Blockade of Estrogen by Hormonal Contraceptives Impairs Fear Extinction in Female Rats and Women
Open accessAbstract
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.
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Extinction memory is sexually dimorphic (better in males).
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- Authors
- Graham, B. M., & Milad, M. R.
- Affiliations
- Harvard University (US)
- Corresponding author
- Milad, Mohammed R.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2013-02
- Volume
- 73
- Issue
- 4
- Pages
- 371-378
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC3557577
- OpenAlex
- W1988611008
- Cited by
- 281
- References
- 33
- Citations by year
- 2026: 4 · 2025: 16 · 2024: 22 · 2023: 31 · 2022: 24 · 2021: 24 · 2020: 24 · 2019: 25 · 2018: 18 · 2017: 19 · 2016: 21 · 2015: 22 · 2014: 21 · 2013: 10
- FWCI
- 8.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH097880, K01MH080346)
- National Center for Research Resources (UL1RR025758)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory Processes and Influences
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- fear extinction, hormonal contraception, estrogen, estradiol, estrogen receptor agonists, anxiety disorders, exposure therapy, female rats, women, memory extinction
- MeSH terms
- Animals, Conditioning, Classical, Contraceptives, Oral, Hormonal, Estrogen Antagonists, Extinction, Psychological, Fear, Female, Galvanic Skin Response, Humans, Nitriles, Phenols, Propionates, Pyrazoles, Levonorgestrel, Rats, Sprague-Dawley, Freezing Reaction, Cataleptic, Rats
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