ABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is considered a hallmark of metabolic syndrome (MetS) and a significant contributor to cardiovascular disease (CVD). With the alarming rates of obesity in the United States and worldwide, efforts at understanding, preventing, and treating MetS and its components are being increasingly undertaken by scientists and clinicians. A strong association between MetS and male sexual problems is already well established. More recent animal and human studies have further evaluated the relationship of NAFLD with male sexual problems and infertility. The molecular and physiological mechanisms correlating these conditions are incompletely established at this time, however.
To review and analyze current literature associating NAFLD with andrologic disorders, including erectile dysfunction (ED), infertility, and hypogonadism.
The PubMed database was searched using terms “erectile dysfunction,” “hypogonadism,” “male infertility,” and “nonalcoholic fatty liver disease” for articles published between January 1980 and June 2018.
We present a summary of the recent clinical and experimental evidence and discuss the possible pathophysiological mechanisms relating NAFLD development and progression to ED, a hypogonadal state, and infertility.
A total of 132 articles were reviewed. These included human observational and clinical studies and animal and basic science research relating NAFLD to the development and progression of ED, hypogonadism, and infertility in men.
There is growing evidence linking NAFLD to male sexual and reproductive dysfunction. A complex interplay of pathophysiological processes underlying these entities and further relating them to the MetS components may ultimately aid the identification and development of novel diagnostic and therapeutic approaches.
Introduction
Nonalcoholic fatty liver disease (NAFLD), considered a hallmark of metabolic syndrome (MetS), is also a significant contributor to cardiovascular disease (CVD). With the alarming rates of obesity in the United States and worldwide, increasing efforts at understanding, prevention, and treatment of MetS and its components have been undertaken by scientists and clinicians. The strong association between MetS and male sexual and reproductive problems, including erectile dysfunction (ED), hypogonadism, and infertility, has been also established. More recent molecular, animal, and human longitudinal studies have further evaluated the relationship of NAFLD to male sexual problems. The molecular and physiological mechanisms correlating these conditions are incompletely established at this time, however.
In this review, we analyze current basic science, animal, observational, and clinical data linking NAFLD to male sexual and reproductive dysfunction.
Methods
This review article is based on a detailed literature search using PubMed. Articles in the English language were searched for such terms “erectile dysfunction,” “male infertility,” “hypogonadism” and “NAFLD.” A total of 132 articles were identified and reviewed.
We present a summary of the recent clinical and experimental evidence and discuss the possible pathophysiologic mechanisms relating NAFLD development and progression to ED, hypogonadism, and infertility.
Results
Definition and Epidemiology of NAFLD
NAFLD is a condition characterized by an increased buildup of triglycerides (TGs) in the liver parenchyma in the absence of excess alcohol use.1 It was first described in 1980 and spans the spectrum from simple steatosis or nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH).2 Simple steatosis is considered a benign condition and is defined as fat comprising 5% of the entire liver weight in the absence of any inflammation.3 NASH is diagnosed once inflammatory changes and hepatocyte injury are observed, and it may further progress to fibrosis, cirrhosis, and, ultimately, hepatocellular carcinoma.4,5 In fact, patients who meet specific histopathological criteria for NASH are at the greatest risk for progression to cirrhosis and account for ∼15%–25% of the NAFLD population as a whole.6 Currently, NASH cirrhosis is the leading cause of chronic liver disease and the second most common indication for liver transplantation in the United States.7
