Metabolic Syndrome, Hepatic Steatosis and Testosterone: A Matter of Sex

Abstract

Hepatic steatosis is considered the hepatic manifestation of metabolic disorders. Its global prevalence is a growing public health concern, estimated to affect over 30% of the population. Steatosis is strictly linked to metabolic dysfunction, leading to the revised terminology of MASLD (metabolic dysfunction-associated steatotic liver disease). The disease often progresses in conjunction with metabolic syndrome components, significantly increasing cardiovascular and overall mortality risks. The interplay between sex hormones and metabolic dysfunction is crucial, with male hypogonadism and female hyperandrogenism exacerbating the risk and severity of hepatic steatosis. In men, testosterone deficiency is associated with increased visceral adiposity and insulin resistance, creating a vicious cycle of metabolic deterioration. Conversely, in women, hyperandrogenism, particularly in conditions like polycystic ovary syndrome, may lead to severe metabolic disturbances, including hepatic steatosis. Estrogen deficiency also contributes to central adiposity and metabolic syndrome. The aim of this paper is to discuss this complex sex-dimorphic relationship.

1. Introduction

Metabolic diseases are dramatically increasing worldwide. The prevalence of obesity has almost tripled from 1975 to 2016. Currently, the WHO reports that 2 billion adults are overweight, and 650 million are obese [1]. The global age-standardized total diabetes prevalence is around 6%, and the total diabetes prevalence exceeds 20% in the age over 65 years [2]. Regarding non-alcoholic fatty liver disease (NAFLD), a recent estimate reported an increase of 58.0% in its incidence from 1994–2006 to 2010–2014 [3]. These numbers increase in all these metabolic alterations, as metabolic syndrome and hepatic steatosis are closely linked. In fact, recently, the terminology used to refer to hepatic steatosis changed from the acronym of NAFLD (non-alcoholic fatty liver disease) to MAFLD (metabolic dysfunction-associated fatty liver disease) [4], and more recently to MASLD (metabolic dysfunction-associated steatotic liver disease) [5]. MASLD is defined by the presence of excess triglyceride at the hepatic level, and one cardiometabolic risk factor among excess weight, glucose alterations, dyslipidemia and high blood pressure [5]. This change in terminology was aimed at better describing the association of hepatic steatosis and metabolic derangements.

Some studies report that hepatic steatosis precedes the manifestation of diabetes and/or metabolic syndrome; therefore, it has been postulated that it could be considered as a risk factor for the onset of both these conditions [6,7,8,9].

1.1. Hepatic Steatosis

The prevalence of hepatic steatosis is increasing worldwide: it was estimated to be around 25% in the general population in 2016 [10], it is currently over 30% [3]. However, the percentages vary depending on the methods used for the assessment (ultrasound or biopsy) and the population studied [3], so in Latin America the prevalence is over 44% [3], and that in patients with excess weight is over 70% [11].

Hepatic steatosis can be considered the hepatic manifestation of metabolic disease. It ranges from the simple hepatic accumulation of triglycerides (steatosis) and liver inflammation (steatohepatitis) to fibrosis and the development of liver cirrhosis. Hepatic steatohepatitis was the second cause of liver transplantation in 2019 [12], and will probably represent the first cause of liver transplantation in Europe in the coming years, considering the high efficacy of new antiviral treatments [13]. Moreover, hepatic steatosis may be associated with increased risk of extrahepatic outcomes [5].

Hepatic steatosis is characterized by an accumulation of triglycerides within hepatocytes, in intracellular lipidic droplets. An imbalance between the synthesis, inflow, oxidation and excretion of triglycerides determines their accumulation, typical of hepatic steatosis [14]. Triglycerides are made up of the esterification of free fatty acids (FFAs) and glycerol. Increased hepatic availability of free fatty acids is due to a combination of factors, such as an increased afflux of fatty acid to the liver for excessive dietary intake, altered lipolysis inhibition in the adipose tissue because of insulin resistance, and increased hepatic de novo lipogenesis [14,15,16]. Free fatty acids can undergo β-oxidation or esterification to triglycerides, with storage in the form of lipid droplets or incorporation into very low-density lipoproteins (VLDLs). The accumulation of high levels of free fatty acids and free cholesterol, as well as other lipid metabolites, leads to lipotoxicity, resulting in mitochondrial dysfunction and oxidative stress.

