Anabolic‐androgenic steroids for alcoholic liver disease

Abstract

Background

Alcohol is one of the most common causes of liver disease in the Western World. Randomised clinical trials have examined the effects of anabolic‐androgenic steroids for alcoholic liver disease.

Objectives

To assess the beneficial and harmful effects of anabolic‐androgenic steroids for patients with alcoholic liver disease based on the results of randomised clinical trials.

Search methods

We searched The Cochrane Hepato‐Biliary Group Controlled Trials Register, The Cochrane Controlled Trials Register in The Cochrane Library, MEDLINE, EMBASE, LILACS, and Science Citation Index Expanded until June 2006. Electronic searches were combined with full text searches. Manufacturers and researchers in the field were also contacted.

Selection criteria

Randomised clinical trials studying patients with alcoholic steatosis, alcoholic fibrosis, alcoholic hepatitis, and/or alcoholic cirrhosis were included. Interventions encompassed anabolic‐androgenic steroids at any dose or duration versus placebo or no intervention. The trials could be double blind, single blind, or unblinded. The trials could be unpublished or published, and no language limitations were applied.

Data collection and analysis

Outcomes are assessed at maximal follow‐up. All analyses were performed according to the intention‐to‐treat method. The statistical package RevMan Analyses was used. The methodological quality of the randomised clinical trials was assessed.

Main results

Combining the results of five randomised clinical trials randomising 499 patients with alcoholic hepatitis and/or cirrhosis demonstrated no significant effects of anabolic‐androgenic steroids on mortality (relative risk (RR) 1.01, 95% confidence interval (CI) 0.79 to 1.29), liver‐related mortality (RR 0.83, 95% CI 0.60 to 1.15), complications of liver disease (RR 1.25, 95% CI 0.74 to 2.10), and liver histology. Anabolic‐androgenic steroids did not significantly affect a number of other outcome measures, including sexual function and liver biochemistry. Anabolic‐androgenic steroids were not associated with a significantly increased risk of non‐serious adverse events (RR 1.14, 95% CI 0.50 to 2.59) or with serious adverse events (RR 4.54, 95% CI 0.57 to 36.30).

Authors' conclusions

This systematic review could not demonstrate any significant beneficial effects of anabolic‐androgenic steroids on any clinically important outcomes (mortality, liver‐related mortality, liver complications, and histology) of patients with alcoholic liver disease.

Plain language summary

No evidence to support anabolic‐androgenic steroids for alcoholic liver disease

Alcohol causes a major part of the liver diseases in the Western World. Several trials have addressed the effects of anabolic‐androgenic steroids for alcoholic liver disease. This systematic review could not demonstrate any significant effects of anabolic‐androgenic steroids on mortality, liver‐related mortality, liver complications, and histology of patients with alcoholic liver disease. Anabolic‐androgenic steroid intervention is not associated with a significant increase in non‐serious adverse events, but with the seldom occurrence of serious adverse events. Accordingly, there is no evidence supporting the use of anabolic‐androgenic steroids for alcoholic liver disease, but further randomised clinical trials may be needed to settle the question.

Background

Alcohol is one of the most common causes of liver diseases in the Western World. Alcoholic liver disease has also become an important cause of liver injury in a number of low‐income countries as economics improve and both cultural and religious indictments against drinking are decreasing. In many countries the incidence of alcoholic liver disease is increasing at a time when the incidence of other liver disorders remains steady or is falling (Morgan 1999).

Alcohol is a major hepatotoxin (Morgan 1999). Alcohol leads to fatty liver (Rubin 1968), alcoholic hepatitis, alcoholic fibrosis (Purhoit 2006), and alcoholic cirrhosis (Morgan 1999). Data from long‐term studies in which patients with alcoholic fatty change and alcoholic hepatitis were followed for up to 13 years demonstrate that alcoholic hepatitis is a predictor of later development of liver fibrosis and cirrhosis (Sørensen 1984; Marbet 1987). Acetaldehyde, the first metabolite of ethanol, may increase transcription of collagen I. Alcohol induced necrosis and inflammation may trigger the scarring and the development of fibrosis and later on the development of cirrhosis.

About 70% of patients with clinical alcoholic hepatitis also have alcoholic cirrhosis at the time of diagnosis (Mendenhall 1984a). Survival is adversely affected by continued alcohol abuse. Five‐years survival in patients with alcoholic cirrhosis who stop drinking is 50% to 75%. Five‐years survival in patients continuing to drink rarely exceed 40% (Powell 1968). The progression of liver fibrosis and cirrhosis in alcoholics is enhanced by the presence of hepatitis B and hepatitis C virus markers (Chang 1994; Corrao 1998; Purhoit 2006).

Men with alcoholic cirrhosis have symptoms such as testicular atrophy, azoospermia, reduced body hair, reduced beard growth, reduced prostatic size as well as gynaecomastia, arterial spiders, female escutcheon, female body habitus, and sexual dysfunction (Gluud 1988a; Van Steenbergen 1993). These findings all suggest that there is an endocrine imbalance of sexual hormones. In accordance, plasma concentrations of non‐protein bound testosterone and non‐sex hormone binding globulin bound testosterone ‐ the biologically active fractions ‐ are generally low or decreased in patients with alcoholic cirrhosis (Gluud 1983; Gluud 1987; Gluud 1988a) and levels of oestrogens are often increased (Gluud 1983; Gluud 1988a).

Few studies have addressed sex hormone disturbances in women with chronic alcoholic liver disease (Becker 1993). In female alcoholics ethanol consumption increases the frequency of menstrual disturbances, abortions, and earlier occurrence of menopause. In postmenopausal women with alcoholic liver disease, the main disturbances of sex hormone metabolism consist of elevated oestrone and non‐sex hormone binding globulin concentrations, while serum concentrations of steroid sulphates and 5‐alfa‐dihydrotestosterone are reduced (Becker 1993).

A questionnaire survey among European hospital‐based specialists in gastroenterology/hepatology demonstrated that 5% to 43% of the specialists, depending on the region, considered using anabolic‐androgenic steroids for alcoholic liver disease (Gluud 1993). Several controlled and uncontrolled clinical studies have been undertaken in order to estimate the beneficial and harmful effects of anabolic‐androgenic steroids for alcoholic liver disease (Gluud 1984; Gluud 1988a). The studies have yielded varying results and the power of the controlled studies has been low. Moreover, previous meta‐analyses on the topic have reached conflicting results due to the accumulation of more trial results and differences regarding inclusion criteria (Gluud 1984; Gluud 1988a).

This Review represents an update of our previous Cochrane systematic review on the topic (Rambaldi 2002, Rambaldi 2003), see other published versions of this review.

Objectives

To assess the beneficial and harmful effects of anabolic‐androgenic steroids versus placebo or no intervention in patients with alcoholic steatosis, alcoholic hepatitis, alcoholic fibrosis, and/or alcoholic cirrhosis.

Methods

Criteria for considering studies for this review

Types of studies

We included only randomised clinical trials. The trials should have used a proper method of randomisation, ie, central randomisation; serially numbered opaque, sealed envelopes; or other description that contains elements convincing of adequate allocation concealment. Trials with quasi‐randomisation were excluded. Randomised clinical trials could be double blind, single blind, or unblinded. The randomised clinical trials could be unpublished or published as an article, an abstract, or a letter. No language limitations were applied.

Types of participants

Patients with alcoholic liver disease according to the diagnostic work‐up used in the individual randomised clinical trial were included. The analyses examined the efficacy of anabolic‐androgenic steroids in the different subgroups of patients with alcoholic liver disease (fatty liver; alcoholic hepatitis; alcoholic fibrosis; alcoholic cirrhosis) as well as combined.

Types of interventions

Peroral or parenteral administration of anabolic‐androgenic steroids at any dose versus placebo or no intervention. Additional interventions were allowed as long as both intervention groups in the individual trial received the additional intervention(s) equally.

Types of outcome measures

All outcomes were assessed at maximal follow‐up.

Primary outcomes 
 (1) Number of patients dying (total and liver‐related death).

