Blockade of Estrogen by Hormonal Contraceptives Impairs Fear Extinction in Female Rats and Women

doi:10.1016/j.biopsych.2012.09.018

Biological Psychiatry

Volume 73, Issue 4, 15 February 2013, Pages 371-378

https://doi.org/10.1016/j.biopsych.2012.09.018 Get rights and content

Background

Fear extinction is a laboratory model of fear inhibition and is the basis of exposure therapy for anxiety disorders. Emerging evidence from naturally cycling female rodents and women indicates that estrogens are necessary to the consolidation of fear extinction. Hormonal contraceptives (HCs) inhibit estrogen production; yet, their effects on fear extinction are unknown.

Methods

We used a cross-species translational approach to investigate the impact of HCs and estradiol supplementation on fear extinction in healthy women (n=76) and female rats (n = 140).

Results

Women using HCs exhibited significantly poorer extinction recall compared with naturally cycling women. The extinction impairment was also apparent in HC-treated female rats and was associated with reduced serum estradiol levels. The impairment could be rescued in HC-treated rats either by terminating HC treatment after fear learning or by systemic injection of estrogen-receptor agonists before fear extinction, all of which restored serum estradiol levels. Finally, a single administration of estradiol to naturally cycling women significantly enhanced their ability to recall extinction memories.

Conclusions

Together, these findings suggest that HCs may impact women’s ability to inhibit fear but that this impairment is not permanent and could potentially be alleviated with estrogen treatment.

Section snippets

Human Participants

In experiment 1, we recruited a cohort of healthy women (n = 13) using combined monophasic HCs (Table S1 in Supplement 1) and contrasted their data to a previously studied cohort of naturally cycling women who underwent the same experimental design while in a high estradiol (H-EST) or low estradiol (L-EST) state, as determined by serum analyses (11) (see Supplement 1 for details). In experiment 5, we recruited a cohort of naturally cycling women (n=31) to participate ∼5 days after the onset of

Experiment 1: HCs Impair Fear Extinction in Healthy Women

Skin conductance responses to conditioned and extinguished stimuli from women using HCs were compared with naturally cycling women who were high (H-EST) or low (L-EST) in estradiol. No group differences were observed across conditioning [F(2,44)=.63, p=.54]. Skin conductance responses at the end of extinction training were significantly less than those during conditioning [F(1,42)=16.30, p<.0001], with no effect of group [F(2,42)=.79, p=.47] or phase-by-group interaction [F(2,42)=.44, p=.65],

Discussion

The present experiments demonstrated that although HCs had little or no effect on fear conditioning and acquisition of extinction, they significantly impaired extinction recall. The impairment was prevented in rats by terminating HCs or by administering ER agonists before extinction training, and pre-extinction estradiol administration also prevented extinction impairments in early-follicular women. Hormonal contraceptives reduce ovarian hormones, and we found that manipulations that increased

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Archival ReportBlockade of Estrogen by Hormonal Contraceptives Impairs Fear Extinction in Female Rats and Women

Background

Methods

Results

Conclusions

Section snippets

Human Participants

Experiment 1: HCs Impair Fear Extinction in Healthy Women

Discussion

Neurosci Biobehav Rev

Neuroscience

Neuroscience

Biol Psychiatry

Am J Obstet Gynecol

Front Neuroendocrinol

Brain Res

Biol Psychiatry

Biol Psychiatry

Cognitive processes during fear acquisition and extinction in animals and humans: Implications for exposure therapy of anxiety disorders

Clin Psychol Rev

Fear extinction as a model for translational neuroscience: Ten years of progress

Annu Rev Psychol

The prefrontal cortex communicates with the amygdala to impair learning after acute stress in females but not in males

J Neurosci

Progesterone at encoding predicts subsequent emotional memory

Learn Mem

Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey replication

Arch Gen Psychiatry

Why do many psychiatric disorders emerge during adolescence?

Nat Rev Neurosci

Archival Report
Blockade of Estrogen by Hormonal Contraceptives Impairs Fear Extinction in Female Rats and Women