In addition to these factors, which are the primary actors in hepatic steatosis development, other factors are implicated, such as diet, genetical predisposition, epigenetic modifications and alterations in the gut microbiota [17,18] (see Figure 1). These latter factors may lead to increased intestinal production of short-chain fatty acids; increased intestinal permeability with consequent increased absorption of fatty acids and hepatic production of triglycerides; and the development of a low-grade chronic inflammation, through the action of lipopolysaccharide (LPS), short-chain fatty acids, trimethylamine-N-oxide (TMAO) and reduced choline [17,19,20,21,22]. Moreover, the alteration in the composition and metabolic capacity of the intestinal microbiota has indirect effects of favoring obesity and type 2 diabetes [22]. At a theorical level, the use of probiotics, prebiotics and symbiotics may be helpful in the correction of gut microbiome alterations, and potentially on their effects on hepatic fat accumulation. However, a definitive conclusion on the beneficial effects of their use is still lacking [23,24,25].

The dietary pattern plays a significant role in the development of hepatic steatosis—the Western diet is well known, being rich in saturated fat, to favor the onset of hepatic steatosis—and, in addition, the timing of food intake seems to influence it as well, even if studies with time-restricted eating did not provide definitive results [26,27].

On the contrary, physical exercise, and its consequent weight loss, is well proven to reduce hepatic triglyceride accumulation [28,29]. A healthy lifestyle, with dietary and behavioral therapy-induced weight loss when needed, and physical exercise, is the current therapy for hepatic steatosis. Diet quality should be improved, and rendered close to the Mediterranean dietary pattern, as well as limiting the consumption of ultra-processed food, which are rich in sugars and saturated fat; avoiding sugar-sweetened beverages and alcohol consumption is also of primary importance [5]. Some pharmacological treatments are giving intriguing results that will probably change the course of treatment in the near future.

1.2. Metabolic Syndrome

The diagnosis of metabolic syndrome is made when at least three among these alterations are present: increased waist circumference—considering ethnicity and gender—high blood pressure, altered blood glucose or diabetes, hypertriglyceridemia and reduced HDL cholesterol levels [30].

At the basis of this condition there are a pro-inflammatory state, oxidative stress and endothelial dysfunction, which overlap and lead to a multiplicity of clinical entities including cardiovascular diseases, non-alcoholic steatohepatitis, chronic kidney disease and neurodegenerative disorders [31].

Metabolic syndrome is an important risk factor for cardiovascular diseases, for both incidence and mortality, as well as for mortality from all causes [32]. Each of its components is an independent risk factor for cardiovascular disease, and their combination increases the rates and severity of cardiovascular illness, which manifests as a spectrum of cardiovascular conditions, such as microvascular dysfunction, coronary atherosclerosis and calcification, cardiac dysfunction, myocardial infarction and heart failure [33]. Moreover, metabolic syndrome-associated alterations, such as fatty liver and insulin resistance, also cooperate in increasing the cardiovascular risk [31,34,35]. The increased hepatic synthesis of triglycerides that occurs in hepatic steatosis, from fatty acids internalized in the hepatocytes and from de novo lipogenesis, leads to an increased synthesis of very-low-density lipoprotein (VLDL), whose plasma concentration consequently increases. The high concentration of VLDL leads to the generation of LDLs and HDLs rich in triglycerides, further elaborated into small dense LDLs, which are more atherogenic due to the easier crossing of the endothelium, and small HDLs that are easily excreted by the kidneys with consequent findings of low levels of HDLs [36].

The first line of approach for the prevention and management of metabolic syndrome and its related comorbidities, such as weight excess and hepatic steatosis, revolves around non-pharmacological methods. These comprise the adoption of a healthy lifestyle, with regular physical activity and correct nutritional habits [5]. Diet also affects physiological functions such as respiratory health, response to infectious illnesses, fertility and quality of sleep, which are often compromised in patients affected by obesity [37,38,39,40,41,42,43,44,45]. As therapeutic options, also in the case of concomitant MASLD, beyond lifestyle modifications, the choice of pharmacological treatments is dependent on the specific metabolic derangements present (diabetes, hypercholesterolemia, high blood pressure) [5].

