How birth control pills may impact mood through the gut-brain axis

How birth control pills may impact mood through the gut-brain axis | Image Credit: © nenetus - © nenetus - stock.adobe.com.

Combined oral contraceptives (COCs) may influence a combined estrogen-gut-brain axis, impacting mood disorders through the gut microbiome, according to a recent study published in Cureus.

Approximately 25% of reproductive-aged women use oral hormonal contraception, with COCs frequently prescribed to prevent unwanted pregnancy. However, COC use has been linked to potential gastrointestinal (GI) and central nervous system (CNS) complications. It also has a role in mood disorders that may be caused by progestin concentration and type.

“However, the addition of progestin in short-menopausal-duration women who have higher circulating pretreatment estradiol and estradiol receptors may not be sufficient to adversely affect mood states,” wrote investigators.

Investigating mood disorders in COC users

Data has indicated increased odds of mood disorders in patients using COCs vs nonusers. Therefore, investigators conducted a study to assess factors that contribute to complications of COCs on the gut microbiome and mood disorders.

Gut microbiome development begins from birth and is influenced by the newborn delivery method. While there is a symbiotic relationship between most gut flora bacteria and the human gut, some strains may lead to adverse effects. A disrupted gut microbiome also leads to increased intestinal permeability and risks of complications.

Drug-induced microbiome disruption

Antibiotics are known to lead to drug-induced disruption of the gut microbiome. This includes COCs, which are made up of progestins and estrogen. One of the components of estrogen is estradiol, which has psychological effects mediated through the estrogen receptor (ER) alpha and beta. ERs expressed in the brain have been linked to the gastrointestinal system.

Progestins reduce estradiol circulation, which may prevent the luteinizing hormone surge needed to release the follicle. This effectively prevents pregnancy.

COC risks

The estrogen-gut axis refers to the relationship between the gut microbiome and estrogens, as the gut microbiome is vital for regulating circulating estradiol levels. However, exogenous hormones introduced to the body through COCs disrupt the estrobolome’s composition, impacting this regulation of estradiol and leading to gut-related complications.

An example of these complications includes an increased risk of Crohn’s disease in women taking combined oral contraceptives, reported in a 2008 meta-analysis. This trial also found further increases in risk based on the length of COC use, becoming insignificant when COCs are discontinued.

The gut-brain axis and mood regulation

Interactions between the gut and brain refer to the gut-brain axis. These occur through the metabolic, neural, endocrine, and immunological pathways, and include the hypothalamic-pituitary-adrenal (HPA) axis, which is mediated by cytokine secretion modification.

The endocrine pathway influencing gut and brain interactions is significantly impacted by cortisol. This acts on the HPA axis and impacts the psychological effects of the intestinal microbiota. Data has also indicated changes in neurotransmitter precursor levels caused by the gut microbiota, impacting central serotonin transmission.

Bacterial species in the gut also lead to the synthesis of other neurotransmitters. Therefore, gut bacteria may directly influence the brain through their metabolites. This can suppress ongoing inflammation in the CNS.

Glutamate metabolism and brain health

Glutamate metabolism is also influenced by the gut, possibly impacting gamma-aminobutyric acid (GABA). Data has shown GABA travels to the CNS through transporters, with metabolites produced by the microbiota entering the GABA neurological system. This highlights how diverse bacteria in the gut promotes healthy brain function.

All of this highlights how the estrogen-gut-brain axis is influenced by COCs. Data has shown an increase in depression risk among patients taking COCs, leading to increased use of antidepressants. Additionally, a longitudinal study highlighted changes in gut microbiome function among COC users.

Conclusion

This data indicates changes in bacterial composition from COCs that may contribute to mental health complications. Therefore, there may exist a combined estrogen-gut-brain axis that explains the role of COCs on mood disorders.

“In light of these new developments that show the impact of COCs on women’s health and the vast majority of women who use these contraceptive modalities, it is imperative that further research is warranted to fully understand their health implications,” wrote investigators.

References

1. Zim A, Bommareddy A. Estrogen-gut-brain axis: Examining the role of combined oral contraceptives on mental health through their impact on the gut microbiome. Cureus. 2025;17(3):e81354. doi:10.7759/cureus.81354
2. Cornish JA, Tan E, Simillis C, Clark SK, Teare J, Tekkis PP. The risk of oral contraceptives in the etiology of inflammatory bowel disease: a meta-analysis. Am J Gastroenterol. 2008;103:2394-400. doi:10.1111/j.1572-0241.2008.02064.x