Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Nov 7:14:1228504.
doi: 10.3389/fendo.2023.1228504. eCollection 2023.

Morphologic alterations of the fear circuitry: the role of sex hormones and oral contraceptives

Affiliations

Morphologic alterations of the fear circuitry: the role of sex hormones and oral contraceptives

Alexandra Brouillard et al. Front Endocrinol (Lausanne). .

Abstract

Background: Endogenous sex hormones and oral contraceptives (OCs) have been shown to influence key regions implicated in fear processing. While OC use has been found to impact brain morphology, methodological challenges remain to be addressed, such as avoiding selection bias between OC users and non-users, as well as examining potential lasting effects of OC intake.

Objective: We investigated the current and lasting effects of OC use, as well as the interplay between the current hormonal milieu and history of hormonal contraception use on structural correlates of the fear circuitry. We also examined the role of endogenous and exogenous sex hormones within this network.

Methods: We recruited healthy adults aged 23-35 who identified as women currently using (n = 62) or having used (n = 37) solely combined OCs, women who never used any hormonal contraceptives (n = 40), or men (n = 41). Salivary endogenous sex hormones and current users' salivary ethinyl estradiol (EE) were assessed using liquid chromatography - tandem mass spectrometry. Using structural magnetic resonance imaging, we extracted surface-based gray matter volumes (GMVs) and cortical thickness (CT) for regions of interest of the fear circuitry. Exploratory whole-brain analyses were conducted with surface-based and voxel-based morphometry methods.

Results: Compared to men, all three groups of women exhibited a larger GMV of the dorsal anterior cingulate cortex, while only current users showed a thinner ventromedial prefrontal cortex. Irrespective of the menstrual cycle phase, never users exhibited a thicker right anterior insular cortex than past users. While associations with endogenous sex hormones remain unclear, we showed that EE dosage in current users had a greater influence on brain anatomy compared to salivary EE levels and progestin androgenicity, with lower doses being associated with smaller cortical GMVs.

Discussion: Our results highlight a sex difference for the dorsal anterior cingulate cortex GMV (a fear-promoting region), as well as a reduced CT of the ventromedial prefrontal cortex (a fear-inhibiting region) specific to current OC use. Precisely, this finding was driven by lower EE doses. These findings may represent structural vulnerabilities to anxiety and stress-related disorders. We showed little evidence of durable anatomical effects, suggesting that OC intake can (reversibly) affect fear-related brain morphology.

Keywords: cortical thickness; fear circuitry; gray matter volume; oral contraceptives; sex hormones; structural MRI.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Sex hormone profiles across study groups. (A) As expected, pre-ovulatory naturally-cycling (NC) women had higher estradiol concentrations compared to the three other groups. Estradiol levels were similar for early follicular NC women, men, and combined oral contraceptive (COC) users. (B) Groups did not differ in progesterone levels. (C) For testosterone, men showed higher concentrations than the three groups of women, pre-ovulatory NC women exhibited greater levels than early follicular NC women, and both NC groups had more testosterone levels than COC users. No differences were found between never users and past users across the three hormones.
Figure 2
Figure 2
Group differences on the (A) bilateral dorsal anterior cingulate cortex (dACC) and (B) bilateral ventromedial prefrontal cortex (vmPFC) based on a region-of-interest approach. **p <.01, *p <.05.
Figure 3
Figure 3
Never users tended to show thicker right anterior insular cortex (AIC) than past users, after adjusting for age and menstrual cycle phase. This difference became significant after adjusting for additional confounds. #p <.08.
Figure 4
Figure 4
Associations between endogenous sex hormones and brain morphology. For the bilateral hippocampus, (A) estradiol was negatively correlated in never users (pM = .040, fraction missing info = .185) and (B) testosterone tended to positively correlate in all participants (pM = .067, fraction missing info = .078). For the bilateral hypothalamus, (C) estradiol was negatively correlated in never users (pM = .014, fraction missing info = .197) and (D) testosterone was positively correlated in all participants (pM = .002, fraction missing info = .128). (E) For the left rostral anterior cingulate cortex (rACC), testosterone was negatively correlated to the cortical thickness in men (pM = .006, fraction missing info = .021). For illustrative purposes, each scatter plot depicts the imputation dataset being the most similar to the pooled p-value of the post hoc result. Error bars represent 95% confidence intervals.
Figure 5
Figure 5
Effect of ethinyl estradiol (EE) doses on the gray matter volume of the (A) anterior insular cortex (AIC), (B) dorsal anterior cingulate cortex (dACC), (C) ventromedial prefrontal cortex (vmPFC), and (D) the cortical thickness of the vmPFC. *p <.05, #p <.08.
Figure 6
Figure 6
Comparison of current users either taking low or high doses of ethinyl estradiol (EE) with never users and men regarding the (A) right anterior insular cortex (AIC) volume, (B) left dorsal anterior cingulate cortex (dACC) volume, (C) bilateral ventromedial prefrontal cortex (vmPFC) thickness, and (D) left vmPFC volume. **p <.01, *p <.05, #p <.08. ns, non-significant.
Figure 7
Figure 7
Effects of progestin androgenicity on the dorsal anterior cingulate cortex (dACC). Results are displayed for (A) gray matter volume and (B) cortex thickness of the three androgenicity groups, as well as additional comparison with never users and past users for (C) gray matter volume and (D) cortex thickness of this region. ***p <.001, **p <.01, #p <.08. ns, non-significant.

Similar articles

Cited by

References

    1. Ekman P. An argument for basic emotions. Cogn Emotion (1992) 6(3/4):169–200. doi: 10.1080/02699939208411068 - DOI
    1. Hartley CA, Phelps EA. Changing fear: the neurocircuitry of emotion regulation. Neuropsychopharmacology (2010) 35(1):136–46. doi: 10.1038/npp.2009.121 - DOI - PMC - PubMed
    1. McLean CP, Asnaani A, Litz BT, Hofmann SG. Gender differences in anxiety disorders: prevalence, course of illness, comorbidity and burden of illness. J Psychiatr Res (2011) 45(8):1027–35. doi: 10.1016/j.jpsychires.2011.03.006 - DOI - PMC - PubMed
    1. Craske MG, Sandman CF, Stein MB. How can neurobiology of fear extinction inform treatment? Neurosci Biobehav Rev (2022) 143:104923. doi: 10.1016/j.neubiorev.2022.104923 - DOI - PubMed
    1. Foa EB, McLean CP. The efficacy of exposure therapy for anxiety-related disorders and its underlying mechanisms: the case of OCD and PTSD. Annu Rev Clin Psychol (2016) 12(1):1–28. doi: 10.1146/annurev-clinpsy-021815-093533 - DOI - PubMed

Substances