Available online 14 October 2022, 101041

Abstract

Combined oral contraceptives (containing synthetic forms of estradiol and progestins) are one of the most commonly used drugs among females. However, their effects on the gut-brain axis have not been investigated to a great extent despite clear evidence that suggest bi-directional interactions between the gut microbiome and endogenous sex hormones. Moreover, oral contraceptives are prescribed during adolescence, a critical period of development during which several brain structures and systems, such as hypothalamic-pituitary-gonadal axis, undergo maturation. Considering that oral contraceptives could impact the developing adolescent brain and that these effects may be mediated by the gut-brain axis, further research investigating the effects of oral contraceptives on the gut-brain axis is imperative. This article briefly reviews evidence from animal and human studies on the effects of combined oral contraceptives on the brain and the gut microbiota particularly during adolescence.

Section snippetsAdolescence and OCs

Adolescence is a critical period of development during which the HPG axis becomes active and undergoes maturation, causing an increase in the production and release of gonadal steroid hormones, and leading to the development of secondary sexual characteristics and sexual maturation (Limesand & Davis, 2018). During this period, the brain also undergoes extensive remodeling and reorganizing leading to structural/functional changes that are driven by endogenous sex hormones (Schulz and Sisk, 2016,

OCs and the brain : Evidence from animal research

Examining the effects of synthetic hormones on the brains of animal models provides important insights into the neurobiological mechanisms through which OCs may alter brain structure and function. Rodent studies have shown that treatment with synthetic hormones reduces plasma estradiol and progesterone concentrations, decreases the volumes of the hippocampus and the cerebral cortex, and increases the expression of type A gamma-aminobutyric acid (GABA) receptors compared to untreated females (

Structural brain changes

Recent work suggests that OCs may change brain structure and function. For example, compared to naturally cycling (NC) females, OC users display reduced cortical thickness in the orbitofrontal and posterior cingulate cortices, right putamen, left amygdala and anterior parahippocampal gyrus (Lisofsky et al., 2016, Petersen et al., 2021, Petersen et al., 2015; Sharma, Smith, et al., 2020). OC users also display increased gray matter volume in the prefrontal cortex, and in the parahippocampal and

The gut microbiome

One possible mechanism mediating the effects of OCs on brain structure and function may be the gut microbiome. The gut microbiome is a complex and dynamic system comprised of trillions of microorganisms (e.g. viruses, bacteria and microorganisms) present in the digestive tract (Gill et al., 2006; Qin et al., 2010). The gut microbiota is responsible for the prevention of diseases via the regulation of a number of immune and metabolic functions (Prakash et al., 2011). Gut dysbiosis is defined as

Future Directions

In light of the evidence discussing the synergistic relationship between the gut brain axis and sex hormones as well as the effects of synthetic hormones on the brain, several questions have yet to be answered. Despite few evidence showing minor changes in gut composition as a function of synthetic hormones (Hua et al., 2022, Mihajlovic et al., 2021), studies remain mostly observational. In addition, the mechanisms through which synthetic hormones affect the gut-brain axis remain unknown. We

Concluding Remarks

In this paper, we provided a brief overview of the literature discussing the effects of oral contraception on brain structure and function, and discussed the necessity to incorporate the on the gut microbiome as an important contributing factor. While it was not the scope of this paper, it is also important to note that other forms of hormonal contraception such as vaginal ring, intradermal patch, intrauterine hormonal device may also impact women’s brain health (Lewis et al., 2019).

Uncited references

Korpela et al., 2021, Sharma et al., 2020a, Sharma et al., 2020b.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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