Considering hormones as sex- and gender-related factors in biomedical research: Challenging false dichotomies and embracing complexity

There is still an unresolved paradox with respect to the immunomodulating role of estrogens. On one side, we recognize inhibition of bone resorption and suppression of inflammation in several animal models of chronic inflammatory diseases. On the other hand, we realize the immunosupportive role of estrogens in trauma/sepsis and the proinflammatory effects in some chronic autoimmune diseases in humans. This review examines possible causes for this paradox. This review delineates how the effects of estrogens are dependent on criteria such as: 1) the immune stimulus (foreign antigens or autoantigens) and subsequent antigen-specific immune responses (e.g., T cell inhibited by estrogens vs. activation of B cell); 2) the cell types involved during different phases of the disease; 3) the target organ with its specific microenvironment; 4) timing of 17beta-estradiol administration in relation to the disease course (and the reproductive status of a woman); 5) the concentration of estrogens; 6) the variability in expression of estrogen receptor alpha and beta depending on the microenvironment and the cell type; and 7) intracellular metabolism of estrogens leading to important biologically active metabolites with quite different anti- and proinflammatory function. Also mentioned are systemic supersystems such as the hypothalamic-pituitary-adrenal axis, the sensory nervous system, and the sympathetic nervous system and how they are influenced by estrogens. This review reinforces the concept that estrogens have antiinflammatory but also proinflammatory roles depending on above-mentioned criteria. It also explains that a uniform concept as to the action of estrogens cannot be found for all inflammatory diseases due to the enormous variable responses of immune and repair systems.

During the past decade there has been a substantial advance in our understanding of estrogen signaling both from a clinical as well as a preclinical perspective. Estrogen signaling is a balance between two opposing forces in the form of two distinct receptors (ER alpha and ER beta) and their splice variants. The prospect that these two pathways can be selectively stimulated or inhibited with subtype-selective drugs constitutes new and promising therapeutic opportunities in clinical areas as diverse as hormone replacement, autoimmune diseases, prostate and breast cancer, and depression. Molecular biological, biochemical, and structural studies have generated information which is invaluable for the development of more selective and effective ER ligands. We have also become aware that ERs do not function by themselves but require a number of coregulatory proteins whose cell-specific expression explains some of the distinct cellular actions of estrogen. Estrogen is an important morphogen, and many of its proliferative effects on the epithelial compartment of glands are mediated by growth factors secreted from the stromal compartment. Thus understanding the cross-talk between growth factor and estrogen signaling is essential for understanding both normal and malignant growth. In this review we focus on several of the interesting recent discoveries concerning estrogen receptors, on estrogen as a morphogen, and on the molecular mechanisms of anti-estrogen signaling.

The underrepresentation of female mice in neuroscience and biomedical research is based on the assumption that females are intrinsically more variable than males and must be tested at each of four stages of the estrous cycle to generate reliable data. Neither belief is empirically based. In a meta-analysis of 293 articles, behavioral, morphological, physiological, and molecular traits were monitored in male mice and females tested without regard to estrous cycle stage; variability was not significantly greater in females than males for any endpoint and was substantially greater in males for several traits. Group housing of mice increased variability in both males and females by 37%. Utilization of female mice in neuroscience research does not require monitoring of the estrous cycle. The prevalence of sex differences at all levels of biological organization, and limitations in generalizing findings obtained with males to females, argue for the routine inclusion of female rodents in most research protocols. Copyright © 2014 Elsevier Ltd. All rights reserved.