2. Metabolic Syndrome and Hepatic Steatosis: Gender Differences

Men and women show gender differences in energy metabolism in terms of energy partitioning, mitochondrial functional capacity, mass and biology of white and brown adipose tissue, and these differences are reflected in glucose, lipid and protein homeostasis during fasting, rest and starvation [46]. In particular, during prolonged physical exercise, women oxidize more lipids than men, who instead preferentially use carbohydrates as the predominant source of fuel; during the rest period, however, women oxidize less fatty acids, which are destinated to be stored [46,47,48]. Estradiol (E2) appears to promote lipid oxidation in skeletal muscle during fasting and exercise and, at the same time, to inhibit hepatic lipid oxidation during feeding and resting states, resulting in a tendency to accumulate fat mass [46]. Estrogens, as demonstrated in murine models, confer protection from insulin resistance through the activation of the ERα pathway in insulin-sensitive tissues [48]. In women, E2 promotes insulin sensitivity by enhancing skeletal muscle fatty acid oxidation, while in men the conversion of testosterone to DHT and E2 is required to promote insulin sensitivity [46]. Estrogens also stimulate insulin synthesis and secretion, protect β-cell function and prevent β-cell apoptosis induced by metabolic damage [48]. In the adipose tissue, estrogen, progesterone and androgen receptors are present, and their expression varies in relation to the depot and the gender. The binding of sex hormones to their receptors in the adipose tissue may promote adipogenesis in certain areas of the body. In particular, in women, estrogen receptors are more present in the gluteal and femoral subcutaneous adipose depots, and this could explain the tendency for the preferential deposition of fat in this area in women [47]. In fact, estrogens promote the accumulation of subcutaneous adipose tissue instead of visceral adipose tissue, probably by stimulating the proliferation of adipocyte precursors at the subcutaneous sites, and lipolysis in the abdominal region. In men, however, visceral adipose tissue accumulation prevails. Their visceral adipocytes are more metabolically active and sensitive to lipolysis than the subcutaneous ones, and lipolysis provides FFAs to the liver for gluconeogenesis and ketogenesis during starvation [46].

Gender differences are also found in the concentrations of leptin, a hormone produced by the adipose tissue, that stimulates the sensation of satiety and therefore reduces food intake. Leptin levels are higher per kilogram of body weight in women than in men, probably because its production is promoted by estrogens and inhibited by androgens [47].

Significant differences in plasma lipid profiles between women in their fertile age and men are present. Premenopausal women have higher concentrations of HDL, LDL, VLDL and triglycerides compared to men of the same age, and this different lipid profile may be at least partially responsible for the reduced cardiovascular risk in young fertile women. Estrogens decrease the synthesis of triglycerides, which is instead increased by progesterone. Testosterone, on the other hand, seems to have a stimulatory effect on de novo lipogenesis and lipid oxidation [49]. In fact, sex hormones play an important role in the pathophysiology of metabolic syndrome and hepatic steatosis, through different mechanisms (Figure 2).

Disorders that cause sexual hormone dysfunction are known to predispose to the onset of metabolic syndrome [50]. Interestingly, the relationship between these metabolic disruptions and androgens shows a sexual dimorphism [51]. The androgen excess in women, on one side, and the androgen deficiency in men, on the other side, do manifest in adverse metabolic phenotypes with similar characteristics. Testosterone, in particular, has an important role in metabolic regulation; therefore, its excess in women and its deficiency in men cause metabolic dysfunction. The serum concentration of testosterone in these two conditions could overlap, defining an adverse concentration range [52]. Of note, in hyperandrogenic women, androgen levels do not reach male serum concentrations; therefore, hyperandrogenic women do not benefit from the metabolic protection that would result from an increase in lean and muscle mass [52]. Sex hormone binding globulin (SHBG) is lower in both men and women with NAFLD in comparison with people without NAFLD [51]. Hepatic steatosis develops and progresses with hypogonadism, independently of sex and the underlying etiology [53].

Conversely, hepatic steatosis may influence the hepatic metabolism of sex steroids. AKR1D1 is an enzyme with 5β-reductase activity. It is mainly expressed in the liver, and its expression is interestingly downregulated in hepatic steatosis [54]. AKR1D1 may play a role in the interconnection of hepatic steatosis and sex steroid metabolism. In fact, it acts in inactivating steroids, and androgens among them [54,55,56].

2.1. Metabolic Syndrome, Hepatic Steatosis and Androgens in Male Hypogonadism

Male hypogonadism is a condition of impairment of gonadal function, characterized by the inability of the testes to produce physiological levels of testosterone and effective spermatogenesis. This picture is accompanied by a clinical syndrome related to testosterone deficiency [57].