The true prevalence of NAFLD is unknown, as individuals in early stages of the disease remain relatively asymptomatic, and there is no reliable noninvasive test that can be used for screening. Most commonly, the disease is diagnosed incidentally, with abnormal levels of liver function laboratory tests, or when abdominal imaging performed for another purpose identifies a liver pattern consistent with steatosis.6 Although liver biopsy remains the standard criterion for the diagnosis and determination of steatosis, grade of inflammation, and stage of fibrosis, its routine use in individuals with NAFLD remains controversial because it is invasive and carries a potential for complications and sampling errors.8 Today, with improvements in the diagnostic accuracy of magnetic resonance imaging, liver biopsy is being used more infrequently to aid accordingly with evaluation of atypical clinical situations.9,–11
Despite these diagnostic challenges, NAFLD is considered the most common liver disease worldwide, with a similar approximate 20% prevalence across both industrialized and developing countries.12 With rapidly increasing rates of obesity and type 2 diabetes mellitus (T2DM), the global prevalence of NAFLD continues to rise, and in the United States it closely parallels that of the obesity epidemic.13 The estimated annual incidence of NAFLD in prospectively followed adults is 3%–5%, and in the primary care setting, NAFLD accounts for at least one-third of cases of suspected chronic liver disease.12
Risk Factors and Etiology of NAFLD
Based on its etiology, NAFLD is subdivided into 2 categories, primary and secondary. Although primary NAFLD is commonly associated with the MetS components, the secondary type can result from hepatotoxic medications, chemotherapeutic agents, metabolic disorders, parenteral nutrition, and autoimmune, biliary, or infectious diseases.2,14 Although the pathophysiology of both types of NAFLD is of great interest to scientists and clinicians, in this article we focus solely on primary NAFLD.
Risk factors for the development of NAFLD include older age, male sex, obesity, obstructive sleep apnea (OSA), adverse dietary and lifestyle habits, as well as components of the MetS, such as insulin resistance (IR), T2DM, and dyslipidemia.15,16
NAFLD occurs in all age groups, with prevalence increasing with age, from 20% in individuals age <20 years to >40% in those age ≥60 years.17 It also has been described in the pediatric population with a prevalence of 2.6%, which increases to 80% in obese children.18 Studies have demonstrated that NAFLD may begin in utero, as higher rates of hepatic steatosis were observed in infants born to obese mothers with gestational diabetes compared with those born to otherwise healthy mothers.19,–21 Furthermore, the incidence rates of NASH and cirrhosis also increase with increasing age, especially in those age >50 years.12
Recent studies evaluating the role of sex in the etiology of NAFLD demonstrate that the disease is more common in younger and middle-aged men and declines after age 50–60 years.22 In contrast, NAFLD spares younger, premenopausal women, and its incidence rises sharply after age 50, reaching a peak at 60–69 years. The possibility of female hormones having a protective effect against NAFLD is supported by evidence suggesting that women on hormonal replacement therapy are significantly less likely to have NAFLD compared with those not receiving hormonal replacement therapy.23,24
Obesity, defined as a body mass index >30 kg/m2, is strongly associated with NAFLD worldwide.25 However, not every obese individual has NAFLD, as its reported prevalence in obese cohorts is between 50% and 90%.26,27 In fact, in the National Health and Nutrition Examination Survey III (NHANES III) study population, only 30% of obese men and 40% of obese women had NAFLD.28 Although the mechanism explaining the influence of obesity on NAFLD development and progression has not been completely elucidated, studies suggest that obesity results in IR, which in turn leads to NAFLD.29 A significant dose–response relationship has been demonstrated, whereby more severe obesity correlates with more advanced disease stages.30 In fact, the likelihood of developing NASH increases with the degree of obesity, and NASH has been reported in 15%–20% of morbidly obese individuals (body mass index >35 kg/m2).31,32
