Inside the Pill

By Mariel Sander

The first time I went to the gynecologist’s office for a checkup, I had no idea what to expect. Though my doctor was friendly, capable, and patient, I left the office with a month’s worth of birth control pills and no information on their biological effects. I didn’t know what side effects to expect, or why they would occur, just that they would most likely disappear after three months.

When I began doing research on how the pill actually affected a woman’s body and brain, I was surprised to find that there had been very few experiments on the topic. Many of the papers I read were outdated and based on more limited surveys. One study  concluded that the side effects of the pill were due to “the significant emotional disturbances associated with the intentional administration of what a woman thinks is a contraceptive,” and provided no biological basis for this claim.

“The pill” euphemistically refers to oral hormonal contraceptives, first marketed in the United States in 1960. In the National Health Statistics Report covering the years 2006-2010, 17 percent of women aged 15 to 44 in the United States reported using the pill as their primary form of contraception. To this day, at least 500 million women have used the pill. When considering hormonal contraceptives, women are often warned of a plethora of side effects, including intense mood swings, weight changes, bleeding, and depression.

The most commonly prescribed form of the pill contains synthetic derivatives of two female sex hormones: progestin and ethinyl estradiol. Progestin mimics progesterone, which suppresses luteinizing hormone (LH). LH typically makes eggs available for fertilization. On the other hand, ethinyl estradiol mimics estrogen in the body, reducing the body’s natural production of estrogen. This mitigates some of the side effects of progestin, such as bleeding outside of menstruation.

The interactions between progestin, ethinyl estradiol, and brain receptors are responsible for most side effects of this popular contraceptive. For example, progestin binds to GABA receptors and augments their ability to regulate anxiety. Additionally, higher estradiol levels tend to enhance serotonin, acting as an antidepressant. These particular effects are positive, but most women have no idea that these secondary interactions with neural components even occur. I certainly had no idea that hormonal contraceptives not only altered women’s hormonal makeups, but also tampered with their brains.

A review published in 2014 reported that different concentrations of progesterone and estradiol were associated with different levels of activation in several parts of the brain, including the amygdala, anterior cingulate cortex, insula, and frontal gyrus. Furthermore, a 2007 study suggested that these neural effects were what prompted the mood changes often experienced by pill users.

The mood study also observed that women who had taken oral contraceptives for two years or less demonstrated reduced positive affect reactivity. What effect would this change have on a woman’s life? It may be more serious than you might think. Positive affect describes the degree to which someone feels positive emotions like excitement; someone with high positive affect reactivity tends to be enthusiastic and active. Conversely, low positive affect is associated with depression; low positive affect reactivity might cause an individual to feel lethargic or less excitable in response to events throughout the day.

Studies have shown that this low positive affect reactivity is particularly pronounced in people with high affect changes due to other medical conditions like bipolar disorder. Women with these medical conditions might experience an even more dramatic flattening of emotional changes over the course of the day, leading to overall depression and lethargy.

Additionally, a 2013 study focused specifically on women who had experienced mood deterioration from the pill. In a double blind experiment, women who had previously experienced negative mood changes from the pill were randomly assigned to two groups: one that received hormonal contraceptives and one that received a placebo. Researchers found that the group taking hormonal contraceptives had significantly less left insula reactivity. Activation in the left insula is associated with positive emotions, so lower reactivity may cause the subject to feel fewer positive emotions.

Other studies found that, outside of affecting mood, hormonal contraceptives also cause pronounced neural changes. One study found an increase in the amount of gray matter. The increase was particularly visualized in areas linked to decision making, such as the prefrontal cortex.

Unfortunately, beyond these few preliminary yet fascinating studies, research on hormonal contraceptives is limited and sometimes contradictory. One group of researchers might find that taking the pill leads to lower rates of mood disorders, while other researchers might find that it leads to significantly higher rates of depression.

Given that hormonal contraceptives are so commonplace, it is surprising that there is not more discussion around their biological effects. Women and adolescent girls taking the pill should be aware of how little is understood about its effect on their minds and bodies, as well as how much research has yet to be conducted.