The Study of Women's Health Across the Nation (SWAN): The Impact of Midlife and the Menopause Transition on Health and Functioning in Early Old Age

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PROJECT SUMMARY SWAN, the Study of Women's Health Across the Nation, has collected a wealth of biopsychosocial and physiologic data on an inception cohort of 3,302 women, most of whom have adhered to follow-up examinations spanning 25 years. Since the original aims of SWAN were to characterize the menopausal transition in women, sex steroid measurements for estradiol (E2) and testosterone (T) have been a crucial part of the project from the start. In the early years of SWAN, state-of-the-art, highly sensitive, direct immunoassays (IA) for E2 and T were developed by the University of Michigan Central Ligand Assay Satellite Services (CLASS) Laboratories. Liquid chromatography/mass spectrometry (LC-MS/MS)-based technology has now largely supplanted IA for hormone measurement. SWAN has adapted to this change by performing all sex steroid assays using LC-MS/MS from Visit 15 onwards. However, all hormone levels performed on the cohort from the baseline (Visit 0) to Visit 13 have been performed using IA and require reconciliation to LC-MS/MS. The proportion of undetectable samples for both E2 and T has also increased over time as the SWAN sample are now all well past their final menses. Correlation of IA to LC-MS/MS sufficient to allow for conversion of one method to the other for hormones is incomplete due to an inability to resolve the lower limit of detection. In the current SWAN-Aging U19 grant, we have planned to reanalyze E2 and T using a contemporary LC-MS/MS-based technology. We now propose to develop and measure E2 and estrone (E1) using an ultrasensitive LC-MS/MS-based assay that will measure reliably as low as 1 pg/mL E2. This assay will be used subsequently for postmenopausal samples from SWAN. The current administrative supplement proposes 1 new aim, Aim 1: To develop an ultrasensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) assay for E1 and E2 that performs with <15% intra- and inter-assay coefficients of variation (CV) at 2 pg/mL and a LLOQ of 1 pg/mL. Accomplishment of this aim will allow us to maximize the use of SWAN assay data moving forward, which has to date resulted in approximately 100,000 serum sex steroid measurements in women who have traversed the menopause and are now all postmenopausal and over the age of 70, and to determine the true circulating E2 increment that is observed in women reporting use of topical vaginal estrogen for treatment of genitourinary syndrome of menopause (GSM).