Older Men and Testosterone
Condition: Hypogonadism
MeSH terms: Hypogonadism
Study type: Interventional

Summary: 
      Male hypogonadism is a clinical situation characterized by a low serum testosterone level in
      combination with a diversity of symptoms and signs such as reduced libido and vitality,
      decreased muscle mass, increased fat mass and depression. Similar symptoms in combination
      with subnormal testosterone levels are seen in some elderly men. Low testosterone levels are
      associated with known cardiovascular risk factors, and men with diabetes and stroke have
      lower testosterone levels than healthy men. Even though several publications have suggested
      that testosterone treatment in hypogonadal men may have beneficial effects, it is still
      uncertain if testosterone substitution in the aging man is indicated. Despite this
      uncertainty the sale of testosterone has increased enormously the last few years.

      We hypothesize that older men with subnormal testosterone levels have a varying degree of
      dysfunction/symptoms both physically and mentally, and that these dysfunction/symptoms can be
      improved with testosterone treatment.
    

Detailed description: 
      Older men and testosterone (Short version of the study protocol)

      Cohort study "How is life as an elderly man when serum testosterone is subnormal?"

      To investigate whether subnormal testosterone levels in elderly men (60-80 years old) is
      associated with clinical symptoms and/or disease, the investigators will ask men with normal
      testosterone (>11.3 nmol/l) and men with subnormal testosterone levels (<11.3 nmol/l) who
      participated in the last Tromsø study 2001 to participate in this study.

      Screening: Blood pressure, clinical examination including prostate examination, blood samples
      (testosterone, SHBG, LH, FSH, albumin and PSA).

      Aproximately 350 men had subnormal testosterone levels in the last Tromsø study and the
      researchers will try to include up to 200 men who still have subnormal testosterone levels
      and up to 200 age matched men who still have normal testosterone levels.

      Procedures

      Symptoms: Aging Male Symptom Score

      Muscle strength and function: The researchers will investigate muscle strength, peak torque
      with isokinetic dynamometry in the knee joint and muscle function (gait, balance and
      movement); Grip Strength

      Neuropsychological tests

        -  Cognitive function level: WAIS

        -  Memory: Wechslers Memory Scale Revised (WMS-R)

        -  Trail making A and B.

        -  Attention and concentration: Knox cube

        -  Cognitive flexibility: Word fluency test and Stroop test

        -  Quality of life: GHQ - 30 with Likert score

        -  Depression: Beck Depression Inventory

      The metabolic syndrome

        -  DEXA (Lunar Prodigy): *Whole body, body composition; *Lumbar spine and hip, bone mineral
           density

        -  CT scan of the abdomen to distinguish intra vs. subcutaneous fat deposits.

        -  Oral glucose tolerance test.

        -  Lipid profile /per oral fat load. (80 men will take part in this investigation)

        -  Examination of the androgen receptor, especially the CAG and GGN polymorphism of the
           androgen receptor has been associated with glucose and fat metabolism.

        -  Blood pressure and heart rate.

        -  Neuroendocrine regulation: LH, FSH, SHBG, estradiol, testosterone, cortisol, ACTH,
           IGF-1, IGFBP-3, TSH, FT4, prolactin and leptin.

        -  Sleep

      Interventions study "Should subnormal testosterone levels be treated?"

      To investigate whether older men with subnormal testosterone levels would benefit from
      physiological testosterone supplementation, the men with subnormal testosterone levels
      participating in the cohort study (approximately 150-200 men) will be asked to participate in
      a one year intervention study.

      Randomization and treatment:

      Double blind randomized (1:1) 1-year study. First injection at inclusion, second after 6
      weeks, the third injection after 16 weeks, the fourth at 28 weeks and the last at 40 weeks.
      Active treatment is Nebido, 1000 mg testosteron undecanoate, a 4 ml intramuscular depot
      injection. Schering AS will supply the study with both Nebido and placebo (containing "castor
      oil" and "benzyl benzoate").

      Registration of adverse events:

      All adverse events will be recorded in the participants CRF. Serious adverse events will be
      reported according to regulations.

      Procedures:

      The above-described procedures for the cohort study will also be performed in the
      intervention study.

      Testosterone levels, hematocrit, creatinine, ALAT and PSA will be controlled at every visit.

      Object variables for both the cohort and intervention study

      Primary:

      Psychosexual quality of life; Muscle strength

      Secondary:

      Muscle function; Body composition; Intraabdominal vs. subcutaneous fat distribution; CAG and
      GGN polymorphism in the androgen receptor gene; Bone mineral density; Per oral glucose
      tolerance test; Lipid profile/fat tolerance test; Neuropsychological test; Neuroendocrine
      regulation Sleep

      Statistics and methods:

      The study will be performed at the Clinical research ward at the University Hospital of North
      Norway.

      Comparisons between the groups will be assessed with non-parametrical tests (Mann-Whitney
      U-test) or ANOVA with a significant level p<0.05. In the intervention study delta-values will
      be used to assess changes during treatment and differences between the study groups. SPSS
      will be used as statistical program.

      Inclusion of patients to the cohort study should be completed during 2006 and the
      intervention study should be completed during 2007.

      Research partner Johan Svartberg, Department of Medicine, University Hospital of North
      Norway, Tromsø, Norway is the responsible investigator.

      Partners: Professor Rolf Jorde and John-Bjarne Hansen MD, PhD, Department of Medicine,
      Professor Johan Sundsfjord, Department of Clinical Chemistry and Professor Knut Waterloo,
      Department of Neurology, University Hospital of North Norway, Tromsø, Norway and Professor
      Aleksander Giwercman, Scanian Andrology Center, Department of Urology, Malmö University
      Hospital, Sweden.
    

Intervention name(s): Nebido (Testosterone Undecanoate)
Intervention type(s): Drug
Intervention MeSH terms: Methyltestosterone; Testosterone; Testosterone undecanoate; Testosterone enanthate; Testosterone 17 beta-cypionate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Men; testosterone; hypogonadal; aging; body composition; quality og life; Muscle strength; Aging male