Secondary outcomes 
 (2) Development of clinical symptoms and complications (ie, ascites, variceal bleeding, hepatic encephalopathy, hepato‐renal syndrome, hepatocellular carcinoma). 
 (3) Liver function. 
 (4) Liver biopsy findings. 
 (5) Liver biochemistry. 
 (6) Alcohol consumption during follow‐up. 
 (7) Adverse events. Adverse events were defined as any untoward medical occurrence that did not have a causal relationship with the treatment, but did result in a dose reduction or discontinuation of treatment. Severe adverse events were defined according to the ICH guidelines (ICH‐GCP 1997) as any event that would increase mortality; were life‐threatening; required inpatient hospitalisation; resulted in a persistent or significant disability; or any important medical event, which may have jeopardised the patient or required intervention to prevent it.

In addition, any data on quality of life and health economics (eg, length of hospitalisation) were compared.

Search methods for identification of studies

See: Hepato‐Biliary Group methods used in reviews.

We searched The Cochrane Hepato‐Biliary Group Controlled Trials Register (June 2006), The Cochrane Central Register of Controlled Trials in The Cochrane Library (Issue 2, 2006), MEDLINE (1950 to June 2006), EMBASE (1980 to June 2006), LILACS (1982 to June 2006), and Science Citation Index EXPANDED (from 1945 to June 2006). See 'Appendix 1' for the search strategies applied to the individual electronic databases.

Further trials were sought by reading the reference lists of the identified studies and through full text searches.

No restrictions of year of publication, language, or publication status were applied.

The principal authors of the identified randomised clinical trials were approached and inquired about additional trials they might know of. Pharmaceutical companies involved in the production of anabolic‐androgenic steroids were contacted in order to obtain additional publications on randomised clinical trials and unpublished randomised clinical trials.

Data collection and analysis

The meta‐analysis was updated following the recommendations given by The Cochrane Collaboration (Higgins 2005).

Trial selection and data extraction 
 The authors independently selected the trials to be included in the review according to the prespecified selection criteria. A third opinion plus discussion resolved disagreements. We wrote to the authors of trials when data were missing in the report. 
 
 Patient characteristics, diagnosis, and treatments 
 The following items were recorded from the individual randomised clinical trials: mean (or median) age, sex ratio, alcohol consumption, form of liver disease, duration and severity of liver disease at entry, a concomitant cause of liver disease, dose of anabolic‐androgenic steroids intervention, type of intervention in the control group and any additional intervention. The diagnostic work‐up before entry was registered. Hepatitis markers were evaluated and type of alcoholic liver disease included in the randomised clinical trial. Development of clinical symptoms and complications, liver function, liver biochemistry, liver biopsy findings, alcohol consumption, quality of life, health economics (ie, length of hospital stay, cost of medication, and cost of additional follow‐up weighted against any gains in health), and adverse events during follow‐up were registered.

Selection and data‐extraction bias 
 All randomised clinical trials considered for inclusion were analysed by the contributors, who conferred about any disagreements.

All randomised clinical trials had the pertinent data extracted by the contributors. All identified trials were listed and trials excluded from the meta‐analysis of the review were identified with the reason for exclusion.

Data on the number of patients with each outcome event, by allocated treatment group, irrespective of compliance of follow‐up, were sought to allow an intention‐to‐treat analysis. If the above data were not available in the trial reports, further information was sought by correspondence with the principal investigator.

Bias Risk 
 The methodological quality of the randomised clinical trials and hence bias risk were assessed using components of methodological quality (generation of the allocation sequence, allocation concealment, blinding, and withdrawals and dropouts) (Schulz 1995; Moher 1998; Kjaergard 2001).

Generation of the allocation sequence 
 The procedure used to create a random sequence ensuring that each participant has a known, unpredictable, and usually equal chance of being assigned to intervention groups. The allocation sequence generation was classified as:

• Adequate, if the allocation sequence was generated by a computer or random number table. Drawing of lots, tossing of a coin, shuffling of cards, or throwing dice may also be considered as adequate if a person who was not otherwise involved in the recruitment of participants performed the procedure.

• Unclear, if the trial was described as randomised, but the method used for the allocation sequence generation was not.

• Inadequate, if a system involving dates, names, or admittance numbers were used for the allocation of patients. Such studies are known as quasi‐randomised studies and were excluded from the review due to the risk of bias.

Allocation concealment 
 The procedure used to conceal the allocation sequence from the investigators who assign participants to the intervention groups. The allocation concealment was classified as:

• Adequate, if the allocation of patients involved a central independent unit, on‐site locked computer, identically appearing numbered drug bottles or containers prepared by an independent pharmacist or investigator, or sealed envelopes. Envelopes should be serially numbered, sealed, and opaque. However, this information is rarely provided, indicating an increased risk of bias. In that case, sealed envelopes may constitute an intermediate category between adequate and unclear.

• Unclear, if the trial was described as randomised, but the method used to conceal the allocation was not described.

• Inadequate, if the allocation sequence was known to the investigators who assigned participants or if the study was quasi‐randomised. Such studies were excluded due to their risk of bias.

Blinding 
 Blinding was classified as:

• Adequate, if the trial was described as double blind and the method of blinding involved identical placebo and active drugs (smell, taste and shape).

• Unclear, if the trial was described as double blind, but the method of blinding was not described.

• Inadequate, not performed, if the trial was not double blind.

Follow‐up 
 The reported follow‐up was classified as:

• Adequate, if the numbers and reasons for dropouts and withdrawals in all intervention groups were described or if it was specified that there were no dropouts or withdrawals.

• Unclear, if the report gave the impression that there had been no dropouts or withdrawals, but this was not specifically stated.

• Inadequate, if the number or reasons for dropouts and withdrawals were not described.

In addition, we had registered whether the randomised clinical trial had reported the use of intention‐to‐treat analysis or not (Gluud 2001). 
 
 Statistical methods 
 All analyses were performed according to the intention‐to‐treat method including all randomised patients. Patients without the outcome variable were considered failures (worst‐case scenario analysis).

Dichotomous data were analysed by calculating the relative risk (RR) and continuous outcomes as weighed mean difference (WMD) or standardised mean difference (SMD) both with 95% confidence intervals.

We performed all analyses on mortality according to the intention‐to‐treat method, ie, including all randomised patients. We used the statistical package RevMan Analyses (RevMan 2003) provided by the Cochrane Collaboration. We examined intervention effects by using both a random‐effects model (DerSimonian 1986) and a fixed‐effect model (Demets 1987) with the significance level set at P < 0.05. If the results of the two analyses led to the same conclusion, we presented only the results of the fixed‐effect model analysis. In case of discrepancies of the two models we reported the results of both models.

Potential causes for heterogeneity were explored by performing subgroup analyses. The review performed subgroup analyses with regard to the stage of alcoholic liver disease, methodological quality of included randomised clinical trials (analysing separately randomised clinical trials with adequate quality components and inadequate quality components (Moher 1998; Kjaergard 2001), and way of administration of anabolic‐androgenic steroids as well as preparation, dose, and duration of anabolic‐androgenic steroids treatment.

Due to the risk of chance, statistical findings among the secondary outcome measures were interpreted conservatively.

We planned to examine potential publication bias (Vickers 1998) and other sources of bias using the funnel plot method (Egger 1997), but due to the few trials identified we did not explore it.

Results

Description of studies

Search results 
 We identified 336 references through electronic searches (until June, 2006) of The Cochrane Hepato‐Biliary Group Controlled Trials Register (n = 45), The Cochrane Library (n = 87), MEDLINE (n = 82), EMBASE (n = 85), LILACS (n = 0), and Science Citation Index EXPANDED (n = 37) (see Appendix 1). We found 43 publications; 13 were included and 30 were excluded. Reading bibliographies identified one further randomised clinical trial (Fenster 1966), which was not identified by the electronic searches.

Included studies 
 In 14 included publications, four randomised clinical trials were described in full paper articles (Fenster 1966; Mendenhall 1984b; CSL 1986; Bonkovsky 1991) and one randomised clinical trial in an abstract form only (Mendenhall 1977).

The individual randomised clinical trials are described in the table 'Characteristics of included studies'.