Depending on which organ of the hypothalamic–pituitary–gonadal (HPG) axis is affected, hypogonadism can be defined as primary or secondary. It is defined as primary when it is due to testicular dysfunction, and is characterized by low testosterone levels and high gonadotropins (hypergonadotropic hypogonadism). The secondary hypogonadism, or central hypogonadism, is due to a hypothalamic–pituitary dysfunction and results in low gonadotrophins levels associated with low testosterone levels (hypogonadotropic hypogonadism). Causes of functional hypogonadism include systemic illness, severe obesity, organ failure and aging [57,58,59].

The association between low testosterone levels and excess weight and metabolic syndrome is well recognized in the literature [60,61]. A downregulation of the HPG axis determines the development of metabolic derangements, and the onset of metabolic syndrome [50]. In fact, low testosterone levels are associated with a higher risk of developing metabolic syndrome over time [62,63]. On the contrary, metabolic syndrome increases the risk of developing hypogonadism [64].

Obesity can be counted among the most frequent secondary causes of hypogonadism in men [65]. In addition, it increases the age-related testosterone decline [66]. Weight loss is able to revert obesity-associated hypogonadism [67].

Many mechanisms are implicated in the relationship between hypogonadism and metabolic derangements, in a complex picture that is still not completely clear.

The excess adipose tissue may lead to the male obesity-associated secondary hypogonadism (MOSH) [52]. In fact, it increases the aromatization of androgens to estradiol, with consequent suppression of the HPG axis and reduction in testosterone levels [52,68,69,70]. Other mechanisms potentially involve insulin resistance in the hypothalamus and pituitary, with consequent reduction in the release of gonadotrophins in response to insulin, and adipose tissue-related inflammation, which may also reduce gonadotrophin secretion [52,57]. In fact, the adipocyte-related cytokines IL-1, IL-6 and TNF-α could potentially exert inhibition on the pituitary axis, determining a suppression of GnRH, with consequently lowered luteinizing hormone (LH) and testosterone levels [71,72,73]. In addition, the pro-inflammatory cytokines such as TNF-α and IL-1 may reduce SHBG levels, resulting in increased free testosterone, which stimulates aromatase activity and the conversion of testosterone to estradiol and acts with negative feedback on the HPG axis [58]. SHBG is also reduced by insulin resistance, since insulin reduces its production in the liver [74]. Moreover, in obesity, excess leptin inhibits the effects of gonadotropins on testes, reducing testosterone production [74,75].

On the contrary, low testosterone levels favor the increase in visceral adiposity, through the increased formation of adipocytes from pluripotent stem cells and the inhibition of lipoprotein lipase, with a consequent worsening of insulin resistance that decreases testosterone further, and an associated reduction in lean and muscle mass, in a vicious circle [52]. Also, an impairment of mitochondrial function may play a role in the development of metabolic derangements [57].

Lower androgens levels in men are also associated with a higher risk of hepatic steatosis [51,76,77,78], also when secondary to androgen deprivation therapy [79]. The lower the testosterone levels, the higher the risk of hepatic steatosis [80]. Conversely, men with NAFLD have lower levels of testosterone [51,80,81].

This association between androgen levels in men and NAFLD is still significant after adjusting for HOMA-I, BMI, visceral adipose tissue and high-sensitivity C-reactive protein (hs-CRP) [77], and this may suggest that the role of androgens in determining NAFLD goes beyond the classical pathway of insulin resistance and inflammation related to visceral fat. Moreover, testosterone levels are inversely associated with inflammatory markers [63,82,83], which are increased in patients with hepatic steatosis [77].

As already evidenced by animal studies, testosterone replacement therapy in hypogonadism favors the regression of the grade of hepatic steatosis that accompanies hypogonadism [84]. The testosterone replacement therapy administered long-term to patients with hypogonadism determines an amelioration of liver steatosis, measured with indirect measurements (fatty liver index) or direct measurements (magnetic resonance), in the context of an evident amelioration of metabolic profile, such as a reduction in BMI, waist circumference and blood pressure; an amelioration of lipidic profile [85,86,87,88]; and a reduction in overall cardiovascular risk [85,87,89]. Testosterone treatment for 18 weeks in men affected by obesity and OSAS, and prescribed a hypocaloric diet and advised on physical activity, brought an improvement in hepatic fat content evaluated with CT, insulin sensitivity and LDL cholesterol, without significantly modifying BMI and waist circumference [90]. On the contrary, Huang et al. did not find any reduction in hepatic fat content evaluated with magnetic resonance, or in insulin resistance, after 6-month testosterone therapy in older men with low testosterone levels and mobility limitation [91]. Similarly, Lee et al. did not observe any amelioration in metabolic profile or in hepatic fat content evaluated with CT in older hypogonadal men [92]. This may suggest an influence of age on the positive effects of the replacement therapy.

