Androgen deprivation therapy (ADT) is one such treatment, and whilst being associated with significant improvements in survival for men with advanced and metastatic PCa, it has been associated with a number of adverse effects. Of particular note is an increased risk of cardiovascular disease and diabetes. ADT has also been associated with gains in fat mass during treatment, and this has been proposed as a potential mediator of the increased cardiometabolic risk. The purpose of this review was to explore this relationship further, highlighting the role body fat distribution (rather than absolute gains in fat mass) has in explaining the development of cardiometabolic disease in non-ADT populations, and providing an overview of our current knowledge of the influence of ADT on body fat distribution
For example, despite having greater total and relative amounts of fat mass, premenopausal females demonstrate improved cardiometabolic risk profiles than their male counterparts. Despite seeming somewhat counterintuitive, part of this discrepancy can be explained by differences in where the fat mass is distributed. Male-pattern weight gain is typically associated with greater amounts of fat mass stored within the abdominal region (apple-shaped fat distribution), whilst female pattern weight gain is typically seen around the hips and thighs (pear-shaped distribution). The former has much stronger associations with cardiometabolic risk factors such as insulin resistance, hypertension and hyperlipidaemia, whilst the latter has much weaker, or even inverse associations.
Furthermore, the development of more advanced imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) have allowed researchers to identify that much of the differences in cardiometabolic risk associated with different patterns of fat distribution are related to the depot of adipose tissue within which fat is stored. Specifically,there is mounting evidence that the accumulation of fat within visceral adipose tissue (VAT; located underneath the abdominal muscular wall surrounding the internal organs) is associated with significantly higher risk of cardiometabolic disease than the accumulation of fat within subcutaneous adipose tissue (SAT; located superficial to muscle and just underneath the skin). It is also worth noting that the accumulation of fat within subcutaneous adipose tissue surrounding the hips and thighs may even protect against the cardiometabolic abnormalities associated with weight gain. It is now understood that these different depots of adipose tissue have different genetic and metabolic profiles.
Adipocytes from VAT have been found to be much more metabolically active, releasing higher amounts of free fatty acids and proinflammatory cytokines which may contribute to insulin resistance and dyslipidemia. In contrast, adipocytes from SAT are considered to function as an ‘energy sink’ that can buffer against the toxic effects of excess lipids that would otherwise be exposed to other important metabolic organs such as the muscle, liver and pancreas, and are associated with a metabolically healthy inflammatory profile and improved insulin sensitivity.
Interestingly, whilst there is clear evidence that ADT is associated with gains in fat mass, there is insufficient evidence to clearly demonstrate where this fat accumulates. Current evidence suggests ADT is associated with significant gains in abdominal fat mass, however it is unclear whether this represents an accumulation of VAT and/or SAT. Results from a small number of studies suggest ADT is associated with gains in SAT within the abdominal region, with variable effects on VAT. This may be a reflection of the small sample sizes, lack of non-ADT control groups and/or use of tools used to assess changes in adipose tissue distribution in studies conducted to date.
Considering the current evidence suggesting ADT is primarily associated with gains in SAT, alternate mechanisms may underlie the increased cardiometabolic risk associated with ADT use (such as a direct effect of ADT on muscle, liver and/or endothelial functioning). However, given a number of the cardiometabolic changes seen during ADT appear similar to those associated with visceral adiposity (along with the limitations of current studies), further research is warranted. We feel that this is an important question to address in order to refine the development and selection of strategies aimed at counteracting the adverse cardiometabolic effects associated with ADT.
Written by: Stephen Foulkes, Institute of Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Australia
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