OSA, defined as either complete or partial airway obstruction caused by pharyngeal collapse during sleep, has been recently linked to IR, MetS, and CVD.33 OSA occurs in approximately 4% of the general population, although this incidence increases by up to 10-fold in obese individuals, and is associated with a higher prevalence of NAFLD.34 This association may be partially mediated by obesity and IR and also independently through altered gas exchange. The chronic intermittent hypoxia to which patients with OSA are subjected can increase levels of proinflammatory cytokines and cause endothelial dysfunction, oxidative stress, and overall metabolic dysregulation, resulting in IR, inflammation, fibrogenesis, and, ultimately, liver injury.33,35,36
A Western-type diet is considered an independent risk factor for the development of NAFLD. Both animal models and human studies demonstrate that diets high in red meat, refined grains, and sugar-rich soft drinks are associated with greater rates of MetS and subsequently NAFLD.34,37 A sedentary lifestyle is considered another significant risk factor for the development of NAFLD and NASH.34 In contrast, gradual weight reduction through proper diet, with or without exercise, can lead to decreases in serum liver enzymes, hepatic fatty infiltration, inflammation, and even fibrosis.38
The MetS—defined as the presence of increased waist circumference in addition to 2 of the following factors: increased blood pressure, increased TG level, elevated fasting plasma glucose level, or reduced high-density lipoprotein cholesterol—is common in patients with NAFLD.39 Because the rates of obesity and thus of MetS are increasing worldwide, it is anticipated that the rate of NAFLD will also continue to rise. In fact, NAFLD is currently considered a hallmark of MetS.40 Associations between NAFLD and CVD, chronic kidney disease, and T2DM are now well established.41,–43 Moreover, the magnitude of these disease states parallels the severity of NAFLD, with NASH (the most clinically relevant subset of NAFLD) playing an active role in the pathogenesis of MetS-associated CVD. In fact, NAFLD is considered a strong independent alarm for the presence of significant CVD.44,45
Pathogenesis of NAFLD
The pathogenesis of NAFLD is complex and still incompletely elucidated. The traditional model explaining progression to NASH is the two-hit hypothesis.46 During the first hit, TGs and free fatty acids (FFAs) accumulate in the liver parenchyma owing to the imbalance between their influx and synthesis and their export and β-oxidation processes. This lipid accumulation makes the liver more susceptible to injury.46 Recently, it has been demonstrated that FFAs, during their esterification and TG formation, can also directly injure liver cells and activate inflammatory pathways.47 Ultimately, the hepatocyte injury is caused by second hit processes, such as inflammation, oxidative stress, and mitochondrial dysfunction, as well as such substances as adipokines and gut-derived endotoxins.47 In addition, a third hit is caused by the liver’s inability to regenerate dead hepatocytes in the presence of oxidative stress, which in turn further exacerbates the liver damage.47
Both hyperinsulinemia and IR are key conditions in the development of NAFLD, mainly contributing to the first hit conditions.48 Under normal conditions, insulin is secreted in response to circulating glucose levels, and among its many functions it promotes FFA storage in the form of lipid droplets. In patients with NAFLD, IR results in increased lipolysis and thus high levels of circulating FFAs. Hyperinsulinemia develops to compensate for IR, which further enhances hepatic TG formation and accumulation, leading to steatosis.49
Obesity also increases the influx of FFAs to the liver and contributes to NAFLD.15 Increased abdominal obesity results in increased levels of proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin-6, and C-reactive protein, and decreased levels of anti-inflammatory adipokines and adiponectin. This imbalanced inflammatory environment further contributes to the development and progression of NAFLD50 (Figure 1).
Schematic of the two-hit hypothesis explaining development and progression of NAFLD. During the first hit, steatosis occurs due to increased levels of FFAs and TGs, influenced by dietary intake and the state of hyperinsulinemia/IR. The imbalanced inflammatory environment, together with the increased levels of oxidative stress and fibrogenesis, constitute the second hit processes leading to the development and progression of NAFLD. Figure 1 is available in color online at www.smr.jsexmed.org.
