Rats given synthetic estrogens used in birth control pills exhibited greater signs of anxiety than those given natural estrogens, researchers have found.The researchers presented their results at ENDO 2024, the Endocrine Society’s annual meeting in Boston, M.A., by a PhD candidate at Midwestern University. The natural estrogen used in this study was the NOMAC-E2 Combined Oral Contraceptive, known as Zoely, and produced by the pharmaceutical company Merck. Researchers had been looking for natural estrogen to use in combined hormonal contraceptive pills since its inception 60 years ago, but these had not been potent enough for those pills to be an effective form of hormonal contraceptive. This changed in 2011 when Zoely was introduced to the market.Â
Three groups of 12 female rats were given either ethinyl estradiol a synthetic estrogen with dienogest, a progestin often combined with it in oral combined hormonal contraception, or estradiol valerate a natural estrogen with dienogest, or a control, delivered via a subcutaneous pump for 28 days. The researchers tested the rats’ spatial awareness and anxiety in a maze test, between days 20-28, and collected serum samples on day 28.Â
The researchers discovered that the rats had similar spatial memory across all three groups. Serum samples also showed that both types of estrogen reduced circulating testosterone and progesterone. The authors note levels of the type of estradiol made in the ovaries were below the detection limit in over half of rats given ethinyl estradiol.
The hypothesis would be that because ethinyl estradiol is having this greater effect on the availability of steroid hormones, it would have a greater effect on the actions that these steroid hormones have on the body, including the brain. Another potential outcome is there’s the feedback loop that’s being halted by the contraceptive treatments between the hypothalamus, the pituitary, and the gonads. Naturally-produced circulating estrogen was below the level of detection in many of the rats given ethinyl estradiol.Â
Researchers saw that with the synthetic ethinyl estradiol group, more than half of the samples in that group had 17-beta estradiol levels that were actually below the limit of detection. And so it could be that even if it’s not the hormone itself from the contraceptive, it may be changing something within the feedback loop that then could be having that effect.
Rat behavior is a far cry from human behavior, so looking at more appropriate measures of mood and behavior in humans would be appropriate. Another takeaway from this study is that it’s always important to examine the components of medications that they use, and to try to include, particularly in the setting of hormonal treatment, the versions of hormones that have the fewest side effects and the best physiologic response.Â
