Secretion of luteinising hormone (LH) by the pituitary stimulates testicular production of testosterone (T) and is under negative feedback control. T is metabolised to dihydrotestosterone (DHT) by 5α-reductase and to estradiol (E2) by aromatase. How activity of population variants in these enzymes impact on the male gonadal axis is unclear.
We examined whether polymorphisms in 5α-reductase (SRD5A2) and aromatase (CYP19A1) genes predict circulating sex hormone concentrations.
Participants and methods
1,865 community-dwelling men aged 50.4±16.8 years. Early morning sera assayed for T, DHT and E2 using mass spectrometry, and sex hormone-binding globulin (SHBG) and LH using immunoassay. Two SRD5A2 and eleven CYP19A1 polymorphisms were analysed by PCR with genotyping successful in >98% of samples. Regression models were adjusted for age and cardiometabolic risk factors.
SRD5A2 polymorphism rs9282858 GA vs GG was associated with higher serum T (+1.5 nmol/L, P<0.001), lower DHT (-0.14 nmol/L, P=0.029) and higher SHBG (+3.3 nmol/L, P=0.001). Four CYP19A1 polymorphisms were associated with higher serum E2 and lower LH: rs2470152 CC/CT vs TT (E2 +3.4 pmol/L, P=0.048; LH -0.47 IU/L, P=0.003), rs17703883 TT/TC vs CC (E2 +7.1 pmol/L, P=0.014; LH -1.62 IU/L, P<0.001), rs2899470 GG/GT vs TT (E2 +3.8 pmol/L, P=0.039; LH -0.54 IU/L, P=0.006) and rs11575899 II/ID vs DD (E2 +7.2 pmol/L, P=0.001; LH -0.78 IU/L, P<0.001). CYP19A1 polymorphisms were associated with larger differences in circulating LH in men aged ≥65 years compared with <60 years. The two-copy haplotype rs10046=T, rs2899470=G, rs11575899=I, rs700518=G and rs17703883=T (prevalence 27.5%) was associated with higher E2 (+6.8 pmol/L, P=0.001) and lower LH (-0.61 IU/L, P=0.001).
A 5α-reductase polymorphism predicts circulating androgens and SHBG, while aromatase polymorphisms predict circulating E2 and LH. Further studies are needed to determine how these functional 5α-reductase and aromatase gene polymorphisms impact on male gonadal axis activity in reproductive and general health outcomes.