OBJECTIVE: Serum levels of sex-hormone-binding globulin (SHBG) have been reported in the literature to increase with age in both sexes. We have investigated the variations in levels of androgens, insulin and IGF-I with age and have evaluated their putative roles to obtain a better understanding of the increase in SHBG. DESIGN: Cross-sectional pilot study of blood samples in healthy elderly subjects aged 50 to 90 years. PATIENTS AND METHODS: Forty-four postmenopausal women and 40 men were classified into three age groups. Subjects who were obese, undernourished or smokers and postmenopausal women receiving hormone replacement therapy were excluded from the study. Body mass index and waist/hip ratio were evaluated in each subject. Fasting levels of blood glucose, insulin, triglycerides, cholesterol, SHBG, testosterone, dehydroepiandrosterone sulfate (DHEAS) and IGF-I were measured. Free testosterone and glucose/insulin ratio were calculated. RESULTS: The results are based on variance analysis of the mean of each parameter in the three age groups. Multiple regression analysis was performed to define the role of age, insulin and IGF-I in the increase in SHBG. The increase in SHBG with age in older men was significant but that in postmenopausal women was not. Decreasing DHEAS with age was confirmed. No significant variations in glucose and insulin were observed with age in our selected population. A positive correlation was observed between insulin and triglycerides in elderly men and women. IGF-I decreased significantly with age in both sexes. Insulin was the main factor explaining SHBG increase with age in women. In men, both age and IGF-I contributed to the SHBG increase. CONCLUSIONS: The factors regulating the increase in SHBG with age appear to be different in the two sexes. Insulin plays a major role in women, whereas a decrease in IGF-I is the predominant regulating factor in men. These results should be thought of as a working hypothesis rather than a reflection of physiology.