Temporal trends in serum testosterone and luteinizing hormone levels indicate an ongoing resetting of hypothalamic-pituitary-gonadal function in healthy men: a systematic review

Background: Male fertility is progressively impairing over time, probably related to a multifactorial genesis, involving mainly lifestyle and environmental factors. Only few data suggest temporal trends in serum testosterone levels. Objective and Rationale: The aim of the study was the evaluation if a Temporal trend in serum testosterone levels exists in healthy men. Search Methods: A systematic search of the literature between 1971 and July 2024 was performed, selecting study groups in which testosterone serum levels were measured for any reason in healthy men. Exclusion criteria were: (i) subjects’ age <18 years old, (ii) conditions affecting testosterone levels, (iii) subjects’ enrolment based on testosterone serum levels and (iv) blood examinations performed in a time-frame interval >10 years. As secondary endpoints, luteinising hormone (LH), follicle-stimulating hormone (FSH), sex hormone binding globulin (SHBG) serum levels and body mass index (BMI) were collected when available. Outcomes: 1,256 papers, accounting for 1,504 study groups, were selected, including 1,064,891 subjects (mean age 42.0+7.0 years). A significant negative linear regression between testosterone serum levels and year of measurement was detected (P = 0.033). The comprehensive decline in testosterone serum levels over the years was confirmed with meta-regression analysis using the number of patients included in each study, subjects’ age and body mass index (BMI) to adjust testosterone trend. No temporal trend was observed regarding BMI in this population. LH serum levels showed a significant decline over the years, adjusting for subjects’ age, while no trend emerged considering FSH. The decline in testosterone serum levels was confirmed adjusting data according to the assay used for testosterone measurement and after matching with environmental and demographic data. Wider Implications: This study is the first comprehensive meta-regression analysis suggesting a progressive decrease in serum testosterone and LH levels in healthy men, independent of age and BMI. The observed decline in both testosterone and LH levels could be a consequence of an ongoing resetting of the hypothalamic-pituitary testicular function.