The interaction between the GH-IGF-I axis and thyroid hormone metabolism is complex and not fully understood. T(4) stimulates IGF-I activity in animals in the absence of GH. On the other hand, GH replacement therapy results in an increase in serum T(3) and a decrease in T(4) and rT(3) levels, suggesting a stimulation of type I deiodinase (D1) activity. Recently, we demonstrated the association of two polymorphisms in D1 (D1a-C/T; T = 34%, and D1b-A/G; G = 10%) with serum iodothyronine levels. Haplotype alleles were constructed, suggesting a lower activity of the D1 haplotype 2 allele (aT-bA) and a higher activity of the haplotype allele 3 (aC-bG). In this study, we investigated whether genetic variations in D1 are associated with the IGF-I system. In 156 blood donors and 350 elderly men, the association of the D1 haplotype alleles with circulating IGF-I and free IGF-I levels was studied. In addition, potential associations with muscle strength and body composition were investigated in the elderly population. Finally, the relation between serum iodothyronine levels and IGF-I levels was studied. In blood donors, haplotype allele 2 was associated with higher levels of free IGF-I (302.9 +/- 22.9 vs. 376.3 +/- 19.1 pg/ml, P = 0.02). In elderly men, haplotype allele 2 also showed an allele dose increase in free IGF-I levels (P(trend) = 0.01) and an allele dose decrease in serum T(3) levels (P(trend) = 0.01), independent of age. Carriers of the D1a-T variant also had a higher isometric grip strength (P = 0.047) and maximum leg extensor strength (P = 0.07) as well as a higher lean body mass (P = 0.03). In blood donors, T(4) and free T(4) were negatively correlated with total IGF-I levels (R = -0.18, P = 0.03 and R = -0.24, P = 0.003), whereas T(3) to T(4) and T(3) to reverse T(3) ratios were positively correlated with total IGF-I (R = 0.31, P < 0.001 and R = 0.18, P = 0.03). Free IGF-I showed a negative correlation with T(4) (R = -0.26, P = 0.001) and T(4)-binding globulin (R = -0.31, P < 0.001) and a positive correlation with T(3) to T(4) ratio (R = 0.21, P = 0.01). In conclusion, a polymorphism that results in a decreased D1 activity is associated with an increase in free IGF-I levels. The pathophysiological significance of this association with IGF-I is supported by an increased muscle strength and muscle mass in carriers of the D1 haplotype 2 allele in a population of elderly men. The association of D1 haplotype allele 2 with serum T(3) levels in the elderly population suggests a relative increase in its contribution to circulating T(3) in old age.