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

Purpose: Male fertility is progressively impairing over time, probably related to a multifactorial genesis. The aim of the study was the evaluation if a Temporal trend in serum testosterone levels exists in healthy men. Methods: A 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) 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. Secondary endpoints: luteinising hormone (LH), follicle-stimulating hormone (FSH), sex hormone binding globulin (SHBG) serum levels and body mass index (BMI). Results: 1,256 papers, accounting for 1,504 study groups, were selected, including 1,064,891 subjects (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 adjusting meta-regression analysis using the number of subjects included in each study, subjects’ age, BMI and the the assay used for testosterone measurement. 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. Conclusion: This study is the first comprehensive 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.