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Sex-specific differences in the effects of local androgen metabolism in the heart as an indicator for the risk of myocardial infarction

Rodenburg, Eline M.a,d; Hofland, Johannesb; van Noord, Charlottea; Visser, Loes E.a,b,c; Dehghan, Abbasa; Barbalic, Majae; Danser, A.H. Janb; Lawson, Kim S.e; Hofman, Alberta; Witteman, Jacquelinea; Boerwinkle, Erice; Uitterlinden, André G.a,b; Stricker, Bruno H.a,d,b; de Jong, Frank H.b

doi: 10.1097/XCE.0000000000000037
Original articles

Aim: Testosterone influences cardiovascular risk and disease in a sex-specific manner. The more potent androgen 5α-dihydrotestosterone (DHT) can be formed through conversion of testosterone by the enzyme 5α-reductase. We hypothesized that, because of the presence of DHT in coronary and myocardial tissues, a sexually dimorphic effect can be observed if differences exist in genetics or mRNA expression in androgen-metabolizing enzymes.

Materials and methods: mRNA levels of steroidogenic enzymes and the androgen receptor (AR) were investigated in human myocardial tissue samples. Subsequently, all participants in the baseline cohort of the Rotterdam Study (RSI) with successful genotyping and without prevalent myocardial infarction (MI, N=5199) were recruited to study the association between single nucleotide polymorphisms (SNPs) within SRD5A1, SRD5A2, and AKR1C3 and incident MI using Cox regression models. Significant results were replicated within the Atherosclerosis Risk in Communities cohort and the second cohort of the RSII.

Results: The expression of SRD5A1, AKR1C3, and AR was found in all myocardial samples, whereas HSD17B3 and SRD5A2 expression levels were low and undetectable, respectively. Myocardial SRD5A1 expression was higher in women than in men. Within SRD5A1, SNP rs248805G>A was significantly associated with incident MI in western European women (hazard ratio 1.49; 95% confidence interval 1.19–1.87). This SNP is tightly linked to the HinfI polymorphism in SRD5A1 (rs248793G>C), of which the minor allele has been associated with a higher DHT/T ratio.

Conclusion: Genetic variation in SRD5A1 is associated with an increased risk of MI in western European women, possibly because of the sex-specific potential of local androgen conversion and effect.

Departments of aEpidemiology

bInternal Medicine

cHospital Pharmacy, Erasmus Medical Center, Rotterdam

dDrug Safety Department, Inspectorate of Health Care, The Hague, The Netherlands

eHuman Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA

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Correspondence to Eline M. Rodenburg, MD, Department of Epidemiology, Erasmus Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands Tel: +31 10 7043392; fax: +31 10 7044657; e-mail:

Received January 15, 2014

Accepted May 29, 2014

© 2014Wolters Kluwer Health Lippincott Williams Wilkins
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