Exploring the Relationship Between Androgen Metabolism, Metabolic Disease and Skeletal Muscle Energy Balance in Men

This study relates to men with hypogonadism, a condition describing a deficiency of androgens such as testosterone. Deficiency of these hormones occurs in men due to testicular (primary) or hypothalamic-pituitary (secondary) problems or may be observed in men undergoing androgen deprivation therapy for prostate cancer. Testosterone plays an important role in male sexual development and health, but also plays a key role in metabolism and energy balance. Men with testosterone deficiency have higher rates of metabolic dysfunction. This results in conditions such as obesity, nonalcoholic fatty liver disease, diabetes, and cardiovascular disease. Studies have confirmed that treating testosterone deficiency with testosterone can reduce the risk of some of these adverse metabolic outcomes, however cardiovascular mortality remains higher than the general population. We know that testosterone deficiency therefore causes metabolic dysfunction. However, research to date has not established the precise mechanisms behind this. In men with hypogonadism there is a loss of skeletal muscle bulk and function. Skeletal muscle is the site of many critical metabolic pathways; therefore it is likely that testosterone deficiency particularly impacts metabolic function at this site. Men with testosterone deficiency also have excess fat tissue, this can result in increased conversion of circulating hormones to a type of hormone which further suppresses production of testosterone. The mechanism of metabolic dysfunction in men with hypogonadism is therefore multifactorial. The purpose of this study is to dissect the complex mechanisms linking obesity, androgens and metabolic function in men. Firstly, we will carry out a series of detailed metabolic studies in men with testosterone deficiency, compared to healthy age- and BMI-matched men. Secondly, we will perform repeat metabolic assessment of hypogonadal men 6 months after replacement of testosterone in order to understand the impact of androgen replacement on metabolism. Lastly, we will perform the same detailed metabolic assessment in men with prostate cancer before and after introduction of a drug which causes testosterone deficiency for therapeutic purposes.

Sex

Male

Minimum age

18 Years

Maximum age

60 Years

Inclusion Criteria \[OBS1 \& IC1\]:

* Able to provide consent
* Ages 18 - 60 years
* BMI 20 - 35 kg / m2

Inclusion Criteria \[IC2\]:

* Able to provide consent
* Ages 40-85 years
* BMI 20 - 35 kg / m2

Exclusion Criteria \[OBS1 \& IC1\]:

* Contraindication to testosterone replacement for patients with hypogonadism
* BMI \<20 or \> 35 kg / m2
* Age \< 18 or \> 60 years
* Diabetes Mellitus
* Confirmed ischaemic heart disease
* In patients with secondary hypogonadism co-existence of any untreated pituitary hormone deficiencies (ACTH, TSH, GH deficiency)
* Glucocorticoid use via any route within the last three months
* Current intake of drugs known to impact upon steroid or metabolic function or intake of such drugs during the six months preceding the planned recruitment

Exclusion Criteria \[IC2\]:

* Diabetes mellitus
* Confirmed ischaemic heart disease
* Any glucocorticoid therapy in the last 3 months (inhaled/transdermal/systemic)
* BMI \<20 or \>35
* Pre-existing hormonal pathology - primary testicular or pituitary pathology
* Age \<40 or \>85