The role of dehydroepiandosterone (DHEA) and its sulphated ester (DHEAS) [together known as DHEA(S)] in humans remains to be fully elucidated. They are the most abundant circulating steroid hormones in humans with the principle source of production being the adrenal glands. In adrenalectomised or hypoadrenal subjects it is not standard clinical practice to replace this hormone. Whilst this lack of DHEA(S) is clearly not life threatening, the published literature on the psychological effects of replacement in this population has shown some benefit in quality of life but data concerning the metabolic effects is conflicting and incomplete. We wish to carry out a study to measure the effect of DHEA(S) replacement in a group of adrenalectomised / hypoadrenal subjects and measure the outcome of a number of psychological and metabolic parameters both prior to and after twelve weeks of 50 mg/day DHEA(S) in a double blind randomised cross over design.

Mood, quality of life and sexual well being will be assessed using validated questionnaires. In addition, we will utilise the GCRC facility to measure body composition using total body water and DEXA. We will measure insulin sensitivity, exercise performance, muscle fatigability and VO2 max. Pre- and post- intervention muscle biopsies will assess DHEA(S) effects on myosin heavy chain isoform expression; skeletal muscle mitochondrial ATP production and be used to assess muscle enzyme levels.

Inclusion criteria:

• Subjects who have been adrenalectomised or have been hypoadrenal (from whatever cause) for > 24 months;
• Subjects who have been on a steady glucocorticoid replacement regime for >12 months;
• Women of child bearing age in whom oestrogen status has been steady for > 6 months - i.e. either on or off the oral contraceptive pill for that time;
• Subjects on other forms of hormone replacement therapy (e.g. thyroxin) in whom dose has remained the same for > 6 months.

Exclusion criteria:

• BMI >35 Kg/m2;
• Individuals with fasting blood glucose above 120mg/dl;
• A history of sex hormone dependant malignancy;
• A history of liver disease;
• Renal failure;
• Cardiovascular disease (other than hypertension);
• Polycythaemia;
• Pregnancy or breastfeeding;
• Cerebrovascular disorders;
• Neurological disorders;
• PSA levels above the age related reference range;
• Use of drugs known to alter mood within the 6 months prior to enrolment;
• Any drug known to affect hepatic biotransformation;
• Evidence of psychiatric disease or dementia;
• Postmenopausal women who have been on hormone replacement therapy for less than six months.