How do sex hormones and birth control affect brain fear circuits?

By Dr. Liji Thomas, MDNov 9 2023Reviewed by Benedette Cuffari, M.Sc.

A new report published in Frontiers of Endocrinology explores how oral contraceptive pill (OCP) use interacts with the current hormonal status to affect the fear circuit structure within the brain.

Study: Morphologic alterations of the fear circuitry: the role of sex hormones and oral contraceptives. Image Credit: KaryB / Shutterstock.com

Fear and female sex hormones

Although fear is both common and necessary to respond to the environment in a suitable manner, excessive fear can weaken and paralyze the individual or prevent proper social functioning. This is evident in anxiety disorders and post-traumatic stress disorder (PTSD).

Women are more vulnerable to these conditions; however, most studies on anxiety have primarily included male animals and men. In fact, as of 2012, less than 2% of papers on fear-related topics were based on the female brain.

Even today, published male-only studies outnumber female-only studies by a factor of nine. This bias is due to the fear that fluctuations in female sex hormone levels would cause unreliable results during the analysis; however, this hypothesis has not been confirmed.

Sex hormones produced by the hypothalamic-pituitary-gonadal (HPG) axis show cyclic patterns in women, which result in the ovarian and menstrual cycles. OCPs are currently used by over 150 million women throughout the world and interfere these cycles.

Combined OCPs (COCPs) are the most common type of prescribed OCPs. These comprise over 30 formulations that contain synthetic estrogen, known as ethinyl estradiol (EE) and progestin, with varying degrees of androgenicity.

Low estradiol levels in the female body promote fear maintenance, whereas high levels are associated with increased neuronal activation within the fear circuits. Sex hormones also regulate neurons that form part of the fear circuits, like the anterior insular cortex (AIC), dorsal anterior cingulate cortex (dACC), rostral anterior cingulate cortex (rACC), and ventromedial prefrontal cortex (vmPFC).

Prior research suggests that OCPs could affect endogenous sex hormone levels, as well as brain morphology, cognitive functioning, and anxiety symptoms. In the current study, researchers explore the possible short- and long-term effects of COCP use on brain fear circuitry structure and the contribution of sex hormones to these changes.

What did the study show?

The current study included healthy women between 23 and 25 years of age. All study participants were on or had previously used OCPs as their sole mode of contraception, with non-users as a control group and a fourth group comprised of men.

The researchers examined the levels of endogenous sex hormones in saliva, as well as the estrogen formulation present in OCPs. Structural magnetic resonance imaging (sMRI) of the brain allowed the gray matter volumes (GMVs) and cortical thickness (CT) to be assessed in the regions linked to fear circuits.

There was no significant difference in hormonal profiles between women who had never used OCPs or past users. Moreover, women, irrespective of OCP use status, had larger GMVs in both dACC regions. Current OCP users had a lower CT in the vmPFC region as compared to men.

Never OCP users had increased CT in the right AIC as compared to past users throughout the menstrual cycle. However, the associations between endogenous sex hormones and GMVs or CTs were less clear.

The results emphasize the key role of EE dosage, rather than salivary EE levels or progestin androgenicity, in affecting brain structure. Thus, the lower the EE dosage, the smaller the cortical GMVs.

These findings indicate that the GMV of the left dACC exhibited sexual dimorphism, which is of importance, as this is a region that promotes feelings of fear. More specifically, OCP users with low EE doses had smaller dACC GMV than men, while this region was larger for never-users or those on high-dose EE OCPs as compared to men.  

Conversely, the fear-inhibiting vmPFC exhibits a lower CT in current users, specifically those on low-dose EE, as compared to men. Never users and high-dose EE users had similar values.  

What are the implications?

Sex hormone exposure during a specific period of early development may permanently affect central nervous system structure. This may explain the lack of anatomical change after starting COCP use; however, this requires further investigation.

The dACC has been associated with fear networks and cognitive reappraisal, as well as emotion identification, description, and control. This may reflect the spectrum of roles played by this region during emotion processing, as well as the network-based maintenance of such complex states that require the interaction of multiple brain regions.

Reduced vmPFC CT could indicate a higher risk for fear extinction during COCP use that reverses once it is discontinued. This indicates that birth control pills do not have long-term effects on brain anatomy in these areas. However, the definitions of never use need to be refined to confirm these findings.

The study findings suggest that the female brain may be structurally susceptible to stress-related illness and anxiety that could be worsened with COCP use. Future studies are needed to elucidate the origin and contributing factors for fear-related illnesses that mostly affect women, especially with respect to sex steroids.