Endothelial Dysfunction in NAFLD and ED
Vascular endothelium not only lines the inside surfaces of blood vessels to provide a protective barrier, but also regulates many vascular-based physiological functions. Via the release and careful balance of various regulatory factors, it controls vascular tone, inflammation, platelet aggregation, and smooth muscle proliferation.51 Aberrant endothelial function may result from various triggers and has been implicated in different pathological processes.52
Atherosclerosis is one of the most common conditions caused by endothelial dysfunction. During its initial early phase, the bioavailability of endothelium-released vasodilators, mainly nitric oxide (NO), decreases, shifting the balance in favor of endothelial vasoconstrictors and initiating thickening of the intima and media and promoting early plaque formation. Once the progressive plaque buildup reaches approximately 40% of the arterial diameter, narrowing of the arterial lumen begins. At this point, the late phase of atherosclerosis begins, and the obstructive vascular changes result in symptomatic vascular disease. Penile erection is largely a vascular process, and vasculogenic ED results from either early changes in endothelium-mediated smooth muscle relaxation or late occlusion of the cavernosal arteries.53 Moreover, maintenance of erection is supported by endothelium-produced NO, and as NO availability decreases, further ED ensues.54
Recently it has been postulated that endothelial dysfunction may be one of the earliest factors associated with liver fat accumulation and subsequent liver damage.55 Liver sinusoidal endothelial cells act in the same way as other vascular endothelial cells and are crucial to anti-inflammatory and antifibrotic processes.56,57 It also has been demonstrated that impaired NO production is involved in promoting and worsening of the liver inflammatory state, resulting in NAFLD and its eventual progression to advanced liver disease (ie, cirrhosis).58 Recently reported human data demonstrate that patients with NAFLD have marked endothelial NO synthase (eNOS) dysfunction, and animal data demonstrate that eNOS deficiency exacerbates early stages of NAFLD.58,59 Because activation of eNOS occurs via the insulin signaling pathway, the IR widely seen in NAFLD, ED, and MetS ultimately may be one of the main factors in eNOS dysfunction.60 NAFLD has been identified as an independent risk factor for CVD, and thus it is very likely that the initial hepatic endothelial dysfunction has an underlying role in this association.61
Clinical Correlates of MetS and ED
ED, defined as the inability to attain and/or maintain an erection satisfactory for sexual intercourse, significantly affects a man’s overall well-being.62 The condition has been reported to affect 52% of men over the course of their adult lifespan in the United States and approximately 322 million men worldwide.63,64 The prevalence of ED increases with increasing age, and as men age, they develop comorbid metabolic conditions that may result from or further contribute to the development of erection problems.65 In some men, ED and MetS share CVD risk factors such as hypertension, dyslipidemia, physical inactivity, and visceral obesity.65,66 As discussed previously, these risk factors lead to inflammatory changes, which in turn negatively affect the structure and function of the penile endothelium and smooth muscle. Multiple clinical and epidemiologic studies support the association of MetS and ED and identify individual metabolic factors (eg, waist circumference) as predictors of more severe ED.67,–70
Because penile erection is mainly a vascular event, alterations in penile vasculature mirror those in the coronary vessels.53 Consequently, ED frequently coexists with CVD, reaching prevalence rates of up to 75%.71,72 The risk of ED depends on the clinical and anatomic severity of the CVD, with reported rates ranging from 22% in men with acute coronary syndrome (ACS) and single vessel occlusion to 55% in those with ACS and multivessel involvement and 65% in those with a chronic coronary condition.73
Prospective angiographic studies demonstrate that approximately 19% of men with ED suffer from subclinical “silent” CVD, and in those patients, CVD is preceded by ED by an average of 2–3 years.74 This epidemiologic phenomenon has been explained by the “artery size” hypothesis of Montorsi et al,75,76 which postulates that smaller penile arteries sustain obstruction earlier than the coronary arteries. Molecular-based studies have proposed alternative explanations for penile vascular dysfunction, suggesting increased permeability of endothelial cell–cell junctions in cavernosal tissue, along with dysfunction in NO/eNOS signaling and increased oxidative stress and expression of local vasoconstrictive mediators, as possible contributing factors.77 Regardless of the underlying etiology, ED is currently considered an independent risk factor for future fatal and nonfatal CVD events and all-cause mortality in patients of all ages with or without known CVD.78,79
The comorbidities of MetS are associated with the release of proatherogenic inflammatory factors, and this increased inflammatory response results in further endothelial dysfunction and subsequent CVD and ED. This pathogenic link among ED, CVD, and MetS is now well established. Because NAFLD is considered a hepatic manifestation of MetS, recent animal and human studies have been directed at evaluating the relationship between NAFLD and ED.40,80,81 These studies confirm that MetS-induced NASH plays an active role in the pathogenesis of ED, and that increased liver and plasma TNF-α levels have a detrimental effect on penile erectile mechanisms.80,81 Moreover, in men with ED and NAFLD, both IR and low serum testosterone (T) levels contribute to the development of ED, and the extent of liver disease corresponds to the severity of ED80,82 (Figure 2). Interestingly, in a series of men with severe ED, severe fibrosis and lipid accumulation were found in the corpora cavernosa at the time of penile prosthesis placement.83 Although the exact mechanism of the corporal lipid accumulation remains unknown at this time, it is plausible that this finding further corroborates a common pathogenic process for both ED and NAFLD.
