搜索结果：Biology of sex differences

BACKGROUND: Women experience adverse drug reactions, ADRs, nearly twice as often as men, yet the role of sex as a biological factor in the generation of ADRs is poorly understood. Most drugs currently in use were approved based on clinical trials conducted on men, so women may be overmedicated. We determined whether sex differences in drug pharmacokinetics, PKs, predict sex differences in ADRs. METHODS: Searches of the ISI Web of Science and PubMed databases were conducted with combinations of the terms: drugs, sex or gender, pharmacokinetics, pharmacodynamics, drug safety, drug dose, and adverse drug reaction, which yielded over 5000 articles with considerable overlap. We obtained information from each relevant article on significant sex differences in PK measures, predominantly area under the curve, peak/maximum concentrations, and clearance/elimination rates. ADRs were identified from every relevant article and recorded categorically as female-biased, male-biased, or not sex-biased. RESULTS: For most of the FDA-approved drugs examined, elevated blood concentrations and longer elimination times were manifested by women, and these PKs were strongly linked to sex differences in ADRs. Of the 86 drugs evaluated, 76 had higher PK values in women; for 59 drugs with clinically identifiable ADRs, sex-biased PKs predicted the direction of sex-biased ADRs in 88% of cases. Ninety-six percent of drugs with female-biased PK values were associated with a higher incidence of ADRs in women than men, but only 29% of male-biased PKs predicted male-biased ADRs. Accessible PK information is available for only a small fraction of all drugs CONCLUSIONS: Sex differences in pharmacokinetics strongly predict sex-specific ADRs for women but not men. This sex difference was not explained by sex differences in body weight. The absence of sex-stratified PK information in public records for hundreds of drugs raises the concern that sex differences in PK values are widespread and of clinical significance. The common practice of prescribing equal drug doses to women and men neglects sex differences in pharmacokinetics and dimorphisms in body weight, risks overmedication of women, and contributes to female-biased adverse drug reactions. We recommend evidence-based dose reductions for women to counteract this sex bias.

Sex differences in the biology of different organ systems and the influence of sex hormones in modulating health and disease are increasingly relevant in clinical and research areas. Although work has focused on sex differences and sex hormones in cardiovascular, musculoskeletal, and neuronal systems, there is now increasing clinical evidence for sex differences in incidence, morbidity, and mortality of lung diseases including allergic diseases (such as asthma), chronic obstructive pulmonary disease, pulmonary fibrosis, lung cancer, as well as pulmonary hypertension. Whether such differences are inherent and/or whether sex steroids play a role in modulating these differences is currently under investigation. The purpose of this review is to define sex differences in lung structure/function under normal and specific disease states, with exploration of whether and how sex hormone signaling mechanisms may explain these clinical observations. Focusing on adult age groups, the review addresses the following: 1) inherent sex differences in lung anatomy and physiology; 2) the importance of certain time points in life such as puberty, pregnancy, menopause, and aging; 3) expression and signaling of sex steroid receptors under normal vs. disease states; 4) potential interplay between different sex steroids; 5) the question of whether sex steroids are beneficial or detrimental to the lung; and 6) the potential use of sex steroid signaling as biomarkers and therapeutic avenues in lung diseases. The importance of focusing on sex differences and sex steroids in the lung lies in the increasing incidence of lung diseases in women and the need to address lung diseases across the life span.

We now know that cancer is many different diseases, with great variation even within a single histological subtype. With the current emphasis on developing personalized approaches to cancer treatment, it is astonishing that we have not yet systematically incorporated the biology of sex differences into our paradigms for laboratory and clinical cancer research. While some sex differences in cancer arise through the actions of circulating sex hormones, other sex differences are independent of estrogen, testosterone, or progesterone levels. Instead, these differences are the result of sexual differentiation, a process that involves genetic and epigenetic mechanisms, in addition to acute sex hormone actions. Sexual differentiation begins with fertilization and continues beyond menopause. It affects virtually every body system, resulting in marked sex differences in such areas as growth, lifespan, metabolism, and immunity, all of which can impact on cancer progression, treatment response, and survival. These organismal level differences have correlates at the cellular level, and thus, males and females can fundamentally differ in their protections and vulnerabilities to cancer, from cellular transformation through all stages of progression, spread, and response to treatment. Our goal in this review is to cover some of the robust sex differences that exist in core cancer pathways and to make the case for inclusion of sex as a biological variable in all laboratory and clinical cancer research. We finish with a discussion of lab- and clinic-based experimental design that should be used when testing whether sex matters and the appropriate statistical models to apply in data analysis for rigorous evaluations of potential sex effects. It is our goal to facilitate the evaluation of sex differences in cancer in order to improve outcomes for all patients.

