Testosterone Replacement in Non-alcoholic Steatohepatitis (TEREPINS)
Condition: Nonalcoholic Steatohepatitis; Hypogonadism
MeSH terms: Fatty Liver; Non-alcoholic Fatty Liver Disease; Hypogonadism
Study type: Interventional
Phase: Phase 2

Summary: 
      The main research questions are: In hypogonadal men with non-alcoholic steatohepatitis
      (NASH), does Testosterone Replacement Therapy (TRT), given for 12 months

        1. improve severity of steatosis on liver biopsy (Primary Question)?

        2. improve severity of associated steatohepatitis on liver biopsy?

        3. reduce liver fat content as assessed by proton Magnetic Resonance Spectroscopy (1H-MRS)?

      The work proposed here is an open pilot study of 10 patients, the main aim of which is to
      assess the effect size of TRT in regard to these end points (regarding which there are no
      published data), thereby allowing power calculations for a more definitive phase II trial.
      Other aims would be assessing recruitment and consent rates, which would also inform the
      design of the larger study.
    

Detailed description: 
      20-35% of adults have non-alcoholic fatty liver disease (NAFLD), which often leads to liver
      inflammation and damage and sometimes to cirrhosis, liver failure and liver cancer; it is now
      a common indication for liver transplantation in the UK. No medical treatment has been shown
      to be effective in preventing its progression.

      Some men with NAFLD have low serum levels of testosterone (male hormone). Often, levels are
      only slightly low and do not cause symptoms. However there are several reasons to think that
      these low levels may be aggravating the liver disease. NAFLD is thought to be caused by
      resistance of tissues to the actions of the hormone insulin (Insulin Resistance or IR). Low
      testosterone levels may cause IR. Treatments for prostatic cancer which lower testosterone
      levels result in both IR and in NAFLD. Mice who cannot produce testosterone also develop
      NAFLD and this is reversed by testosterone replacement.

      The investigators therefore speculate that testosterone replacement in men with NAFLD and low
      blood testosterone levels will reduce liver fat. Investigators will study 10 men with NAFLD
      and some inflammation or scarring (proven on liver biopsy performed for clinical diagnosis)
      and who have mildly reduced testosterone levels. Investigators will see if giving a 12 month
      course of Testosterone Replacement Therapy (TRT) to these men will lessen the severity of
      their liver damage.

      Consented patients will be seen after 6, 18, 30, 42 and 52 weeks. Patients will undergo a
      baseline clinical assessment, blood tests, an ultra sound scan, magnetic resonance scanning
      of the liver (to estimate liver fat), and a repeat liver biopsy to end the study.

      Patients will complete questionnaires, and undergo clinical assessment, blood tests, an
      ultrasound scan, and magnetic resonance (MR) scanning of the liver (to estimate liver fat) at
      baseline. Patients will have clinical assessments and blood tests at 6-weekly intervals for
      12 months. At 12 months patients will have a repeat liver biopsy, ultrasound and MR scan.
    

Intervention name(s): testosterone undecanoate
Intervention type(s): Drug
Intervention description(s): Preparation: 1 gram in 4 ml of oily base. Requires no special storage conditions. Proposed regime: 1 mg as a single intramuscular injection at 0, 6, 18, 30 and 42 weeks
Other intervention name(s): Nebido
Intervention MeSH terms: Methyltestosterone; Testosterone; Testosterone undecanoate; Testosterone enanthate; Testosterone 17 beta-cypionate
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; hypogonadism; testosterone replacement therapy