The influence of gonadal hormones on conditioned fear extinction in healthy humans
M R Milad, M A Zeidan, A Contero, R K Pitman, A Klibanski, S L Rauch, J M Goldstein, M R Milad, M A Zeidan, A Contero, R K Pitman, A Klibanski, S L Rauch, J M Goldstein
Abstract
Recent rodent studies suggest that gonadal hormones influence extinction of conditioned fear. Here we investigated sex differences in, and the influence of estradiol and progesterone on, fear extinction in healthy humans. Men and women underwent a two-day paradigm in which fear conditioning and extinction learning took place on day 1 and extinction recall was tested on day 2. Visual cues were used as the conditioned stimuli and a mild electric shock was used as the unconditioned stimulus. Skin conductance was recorded throughout the experiment and used to measure conditioned responses (CRs). Blood samples were obtained from all women to measure estradiol and progesterone levels. We found that higher estradiol during extinction learning enhanced subsequent extinction recall but had no effects on fear acquisition or extinction learning itself. Sex differences were only observed during acquisition, with men exhibiting significantly higher CRs. After dividing women into low- and high-estradiol groups, men showed comparable extinction recall to high-estradiol women, and both of these groups showed higher extinction recall than low-estradiol women. Therefore, sex differences in extinction memory emerged only after taking into account women's estradiol levels. Lower estradiol may impair extinction consolidation in women. These findings could have practical applications in the treatment of anxiety disorders through cognitive and behavioral therapies.
Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2881679/bin/nihms-199505-f0001.jpg)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2881679/bin/nihms-199505-f0002.jpg)
Figure 3
Conditioned responses (SCRs) of high…
Figure 3
Conditioned responses (SCRs) of high (HP) and low progesterone (LP) women across each…
Figure 4
Conditioned responses (SCRs) of men…
Figure 4
Conditioned responses (SCRs) of men and all women across each session of the…
Figure 5
Percent extinction retention for men,…
Figure 5
Percent extinction retention for men, women with high estradiol (HE) levels, and women…
- Low levels of estradiol are associated with elevated conditioned responding during fear extinction and with intrusive memories in daily life.Wegerer M, Kerschbaum H, Blechert J, Wilhelm FH. Wegerer M, et al. Neurobiol Learn Mem. 2014 Dec;116:145-54. doi: 10.1016/j.nlm.2014.10.001. Epub 2014 Oct 22. Neurobiol Learn Mem. 2014. PMID: 25463649 Free PMC article.
- Stress exposure prior to fear acquisition interacts with estradiol status to alter recall of fear extinction in humans.Antov MI, Stockhorst U. Antov MI, et al. Psychoneuroendocrinology. 2014 Nov;49:106-18. doi: 10.1016/j.psyneuen.2014.06.022. Epub 2014 Jul 8. Psychoneuroendocrinology. 2014. PMID: 25080403
- Estrous cycle phase and gonadal hormones influence conditioned fear extinction.Milad MR, Igoe SA, Lebron-Milad K, Novales JE. Milad MR, et al. Neuroscience. 2009 Dec 15;164(3):887-95. doi: 10.1016/j.neuroscience.2009.09.011. Epub 2009 Sep 15. Neuroscience. 2009. PMID: 19761818 Free PMC article.
- Gonadal steroid hormones and emotional memory consolidation: A systematic review and meta-analysis.Hsu CK, Ney LJ, Honan C, Felmingham KL. Hsu CK, et al. Neurosci Biobehav Rev. 2021 Nov;130:529-542. doi: 10.1016/j.neubiorev.2021.09.010. Epub 2021 Sep 10. Neurosci Biobehav Rev. 2021. PMID: 34517034 Review.
- Mechanisms of estradiol in fear circuitry: implications for sex differences in psychopathology.Cover KK, Maeng LY, Lebrón-Milad K, Milad MR. Cover KK, et al. Transl Psychiatry. 2014 Aug 5;4(8):e422. doi: 10.1038/tp.2014.67. Transl Psychiatry. 2014. PMID: 25093600 Free PMC article. Review.
- Translational studies of estradiol and progesterone in fear and PTSD.Seligowski AV, Hurly J, Mellen E, Ressler KJ, Ramikie TS. Seligowski AV, et al. Eur J Psychotraumatol. 2020 Feb 18;11(1):1723857. doi: 10.1080/20008198.2020.1723857. eCollection 2020. Eur J Psychotraumatol. 2020. PMID: 32158516 Free PMC article. Review.
- The role of catecholamines in modulating responses to stress: Sex-specific patterns, implications, and therapeutic potential for post-traumatic stress disorder and opiate withdrawal.Ross JA, Van Bockstaele EJ. Ross JA, et al. Eur J Neurosci. 2020 Jul;52(1):2429-2465. doi: 10.1111/ejn.14714. Epub 2020 Apr 20. Eur J Neurosci. 2020. PMID: 32125035 Free PMC article. Review.
- Nervous and Endocrine System Dysfunction in Posttraumatic Stress Disorder: An Overview and Consideration of Sex as a Biological Variable.Seligowski AV, Harnett NG, Merker JB, Ressler KJ. Seligowski AV, et al. Biol Psychiatry Cogn Neurosci Neuroimaging. 2020 Apr;5(4):381-391. doi: 10.1016/j.bpsc.2019.12.006. Epub 2019 Dec 19. Biol Psychiatry Cogn Neurosci Neuroimaging. 2020. PMID: 32033924 Free PMC article. Review.
- Acute ovarian hormone treatment in freely cycling female rats regulates distinct aspects of heroin seeking.Vazquez M, Frazier JH, Reichel CM, Peters J. Vazquez M, et al. Learn Mem. 2019 Dec 16;27(1):6-11. doi: 10.1101/lm.050187.119. Print 2020 Jan. Learn Mem. 2019. PMID: 31843977 Free PMC article.
- Pharmacological interventions during the process of reconsolidation of aversive memories: A systematic review.Bolsoni LM, Zuardi AW. Bolsoni LM, et al. Neurobiol Stress. 2019 Aug 21;11:100194. doi: 10.1016/j.ynstr.2019.100194. eCollection 2019 Nov. Neurobiol Stress. 2019. PMID: 31832508 Free PMC article. Review.
- Research Support, N.I.H., Extramural
- Adolescent
- Adult
- Conditioning, Classical*
- Estradiol / blood*
- Extinction, Psychological*
- Fear*
- Female
- Humans
- Male
- Progesterone / blood*
- Sex Factors
- Young Adult
- Progesterone
- Estradiol
- Full Text Sources
- Medical
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2881679/bin/nihms-199505-f0003.jpg)
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2881679/bin/nihms-199505-f0004.jpg)
![Figure 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2881679/bin/nihms-199505-f0005.jpg)
Source: PubMed