ABSTRACT The adrenal androgen precursors dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are known to contribute to fetal development and adrenarche. The role of adrenal androgens following puberty and throughout adulthood has been poorly understood. The adrenal glands are also the source of unique 11- oxygenated metabolites of androstenedione (A4) and testosterone (T), collectively termed 11-oxyandrogens. Of these, 11-ketotestosterone (11KT) and its 5α-reduced product, 11-ketodihydrotestosterone (11K-DHT), are bioactive androgens, with potency equivalent to testosterone (T) and dihydrotestosterone (DHT), respectively. These 11-oxyandrogens are central to the pathophysiology of several disorders of androgen excess, including congenital adrenal hyperplasia, premature adrenarche, or castration-resistant prostate cancer. The role of 11- oxyandrogens during physiological aging is unknown. The traditional androgens androstenedione (A4) and testosterone (T), which also derive from the gonads, as well as the major adrenal androgen precursors, DHEA and DHEAS, decline with aging. Intriguingly, we have recently found that the production of 11-oxyandrogens remains sustained in aging individuals of both sexes. Moreover, our preliminary data suggest that 11KT is associated inversely with bone degradation biomarkers, and directly with hemoglobin and hematocrit. The overall objectives of this application are: 1) to define the trends of circulating 11-oxyandrogens in men and women throughout adulthood, with particular focus on aging; 2) to determine the implications of 11- oxyandrogens on aging-related clinical outcomes, including bone, metabolic, and cardiovascular pathology; 3) to define the bioactivity potential of 11-oxyandrogens. Three specific aims have been designed to address critical gaps in our knowledge of adrenal androgen function throughout adulthood and aging. • In Aim 1, we will characterize for the first time the longitudinal patterns of circulating 11-oxyandrogens in women, beginning with reproductive stages, and following menopause. We will use mass spectrometry to quantify traditional sex- steroids and 11-oxyandrogens in over 3,000 serum biospecimens from 569 women included in the Study of Women Across the Nation (SWAN). • In Aim 2, we will test the working hypothesis that 11KT has direct implications on bone and cardiovascular health. We will quantify an extensive set of steroids, including 11- oxyandrogens, in over 2400 men and women, participants in the Dallas Heart Study (DSH). We will use the rich datasets from both the SWAN and DHS, which include comprehensive health history and wellbeing survey instruments (both studies), as well as laboratory and imaging evaluations of bone, metabolic, and cardiovascular health (DHS). • In Aim 3, we will test the bioavailability of 11-oxyandrogens and their potential to be aromatized to 11-oxyestrogens. Together, this work will reframe our understanding of bioactive androgens in human health and disease.

PROJECT NARRATIVE The adrenal glands produce androgen precursors, which are known to be important during fetal and early development. Recent data suggest that a set of unique adrenal androgens, called 11-oxyandrogens, might play important roles in aging individuals. The proposed research aims to deeply characterize the patterns of 11- oxyandrogens in aging men and women, and to derive associations between 11-oxyandrogens and various age- related health outcomes, including bone, metabolic, cardiovascular, and general wellbeing.