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doi:10.1111/jgh.12695

REVIEW

Testosterone in men with advanced liver disease: Abnormalities and implications Marie Sinclair,*,‡ Mathis Grossmann,†,‡ Paul J Gow*,‡ and Peter W Angus*,‡ *Liver Transplant Unit, †Endocrine Unit, The Austin Hospital, Heidelberg and ‡Department of Medicine, Austin Health, The University of Melbourne, Melbourne, Victoria, Australia

Key words advanced liver disease, cirrhosis, sarcopenia, testosterone. Accepted for publication 3 July 2014. Correspondence Dr Marie Sinclair, Liver Transplant Unit, The Austin Hospital, 145 Studley Road, Melbourne, Vic. 3084, Australia. Email: [email protected]

Abstract Serum testosterone is reduced in up to 90% of men with cirrhosis, with levels falling as liver disease advances. Testosterone is an important anabolic hormone, with effects on muscle, bone, and hematopoiesis. Many of the features of advanced liver disease are similar to those seen in hypogonadal men, including sarcopenia, osteoporosis, gynecomastia, and low libido. However, the relative contribution of testosterone deficiency to the symptomatology of advanced liver disease has not been well established. More recently, it has been demonstrated that low testosterone in men with cirrhosis is associated with increased mortality, independent of the classically recognized prognostic factors, such as the Model for End-Stage Liver Disease score. Only several small clinical trials have examined the role of testosterone therapy in men with cirrhosis, none of which have resolved the issue of whether or not testosterone is beneficial. However, in men with organic hypogonadism due to structural hypothalamic–pituitary–testicular axis disease, testosterone therapy has been shown to improve muscle mass and bone mineral density, increase hemoglobin, and reduce insulin resistance. Despite initial concerns linking testosterone with hepatocellular carcinoma, more recent data suggest that this risk has been overstated. There is, therefore, now a strong rationale to assess the efficacy and safety of testosterone therapy in cirrhosis in well-designed randomized controlled trials.

Introduction Testosterone (T) levels are generally low in men with advanced liver disease and progressively fall with increasing severity of liver disease.1 Many clinical sequelae of advanced liver disease, such as anemia, sarcopenia, bone disease, and gynecomastia are also seen in hypogonadism. Therefore, low T levels may contribute to at least some of these manifestations. In addition, T deficiency has recently been identified as an independent prognostic marker in cirrhosis.2 Few prospective studies have examined the potential health benefits of T treatment in this condition. In this review, we particularly focus on observational and mechanistic studies assessing the possible adverse health effects of reduced circulatory androgens in men with cirrhosis, discuss implications for future trials of T replacement therapy, and provide directions for future research. The material discussed is based on peer-reviewed journals identified by searching the PubMed database from 1960 to 2013, using the terms “testosterone,” “androgen,” “sex hormone,” “cirrhosis,” and “chronic liver disease.” Overview of androgen function. Androgens are essential for establishing and maintaining male sexual characteristics. 244

They also have anabolic actions on nonreproductive tissues, including muscle and bone. The actions of T are summarized in Figure 1. T is the main male androgen and is secreted from testicular Leydig cells in response to pituitary luteinizing hormone (LH), which is in turn stimulated by pulsatile secretion of hypothalamic gonadotropin-releasing hormone (GnRH). T suppresses LH and GnRH in a classical endocrine feedback loop. This feedback loop is known as the hypothalamic–pituitary–testicular (HPT) axis, and is represented in Figure 2. Adrenal androgens, such as dehydroepiandrosterone, also exert androgenic actions following conversion to T but contribute little to total androgenic action in men.3 T is both a hormone, directly regulating transcription via the androgen receptor (AR), as well as a pro-hormone. T is aromatized to estradiol (E2), a ligand for E2 receptors alpha and beta. Some important biological actions of T, such as effects on bone, fat, and brain, may be dependent on this aromatization.3 In the bloodstream, T is highly protein-bound, with only 2% of the hormone circulating as free T. Sex hormone binding globulin (SHBG) is produced in the liver and binds approximately 40% of T with extremely high affinity. Albumin binds T with lower affinity and carries approximately 50%. For clinical purposes, measurement of total T by immunoassay on a morning blood sample

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Brain libido, mood Skin: body hair growth, male pattern balding, sebum production

Bone: bone mineral density

Metabolism: Increased lipolysis, reduction of insulin resistance

Male sexual organs: penile growth, spermatogenesis, prostate growth and function

Bone marrow: stimulation of red blood cell production, possible suppression of immune system

Figure 1

Muscle: increase in strength and volume

Effect of testosterone on target organs.

