A Short History of the Consideration of Sex Differences in Biomedical Research — Lessons for the In Vitro Community from Animal Models and Human Clinical Trials

Abstract

In recent decades, it has become clear that in many fields — such as drug development, particularly with regard to drug dosage and specific disease treatment — the sex of a patient must be taken into consideration, in view of the fact that male and female physiology and pathophysiology show many differences of practical concern. While, in the last decade or so, considerable efforts have been undertaken to consider the sex of the animals during the planning of experiments, this topic has just started to be acknowledged in in vitro studies. Cells in such studies seem mainly to be used according to their availability, without considering the sex of the original donor. Even when such information is available, experimental data are reported without overtly detailing this information. In recent years, the increasing complexity of in vitro models (e.g. stem cell-based, 3-D cultures, organoids, or organ-on-a-chip technologies) has contributed to systems that better resemble the human in vivo situation. However, the issue of the sex of the experimental organisms being used has not yet been properly taken up by the cell culture community. Thus, alongside the increasing complexity of multicell-type models, we now see in vitro models that incorporate cells from both male and female origin — this representing, in fact, a genetic chimaera. Here, we aim to discuss where we are currently, with respect to considering the sex of any animals or humans used in experiments, and we try to identify what is lacking in the cell culture field, in order to help facilitate change.

Mammary Glands of Women, Female Dogs and Female Rats: Similarities and Differences to Be Considered in Breast Cancer Research

“…In recent years, the increasing complexity of 3D in vitro models (e.g., spheroids/organoids, or organ-on-a-chip technologies) has contributed to the development of testing platforms that better recapitulate the tumor microenvironment found in vivo in humans. In this respect, it is recognized that 3D cell cultures are superior to 2D cultures in mimicking natural tissue physiology, cell–cell contacts, cell–matrix interactions and the different components of the tumor microenvironment, as well as major tumor hallmarks [ 219 , 220 , 221 ].…”

Sex and Brain: The Role of Sex Chromosomes and Hormones in Brain Development and Parkinson’s Disease

“…The sex of cells and cell lines could be determined based on an analysis of the expression profile of the amelogenin gene, which is encoded by both X and Y chromosomes (AMELX and AMELY, respectively) and can be easily distinguished by using PCR because they present different lengths [231]. However, the sex of cells may change over time or after several passages in culture, even in established cell lines [224].…”

Editorial

“…Gutleb and Gutleb discuss the issue of sex differences in biomedical research, noting sex-related bias in studies in animals or humans and how this has led, for example, to greater incidence of side-effects of certain drugs in women. 10 For in vitro methods, using human or animal cell cultures, there is generally a lack of consideration or reporting of the sex of donors of the cells. In this report the current state-of-affairs is discussed, as well as the need to recognise and account for potential sex-related differences, moving forward.…”