Daniel McConnell - US grants

To assess endocrine changes in midlife women, the University of Michigan's Central Ligand Assay Satellite Services (CLASS) laboratory will continue to support the Study of Women's Health Across the Nation (SWAN). We will use state-of-the-science, automated assays for all the major reproductive axis hormones (i.e., LH, FSH, estradiol, progesterone, and testosterone), adrenal markers of aging (DHEAS), other endocrine markers (TSH, sex hormone binding globulin {SHBG}) and new ovarian markers which have the potential to allow us to hormonally define the menopausal transition and the postmenopause with greater precision (inhibin A and B, estrone). In order to continue to support the Daily Hormone Study (DHS), CLASS will complete development and utilize sensitive and specific urinary assays for LH, FSH and the principal urinary metabolites of estradiol and progesterone, estrone conjugates and pregnanediol glucuronide, respectively. Our specific goals for the proposed project period are to: 1) utilize, implement and develop state-of-the-science, reliable, precise and cost-effective analytical methods that meet all study needs (analyte selection, limits of detection, range of performance), minimize variability, provide long-term stability and maximize reliability; 2) incorporate quality assurance procedures that minimize error and variability as assessed by rigorous quality control procedures; 3) utilize and develop additional electronic data handling and analysis procedures that, in addition to reducing labor costs, minimize the need for manual intervention and nearly eliminate the possibility of errors; 4) utilize sample labeling and handling systems that ensure continuous association between a labeled sample and data identified with the tube while maximizing the likelihood that the integrity of a sample is preserved unmodified; and 5) develop a temporary storage repository. In this manner, we will continue to play a key role in the advancement of the scientific goals of the parent SWAN study.

DESCRIPTION (provided by applicant): The Study of Women's Health Across the Nation (SWAN) is a multicenter, multiethnic, community based longitudinal study designed to characterize the biological, symptomatic and psychosocial changes that occur during the menopausal transition and the effects of these changes on women's health during and after the transition. Current and prior funding (SWAN I and II) has supported seven years of follow-up, at the end of which 60%of observable transitions to postmenopause will have occured. This competitve renewal application (SWAN III) requests funding to complete 10 cohort follow-up visits. This will allow us to capture 91% of observable transitions to postmenopause and obtain a more representative sample. The additional data will a focus on the late perimenopausal and early postmenopausal periods that have not been well studied. As women reach the end of early postmenopause (two years following the final menstrual period), we will shift from an annual to a bi-annual follow-up schedule with mail and telphone contact in the alternating years. This will set the stage for cost-effective and less intensive follow-up beyond SWAN III. We will continue our current observations and undertake new science in each of the four scientific project areas (ovarian aging; symptoms, risk factors, functioning and aging; cardiovascular risk factors; and determinants and outcomes of bone mass). New science includes measurement of vascular stiffness to assess early cardiovascular disease, vertebral morphometry using newly developed DEXA technology bone and body composition and circulating androgens as markers androgen biosynthesis. The latter will use an assay system developed by SWAN investigators. In addition, we will focus on linking the menopause and midlife experiences to age-related outcomes and chronic diseases, including physical and cognitive function. The additional follow-up will contribute to and expand the SWAN biological specimen repository (annual blood and urine samples as well as DNA and immortalized cells), a separately funded component that provides opportunities to address future hypotheses about health, disease, and aging. SWAN III will allow us to bring to fruition many of the original goals of SWAN. By building upon the rich foundation developed during SWAN I and II, and ultimately linking these data to age-related health outcomes, we will achieve unparalleled new insights into the role of the menopause on the health of American women.