Hypothalamus H

GnRH + Anterior pituitary P



LH + – Testes T

Testosterone Figure 2 Hypothalamic–pituitary–testicular axis. GnRH, gonadotropinreleasing hormone; LH, luteinizing hormone.

is the mainstay for biochemical diagnosis of androgen deficiency.3 Free T is calculated using total T and SHBG according to Vermeulen’s or other formula by mass-action equations.4 The reference method of determining free T by equilibrium dialysis is restricted to research settings, but calculated free T is considered a

reasonable approximation. Free T is a more accurate measure of androgen status than total T in conditions of altered SHBG.5 SHBG production is altered in chronic liver disease; however, the accuracy and clinical implications of free T calculations specifically in this setting have not been fully elucidated.4 Effects on muscle and bone. Clinical trials of T have demonstrated dose-dependent increases in muscle mass extending well into the supra-physiological range.6 Therefore, clinically significant gains in muscle can be observed in both hypogonadal and eugonadal men. This gain is due to hypertrophy of both type 1 (slow twitch) and type 2 (fast twitch) muscle fibers. At the cellular level, T has effects on cellular differentiation and proliferation of myocytes, and also regulates muscle protein turnover. T thereby increases satellite cell replication and activation and the number of myonuclei.7 Although bone mineral density (BMD) is closely linked to sex hormone profile, many observational studies suggest that circulating E2 is more important than T.8 However, ARs have been identified in osteoblasts at the site of bone formation, and ARs in osteoclasts have been shown to inhibit bone resorption in rat models.9 It has been established that replacing T in hypogonadal men leads to increased BMD due to increased bone formation, although this may be in part due to aromatization to E2.8,10 Unlike the dose-dependent relationship observed with muscle mass, the positive relationship between T and BMD is only apparent in men with hypogonadism.11 Androgens, fat mass, and glucose metabolism. Androgens also play a role in the regulation of fat mass. Activation of ARs in adipocyte precursors blocks adipocyte differentiation, decreases lipid storage, and increases lipolysis.12 Randomized controlled trials have shown that T treatment leads to modest reductions in fat mass.13 While epidemiological studies have consistently associated low T with an increased risk of diabetes, the effects of T treatment on glucose metabolism are less clear.14 Some data suggest that it can reduce insulin resistance, improve glycemic control and lipid profile, and reduce visceral adiposity.13,15 There is as yet little research examining the effect of T therapy on the associated condition of nonalcoholic fatty liver disease (NAFLD); however, some promising results have been reported.15 Hematopoiesis and immune function. T increases the hematocrit by stimulating erythropoiesis, and polycythemia is the most common dose-limiting adverse effect of T treatment, with the hematocrit rising in a dose-dependent fashion.16 T does not appear to affect erythropoietin production or soluble transferrin receptor levels, but there are possible direct effects on bone marrow, including increasing the number of burst-forming units and erythropoietin-responsive cells.17 More recent data suggest that T-mediated suppression of the master iron-regulatory-peptide, hepcidin, also plays a major role.18 There is considerable evidence that T has a suppressive effect on both the innate and adaptive immune system. T has been shown to reduce macrophage activation, lymphocyte numbers, and cytokine levels, including interleukin-2 (IL-2).19,20 T therapy has also been shown to have modest effects on disease activity in autoimmune conditions, such as multiple sclerosis and rheumatoid arthritis.20 In

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contrast to this, low T pre-liver transplant has recently been linked with a reduced risk of post-transplant rejection.21 This, however, may simply reflect the severity of systemic illness and associated immunosuppression in patients with liver failure. Sequelae of testosterone deficiency. There are no universally agreed reference ranges for total T as different assays quote different ranges. Using gold standard mass spectrometry technology, an Australian study using a reference panel of 124 healthy, reproductively normal young men reported a reference range of 10–27.6 nmol/L.22 In a reference sample of 456 young men from the Framingham Heart Study cohort, also using mass spectrometry, reference ranges were comparable.23 While most studies suggest that testosterone levels gradually decrease during aging, recent evidence suggests that this decrease may be due to accumulation of age-associated comorbidities rather than aging itself. Deficiency of androgens can result in nonspecific symptoms that have overlapping features with other conditions, which also makes diagnosis of hypogonadism difficult. Common features of hypogonadism include low libido and impotence, as well as weakness, fatigue, and depression. Clinical, biochemical, and radiological findings seen in hypogonadism include feminization of body shape, gynecomastia, loss of body hair, testicular atrophy, muscle wasting, abdominal obesity, insulin resistance, diabetes, anemia, dyslipidemia, and osteoporosis.24,25 There is as yet little data available on the impact of hypogonadism on immune function. In men with established hypogonadism, each of these clinical sequelae can be associated with significant morbidity. A recent meta-analysis of multiple observational studies also demonstrated a link between low serum T and increased all-cause mortality.26 Being observational, this meta-analysis does not establish causality. Sex hormone changes in cirrhosis. Low serum T has been reported in up to 90% of men with cirrhosis.2,27 The extent of androgen deficiency increases in parallel with worsening severity of liver failure, as classified by the Child Pugh score.28 Low T is thought to contribute to many of the clinical features of advanced liver disease in men, including altered body hair distribution, gynecomastia, testicular atrophy, muscle wasting, impaired sexual function, anemia, and fatigue.29 There are most likely multiple factors that contribute to T deficiency in cirrhosis, and all levels of the HPT axis can be affected. In some cases of alcoholic cirrhosis, there is direct testicular injury from ethanol, and LH is elevated, consistent with primary hypogonadism.30 More commonly, cirrhosis is associated with central hypogonadism, where pituitary production of LH is either inappropriately normal, or even suppressed, despite low levels of circulating T. In end-stage cirrhosis, LH is almost universal low.28 Severe systemic disease of any etiology, including liver failure, can downregulate GnRH secretion by the hypothalamus and lead to secondary testicular failure. This is thought to be at least partly due to direct effects of elevated inflammatory cytokines, such as IL-1, IL-6, and tumor necrosis factor alpha.31 The functional nature of the HPT axis suppression in cirrhosis is supported by the finding that T and SHBG levels commonly return to normal following liver transplant. However, HPT axis suppres246