Testosterone reduces de novo hepatic lipid synthesis, and promotes fatty acid oxidation and fat export from the liver [93]. Moreover, it acts as an anti-inflammatory agent, reducing nuclear factor kB (NF-kB) signaling and oxidative stress [93].

The mechanisms through which testosterone is able to influence metabolism involve the androgen receptor (AR). As some animal studies suggest, its function is necessary to mediate the effects of testosterone on the expression of key metabolic genes in the liver. Deletion of the AR in mice determines enhanced de novo lipogenesis and increased expression of lipogenic genes in the liver such as sterol regulatory element-binding protein 1c (SREBP-1c) and acetyl-coenzyme A carboxylase (ACC). Furthermore, reduced expression of PPAR-α reduces fatty acid degradation via β-oxidation [93].

2.2. Metabolic Syndrome, Hepatic Steatosis and Androgens in Female Hyperandrogenism

On the contrary, in women it is hyperandrogenism that is associated with a higher incidence of hepatic steatosis. Regardless of the underlying cause, hyperandrogenic disorders in women clinically manifest with hirsutism, acne, androgenetic alopecia, deepened voice, breast atrophy, increased muscle mass and clitoral enlargement [94].

Female hyperandrogenism derives from an excessive secretion of androgens by the ovaries and/or adrenals and can affect both premenopausal and postmenopausal women. The most common cause of androgen excess is polycystic ovary syndrome (PCOS); other hyperandrogenic disorders include poorly controlled congenital adrenal hyperplasia, ovarian hyperthecosis and androgen-secreting tumors of ovarian or adrenal origin [94].

Increased androgen levels are also found in female-to-male transgender patients who are administered long-term testosterone therapy to induce virilization and suppress female secondary sexual characteristics [95]. During the menopausal transition, a physiological transition from estrogenic to androgen dominance occurs [94].

As mentioned, the most common cause of hyperandrogenism in women is PCOS. The diagnostic criteria for PCOS according to the Rotterdam consensus of 2004 are based on the presence of at least two among the following features: clinical and/or biochemical hyperandrogenism, chronic oligo-anovulation and polycystic ovarian morphology [96]. Women with PCOS have a higher risk of developing type 2 diabetes, hypertension and coagulative pathologies long-term, and a higher risk of cardiovascular morbidity and mortality [97,98]. It is well known that PCOS is associated with a higher risk of hepatic steatosis [95,99,100,101]. Kumarendran et al. conducted a study aimed at evaluating the incidence of NAFLD in women suffering from PCOS by comparing them with a control group of corresponding age and BMI. Women with PCOS showed a higher rate of NAFLD, and, in particular, serum testosterone levels above 3 nmol/L and SHBG levels below 30 nmol/L were associated with an increased risk of NAFLD [102]. Elevated levels of free testosterone in premenopausal women have been shown to be associated with NAFLD, independently from insulin resistance, body mass index, waist circumference and serum lipids [103]. In fact, confirming the role of hyperandrogenism, among the four phenotypes of PCOS, the phenotypes associated with more serious manifestations are the hyperandrogenic ones A, B and C, while the non-hyperandrogenic phenotype D shows a milder form of disease with lower BMI and lower levels of total cholesterol, low-density lipoprotein, fasting insulin and HOMA-IR, associated with higher levels of SHBG, high-density lipoprotein and insulin sensitivity measured with the quantitative insulin sensitivity control index (QUICKI) [104,105].

In particular, in patients with PCOS, testosterone inhibits the proliferation and differentiation of preadipocytes into mature adipocytes resulting in compensatory hypertrophy of dysfunctional adipocytes, which produces large quantities of adipokines, cytokines and chemoattractant proteins that attract monocytes and macrophages. The resulting inflammatory process within the dysfunctional adipocyte is associated with abnormal lipid metabolism, reduced insulin sensitivity, type 2 diabetes mellitus, NAFLD and increased cardiovascular risk [106].