Complex interrelationship of NAFLD, MetS, and male sexual dysfunction. Figure 2 is available in color online at www.smr.jsexmed.org.
T and Its Function
T, the most important and abundant androgen in blood, is synthesized mainly in a continuous fashion in the Leydig cells of the testes. Cholesterol, either originating from low-density lipoprotein or synthesized de novo from the acetyl-coenzyme A in Leydig cells, is the starting substrate for T synthesis. Only a very small amount of T remains stored in the testes, with the majority secreted into blood. The mechanism of T transport from the Leydig cells is incompletely understood. During transport, the majority of T is bound to albumin or sex hormone–binding globulin (SHBG), a substance produced by the hepatocytes. In normal men, only 2% of total T circulates as a free substance, 44% is bound to SHBG, and 54% is bound to albumin. The hepatocyte production of SHBG is regulated by the sex steroids, with androgens inhibiting production and estrogens stimulating production.
T is important in every phase of a man’s life, starting with differentiation of sexual organs during embryonal stages, extending through puberty when further development into manhood occurs, and ending in adulthood with its maintenance roles. T has a major role in the control of sexual function, modulating central arousal, ensuring structural integrity of the corpus cavernosum, and influencing psychological symptoms. On a molecular level, it contributes to endothelial and smooth muscle homeostasis via the reduction of proinflammatory markers in both penile and cardiac vascular beds. Low T levels result in reduction of nocturnal and morning sex-induced erections, decreased ejaculate volume, delayed onset of ejaculation, and, ultimately, infertility.
Hypogonadism and MetS
Adult-onset hypogonadism (AOH) is a clinical and biochemical syndrome encompassing biochemically assayed T deficiency, associated signs and symptoms (ie, reduced energy and stamina, depressed mood, increased irritability, difficulty concentrating, decreased libido, ED, diminished penile sensation, difficulty attaining orgasm, and ejaculatory problems), and low or normal gonadotropin levels. AOH is a distinct entity from classical primary (testicular failure) or secondary (hypothalamic or pituitary failure) hypogonadism and occurs mainly in middle-aged and older men.84 Studies demonstrate a prevalence of approximately 12%, which may increase with age.85,86 T deficiency has proinflammatory and proapoptotic effects on endothelial cells, and as a result has been demonstrated to contribute to increased risks of MetS, T2DM, and CVD independent of age and obesity.87,88 Numerous studies have demonstrated that men with MetS have lower levels of SHBG and total and free T compared with healthy men.89,–91 Moreover, it has been consistently demonstrated that circulating levels of T are inversely related to MetS, regardless of race or ethnicity.92 Consequently, men with MetS have a 2-fold greater risk of developing hypogonadism, and men with higher total T levels are at lower risk.93,94 Studies evaluating the MetS components individually have identified waist circumference as the strongest correlative factor for low T levels, even in nondiabetic men.89,95
Although the associations between T deficiency and MetS and T2DM are well established, the exact pathophysiological mechanisms remain incompletely understood. Obesity-related decreases in SHBG and increases in aromatase activity, potentiated by IR, provide some insight. Increased insulin levels resulting from IR suppress hepatic production of SHBG, which in turn results in decreased delivery of T to peripheral tissues and increased free T. Free T provides a negative feedback onto the hypothalamic-pituitary-gonadal axis, ultimately resulting in decreased release of gonadotropins. Increasing IR is also associated with a decrease in overall Leydig cell T secretion.96 Moreover, excess T levels are converted locally by aromatase into estradiol (E2), which provides an additional negative feedback onto the already affected hypothalamic-pituitary-gonadal axis.97 In addition, the increase in adipose tissue is associated with increased aromatase activity, further converting T to E2, which leads to diminished T levels and preferential deposition of visceral fat.