sion may persist in the early post-transplant period, possibly due to the well-described suppressive effects of high dose glucocorticoids on the gonadal axis.32 In approximately 20% of male liver transplant recipients, T levels are still below the normal range 12 months post-transplant,1,27 and therefore postoperative monitoring of androgen status should be considered in all patients with low pretransplant T levels, especially if clinical features of androgen deficiency do not resolve. SHBG levels are commonly elevated in cirrhosis, and this appears to be due to increased hepatic production.1,28 This is counterintuitive given that most hepatic protein synthesis is reduced in cirrhosis. One hypothesis is that SHBG elevation is secondary to reduced T production itself, since androgens usually suppress SHBG production. Estrogens act to stimulate SHGB production, and this may also be an important driver in those cirrhotics whose serum estrogen is elevated.33 The result of increased SHBG is increased high-affinity binding of an already reduced serum T, leading to an even more marked reduction in free T, as demonstrated in Figure 3. Indeed, due to SHBG elevation, men with cirrhosis may be clinically hypogonadal despite having a total T within the normal male reference range. The relationships between SHBG level and severity of liver disease are complex. SHBG appears to be elevated until clinical decompensation occurs, following which levels return to the normal range.34 This may be because in end-stage liver disease, synthetic capacity is so severely reduced that SHBG levels are low despite the strong hormonal stimuli to increase its secretion. Estrogen levels are frequently elevated in men with cirrhosis.28,35 This may reflect increased peripheral aromatization of T to E2, the cause of which is unclear. Alternatively, it may be that hepatic metabolism of estrogens is impaired or bypassed via portosystemic shunting.36 However some data suggest the converse, that estrogen levels are comparable in men with cirrhosis and normal controls.37 Regardless, SHBG binds T more strongly than it binds E2; hence, the free estrogen-to-androgen ratio is generally elevated in cirrhosis independent of any change in total estrogen. This ratio is thought to be important for the development of features of feminization, such as gynecomastia.38 Generally, the etiology of cirrhosis does not strongly influence the severity of sex hormone imbalance. The only factor consistently associated with differences in sex hormone levels is Child Pugh score.28,30,35 However, it should be noted that some studies have reported lower T levels in alcoholic cirrhosis compared with other etiologies. This may reflect direct gonadotoxicity in combination with an upregulation of SHBG production by alcohol that can further reduce free T levels.39 Spironolactone, an aldosterone antagonist that is widely used to reduce sodium and fluid retention in cirrhosis, contributes to the development of gynecomastia by acting as a competitive antagonist at the AR. In addition, T levels have been shown to be lower and estrogen levels higher in men on spironolactone, which leads to an increased estrogen–androgen ratio and further contributes to feminization.40

Significance of low testosterone in cirrhosis. Common clinical features of cirrhosis include feminization of body shape and gynecomastia, which is primarily due to an

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Hypothalamus GnRH: Normal, ↓ or ↑ ER

Target Organ

+ Anterior pituitary

AR

E2: Normal or ↑

LH: Normal, ↓ or ↑ Aromatase

5-DHT: ↓

+ Free testosterone (2%): ↓ Testes Testosterone: ↓

Albumin-bound (low affinity) testosterone (44%)

SHGB-bound (high affinity) testosterone (54%): ↑ Figure 3 Abnormal sex hormone regulation in chronic liver disease. Changes that can be seen in chronic liver disease as compared with controls are marked as either increased (↑), decreased (↓), or normal. 5-DHT, 5-dihydrotestosterone; AR, androgen receptor; GnRH, gonadotropin-releasing hormone; E2, estradiol; ER, estrogen receptor; LH, luteinizing hormone; SHBG, sex hormone binding globulin.

