In women, sex hormone-binding globulin (SHBG) concentrations are the result of a balanced effect of stimulatory and inhibitory factors. Estrogens represent the principal stimulatory hormones, whereas androgens, insulin, excess body fat, and the pattern of body fat distribution have inhibitory effects. Menopause is characterized by major changes in blood sex steroid concentrations, notably a marked reduction of estradiol levels. In this study, we therefore investigated the relationship between hormonal and nonhormonal regulatory factors of SHBG and its blood levels in two groups of premenopausal and postmenopausal women characterized by normal-high or reduced estrogen concentrations. The data were obtained from an analysis of the cross-sectional database obtained during the first survey of the Virgilio-Menopause-Health Project, an epidemiologic longitudinal study aimed at investigating the impact of menopause on body weight, fat distribution, and related major metabolic, hormonal, and cardiovascular risk factors. A total of 329 women, 133 in premenopause and 196 in postmenopause without diabetes, thyroid diseases, or relevant cardiovascular, renal, and hepatic dysfunction, were included in the study. A clinical history (including dietary and physical-activity habits), anthropometry (body mass index [BMI], waist to hip ratio [WHR], and bioelectrical impedance analysis [BIA]), and morning blood samples in the fasting state for sex hormones, insulin, and biochemistry were available for all the women. Premenopausal and postmenopausal women showed no significant difference in SHBG concentrations (38.7 +/- 17.9 v 36.6 +/- 17.5 nmol/L, respectively). On the contrary, postmenopausal women were characterized by a marked reduction of estradiol levels and significantly lower levels of testosterone. After adjusting for age, insulin was lower and the glucose to insulin ratio was higher in postmenopause than in premenopause. Age-adjusted values for all anthropometric parameters were not significantly different in the two groups. In simple correlation models, SHBG was significantly and negatively correlated with BMI, WHR, and insulin and testosterone levels in both premenopausal and postmenopausal women, whereas estradiol levels correlated positively and significantly with SHBG only in the premenopausal group. A significant positive correlation between the glucose to insulin ratio and SHBG was present in both groups. Using multiple regression models, in the premenopausal group, SHBG levels were correlated positively with estradiol and negatively with testosterone and insulin, but not with the WHR. On the contrary, in the postmenopausal group, SHBG values had a significant negative correlation with the WHR, whereas the relationship with estradiol was not significant; moreover, the relationship with testosterone and insulin, although significant, became less marked. In conclusion, this study indicates that (1) there is no significant difference in SHBG blood concentrations between premenopause and postmenopause; (2) SHBG values are correlated positively with estradiol and negatively with insulin and testosterone concentrations, but the predictive value of these variabiles on SHBG appears to be different in premenopause and postmenopause; and (3) SHBG levels decrease with increasing WHRs, particularly in the postmenopausal group. Therefore, determinants of SHBG blood concentrations are likely to change on passing from premenopausal to postmenopausal status. In particular, there seems to be a threshold level for which estradiol is an important determinant of SHBG blood concentrations.