Most doctors have seen patients who say, “I was taking my pill perfectly. I took it every day, and I got pregnant,” Lazorwitz said. “But no one knows why.
“The kind of historic viewpoint has been that they must have missed the pill; they must have done something wrong,” he said. That explanation wasn’t good enough for him: “I started talking with a pharmacogeneticist at the University of Colorado and came upon this fascinating area that hadn’t yet been applied really to women’s health care or at all to birth control.”
Pharmacogenetics looks at how genetic factors affect an individual’s reaction to a drug. For the new study, Lazorwitz and his colleagues focused on a genetic variant called CYP3A7*1C, which is carried by about 5% of the overall population.
This variant refers to the CYP3A7 gene, Lazorwitz said. “It’s an interesting gene that is only typically active in the fetal stage of life.”
In most people, this gene codes for a protein (in the form of an enzyme), also called CYP3A7, during their earliest development in the womb; then, the gene turns off, and they no longer express that enzyme.
Women and men with the variant “keep making the enzyme,” Lazorwitz said.
“That enzyme — and we know this from other studies as well — seems to break down the steroid hormones,” he said. These hormones are naturally made by our bodies, yet they are also contained in birth control, he explained.
For their study, Lazorwitz and his colleagues enrolled 350 women, most in their early 20s, who had been using etonogestrel implants for an average of 25.7 months. Placed under the skin of a woman’s arm, this long-term option releases a steady, low dose of hormones into her bloodstream to stop the release of an egg and prevent pregnancy.
The researchers measured each participant’s blood concentration of etonogestrel and tested her DNA, searching for specific genetic variants, including CYP3A7*1C, that could affect hormone metabolism.
About 5% of the women carried the CYP3A7*1C variant, which is the same as in the general population. Of these, nearly 28% showed etonogestrel blood concentration levels below 90 picograms per milliliter, the hormonal threshold intended for the implant,. Yet a higher body mass index (BMI) and longer of implant use also showed an association with lower blood concentration levels of the hormone.
The variant may influence a woman’s hormone concentration levels, but because the implant has “enough extra hormone,” it probably does not impact the efficacy of the birth control, Lazorwitz said. The implant also thickens the mucus in a woman’s cervix, which may keep sperm from reaching the egg.
“I don’t think it’s going to affect how well the implant works,” he said.
However, the pill aims for a lower level of hormones circulating in a woman’s bloodstream, and that may place her in jeopardy of becoming pregnant if she’s a carrier of the genetic variant — but this has not been proved.
The study “raises the concern,” Lazorwitz said, but more research is needed.
Considering all the variables
The study was “well-performed” and is a “great first step.” However, similar results have been found with other medications — a change in “circulating plasma levels or something like that” — that “ultimately didn’t pay off,” with differences in efficacy seen in different patients, said Scott, who was not involved in this new research.
The new findings show “an association between genetics and the pharmacokinetics of the medication,” not between genetics and unintended pregnancy, Scott said.
Lazorwitz and his colleagues, who also looked at other factors such as BMI in addition to genetics, acknowledged that genetics “accounts for only 20%” of variability in the level of circulating hormones, Scott noted: “So what that suggests is there are other variabilities that are still not known.”
Still, he believes, just as Lazorwitz does, that because the “enzyme is already known to be involved in hormone metabolism,” there might be something in the findings that could have “clinical utility, because carriers of this allele have lower etonogestrel concentrations and therefore would be at higher risk” for an unintended pregnancy.
Scott’s own research includes evaluating evidence from association studies like this one and translating them for actual medical care, ultimately providing actionable intelligence to doctors.
“When we talk about precision medicine and things like that, it’s very important to remember to consider all variables and not just genetics,” Scott said. However, “unintended pregnancies would really warrant the ability to identify individuals who are susceptible” to less effective outcomes when using birth control.
“There’s so much we don’t know about birth control. There seem to be things outside of a woman’s control like genetics that could impact how well birth control works,” he said. ” And we need to start taking those things in consideration.”