increase in the estrogen-to-androgen ratio. Reduced libido is also frequent and may be due to multiple factors, but it is likely that T is a significant contributor.29 A recent observational study of 171 male patients referred for liver transplant found a significant association between reduced T levels and mortality.2 Reductions in both free and total T were significant predictors of death, independent of both the Model for End-stage Liver Disease (MELD) score and serum sodium. Because this study was observational, no inferences regarding causality can be made, but it remains possible that low T contributes to increased mortality. Muscle wasting is a frequent complication of cirrhosis, and an independent association between sarcopenia and mortality in patients with cirrhosis has recently been identified.41 In one study, this mortality increase was attributed to an increase in infectionrelated deaths.42 Thus, one possible explanation for the link between low T levels and mortality2 is that low T directly contributes to muscle wasting, frailty, and subsequent risk of infectionrelated death. The prevalence of metabolic bone disease is over 60% in patients referred for liver transplant.43 Impaired new bone formation is the main defect. Contributing factors include impaired osteoblast activity due to alcohol abuse and iron overload, impaired calcium absorption due to hyperbilirubinemia and low vitamin D, and low levels of bone trophic factors.44 Despite the known effects of T on bone, there has been little research examining the relationship between androgen status and bone density in

male cirrhotics. T deficiency may significantly contribute, and thus T therapy may be beneficial. Up to 80% of patients with cirrhosis have insulin resistance, which is thought to primarily result from impaired peripheral uptake of glucose. Hepatitis C virus (HCV) infection can contribute by affecting insulin signaling pathways, and insulin resistance is widespread in NAFLD.45 It is now recognized that insulin resistance directly contributes to the progression of liver fibrosis and hepatocellular carcinoma (HCC) risk, and the evidence for this is strongest in patients with HCV and NAFLD.46,47 Given that T deficiency is associated with increased insulin resistance,25 low T may contribute to this phenomenon in men with cirrhosis. Hypogonadism may also contribute to other clinical features and complications of cirrhosis, such as anemia, fatigue, and depression. While it appears plausible that low serum T in men with cirrhosis plays a role in some or all of these sequelae, this is yet to be demonstrated in prospective clinical trials.

Studies of testosterone therapy in cirrhosis. A number of studies have examined the effects of T therapy in men with cirrhosis. Limitations of these include small sample size, poor study design, heterogeneous patient groups, and suboptimal drug delivery. Most trials were conducted many years ago, and despite promising early results the possible health benefits of T in men with cirrhosis have been little explored in recent years. While no trial revealed an increase in significant adverse events from T

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Table 1

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Summary of prior trials of testosterone therapy in cirrhosis Patients

Wells49 Fenster52 Puliyel et al.50 Gluud et al.48 Yurci et al.53

97 M 32 M 14 M 17 W 221 M 12 M

Cirrhosis etiology

Low T at entry

Drug

Duration

Significant findings

Any

No

IM T versus prednisolone versus placebo

1–24 months

Alcohol Any

No No

IM T versus methenolone versus placebo IM T versus placebo

1 month 1 month

Alcohol Any

No yes

Oral T versus placebo Topical T gel No placebo arm

30 months 6 months

↓ Mortality ↑ Albumin Nil ↑ Albumin ↓ Edema ↓ Gynecomastia ↑ Muscle strength ↓ Gynecomastia

IM, intramuscular; M, men; T, testosterone; W, women.

therapy in cirrhosis, even in those with advanced disease, larger trials are needed to conclusively demonstrate safety.48–51 Table 1 provides a summary of existing trials of T therapy in cirrhosis. In one of the earliest and largest trials, 97 male patients with biopsy-proven cirrhosis of any etiology were identified on hospital admission and randomized to receive either prednisolone, intramuscular T, or placebo for at least 4 weeks of duration, extending up to 86 weeks in some patients.49 Patients were included independent of baseline T levels. Patients in both the T and prednisolone arm had an increase in serum albumin compared with placebo. Mortality was reduced from 55% in the placebo arm to 31% in those on T and 26% in the prednisolone group. The findings of this study should be interpreted with caution since treatment duration, patient attendance, and follow-up were highly variable, and treatment allocation was not randomized. A smaller study enrolled 21 patients with biopsy-proven cirrhosis of any etiology, including one-third female participants.50 Twelve patients received intramuscular T and nine controls received standard of care. After 4 weeks, albumin and energy levels improved and edema decreased in the active arm. A Cochrane review in 2006 examined T therapy in men with alcoholic liver disease and identified five randomized controlled trials that met inclusion criteria, which included a total of 499 patients. No significant impact on liver histology or mortality was identified; however, a significant reduction in gynecomastia was observed. There was no increase in adverse effects in men on T. The interpretation of this review is limited by the fact that only two trials were in cirrhotics. Furthermore, low T was not an entry requirement, which may have reduced the ability of these studies to identify benefits of T treatment.51 The largest published study to date on T therapy in men with cirrhosis comes from the Copenhagen Study Group for Liver Diseases.48 It included 221 men with alcoholic cirrhosis, of whom 134 were randomized to receive oral T three times per day, and 87 placebo, for a median duration of 30 months. Both T and E2 levels rose on active treatment, as did the T-to-E2 ratio. There was a significant reduction in gynecomastia observed from 6 months. No difference in liver biochemistry, histology, or mortality was seen. It is unclear how many patients had low T at recruitment, but deficiency was not required. Importantly, 52% of these patients had active alcoholic hepatitis at recruitment, and many ceased alcohol intake during the trial, which may have confounded the results. 248

