FSH was an independent risk factor for MAFLD as well as moderate-to-severe MAFLD. FSH is a glycoprotein

peptide hormone synthesized by the anterior pituitary gland that affects both the reproductive and nonreproductive systems. A recent study has demonstrated that FSH regulates hepatic lipid

metabolism in mice [39]. Additionally, a cross-sectional study has reported that high FSH level is associated with MAFLD in men aged over 80 years old [40]. Moreover, a recent study in a

Chinese elderly population (over 60 years old) consisting of both men and women has found that FSH is negatively associated with NAFLD in both men and women [41]. Our data were inconsistent

with these reports, which may be due to the difference in study populations. The above studies enrolled an elderly population, while our study had a much younger population. Here, we also

determined that FSH had an excellent diagnostic value for MAFLD, with an AUC of 0.992 alone and 0.996 after adjusting age confounder, indicating that FSH may be a potential diagnostic

biomarker for MAFLD. Our data suggest that MAFLD is related to male hormones. Previous studies have suggested a link between metabolic dysfunction and male reproductive health [42, 43].

Metabolic syndrome was reported to be associated with a decline in TT while no alterations in gonadotropin levels, and it was associated with hypogonadism, poor sperm morphology, testis

ultrasound inhomogeneity, and erectile dysfunction [44]. A meta-analysis of 21 studies revealed a J-shaped association between body mass index and abnormal sperm count [45]. Obesity is

negatively correlated with TT, LH, and SHBG [46], and affects male-factor infertility [47]. Our findings and these studies confirmed that metabolic dysfunction may affect male reproduction

health by regulating male hormones. However, further experiments are needed to uncover the underlying mechanism. This study has several limitations. First, this was a retrospective study and

the inherent bias associated with such a study design cannot be avoided. Second, crucial data on marital or fertility status, and history of (in)fertility were not collected. Male sex

hormones have been shown to correlate with male fertility status [48], which underscores the significance of these missing data. Therefore, our conclusion that FSH is a risk factor for MAFLD

should be applied with caution due to the lack of male fertility data. Third, we did not collect data on semen parameters and testicular ultrasound. However, FSH plays a crucial role in the

regulation of spermatogenesis [49]. and acts on Sertoli cells, the main component of the seminiferous tubules [50]. Increased levels of FSH may indicate abnormal spermatogenesis or

testicular damage. Therefore, the findings of this study should be interpreted with careful consideration of these unexamined factors. In conclusion, the present study identified that FSH is

an independent risk factor for both MAFLD and moderate-to-severe MAFLD and that it had a diagnostic value for MAFLD, with an AUC value of 0.992 alone and 0.996 after adjusting the age

confounder. Therefore, FSH may be a potential diagnostic and predictive biomarker for MAFLD, which warrants further clinical studies. DATA AVAILABILITY All the data were included in this

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  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS This work was supported by grants from the National Natural Science Foundation of China (Grant number: 82002397), Natural

Science Foundation of Hunan Province, (Grant Number: 2021JJ40868; 2023JJ60410), Scientific Research Project of Hunan Provincial Health Commission (202207012427,202206032424). Changsha Soft

Science Project (Grant Number: kh2302010). Thanks for the support of National Traditional Chinese Medicine Advantage Specialist (Surgery) Funding. AUTHOR INFORMATION Author notes * These

authors contributed equally: Dong-Hua Bin, Fang Liu, Ke-Ping Peng. AUTHORS AND AFFILIATIONS * Department of Anus and Intesine, The First Hospital of Hunan University of Chinese Medicine,

Changsha, China Dong-Hua Bin & Min Zhan * Department of Ultrasoud, The First Hospital of Hunan University of Chinese Medicine, Changsha, China Fang Liu * Department of

Otorhinolaryngology-Head and Neck surgery, The first Hospital, Hunan University of Chinese Medicine, Changsha, China Ke-Ping Peng * Department of Ultrasoud, The Second Xiangya Hospital,

Central South University, Changsha, China Yan Tan, Qiao Liu, Wang Tang & Gui-Xiang Tian * Centre for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, China

Zeng-Nan Mo * Department of Medical Equipment, The Second Xiangya Hospital, Central South University, Changsha, China Xiong-Jun Peng Authors * Dong-Hua Bin View author publications You can

also search for this author inPubMed Google Scholar * Fang Liu View author publications You can also search for this author inPubMed Google Scholar * Ke-Ping Peng View author publications

You can also search for this author inPubMed Google Scholar * Min Zhan View author publications You can also search for this author inPubMed Google Scholar * Yan Tan View author publications

You can also search for this author inPubMed Google Scholar * Qiao Liu View author publications You can also search for this author inPubMed Google Scholar * Wang Tang View author

publications You can also search for this author inPubMed Google Scholar * Zeng-Nan Mo View author publications You can also search for this author inPubMed Google Scholar * Xiong-Jun Peng

View author publications You can also search for this author inPubMed Google Scholar * Gui-Xiang Tian View author publications You can also search for this author inPubMed Google Scholar

CONTRIBUTIONS D.-H.B., F.L., K.P.-P. performed experiments, analyzed data, and reviewed manuscripts. M.Z., Y.T., Q.L., W.T., and Z.-N.M. organized the study and supervised experiments.

G.-X.T. and X.-J.P. designed the project and prepared the manuscript. CORRESPONDING AUTHORS Correspondence to Xiong-Jun Peng or Gui-Xiang Tian. ETHICS DECLARATIONS COMPETING INTERESTS The

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ARTICLE Bin, DH., Liu, F., Peng, KP. _et al._ The relationship between follicle-stimulating hormone and metabolic dysfunction-associated fatty liver disease in men. _Nutr. Diabetes_ 14, 52

(2024). https://doi.org/10.1038/s41387-024-00314-1 Download citation * Received: 17 October 2023 * Revised: 19 June 2024 * Accepted: 04 July 2024 * Published: 11 July 2024 * DOI:

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