Understanding sex and gender is critical to understanding human health and disease. Although “sex” is often incorrectly thought to have the same meaning as “gender,” the terms describe different but connected constructs. Sex and gender shape health independently as distinct factors, as well as interactively through the many ways in which they intersect and influence each other.  It is important to understand the differences and interactions between sex and gender to better understand how they affect health and why they are important in medical practice and health research.  

Sex

Sex is a multidimensional biological construct based on anatomy, physiology, genetics, and hormones. (These components are sometimes referred to together as “sex traits.”)  All animals (including humans) have a sex. As is common across health research communities, NIH usually categorizes sex as male or female, although variations do occur. These variations are called differences in sex development (DSD) or intersex conditions.   

Importance of Considering Sex as a Biological Variable in Health Research 

Scientists have observed important sex differences across key pathways and processes, such as how the body fights disease (immune system), processes pain (nervous system), and maintains heart health (cardiovascular system).  A growing body of health research demonstrates how these sex differences can influence a person’s vulnerability to disease, experience of symptoms, and response to treatment.

Until recent decades, however, the vast majority of clinical research was conducted with exclusively or predominantly male participants. In addition, most preclinical research with animal and cell models—used to inform our knowledge of human biology and disease—studied almost exclusively male cells or male animals. Despite this narrow approach, the research findings and medical treatments developed from this knowledge were often (and sometimes continue to be) assumed to apply to the whole population.  

This systemic lack of female representation (as well as omissions of transgender and intersex populations and people with DSD) at all stages of the research process has resulted in gaps in our medical knowledge. This evidence gap continues to affect the quality of care patients receive—contributing to delayed diagnosis or misdiagnosis for female patients.  In addition, the underrepresentation of female participants in clinical studies and the lack of sex-based analysis of data have led to medications that have lower efficacy and greater toxicity for female patients.  

Since 2016, the NIH Policy on Sex as a Biological Variable (SABV) has helped ensure NIH-funded research rigorously addresses sex as a factor in health and disease.  

Gender 

Gender is relevant only for research with humans (not other animals). Gender can be broadly defined as a multidimensional construct that encompasses gender identity and expression, as well as social and cultural expectations about status, characteristics, and behavior as they are associated with certain sex traits. Understandings of gender vary throughout historical and cultural contexts.
 
A person’s gender identity (e.g., woman, man, trans man, gender-diverse, nonbinary) is self-identified, may change throughout their life, and may or may not correspond to a society’s cultural expectations based on their biological sex traits. For example, a person with typical female (sex term) sex traits may or may not be a woman (gender identity). Although gender is often portrayed and understood in Western cultures using binary categories (man or woman) and is often assumed at birth based on a person’s sex traits, many cultures throughout history have recognized a diversity of forms of gender identity and gender expression (how a person communicates their gender to others through behavior and appearance). 

Gender roles and norms are a society’s cultural expectations and perceptions about how a person of a certain gender should behave, act, or express themself. Gendered relations are interpersonal interactions and group dynamics that are shaped by individual and societal concepts of gender. These relations are embedded in interpersonal relationships, social structures, and larger systems of power such as political, economic and cultural institutions. 

As a domain of gender, power describes the structures and systems of inequity that are based upon gender and which reproduce, shape, and constrain opportunities and experiences for individuals and groups – for example, structural sexism, gender-based violence, and patriarchy.  Gender equality (the absence of gender-based discrimination) and gender equity (ensuring every person has access to care, services, and opportunities tailored to their unique needs, circumstances, and goals) are key to addressing health disparities and advancing health for everyone.  

Importance of Considering Gender as a Social and Structural Variable in Health Research 

A person’s gender can affect their physical and mental health and well-being in many ways and is an important factor in understanding the health of all individuals. For example, gender inequalities in a society have been shown to limit girls’ and women’s access to health services.  Gender norms and roles (such as cultural expectations and definitions of masculinity) influence the willingness and likelihood of boys and men to seek health services.  Gender norms, gender roles, and gendered power relations (such as a society’s perception of “women’s work” or “a woman’s role”) contribute to the disproportionate burden of caregiving duties borne by women and women’s vulnerability to negative health impacts associated with caregiver stress.