A second smaller trial conducted in alcoholic cirrhotics included 32 male subjects. Again, T deficiency was not a requirement for study entry. Nine men received intramuscular T, 12 men received the synthetic anabolic steroid methenolone, and 11 received placebo. The short treatment duration of only 1 month and small patient numbers may explain why no major differences were demonstrated among the three groups. However, treatment was well tolerated with no increase in adverse events.52 The most recent study of T therapy in cirrhosis and the only one to restrict enrollment to patients with documented T deficiency was published in 2011.53 Twelve men with cirrhosis of various etiologies and low free T were recruited for this uncontrolled unblinded study. T gel was administered to all subjects for 6 months. At trial completion, muscle strength as assessed by hydraulic hand dynamometer had significantly improved and gynecomastia was reduced. While BMD did not change, this study was not powered for this outcome. Again, there were no significant adverse events. Thus, reduction in gynecomastia appears to be the only consistent finding across existing studies of T therapy in liver disease. Reassuringly, the safety profile of T in cirrhosis is excellent, with no study reporting a significant increase in adverse events compared with placebo. Given the inconclusive findings and design flaws of previous trials, there is clearly a need for well designed, randomized, placebo-controlled studies. Such studies should focus on cirrhotic men with unequivocally reduced T who have clinical symptoms and signs of androgen deficiency. Such men would be most likely to benefit given that recent studies have shown that both sarcopenia and low T levels are independent predictors of mortality.2,42

Testosterone and HCC. Many clinicians are hesitant to consider T therapy in cirrhosis because of concerns about the possible role of T in hepatocarcinogenesis. Epidemiological studies have demonstrated that HCC is more common in men than women, and patient survival from unresectable HCC is worse in men,54 although some of this difference could be due to higher rates of cirrhosis and alcohol co-ingestion. Observational studies investigating the link between serum T and HCC incidence have produced conflicting findings. A large cohort study in Taiwan identified an increased rate of HCC development with higher T levels; however, it is important to note that this included mainly noncirrhotic men, the majority of whom had

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T levels in the normal range.55 A small retrospective study of Japanese men with cirrhosis also suggested a possible link between HCC and higher T levels.56 In contrast, in largely cirrhotic Caucasian patients, those with low T had higher rates of HCC than those with normal levels.57 This perhaps reflects increased severity of liver disease in cirrhotic patients with HCC. Importantly, more recent prospective observational and case control studies have identified no link between T levels and HCC.58 One proposed mechanism by which T could affect hepatocarcinogenesis is via ARs that are expressed in both normal liver and in HCC tissue. AR population density can be increased in tumor tissue as compared with surrounding liver, and micro-RNA dysregulation in HCC has been shown to be influenced by AR pathways.59 However, over one third of HCCs contain no ARs at all,60 and despite AR presence in some HCC there is abnormal T metabolism within tumor cells; this results in less active androgen metabolites and minimal hormonal binding to ARs in tumor cells.61 Upregulation of AR expression in some HCC may, therefore, be a secondary response to low circulating T as opposed to being involved in tumorigenesis. In addition, gender differences have been discovered in IL-6 production in mice with HCC, suggesting that estrogen inhibition of IL-6 is responsible for reduced liver cancer risk in women.62 Such theories are in early stages of investigation but provide an alternative scientific explanation for the gender disparity in HCC. There are reports of HCC developing in men on androgen therapy; however, these are exclusively confined to superseded formulations. In 1972, four cases of HCC were reported in patients on oral oxymetholone, a 17 alpha-alkylated androgen.63 Further cases were reported subsequently, all related to similar oral preparations of T.64 This 17 alpha-alkylation uniquely facilitates hepatotoxicity via its resistance to first-pass hepatic metabolism, and 17-alkylated androgens are no longer approved by drug regulatory authorities. No HCCs have been reported in association with currently used transdermal, subcutaneous, or intramuscular T formulations. Indeed, because of the virtual absence of hepatotoxicity of currently available T preparations, endocrine guidelines consider monitoring of liver function unnecessary.65 The specific question of T-responsiveness of HCC has been addressed in trials of anti-androgen therapies, which have failed to demonstrate any benefit. The largest trial of 244 patients with unresectable HCC investigated the effect of both anti-androgens and GnRH agonist therapy versus placebo and again showed no significant survival benefit.60,66