DESCRIPTION (provided by applicant): This one year competing renewal is submitted as one of a set of nine component applications (including seven clinic sites, the Coordinating Center and a Central Endocrinology Laboratory) to augment the last year of the current five-year renewal (SWAN II) of the nine originally funded applications in response to RFA AG-94-002, "Menopause and Health in Aging Women." The purpose of this renewal is to complete a sixth annual follow-up visit on approximately 2470 women across clinical sites and a final annual cycle of daily urine collections on approximately 550 women. Each of these data collection activities requires a two-year period for completion. The SWAN II application included funding to finish Visit 02 to the Visit 00 and Visit 01 data collections, to undertake Visits 03, 04 and 05 data collections and to spend the final year on analyses. Preliminary data now available from Visits 00-03 indicate that the original and continuing aims of this important study cannot be addressed with the currently funded five years of follow-up observation as the number of menopause transitions will be insufficient. Projections indicate that nine years of follow up will be required. Bridging funding (this supplement application) is needed so that a one year gap in cohort follow-up to complete a Visit 06 can be closed. A competing renewal for five years (SWAN III) must be predicated on continuing data collection so that cohort retention, follow-up integrity and certified staff availability is assured. Hence there is a need to obtain this supplemental funding to bridge the time in the SWAN II that was planned for closeout and data analysis. To assess endocrine changes in midlife women, the University of Michigan?s Central Ligand Assay Satellite Services (CLASS) laboratory will continue to support SWAN by using state-of-the-science, automated assays for all the major reproductive axis hormones (LH, FSH, E2, P, and T), adrenal markers of aging (DHEAS), other endocrine markers (TSH, SHBG) and new ovarian markers which have the potential to allow us to hormonally define the menopausal transition and the postmenopause with greater precision (inhibin B, estrone). In order to continue to support the Daily Hormone Study, CLASS will utilize sensitive and specific urinary assays for LH, FSH and the principal urinary metabolites of estradiol and progesterone, estrone conjugates and pregnanediol glucuronide, respectively. To assess endocrine changes in midlife women, the University of Michigan?s Central Ligand Assay Satellite Services (CLASS) laboratory will continue to support SWAN by using state-of-the-science, automated assays for all the major reproductive axis hormones (LH, FSH, E2, P, and T), adrenal markers of aging (DHEAS), other endocrine markers (TSH, SHBG) and new ovarian markers which have the potential to allow us to hormonally define the menopausal transition and the postmenopause with greater precision (inhibin B, estrone). In order to continue to support the Daily Hormone Study, CLASS will utilize sensitive and specific urinary assays for LH, FSH and the principal urinary metabolites of estradiol and progesterone, estrone conjugates and pregnanediol glucuronide, respectively.

DESCRIPTION (provided by applicant): Examining the hormonal dynamics that characterize the menopausal transition by accurately assaying reproductive ligands is central to understanding the impact of menopause on women's health from midlife through old age. Fundamentally, the Endocrinology of the Menopause/CLASS Laboratory component will examine the dynamics and provide the endocrinologic scaffolding for all other projects in SWAN. We will characterize the hormonal changes associated with the menopausal transition and precisely relate these to their clinical manifestations, explore new areas of endocrine importance, and extend the study of hormonal characteristics from the early to late postmenopause. We will challenge the traditional concept of the menopausal transition as simply a loss of ovarian estradiol secretion to a more integrated and data driven model of a shift from an estrogen dominant to an androgen dominant balance of sex steroids modulated by a dynamic hepatic globulin system. Through SWAN I, II and III we have shown, both cross-sectionally and longitudinally: 1) sex hormone binding globulin (SHBG) to be most strongly associated with cardiovascular risk factors, metabolic syndrome, body composition, insulin, and glucose levels;2) androgens to be strongly associated with cardiovascular risk factors, metabolic syndrome, body composition, insulin and glucose levels, and sexual function;3) follicle stimulating hormone to be strongly associated with bone loss, vasomotor symptoms and timing of the final menstrual period;4) a transient increase in adrenal androgen secretion coincides with the late perimenopausal drop in estradiol secretion;5) only modest associations of estradiol with vasomotorsymptoms, metabolic and hemostatic factors but not bone loss. These findings provide endocrinological support for the evolution in thinking of the menopausal transition as an integrated shift from an estrogen dominant to an androgen dominant state with health risks associated with the magnitude of that shift. To characterize completely the natural history of the menopausal transition, we will pursue the following Specific Aims: 1) Add measures of circulating A and E1 to the annually measured T and E2 to provide a more complete estimate of total circulating estrogens and androgens. We shall calculate the equilibrium among these four steroids and the relationship of the equilibrium to SHBG, both cross-sectionally and longitudinally;2) Measure the isoforms of SHBG and relate the relative proportions to sex steroid levels and ethnic differences, both cross-sectionally and longitudinally;and 3) Determine the degree to which the measured circulating adrenal androgens are associated with health outcomes in women traversing the menopause. We will continue serum sampling of previously measured hormones. RELEVANCE (See instructions): These studies will increase our understanding of the hormonal physiology of the entire menopausal transition and assist in the development of evidence-based paradigms for treating peri- and postmenopausal health concerns.