Roughly speaking, sex can be considered in terms of three categories: genotypic sex, phenotypic sex, and gender. Genotypic sex refers specifically to an individual's two sex chromosomes. Most people have either two X chromosomes (genotypic female) or an X and a Y chromosome (genotypic male). Phenotypic sex refers to an individual's sex as determined by their internal and external genitalia, expression of secondary sex characteristics, and behavior. If everything proceeds according to plan during development, the XX genotype leads to a person with ovaries, oviducts, uterus, cervix, clitoris, labia, and vagina—i.e., a phenotypic female. By the same token, the XY genotype leads to a person with testicles, epididymis, vas deferens, seminal vesicles, penis, and scrotum—a phenotypic male. Gender refers more broadly to an individual's subjective perception of their sex and their sexual orientation, and is therefore harder to define than genotypic or phenotypic sex. Generally speaking, gender identity entails self-appraisal according to the traits most often associated with one sex or the other (called gender traits), and these can be influenced to some degree by cultural norms. Sexual orientation also entails self-appraisal in the context of culture. For purposes of understanding the neurobiology of sex, it is helpful to think of genotypic sex as largely immutable, phenotypic sex as modifiable (by developmental processes, hormone treatment, and/or surgery), and gender as a more complex construct that is determined culturally as well as biologically.

Clearly, then, genotypic sex, phenotypic sex, and gender are not always aligned. Variations in alignment can be minor, or they can challenge the usual definitions of female and male and lead to psychosocial conflicts and sexual dysfunction. Genetic variations include individuals who are XO (Turner's syndrome), XXY (Klinefelter's syndrome), or XYY. Each of these genotypes has its own particular phenotype. Other genetic variations arise from mutations in genes coding for hormone receptors or for the hormones themselves. For instance, a metabolic disorder that leads to overactive adrenals during maturation, called congenital adrenal hyperplasia (CAH), causes abnormally high levels of circulating androgens and hence, along with severe salt imbalance, an ambiguous sexual phenotype. In addition to having a large clitoris and fused labia at birth, females with CAH typically exhibit “tomboyish” behavior as children and tend to form homosexual relationships as adults. High levels of circulating androgens from the adrenals may cause sexually dimorphic brain circuitry to have a male rather than female organization, leading to more aggressive play and the eventual choice of a female sexual partner.

An example of a mutation in a gene responsible for hormone receptors is androgen insensitivity syndrome (AIS), also called testicular feminization. The receptor deficiency leads to the development of the internal genitalia of a male and the external genitalia of a female in an individual who is genotypically XY. Thus, people with androgen insensitivity syndrome look like females and self-identify as female, even though they have a Y chromosome. Since they are generally not aware of their condition until puberty, when they fail to menstruate, they see themselves and are experienced by others as female. Thus, their gender identity matches external sexual phenotype, but not genotype. Although this syndrome is relatively uncommon (about 1 in 4000 births), there are some well-known examples of individuals thought or known to have had AIS (e.g., Joan of Arc and Wallis Simpson, the woman for whom King Edward of England gave up his throne).

Another variation in the alignment of genotype, phenotype, and gender is genotypic males who are phenotypic females early in life, but whose sexual phenotype changes at puberty. As infants and children, these individuals are phenotypic females because they lack an enzyme, 5-α-reductase, that promotes the early development of male genitalia. Such children have somewhat ambiguous but generally female-appearing genitalia (they have labia with an enlarged clitoris, and undescended testes). As a result, they are generally raised as females. At puberty, however, when the testicular secretion of androgen becomes high, the clitoris develops into a penis and the testes descend, changing these individuals into phenotypic males. In the Dominican Republic and Haiti, where this congenital syndrome has been thoroughly studied in a particular pedigree, the condition is referred to colloquially as “testes-at-twelve.” Such individuals generally exhibit male gender behavior at puberty, and most eventually live as males.

The term used to describe all these variations is “intersexuality.” Taken together, these individuals make up approximately 1–2% of all live births. In addition to the more clearly defined categories of Klinefelter's syndrome, Turner's syndrome, CAH, AIS, and 5-α-reductase deficiency, subtle permutations and combinations of genes, hormones, and environment give rise to a large number of biological and behavioral possibilities. In all these permutations and combinations, the relevant brain circuitry established early in development generally determines sexual behavior and identity.

Understanding sex and gender is critical to understanding health and to diagnosing and treating disease and illness. Disparities in the prevalence and severity of several conditions point to the need for further research in this area. For example:  

• Women are nearly twice as likely as men to be diagnosed with depression. 
• Women and men have heart attacks at similar rates, but women are more likely to die as a result.
• Women make up about 78% of patients with autoimmune diseases. 
• Women are more likely to have chronic pain than men, but women are less likely to receive treatment. 

