This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc.
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The importance of sex differences in pharmacology research. / Gogos, Andrea; Langmead, Christopher; Sullivan, Jennifer C.; Lawrence, Andrew J.In: British Journal of Pharmacology, Vol. 176, No. 21, 01.11.2019, p. 4087-4089.
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TY - JOUR
T1 - The importance of sex differences in pharmacology research
AU - Gogos, Andrea
AU - Langmead, Christopher
AU - Sullivan, Jennifer C.
AU - Lawrence, Andrew J.
N1 - Funding Information: This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc There still exists a sex bias in preclinical research where male subjects are primarily used. In this themed section of the British Journal of Pharmacology, we discuss why this problem exists and how it might contribute to translation and reproducibility issues in research. The articles here highlight sex differences in psychiatric disorders, addiction, dementias, metabolic diseases, and cardiovascular risk. The role of sex hormones, and inflammatory processes as mediators of the observed sex differences, is discussed. Given the variety of disorders highlighted in this issue that show sex differences, these articles underscore the importance of examining both sexes in research. ). Similar policies are now being introduced by funding bodies around the world. The repercussions of a history of selectively studying males is not only the lack of knowledge but also the potential for harm when attempting to treat females with drugs developed and tested only in males. It has been acknowledged that some of the issues with translation and reproducibility that have plagued preclinical research may be driven by the inadequate inclusion of females or inadequate analysis of data to allow for sex‐specific conclusions. Astonishingly, even when the disease of interest is a female‐prevalent disorder, a male bias exists. Only 56% of the studies researching female‐prevalent disorders reported which sex was used, and of these, only 12% included female animals or both sexes (Yoon et al., ). This problem is emphasized in the review by Kokras, Hodes, Bangasser, and Dalla ( ) in this issue. Here, they describe how compounds based on the hypothalamic–pituitary–adrenal (HPA) axis, that have potential as new therapeutic targets for depression have not translated successfully. Depression is twice as likely to occur in women, compared to men, and Kokras et al. ( ) propose that sex differences in the function of various HPA axis elements may well contribute to the failure of novel HPA axis‐based drugs in clinical trials. In 2014, the National Institutes of Health in the United States released policies stating that, for preclinical research to be funded, sex as a biological variable must be considered and single sex studies must be justified (Clayton & Collins, ). In this issue, Karp and Reavey ( ) consider why the male bias exists and highlight reasons to include females in biomedical research. Notably, they provide a solution for changing the current standard practice of sex bias in preclinical research and the resistance to change. They suggest using organisational change theory as a tool to shape strategies needed at an individual and institute level to change the ). Encouragingly, since the introduction of policies to promote the consideration and inclusion of both sexes in preclinical research, a large number of papers, including original research and reviews, have been published highlighting significant sex differences. In this issue, we provide an up‐to‐date account on how sex influences disease processes, response to therapeutics, and therefore drug development. In a large study that consolidates the importance of sex, the International Mouse Phenotyping Consortium examined 10 institutes, 14,000 wild type, and over 40,000 mutant mice for 234 traits. They found that sex was often a significant source of variation and a modifier of treatment effects (Karp et al., status quo and create a scientific environment that automatically implements sex sensitive approaches (Karp & Reavey, ) describe the sex differences in prevalence, onset, symptom profiles, and disease outcome that are evident in three psychiatric disorders: schizophrenia bipolar disorder post‐traumatic stress disorder ) details the clinical evidence that oestradiol progesterone ) provides evidence that oestradiol acutely and rapidly regulates dopamine ) provide evidence that sex differences influence processing of fear, but not safety‐based behaviour in C57Bl/6J mice. Female mice exhibited decreased fear recall following conditioning but slower fear extinction, whereas the acquisition and recall of safety were not overtly influenced by sex (Clark et al., ). Sex differences have been observed in many disorders, from psychiatric disorders including schizophrenia and anxiety, through to substance abuse, dementias, and even metabolic disorders such as cardiovascular disease and obesity, highlighting the need to consider sex in all realms of preclinical research. In this issue, Gogos, Ney, Seymour, Van Rheenen, and Felmingham ( , and . Likely candidates to explain these sex differences are