The steep rise of type 2 diabetes mellitus (T2DM) and associated complications go along with mounting evidence of clinically important sex and gender differences. T2DM is more frequently diagnosed at lower age and body mass index in men; however, the most prominent risk factor, which is obesity, is more common in women. Generally, large sex-ratio differences across countries are observed. Diversities in biology, culture, lifestyle, environment, and socioeconomic status impact differences between males and females in predisposition, development, and clinical presentation. Genetic effects and epigenetic mechanisms, nutritional factors and sedentary lifestyle affect risk and complications differently in both sexes. Furthermore, sex hormones have a great impact on energy metabolism, body composition, vascular function, and inflammatory responses. Thus, endocrine imbalances relate to unfavorable cardiometabolic traits, observable in women with androgen excess or men with hypogonadism. Both biological and psychosocial factors are responsible for sex and gender differences in diabetes risk and outcome. Overall, psychosocial stress appears to have greater impact on women rather than on men. In addition, women have greater increases of cardiovascular risk, myocardial infarction, and stroke mortality than men, compared with nondiabetic subjects. However, when dialysis therapy is initiated, mortality is comparable in both males and females. Diabetes appears to attenuate the protective effect of the female sex in the development of cardiac diseases and nephropathy. Endocrine and behavioral factors are involved in gender inequalities and affect the outcome. More research regarding sex-dimorphic pathophysiological mechanisms of T2DM and its complications could contribute to more personalized diabetes care in the future and would thus promote more awareness in terms of sex- and gender-specific risk factors.

BACKGROUND: Sex differences in the incidence and outcomes of several cancers are well established. Multiple myeloma (MM) is a malignant plasma cell dyscrasia accounting for 2% of all new cancer cases in the UK. There is a clear sex disparity in MM incidence, with 57% of cases in males and 43% in females. The mechanisms behind this are not well understood and the impact of sex on patient outcomes has not been thoroughly explored. PATIENTS AND METHODS: We investigated the association of sex with baseline disease characteristics and outcome in 3894 patients recruited to the phase III UK NCRI Myeloma XI trial, in which treatment exposure to lenalidomide predominated. RESULTS: Females were significantly more likely to have the molecular lesions t(14;16) and del(17p) and were more likely to meet the cytogenetic classification of high-risk (HiR) or ultra-high-risk disease (UHiR). There was no difference in progression-free survival (PFS) or overall survival (OS) between the sexes in the overall population. CONCLUSION: Our data suggest that the genetic lesions involved in the initiation and progression of MM may be different between the sexes. Although females were more likely to have the poor prognosis lesions t(14;16) and del(17p), and were more likely to be assessed as having HiR or UHiR disease, this was not associated with reduced PFS or OS. In female patients the trial treatment may have been able to overcome some of the adverse effects of high-risk cytogenetic lesions. MicroAbstract Multiple myeloma (MM) is more common in males compared to females but the reasons behind this are not well understood and the impact of sex on patient outcomes is unclear. This study demonstrates fundamental differences in genetic lesions underlying the biology of MM between males and females. However, we found that progression-free survival and overall survival were the same in both sexes.

