Dataset Information

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

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.

SUBMITTER: Brouillard A

PROVIDER: S-EPMC10661904 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

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

Brouillard Alexandra A Davignon Lisa-Marie LM Turcotte Anne-Marie AM Marin Marie-France MF

Frontiers in endocrinology 20231107

<h4>Background</h4>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.<h4>Objective</h4>We investigated the current and lasting effects of OC use, as well as the interplay between the current hor ...[more]

PMID: 38027091

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Project description:In vitro signals indicate that ziritaxestat is a weak cytochrome P450 (CYP) 3A4 inhibitor and inducer. Therefore, potential drug-drug interactions (DDIs) with oral contraceptives were examined at a time when ziritaxestat was under development for treatment of fibrotic diseases. This open-label, crossover (fixed sequence) DDI study enrolled healthy, nonpregnant women aged 18-65 years (n = 15) who were using highly effective contraception, such as a nonhormonal intrauterine device, bilateral tubal occlusion, or sexual abstinence. A single dose of oral contraceptive (0.03 mg ethinyl estradiol (EE) and 3 mg drospirenone (DRSP)) was administered on days 1, 8, and 18, and ziritaxestat 600 mg once daily was administered from days 8 to 23. Co-administration resulted in a 2.8-fold and 2.4-fold increase in EE maximum plasma concentration (Cmax ) and area under the plasma drug concentration-time curve from time zero to infinity (AUC0-inf ), respectively (day 18 vs. day 1). DRSP Cmax and AUC0-inf increased by 1.1-fold and 1.2-fold, respectively. DRSP is a CYP3A4 substrate, meaning increased EE exposure with ziritaxestat was not due to CYP3A4 inhibition. Ziritaxestat inhibition of EE glucuronidation and sulfation was quantified by liquid chromatography with tandem mass spectrometry in day 1 and day 18 plasma samples after EE conjugate hydrolysis. The ratio of EE AUC from time of administration up to the time of the last quantifiable concentration (AUClast ) with/without hydrolysis by arylsulfatase was substantially lower on day 18 vs. day 1, suggesting ziritaxestat is a potent inhibitor of sulfation; EE glucuronidation was largely unaffected by ziritaxestat. In vitro assessment confirmed ziritaxestat is a potent inhibitor of sulfotransferase family 1E member 1 (half-maximal inhibitory concentration < 0.8 μM). These findings highlight the importance of assessing enzymes other than CYP3A4 when investigating potential DDIs with oral contraceptives.

Dataset Information

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

Background

Objective

Methods

Results

Discussion

Publications

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

Similar Datasets

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