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In 2006, a Canadian study reported that total and bioavailable testosterone were significantly lower in middle-aged depressed men (40–65 years) who had considerably higher BDI and Hamilton depression scores than men enrolled in the Rancho Bernardo Study . Several studies have shown that certain chronic medical disorders, especially type 2 diabetes, may be more important in promoting testosterone decline than increasing age 2, 16, 19, 20. Although most studies on testosterone decline during aging have involved older men, a recent longitudinal study of young, healthy men (average age 34) found that the age at baseline did not predict changes in the trajectories of testosterone, dihydrotestosterone, androstenedione, and estradiol measured by LC–MS/MS mass spectrometry over a twelve-year period . Other cross-sectional research found that free testosterone levels decreased more rapidly at a rate of 1.5–2.0% in older men due to the age-dependent upregulation of SHBG . Other men, however, experience a substantial age-related decline in total testosterone into the clinical hypogonadal range below 280–300 ng/dl (9.7–10.4 nmol/L SI units).
This study underscores the importance of stress management and regular physical activity in maintaining healthy testosterone levels. Meghana S. Pagadala (MSP) provided important information about gene variants regulating testosterone that were identified in the GWAS of morning testosterone levels she completed. Recent GWAS research has identified significant associations of GCKR, BAIAP2L1, JMJD1C, FKBP4, SERPINA1, SHBG, FAM9B, and other gene variants with total testosterone levels 21–23, 127 (Fig. 2). Important considerations are that major depressive disorder is a clinically heterogeneous phenotype with depressed individuals differing in inherited polygenic determinants, onset and clinical course, symptom complexes, and comorbidities that contribute to potential multifactorial differences in pathophysiology. The studies reviewed here also suggest that a substantial deficiency in testosterone can cause a depressive-like state that can  respond to TRT. Using PET imaging, a recent study has reported that testosterone regulates hippocampal serotonin 5-HT4 receptors and increases brain serotonergic  function . Other research has found that testosterone promotes an antidepressant response by activating androgen receptor signaling via the MAPK-ERK2 cascade in the hippocampus 12, 117.
The safety of TRT has only been established for management of symptomatic hypogonadism and is recommended by the American Urological Association and Endocrine Society guidelines. The role of sex hormones in headache medicine is an emerging area of interest, though current literature largely focuses on female hormones and their association with migraines. Placebo-controlled trials are necessary to ascertain the role and safety of TRT in men with epilepsy. There is no evidence supporting the role of TRT for management of epilepsy.
Basal secretion of LH and FSH, LH pulse frequency, and GnRH-stimulation gonadotropin secretion by the anterior pituitary are not altered in major depressive disorder indicating that anterior pituitary gonadotropin dysregulation may not contribute to low testosterone levels 36, 43, 44. Subsequent neuroendocrine research including meta-analyses  have found that basal testosterone levels and 24-h testosterone secretion are abnormally low in men with major depressive episodes 25, 36, 43. The role of hypothalamic–pituitary–adrenal hypersecretion observed in severe major depressive episodes and the well-known ability of high cortisol to suppress the hypothalamic-pituitary–gonadal axis in the relationship of testosterone and depression requires further investigation. In addition to being a prospective study, another strength of the HIMS study was measuring total testosterone levels using LC–MS/MS mass spectrometry, which is a critical methodology for accurately measuring hypogonadal testosterone levels . This study also reported that low levels of dihydrotestosterone, estradiol, and free testosterone (calculated) did not confer risk for developing incident depression. Further investigation is required to elucidate the role of estradiol and its interaction with testosterone in depression especially in older men with hypogonadal testosterone level, which has been difficult to study due in part to mass spectrometry being necessary for specific, sensitive, and quantitative measurement.
The Baltimore Longitudinal Study of Aging has reported that 80% of 60-year-old men and 50% of 80-year-old men exhibit total testosterone levels within the normal range of young men 14, 15. The complex mechanisms governing testosterone hormone action regulate many physiological systems, modulate clinical disorders, and contribute to health outcome. Testicular androgens have crucial roles in physiological homeostasis, health outcome, and disease pathophysiology. Important considerations going forward are that major depressive disorder is a heterogeneous phenotype with depressed individuals differing in inherited polygenic determinants, onset and clinical course, symptom complexes, and comorbidities that contribute to potential multifactorial differences in pathophysiology. Considerable research has shown that testosterone regulates many physiological systems, modulates clinical disorders, and contributes to health outcome. Table 1 summaries the role of androgen in various neurological disorders.
Interestingly, in two randomized, double-blind, placebo-controlled clinical trials completed in 2009, testosterone treatment of men with dysthymic disorder, which is a milder, but persistent depressive disorder characterized by an early, insidious onset and a chronic course, had a stronger antidepressant effect 84, 85. In the Testosterone Trials cohort of hypogonadal men were characterized  as having two morning total testosterone levels less than 275 ng/dl (9.53 nmol/L SI units), sexual dysfunction, and diminished physical functioning including low vitality. The Testosterone Trials consisting of seven double-blind, placebo-controlled trials has been the largest investigation to date of the efficacy and benefits of testosterone replacement therapy (TRT) in men older than 65 years who have developed age-related hypogonadism based on strict clinical criteria 15, 70–72. The significant association of ADT with depression held when the meta-analysis was restricted to studies of localized prostate cancer or a clinical diagnosis of a depressive disorder rather than a depressive inventory by a physician or patient self-report. Androgen deprivation therapy has been reported to provoke depressive symptoms and increase the incidence of major depressive episodes in many but not all studies.
There have been two meta-analyses strongly supporting the relationship of androgen deprivation therapy with depression. Again, there was a dose–response positive relationship between the duration of ADT treatment and the risk for depression . In 2021, the role of ADT in depression was assessed  in a new study of younger men (aged 40–64 years) with nonmetastatic prostate cancer with and without ADT using the TRICARE insurance data and controlling for a past diagnosis of depression 66, 68. An earlier population-based analysis of the SEER-Medicare database also reported a significantly increased incidence of a depressive disorders in men with prostate cancer after ADT compared to men with prostate cancer not receiving ADT and men without cancer . This study uniquely investigated the time-dependence for adverse effects of ADT on mood demonstrating a dose–response relationship of ADT duration and depression. The association of androgen deprivation therapy and depression represents the most extensively studied psychiatric outcome variable due to its detrimental impact on survivorship 49, 51. However, androgen deprivation therapy has been shown to have a substantially stronger  induction of depression.

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