Conclusions In men with cirrhosis, testosterone levels fall in parallel with worsening severity of liver disease. Elevated SHBG in cirrhosis means that the prevalence and severity of testosterone deficiency may be underestimated if only total testosterone is measured. Calculation of free testosterone appears to provide a more accurate measure of androgen status in this setting. Importantly, low testosterone may be a useful prognostic marker in men with cirrhosis, as it predicts mortality independent of the MELD score. The recent finding that muscle wasting is also associated with increased mortality in cirrhosis provides one possible explanation for this finding. Testosterone deficiency may contribute to many of the complications of cirrhosis in men, and may also influence

Testosterone in men with liver disease

mortality. The potential benefits of testosterone therapy have not yet been adequately investigated in long-term studies. Further prospective research is clearly required to evaluate both the impact of testosterone deficiency on clinical outcomes and the safety and efficacy of testosterone therapy in men with chronic liver disease.

References 1 Handelsman DJ, Strasser S, McDonald JA, Conway AJ, McCaughan GW. Hypothalamic-pituitary-testicular function in end-stage non-alcoholic liver disease before and after liver transplantation. Clin. Endocrinol. (Oxf). 1995; 43: 331–7. 2 Grossmann M, Hoermann R, Gani L et al. Low testosterone levels as an independent predictor of mortality in men with chronic liver disease. Clin. Endocrinol. (Oxf). 2012; 77: 323–8. 3 Kovacs WJ, Ojeda SR. Textbook of Endocrine Physiology, 6th edn. New York, NY: Oxford University Press, 2011. 4 Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J. Clin. Endocrinol. Metab. 1999; 84: 3666–72. 5 van den Beld AW, de Jong FH, Grobbee DE, Pols HA, Lamberts SW. Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men. J. Clin. Endocrinol. Metab. 2000; 85: 3276–82. 6 Bhasin S, Woodhouse L, Casaburi R et al. Testosterone dose-response relationships in healthy young men. Am. J. Physiol. Endocrinol. Metab. 2001; 281: E1172–81. 7 Sinha-Hikim I, Roth SM, Lee MI, Bhasin S. Testosterone-induced muscle hypertrophy is associated with an increase in satellite cell number in healthy, young men. Am J Physiol Endocrinol Metab. 2003; 285: E197–205. 8 Vanderschueren D, Bouillon R. Androgens and bone. Calcif. Tissue Int. 1995; 56: 341–6. 9 Abu EO, Horner A, Kusec V, Triffitt JT, Compston JE. The localization of androgen receptors in human bone. J. Clin. Endocrinol. Metab. 1997; 82: 3493–7. 10 Amory JK, Watts NB, Easley KA et al. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J. Clin. Endocrinol. Metab. 2004; 89: 503–10. 11 Snyder PJ, Peachey H, Hannoush P et al. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J. Clin. Endocrinol. Metab. 1999; 84: 1966–72. 12 Singh R, Artaza JN, Taylor WE et al. Testosterone inhibits adipogenic differentiation in 3T3-L1 cells: nuclear translocation of androgen receptor complex with beta-catenin and T-cell factor 4 may bypass canonical Wnt signaling to down-regulate adipogenic transcription factors. Endocrinology 2006; 147: 141–54. 13 Boyanov MA, Boneva Z, Christov VG. Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. Aging Male. 2003; 6: 1–7. 14 Grossmann M. Testosterone and glucose metabolism in men: current concepts and controversies. J. Endocrinol. 2014; 220: R37–55. 15 Haider A, Gooren LJ, Padungtod P, Saad F. Improvement of the metabolic syndrome and of non-alcoholic liver steatosis upon treatment of hypogonadal elderly men with parenteral testosterone undecanoate. Exp. Clin. Endocrinol. Diabetes 2010; 118: 167–71. 16 Fernandez-Balsells MM, Murad MH, Lane M et al. Clinical review 1: adverse effects of testosterone therapy in adult men: a systematic

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17

18

19

20

21

22

23

24

25

26

27

28

29

30

31 32

33 34

M Sinclair et al.

