Women have historically been underrepresented in drug research, except in the case of female-specific diseases such as breast cancer. This is partly due to the complexity of the menstrual cycle, where fluctuations in hormone levels can affect results. Additionally, researchers are concerned about potential damage to the egg cells, or unborn children. This is why medical research still primarily focuses on male subjects and animals. The rationale is that those research models provide less hormonal variation that could affect the results. But, as a consequence, we have significantly less knowledge of how drugs work in women.
Women have historically been underrepresented in drug research, except in the case of female-specific diseases such as breast cancer. This is partly due to the complexity of the menstrual cycle, where fluctuations in hormone levels can affect results. Additionally, researchers are concerned about potential damage to the egg cells, or unborn children. This is why medical research still primarily focuses on male subjects and animals. The rationale is that those research models provide less hormonal variation that could affect the results. But, as a consequence, we have significantly less knowledge of how drugs work in women.
Blind spot
The effect of the menstrual cycle on the body is more significant than previously thought. “Scientists are only now beginning to realize this,” says Sabine Linn, an internist-oncologist at the Netherlands Cancer Institute. “It is becoming increasingly clear that there is a blind spot in drug research.”
Jacco van Rheenen, a researcher at the Netherlands Cancer Institute and Oncode Institute, first became aware of this blind spot when two researchers in his group pointed out a striking discovery. “We were studying how chemotherapy can alter cancer cells, making them more resistant to therapy. But we only observed this difference in some of the mice; in others, it didn’t seem to happen. And we know that women with breast cancer respond variably to chemotherapy, but we don’t know why that is.”
Different phases
The two researchers suggested that the estrous cycle, the mouse version of the menstrual cycle, may play a role. “They proposed that the measurements may have been taken during different stages of their cycle. I didn’t pay much attention to that at first, as I didn’t think the cycle would greatly affect the cells. But when I showed the results to my wife, she said, ‘That makes sense, right? Of course, there would be an effect!’ That got me thinking. We then started mapping this out in greater detail.”
Meanwhile, recent research by Van Rheenen, Colinda Scheele and their colleagues underlined that the menstrual cycle influences the behavior of breast (cancer) cells. This convinced him that the cycle has a greater effect on the body than previously thought. “I notice that these findings evoke different reactions at medical conferences. Some colleagues, especially men, respond with skepticism, as I did initially. But many women agree and recognize the possible effects of the cycle.”
Sensitive to chemotherapy
The team of researchers found that the estrous cycle impacts the sensitivity of breast cancer to chemotherapy. “We observed a sensitive phase of the cycle in which the chemotherapy killed more cancer cells,” says Scheele, who is again collaborating with Van Rheenen in this study. “The sensitivity to the chemotherapy remained, even after the cycle stopped as a result of the treatment. In short, the moment of administering the first dose of chemotherapy was vital in its effect.”
The researchers already knew that chemotherapy works better when a certain type of immune cell is less present in the breast tissue. “We saw that the level of immune response in that tissue varied per phase,” says Scheele. “The permeability of the blood vessels, through which the chemotherapy enters the tissue, also appeared to depend on the moment in the menstrual cycle.” The sensitivity of the cancer cells to the treatment also differed per phase.
New patient study
The researchers checked these findings in previously recorded data from 55 treated women. “We found evidence that even in women with breast cancer, the menstrual cycle played a role in the effectiveness of chemotherapy,” says Van Rheenen. “That’s an interesting finding. But because the group was small and we did not set up the study specifically to answer this question, we cannot draw a definitive conclusion yet.”
That’s why the researchers are now setting up a national study funded by Oncode Institute. “We want to specifically study the treatment of women with triple-negative breast cancer, as their treatment regimen starts with chemotherapy,” says Linn. “We aim to draw one extra tube of blood from 100 women, right before they start chemotherapy. That will allow us to determine where these women are in their cycle, analyze for whom the treatment works well, and whether there is a link between treatment outcome and the menstrual cycle. Nothing changes about the treatment itself.”
Unborn child
The researchers anticipate that some drugs may work better during a certain phase of the menstrual cycle than others. “Just think about the many changes occurring in a body under the influence of hormones,” says Van Rheenen. “For one, they cause fluctuations in body temperature, affecting your blood circulation.” Linn adds that the immune system also has an effect on the treatment: “The cycle prepares the woman for a potential pregnancy. An unborn child is based on 50% of foreign material from the father. It can only grow if the immune system tolerates it during that time.”
“I hope that we will have a better understanding of the effects of the menstrual cycle on chemotherapy in five years,” says Linn. “That hasn’t been addressed before. This study highlights the importance of research on the cycle and women-inclusive medical practice in general.” Scheele agrees: “More research in this area will ultimately lead to better health for the female half of the world’s population.”