DESCRIPTION (provided by applicant): This competing renewal application is to provide for ontinued maintenance of and activities associated with the SWAN Repositories of serum, plasma, urine, DNA and transformed cells generated from a 10-year study of a population of 3302 women from 5 ethnic groups who have been evaluated annually prior to, during and following the menopausal transition. These Repositories, an arm of the Study of Women's Health Across the Nation (SWAN), are meant to support, facilitate and extend the Core SWAN;additionally, the Repositories provide a mechanism for opening the resources of SWAN to the greater scientific community. Implementing activities associated with three proposed specific aims of this competing renewal will 1) provide for the continued management of the current 1.7 million Repository specimens and the additional specimens that will accrue as a result of fielding SWAN IV in 2009 to 2014;2) expand the DNA Repository, the most frequently requested specimen type that is uniquely renewable because of our investment in cell immortalization;3) promote effective information interchange about the SWAN Study, its data and the Repository resources through development of a 2-level web-based "data warehouse";4) provide for continued administration of the application review process for specimen utilization and administrative management of specimen distribution including Material Transfer Agreements;5) engage in strategies to promote utilization of specimens;and, 6) expand the scope of the genetics studies associated with the SWAN study and its Repository.

DESCRIPTION (provided by applicant): This is the amended competing renewal application of the Study of Women's Health Across the Nation (SWAN), a 7-site longitudinal cohort study initiated in 1994 in response to RFA AG-94-002. SWAN was mandated to characterize the chronology of the biological and psychosocial antecedents and sequelae of the menopausal transition (MT) and the effect of this transition on subsequent health and risk factors for age- related disease, and to extend this information from White women to ...the range of peri-menopausal experiences in women of other racial/ethnic background(s). A total of 3302 Black, Chinese, Japanese, Hispanic and White women were enrolled, with 78% completing up to 13 visits spanning the premenopause to early post-menopause (PM). Thus far, SWAN has described the natural history of the MT -- its timing, patterns of hormonal changes, and symptoms and factors related to them - and their relation to disease risk indicators. During SWAN V, we will extend observations through the late PM, a necessary step to assess the impact of the MT on age-related diseases. Our specific aims are to: 1) complete the characterization of the natural history of reproductive aging through the late PM; 2) evaluate the impact of reproductive aging through the late PM on health outcomes clinically relevant to women in their 60s and 70s, including: cognitive and physical function, psychological well-being, sleep, bone and cardiometabolic health, urogenital symptoms, sexual function and vaginal health; and 3) identify potential underlying mechanisms linking reproductive aging and health by assessing the relation of inflammation, hemostasis and adipokines to the occurrence and progression of biological, functional and clinical outcomes and delineating the interrelationships of body size and composition, race/ethnicity and socioeconomic status with these outcomes. The SWAN V Core protocol will be completed at 7 study sites, with bone and cardiovascular studies at 4 sites and actigraphy studies in a subset of women at all sites. Longitudinal specimens from the SWAN Repository will enable characterization of skeletal markers, adrenal hormones, hemostasis, inflammation, and adipokines across the MT into PM. The Coordinating Center will provide the necessary organizational infrastructure, statistical resources, and timely dissemination of high quality SWAN data. The CLIA-certified Central Laboratory will perform or coordinate with other laboratories to provide accurate, high volume assays, adopting new methods as needed to provide state- of-the-art data. SWAN is uniquely positioned to fill important scientific gaps in understanding of the impact of the MT on women's health in their 60s and 70s and to facilitate the application of new knowledge to clinical practice. With 1.5 decades of both calendar time and menopause time, SWAN V can disaggregate the contributions of aging and the MT to women's health, address difficult and critical questions about the temporal nature of MT-disease associations, assess differences by race/ethnicity, and provide insights into modifiable factors relevant to the design of innovative prevention and treatment programs for aging women.