The five trials reported random allocation of 499 patients with alcoholic liver disease (n = 499) to anabolic‐androgenic steroids. All the randomised clinical trials compared anabolic‐androgenic steroids versus placebo except the Bonkovsky trial (Bonkovsky 1991), which compared anabolic‐androgenic steroids versus no intervention.

The entry criteria in the randomised clinical trials varied, but the inclusion criteria were generally of good quality making it highly likely that all patients did in fact have alcoholic liver disease. Patients with alcoholic hepatitis were included in three trials (Mendenhall 1977; Mendenhall 1984b; Bonkovsky 1991). Mendenhall et al (Mendenhall 1977) did not give the proportion of patients also having cirrhosis. However, in the two other trials the proportion of patients with cirrhosis was 71.1% (Mendenhall 1984b) and 54.0% (Bonkovsky 1991).

Patients with alcoholic cirrhosis were included in two randomised clinical trials (Fenster 1966; CSL 1986). Fenster et al (Fenster 1966) did not report the proportion of patients also having alcoholic hepatitis. In the other trial (CSL 1986) the proportion of patients also having histological alcoholic hepatitis was 51.1% (Gluud 1987).

A total of 447 (89.6%) patients were males (Mendenhall 1977; Mendenhall 1984b; CSL 1986; Bonkovsky 1991), while 20 (2.0%) patients were females (Bonkovsky 1991). The exact figure of males and females is not given for 32 (6.4%) patients (Fenster 1966). However, the sex ratio was quite balanced between the two groups of this trial.

The experimental treatment consisted of oxandrolone 80 mg per day orally in three randomised clinical trials (Mendenhall 1977; Mendenhall 1984b; Bonkovsky 1991), micronized‐free testosterone 600 mg day (200 mg three times per day) orally in one randomised clinical trial (CSL 1986), and 100 mg of testosterone propionate or methenolone enanthate every other day intramuscularly in the Fenster 1966 trial.

The duration of the treatment varied from 21 days in Mendenhall 1977 and Bonkovsky 1991, over one month in Fenster 1966 and Mendenhall 1984b to 36 months in CSL 1986.

Excluded studies 
 A total of 22 studies, described in 30 publications, were excluded mainly because they were observational studies or case series. The reasons for exclusion are listed in the table 'Characteristics of excluded studies'. Two of these described randomised clinical trials including patients with mixed aetiologies (Wells 1960; Puliyel 1977). All patients had liver cirrhosis in the Wells trial (Wells 1960), but the aetiology of the cirrhosis was not given. Only 18/53 patients had a history of alcoholism. All patients had also liver cirrhosis in the Puliyel trial (Puliyel 1977), but there were no data on aetiology. These two randomised clinical trials are excluded, due to the fact that only a small proportion of included patients were considered to have alcoholic liver disease. 
 
 We also excluded the Mendenhall 1993a trial because it examined the combination of two interventions (oxandrolone plus nutritional support) versus placebo. However, we have included this trial in a sensitivity analysis in order to examine the robustness of our findings.

Risk of bias in included studies

Only one of the five randomised clinical trials provided a sample size estimation, which was based on mortality (CSL 1986).

The method to generate the allocation sequence was considered adequate in two randomised clinical trials (CSL 1986; Bonkovsky 1991) and three randomised clinical trials described adequate allocation concealment (Mendenhall 1984b; CSL 1986; Bonkovsky 1991).

All randomised clinical trials but one (Bonkovsky 1991) were described as double blind. However, the placebo was described as having an identical appearance only in two randomised clinical trials (Fenster 1966; CSL 1986).

There was a fair description of follow‐up and withdrawals/drop‐outs in three trials (Fenster 1966; Mendenhall 1984b; CSL 1986). None of the trials stated that they used an intention‐to‐treat method to evaluate their data. All the trials but one presumably used intention‐to‐treat analysis (Fenster 1966).

Effects of interventions

Mortality 
 Combining the results of the five randomised clinical trials demonstrated no significant effect of anabolic‐androgenic steroids on mortality (RR 1.01, 95% confidence interval (CI) 0.79 to 1.29). In the anabolic‐androgenic steroids group 87/275 (31.6%) patients died versus 73/224 (32.6%) patients in the control group (Analysis 1.1).

1.1. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 1 Mortality.

A worst‐case scenario analysis (all patients who dropped‐out or were withdrawn were considered dead) did not change the estimate of no significant effect of anabolic‐androgenic steroids on mortality (Analysis 3.1).

3.1. Analysis.

Comparison 3 Sensitivity analyses, Outcome 1 Mortality ‐ worst‐case scenario.

Subgroup analysis stratifying the trials according to the adequacy of the single methodologic quality components (generation of the allocation sequence, allocation concealment, blinding, and follow‐up) did not demonstrate significant differences regarding the effect of anabolic‐androgenic steroids on mortality between trials with and without adequate methodology (Analysis 3.2; Analysis 3.3; Analysis 3.4; Analysis 3.5). Comparing the estimate of anabolic‐androgenic steroids intervention effect in adequately blinded trials (RR 1.25, 95% CI 0.79 to 1.98) to that in unblinded trials (RR 0.89, 95% CI 0.68 to 1.18) demonstrated no significant difference between the two estimates (z = ‐0.87 P = 0.38). Comparing trials with adequate methodology regarding all four components to trials with one or more inadequate components gave results similar to Analysis 3.2.

3.2. Analysis.

Comparison 3 Sensitivity analyses, Outcome 2 Mortality and generation of the allocation sequence.

3.3. Analysis.

Comparison 3 Sensitivity analyses, Outcome 3 Mortality and allocation concealment.

3.4. Analysis.

Comparison 3 Sensitivity analyses, Outcome 4 Mortality and double blinding.

3.5. Analysis.

Comparison 3 Sensitivity analyses, Outcome 5 Mortality and follow‐up.

The RR of death of the trials with a follow‐up duration within 21 days was 1.00 (95% CI 0.16 to 6.30), while the RR of the randomised clinical trials with a follow‐up duration of at least six months was 1.01 (95% CI 0.79 to 1.29) (Analysis 3.6).

3.6. Analysis.

Comparison 3 Sensitivity analyses, Outcome 6 Mortality ‐ duration of follow‐up.

The RR of death of the trials evaluating oxandrolone was 0.78 (95% CI 0.54 to 1.13); the RR of the trial evaluating testosterone was 1.19 (95% CI 0.72 to 1.98); and the RR of the trial evaluating testosterone propionate or methenolone was 1.57 (95% CI 0.53 to 4.65) (Analysis 3.7).

3.7. Analysis.

Comparison 3 Sensitivity analyses, Outcome 7 Mortality ‐ different treatment.

The RR of death of the randomised clinical trials including patients with alcoholic hepatitis was 0.89 (95% CI 0.68 to 1.18); the RR of the trials including patients with alcoholic cirrhosis was 1.25 (95% CI 0.79 to 1.98) (Analysis 3.8).

3.8. Analysis.

Comparison 3 Sensitivity analyses, Outcome 8 Mortality ‐ stage of alcoholic liver disease.

Sensitivity analysis adding the excluded trial (Mendenhall 1993b) treating patients with oxandrolone plus nutritional supplement versus placebo did not change this estimate significantly; RR 0.99 (95% CI 0.81 to 1.21) (Analysis 3.9). In the treatment group 128/412 (31.1%) patients died versus 116/360 (32.2%) patients in the control group.

3.9. Analysis.

Comparison 3 Sensitivity analyses, Outcome 9 Mortality ‐ according to co‐intervention.

Liver‐related mortality 
 No significant effect of anabolic‐androgenic steroids on liver‐related mortality could be demonstrated (RR 0.83, 95% CI 0.60 to 1.15). In the anabolic‐androgenic steroids group 50/227 (22.0%) patients died versus 53/187 (28.3%) patients in the control group (Analysis 1.2).

1.2. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 2 Liver‐related mortality.

Liver‐related complications 
 None of the trials considered variceal bleeding or hepato‐renal syndrome as outcome measures.