With the aging of the population, the burden of Alzheimer's disease (AD) is rapidly expanding. More than 5 million people in the US alone are affected with AD and this number is expected to triple by 2050. While men may have a higher risk of mild cognitive impairment (MCI), an intermediate stage between normal aging and dementia, women are disproportionally affected with AD. One explanation is that men may die of competing causes of death earlier in life, so that only the most resilient men may survive to older ages. However, many other factors should also be considered to explain the sex differences. In this review, we discuss the differences observed in men versus women in the incidence and prevalence of MCI and AD, in the structure and function of the brain, and in the sex-specific and gender-specific risk and protective factors for AD. In medical research, sex refers to biological differences such as chromosomal differences (eg, XX versus XY chromosomes), gonadal differences, or hormonal differences. In contrast, gender refers to psychosocial and cultural differences between men and women (eg, access to education and occupation). Both factors play an important role in the development and progression of diseases, including AD. Understanding both sex- and gender-specific risk and protective factors for AD is critical for developing individualized interventions for the prevention and treatment of AD.

Previous attempts have been made to address sleep disorders in women; however, significant knowledge gaps in research and a lack of awareness among the research community continue to exist. There is a great need for scientists and clinicians to consider sex and gender differences in their sleep research to account for the unique biology of women. To understand the role of sex differences in sleep and the state of women's sleep health research, the Society for Women's Health Research convened an interdisciplinary expert panel of well-established sleep researchers and clinicians for a roundtable meeting. Focused discussions on basic and clinical research along with a focus on specific challenges facing women with sleep-related problems and effective therapies led to the identification of knowledge gaps and the development of research-related recommendations. Additionally, sex differences in sleep disorders were noted and discussed in the context of underlying hormonal differences. Differences in sleep behavior and sleep disorders may not only be driven by biological factors but also by gender differences in the way women and men report symptoms. Progress has been made in identifying sex and gender differences in many areas of sleep, but major research gaps in the areas of epidemiology, sleep regulation, sleep quality, diagnosis, and treatment need to be addressed. Identifying the underlying nature of sex and gender differences in sleep research has potential to accelerate improved care for both men and women facilitating better diagnosis, treatment, and ultimately prevention of sleep disorders and related comorbid conditions.