To better understand and address these gaps, it is important to consider how both sex and gender influence these disparities. It is also important to understand that sex and gender are interconnected but distinct concepts, and that each affect health as both independent and interactive factors. The below graphic presents a few examples of sex and gender influences across various areas of health and disease to illustrate the distinction between sex and gender and highlight the importance of understanding them as factors in health and disease. Please note that each example presented below is just one of many possible examples for each area.

A note on terminology:

“Male” and “female” refer to sex assigned at birth. In addition, while we use the terms “male” and “female” for the purposes of this discussion, we recognize that sex is not a binary variable and variations do occur. These variations are called differences in sex development (DSD) or intersex conditions.

According to the National Institute on Aging, getting older can come with a variety of health challenges. But you can take action to maintain good health and reduce your risk of disease and disability. Exercise, good nutrition, regular health screenings, getting vaccines, having enough sleep, and participating in activities you enjoy are just a few ways to promote healthy aging. Here are some facts about men and women and healthy aging/longevity:

• Globally, women live longer but suffer more physical limitations than men in later life.
• Compared to men, women actually have worse health throughout their lives.
• The effects of the environment can influence how men and women age.
• The biological factors influencing aging are not well known.

Drinking alcohol is a common activity in most cultures around the world, for both women and men. However, while drinking in moderation may be considered generally safe, alcohol abuse poses many risks to a woman's health. For example, although men are more likely to drink alcohol than are women, and men often drink more and more frequently, women are more vulnerable to some of alcohol's harmful effects. These effects are based on both gender- and sex-based factors, and they include differences in metabolism. In addition, alcohol use by women is also linked to many other physical and psychosocial health issues, such as unprotected sex, illicit drug use, and intimate partner violence. Here are some of the facts about women and alcohol use.

• Moderate, or low-risk, drinking for women is defined as no more than three drinks on any single day and no more than seven drinks per week.
• Low to moderate alcohol consumption in women, defined as fewer than three drinks per day, increases the risk of certain cancers, including breast cancer.
• After drinking similar amounts, women have higher blood levels of ethanol than do men, and women are more susceptible to alcoholic liver disease such as hepatitis.
• A woman's moderate alcohol intake may reduce her coronary heart disease risk, although details remain unclear.
• Research showed that female college-student drinkers exceeded NIH-defined guidelines for weekly drinking more frequently than did their male counterparts, which may have long-term consequences on drinking behavior in these women.
• The drug naltrexone is used to treat alcohol dependence, but it does not work for everyone. A small study showed that naltrexone worked better in women to reduce alcohol's positive subjective effects, suggesting it may be useful in therapy for alcohol dependence in women.
• Research with the model organism Drosophila (fruit flies) showed that female fruit flies are more prone to the sedative effects of alcohol than are male flies.
• No amount of drinking during pregnancy is safe. However, 20 to 30 percent of women drink at some time during pregnancy, which includes the period of time before a woman knows she is pregnant.

When it comes to cognitive aging and Alzheimer’s disease, the differences between men and women may be related to genetics. According to an NIA-supported study published in JAMA Neurology, August 2021, genes contained in the X chromosome may hold the key to differences between men and women in aging and Alzheimer’s-related cognitive decline.

Cognitive changes can affect memory, attention, and executive functions such as planning and self-control. These changes can occur as a result of the natural process of aging or dementia such as Alzheimer’s. Sometimes, cognitive changes are accompanied by changes in the brain such as the formation of neurofibrillary tangles, a hallmark characteristic of the brain tissue associated with Alzheimer’s. The tangles involve the twisting of tau protein threads of the nerve cells in the brain tissue. The rate and degree of cognitive decline, as well as the extent of neurofibrillary tangles, differ between men and women.

In this study, scientists led by a team at the University of California, San Francisco, analyzed genetic and clinical data from a joint cohort consisting of two long-term studies: the Religious Orders Study and the Rush Memory and Aging Project. The scientists gathered genetic data from the brain tissue of 508 autopsied individuals via RNA sequencing, a technique used to measure how many copies of specific genes are present in a human’s cells at a given time.

The scientists also gathered data about participants’ cognitive function over several years to assess changes in cognition, including memory and attention. Participants did not have dementia at the time of their enrollment in the studies and were monitored periodically until their death. Using genetic and clinical data, the scientists examined associations of cognitive changes and levels of neurofibrillary tangles with genes on the X chromosome.

The X chromosome is one of the two sex chromosomes in humans (the Y chromosome is the other). Women have two X chromosomes, and men have one X and one Y. Unlike the Y chromosome, which contains just 50 to 60 genes, the X chromosome contains hundreds of genes, many of which are related to brain function. However, not much is known about how the expression of X chromosome-linked genes affects brain changes in aging and Alzheimer’s. Gene expression is the process by which the instructions in our DNA are converted into a functional product, such as a protein.

