An alternate pathway for androgen regulation of brain function: Activation of estrogen receptor beta by the metabolite of dihydrotestosterone, 5α-androstane-3β,17β-diol

Handa, Robert J.; Pak, Toni R.; Kudwa, Andrea E.; Lund, Trent D.; Hinds, Laura R.

doi:10.1016/j.yhbeh.2007.09.012

Cited by 184 publications

(127 citation statements)

References 132 publications

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“…A similar variety of receptor-mediated mechanisms has been shown for T and its 5α-reduced metabolites; whereas 5α-DHT and T activate androgen receptors (AR), 3α-diol and 3β-diol act as a positive allosteric modulator of GABA-A receptor and an ERβ agonist, respectively [28,43]. Although several authors posited the involvement of membrane-bound receptors to account for several rapid actions of T, the molecular identity of these targets remains currently elusive [44].…”

Section: Functions Of 5α-rs In the Central Nervous Systemmentioning

confidence: 67%

Adverse effects of 5α-reductase inhibitors: What do we know, don’t know, and need to know?

Traish

Melcangi

Bortolato

et al. 2015

Rev Endocr Metab Disord

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Steroids are important physiological orchestrators of endocrine as well as peripheral and central nervous system functions. One of the key processes for regulation of these molecules lies in their enzymatic processing by a family of 5α-reductase (5α-Rs) isozymes. By catalyzing a key rate-limiting step in steroidogenesis, this family of enzymes exerts a crucial role not only in the physiological control but also in pathological events. Indeed, both 5α-R inhibition and supplementation of 5α-reduced metabolites are currently used or have been proposed as therapeutic strategies for a wide array of pathological conditions. In particular, the potent 5α-R inhibitors finasteride and dutasteride are used in the treatments of benign prostatic hyperplasia (BPH), as well as in male pattern hair loss (MPHL) known as androgenetic alopecia (AGA). Recent preclinical and clinical findings indicate that 5α-R inhibitors evoke not only beneficial, but also adverse effects. Future studies should investigate the biochemical and physiological mechanisms that underlie the persistence of the adverse sexual side effects to determine why a subset of patients is afflicted with such persistence or irreversible adverse effects. Also a better focus of clinical research is urgently needed to better define those subjects who are likely to be adversely affected by such agents. Furthermore, research on the non-sexual adverse effects such as diabetes, psychosis, depression, and cognitive function are needed to better understand the broad spectrum of the effects these drugs may elicit during their use in treatment of AGA or BPH. In this review, we will summarize the state of art on this topic, overview the key unresolved questions that have emerged on the pharmacological targeting of these enzymes and their products, and highlight the need for further studies to ascertain the severity and duration of the adverse effects of 5α-R inhibitors, as well as their biological underpinnings.

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Section: Functions Of 5α-rs In the Central Nervous Systemmentioning

confidence: 67%

Adverse effects of 5α-reductase inhibitors: What do we know, don’t know, and need to know?

Traish

Melcangi

Bortolato

et al. 2015

Rev Endocr Metab Disord

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“…The testosterone metabolite, 3α-androstanediol, may have actions via ERβ [78]. Indeed, we have demonstrated that the performance enhancing effects of 3α-diol are attenuated with co-administration of AS-ODNs that are targeted against ERβ, but not ERα, when administered to the hippocampus [74].…”

Section: Erβ-mediated Actions In the Hippocampus For E 2 'S Functionamentioning

confidence: 85%

Rapid and estrogen receptor beta mediated actions in the hippocampus mediate some functional effects of estrogen

Walf

Frye

2008

Steroids

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The steroid hormone, estradiol (E 2 ), has numerous targets in the central nervous system, including the hippocampus, which plays a key role in cognition and affective behavior. This review focuses on our evidence from studies in rodents that E 2 has diverse mechanisms in the hippocampus for its functional effects E 2 has rapid, membrane-mediated effects in the hippocampus to enhance cognitive performance. Administration of E 2 to the hippocampus of rats for 10 minutes following training enhances performance in a hippocampus-mediated task. Increased cell firing in the hippocampus occurs within this short time frame. Furthermore, administration of free E 2 or an E 2 conjugate, E 2 :bovine serum albumin (BSA), to the hippocampus produces similar performance-enhancing effects in this task, suggesting that E 2 has membrane actions in the hippocampus for these effects. Further evidence that E 2 has rapid, membrane-mediated effects is that co-administration of E 2 and inhibitors of mitogen activated protein kinase (MAPK), rather than intracellular E 2 receptors (ERs) or protein synthesis, attenuate the enhancing effects of E 2 in this task. Despite these data that demonstrate E 2 can have rapid and/or membrane-mediated effects in the hippocampus, there is clear evidence to suggest that intracellular ERs, particularly the β (rather than α) isoform of ERs, may be important targets for E 2 's functional effects for hippocampal processes. Administration of ligands that are specific for ERβ, but not ERα, have enhancing effects on hippocampal processes similar to that of E 2 (which has similar affinity for ERα and ERβ). These effects are attenuated when ERβ expression is knocked down in transgenic models or with central administration of antisense oligonucleotides. Thus, there may be a convergence of E 2 's actions through rapid, membranemediated effects and intracellular ERs and in the hippocampus for these functional effects.

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“…In contrast, in vitro studies suggest that some aspects of androgen protection, including regulation of A␤ generation via APP proteolysis, may be mediated indirectly after aromatization to estradiol . Recent work, suggesting that a metabolite of DHT, 5␣-androstane-3␤,17␤-diol, is active at ER␤, not ER␣ or AR (Lund et al, 2006;Pak et al, 2007;Handa et al, 2008), could also suggest that AR and/or ER␤, but not ER␣, mediate the effects of DHT on A␤ levels in males. Further work will clearly be important to understand to what degree the direct application of hormones to cultured neurons, which are capable of producing their own steroids in vitro (Prange-Kiel and Rune, 2006), reflects the effects of systemic hormones in vivo.…”

Section: B Preclinical Studiesmentioning

confidence: 99%

Estrogen Actions in the Brain and the Basis for Differential Action in Men and Women: A Case for Sex-Specific Medicines

2010

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An alternate pathway for androgen regulation of brain function: Activation of estrogen receptor beta by the metabolite of dihydrotestosterone, 5α-androstane-3β,17β-diol

Cited by 184 publications

References 132 publications

Adverse effects of 5α-reductase inhibitors: What do we know, don’t know, and need to know?

Adverse effects of 5α-reductase inhibitors: What do we know, don’t know, and need to know?

Rapid and estrogen receptor beta mediated actions in the hippocampus mediate some functional effects of estrogen

Estrogen Actions in the Brain and the Basis for Differential Action in Men and Women: A Case for Sex-Specific Medicines

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