The low T levels resulting from the foregoing molecular processes can further worsen an individual’s metabolic profile, increase abdominal fat, and even exacerbate obesity-associated ED.98 Recent clinical and animal data suggest that T also may confer some of its beneficial effects on hepatic lipid metabolism via conversion to E2 and subsequent activation of estrogen receptor α.99,100 The protective role of E2 in NAFLD has not yet been fully elucidated, however.
Hypogonadism and NAFLD: Possible Etiologies
Numerous studies have demonstrated that low serum T levels in men are associated with an increased risk of abdominal obesity, metabolic syndrome, and IR.101,–103 Based on this observation, a similar correlation between hepatic steatosis and serum T can be expected, but this has not yet been fully investigated. An analysis of NHANES III data revealed an association between low T levels and an increased risk of NAFLD in men and postmenopausal women, an association that persisted even after adjustments for obesity and other metabolic risk factors.104 In addition, an inverse association between serum T level and NAFLD was reported in a retrospective observational cross-sectional study of healthy Korean men.105
A proposed pathological mechanism for the correlation of low T and NAFLD is the inverse relationship between total T level and IR in men. T is linked to direct insulin regulation in men by interfering with insulin signaling in peripheral tissues. Depending on its biochemical levels, T can either result in improved insulin sensitivity or contribute to IR.106 Hyperinsulinemia results in increased de novo hepatic lipogenesis, increased adipose tissue lipolysis, increased efflux of FFAs to the liver, and the development of steatosis with progression to NAFLD.107
Chronic low-grade inflammation may be another possible link between T and NAFLD. The inflammatory state resulting from increased secretion of hepatic inflammatory cytokines such as TNF-α and interleukin-6 may directly affect the pituitary gland, reducing luteinizing hormone secretion, which suppresses Leydig cell secretion of T.108 The subsequent decrease in total T level further propagates this complex disease state.
Several recent studies have found low levels of SHBG, a protein produced by the liver that transports T and regulates its bioavailability at the tissue level, in obese individuals, men with T2DM, and men with NAFLD109,110 (Figure 3). SHBG also influences glucose homeostasis and lipid metabolism and may have a crucial role in the development of NAFLD itself, as well as IR in patients with NAFLD.111,112 In contrast, increased plasma SHBG levels have been strongly associated with decreased liver fat as a result of lifestyle intervention, suggesting that increased SHBG levels may reduce lipogenesis and hepatic lipid accumulation.111,113
Decreased hepatic SHBG synthesis in NAFLD results in hypogonadism by altered T feedback of the hypothalamic-pituitary-gonadal axis (HPGA). 1, IR suppresses hepatic production of SHBG. 2, Decreased SHBG results in an increase of free T, which provides negative feedback to the HPGA. 3, HPGA suppression decreases the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). 4, E2, converted from free T, provides negative feedback to the HPGA. 5, Chronic inflammatory cytokines directly suppress LH release. 6, Production of T is decreased, resulting in hypogonadism. Figure 3 is available in color online at www.smr.jsexmed.org.