review and meta-analysis. J. Clin. Endocrinol. Metab. 2010; 95: 2560–75. Coviello AD, Kaplan B, Lakshman KM, Chen T, Singh AB, Bhasin S. Effects of graded doses of testosterone on erythropoiesis in healthy young and older men. J. Clin. Endocrinol. Metab. 2008; 93: 914–19. Bachman E, Feng R, Travison T et al. Testosterone suppresses hepcidin in men: a potential mechanism for testosterone-induced erythrocytosis. J. Clin. Endocrinol. Metab. 2010; 95: 4743–7. Muehlenbein MP, Bribiescas RG. Testosterone-mediated immune functions and male life histories. Am. J. Hum. Biol. 2005; 17: 527–58. Gold SM, Chalifoux S, Giesser BS, Voskuhl RR. Immune modulation and increased neurotrophic factor production in multiple sclerosis patients treated with testosterone. J. Neuroinflammation 2008; 5: 32. Sinclair M, Angus P, Gow P, Hoermann R, Mogilevski T, Grossmann M. Low serum testosterone levels pre-liver transplantation are associated with reduced rates of early acute allograft rejection in men. Transplantation 2014; 98: 788–92. Sikaris K, McLachlan RI, Kazlauskas R, de Kretser D, Holden CA, Handelsman DJ. Reproductive hormone reference intervals for healthy fertile young men: evaluation of automated platform assays. J. Clin. Endocrinol. Metab. 2005; 90: 5928–36. Bhasin S, Pencina M, Jasuja GK et al. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. J. Clin. Endocrinol. Metab. 2011; 96: 2430–9. Meier C, Nguyen TV, Handelsman DJ et al. Endogenous sex hormones and incident fracture risk in older men: the Dubbo Osteoporosis Epidemiology Study. Arch. Intern. Med. 2008; 168: 47–54. Grossmann M, Thomas MC, Panagiotopoulos S et al. Low testosterone levels are common and associated with insulin resistance in men with diabetes. J. Clin. Endocrinol. Metab. 2008; 93: 1834–40. Araujo AB, Dixon JM, Suarez EA, Murad MH, Guey LT, Wittert GA. Clinical review: endogenous testosterone and mortality in men: a systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 2011; 96: 3007–19. Monegal A, Navasa M, Guanabens N et al. Bone disease after liver transplantation: a long-term prospective study of bone mass changes, hormonal status and histomorphometric characteristics. Osteoporos. Int. 2001; 12: 484–92. Zietz B, Lock G, Plach B et al. Dysfunction of the hypothalamic-pituitary-glandular axes and relation to Child-Pugh classification in male patients with alcoholic and virus-related cirrhosis. Eur. J. Gastroenterol. Hepatol. 2003; 15: 495–501. Zifroni A, Schiavi RC, Schaffner F. Sexual function and testosterone levels in men with nonalcoholic liver disease. Hepatology 1991; 14: 479–82. Mowat NA, Edwards CR, Fisher R, McNeilly AS, Green JR, Dawson AM. Hypothalamic-pituitary-gonadal function in men with cirrhosis of the liver. Gut 1976; 17: 345–50. Jones TH, Kennedy RL. Cytokines and hypothalamic-pituitary function. Cytokine 1993; 5: 531–8. MacAdams MR, White RH, Chipps BE. Reduction of serum testosterone levels during chronic glucocorticoid therapy. Ann. Intern. Med. 1986; 104: 648–51. Burke CW, Anderson DC. Sex-hormone-binding globulin is an oestrogen amplifier. Nature 1972; 240: 38–40. Maruyama Y, Adachi Y, Aoki N, Suzuki Y, Shinohara H,