Anabolic‐androgenic steroids did not significantly affect the incidence of patients with ascites, hepatic encephalopathy, hepatocellular carcinoma, pretibial edema, prostatic hypertrophia, sexual dysfunction, weight (Analysis 1.3; Analysis 1.4; Analysis 1.5; Analysis 1.7; Analysis 1.9; Analysis 1.10; Analysis 1.11). Anabolic‐androgenic steroids reduced, however, significantly the prevalence of patients with gynaecomastia (RR 0.32, 95% CI 0.15 to 0.72, P < 0.05) (Analysis 1.8). 
 
 Combining the results of four trials (Fenster 1966; Mendenhall 1984b; CSL 1986; Bonkovsky 1991) demonstrated no significant effect of anabolic‐androgenic steroids on the combined outcome measure consisting of ascites, hepatic encephalopathy, and hepatocellular carcinoma (RR 1.25, 95% CI 0.74 to 2.10) (Analysis 1.6). 
 
 Liver haemodynamics and function 
 Only one randomised clinical trial (CSL 1986) determined liver haemodynamics and liver function in 34 patients (22 in the anabolic‐androgenic steroids group and 12 in the control group of the trial, which used skewed randomisation) after one year. No significant effect of testosterone could be found on portal pressure (Analysis 1.12), indocyanine green clearance (Analysis 1.13), and galactose elimination capacity (Analysis 1.14). 
 
 Liver histology 
 There were no significant effects of anabolic‐androgenic steroids on either histological improvement of liver biopsy findings (Fenster 1966) or histological changes in the liver (CSL 1986) (Analysis 1.15; Analysis 1.16; Analysis 1.17; Analysis 1.18; Analysis 1.19; Analysis 1.20):

1.3. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 3 Ascites.

1.4. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 4 Hepatic encephalopathy.

1.5. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 5 Hepatocellular carcinoma.

1.7. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 7 Pretibial edema.

1.9. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 9 Prostatic hypertrophia.

1.10. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 10 Sexual dysfunction.

1.11. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 11 Weight (kg).

1.8. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 8 Gynaecomastia.

1.6. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 6 Total number of complications (ascites, hepatic encephalopathy, hepatocellular carcinoma).

1.12. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 12 Portal pressure (mmHg).

1.13. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 13 Indocyanine green clearance (ml plasma/min).

1.14. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 14 Galactose elimination capacity (mmol/min).

1.15. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 15 Biopsy finding, improvement (fat).

1.16. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 16 Biopsy finding, significant improvement in follow‐up specimens (fatty).

1.17. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 17 Biopsy finding, improvement (inflammatory cells).

1.18. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 18 Biopsy finding, significant improvement in follow‐up specimens (hepatitis).

1.19. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 19 Biopsy finding, improvement (acute necrosis).

1.20. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 20 Biopsy finding, significant improvement in follow‐up specimens (focal necrosis).

Sexual function 
 The CSL 1986 trial evaluated sexual function in men with alcoholic cirrhosis (Gluud 1988b). At entry, 67% (95% confidence limits 61% to 74%) of 221 patients complained of sexual dysfunction (defined as problems with sexual desire, erection, or ejaculation). During follow‐up (median 30 months (range 1 to 40 months) sexual dysfunction in the total patient group improved significantly (P < 0.05) at 6, 12, and 24 months follow‐up. However, there were no significant differences between the testosterone treated and the placebo treated patients regarding the proportion of patients with sexual dysfunction at any time during follow up (1, 6, 12, 24, and 36 months). At 12 months follow‐up the RR of sexual dysfunction was 1.11 (95% CI 0.83 to 1.48) (Analysis 1.34).

1.34. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 34 Sexual dysfunction at 12 months follow‐up.

Liver biochemistry and other biochemical outcome measures 
 Anabolic‐androgenic steroids significantly increased serum (s)‐testosterone and blood (b)‐haemoglobin levels: 
 ‐ s‐testosterone (mmol/l): WMD 31.90 (95% CI 11.99 to 51.81) P < 0.005 (Analysis 1.27); 
 ‐ b‐haemoglobin (mmol/l): WMD 0.60 (95% CI 0.13 to 1.07) P < 0.05 (Analysis 1.26); 
 ‐ s‐IgM (g/l): WMD ‐0.80 (95% CI ‐1.34 to ‐0.26) (Analysis 1.31) and significantly decreased s‐immunoglobulin (Ig) levels.

1.27. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 27 Serum‐testosterone (nmol/l).

1.26. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 26 Blood‐haemoglobin (mmol/l).

1.31. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 31 Serum‐immunoglobulin M (g/l).

However, anabolic‐androgenic steroids did not significantly affect the majority of the outcome biochemical measures: 
 ‐ s‐bilirubin (mg/dl): WMD 0.01 (95% CI ‐0.25 to 0.27) (Analysis 1.21); 
 ‐ plasma prothrombin time (each study used different units): SMD 0.22 (95% CI ‐0.10 to 0.55) (Analysis 1.22); 
 ‐ s‐albumin (g/dl): WMD 0.16 (95% CI ‐0.04 to 0.36) (Analysis 1.23); 
 ‐ s‐alkaline phosphatases ((U/l): WMD ‐2.51 (95% CI ‐9.86 to 4.85) (Analysis 1.24); 
 ‐ s‐aspartate aminotransferase (U/I): WMD ‐16.69 (95% CI ‐42.24 to 8.86) (Random‐effects model) (Analysis 1.25); 
 ‐ s‐creatinine (umol/l): WMD 3.20 (95% CI ‐10.16 to 16.56) (Analysis 1.28); 
 ‐ s‐Ig G (g/l): WMD ‐1.20 (95% CI ‐3.06 to 0.66) (Analysis 1.29); 
 ‐ s‐IgA (g/l): WMD ‐0.20 (95% CI ‐1.19 to 0.79) (Analysis 1.30).

1.21. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 21 Serum‐bilirubin (mg/dl).

1.22. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 22 Prothrombin time.

1.23. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 23 Serum‐albumin (g/dl).

1.24. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 24 Serum‐alkaline phosphatases (U/l).

1.25. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 25 Serum‐aspartate aminotransferase (U/l).

1.28. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 28 Serum‐creatinine (umol/l).

1.29. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 29 Serum‐immunoglobulin G (g/l).

1.30. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 30 Serum‐immunoglobuilin A (g/l).

Adverse events 
 Only two of the five trials reported adverse events (CSL 1986; Bonkovsky 1991). Anabolic‐androgenic steroids had no significant effect on the occurrence of non‐serious adverse events (RR 1.14; 95% CI 0.50 to 2.59). In the anabolic‐androgenic steroids group 11/152 (7.2%) patients had non‐serious adverse events versus 8/108 (7.4%) patients in the control group (Analysis 2.1). The adverse events observed in the anabolic‐androgenic steroids group encompassed mild nausea (n = 4 patients), which was managed by giving oxandrolone with food; and diffuse complaints (n = 5 patients). The adverse events observed in the control group encompassed diffuse complaints (n = 6 patients).

2.1. Analysis.

Comparison 2 Adverse events, Outcome 1 Non‐serious adverse events.

Anabolic‐androgenic steroids had no significant effect on the occurrence of serious adverse events, although there was a trend (RR 4.54; 95% CI 0.57 to 36.30). In the anabolic‐androgenic steroids group 7/152 (4.6%) patients had serious adverse events versus 1/108 (0.9%) patient in the control group (Analysis 2.1). The adverse events observed in the anabolic‐androgenic steroids group encompassed vascular thrombosis in the portal or hepatic veins (n = 3 patients), myocardial infarct (n = 1 patient), and polycythaemia (n = 3 patients). The adverse event observed in the control group encompassed polycythaemia (n = 1 patient) (Analysis 2.2).

2.2. Analysis.

Comparison 2 Adverse events, Outcome 2 Serious adverse events.

Quality of life and health economics 
 Only one trial measured quality of life employing crude measures, ie, numbers of days with normal activity and number of days in hospital within the last 100 days (CSL 1986).

At 12 months, the number of days with normal activity (ie, activity similar to premorbid activity) within the last 100 days was not significantly different between placebo and testosterone treatment: WMD 3.10 (95% CI ‐12.55 to 18.75) (Analysis 1.32).

1.32. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 32 Number of days with normal activity within the last 100 days at 12 months follow‐up.

