Testosterone increases and estradiol decreases middle cerebral artery occlusion lesion size in male rats

Hawk, Toni; Zhang, Y. Q.; Rajakumar, G.; Day, Arthur L.; Simpkins, James W.

doi:10.1016/s0006-8993(98)00327-8

Cited by 165 publications

(137 citation statements)

References 15 publications

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“…Although estradiol is considered neuroprotective, some literature suggests that testosterone exacerbates CNS damage. [23][24][25] Given our findings suggesting that higher ratios are protective, the dynamic balance between availability of testosterone as a substrate for estradiol, in contrast to the potential detrimental effects of testosterone on CNS function and survival, may be what the CSF E2/T ratios capture that is relevant to TBI outcome. For rs2470152, subjects with the C/C genotype had lower serum testosterone, compared to the remaining TBI cohort.…”

Section: Discussionmentioning

confidence: 85%

“…There were 6 healthy men and 7 healthy women enrolled (22-62 years of age), including 1 menopausal woman. For premenopausal women, 2 had samples collected during the follicular phase (days 5-10), and 4 had samples collected in the luteal phase (days [18][19][20][21][22][23]. Potential control subjects who were pregnant, had hormone or contraception therapy, or history of an endocrine disorder were excluded.…”

Section: Study Design and Subjectsmentioning

confidence: 99%

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Impact of Aromatase Genetic Variation on Hormone Levels and Global Outcome after Severe TBI

Garringer

Niyonkuru

McCullough

et al. 2013

Journal of Neurotrauma

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Although experimental traumatic brain injury (TBI) studies support estradiol as a neuroprotectant and potent stimulator of neuroplasticity, clinical studies suggest a negative association between endogenous estradiol profiles and mortality/poor outcomes. However, no studies have evaluated associations with cerebral spinal fluid (CSF) hormone profiles and aromatase gene (cytochrome P450 [CYP]19A1) variability on clinical TBI outcomes. We evaluated 110 adults with severe TBI. Average and daily estradiol, testosterone, and estradiol/testosterone ratios (E2:T) were measured using CSF and serum samples and compared to healthy controls. Eighteen tagging and four functional single-nucleotide polymorphisms (SNPs) for CYP19A1 were genotyped and compared to hormones, acute mortality, and Glasgow Outcome Scale (GOS) scores 6 months post-TBI. TBI subjects had lower CSF estradiol over time versus controls. CSF testosterone was initially high, but declined over time. E2/T ratios were initially low, compared to controls, but rose over time. Higher mean E2/T ratio in bivariate analysis was associated with lower mortality ( p = 0.019) and better GOS-6 scores ( p = 0.030). rs2470152 influenced CSF E2/T ratio and also serum and CSF testosterone ( p £ 0.05 all comparisons). Multiple-risk SNPs rs2470152, rs4646, and rs2470144 were associated with worse GOS-6 scores ( p £ 0.05, all comparisons), and those with > 1 risk SNP variant had a higher risk for poor outcome, compared with those with £ 1 risk variant. TBI results in low CSF estradiol and dynamic CSF testosterone and E2/T ratio. In contrast to clinical serum hormone studies, higher CSF E2/T ratio was associated with better outcome. Further, genetic variation in CYP19A1 influences both hormone dynamics and outcome post-TBI.

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Section: Discussionmentioning

confidence: 85%

Section: Study Design and Subjectsmentioning

confidence: 99%

Impact of Aromatase Genetic Variation on Hormone Levels and Global Outcome after Severe TBI

Garringer

Niyonkuru

McCullough

et al. 2013

Journal of Neurotrauma

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“…Furthermore, the role of androgens in male stroke is unclear, and current data are surprisingly few and contradictory. In male rats, castration and subsequent testosterone loss either decreases or has little effect on the ischemic histological damage (Hawk et al, 1998;Toung et al, 1998;Yang et al, 2002). Other reports indicate that testosterone replacement in castrates exacerbates injury (Hawk et al, 1998;Yang et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Deleterious Effects of Dihydrotestosterone on Cerebral Ischemic Injury

