The combined hormonal contraceptive pill is the second most popular form of contraception in the United States, besides condoms. A recent study has found that rats given synthetic estrogens used in birth control pills exhibited more behaviors associated with anxiety compared to rats given natural estrogens. The study also showed that synthetic estrogens were associated with higher sex hormone-binding globulin and lower steroid hormone levels when compared to natural ones. The researchers presented their results at ENDO 2024, where they discussed the differences between natural and synthetic estrogens in terms of behavioral side effects. The natural estrogen used in the study was NOMAC-E2 Combined Oral Contraceptive, known as Zoely, while the synthetic estrogen commonly used in most combined hormonal contraceptive pills is ethinyl estradiol.
Abigail Hegwood, the P.h.D. candidate who carried out the study, aimed to investigate the new natural estrogen on the market as there was little epidemiological data on the side effects of specific progestins and estrogens. The study involved three groups of female rats given different types of estrogens, including ethinyl estradiol, estradiol valerate, and a control group. The rats were tested for spatial awareness and anxiety in a maze test, with serum samples collected on day 28. The researchers found that rats given synthetic estrogens showed different responses to the spatial memory task in the maze test, believed to be associated with anxiety-like behaviors. Both types of estrogen also reduced circulating testosterone and progesterone in the rats.
Research has shown that higher levels of testosterone and E2 can reduce anxiety-related behaviors and improve spatial memory, but the study found that rats given synthetic estrogens had hormone-binding globulin that rendered steroid hormones in the blood unavailable for use. The researchers proposed that the effect of synthetic estrogens on the brain may be responsible for the observed behavioral differences. Supervisor Alesia Prakapenka noted that the synthetic ethinyl estradiol group had 17-beta estradiol levels below the detection limit in more than half of the rats studied. This observation suggests that hormonal contraception may have potential impacts on the feedback loop between the hypothalamus, pituitary, and gonads.
While it is possible that combined hormonal contraception could have an effect on the brain and behavior, the influence is likely to be small, according to Professor Jonathan Schaffir, who was not involved in the research. He emphasized the importance of examining the components of medications used in hormonal treatment and creating new medications with fewer side effects and better physiologic responses. Prakapenka also highlighted the need to consider individual differences in hormonal contraception choices, similar to the approach taken in menopausal hormone therapy. Overall, the study sheds light on the potential differences between natural and synthetic estrogens in hormonal contraception and their effects on behavior.