Male Health Comorbidities and Infertility
Fertility problems are related to a complex interplay of genetic, environmental, lifestyle, and hormonal factors, and data indicate that aberrant semen parameters can be indicative of a man’s overall health.114,115 The reverse is also well known; many men with comorbid conditions are infertile, as their poor health and necessary medical treatments can affect semen quality. Obesity, T2DM, and hypertension have been demonstrated to adversely affect semen parameters, especially sperm quality and overall ejaculate volume.116,117 To explore this issue further, Eisenberg et al118 stratified a cohort of 9,387 men by the Charlson Comorbidity Index (CCI) and evaluated their scores against measured semen parameters. The severity of comorbidity was inversely correlated with semen quality, as men with higher CCI scores (>1) had lower semen volume, sperm concentration, sperm motility, total sperm count, and morphology scores. Not surprisingly, significantly higher rates of semen abnormalities were seen in men with genitourinary, endocrine, nutritional, or metabolic disorders had. In addition, men with CVD (including hypertension, peripheral vascular disease, cerebrovascular disease, and nonischemic heart disease) had higher rates of semen abnormalities.118 All these findings further link components of MetS (T2DM, obesity, and hyperlipidemia) to male infertility. Moreover, NAFLD is strongly associated with comorbid metabolic disorders, endocrine disorders, and CVD, and recent studies suggest that it also affects semen quality.119
Hepatocyte and Sertoli Cell Aquaporins
A highly plausible mechanism linking NAFLD and infertility involves aquaporins (AQPs). These ubiquitous channel proteins permeate water, small solutes, and certain gases across biological membranes.120 The 13 AQP homologs in mammals (AQP0–12) have various biophysiological functions. AQP3 and AQP7 are expressed in adipocytes, and AQP9 is expressed mainly in hepatocytes. AQP9 facilitates the uptake of glycerol into hepatocytes for its further processing through gluconeogenesis or TG synthesis.121 In previous studies in a mouse model and in human subjects with obesity, IR and NAFLD were associated with diminished AQP9 activity and hepatocyte glycerol permeability.122,123 Based on these observations, a molecular model involving AQPs in the pathogenesis of NAFLD has been proposed. In healthy individuals, glycerol exported via AQP3 and AQP7 from adipocytes is taken up by AQP9 into hepatocytes and used for gluconeogenesis.
During initial phases of steatosis, in the setting of obesity-associated IR, adipocyte AQP3 and AQP7 are up-regulated and drive increased glycerol output. Initially, AQP9 levels also increase to accommodate an increased glycerol load. As excess fat accumulates, AQP9 levels ultimately decrease to counteract liver glycerol permeability and, ultimately, protect the liver from further steatosis and hyperglycemia.121
AQP9, along with AQP0, AQP4, and AQP8, is also expressed in Sertoli cells, Leydig cells, spermatocytes, and the epididymis. Its permeability not only to water, but also to urea, glycerol, and monocarboxylic (lactic and acidic) acids suggests a role in testicular metabolism. Because increased testicular glycerol levels may compromise spermatogenesis and disrupt the blood-testis barrier, AQP9 may play a crucial role in spermatogenesis, especially in men with obesity, IR, or T2DM124 (Figure 4). It is further speculated that AQPs, when dysregulated by different disease states, may contribute to male fertility problems. With improved understanding of AQP function and dysfunction, it is possible that exciting new fertility and metabolic diagnostic and therapeutic advancements will be available in the near future.
Role of aquaporin homologues in hepatocyte gluconeogenesis and Sertoli cell glycerol transport. Glycerol exported via AQP3 and AQP7 from adipocytes is taken up by AQP9 into hepatocytes and used for gluconeogenesis. AQP9, also expressed in Sertoli cells, leads to increased testicular glycerol levels, which in turn compromises spermatogenesis, especially in men with obesity, IR, or MetS. Figure 4 is available in color online at www.smr.jsexmed.org.