Cheng

Alkayed

Hurn

2007

J Cereb Blood Flow Metab

103

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Outcome from cerebral ischemia is sexually dimorphic in many experimental models. Male animals display greater sensitivity to ischemic injury than do their female counterparts; however, the underlying mechanism is unclear. The present study determined if the potent and nonaromatizable androgen, dihydrotestosterone (DHT), exacerbates ischemic damage in the male rat and alters postischemic gene expression after middle cerebral artery occlusion. At 22 h reperfusion, removal of androgens by castration provided protection from ischemic injury in both cortex and striatum (2,3,5-triphenyltetrazolium chloride (TTC) histology), whereas DHT replacement (50 mg subcutaneous implant) restored infarction volume to that of the intact male; testosterone (50 mg) had similar but less potent effects. We utilized microarray and real-time quantitative polymerase chain reaction (PCR) to identify genes differentially expressed at 6 h reperfusion in periinfarct cortex from castrated rats with or without DHT replacement. We identify, for the first time, a number of gene candidates that are induced by DHT with or without ischemia, many of which could account for cell death through enhanced inflammation, dysregulation of blood-brain barrier and the extracellular matrix, apoptosis, and ionic imbalance. Our data suggest that androgens are important mediators of ischemic damage in male brain and that transcriptional mechanisms should be considered as we seek to understand innate male sensitivity to cerebral ischemia.

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“…This advantage is abolished in ovariectomized animals, due to the loss of endogenous female sex hormones (Simpkins et al , 1997 ;Alkayed et al , 1998Alkayed et al , , 2000Hawk et al , 1998 ;Liao et al , 2001 ;Gibson et al , 2005 ;Park et al , 2006 ;Dra č a, 2009 ;Selvamani and Sohrabji , 2010 ), and the consequences of cerebral ischemia in aged animals are more severe than in young animals (Davis et al , 1995 ;Alkayed et al , 1998 ).…”

Section: Neuroprotectionmentioning

confidence: 99%

“…17 β -Estradiol salvages the brain from ischemic injury, even enhancing recovery and reducing infarct size in ovariectomized (Simpkins et al , 1997 ;Selvamani and Sohrabji , 2010 ) and reproductively senescent or aged females (Alkayed et al , 2000 ;Liao et al , 2001 ), as well as in male animals (Hawk et al , 1998 ). In the case of acyclic females, this is subject to administration of 17 β -estradiol at the onset of senescence or ovariectomy and not in older acyclic females (Bake and Sohrabji , 2004 ;Suzuki et al , 2009 ;Selvamani and Sohrabji , 2010 ).…”

Section: Neuroprotectionmentioning

confidence: 99%

Interrelation between inflammation, thrombosis, and neuroprotection in cerebral ischemia

Spuy¹,

Pretorius²

2012

Reviews in the Neurosciences

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Stroke by mechanism of thrombotic cerebral ischemia is one of the leading causes of death and/or disability worldwide. Current research is under consensus that there are sex-based differences in both the prevalence and presentation of stroke and thrombosis. Here we discuss the interrelation between thrombosis and infl ammation and call attention to points in the cerebral ischemic cascade where estrogen may be involved in neuroprotection. Cerebral ischemia triggers a series of events including infl ammation, which is deeply interrelated with thrombosis; infl ammation not only produces local thrombosis, but thrombosis can also amplify infl ammation especially through the synergism of leukocyte and platelet activity. Research involving experimental animal models of cerebral ischemia has shown that sex hormones, especially estrogen, offer a degree of neuroprotection. Mechanisms of this neuroprotection may be linked to certain anti-infl ammatory properties of estrogen, as well as estrogen ' s regulation of thrombosis through the lowering of coagulation factors, among others. It is also understood that sex hormones alter the function and morphology of platelets and fi brin networks, and changes in platelet and fi brin network morphology offer one of the earliest confi rmations of infl ammation. Sex hormone levels, infl ammatory processes, and thrombotic mechanisms are profoundly interconnected in predicting the outcome of cerebral ischemia.

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Testosterone increases and estradiol decreases middle cerebral artery occlusion lesion size in male rats

Cited by 165 publications

References 15 publications

Impact of Aromatase Genetic Variation on Hormone Levels and Global Outcome after Severe TBI

Impact of Aromatase Genetic Variation on Hormone Levels and Global Outcome after Severe TBI

Deleterious Effects of Dihydrotestosterone on Cerebral Ischemic Injury

Interrelation between inflammation, thrombosis, and neuroprotection in cerebral ischemia

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