Elevated testosterone in females reveals a robust sex difference in altered androgen levels during chronic alcohol withdrawal

Forquer, Melissa R.; Hashimoto, Joel G.; Roberts, Melissa L.; Wiren, Kristine M.

doi:10.1016/j.alcohol.2010.08.013

Cited by 21 publications

(11 citation statements)

References 61 publications

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“…The GABA A R-active testosterone metabolites, 3α,5α-and 3α,5β-androstanediol, were decreased by 32 or 39% (3α,5α-) and by 78 or 70% (3α,5β-) during ethanol withdrawal in WSP-1 and WSR-1 mice, respectively. Recent work indicated that serum testosterone was significantly decreased at the 8 hr withdrawal time point in male WSP and WSR mice (Forquer et al, 2011), suggesting that ethanol withdrawal produced a similar suppression in the biosynthesis of testosterone and its GABA A R-active metabolites in male WSP and WSR mice in the present study. This finding is consistent with the reported decrease in plasma testosterone levels in male alcoholics (e.g., Castilla-Garcia et al, 1987; Iturriaga et al, 1999; Krüger et al, 2006; Maneesh et al, 2006; Martinez-Riera et al, 1995; Ruusa et al, 1997; Sierksma et al, 2004; Ylikahri et al, 1980).…”

Section: Discussionsupporting

confidence: 73%

Quantification of ten neuroactive steroids in plasma in Withdrawal Seizure-Prone and -Resistant mice during chronic ethanol withdrawal

et al. 2014

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Rationale The rapid membrane actions of neuroactive steroids, particularly via an enhancement of γ-aminobutyric acidA receptors (GABAARs), participate in the regulation of central nervous system excitability. Prior evidence suggests an inverse relationship between endogenous GABAergic neuroactive steroid levels and behavioral changes in excitability during ethanol withdrawal. Objectives Previously, we found that ethanol withdrawal significantly decreased plasma allopregnanolone (ALLO) levels, a potent GABAergic neuroactive steroid, and decreased GABAAR sensitivity to ALLO in Withdrawal Seizure–Prone (WSP) but not in Withdrawal Seizure–Resistant (WSR) mice. However, the effect of ethanol withdrawal on levels of other endogenous GABAAR-active steroids is not known. Methods After validation of a gas chromatography-mass spectrometry method for the simultaneous quantification of 10 neuroactive steroids, we analyzed plasma from control male WSP-1 and WSR-1 mice and during ethanol withdrawal. Results We quantified levels of 9 neuroactive steroids in WSP-1 and WSR-1 plasma; levels of pregnanolone were not detectable. Basal levels of 5 neuroactive steroids were higher in WSR-1 versus WSP-1 mice. Ethanol withdrawal significantly suppressed 5 neuroactive steroids in WSP-1 and WSR-1 mice, including ALLO. Conclusions Due to lower basal levels of some GABAAR-active steroids in WSP-1 mice, a withdrawal-induced decrease in WSP-1 mice may have a greater physiological consequence than a similar decrease in WSR-1 mice. Because WSP-1 mice also exhibit a reduction in GABAAR sensitivity to neuroactive steroids during withdrawal, it is possible that the combined decrease in neuroactive steroids and GABAAR sensitivity during ethanol withdrawal in WSP-1 mice represents a neurochemical substrate for severe ethanol withdrawal.

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Section: Discussionsupporting

confidence: 73%

Quantification of ten neuroactive steroids in plasma in Withdrawal Seizure-Prone and -Resistant mice during chronic ethanol withdrawal

et al. 2014

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“…exposed to circulating hormones which are protective under certain conditions like stroke. Our previous data suggest that levels of estradiol drop following ethanol exposure in both sexes, thus minimizing any influence these factors might have on the observed results (36). Nevertheless, these studies do identify direct effects of chronic alcohol exposure in the astrocyte population that are fundamentally sexually dimorphic, and independent of other influences.…”

Section: Figurementioning

confidence: 89%

Astrocyte Dysfunction Induced by Alcohol in Females but Not Males

et al. 2015

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Chronic alcohol abuse is associated with brain damage in a sex-specific fashion, but the mechanisms involved are poorly described and remain controversial. Previous results have suggested that astrocyte gene expression is influenced by ethanol intoxication and during abstinence in vivo. Here, bioinformatic analysis of astrocyte-enriched ethanol-regulated genes in vivo revealed ubiquitin pathways as an ethanol target, but with sexually dimorphic cytokine signaling and changes associated with brain aging in females and not males. Consistent with this result, astrocyte activation was observed after exposure in female but not male animals, with reduced S100β levels in the anterior cingulate cortex and increased GFAP(+) cells in the hippocampus. In primary culture, the direct effects of chronic ethanol exposure followed by recovery on sex-specific astrocyte function were examined. Male astrocyte responses were consistent with astrocyte deactivation with reduced GFAP expression during ethanol exposure. In contrast, female astrocytes exhibited increased expression of Tnf, reduced expression of the neuroprotective cytokine Tgfb1, disrupted bioenergetics and reduced excitatory amino acid uptake following exposure or recovery. These results indicate widespread astrocyte dysfunction in ethanol-exposed females and suggest a mechanism that may underlie increased vulnerability to ethanol-induced neurotoxicity in females.

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“…Such studies should preferably include different age groups to analyze the interaction with hormonal changes during life-time. For example, elevated testosterone levels in female mice chronically exposed to ethanol, and less reduction of estrogen levels during withdrawal compared to male mice, suggest an important role of altered androgen signaling in the sexually dimorphic response to alcohol abuse [33]. …”

Section: Resultsmentioning

confidence: 99%

Sex-Dependent Decrease of Sphingomyelinase Activity During Alcohol Withdrawal Treatment

Mühle

Amova

Biermann

et al. 2014

Cell Physiol Biochem

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Background: In vitro and in vivo studies have demonstrated the role of the acid sphingomyelinase (ASM) in pathophysiological processes and alterations in response to ethanol exposure. Cellular and plasmatic ASM activities are increased in male alcohol dependent patients and decrease during physical withdrawal. Methods: Here, we analyzed the time course of ASM in male and also female acutely intoxicated patients during alcohol withdrawal and compared the activity levels to those under long-term maintenance treatment. Craving and further psychometric parameters were assessed by questionnaires. Results: The gradual decrease of serum ASM was confirmed in males (p<0.001) and continued to lower activities in long-term patients (p=0.001). The trend was similar in females (p=0.178), although the initial enzyme activities were significantly lower (p=0.035). ASM activity strongly correlated with the body mass index in males. The initial ASM activity and its decline during the first two days were associated with the improvement in scores for the Beck depression inventory, the obsessive compulsive drinking and the withdrawal syndrome scales. Conclusion: These data support the potential of ASM as a biomarker for the course of withdrawal therapy in males and provide the first associations of this enzyme with psychological variables such as craving and depression.

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Elevated testosterone in females reveals a robust sex difference in altered androgen levels during chronic alcohol withdrawal

Cited by 21 publications

References 61 publications

Quantification of ten neuroactive steroids in plasma in Withdrawal Seizure-Prone and -Resistant mice during chronic ethanol withdrawal

Quantification of ten neuroactive steroids in plasma in Withdrawal Seizure-Prone and -Resistant mice during chronic ethanol withdrawal

Astrocyte Dysfunction Induced by Alcohol in Females but Not Males

Sex-Dependent Decrease of Sphingomyelinase Activity During Alcohol Withdrawal Treatment

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