NAFLD and Impaired Reproductive Function
Whether NAFLD impairs male reproductive function is unclear; however, it is well established that serum T is essential for proper testis development and germ cell differentiation and is a prerequisite for normal spermatogenesis.125,126 Clinical studies indicate that men with NAFLD have significantly lower levels of serum T and SHBG compared with healthy individuals.105,109 Moreover, in a multivariate analysis, Li et al119 showed that altered sperm parameters are significantly associated with NAFLD; sperm concentration, sperm count, and total sperm motility were significantly decreased, although no significant differences in semen volume and morphology were found. These observations in humans corroborate previous experimental findings in animals and add to our overall knowledge of the potential effects of NAFLD on reproductive function. An earlier study evaluating reproductive function of male rats with NAFLD demonstrated decreased serum and testicular T levels and decreased expression of steroidogenic acute regulatory (StAR) protein (responsible for the transport of cholesterol into mitochondria and a crucial step in T synthesis) and overall number of Leydig cells in testes, along with reduced weight of reproductive organs and sperm quality.127
The mechanisms linking NAFLD to sperm abnormalities are most likely the same ones responsible for low T and SHBG, as discussed above. It is also hypothesized that the sperm quality may be directly affected by fat redistribution in the liver and increased systemic levels of inflammation. Increased amounts of adipose tissue in the groin and scrotal areas may increase local testicular temperature to a level that further affects sperm quality.
Future directions
Based on this review of the recent literature, MetS, NAFLD, and sexual and reproductive disorders share common pathophysiological mechanisms. As further insight is gained into the complex interplay of these molecular pathways, better diagnostic and therapeutic options for ED, hypogonadism, and infertility can be anticipated in the near future. Given the lack of noninvasive screening tests for NAFLD, perhaps SHBG could serve that function. Because SHBG is uniquely synthesized by hepatocytes and decreased levels are related to IR and NAFLD, why not use it as a biomarker or a potential therapeutic target?
Recently, T itself has been found to influence functions of microRNA in the mouse liver and to elicit effects on hormone-sensitive lipase in the adipose tissue and heart of male rats.128,–130 Although these animal findings do not have clearly established molecular mechanisms, and their human correlates remain unknown at this time, T possibly regulates the activity of human microRNAs and hepatic lipase as well. This possibility may have significant therapeutic implications. Decreased endogenous T synthesis in Leydig cells, resulting from decreased levels of StAR protein, potentially can be up-regulated with new formulations. Given that standard T replacement therapy further impedes endogenous T production and thus fertility, perhaps novel treatments focusing on the cholesterol conversion into T will become new treatment options. As discussed in previous sections, AQPs (especially AQP9) present in hepatocytes and Sertoli cells are responsible for glycogen transport in those cells. These proteins represent another promising mechanism linking NAFLD to infertility. If a common link can be proven, they may become new targets for infertility therapy.
Conclusion
MetS, NAFLD, and andrologic conditions such as ED, hypogonadism, and infertility share common cardiometabolic risk factors and are closely related to one another via a complex interplay of molecular and physiological processes. Sexual and reproductive conditions are prevalent among men, and their presence often points to the presence of systemic disease. The underlying chronic inflammatory state and endothelial dysfunction of MetS link sexual and reproductive difficulties to this condition and its components, further characterizing cardiovascular health in men. Sexual health is considered a cornerstone of a man’s overall health, and evaluation and treatment of sexual complaints provides an important gateway into the identification and treatment of other important medical conditions, such as NAFLD, obesity, T2DM, NAFLD, hypertension, and hyperlipidemia, to improve overall health status.131 Cardiac, endocrine, and perhaps hepatic assessment, followed by aggressive risk factor modification and treatment of underlying metabolic risk factors, should be offered to every patient presenting with ED, hypogonadism, or infertility.
Funding
None.
References
Author notes
Conflicts of interest: The authors report no conflicts of interest.
