Disrupted production of the steroid hormones cortisol and DHEA may be at the root of body fat and metabolic changes in people taking protease inhibitors, according to a group of French researchers. A team from the Pasteur Institute found a significant correlation between lipid alterations, body fat changes and levels of the steroid hormone DHEA. The team suggests that steroid hormone production may be disrupted by the effects of protease inhibitors on cytochrome p450, a liver enzyme involved in the production of the steroid hormones.
The group tested 37 men on anti-retroviral therapy and 20 HIV-negative patients for a variety of immunological, metabolic and body fat changes, and found:
- 23/37 had body fat changes (lipodystrophy)
- changes were not related to particular drugs (35/37 were taking at least one PI and all were taking NRTIs)
- CD8+ cells were significantly higher in those with lipodystrophy, and were likely to have increased further after starting therapy, in those with lipodystrophy
- VLDL cholesterol was significantly higher in the lipodystrophy group
- So were all triglyceride measurements (but these measures were also elevated in those on HAART without lipodystrophy)
- Lipid ratios indicating atherogenic risk (coronary artery disease) pointed to significantly elevated risk in those with lipodystrophy
- Insulin concentration was significantly elevated compared with the control group; so too was serum leptin
- Cortisol levels were significantly higher in those on HAART, but there was no difference between those with and without lipodystrophy
- DHEA levels were significantly lower in the lipodystrophy group, and the ratio of cortisol to DHEA was markedly higher in the lipodystrophy group compared to the other groups.
- An elevation in this ratio was significantly correlated with lipid ratios indicating increased atherogenic risk
What do these findings mean?
DHEA acts as an anti-glucocorticoid, controlling levels of cortisol. If DHEA levels are suppressed, the authors of the report suggest that will permit cortisol levels to rise, encouraging an increase in lipid production. DHEA is also involved in the regulation of lipid production, and has been shown to reduce serum cholesterol and body fat in healthy men.
DHEA also regulates insulin secretion. A decline in DHEA levels could become self-perpetuating, because such a decline will also allow increased insulin secretion, an increase in insulin resistance and the knock-on effect of a further reduction in DHEA levels.
These hormones are involved in the regulation of fat deposits in both peripheral tissues (the arms and the legs) and the central adipose tissue. Elevated cortisol levels could stimulate fat cells in peripheral tissue to release stored fats, while the decline in DHEA levels will block the storage of fat in peripheral tissue. Meanwhile, circulating fat is being mopped up by central fat deposits, leading to the characteristic fat belly.
Cautions
However, it should be borne in mind that changes in the DHEA: cortisol ratio have been observed in people with AIDS prior to HAART, and that this study was conducted only in men. Individuals who developed lipodystrophy tended to have lower CD4 counts before commencing HAART, but similar weight before commencing HAART. Furthermore, hormonal changes in women may differ, and average DHEA levels in women have been observed to be lower. Another puzzle is the relationship seen in this study between strong CD8+ responses and increased lipodystrophy risk: in people with high levels of cytotoxic T-cells and fully suppressed viral load, one would expect to find high DHEA levels as a consequence of improved IL-2 production.
The need for studies
DHEA is already used quite frequently by people with HIV as an anti-depressant, as an energy booster and as an aid to building muscle (it is a precursor of testosterone). This makes it important to tell your doctor if you are using DHEA and also taking anti-retroviral therapy, so that any effects of DHEA can be detected in any clinical study you might take part in.
In order to determine if DHEA supplementation has any effect on the development, severity or reduction of body fat changes, large scale trials will be needed. At the moment DHEA is being marketed on the internet as the `wonder hormone' capable of burning fat, increasing energy and reversing ageing. Many different forms are available - read the factsheet at DAAIR's website on DHEA if you are interested in finding out more.
Reference
Christeff N & Gougeon L et al. Lipodystrophy defined by a clinical score in HIV-infected men on highly active antiretroviral therapy: correlation between dyslipidaemia and steroid hormone alterations. AIDS 13: 2251-2260, 1999.