The role of testosterone, the AR, and HPG axis in depression in aging Men

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madman

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The role of testosterone, the androgen receptor, and hypothalamic-pituitary-gonadal axis in depression in aging Men (2022)
Richard L. Hauger · Ursula G. Saelzler · Meghana S. Pagadala · Matthew S. Panizzon


Abstract

Considerable research has shown that testosterone regulates many physiological systems, modulates clinical disorders, and contributes to health outcomes. However, studies on the interaction of testosterone levels with depression and the antidepressant effect of testosterone replacement therapy in hypogonadal men with depression have been inconclusive. Current findings indicate that low circulating levels of total testosterone meeting stringent clinical criteria for hypogonadism and testosterone deficiency induced by androgen deprivation therapy are associated with increased risk for depression and current depressive symptoms. The benefits of testosterone replacement therapy in men with major depressive disorder and low testosterone levels in the clinically defined hypogonadal range remain uncertain and require further investigation. 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. Furthermore, polygenic mechanisms are likely to be critical to the biological heterogeneity that influences testosterone-depression interactions. A genetically informed precision medicine approach using genes regulating testosterone levels and androgen receptor sensitivity will likely be essential in gaining critical insight into the role of testosterone in depression.





Introduction

Testicular androgens have crucial roles in physiological homeostasis, health outcome, and disease pathophysiology. Testosterone and the more biologically active androgen, dihydrotestosterone (DHT), formed by the conversion of testosterone by 5α-reductase, act as the primary sex hormones in men regulating male sexual development during puberty and spermatogenesis and sexual function in adulthood [1–3] (Fig. 1). Other classical, well-established roles of testosterone include stimulation of erythropoiesis and maintenance of muscular strength and volumetric bone density mass [4, 5] (Fig. 1). Subsequent research, however, has discovered that androgens have more extensive physiological actions regulating cardiovascular, metabolic, hepatic, and immune systems and, importantly, the central nervous system [6–10] (Fig. 1).

The prevalence of major depressive disorder is twofold higher in women compared to men suggesting that physiological levels of testosterone in the healthy range may reduce the risk of depression [11]. Preclinical research has provided further evidence that androgens may reduce the risk of depression in men due to their antidepressant and neuroprotective actions in the hippocampus, limbic system, and other brain regions regulating mood [12, 13]. Considerable work has shown that low testosterone levels, clinical hypogonadism, pharmacologically induced testosterone deficiency by androgen deprivation therapy, and androgen receptor antagonist treatment are significantly associated with depression in men, although some studies have not observed this effect. An important research question is whether low testosterone levels are a trait biomarker for depression risk or a state biomarker associated with a major depressive episode and its severity. Alternatively, however, low testosterone levels may be a result of co-morbid medical conditions associated with depression. The focus of this review will assess the role of testosterone in mood regulation regarding the above important issues.






2 Testosterone levels, hypogonadism, and depression
2.1 Testosterone decline and hypogonadism during aging
2.2 Relationship of circulating levels of testosterone and depression
2.3 Relationship of testosterone deficiency in hypogonadism and depression
2.4 Hypogonadotropic hypogonadism and depression
2.5 Meta‑analyses of testosterone levels and depression





3 Hypothalamic‑pituitary–gonadal axis in depression
3.1 Regulation of the hypothalamic-pituitary-gonadal axis
3.2 Dysregulation of the hypothalamic-pituitary-gonadal axis and depression





4 Androgen deprivation therapy and depression
4.1 Androgen deprivation therapy and testosterone levels
4.2 Studies of androgen deprivation therapy and depression
4.3 Meta‑analyses of androgen deprivation therapy and depression
4.4 Androgen receptor antagonist, androgen synthesis inhibitor, and depression





5 Testosterone replacement therapy and depression
5.1 Testosterone trials
5.2 Testosterone treatment and depression





6 Androgen receptor regulation and depression
6.1 Molecular biology of androgen receptor structure
6.2 Canonical and non‑canonical androgen receptor signaling
6.3 Androgen receptor genetics and depression





7 Neuronal and molecular mechanisms mediating testosterone and depression




8 Summary, conclusions, and future directions


Current findings indicate that low circulating levels of total testosterone meeting stringent clinical criteria for hypogonadism and testosterone deficiency induced by androgen deprivation therapy are associated with increased risk for depression and current depressive symptoms. Furthermore, the Testosterone Trials and other studies have reported that testosterone replacement therapy may only be beneficial in men with a dysthymic disorder or subsyndromal depression that does not meet the criteria for the major depressive syndrome. These findings suggest that hypogonadal levels of testosterone can dysregulate mood and induce depressive symptoms. The studies reviewed here also suggest that a substantial deficiency in testosterone can cause a depressive-like state that can respond to TRT. At present, there is no clinical justification to use TRT as an antidepressant treatment for major depressive disorder. Therefore, the benefits of testosterone replacement therapy on major depressive disorder in men with clinically defined hypogonadism remains uncertain and will hopefully be elucidated by the TRAVERSE Trial and other ongoing research.

