Aging-induced changes in sex-steroidogenic enzymes and sex-steroid receptors in the cortex, hypothalamus and cerebellum

Munetomo, Arisa; Hojo, Yasushi; Higo, Shimpei; Kato, Asami; Yoshida, Kotaro; Shirasawa, Takuji; Shimizu, Takahiko; Barron, Anna M.; Kimoto, Tsunenobu; Kawato, Suguru

doi:10.1007/s12576-015-0363-x

Cited by 31 publications

(22 citation statements)

References 32 publications

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“…Regional regulation of AR has also been suggested by a previous study showing that aging induced a decreased expression of brain androgen synthesis enzymes in both the cerebral cortex and cerebellum, but the expression of AR was decreased only in the cerebral cortex and was not affected in the cerebellum [52]. …”

Section: Discussionmentioning

confidence: 65%

“…This finding suggests that the expression of ERα and that of ERβ are regulated by different mechanisms in the cerebral cortex. Indeed, a differential regulation of ERα and ERβ in the cerebral cortex has been previously observed in aged male rats [52]. In addition, low sex steroid levels were associated with a high expression of classical steroid receptors (i.e., AR and ER) in the brain of tropical male passerine birds [53].…”

Section: Discussionmentioning

confidence: 99%

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Effects of Subchronic Finasteride Treatment and Withdrawal on Neuroactive Steroid Levels and Their Receptors in the Male Rat Brain

et al. 2015

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The enzymatic conversion of progesterone and testosterone by the enzyme 5alpha-reductase exerts a crucial role in the control of nervous function. The effects of finasteride in the brain, an inhibitor of this enzyme used for the treatment of human benign prostatic hyperplasia and androgenic alopecia, have been poorly explored. Therefore, the effects of a subchronic treatment with finasteride at low doses (3 mg/kg/day) and the consequences of its withdrawal on neuroactive steroid levels in plasma, cerebrospinal fluid and some brain regions as well as on the expression of classical and non-classical steroid receptors have been evaluated in male rats. After subchronic treatment (i.e., for 20 days) the following effects were detected: (i) depending on the compartment considered, alteration in the levels of neuroactive steroids, not only in 5alpha-reduced metabolites but also in its precursors and in neuroactive steroids from other steroidogenic pathways and (ii) an upregulation of the androgen receptor in the cerebral cortex and beta3 subunit of the GABA-A receptor in the cerebellum. One month after the last treatment (i.e., withdrawal period), some of these effects persisted (i.e., the upregulation of the androgen receptor in the cerebral cortex, an increase of dihydroprogesterone in the cerebellum, a decrease of dihydrotestosterone in plasma). Moreover, other changes in neuroactive steroid levels, steroid receptors (i.e., an upregulation of the estrogen receptor alpha and a downregulation of the estrogen receptor beta in the cerebral cortex) and GABA-A receptor subunits (i.e., a decrease of alpha 4 and beta 3 mRNA levels in the cerebral cortex) were detected. These findings suggest that finasteride treatment may have broad consequences for brain function.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Effects of Subchronic Finasteride Treatment and Withdrawal on Neuroactive Steroid Levels and Their Receptors in the Male Rat Brain

et al. 2015

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“…Sex differences in neurosteroids in both normal and pathological aging are not well described. In male rodents, recent work indicates that normal aging is associated with decreased expression of several enzymes that contribute to testosterone synthesis (Munetomo et al 2015), which suggests possible age-related changes in steroid synthesis. Comparison of young adult and aged non-transgenic and 3xTg-AD male mice reveals changes in levels of numerous neurosteroids by aging and or AD-related transgenes (Caruso et al 2013).…”

Section: Alzheimer’s Disease and The Activational Effects Of Sex Stermentioning

confidence: 99%

Sex and the development of Alzheimer's disease

Pike

2016

J of Neuroscience Research

338

208

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Men and women exhibit differences in the development and progression of Alzheimer’s disease (AD). The factors underlying the sex differences in AD are not well understood. This review emphasizes the contributions of sex steroid hormones to the relationship between sex and AD. In women, events that decrease lifetime exposure to estrogens are generally associated with increased AD risk, whereas estrogen-based hormone therapy administered near the time of menopause may reduce AD risk. In men, estrogens do not exhibit age-related reduction and are not significantly associated with AD risk. Rather, normal age-related depletions of testosterone in plasma and brain predict enhanced vulnerability to AD. Both estrogens and androgens exert numerous protective actions in the adult brain that increase neural functioning and resilience as well as specifically attenuate multiple aspects of AD-related neuropathology. Aging diminishes the activational effects of sex hormones in sex-specific manners, which is hypothesized to contribute to the relationship between aging and AD. Sex steroid hormones may also drive sex differences in AD through their organizational effects during developmental sexual differentiation of the brain. Specifically, sex hormone actions during early development may confer inherent vulnerability of the female brain to development of AD in advanced age. The combined effects of organizational and activational effects of sex steroids yield distinct sex differences in AD pathogenesis, a significant variable that must be more rigorously considered in future research.

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“…The lack of effects might be caused by the altered pharmacokinetic profile of testosterone [40] or by the complex metabolism of testosterone in the brain. In particular, aromatase converting testosterone to estradiol, but also androgen and estrogen receptors are differentially expressed in some regions of the aging rat brain as recently described [41]. This underscores the importance of conducting experiments focusing on the effects of exogenous testosterone on brain functions in animals of various age including very old rats as in this experiments.…”

Section: Discussionmentioning

confidence: 55%

No effect of testosterone on behavior in aged Wistar rats

Borbélyová

Domonkos

Bábíčková

et al. 2016

Aging

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In men, aging is accompanied by a gradual decline in androgen secretion. Studies suggest beneficial effects of endogenous and exogenous testosterone on affective behavior and cognitive functions. The aim of this study was to describe behavioral and cognitive sex differences and to analyze the effects of long-term androgen deficiency in aged male rats. Thirty-months old rats divided into three groups (males, females and males gonadectomized as young adults) underwent a battery of behavioral tests assessing locomotor activity, anxiety, memory, anhedonia, sociability and depression-like behavior. No major effect of gonadectomy was found in any of the analyzed behavioral measures in male rats. The only consistent sex difference was confirmed in depression-like behavior with longer immobility time observed in males. In an interventional experiment, a single dose of testosterone had no effect on gonadectomized male and female rats in the forced swim test. In contrast to previous studies this comprehensive behavioral phenotyping of aged rats revealed no major role of endogenous testosterone. Based on our results long-term hypogonadism does not alter the behavior of aged male rats, neither does acute testosterone treatment. Whether these findings have any consequences on androgen replacement therapy in aged men remains to be elucidated.

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Aging-induced changes in sex-steroidogenic enzymes and sex-steroid receptors in the cortex, hypothalamus and cerebellum

Cited by 31 publications

References 32 publications

Effects of Subchronic Finasteride Treatment and Withdrawal on Neuroactive Steroid Levels and Their Receptors in the Male Rat Brain

Effects of Subchronic Finasteride Treatment and Withdrawal on Neuroactive Steroid Levels and Their Receptors in the Male Rat Brain

Sex and the development of Alzheimer's disease

No effect of testosterone on behavior in aged Wistar rats

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