Medicate at the right time of the menstrual cycle

BarcelonaOn February 11th we celebrate the International Day of Women and Girls in Science. It seems incredible that we still need reminders of the need to make women scientists visible and promote vocations, but this year I would also like to remember that – perhaps as a consequence of the fact that women were not encouraged to access science careers for years – women have not been the subjects of biomedical research. I suppose we were considered unimportant. Little is known about the physiology and metabolism of the female biological sex, beyond its ability to conceive and bear children. Infertility is a taboo, and menopause is not talked about. Even in old age, men and women are not equal, and neither the medications, nor the doses, nor the diseases that affect us are similar or comparable.

Medicine and biomedical research have made great strides over the last century, but always using men (white, of average weight and age) as the sole subject of study and standard, and male rats and mice as animal models, disregarding the differences –which are quite obvious, by the way– between the sexes. Women are the great unknown and forgotten. This lack of knowledge means, for example, that, even though we know that the menstruating female body undergoes substantial physiological changes during the cycle, they have not been thoroughly investigated, nor has the effect of medications on the various organs according to cyclical hormonal peaks.

As for breast cancer, around 30% of affected women are premenopausal. There are breast cancers that respond to estrogen and some that do not, and precision medicine in cancer takes these differences into account. One strategy is to administer chemotherapy prior to surgery to remove the tumor, since the tumor is smaller and the chances of removal are higher. However, the remission rate and response to chemotherapy remain variable and unpredictable, meaning more research is still needed.

Just this January they have just been published in Nature the results of a group of Dutch researchers studying the evolution of breast cancer in response to chemotherapy using females of various strains of mice. The initial results were discouraging because they observed unexpected variations within the study groups that they could not explain, until they realized that The time of the cycle at which the first dose of chemotherapy was administered could be a relevant parameter.

In mice, the hormonal cycle of fertile females is basically divided into estrous (first part of the cycle until ovulation, with low progesterone and a final peak of estrogen) and diestrous (second part of the cycle, luteal phase, with high progesterone levels). Once the first dose of chemotherapy is administered, the eggs stop working and the cycle stops until the entire treatment is finished (this happens in both mice and women). Well, unexpectedly and very interestingly, researchers have identified that, very clearly, The best determinant of successful response to chemotherapy is the time of the estrous cycle at which the first dose is administered.. In the diester, when progesterone levels rise, the tumor does not respond as well to chemotherapy as it does when the first dose is administered in the strait.

The explanation for this differential response is multiple and not directly related to hormonal peaks, since it is observed in all types of mammary tumor analyzed in mice. The factors that would intervene in this differential response would be that, in stress, the calibre of the blood vessels is greater (they are thicker and, therefore, there is greater blood volume). In addition, it coincides with the moment when the tumour cells are replicating and the number of infiltrating macrophages is lower. Under these conditions, the tumour cells would be more vulnerable and would be reached by a greater quantity of the toxic chemotherapeutic compound, which would be more effective.

In contrast, in the right, the blood supply is lower and, on the other hand, the number of macrophages that would "clean" the chemotherapeutic compound is greater, and the tumor cells would begin a differentiation process (called epithelial-mesenchymal transition) that would make them less receptive to chemo. And now, one might ask, what happens in humans? This group performs a retrospective study in a small cohort of menstruating women with breast cancer, and the results would agree, since women who received the first dose of chemotherapy during the first part of the menstrual cycle had better prospects for remission of breast tumors.

Obviously, with due caution, since these results correspond to a proof of principle in female mice, these results need to be replicated in much larger cohorts of women, but when you think about it… What a great step it would be if a small change in the therapeutic schedule could improve the results of chemotherapy in women! What perspectives of progress in precision medicine could be opened up for all, just by the mere fact that research puts women in the spotlight!