Anabolic‐androgenic steroids did not significantly affect the number of days in hospital within the last 100 days at 12 months follow up (CSL 1986): WMD 0.50 (‐2.27 to 3.27) (Analysis 1.33). We were unable to identify other data on health economics.

1.33. Analysis.

Comparison 1 Anabolic‐androgenic steroids versus control, Outcome 33 Number of days in hospital within the last 100 days at 12 months follow‐up.

Funnel plot asymmetry 
 Due to the paucity of randomised clinical trials and observed outcome measures reported in the included randomised clinical trials we did not try to analyse for funnel plot asymmetry.

Discussion

We could not demonstrate any significant effects of anabolic‐androgenic steroids on mortality, liver‐related mortality, liver complications, liver histology, and liver biochemistry when tested against placebo or no intervention in patients with alcoholic hepatitis and/or cirrhosis. We were unable to identify any randomised trials in patients with alcoholic steatosis.

Performing subgroup analysis considering methodological quality of the randomised clinical trials, contrasting high‐quality trials versus low‐quality trials did not reveal any significant influence of anabolic‐androgenic steroids on the RR of mortality. This observation may not be in accordance with empirical studies suggesting significant overestimation of intervention effects in unblinded randomised clinical trials (Schulz 1995; Kjaergard 2001), but is likely due to insufficient power. Subgroup analyses taking different treatments (oxandrolone, testosterone, methenolone), stage of liver disease (mainly alcoholic hepatitis or alcoholic cirrhosis), or duration of follow‐up into consideration showed no significant effect of anabolic‐androgenic steroids versus control in any of the subgroups.

The lack of effect of anabolic‐androgenic steroids on mortality was also observed taking into consideration the excluded trial evaluating oxandrolone plus nutritional support versus placebo (Mendenhall 1993b). We excluded this randomised clinical trial because it evaluated the combination of anabolic‐androgenic steroids plus another intervention. On the other hand, nutrition has no verified effect on mortality of patients with alcoholic hepatitis (Cabré 2000; Cabré 2001; Koretz 2001). Accordingly, the present results confirm our previous meta‐analyses on anabolic‐androgenic steroids for alcoholic liver disease (Gluud 1988a, see other published versions of this review).

Some trials have claimed that oxandrolone may provide beneficial effects in patients with alcoholic hepatitis. In a six‐month conditional analysis, removing patients that died within the first two months after randomisation, Mendenhall and associates (Mendenhall 1984a) observed a significant effect of oxandrolone on mortality in patients with moderate disease. Such analyses are difficult to interpret. First, by removing the patients who died early (within one or two months) you are not likely to have a randomised comparison any more. Secondly, this analysis was based on a subgroup analysis of patients. Mendenhall and associates (Mendenhall 1993b) could not demonstrate any significant effect of oxandrolone plus nutritional support versus placebo. In a subgroup of patients with moderate malnutrition and adequate caloric intake, however, oxandrolone plus nutritional support reduced six‐month mortality significantly. Subgroup analyses are often misleading (Yusuf 1991; Oxman 1992; Assmann 2000). Because of such risks researchers need to be cautious about subgroup analyses and the interpretation of the results of the ones that they feel compelled to do.

Anabolic‐androgenic steroids were without any significant effect on liver histology and liver haemodynamics. We were also unable to detect any significant influence of anabolic‐androgenic steroids on liver‐related mortality, ascites, hepatic encephalopathy, hepatocellular carcinoma, pretibial oedema, and weight. Anabolic‐androgenic steroids were also without significant effect on all other liver biochemical and liver function variables. However, anabolic‐androgenic steroids significantly increased the b‐haemoglobin concentration (CSL 1986). These observations may be real, but even then cannot establish any therapeutic indication for anabolic‐androgenic steroids in alcoholic liver disease.

Aromatisable anabolic‐androgenic steroids lead to a significant increase in plasma oestrogen concentrations. This increase is significantly higher in patients with liver cirrhosis than in controls (Gluud 1988a). Due to a higher increase in testosterone than in concentrations of oestrogens, the oestrogen/testosterone‐ratio decreases during testosterone administration (Gluud 1988a). In accordance, a significant decrease was observed in the proportion of patients with gynaecomastia in the testosterone treated group (CSL 1986). This effect may not, however, establish an indication for using testosterone in these patients considering the risk of serious adverse events and the fact that symptomatic gynaecomastia may be treated with surgical ablation.

According to the observations of the CSL trial (CSL 1986), the testosterone‐treated patients did not differ significantly from the placebo‐treated patients regarding changes in sexual function (Gluud 1988a; Gluud 1988b). On the positive side, a number of the male cirrhotic patients showed improvements of their sexual function irrespective of the treatment offered to the patients (Gluud 1988b).

Anabolic‐androgenic steroids were not associated with a significant increase in non‐serious adverse events. There was a trend for the treated group to have more serious adverse events, but that did not achieve statistical significance (P = 0.15). Three patients with portal or hepatic thrombosis, one with myocardial infarction, and three with polycythaemia constituted the serious adverse events reported in the anabolic‐androgenic steroids group versus one with polycythaemia in the control group. We observed that testosterone increased b‐haemoglobin. It has been claimed that oxandrolone increases clotting factors in cirrhotic patients with vitamin K resistant hypoprothrombinaemia (Tamburro 1967). It cannot be excluded that testosterone may increase the incidence of thrombosis, possibly via an increase in estrogens during anabolic‐androgenic steroids administration (Lewis 1983; Gluud 1988b). Acute myocardial infarction and stroke have been reported as serious adverse events in several athletes using androgens (Ferenchick 1991).

Accordingly, we have been unable to identify any convincing evidence supporting anabolic‐androgenic steroids for alcoholic liver disease patients. However, this review does not preclude the possibility of a beneficial effect of anabolic‐androgenic steroids in alcoholic liver disease; or in other form of liver disease (Shahidi 2001). Evidence about how much medical interventions work may change over time. Ioannidis and Lau (Ioannidis 2001) recently applied 'recursive cumulative meta‐analyses' of randomised clinical trials to evaluate the relative change in the pooled treatment effect over time for 60 medical interventions within pregnancy/perinatal medicine and cardiology. With 500 accumulated patients, the pooled relative risk may change by about 0.6 to 1.7 fold in the immediate future. When 2000 patients have been randomised, the pooled relative risk may change by 0.7 to 1.3 fold.

Meta‐analyses and randomised clinical trials have been unable to demonstrate significant effects of colchicine (Rambaldi 2005a), glucocorticosteroids (Christensen 1995; Gluud 2001), insulin/glucagon (Trinchet 1992), milk thistle (Flora 1998; Rambaldi 2005b), propylthiouracil (Rambaldi 2005c), parenteral amino acid supplementation (Mezey 1991), amlodipine (Bird 1998), and polyenylphosphatidylcholine (Lieber 2000; Lieber 2003) for alcoholic liver disease. At present, S‐adenosyl‐L‐methionine (Mato 1999) and pentoxifylline (Akriviadis 2000) may seem promising interventions for alcoholic liver disease (Mato 1999), but more randomised clinical trials are needed before S‐adenosyl‐L‐methionine can be recommended (Rambaldi 2006) and this also applies to pentoxifylline, which has only been evaluated in one published randomised trial including patients with severe alcoholic hepatitis. Abstinence from ethanol remains the best intervention for alcoholic liver disease (Poynard 1994).

Authors' conclusions

Implications for practice.

This systematic review could not demonstrate any significant beneficial effect of anabolic‐androgenic steroids on mortality, liver‐related mortality, liver complications, and liver histology of patients with alcoholic liver disease.

Implications for research.

The absence of evidence for an effect of anabolic‐androgenic steroids on clinically relevant outcome variables, however, does not mean that there is evidence of lack of effect. If researchers wish to conduct new randomised clinical trials they ought to be large and closely monitored for the occurrence of adverse events. We recommend that investigators report their trials according to guidelines described in the CONSORT Statement (www.consort‐statement.org).

What's new

Date	Event	Description
23 September 2008	Amended	Converted to new review format.