The excess of androgens promotes the development of an atherogenic lipid profile due to a direct effect on the metabolism of liver lipoproteins [94] and the formation of reactive oxygen species induced by hs-CRP and adipokines, which cause inflammation and consequently arterial stiffness and endothelial dysfunction that lead to atherogenesis and arterial hypertension [94,107,108,109].

Comparing non-hyperandrogenic women with women with hyperandrogenic PCOS, an increase in the average thickness of the carotid intima is found independently of obesity, and related to testosterone and androstenedione levels [110], as well as endothelial dysfunction and an upregulation of sodium channels in the proximal tubules with an increase in the speed of reabsorption of liquids and therefore an increase in extracellular volume and consequently in blood pressure [111].

In women with hyperandrogenism, the overactivation of the sympathetic nervous system, as well as abdominal adiposity, insulin resistance and sodium retention, contributes to the increase in blood pressure and systemic inflammation, and therefore the higher cardiovascular risk [94,112].

In addition, hyperandrogenism determines a change in the distribution of fat from the gynoid, gluteal–femoral type, to the android, abdominal type, in which adipose tissue is mainly localized within the intraperitoneal cavity which drains directly to the liver through the portal circulation, influencing the intermediate metabolism with its secretory products [52,95]. Moreover, androgen excess is associated with a suppression of lipolysis and an increase in lipogenesis, with a consequent accumulation of fat beyond the storage capacity of the adipocytes and its consequent accumulation in other sites, especially in the liver [111].

Visceral fat, for its part, fuels the excess of androgens of ovarian and/or adrenal origin directly through the action of adipokines and inflammatory mediators and indirectly through the induction of insulin resistance and hyperinsulinism [52]. There are several hypotheses on the possible mechanism linking hyperandrogenism and insulin resistance, including dysregulation in the steps of the insulin signaling cascade, mitochondrial dysfunction and lipid accumulation. Hyperandrogenism can also compromise the insulin sensitivity of skeletal muscle tissue [111]. A study on mice has shown that hyperandrogenism stimulates, through androgen receptors, pancreatic beta cells, increasing insulin secretion [113]. In turn, insulin further fuels hyperandrogenism as it amplifies the theca cell response to LH by acting on ovarian insulin receptors [114]; increases the production of androgens in adipose tissue, resulting in lipotoxicity; and suppresses the production of SHBG increasing serum levels of free testosterone [115]. Hyperandrogenemia could be a consequence of low SHBG levels, and low SHBG levels could therefore be the main predictor of the consequent metabolic dysfunction [116]. The concentration of free testosterone in the plasma is in fact strongly influenced by SHBG levels since 65% of testosterone is bound to this globulin; women with low SHBG levels may also have normal levels of total testosterone, but increased free testosterone levels. Therefore, low serum concentrations of SHBG are considered a biomarker of metabolic alterations as they are associated with insulin resistance, hyperandrogenism and abnormal glucose and lipid metabolism in patients with PCOS [117]. Women with a higher free androgen index (FAI), one of the best indicators of hyperandrogenism in women affected by PCOS, have a greater tendency to present adverse metabolic profiles [105]. However, no association between testosterone levels and insulin resistance has been observed in women taking antiandrogen contraceptive hormonal therapy [118]. In women suffering from PCOS and treated with the anti-androgen flutamide, the altered distribution of adipose tissue is corrected; in fact, a decrease in the ratio between visceral and subcutaneous fat is observed [95].

In postmenopause, hyperandrogenic disorders in women are rare and mainly attributable to ovarian hyperthecosis and virilizing ovarian tumors, for which bilateral oophorectomy represents the definitive treatment. Some studies in postmenopausal women demonstrate an independent association between bioavailable testosterone and hepatic steatosis, diagnosed with fatty liver index (FLI), a surrogate marker of liver fat accumulation [119], or by hepatic biopsy [120]. However, long-term normalization of testosterone levels does not appear to improve metabolic alterations, suggesting that prolonged hyperandrogenism may be responsible for an irreversible condition of accumulation of fat mass, hyperinsulinemia and lipotoxicity [115]. The molecular mechanisms through which excess androgens in females determine hepatic steatosis remain not completely defined, but involve increased lipogenesis through increased expression of SREBP-1c, fatty acid synthase (FAS) and ACC, and reduced fatty acid oxidation and hepatic lipid export [93]. Hyperandrogenism may lead to a hyperactivation of the androgen receptor in the central nervous system, liver, skeletal muscle, adipose tissue and pancreatic beta cells [121], with the development of the metabolic alterations already described.

