Sex hormone binding globulin (SHBG) is a plasma glycoprotein responsible for high-affinity binding and transport of sex steroids. In men there is a large interindividual variation of SHBG levels, and consequently of serum total testosterone (T) and serum total estradiol (E2) levels. Family and twin studies suggested a strong genetic contribution to this variation, besides a hormonal and metabolic influence. The aim of this study was to examine the influence of a missense mutation (Asp327Asn), resulting in an additional N-glycosylation site, and a (TAAAA)n-repeat in the promotor region, resulting in altered transcription, on SHBG and sex steroid serum levels in a population of healthy men covering several decades of adult life. SHBG and hormone levels were measured in 1485 healthy men (aged 24 to 86 years). Carriers of the Asn327 allele were identified using restriction analysis; the number of TAAAA-repeats was determined by fragment analysis. Prevalence of the variant Asn-allele was 21.5%. The Asn-allele was associated with higher SHBG (Asp/Asn and Asn/Asn 27.1 nmol/l; Asn/Asn 24.8 nmol/l; P<0.001) and T levels (Asp/Asn and Asn/Asn 497 ng/dl; Asn/Asn 471 ng/dl; P=0.01), whereas for E2 no differences were found. For the (TAAAA)n-repeat, 7 different alleles were observed ranging from 5 to 11 TAAAA repeats with six, eight or nine repeats occurring the most frequently. Carriers of six TAAAA-repeats presented with significant higher SHBG (13.6%; P<0.001), T (9.9%;P<0.001) and E2 levels (6.1%; P=0.002) compared with non-carriers. For free T a marginal increase was found for carriers, whereas free E2 did not differ between carriers and non-carriers. Our findings show that the Asp327Asn polymorphism and the (TAAAA)n-repeat contribute to the interindividual variation in total serum T levels in healthy men through variation in SHBG concentrations.
03 - 07 May 2008
European Society of Endocrinology