Androgens: clinical research and therapeutics最新文献

Androgens play a pivotal role during development. These gonadal hormones and their receptors exert organizational actions that shape brain morphology in regions controlling the stress regulatory systems in a male-specific manner. Specifically, androgens drive sex differences in the hypothalamic/pituitary/adrenal (HPA) axis and corresponding hypothalamic neuropeptides. While studies have examined the role of estradiol and its receptors in sex differences in the HPA axis and associated behaviors, the role of androgens remains far less studied. Androgens are generally thought to modulate the HPA axis through the activation of androgen receptors (ARs). They can also impact the HPA axis through reduction to estrogenic metabolites that can bind estrogen receptors in the brain and periphery. Such regulation of the HPA axis stress response by androgens can often result in sex-biased risk factors for stress-related disorders, such as anxiety and depression. This review focuses on the biosynthesis pathways and molecular actions of androgens and their nuclear receptors. The impact of androgens on hypothalamic neuropeptide systems (corticotropin-releasing hormone, arginine vasopressin, oxytocin, dopamine, and serotonin) that control the stress response and stress-related disorders is discussed. Finally, this review discusses potential therapeutics involving androgens (androgen replacement therapies, selective AR modulator therapies) and ongoing clinical trials.

Androgens are synthesized in the brain, gonads, and adrenal glands, in both sexes, exerting physiologically important effects on the structure and function of the central nervous system. These effects may contribute to the incidence and progression of neurological disorders such as autism spectrum disorder, schizophrenia, and Alzheimer's disease, which occur at different rates in males and females. This review briefly summarizes the current state of knowledge with respect to the neuroplastic effects of androgens, with particular emphasis on the hippocampus, which has been the focus of much of the research in this field.

The aromatase cytochrome P450 (P450arom) enzyme, or estrogen synthase, which is coded by the CYP19A1 gene, is widely expressed in a subpopulation of excitatory and inhibitory neurons, astrocytes, and other cell types in the human brain. Experimental studies in laboratory animals indicate a prominent role of brain aromatization of androgens to estrogens in regulating different brain functions. However, the consequences of aromatase expression in the human brain remain poorly understood. Here, we summarize the current knowledge about aromatase expression in the human brain, abundant in the thalamus, amygdala, hypothalamus, cortex, and hippocampus and discuss its role in the regulation of sensory integration, body homeostasis, social behavior, cognition, language, and integrative functions. Since brain aromatase is affected by neurodegenerative conditions and may participate in sex-specific manifestations of autism spectrum disorders, major depressive disorder, multiple sclerosis, stroke, and Alzheimer's disease, we discuss future avenues for research and potential clinical and therapeutic implications of the expression of aromatase in the human brain.

Adult neurogenesis in the hippocampus is modulated by steroid hormones, including androgens, in male rodents. In this review, we summarize research showing that chronic exposure to androgens, such as testosterone and dihydrotestosterone, enhances the survival of new neurons in the dentate gyrus of male, but not female, rodents, via the androgen receptor. However, the neurogenesis promoting the effect of androgens in the dentate gyrus may be limited to younger adulthood as it is not evident in middle-aged male rodents. Although direct exposure to androgens in adult or middle age does not significantly influence neurogenesis in female rodents, the aromatase inhibitor letrozole enhances neurogenesis in the hippocampus of middle-aged female mice. Unlike other androgens, androgenic anabolic steroids reduce neurogenesis in the hippocampus of male rodents. Collectively, the research indicates that the ability of androgens to enhance hippocampal neurogenesis in adult rodents is dependent on dose, androgen type, sex, duration, and age. We discuss these findings and how androgens may be influencing neuroprotection, via neurogenesis in the hippocampus, in the context of health and disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. A greater prevalence and incidence of PD are reported in men than in women, suggesting a potential contribution of sex, genetic difference and/or sex hormones. This review presents an overview of epidemiological and clinical studies investigating sex differences in the incidence and symptoms of PD. This sex difference is replicated in animal models of PD showing an important neuroprotective role of sex steroids. Therefore, although gender and genetic factors likely contribute to the sex difference in PD, focus here will be on sex hormones because of their neuroprotective role. Androgens receive less attention than estrogen. It is well known that endogenous androgens are more abundant in healthy men than in women and decrease with aging; lower levels are reported in PD men than in healthy male subjects. Drug treatments with androgens, androgen precursors, antiandrogens, and drugs modifying androgen metabolism are available to treat various endocrine conditions, thus having translational value for PD but none have yet given sufficient positive effects for PD. Variability in the androgen receptor is reported in humans and is an additional factor in the response to androgens. In animal models of PD used to study neuroprotective activity, the androgens testosterone and dihydrotestosterone have given inconsistent results. 5α-Reductase inhibitors have shown neuroprotective activity in animal models of PD and antidyskinetic activity. Hence, androgens have not consistently shown beneficial or deleterious effects in PD but numerous androgen-related drugs are available that could be repurposed for PD.