History

Protocol first published: Issue 2, 2001
 Review first published: Issue 1, 2003

Date	Event	Description
21 August 2006	Amended	Amendment.

Appendices

Appendix 1. Search Strategies

Database	Time of search	Search strategy
The Cochrane Hepato‐Biliary Group Controlled Trials Register, 45 hits	June 2006.	(steroid* OR androgenic OR anabolic OR testosterone OR oxandrolone OR methandrostenolon OR 'methenolone enanthate') AND (alcoholic and ('liver disease*' or steatosis or fibrosis or hepatitis or cirrhosis))
The Cochrane Central Register of Controlled Trials (CENTRAL/CCTR) in The Cochrane Library, 87 hits	Issue 2, 2006.	#1 STEROIDS explode all trees (MeSH) 26594 #2 (steroid* or androgenic or anabolic or testosterone or oxandrolone or methandrostenolon or (methenolone next enanthate)) 10098 #3 (#1 or #2) 31763 #4 LIVER DISEASES ALCOHOLIC explode all trees (MeSH) 330 #5 (alcoholic and ((liver next disease*) or steatosis or fibrosis or hepatitis or cirrhosis)) 680 #6 (#4 or #5) 683 #7 (#3 and #6) 111
MEDLINE (WinSPIRS 5.0), 82 hits	1950 to June 2006.	#1 555154 explode "Steroids"/ all subheadings #2 243711 steroid* or androgenic or anabolic or testosterone or oxandrolone or methandrostenolon or methenolone enanthate #3 666273 #1 or #2 #4 9371 explode "Liver‐Diseases‐Alcoholic"/ all subheadings #5 13656 alcoholic and (liver disease* or steatosis or fibrosis or hepatitis or cirrhosis) #6 13847 #4 or #5 #7 889 #3 and #6 #8 536466 random* or blind* or placebo* or meta‐analysis #9 82 #7 and #8
EMBASE (WinSPIRS 5.0), 85 hits	1980 to June 2006.	#1 332319 explode "steroid"/ all subheadings #2 179516 steroid* or androgenic or anabolic or testosterone or oxandrolone or methandrostenolon or methenolone enanthate #3 390950 #1 or #2 #4 6036 explode "alcohol‐liver‐disease"/ all subheadings #5 7201 alcoholic and (liver disease* or steatosis or fibrosis or hepatitis or cirrhosis) #6 9230 #4 or #5 #7 613 #3 and #6 #8 469358 random* or blind* or placebo* or meta‐analysis #9 85 #7 and #8
Science Citation Index Expanded, 37 hits (http://portal.isiknowledge.com/portal.cgi?DestApp=WOS&Func=Frame)	1945 to June 2006.	http://portal.isiknowledge.com/portal.cgi?DestApp=WOS&Func=Frame #1 >100,000 TS=(steroid* OR androgenic OR anabolic OR testosterone OR oxandrolone OR methandrostenolon OR 'methenolone enanthate') #2 8,661 TS=(alcoholic and ('liver disease*' or steatosis or fibrosis or hepatitis or cirrhosis)) #3 195 #2 AND #1 #4 >100,000 TS=(random* or blind* or placebo* or meta‐analysis) #5 37 #4 AND #3
LILACS, 0 hits (http://bases.bireme.br/cgi‐bin/wxislind.exe/iah/online/)	1982 to June 2006.	Steroid * and alcoholic and (hepatitis or liver disease)

Data and analyses

Comparison 1. Anabolic‐androgenic steroids versus control.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality	5	499	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.79, 1.29]
2 Liver‐related mortality	3	433	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.60, 1.15]
3 Ascites	4	224	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.47, 1.63]
4 Hepatic encephalopathy	4	225	Risk Ratio (M‐H, Fixed, 95% CI)	1.34 [0.53, 3.42]
5 Hepatocellular carcinoma	4	465	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.13, 2.66]
6 Total number of complications (ascites, hepatic encephalopathy, hepatocellular carcinoma)	4	465	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.74, 2.10]
7 Pretibial edema	1	96	Risk Ratio (M‐H, Fixed, 95% CI)	0.51 [0.12, 2.17]
8 Gynaecomastia	1	95	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.15, 0.72]
9 Prostatic hypertrophia	1	91	Risk Ratio (M‐H, Fixed, 95% CI)	2.18 [0.64, 7.39]
10 Sexual dysfunction	1	94	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.58, 1.42]
11 Weight (kg)	1	93	Mean Difference (IV, Fixed, 95% CI)	‐0.40 [‐6.26, 5.46]
12 Portal pressure (mmHg)	1	34	Mean Difference (IV, Fixed, 95% CI)	1.84 [‐2.19, 5.87]
13 Indocyanine green clearance (ml plasma/min)	1	28	Mean Difference (IV, Fixed, 95% CI)	‐33.26 [‐131.01, 64.49]
14 Galactose elimination capacity (mmol/min)	1	31	Mean Difference (IV, Fixed, 95% CI)	‐0.24 [‐0.74, 0.26]
15 Biopsy finding, improvement (fat)	1	10	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.71, 1.86]
16 Biopsy finding, significant improvement in follow‐up specimens (fatty)	1	126	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.68, 1.33]
16.1 Fatty change	1	126	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.68, 1.33]
17 Biopsy finding, improvement (inflammatory cells)	1	10	Risk Ratio (M‐H, Fixed, 95% CI)	1.50 [0.34, 6.70]
18 Biopsy finding, significant improvement in follow‐up specimens (hepatitis)	1	126	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.48, 1.89]
18.1 alcoholic hepatitis	1	126	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.48, 1.89]
19 Biopsy finding, improvement (acute necrosis)	1	10	Risk Ratio (M‐H, Fixed, 95% CI)	1.8 [0.81, 3.99]
20 Biopsy finding, significant improvement in follow‐up specimens (focal necrosis)	1	126	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.76, 1.10]
20.1 Focal necrosis	1	126	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.76, 1.10]
21 Serum‐bilirubin (mg/dl)	3	165	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.25, 0.27]
22 Prothrombin time	3	163	Std. Mean Difference (IV, Fixed, 95% CI)	0.22 [‐0.10, 0.55]
23 Serum‐albumin (g/dl)	2	123	Mean Difference (IV, Fixed, 95% CI)	0.16 [‐0.04, 0.36]
24 Serum‐alkaline phosphatases (U/l)	2	120	Mean Difference (IV, Fixed, 95% CI)	‐2.51 [‐9.86, 4.85]
25 Serum‐aspartate aminotransferase (U/l)	3	164	Mean Difference (IV, Random, 95% CI)	‐16.69 [‐42.24, 8.86]
26 Blood‐haemoglobin (mmol/l)	1	94	Mean Difference (IV, Fixed, 95% CI)	0.60 [0.13, 1.07]
27 Serum‐testosterone (nmol/l)	1	89	Mean Difference (IV, Fixed, 95% CI)	31.90 [11.99, 51.81]
28 Serum‐creatinine (umol/l)	1	95	Mean Difference (IV, Fixed, 95% CI)	3.20 [‐10.16, 16.56]
29 Serum‐immunoglobulin G (g/l)	1	91	Mean Difference (IV, Fixed, 95% CI)	‐1.20 [‐3.06, 0.66]
30 Serum‐immunoglobuilin A (g/l)	1	90	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐1.19, 0.79]
31 Serum‐immunoglobulin M (g/l)	1	91	Mean Difference (IV, Fixed, 95% CI)	‐0.80 [‐1.34, ‐0.26]
32 Number of days with normal activity within the last 100 days at 12 months follow‐up	1	147	Mean Difference (IV, Fixed, 95% CI)	3.10 [‐12.55, 18.75]
33 Number of days in hospital within the last 100 days at 12 months follow‐up	1	96	Mean Difference (IV, Fixed, 95% CI)	0.5 [‐2.27, 3.27]
34 Sexual dysfunction at 12 months follow‐up	1	147	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.83, 1.48]

Comparison 2. Adverse events.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Non‐serious adverse events	2	260	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.50, 2.59]
2 Serious adverse events	2	260	Risk Ratio (M‐H, Fixed, 95% CI)	4.54 [0.57, 36.30]

