Context: Whether menopause-related changes in sex steroids account for midlife weight gain in women or whether weight drives changes in sex steroids remains unanswered.

Objective: The objective of the study was to characterize the potential reciprocal nature of the associations between sex hormones and their binding protein with waist circumference in midlife women.

Design, Setting, and Participants: The study included 1528 women (mean age 46 yr) with 9 yr of follow-up across the menopause transition from the observational Study of Women's Health Across the Nation.

Main Outcome Measures: Waist circumference, SHBG, testosterone, FSH, and estradiol were measured.

Results: Current waist circumference predicted future SHBG, testosterone, and FSH but not vice versa. For each sd higher current waist circumference, at the subsequent visit SHBG was lower by 0.04-0.15 sd, testosterone was higher by 0.08-0.13 sd, and log(2) FSH was lower by 0.15-0.26 sd. Estradiol results were distinct from those above, changing direction across the menopause transition. Estradiol and waist circumference were negatively associated in early menopausal transition stages and positively associated in later transition stages (for each sd higher current waist circumference, future estradiol was lower by 0.15 sd in pre- and early perimenopause and higher by 0.38 sd in late peri- and postmenopause; P for interaction

Conclusions: These Study of Women's Health Across the Nation data suggest that the predominant temporal sequence is that weight gain leads to changes in sex steroids rather than vice versa.