Biologic and Molecular Mechanisms for Sex Differences in Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics: Part I

Abstract The escalating prevalence of individuals becoming overweight and obese is a rapidly rising global health problem, placing an enormous burden on health and economic systems worldwide. Whilst obesity has well described lifestyle drivers, there is also a significant and poorly understood component that is regulated by genetics. Furthermore, there is clear evidence for sexual dimorphism in obesity, where overall risk, degree, subtype and potential complications arising from obesity all differ between males and females. The molecular mechanisms that dictate these sex differences remain mostly uncharacterised. Many studies have demonstrated that this dimorphism is unable to be solely explained by changes in hormones and their nuclear receptors alone, and instead manifests from coordinated and highly regulated gene networks, both during development and throughout life. As we acquire more knowledge in this area from approaches such as large-scale genomic association studies, the more we appreciate the true complexity and heterogeneity of obesity. Nevertheless, over the past two decades, researchers have made enormous progress in this field, and some consistent and robust mechanisms continue to be established. In this review, we will discuss some of the proposed mechanisms underlying sexual dimorphism in obesity, and discuss some of the key regulators that influence this phenomenon.

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Skeletal Muscle Wasting: The Estrogen Side of Sexual Dimorphism

AJP Cell Physiology ◽

10.1152/ajpcell.00333.2021 ◽

2021 ◽

Author(s):

Shawna L. McMillin ◽

Everett C. Minchew ◽

Dawn A. Lowe ◽

Espen E. Spangenburg

Keyword(s):

Sex Differences ◽

Sexual Dimorphism ◽

Molecular Mechanisms ◽

Muscle Wasting ◽

Physiological Mechanisms ◽

Skeletal Muscle Wasting ◽

Muscle Biology ◽

Experimental Approaches ◽

The Impact ◽

Equal Efficacy

The importance of defining sex differences across various biological and physiological mechanisms is more pervasive now than it has been over the last 15-20 years. As the muscle biology field pushes to identify small molecules and interventions to prevent, attenuate or even reverse muscle wasting, we must consider the effect of sex as a biological variable. It should not be assumed that a therapeutic will affect males and females with equal efficacy or equivalent target affinities under conditions where muscle wasting is observed. With that said, it is not surprising to find that we have an unclear or even a poor understanding of the effects of sex or sex hormones on muscle wasting conditions. Although recent investigations are beginning to establish experimental approaches that will allow investigators to assess the impact of sex-specific hormones on muscle wasting, the field still has not established enough published scientific tools that will allow the field to rigorously address critical hypotheses. Thus, the purpose of this review is to assemble a current summary of knowledge in the area of sexual dimorphism driven by estrogens with an effort to provide insights to interested physiologists on necessary considerations when trying to assess models for potential sex differences in cellular and molecular mechanisms of muscle wasting.

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CBMT-45. SEX-SPECIFIC METABOLIC ADAPTIONS IN GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.167 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi42-vi43

Author(s):

Jasmin Sponagel ◽

Shanshan Zhang ◽

Prakash Chinnaiyan ◽

Joshua Rubin ◽

Joseph Ippolito

Keyword(s):

Sex Differences ◽

Sexual Dimorphism ◽

Molecular Mechanisms ◽

Treatment Strategies ◽

Tca Cycle ◽

Metabolic Reprogramming ◽

Mitochondrial Activity ◽

Male And Female ◽

Glutamine Deprivation ◽

Novel Treatment Strategies

Abstract Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. GBM occurs more commonly in males, but female patients survive significantly longer. Understanding the molecular mechanisms that underlie those sex differences could support novel treatment strategies. In this regard, we found that male and female GBM patient samples differ in their metabolite abundance and that male patients exhibit a significantly higher abundance of TCA cycle metabolites. We confirmed those findings in a murine model of GBM, which has previously yielded important insights into sexual dimorphism in GBM. Strikingly, sex differences in TCA cycle flux were entirely driven by glutamine flux, not glucose flux, suggesting a sex-specific role for glutamine in GBM. Metabolic manipulation through glutamine deprivation resulted in a greater growth inhibition in male GBM cells. Glutamine itself can be utilized for anabolic reactions or it can be converted to glutamate by glutaminase. Only male GBM cells were sensitive to pharmacological glutaminase inhibition with BPTES or CB-839, suggesting that male GBM cells are glutamate dependent while female GBM cells are not. Concordantly, we found significantly higher glutaminase levels in male GBM cells. Furthermore, we found that numerous metabolites (including NADH, ATP, and glutathione) involved in cellular processes downstream of glutamate were more abundant in male GBM cells. In contrast, female GBM cells were resistant to low glutamine conditions and glutaminase inhibitors unless glutamine-synthase activity was disrupted, suggesting that glutamine synthesis might play a more prominent role in female GBM. Together, these data indicate that male and female GBM differ in their metabolic adaptions. Male GBM utilize glutamate to fuel the TCA cycle and mitochondrial activity while female GBM synthesize and utilize glutamine itself. This sexual dimorphism in metabolic reprogramming reveals novel sex specific metabolic targets for GBM and underlines the importance of considering sex in metabolic targeting approaches.