Comparison 3. Sensitivity analyses.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality ‐ worst‐case scenario	5	499	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.86, 1.25]
2 Mortality and generation of the allocation sequence	5	499	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.79, 1.29]
2.1 Adequate generation of the allocation sequence	2	260	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.72, 1.98]
2.2 Inadequate generation of the allocation sequence	3	239	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.72, 1.24]
3 Mortality and allocation concealment	5	499	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.79, 1.29]
3.1 Adequate allocation concealment	2	394	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.76, 1.26]
3.2 Inadequate allocation concealment	3	105	Risk Ratio (M‐H, Fixed, 95% CI)	1.38 [0.54, 3.50]
4 Mortality and double blinding	5	499	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.79, 1.29]
4.1 Adequately blinded	2	253	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.79, 1.98]
4.2 Inadequately blinded	3	246	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.68, 1.18]
5 Mortality and follow‐up	5	499	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.79, 1.29]
5.1 Adequate follow‐up	4	465	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.79, 1.29]
5.2 Inadequate follow‐up	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.16, 6.30]
6 Mortality ‐ duration of follow‐up	5	499	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.79, 1.29]
6.1 Short‐term follow‐up (within 21 days)	2	73	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.16, 6.30]
6.2 Long‐term follow‐up (at least six months)	3	426	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.79, 1.29]
7 Mortality ‐ different treatment	5	499	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.79, 1.29]
7.1 Oxandrolone	3	246	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.68, 1.18]
7.2 Testosterone	1	221	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.72, 1.98]
7.3 Testosterone propionate or methenolone	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	1.57 [0.53, 4.65]
8 Mortality ‐ stage of alcoholic liver disease	5	499	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.79, 1.29]
8.1 Alcoholic hepatitis	3	246	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.68, 1.18]
8.2 Alcoholic cirrhosis	2	253	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.79, 1.98]
9 Mortality ‐ according to co‐intervention	6	772	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.81, 1.21]
9.1 Anabolic‐androgenic steroids	5	499	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.79, 1.29]
9.2 Anabolic‐androgenic steroids plus nutritional therapy	1	273	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.66, 1.35]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Bonkovsky 1991.

Methods	Sample size: no justification. Generation of the allocation sequence: adequate, by random number table. Allocation concealment: adequate, by opaque envelope technique. Blinding: inadequate, unblinded. Intention‐to‐treat analysis: not described, but presumably used. Follow‐up: adequate.
Participants	Multicentre clinical trial including 39 patients (19 men and 20 women) from three hospitals, with severe alcoholic hepatitis. Eight patients (three men and five women) were allocated to the oxandrolone group (Experimental I), mean age (SEM) 39 ± 3 years, range 32 to 46 years. Ten patients (five men and five women) were allocated to the oxandrolone plus nutritional supplementation group (Experimental II), mean age (SEM) 46 ± 4 years, range 36‐51 years. Twelve patients (seven men and five women) were allocated to the control group (Control I), with a mean age (SEM) 41± 2 years, range 35 to 46 years; nine patients (four men and five women) were allocated to the control group treated with nutritional supplementation (Control II), with a mean age (SEM) 44± 2 years, range 37 to 49 years. Inclusion criteria: history of excessive drinking; liver biochemistry: s‐aspartate aminotransferase < 500 U/L, ratio of s‐transaminases > 1.5, s‐albumin< 3.0 g/dl, s‐bilirubin > 5 mg/dl, and prothrombin time < 6 seconds above control; cessation of alcohol intake 5 to 14 days before entry into the trial. Liver biopsies showed florid alcoholic hepatitis in all patients, having a biopsy (n = 31). Exclusion criteria: recent severe gastrointestinal bleeding; severe degree of ascites; severe degree of encephalopathy; renal insufficiency; sepsis; acute pancreatitis; haemodynamic instability; advanced pulmonary disease; diabetes mellitus; active malignancy.
Interventions	There was a 10‐day baseline period of observation during which dietary and intravenous intakes and weights were recorded daily, and weekly routine and special quantitative tests of liver function were calculated. Experimental I: oxandrolone (20 mg orally four times a day). Experimental II: oxandrolone (20 mg orally four times a day) plus nutritional supplementation consisting of two liters of 3.5% crystalline amino acids in 5% dextrose given by peripheral vein. Control I: no intervention consisting of standard therapy (alcohol abstinence, a balanced nutritionally adequate diet, and multivitamins). Control II: nutritional supplementation consisting of two liters of 3.5% crystalline amino acids in 5% dextrose given by peripheral vein plus no intervention (standard therapy). Duration of treatment and of follow‐up: 21 days.
Outcomes	Mortality. Biochemistry and function. Liver histology. Adverse events.
Notes	Sent letter. H. Bonkovsky answered the letter in 2001.
Risk of bias
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

CSL 1986.

Methods	Sample size: based on mortality. Generation of the allocation sequence: adequate, by random numbers (skewed randomisation 3:2; testosterone versus placebo). Allocation concealment: adequate, by serially numbered sealed boxes. Blinding: adequate, double blind with placebo of identical appearance, smell, and taste. Intention‐to‐treat analysis: not mentioned, but used. Follow‐up: adequate more than 10% of the patients dropped out or were withdrawn.
Participants	Multicentre clinical trial including 221 men from five medical departments. Of these 134 patients (53 years, range 24 to 79 years) were allocated to the testosterone group and 87 (53 years, range 29 to 78) to the placebo group. Inclusion criteria: daily ethanol consumption above 50 grams for more than two years; liver cirrhosis diagnosed by liver biopsy for the first time within the last six months; specific etiology of cirrhosis other than ethanol could be excluded. Exclusion criteria: a) unable to cooperate; b) refusal of informed consent; c) hepatitis B surface antigen positive; d) hepatocellular carcinoma; e) other malignancies; f) other reasons.
Interventions	Experimental: micronized‐free testosterone tablets 200 mg (two tablets), three times daily. Control: placebo (two tablets three times daily). Patients were advised not to drink alcoholic beverages, and were offered the standard treatment. Duration of treatment and of follow‐up: 36 months.
Outcomes	Mortality. Complications. Biochemistry and function. Liver histology. Adverse events. Gynaecomastia. Sexual dysfunction. Quality of life. Number of days in hospital.
Notes	Data on mortality, ascites, hepatic encephalopathy, hepatocellular carcinoma, pretibial edema, prostatic hypertrophia, sexual dysfunction, gynaecomastia were for patients followed‐up and treated for 24 months.
Risk of bias
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Fenster 1966.

Methods	Sample size: no justification. Generation of the allocation sequence: unclear, no information. Allocation concealment: unclear, no information. Blinding: adequate, double blind with placebo of identical appearance. Intention‐to‐treat analysis: not used. Follow‐up: adequate, more than 10% of the patients dropped out or were withdrawn.
Participants	Thirty‐two patients were included in the trial. Patients were divided in three treatment groups: 1) nine patients with testosterone; 2) twelve patients with methenolone; 3) eleven patients with placebo. Inclusion criteria: clinical and laboratory evidence of chronic alcoholic liver disease; evidence of active parenchymal dysfunction, as distinct from manifestations of portal hypertension. Exclusion criteria: gastrointestinal bleeding or suspicion of prostatic carcinoma.
Interventions	Experimental I: testosterone propionate intramuscularly 100 mg every other day. Experimental II: methenolone enanthate intramuscularly 100 mg every other day. Control: placebo injection. Duration of the treatment: one month. Duration of follow‐up: at least six months.
Outcomes	Mortality. Biochemistry. Liver histology. Since both testosterone and methenolone are anabolic‐androgenic steroids we combined the results. There was not significant difference in mortality and biochemistry between the testosterone and methenolone groups.
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Mendenhall 1977.

