Endocrine Abstracts

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.