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Yamamoto T. Mechanism of feminization in male patients with non-alcoholic liver cirrhosis: role of sex hormone-binding globulin. Gastroenterol. Jpn. 1991; 26: 435–9. Bandyopadhyay SK, Moulick A, Saha M, Dutta A, Bandyopadhyay R, Basu AK. A study on endocrine dysfunction in adult males with liver cirrhosis. J. Indian Med. Assoc. 2009; 107: 866, 8–9. Gordon GG, Olivo J, Rafil F, Southren AL. Conversion of androgens to estrogens in cirrhosis of the liver. J. Clin. Endocrinol. Metab. 1975; 40: 1018–26. Green JR, Mowat NA, Fisher RA, Anderson DC. Plasma oestrogens in men with chronic liver disease. Gut 1976; 17: 426–30. Braunstein GD. Gynecomastia. N. Engl. J. Med. 1993; 328: 490–5. Iturriaga H, Lioi X, Valladares L. Sex hormone-binding globulin in non-cirrhotic alcoholic patients during early withdrawal and after longer abstinence. Alcohol. Alcohol. 1999; 34: 903–9. Rose LI, Underwood RH, Newmark SR, Kisch ES, Williams GH. Pathophysiology of spironolactone-induced gynecomastia. Ann. Intern. Med. 1977; 87: 398–403. Durand F, Buyse S, Francoz C et al. Prognostic value of muscle atrophy in cirrhosis using psoas muscle thickness on computed tomography. J. Hepatol. 2014; 60: 1151–7. Montano-Loza AJ, Meza-Junco J, Prado CM et al. Muscle wasting is associated with mortality in patients with cirrhosis. Clin. Gastroenterol. Hepatol. 2012; 10: 166–73. Alcalde Vargas A, Pascasio Acevedo JM, Gutierrez Domingo I et al. Prevalence and characteristics of bone disease in cirrhotic patients under evaluation for liver transplantation. Transplant Proc. 2012; 44: 1496–8. Rouillard S, Lane NE. Hepatic osteodystrophy. Hepatology 2001; 33: 301–7. Kawaguchi T, Taniguchi E, Itou M, Sakata M, Sumie S, Sata M. Insulin resistance and chronic liver disease. World J. Hepatol. 2011; 3: 99–107. D’Souza R, Sabin CA, Foster GR. Insulin resistance plays a significant role in liver fibrosis in chronic hepatitis C and in the response to antiviral therapy. Am. J. Gastroenterol. 2005; 100: 1509–15. Hung CH, Wang JH, Hu TH et al. Insulin resistance is associated with hepatocellular carcinoma in chronic hepatitis C infection. World J. Gastroenterol. 2010; 16: 2265–71. Gluud C, Hardt F, Juhl E. Testosterone treatment of men with alcoholic cirrhosis: a double-blind study. The Copenhagen Study Group for Liver Diseases. Hepatology 1986; 6: 807–13. Wells R. Prednisolone and testosterone propionate in cirrhosis of the liver. A controlled trial. Lancet 1960; 2: 1416–19. Puliyel MM, Vyas GP, Mehta GS. Testosterone in the management of cirrhosis of the liver—a controlled study. Aust. N. Z. J. Med. 1977; 7: 17–30. Rambaldi A, Gluud C. Anabolic-androgenic steroids for alcoholic liver disease. Cochrane Database Syst. Rev. 2006; 4: CD003045. Fenster F. The nonefficacy of short-term anabolic steroid therapy in alcoholic liver disease. Ann. Intern. Med. 1966; 65: 738–44. Yurci A, Yucesoy M, Unluhizarci K et al. Effects of testosterone gel treatment in hypogonadal men with liver cirrhosis. Clin. Res. Hepatol. Gastroenterol. 2011; 35: 845–54. Buch SC, Kondragunta V, Branch RA, Carr BI. Gender-based outcomes differences in unresectable hepatocellular carcinoma. Hepatol. Int. 2008; 2: 95–101. Yu MW, Chen CJ. Elevated serum testosterone levels and risk of hepatocellular carcinoma. Cancer Res. 1993; 53: 790–4. Tanaka K, Sakai H, Hashizume M, Hirohata T. Serum testosterone:estradiol ratio and the development of hepatocellular carcinoma among male cirrhotic patients. Cancer Res. 2000; 60: 5106–10.

Journal of Gastroenterology and Hepatology 30 (2015) 244–251 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd

M Sinclair et al.

57 Montalto G, Miceli M, Soresi M et al. Sex hormones in patients with liver cirrhosis and hepatocellular carcinoma. Oncol. Rep. 1997; 4: 173–6. 58 Lukanova A, Becker S, Husing A et al. Pre-diagnostic plasma testosterone, sex hormone binding globulin, IGF-I and hepatocellular carcinoma: etiological factors or risk markers? Int. J. Cancer 134: 164–73. 59 Chen PJ, Yeh SH, Liu WH et al. Androgen pathway stimulates microRNA-216a transcription to suppress the tumor suppressor in lung cancer-1 gene in early hepatocarcinogenesis. Hepatology 2012; 56: 632–43. 60 Boix L, Castells A, Bruix J et al. Androgen receptors in hepatocellular carcinoma and surrounding liver: relationship with tumor size and recurrence rate after surgical resection. J. Hepatol. 1995; 22: 616–22. 61 Granata OM, Carruba G, Montalto G et al. Altered androgen metabolism eventually leads hepatocellular carcinoma to an impaired hormone responsiveness. Mol. Cell Endocrinol. 2002; 193: 51–8.

Testosterone in men with liver disease

62 Naugler WE, Sakurai T, Kim S et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 2007; 317: 121–4. 63 Johnson FL, Lerner KG, Siegel M et al. Association of androgenic-anabolic steroid therapy with development of hepatocellular carcinoma. Lancet 1972; 2: 1273–6. 64 Farrell GC, Joshua DE, Uren RF, Baird PJ, Perkins KW, Kronenberg H. Androgen-induced hepatoma. Lancet 1975; 1: 430–2. 65 Bhasin S, Cunningham GR, Hayes FJ et al. Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 2006; 91: 1995–2010. 66 Grimaldi C, Bleiberg H, Gay F et al. Evaluation of antiandrogen therapy in unresectable hepatocellular carcinoma: results of a European Organization for Research and Treatment of Cancer multicentric double-blind trial. J. Clin. Oncol. 1998; 16: 411–17.

Journal of Gastroenterology and Hepatology 30 (2015) 244–251 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd

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Testosterone in men with advanced liver disease: abnormalities and implications.

Serum testosterone is reduced in up to 90% of men with cirrhosis, with levels falling as liver disease advances. Testosterone is an important anabolic...
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