The birth control pill has a long and winding history. First envisioned by Nurse Margaret Sanger in the 1910s (she founded what would later be Planned Parenthood), the first oral contraceptive was created with the idea of empowering women by letting them choose when and how many children they wanted to birth. However, due to complications with the synthesis of hormones, drastic side-effects, obscenity laws preventing the recruitment of volunteers in clinical trials, and at one point even the relocation of the study to Puerto Rico, the pill was only ready by 1957 and wasn’t available for wide-spread use until 1960. Sixty years after the pill’s original conception, researchers are still studying some of its side-effects. Laura Gravelsins – a PhD student in the Einstein Lab – is investigating some of the lesser known consequences of the birth control pill, looking into how synthetic hormones from the pill interact with a gene that affects working memory – the COMT gene.
Gravelsins, who has been a researcher in the Einstein Lab for the past 4 years, is interested in the intersection between hormones, gender, and cognition. “What caught my attention is how little we know about whether oral contraceptives influence the brain and behaviour,” she explained. “We know that estrogens impact cognition. A lot of research has shown that there are cognitive changes throughout the [menstrual] cycle as well as sex differences in cognition.” According to Gravelsins, this hints that hormones are important for how we remember things and other aspects of brain function, and therefore, taking a pill that alters your hormones might have some kind of impact on memory and learning. But the literature on this subject is lacking. “When I did a literature search to find out what is known about how oral contraceptives impact brain function, I was surprised to find little research on this topic,” she recalls. “This was incredibly shocking.” While most of the research available was about the pill’s effect on body systems, there was very little about the pill’s effect on the brain. Gravelsins’s study sought to add to this tiny body of work to better understand how the ingestion of the pill might affect our memory.
How does the pill work?
“If you were a naturally cycling woman (that is, you’re not taking the pill), you’d naturally have fluctuations in 17-B-estradiol (a kind of estrogen) and progesterone (a female sex hormone) over the course of a month,” Gravelsins details. “Estradiol is at its highest during ovulation – which is around day 14 of the cycle – and then diminishes around the later and early phases of the cycle, and is particularly low during menstruation.”
Similar to how our body produces these hormones, oral contraceptives contain synthetic versions of 17 –B– Estradiol and progesterone. “A commonly used synthetic estrogen in the pill is ethinyl estradiol,” Gravelsins expands. “The progestin [synthetic progesterone] component is highly variable from pill to pill, which is interesting as it brings to light how many pill options are out there for women taking oral contraceptives.” She further explains why different pill progestins have varying impacts on the brain and behavior – synthetic progesterone varies in terms of its androgenecity, its ability to act like an androgen (a class of hormones that play a role in male traits and reproductive activity such as testosterone) and bind to androgen receptors in the brain. Furthermore, “Oral contraceptives stop you from ovulating (that is, the release of an egg from the ovary). Ovulation is triggered by a large increase in estrogen in naturally cycling women,” she explains. “Oral contraceptives work by levelling out your cycle, so there’s more of a constant, low-level production of ovarian hormones when taking the pill.” For Gravelsins, this was an interesting feature of the pills and a big focus of her study. “Even though the pill stabilizes the hormones that your body produces, the levels of synthetic hormones in the pill are not constant. That’s a feature of any drug you take orally due to its pharmacokinetics (the course of the drug’s absorption, distribution, metabolism, and excretion),” she reasons.
This is perhaps the most interesting feature of the oral contraceptive pill – that even though the pill stabilizes the hormones your body produces, you will experience spikes of the synthetic hormones in the pill one or two hours after taking it, which will gradually decline throughout the day. Gravelsins mentions that this adds to the complexity of taking the pill, and has not been accounted for in any study that investigates cognition in women who are taking oral contraceptives.
What do genetics have to do with it?
“I had a particular interest in working memory,” Gravelsins comments on her study. Working memory is similar to short term memory, but involves manipulating (for example, reorganizing and updating) information. “What inspired me was a paper by Jacobs and D’esposito (2011) that showed fluctuations of estradiol over the course of the menstrual cycle interacts with genetics – particularly a gene called COMT, or the catechol-o-methyltransferase gene, which comes in multiples forms due to a genetic polymorphism (a single base change in the genetic code) to impact working memory,” she expresses. (This is similar to someone writing a word and swapping one letter out for another, causing the word to change in meaning). The different forms of the COMT gene influence levels of dopamine, a neurotransmitter that is very important for working memory. The Jacobs and D’esposito study showed women with low levels of dopamine (regulated by the COMT gene) benefit from high levels of estradiol on a working memory task, while women with high levels of dopamine benefit from low levels of estradiol. Inspired by the findings of this paper, Gravelsins was interested in seeing whether taking the pill and the spikes in synthetic hormones experienced after taking the pill interacted with dopamine levels to influence working memory.
The study
Gravelsins and other researchers in the Einstein lab recruited two groups of women aged 18 – 30 years: one group contained women taking the pill, and other included naturally cycling women. The women were tested at times that would correspond to the levels of natural or synthetic estrogens in their body. For example, for the naturally cycling women, they were tested in the early follicular phase (around Day 1-5 of the cycle when estradiol levels are low) and then again in the late follicular phase of the cycle (around Day 9-14 when estradiol levels are high). Similarly, for the women taking oral contraceptives, they were tested 1-2 hours after taking the pill (when synthetic estrogen levels were expected to be high), and then again 24 hours after taking the pill (when synthetic estrogen levels were expected to be at their lowest point). Furthermore, the women were genotyped for the COMT gene to see which variant they had, and as a result, how much dopamine their bodies would produce. Using a range of neuropsychological tests, the team tested the participants’ working memory and planning strategies.
“We didn’t find that time of pill ingestion influenced performance on any of our measures,” Gravelsins highlights, “but I should add that this doesn’t mean that time of pill ingestion doesn’t matter for other cognitive domains. We were specifically looking at working memory.” However, she hopes that making the first stab at the interactions between pill time, genetics, and women taking oral contraceptives with her study opens the door for other studies to look at this too, but in different aspects of cognition. Interestingly, her team did find that in women taking oral contraceptives, the COMT gene alone influenced participants’ working memory – the participants with the variant of the gene that allowed for more available dopamine outperformed those with the variant of the gene that allowed for less available dopamine. “This is consistent with post-menopausal women who have low endogenous [naturally available] estradiol, as well as other populations that have low estradiol, such as men,” Gravelsins clarifies. “In naturally cycling women, we see cycle-gene [estradiol and COMT genotype] interactions.”
Going forward, Gravelsins wants researchers to look into the metabolism of the pill and other aspects of cognition. “My study specifically examined working memory, but there are so many other domains of learning, memory, and emotion that we need to investigate for impacts of the pharmacokinetics of the pill,” she believes. Furthermore, a growing body of research on the topic will be able to better aid doctors and patients who are prescribed with the pill in the future. Drawing from her own experience, Gravelsins recounts her experience of consulting with doctors when she was about to go on the pill. “I was asked about blood clots and osteoporosis, but I wasn’t informed about mood symptoms or learning or memory changes that might take pace when taking the pill,” she remembers. “Similar to many other women, after taking the pill for a few weeks, I noticed it resulted in changes to my mood.”
As Gravelsins’ study shows, there are so many ways cognition is possibly influenced by our environment that we may not be aware of – the influence of estradiol and genes on memory is just one of them. And while the birth control pill is by no means a recent invention, there’s still so much about the pill and synthetic hormones that we don’t know.
Situated Neuroscience 