gonadal hormones. The review by Gogos et al. ( and are dysregulated in females with these psychiatric disorders and concludes that low levels of oestradiol may increase the risk of disease development and worsen symptom severity. Interestingly, original research by Yoest, Cummings, and Becker ( release in females and dopamine reuptake in males in the nucleus accumbens shell. Post‐traumatic stress disorder is a female‐prevalent disorder characterised by impaired fear inhibition. Using mouse models of fear inhibition, Clark, Drummond, Hoyer, and Jacobson ( ) demonstrated that sex was a significant factor that mediates the effects of early life stress on responsiveness to cocaine Addiction vulnerability involves complex gene × environment interactions leading to a pathological response to drugs. Identification of the genes mediating these interactions is an important step in understanding the underlying neurobiology and in identifying potential targets for pharmacotherapy. Yet rarely have such analyses examined sex‐specific influences. Bagley, Szumlinski, and Kippin ( . ) present a review on sex differences in neurodegenerative and neurovascular disease ( Alzheimer's disease ). In this issue, Hornarpisheh and McCullough ( , cerebral amyloid angiopathy and stroke). They suggest that sex differences in brain structure, molecular and genetic markers, and cumulative oestrogen exposure are key risk factors for Alzheimer's disease, while sex differences in stroke may be driven by sex hormones, or differences in microglial function and in the immunoregulatory role of microRNAs. They also outline sex differences in the response to various approved pharmacological therapies for these dementias (Hornarpisheh & McCullough, ) review the literature on sex differences in metabolic disease and how this may be mediated by inflammatory pathways. Men have a higher risk of metabolic diseases, such as diabetes, compared to pre‐menopausal women. This review outlines how oestradiol and sex‐specific behaviours play a role in the observed sex differences in immune function, metabolic syndrome ). Arterial stiffness is an independent predictor of cardiovascular disease risk. The review by DuPont, Kenney, Patel, and Jaffe ( ) details evidence that there are sex differences in the time course of aging‐related arterial stiffness and the associated cardiovascular disease risk which increases disproportionately in post‐menopausal women. The authors focus on sex differences in vascular stiffness induced by aging, obesity, hypertension ). The review by Taylor, Ramirez, and Sullivan ( ) examines sex differences in high‐fat diet‐ and obesity‐induced increases in blood pressure and vascular dysfunction, with a particular focus on the role of the immune system and inflammatory processes. They conclude that women have higher rates of obesity and are more susceptible to hypertension and vascular dysfunction due to a number of different factors, including dysregulation in the immune cell response and cytokine/adipokine profiles to promote inflammation (Taylor et al., ). Given the variety of mediators of metabolic disorders and vascular dysfunction that show sex differences, these reviews underscore the importance of examining both sexes in such studies. As discussed in this issue, sex differences are observed in disorders beyond the brain. Henstridge, Abildgaard, Lindegaard, and Febbraio ( , various tissues relevant to inflammatory‐related metabolic syndrome, and several pro‐ and anti‐inflammatory cytokines (Henstridge et al., and sex‐specific risk factors, as well as the impact of hormonal status, diet, and exercise on vascular stiffness (DuPont et al., ). Future studies require a more considered approach in regard to the mechanism(s) underlying a sex difference, be it (a) the presence of certain gonadal hormones, (b) sex chromosomes, and (c) sex‐specific behaviours. As targeted, personalised medicine approaches should increasingly produce effective treatments for patients, developing treatments based on sex is a goal that is in reach. In conclusion, the literature in this issue suggests that women may be more likely than men to suffer from certain diseases, depending on their hormonal (menopausal) status; yet females remain understudied. Further, the mechanisms underlying these disorders are unclear. Therefore, it is imperative that researchers do not exclude 50% of the population by selecting to examine only males. Repeatedly, the take‐home message from the articles in this issue is that studying both males and females is necessary in all research, including cells, animals, and humans, that “the default position should be to automatically study both sexes and account for sex as a source of variation” (Karp & Reavey,
PY - 2019/11/1
Y1 - 2019/11/1
N2 - This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc.
AB - This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc.
UR - http://www.scopus.com/inward/record.url?scp=85075549200&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85075549200&partnerID=8YFLogxK
U2 - 10.1111/bph.14819
DO - 10.1111/bph.14819
M3 - Editorial
C2 - 31769019
AN - SCOPUS:85075549200
VL - 176
SP - 4087
EP - 4089
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 21