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. Furthermore, polygenic mechanisms are likely to be critical to the biological heterogeneity that influences testosterone-depression interactions. A recent study has identified certain regulatory variants linked to genetic risk for major depressive disorder in a GWAS, which includes hippocampal transcription factors enriched for ZMIZ1, a zinc finger co-activator that increases ligand-dependent transcription of the androgen receptor and promotes androgen receptor sumoylation required for androgen receptor function [124]. Research on male twins has provided heritability estimates of 57–58% for total testosterone [125, 126]. Genome-wide association studies (GWAS) from the UK Biobank and other large cohorts have identified the SNP-based heritability for total testosterone to be ~ 20% and free testosterone to be ~ 15% [21–23, 127]. 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). Polygenic scores derived from testosterone GWAS data predict testosterone levels and their association with important phenotypes and clinical disorders. As mentioned earlier, a recent investigation of 169,886 male participants (40–69 years) without a history of depression in the prospective UK Biobank study reported that hypogonadal men with very low total testosterone levels (<6.0 nmol/L; 173 ng/dl) had a high incidence of developing a major depressive episode over a five-year period [adjusted OR=1.60] [33]. The association of major depressive disorder incidence with testosterone levels in the severe hypogonadal range had the largest effect size among the 57 laboratory tests analyzed in the UK Biobank. Using the UK Biobank genetic database, Mendelian randomization analyses found a beneficial, protective effect of genetically predicted, lifelong free testosterone on depression in men [22]. A genetically informed precision medicine approach using genes regulating testosterone levels and androgen receptor sensitivity will likely provide critical insight into the role of testosterone in depression.
 

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madman

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Fig. 1 Regulation of the hypothalamic-pituitary-gonadal axis, testicular synthesis of androgens, and physiological actions of testosterone resulting from androgen receptor signaling in targeted tissues. The complex, multilevel regulation of the hypothalamic-pituitary-gonadal axis is mediated by stimulatory and inhibitory neurocircuits acting on gonadotropin-releasing hormone (GnRH) neurons in the arcuate/infundibular nucleus and medial preoptic area of the hypothalamus. Testosterone secreted by the testis exerts negative feedback control of hypothalamic GnRH release, while estradiol formed by 5α-reductase conversion of testosterone exerts negative feedback control of anterior pituitary luteinizing hormone (LH) secretion. Synthesis of testosterone and dihydrotestosterone (DHT) by the testis is stimulated by LH activating G protein-coupled LH receptors in Leydig cells. ACTH-stimulated synthesis of DHEA, 5-Adiol and androstenedione by adrenocortical cells may contribute to the testicular synthesis of testosterone and DHT via the “backdoor” pathway, although some studies indicate that DHEA and 5-Adiol secreted by the adrenal cortex may serve as substrates for peripheral conversion of testosterone by androgen receptor-regulated target tissues. Testosterone and DHT secreted by the testis bind to and activate the androgen receptor (AR) expressed in peripheral organs and the central nervous system. The slower genomic actions resulting from classical, canonical androgen receptor signaling involve the dissociation of cytosolic AR from heat shock proteins, translocation of AR with chaperones to the nucleus, and then binding of AR and co-regulators to androgen response elements on target genes to activate or repress their expression. In contrast, rapid, non-genomic actions result in membrane androgen receptors signaling via downstream Akt and ERK-MAP kinase pathways. The complex mechanisms governing testosterone hormone action regulate many physiological systems, modulate clinical disorders, and contribute to health outcomes. The dotted line indicates an inhibitory action, while the solid line indicates a stimulatory action.
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madman

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Fig. 2 Chromosome idiogram map of gene variants that have a significant genome-wide association with testosterone. The localization of testosterone gene variants to specific chromosomes is depicted. Gene variants were identified to have genome-wide significance for regulating testosterone based on GWAS studies of morning total testosterone levels in the UK Biobank and Million Veteran Program [21–23, 127].
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