Methods	Sample size: no justification. Generation of the allocation sequence: unclear, no information. Allocation concealment: unclear, no information. Blinding: unclear, described as double blind, but no information on how blinding was achieved. Intention‐to‐treat analysis: not mentioned, but presumably used. Follow‐up: not described.
Participants	Thirty‐four patients with alcoholic hepatitis were included in the trial. Inclusion criteria: ethanol ingestion > 100 g/day for at least one year; hepatomegaly ( > 12 cm) and significant jaundice (bilirubin > 5 mg/dl). Liver biopsy was obtained in about 70% of patients to confirm the diagnosis.
Interventions	Experimental I: oxandrolone 80 mg/day orally x 14 days then decreased over a period of seven days. Experimental II: prednisolone 60 mg orally per day for four days, then a decreasing dosage per 16 days. Control: placebo. Additional treatment: supportive care. Duration of treatment and of follow‐up: 21 days.
Outcomes	Mortality. Biochemistry. Liver histology. Rate of improvement.
Notes	Sent letter. C.L. Mendenhall answered the letter. Only published as abstract.
Risk of bias
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Mendenhall 1984b.

Methods	Sample size: no justification. Generation of the allocation sequence: unclear ‐ no information. Allocation concealment: adequate, using centralised randomisation. Blinding: unclear, described as double blind, but no information on how blinding was achieved. Intention‐to‐treat analysis: not mentioned but presumably used. Follow‐up: adequate, more than 10% of the patients dropped out or were withdrawn.
Participants	Multicentre clinical trial including 173 men from six Veteran Administration Medical Centers, 88 (mean age plus standard deviation (SD) 50.4± 9.2 years) in the placebo group and 85 (mean age plus SD 52.2± 8.2 y) in the oxandrolone group. Inclusion criteria: history of alcoholism and liver disease enough to warrant treatment. Exclusion criteria: conditions that precluded the use of prednisolone; clinical or laboratory features atypical of alcoholic hepatitis without biopsy confirmation of the diagnosis; inability or unwillingness to participate; biopsy‐confirmed liver disease other than alcoholic hepatitis; parenteral drug abuse or a positive test for hepatitis B surface antigen; diseases unrelated to the liver disease that would have complicated the interpretation of therapy; unrelated conditions that required corticosteroid therapy either currently or in the recent past; and miscellaneous reasons.
Interventions	Experimental I: oxandrolone 80 mg orally day per 30 days. Experimental II: prednisolone 60 mg orally per day for four days, then a decreasing dosage per 30 days. Control: placebo. Duration of treatment: 30 days. Patients were then followed and evaluated monthly at outpatient clinics. If alcoholic hepatitis recurred and required re hospitalisation, the patient was reassigned to the same therapy for 30 days with his permission. Duration of follow‐up: one year.
Outcomes	Mortality. Complications. Biochemistry. Liver histology. Adverse events. Nutritional status.
Notes	Sent letter. C.L. Mendenhall answered the letter in 2001. The data on patients allocated to the glucocorticosteroid arm were excluded.
Risk of bias
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Mendenhall 1993b.

Methods	We excluded this randomised clinical trial because patients were treated with nutritional support and oxandrolone (two interventions) versus placebo as it was stated in the protocol. Since the etiology of the liver disease is alcoholic hepatitis we consider this randomised clinical trial only for sensitivity analysis.
Participants	Multicentre clinical trial including 273 men: 137 underwent active treatment; 136 received placebo.
Interventions	Experimental: The active treatment consisted of oxandrolone 80 mg/die accompanied by high‐calorie, high‐protein food supplement. Control: placebo treatment consisted of placebo tablets accompanied by the low calorie, low‐protein food supplement.
Outcomes
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	D ‐ Not used

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Eberhardt 1975	The study is quasi‐randomised. In 66 patients with mostly alcoholic liver disease, the effect of vitamin B versus clostebol (Steranabol) was tested.
Fiegel 1959	The study is observational (case series). The intervention consisted of the administration of high doses of androgenic derivates (durabolin) combined with vitamins and glucocorticosteroids to patients with liver cirrhosis.
Figueroa 1973	The study is observational (case series). Thirty patients with alcoholic and non‐alcoholic liver disease received mesterolone 75 mg per day per three months. No adverse events were observed.
Franken 1963	A non‐randomised study evaluating methandrostenolone versus prednisone in 51 patients with liver cirrhosis of mixed etiologies.
Gill 1984	The randomised clinical trial evaluated depo‐testosterone, prednisolone, and amino acid supplement versus placebo in patients with severe alcoholic hepatitis.
Girolami 1958	The study is observational (case series). Fifty cases of liver cirrhosis were treated with high dosages of testosterone. No serious adverse events were reported.
Gluud 1981	The study is a three‐armed parallel‐group randomised clinical trial comparing testosterone concentrations during 28 days of administration of three testosterone preparations to 24 patients with alcoholic cirrhosis (intramuscular Triolandren® (combination of short‐ and long‐acting testosterone); intramuscular testosterone propionate (short‐acting testosterone); peroral micronized testosterone) (total dose administered during the study 0.7 g, 1.2 g, and 22.4 g, respectively). No adverse events were observed. This trial was excluded due to the lack of a control group.
Hirayama 1970	The trial is not randomised. The effect of short‐term treatment with methenolon and stanozolol for patients with compensated liver cirrhosis was studied.
Islam 1973	The study is quasi‐randomised. Testosterone propionate was given to 32 patients with liver cirrhosis with ascites. Liver complications and survival rates differed significantly from those in the control group of 38 cases. After four years, the survival rate in testosterone group was 65.6%, and in the control group 36.8%.
Jabbari 1967	The study is observational (three cases). Patients with alcoholic fatty liver were treated with either norethandrolone (n = 2 patients) or Anavar (n = 1 patient).
Kley 1979	The study is observational (case series). The effect of testosterone enanthate administration was studied in patients with cirrhosis of the liver by the measurement of testosterone, androstenedione, estrone, and estradiol as well as free testosterone and free estradiol in the plasma.
Knobel 1975	The study is observational (case series). Fifteen patients with histologically proven liver cirrhosis were treated for four weeks with metenolonenanthate.
Leevy 1962	The study is observational (case series). Norethandrolone was given to 270 patients with fatty liver.
Lindner 1967	The study is observational (case series). In 186 patients with alcoholic and non‐alcoholic liver cirrhosis, methenolone acetate was given for a mean time of 94 weeks.
Mendenhall 1974	The study is observational (case series). Nine patients with varying degrees of fatty liver were studied. The authors evaluated hepatic lipoprotein release after norethandrolone administration.
Mendenhall 1993a	A randomised clinical trial involving 273 men was performed to evaluate the efficacy of oxandrolone in combination of an enteral food supplement versus no intervention in patients with severe alcoholic hepatitis. There was no significant reduction in the mortality rate in patients treated with oxandrolone and nutritional therapy.
Müting 1965	The study is observational (case series). In 24 patients with compensated liver cirrhosis, the effect on the lipoprotein metabolism of treatment with nandrolondecanoate was evaluated.
Puliyel 1977	The study is randomised, but the etiology of the liver disease was not given. In 23 patients with cirrhosis the effect of testosterone was studied.
Rosenak 1950	The study is observational (case series). In 12 patients with liver cirrhosis the effect of testosterone was evaluated on the protein metabolism.
Seifert 1967	The study is observational (case series) studying methenolone acetate for 33 patients with liver cirrhosis.
Tamburro 1967	The authors investigated clotting factors in 14 patients with liver cirrhosis before and after the therapy with Anavar®.
Wells 1960	The study is randomised, but the etiology of the liver cirrhosis was mixed. In 53 patients the effect of testosterone on mortality and other outcomes was studied.

Contributions of authors

AR drafted the protocol, coordinated the identification of studies, selected trials for inclusion, performed data extraction, and drafted the review. CG checked and revised all these processes. Both are guarantors for the review.

Sources of support

Internal sources

• The Copenhagen Trial Unit, Denmark.

External sources

• The Copenhagen Hospital Corporation's Research Council Grant on Getting Research into Practice (GRIP), Denmark.

• The 1991 Pharmacy Foundation, Denmark.

• The Danish Medical Research Council Grant on Getting Research into Practice (GRIP), Denmark.

Declarations of interest

Christian Gluud has been the principle and coordinating investigator on a randomised trial on testosterone for alcoholic cirrhosis (CSL 1986) as well as the author of two previous meta‐analyses on the topic (Gluud 1984; Gluud 1988a).

Edited (no change to conclusions)