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Smoking, sex, risk factors and abdominal aortic aneurysm: is it all down to testosterone?
  1. C Mary Schooling
  1. School of Urban Public Health, Hunter College and CUNY School of Public Health, New York, New York, USA
  1. Correspondence to Professor C Mary Schooling, School of Urban Public Health, Hunter College, 2180 Third Avenue, New York, NY 10035, USA; mschooli{at}hunter.cuny.edu

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Jahangir et al1 provided a fascinating analysis showing, among older people, a higher risk of abdominal aortic aneurysm (AAA) in those with normal body mass index (BMI), those who smoke and in men. Although AAA is relatively rare, ruptured AAA has a high mortality rate, so prevention, based on reversible risk factors, is important. The observed association of normal BMI with AAA may be an artefact of weight loss due to ill-health in older people. Men often have higher rates than women of cardiovascular disease, for reasons which have not been clearly explained. Smoking undoubtedly causes AAA and is a major modifiable target of intervention.

Alternatively, a more comprehensive unifying hypothesis providing aetiology based insight for further interventions could be constructed. Unexpectedly, recent promotion of testosterone replacement among older men has highlighted that testosterone plays a role in cardiovascular disease.2 Consistent with this insight in a mouse model, castration of male mice inhibits AAA and androgen administration provokes AAA.3 Moreover, smoking and obesity may affect androgens. Nicotine and/or its metabolites, including cotinine and trans-3′-hydroxycotinine (3HC), share a disposal pathway with androgens, because they are inactivated by the uridine 5′-diphospho-glucuronosyltransferase (UGT) superfamily enzymes:4 ,5 the UGT2B10 enzyme for nicotine and cotinine, the UGT2B17 enzyme for 3HC,4 and the UGT2B7, UGT2B15 and UGT2B17 enzymes for androgens.5 As such, nicotine (and/or its metabolites) may competitively inhibit androgen glucuronidation and thereby raise androgen levels, consistent with the higher testosterone observed in smokers.6 In contrast, obesity, particularly in men, reduces testosterone because of the conversion of testosterone to oestrogen in fat cells.

Smoking, sex and risk factors for AAA1 could be parsimoniously explained in terms of testosterone causing AAA in people as in mice, with smoking and male sex increasing the risk of AAA because they both result in higher testosterone, while obesity, particularly for men, could protect against AAA by lowering testosterone. More importantly, such mechanistic insight suggests an additional prevention mechanism for AAA, because a proven prevention and treatment agent for cardiovascular disease, statins, also reduces testosterone.7 Given that AAAs may go undetected, if statins were definitively shown to protect against or reduce progression of AAA, it would provide another reason for the widespread promotion of statins in older people. Of course, not every aspect of this explanation has been rigorously tested, but a theory stands or falls by its predictive power, so the key question here from a theoretical and practical perspective is the role of statins, and potentially other antiandrogens, in the prevention and treatment of AAA.

References

Footnotes

  • Competing interests None.

  • Provenance and peer review Not commissioned; internally peer reviewed.

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