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Sex differences in lipid metabolism and metabolic disease risk

Biochemistry and Cell Biology ◽

10.1139/o11-067 ◽

2012 ◽

Vol 90 (2) ◽

pp. 124-141 ◽

Cited By ~ 36

Author(s):

Michael G. Sugiyama ◽

Luis B. Agellon

Keyword(s):

Metabolic Disease ◽

Sex Differences ◽

Body Fat ◽

Molecular Mechanisms ◽

Sex Chromosome ◽

Disease Risk ◽

Treatment Strategies ◽

Metabolic Complications ◽

Metabolic Disease Risk ◽

Organ Systems

The ability of nutrients to regulate specific metabolic pathways is often overshadowed by their role in basic sustenance. Consequently, the mechanisms whereby these nutrients protect against or promote a variety of acquired metabolic syndromes remains poorly understood. Premenopausal women are generally protected from the adverse effects of obesity despite having a greater proportion of body fat than men. Menopause is often associated with a transformation in body fat morphology and a gradual increase in the susceptibility to metabolic complications, eventually reaching the point where women and men are at equal risk. These phenomena are not explained solely by changes in food preference or nutrient intake suggesting an important role for the sex hormones in regulating the metabolic fate of nutrients and protecting against metabolic disease pathophysiology. Here, we discuss how differences in the acquisition, trafficking, and subceullular metabolism of fats and other lipid soluble nutrients in major organ systems can create overt sex-specific phenotypes, modulate metabolic disease risk, and contribute to the rise in obesity in the modern sedentary climate. Identifying the molecular mechanisms underpinning sex differences in fat metabolism requires the unravelling of the interactions among sex chromosome effects, the hormonal milieu, and diet composition. Understanding the mechanisms that give rise to sex differences in metabolism will help to rationalize treatment strategies for the management of sex-specific metabolic disease risk factors.

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Sex differences on adipose tissue remodeling: from molecular mechanisms to therapeutic interventions

Journal of Molecular Medicine ◽

10.1007/s00109-020-01890-2 ◽

2020 ◽

Vol 98 (4) ◽

pp. 483-493 ◽

Cited By ~ 4

Author(s):

Alexandra Moreira-Pais ◽

Rita Ferreira ◽

João Sérgio Neves ◽

Rui Vitorino ◽

Daniel Moreira-Gonçalves ◽

...

Keyword(s):

Sex Differences ◽

Adipose Tissue ◽

Molecular Mechanisms ◽

Tissue Remodeling ◽

Therapeutic Interventions ◽

Adipose Tissue Remodeling

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Sex differences in severity and mortality from COVID-19: are males more vulnerable?

Biology of Sex Differences ◽

10.1186/s13293-020-00330-7 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 2

Author(s):

Ajay Pradhan ◽

Per-Erik Olsson

Keyword(s):

Sex Differences ◽

Immune System ◽

Immune Responses ◽

Molecular Mechanisms ◽

Viral Infections ◽

Basic Research ◽

Contributing Factors ◽

High Infection ◽

Males And Females

Abstract Coronavirus disease 2019 (COVID-19) has shown high infection and mortality rates all over the world, and despite the global efforts, there is so far no specific therapy available for COVID-19. Interestingly, while the severity and mortality of COVID-19 are higher in males than in females, the underlying molecular mechanisms are unclear. In this review, we explore sex-related differences that may be contributing factors to the observed male-biased mortality from COVID-19. Males are considered the weaker sex in aspects related to endurance and infection control. Studies show that viral RNA clearance is delayed in males with COVID-19. A recent study has indicated that the testis can harbor coronavirus, and consequently, males show delayed viral clearance. However, the role of testis involvement in COVID-19 severity and mortality needs further research. Males and females show a distinct difference in immune system responses with females eliciting stronger immune responses to pathogens. This difference in immune system responses may be a major contributing factor to viral load, disease severity, and mortality. In addition, differences in sex hormone milieus could also be a determinant of viral infections as estrogen has immunoenhancing effects while testosterone has immunosuppressive effects. The sex-specific severity of COVID-19 infections indicates that further research on understanding the sex differences is needed. Inclusion of both males and females in basic research and clinical trials is required to provide critical information on sex-related differences that may help to better understand disease outcome and therapy.