SWAN-Aging will test the relation of midlife health and the menopause transition (MT) to successful aging in women. The Laboratory Services Core (Core 2) provides critical support for addressing the scientific aims of three integrated Projects: Project 1 will evaluate how the MT and midlife health relate to preservation of cognitive function (avoiding cognitive decline and onset of mild cognitive impairment), sleep, genitourinary and sexual function, and quality of life in early old age; Project 2 will test how the MT relates to cardiac health and cardiovascular disease (CVD) events in women in early old age and test how cardiac health relates to early markers of physical impairment, Alzheimer?s disease, and vascular dementia at a critical period in the lifespan; and Project 3 will examine the role of the MT and midlife health on musculoskeletal and physical function. Core 2 will be based at The Clinical Ligand Assay Satellite Services (CLASS) Laboratory which will directly support SWAN-Aging aims by coordinating biomarker assays run at CLASS and at two other labs. CLASS has been the Central Laboratory for endocrine and cytokine assays since SWAN?s inception and has assumed responsibility for creating biosample collection kits, coordination of shipping to and from clinical sites, receiving frozen samples, biobanking, and coordinating or performing all metabolic and cardiovascular assays. Core 2 will provide oversight for all laboratory components and will support the Projects by providing reliable and valid measures of sex hormones (by Liquid Chromatography Tandem Mass Spectroscopy), cardio-metabolic health (glucose, insulin, lipids, galectin-3), and biomarkers relevant to multisystem aging (IL-10, NTproBNP). Core 2 will coordinate with the Administrative Core (Core 1) and the Data Collection and Data Management Core (Core 3) to ensure the quality of specimen collections and data transfer, and will: 1) Oversee preparation and transfer of 46,500 new specimens collected at clinic visits and retrieve 16,400 stored samples from the Repository; 2) Conduct high quality assays meeting the standards of CAP and Biorepository guidelines, including more sensitive sex hormone assays; 3) Provide assay results to Core 3 in a timely fashion for data cleaning and analysis; 4) Provide leadership on the interpretation of assay results for scientific aims testing relationships of hormones, cardiovascular markers, and cytokines to CVD events, bone health, sleep, psychosocial well-being, physical function, and multiple domains of cognition to detect cognitive impairment (executive and visual-spatial function, language fluency) and the functional impact of cognitive deficits (cognitively demanding instrumental activities of daily living). Rigorous measurement of the proposed markers over midlife uniquely position SWAN-Aging to test novel predictors of changes in physical and cognitive function and the onset of multi-morbidity, disability, and cognitive impairment in women. Identifying remediable risk factors for dementia risk early in the natural history of cognitive impairment is critical to promoting healthy aging and to preventing dementias, including Alzheimer?s Disease and vascular dementia, in women.

PROJECT SUMMARY This U19 application, referred to as SWAN-Aging, is designed to determine the extent to which midlife health, and specifically the menopause transition (MT), affects successful aging in women. This proposal capitalizes on the rich resources of the Study of Women's Health Across the Nation (SWAN), a longitudinal cohort study initiated in 1994 to characterize the physiological and psychosocial changes that occur during the MT. A total of 3302 Black, Chinese, Japanese, Hispanic and White women were enrolled at seven sites, with 74% of still- living women completing up to 16 visits spanning the pre-menopause to post-menopause. SWAN has described the natural history of the MT -- its timing, patterns of hormonal changes, and symptoms ? and their relation to midlife health indicators. In SWAN-Aging, we will extend follow-up of the SWAN cohort into early old age (66-75 years) and will prospectively link comprehensive longitudinal characterization of both the MT and midlife health indicators to functioning and health across multiple domains in early old age, a pivotal time of transition into old age when adverse changes in health and functioning begin to accumulate. The global specific aims of this U19 application are to: 1) determine the impact of MT characteristics and trajectories of midlife health indicators on the preservation of cognitive, physical, genitourinary, sexual, and psychosocial function and sleep in early old age; 2) determine the impact of MT characteristics and trajectories of midlife health indicators on risk of adverse health outcomes, including falls, osteoporosis and fractures, poor cardiometabolic function, cardiovascular events and early mortality; 3) determine if racial/ethnic disparities in health and functioning in early old age are attributable to midlife racial/ethnic differences in MT characteristics and midlife health indicators; and 4) translate the SWAN and SWAN-Aging findings for women and their health care providers. These aims will be achieved through three integrated scientific Projects that are organized around key health domains (functioning, cardiometabolic health and musculoskeletal health) and linked by a common focus on MT characteristics and midlife changes in health indicators as key exposures. The three Projects will be supported by three Cores which will a) provide the necessary organizational infrastructure to conduct this study and to disseminate results to the research and medical communities; b) conduct accurate, high volume assays, adopting new methods as needed to provide state-of-the-art laboratory data, and c) oversee the design and conduct of the core clinic visit, data collection and data management, and the creation of the analytic datasets. SWAN-Aging will include one clinic visit and a National Death Index search to ensure complete mortality ascertainment for the cohort. SWAN-Aging is uniquely positioned to fill important scientific gaps in understanding of the impact of the MT and midlife indicators on women's health and functioning in early old age and to facilitate the application of new knowledge to clinical practice. This study will provide valuable insights into modifiable factors relevant to the design of future prevention and treatment programs.