The invention of hormonal contraceptives (HCs) in the mid-1950s was one of the most important medical breakthroughs of the 20th century. In addition to the sweeping socioeconomic changes fomented by enabling much greater control over when pregnancy is initiated, HCs have revolutionized women’s health by helping to control a swath of hormone-mediated conditions. Among other benefits, HCs can help control unpredictable menstrual cycles, lessen the effects of premenstrual syndrome and premenstrual dysphoric disorder, and reduce the risks of several serious forms of cancer.

Despite the importance and widespread use of HCs, some of their effects and mechanisms of action are still not well understood. For example, studies of their effects on depression, anxiety, and overall mood have had conflicting results. Some studies have shown improvements for people taking HCs, while others have shown that HCs lead to adverse mood effects, including anxiety and depression in some individuals. 

The reasons for those ambivalent findings are complex, but one important factor may be that different types of HCs simply have different effects on mood. HCs come in multiple forms, including the combination pill, which includes both a synthetic estrogen and progesterone components, and the “mini-pill,” which includes only a synthetic progesterone. While ethinyl estradiol is typically the synthetic estrogen used in combined formulations, the synthetic progesterone component varies, each with distinct effects on the brain. Most previous studies of how HCs affect mood have grouped all HCs together rather than comparing different formulations. In other words, previous studies have mostly examined differences in mood for those taking HCs compared to those who are not, but they have rarely compared the effects of different formulations of HCs against each other. Future research comparing different formulations is important because, among other things, it may help physicians determine which kinds of contraceptives to prescribe based on risk factors such as diagnoses of depression or anxiety.

Kristen Schuh, a Biopsychology PhD working with Dr. Natalie Tronson, is developing a mouse model to explore those important distinctions. A mouse model, Schuh explains, is useful in tandem with human studies because it allows researchers to eliminate confounding variables that are hard to avoid in human research. 

“I really want to figure out what factors determine why some people experience depression on HCs and others experience an improved mood,” says Schuh. “But that is actually very hard to study in humans because there are many variables we can’t control for, such as the amount of time they are on birth control, genetic predispositions to different disorders, and stress exposures across their lifespan. By using mice, we can control for those things.”

Of course, there is at least one major limitation with using mice for such studies: We cannot talk to them, so we can’t ask them how they’re feeling directly. Therefore, Schuh’s research uses well-established behavioral tasks to observe depression- and anxiety-like behavior. For example, loss of pleasure, a key feature of depression, can be assessed using a sucrose preference test. Mice, like people, typically like sugar, so when they stop preferring the sugar water over regular water, they are showing depression-like behavior. Another behavioral test they use is called the forced swim test. They place the mouse in a beaker with water and watch their behavior for 6 minutes before drying them and returning them to their homecage. More time spent immobile and not swimming or climbing the walls of the beaker is categorized as a more passive coping style that resembles some depression-like behaviors. 

Based on Schuh’s research so far, those last two factors—pleasure (or lack thereof) and depression-like behavior in the forced swim test—appear to be especially influenced by one of the most common HC formulations, ethinyl estradiol and levonorgestrel. Schuh explains that mice taking this formulation have shown a pronounced anhedonia (reduction of pleasure felt for normally pleasurable things) compared to mice who are not taking them. Mice taking these HCs are less motivated to drink sugar water compared to regular water. Additionally, mice that experienced a stressor before being exposed to HCs are more vulnerable to changes in stress-coping styles and depression-like behavior in the forced swim test. Taken together, Schuh’s research suggests that certain HCs may cause adverse mood changes and this is modulated by prior stressors.

But things get even more interesting when different formulations of hormones are compared. For example, mice taking ethinyl estradiol and levonorgestrel, a commonly prescribed progestin, experience a blunted stress response. But mice taking drospirenone, a newer progestin, do not appear to experience this same effect. 

While this research is still in its early stages, Schuh hopes it will ultimately help scientists develop HCs with fewer negative side effects, as well as enable physicians to prescribe the most appropriate HCs for their patients. 

“If we can understand what contraceptives will work best for which patients, we can improve mental health and well-being for so many people,” Schuh says. “The goal is to eliminate the guess and check from prescribing hormonal contraceptives.”