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Sex and gender differences in hypertensive kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00206.2017 ◽

2017 ◽

Vol 313 (4) ◽

pp. F1009-F1017 ◽

Cited By ~ 18

Author(s):

Jennifer C. Sullivan ◽

Ellen E. Gillis

Keyword(s):

Sex Differences ◽

Experimental Animal ◽

Animal Studies ◽

Molecular Mechanisms ◽

Kidney Injury ◽

Science Research ◽

The United States ◽

Sex And Gender ◽

Participation Of Women ◽

And Gender

Hypertension is a complex, multifaceted disorder, affecting ~1 in 3 adults in the United States. Although hypertension occurs in both men and women, there are distinct sex differences in the way in which they develop hypertension, with women having a lower incidence of hypertension until the sixth decade of life. Despite observed sex differences in hypertension, little is known about the molecular mechanisms underlying the development of hypertension in females, primarily because of their underrepresentation in both clinical and experimental animal studies. The first goal of this review is to provide a concise overview of the participation of women in clinical trials, including a discussion of the importance of including females in basic science research, as recently mandated by the National Institutes of Health. The remaining portion of the review is dedicated to identifying clinical and experimental animal studies that concentrate on gender and sex differences in hypertensive kidney disease, ending with a proposed role for T cells in mediating sex differences in blood pressure.

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Evolution of Courtship Songs in Xenopus: Vocal Pattern Generation and Sound Production

Cytogenetic and Genome Research ◽

10.1159/000433483 ◽

2015 ◽

Vol 145 (3-4) ◽

pp. 302-314 ◽

Cited By ~ 8

Author(s):

Elizabeth C. Leininger ◽

Darcy B. Kelley

Keyword(s):

Sex Differences ◽

Evolutionary History ◽

Molecular Mechanisms ◽

Sound Production ◽

Pattern Generation ◽

Model Species ◽

Extant Species ◽

Evolutionary Trajectories ◽

Strong Candidate ◽

Species Specific

The extant species of African clawed frogs (Xenopus and Silurana) provide an opportunity to link the evolution of vocal characters to changes in the responsible cellular and molecular mechanisms. In this review, we integrate several robust lines of research: evolutionary trajectories of Xenopus vocalizations, cellular and circuit-level mechanisms of vocalization in selected Xenopus model species, and Xenopus evolutionary history and speciation mechanisms. Integrating recent findings allows us to generate and test specific hypotheses about the evolution of Xenopus vocal circuits. We propose that reduced vocal sex differences in some Xenopus species result from species-specific losses of sexually differentiated neural and neuromuscular features. Modification of sex-hormone-regulated developmental mechanisms is a strong candidate mechanism for reduced vocal sex differences.

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Clinically Important sex differences in GBM biology revealed by analysis of male and female imaging, transcriptome and survival data

10.1101/232744 ◽

2017 ◽

Cited By ~ 4

Author(s):

Wei Yang ◽

Nicole M. Warrington ◽

Sara J. Taylor ◽

Eduardo Carrasco ◽

Kyle W. Singleton ◽

...

Keyword(s):

Cell Cycle ◽

Sex Differences ◽

Survival Data ◽

Molecular Mechanisms ◽

Quantitative Imaging ◽

Outcome Data ◽

Integrin Signaling ◽

Chemotherapy Sensitivity ◽

Male And Female

AbstractSex differences in the incidence and outcome of human disease are broadly recognized but in most cases not adequately understood to enable sex-specific approaches to treatment. Glioblastoma (GBM), the most common malignant brain tumor, provides a case in point. Despite well-established differences in incidence, and emerging indications of differences in outcome, there are few insights that distinguish male and female GBM at the molecular level, or allow specific targeting of these biological differences. Here, using a quantitative imaging-based measure of response, we found that temozolomide chemotherapy is more effective in female compared to male GBM patients. We then applied a novel computational algorithm to linked GBM transcriptome and outcome data, and identified novel sex-specific molecular subtypes of GBM in which cell cycle and integrin signaling were identified as the critical determinants of survival for male and female patients, respectively. The clinical utility of cell cycle and integrin signaling pathway signatures was further established through correlations between gene expression and in vitro chemotherapy sensitivity in a panel of male and female patient-derived GBM cell lines. Together these results suggest that greater precision in GBM molecular subtyping can be achieved through sex-specific analyses, and that improved outcome for all patients might be accomplished via tailoring treatment to sex differences in molecular mechanisms.One Sentence SummaryMale and female glioblastoma are biologically distinct and maximal chances for cure may require sex-specific approaches to treatment.

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