3. The Role of Estrogens: Hypogonadism in Females

Estrogen deficiency, in particular 17-β estradiol, is associated with central adiposity, dyslipidemia, hepatic steatosis, type 2 diabetes mellitus, metabolic syndrome and, therefore, the development of cardiovascular diseases. Although the implicated mechanisms are not well understood, the metabolic effects of estrogen are mediated primarily by estrogen receptor α through genomic, non-genomic and mitochondrial mechanisms that regulate insulin signaling, substrate oxidation and energy levels [122]. 17-β estradiol centrally regulates energy homeostasis and inhibits feeding through estrogen receptor α; it also stimulates energy expenditure through the modulation of the thermogenesis of brown adipose tissue acting on the ventromedial nucleus of the hypothalamus [123]. It can also influence insulin action through genomic and nongenomic effects that include oxidative stress and nitric oxide production. Estrogen receptor α is thought to have a positive effect on insulin signaling and glucose transporter protein type-4 (GLUT4) expression, whereas receptor β may reduce the expression of GLUT4 in skeletal muscle [122].

In hepatocytes, estrogens reduce gluconeogenesis and insulin resistance, limit free fatty acid absorption and de novo lipogenesis, and promote fatty acid oxidation and export, thus preventing lipotoxicity and the generation of oxygen reactants. These are responsible for the activation of pro-inflammatory and pro-apoptotic processes, which have a key role in the pathogenesis of NAFLD [124,125,126,127]. Oxidative stress is the main cause of many age-related cardiovascular diseases, including hypertensive heart disease and heart failure and, in this regard, it has been shown that some estrogen-mediated functions on the cardiovascular system are related to the reduction in oxidative stress [128]. Estrogens reduce inflammation, thus fighting atherosclerosis [129], and stabilize atherosclerotic plaques by reducing the expression of matrix metalloproteinases and the production of plasminogen activator inhibitor–1 (PAI-1) [130]. Furthermore, high concentrations of estrogen inhibit endothelin synthesis and block calcium channels through the production of prostacyclin, ultimately inducing vasodilation [131].

Estrogen deficiency in women may result from natural menopause, may occur prematurely due to early menopause or primary ovarian failure (hypergonadotropic hypogonadism), or may be due to organic, genetic or acquired disorders causing hypopituitarism or functional hypothalamic amenorrhea (hypogonadotropic hypogonadism) [132]. Functional hypothalamic amenorrhea is associated with chronic anovulation resulting from a functional reduction in the gonadotropin-releasing hormone (GnRH) drive, triggered by excessive exercise, nutritional deficiencies, psychological stressors or chronic disease [133]. The administration of selective estrogen receptor modulator (SERM) in patients diagnosed with breast cancer is associated with a higher risk of developing fatty liver and alanine aminotransferase (ALT) elevation; however, the ALT elevation was reverted at the discontinuation of the therapy [134].

In the postmenopausal period, total fat mass and abdominal fat increase, and lean mass decreases, regardless of aging [135,136]. The excess visceral adipose tissue is responsible for the synthesis and secretion of bioactive substances such as adipokines, pro-inflammatory cytokines, reactive oxygen species, prothrombotic factors and vasoconstrictors [135]. Furthermore, in menopause, a decrease in insulin sensitivity is observed with a consequent predisposition to diabetes, an increase in LDL cholesterol and triglycerides and a decrease in HDL cholesterol, and therefore a tendency for atherogenesis and high blood pressure [136]. Dysmetabolic effects are also observed in women after surgical menopause, in which the incidence of metabolic syndrome has been found to be higher than in women undergoing natural menopause [137]. Hormone replacement therapy during menopause is able to reverse these metabolic alterations and therefore restore the protection offered by estrogens [136,138].

4. Conclusions

The interplay between testosterone and metabolism is complex and still not completely clarified. The protection offered by sex hormones (testosterone in men, estrogens in women) is fundamental for a healthy cardiometabolic profile, thanks to the pleiotropic effects of sex hormones. On the contrary, hypogonadism in both sexes and hyperandrogenism in women are associated with an adverse cardiometabolic phenotype, with fat liver deposition. The management of hepatic steatosis should therefore include a clinical evaluation in an endocrinological setting, as already happens for metabolic syndrome and excess weight, to identify the patients in which hormonal alterations may occur and to establish the most appropriate and effective medical management.