OR25-01 Longitudinal Changes in the Hypothalamic-Pituitary-Testicular (HPT) Axis in Men with Longevity

Disclosure: D. He: None. T. Gao: None. N. Barzilai: None. S. Milman: None. S. Aleksic: None. Background: Aging in men is associated with a reduction in testosterone (T) levels. In men aged 50 - 80, the decline in T mainly occurs due to hypothalamic-pituitary dysfunction, which results from unhealthy aging characterized by obesity and metabolic disorders. The changes in the HPT axis in men with longevity are less understood. Our recent cross-sectional study in men aged 90 and older showed high prevalence of testicular dysfunction which was not associated with metabolic health. We now explore the longitudinal changes in the HPT axis in men with longevity to better understand their relationship with metabolic health and survival. Methods: In an observational study of community-dwelling Ashkenazi Jewish men (n = 68, mean age (SD) at baseline sample 84 ± 4 years), levels of total T (TT, LC/MS), LH, and SHBG were measured in longitudinal serum samples (a median of 3 measures per subject, age at final sample 89 ± 3 years). Men were followed for survival after the final sample. Free T (FT) was calculated per Vermeulen et al. Men treated with T or GnRH agonists were excluded. Metabolic measures included BMI, A1c, and serum lipids. Individual longitudinal trajectories of TT, FT, LH, and SHBG were estimated with linear regression. Biochemical gonadal phenotypes were determined based on the levels of TT and LH. Results: Baseline and final levels of TT, FT, LH, and SHBG were, respectively: 417 ± 173 and 346 ± 187 ng/dL (TT), 6.0 ± 2.4 and 4.7 ± 2.5 ng/dL (FT), 8.0 [5.1, 14.4] and 10.0 [5.9, 20.4] mIU/mL (LH), and 58 ± 20 and 63 ± 23 nmol/L (SHBG), with average change rate/year of −17 ± 47 ng/dL (TT), −0.3 ± 0.5 ng/dL (FT), 0.7 ± 2.2 mIU/mL (LH) and 0.9 ± 4.1 nmol/L (SHBG). At baseline, the most prevalent biochemical gonadal phenotype was eugonadism (54%), followed by compensated testicular dysfunction (24%), testicular dysfunction (10%), and hypothalamic-pituitary dysfunction (12%), while respective prevalence rates at the final sample were 40%, 24%, 29%, and 7%. Baseline TT (p=0.002), age (p=0.02), and history of cancer (p=0.01) predicted more negative trajectory, while the history of cardiovascular disease (p=0.02) predicted more positive trajectory of TT. Neither TT, FT, LH nor SHBG trajectories were significant predictors of final BMI, A1c, or serum lipid levels. Positive TT trajectory was associated with shorter survival, after adjustment for SHBG, age, and comorbidities (HR 6.61 [1.46, 29.8], p=0.01). Conclusions: This is one of the first longitudinal studies of the HPT axis in community-dwelling men with longevity. As men survive into the late 80s, they increasingly develop testicular dysfunction while hypothalamic-pituitary dysfunction is rare. Changes in testosterone levels do not seem to predict metabolic dysfunction; however, an increase in total testosterone with aging may be associated with reduced survival. These findings need to be explored further in larger and ethnically diverse cohorts. Presentation Date: Saturday, June 17, 2023