Evaluation of Sex Differences in Preclinical Pharmacology Research: How Far Is Left to Go?

Abstract

Until the last quarter of the 20th century, sex was not recognized as a variable in health research, nor was it believed to be a factor that could affect health and illness. Researchers preferred studying male models for a variety of reasons, such as simplicity, lower costs, hormone confounding effects, and fear of liability from perinatal exposure in case of pregnancy. Equitable representation is imperative for determining the safety, effectiveness, and tolerance of therapeutic agents for all consumers. Decades of female models’ underrepresentation in preclinical studies has resulted in inequality in the understanding, diagnosis, and treatment of disease between the sexes. Sex bias has been highlighted as one of the contributing factors to the poor translation and replicability of preclinical research. There have been multiple calls for action, and the inclusion of sex as a biological variable is increasingly supported. However, although there has been substantial progress in the efforts to include more female models in preclinical studies, disparities today remain. In the present review, we consider the current standard practice of the preclinical research setting, why the sex bias exists, why there is the need to include female models, and what risks may arise from continuing this exclusion from experimental design.

Therapeutic potential of stilbenes in neuropsychiatric and neurological disorders: A comprehensive review of preclinical and clinical evidence

“…Finally, the response to treatment may differ between men and women and these differences are mostly due to anatomical, physiological, and hormonal factors. The gender-specific pharmacokinetics and pharmacodynamics (Allegra et al, 2023) raise the importance of including both females and males in preclinical and most notably in clinical trials evaluating the effects of stilbenes for neuropsychiatric and neurological disorders.…”

Sex Matters–Insights from Testing Drug Efficacy in an Animal Model of Pancreatic Cancer

“…While progress has been made in incorporating female participants in clinical trials, the extension of this inclusion to animal experiments is still insufficient [6,7]. The omission of females from preclinical research was motivated by concerns among researchers about potential variations induced by the estrus cycle, along with apprehensions about increased costs [8,9]. However, since hormonal differences play an important role not only in the development of diseases such as anxiety and depression, asthma, and inflammatory bowel disease but also in pharmacokinetics, it was important to establish guidelines that define sex as a biological variable [10][11][12][13][14].…”