BACKGROUND: Global development goals increasingly rely on country-specific estimates for benchmarking a nation's progress. To meet this need, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 estimated global, regional, national, and, for selected locations, subnational cause-specific mortality beginning in the year 1980. Here we report an update to that study, making use of newly available data and improved methods. GBD 2017 provides a comprehensive assessment of cause-specific mortality for 282 causes in 195 countries and territories from 1980 to 2017. METHODS: The causes of death database is composed of vital registration (VR), verbal autopsy (VA), registry, survey, police, and surveillance data. GBD 2017 added ten VA studies, 127 country-years of VR data, 502 cancer-registry country-years, and an additional surveillance country-year. Expansions of the GBD cause of death hierarchy resulted in 18 additional causes estimated for GBD 2017. Newly available data led to subnational estimates for five additional countries-Ethiopia, Iran, New Zealand, Norway, and Russia. Deaths assigned International Classification of Diseases (ICD) codes for non-specific, implausible, or intermediate causes of death were reassigned to underlying causes by redistribution algorithms that were incorporated into uncertainty estimation. We used statistical modelling tools developed for GBD, including the Cause of Death Ensemble model (CODEm), to generate cause fractions and cause-specific death rates for each location, year, age, and sex. Instead of using UN estimates as in previous versions, GBD 2017 independently estimated population size and fertility rate for all locations. Years of life lost (YLLs) were then calculated as the sum of each death multiplied by the standard life expectancy at each age. All rates reported here are age-standardised. FINDINGS: At the broadest grouping of causes of death (Level 1), non-communicable diseases (NCDs) comprised the greatest fraction of deaths, contributing to 73·4% (95% uncertainty interval [UI] 72·5-74·1) of total deaths in 2017, while communicable, maternal, neonatal, and nutritional (CMNN) causes accounted for 18·6% (17·9-19·6), and injuries 8·0% (7·7-8·2). Total numbers of deaths from NCD causes increased from 2007 to 2017 by 22·7% (21·5-23·9), representing an additional 7·61 million (7·20-8·01) deaths estimated in 2017 versus 2007. The death rate from NCDs decreased globally by 7·9% (7·0-8·8). The number of deaths for CMNN causes decreased by 22·2% (20·0-24·0) and the death rate by 31·8% (30·1-33·3). Total deaths from injuries increased by 2·3% (0·5-4·0) between 2007 and 2017, and the death rate from injuries decreased by 13·7% (12·2-15·1) to 57·9 deaths (55·9-59·2) per 100 000 in 2017. Deaths from substance use disorders also increased, rising from 284 000 deaths (268 000-289 000) globally in 2007 to 352 000 (334 000-363 000) in 2017. Between 2007 and 2017, total deaths from conflict and terrorism increased by 118·0% (88·8-148·6). A greater reduction in total deaths and death rates was observed for some CMNN causes among children younger than 5 years than for older adults, such as a 36·4% (32·2-40·6) reduction in deaths from lower respiratory infections for children younger than 5 years compared with a 33·6% (31·2-36·1) increase in adults older than 70 years. Globally, the number of deaths was greater for men than for women at most ages in 2017, except at ages older than 85 years. Trends in global YLLs reflect an epidemiological transition, with decreases in total YLLs from enteric infections, respiratory infections and tuberculosis, and maternal and neonatal disorders between 1990 and 2017; these were generally greater in magnitude at the lowest levels of the Socio-demographic Index (SDI). At the same time, there were large increases in YLLs from neoplasms and cardiovascular diseases. YLL rates decreased across the five leading Level 2 causes in all SDI quintiles. The leading causes of YLLs in 1990-neonatal disorders, lower respiratory infections, and diarrhoeal diseases-were ranked second, fourth, and fifth, in 2017. Meanwhile, estimated YLLs increased for ischaemic heart disease (ranked first in 2017) and stroke (ranked third), even though YLL rates decreased. Population growth contributed to increased total deaths across the 20 leading Level 2 causes of mortality between 2007 and 2017. Decreases in the cause-specific mortality rate reduced the effect of population growth for all but three causes: substance use disorders, neurological disorders, and skin and subcutaneous diseases. INTERPRETATION: Improvements in global health have been unevenly distributed among populations. Deaths due to injuries, substance use disorders, armed conflict and terrorism, neoplasms, and cardiovascular disease are expanding threats to global health. For causes of death such as lower respiratory and enteric infections, more rapid progress occurred for children than for the oldest adults, and there is continuing disparity in mortality rates by sex across age groups. Reductions in the death rate of some common diseases are themselves slowing or have ceased, primarily for NCDs, and the death rate for selected causes has increased in the past decade. FUNDING: Bill & Melinda Gates Foundation.

Females and males differ significantly in gross anatomy and physiology of the lower urinary tract, and these differences are commonly discussed in the medical and scientific literature. However, less attention is dedicated to investigating the varied development, function, and biology between females and males on a cellular level. Recognizing that cell biology is not uniform, especially in the lower urinary tract of females and males, is crucial for providing context and relevance for diverse fields of biomedical investigation. This review serves to characterize the current understanding of biological sex differences between female and male lower urinary tracts, while identifying areas for future research. First, the differences in overall cell populations are discussed in the detrusor smooth muscle, urothelium, and trigone. Second, the urethra is discussed, including anatomic discussions of the female and male urethra followed by discussions of cellular differences in the urothelial and muscular layers. The pelvic floor is then reviewed, followed by an examination of the sex differences in hormonal regulation, the urinary tract microbiome, and the reticuloendothelial system. Understanding the complex and dynamic development, anatomy, and physiology of the lower urinary tract should be contextualized by the sex differences described in this review.

BACKGROUND: The sex of an individual affects glucose homeostasis and the pathophysiology, incidence, and prevalence of diabetes as well as the response to therapy. SCOPE OF THE REVIEW: This review focuses on clinical and experimental sex differences in islet cell biology and dysfunction during development and in adulthood in human and animal models. We discuss sex differences in β-cell and α-cell function, heterogeneity, and dysfunction. We cover sex differences in communication between gonads and islets and islet-cell immune interactions. Finally, we discuss sex differences in β-cell programming by nutrition and other environmental factors during pregnancy. MAJOR CONCLUSIONS: Important sex differences exist in islet cell function and susceptibility to failure. These differences represent sex-related biological factors that can be harnessed for gender-based prevention of and therapy for diabetes.

Here we review and extend a new unitary model for the pathophysiology of involutional osteoporosis that identifies estrogen (E) as the key hormone for maintaining bone mass and E deficiency as the major cause of age-related bone loss in both sexes. Also, both E and testosterone (T) are key regulators of skeletal growth and maturation, and E, together with GH and IGF-I, initiate a 3- to 4-yr pubertal growth spurt that doubles skeletal mass. Although E is required for the attainment of maximal peak bone mass in both sexes, the additional action of T on stimulating periosteal apposition accounts for the larger size and thicker cortices of the adult male skeleton. Aging women undergo two phases of bone loss, whereas aging men undergo only one. In women, the menopause initiates an accelerated phase of predominantly cancellous bone loss that declines rapidly over 4-8 yr to become asymptotic with a subsequent slow phase that continues indefinitely. The accelerated phase results from the loss of the direct restraining effects of E on bone turnover, an action mediated by E receptors in both osteoblasts and osteoclasts. In the ensuing slow phase, the rate of cancellous bone loss is reduced, but the rate of cortical bone loss is unchanged or increased. This phase is mediated largely by secondary hyperparathyroidism that results from the loss of E actions on extraskeletal calcium metabolism. The resultant external calcium losses increase the level of dietary calcium intake that is required to maintain bone balance. Impaired osteoblast function due to E deficiency, aging, or both also contributes to the slow phase of bone loss. Although both serum bioavailable (Bio) E and Bio T decline in aging men, Bio E is the major predictor of their bone loss. Thus, both sex steroids are important for developing peak bone mass, but E deficiency is the major determinant of age-related bone loss in both sexes.

The prevalence of type 2 diabetes mellitus is increasing in both sexes, but men are usually diagnosed at a younger age and lower body fat mass than women. Worldwide, an estimated 17.7 million more men than women have diabetes mellitus. Women appear to bear a greater risk factor burden at the time of their type 2 diabetes diagnosis, especially obesity. Moreover, psychosocial stress might play a more prominent role in diabetes risk in women. Across their lifespan, women experience greater hormone fluctuations and body changes due to reproductive factors than men. Pregnancies can unmask pre-existing metabolic abnormalities, resulting in the diagnosis of gestational diabetes, which appears to be the most prominent risk factor for progression to type 2 diabetes in women. Additionally, menopause increases women's cardiometabolic risk profile. Due to the progressive rise in obesity, there is a global increase in women with pregestational type 2 diabetes, often with inadequate preconceptual care. There are differences between men and women regarding type 2 diabetes and other cardiovascular risk factors with respect to comorbidities, the manifestation of complications and the initiation of and adherence to therapy. Women with type 2 diabetes show greater relative risk of CVD and mortality than men. Moreover, young women with type 2 diabetes are currently less likely than men to receive the treatment and CVD risk reduction recommended by guidelines. Current medical recommendations do not provide information on sex-specific or gender-sensitive prevention strategies and management. Thus, more research on sex differences, including the underlying mechanisms, is necessary to increase the evidence in the future. Nonetheless, intensified efforts to screen for glucose metabolism disorders and other cardiovascular risk factors, as well as the early establishment of prophylactic measures and aggressive risk management strategies, are still required for both men and women at increased risk of type 2 diabetes. In this narrative review we aim to summarise sex-specific clinical features and differences between women and men with type 2 diabetes into risk factors, screening, diagnosis, complications and treatment.

Sex differences in human health and disease can range from undetectable to profound. Differences in brain tumor rates and outcome are evident in males and females throughout the world and regardless of age. These observations indicate that fundamental aspects of sex determination can impact the biology of brain tumors. It is likely that optimal personalized approaches to the treatment of male and female brain tumor patients will require recognizing and understanding the ways in which the biology of their tumors can differ. It is our view that sex-specific approaches to brain tumor screening and care will be enhanced by rigorously documenting differences in brain tumor rates and outcomes in males and females, and understanding the developmental and evolutionary origins of sex differences. Here we offer such an integrative perspective on brain tumors. It is our intent to encourage the consideration of sex differences in clinical and basic scientific investigations.