The scientists found that the expression levels of 19 genes on the X chromosome were linked to changes in cognition and quantity of neurofibrillary tangles. In women, this increased expression was associated with slower cognitive decline. The expression of these genes was not increased in men. This may suggest that specific genes on the X chromosome help protect women from cognitive decline in aging and Alzheimer’s.

In contrast, the expression of three X chromosome genes associated with neurofibrillary tangles was increased in men. This may suggest that men could be more at risk of developing Alzheimer’s-related pathological changes than women.

Because this study used a sample population that was 98% white, future studies must be conducted on a more diverse sample. Nonetheless, the expression of X chromosome genes may uncover some of the genetic differences in cognitive aging and Alzheimer’s between men and women. Research to further examine the role of X chromosome genes in aging and Alzheimer’s could help advance personalized treatment options for both men and women.

This research was funded in part by NIA grants RF1AG068325, P30AG10161, R01AG15819, R01AG17917, U01AG61356, U01AG46152, R01AG36836, R01AG060393, and R01AG062588.

These activities relate to NIH’s AD+ADRD Research Implementation Milestone 2.D, “Create programs in basic, translational and clinical research aimed at comprehensive understanding of the impact of sex differences on the trajectories of brain aging and disease, phenotypes of AD and ADRD risk and responsiveness to treatment.”

Reference: Davis EJ, et al. Sex-specific association of the X chromosome with cognitive change and tau pathology in aging and Alzheimer Disease. JAMA Neurology. 2021 Aug 23;e212806. doi: 10.1001/jamaneurol.2021.2806.

As an electrically controlled organ, the heart beats when a wave of electricity courses through heart muscle in a defined regular path. Any disruption of this path of conduction, called an arrhythmia, causes the heart to beat irregularly. An arrhythmia can be very mild, even undetectable, or serious and fatal. Sex and gender differences are known to affect heart rhythms. Here are some examples.

• Certain medications, including the allergy drug Seldane and the gastrointestinal drug Propulsid (both of which have been taken off the market in the United States) trigger a potentially fatal heart arrhythmia more often in women than in men.
• A 2009 study showed that women are more likely than men to have complications from implantable cardiac defibrillators, devices that monitor heart rhythms and deliver shocks when needed to restore a normal heartbeat.
• Although men are more likely than women to experience a usually mild condition known as atrial flutter (heart palpitations), surgical treatment (ablation) of this arrhythmia affects women and men differently, according to a 2013 study. Although less women than men are treated with ablation, women are more likely to experience surgical complications and also more likely to have atrial flutter after the surgery.

Thought to be one of the most complicated systems in the human body, our immune system has effects on most aspects of health and disease. It protects us from harm, such as infectious organisms, and it helps us heal through wound healing and other processes. Most of the time, our immune system does a remarkable job distinguishing outside invaders from our own cells, but sometimes it mistakenly attacks the body's own organs, tissues, and cells. Autoimmune disorders are the result, and they appear to be on the rise.

Autoimmune disorders are a major issue for women's health, since the prevalence of these conditions is much higher in women, and some are more prevalent in women that are Black, Hispanic, American Indian, Hawaiian/Pacific Islander, or Asian. More than 80 types of autoimmune conditions exist, but some examples include inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, Sjögren's syndrome, and lupus.

Estimates say that about 80 percent of those affected by autoimmune disorders are women, but a few autoimmune disorders, such as type-1 diabetes and ankylosing spondylitis, are more common in men than in women. Disease severity also differs by sex: for example, although more women get lupus and multiple sclerosis than do men, these conditions affect males more severely.

• Researchers often study multiple sclerosis (MS) in mice: they get a similar condition called experimental autoimmune encephalomyelitis (EAE). Some of these studies are showing promise in humans, such as one small clinical trial that found a protective role for testosterone in males with MS.
• Certain brain regions were thinner than other brain regions in women with the painful condition irritable bowel syndrome. The changes corresponded with pain severity and did not occur in men with the disorder, suggesting that different brain mechanisms might be causing this type of pain in females and males.
• Novel transgenic mouse models can distinguish between the effects of sex hormones (such as estrogen and testosterone) and sex chromosomes (XX and XY) on disease. Scientists have learned that, in mice, the female chromosome set (XX) stimulates the development of lupus.
• Gene expression in the salivary glands, which are impaired in Sjögren's syndrome, differs markedly between women and men.
• Lupus flare-ups can signal pre-term birth in pregnant women with a mild version of the condition. A 2013 study showed that certain molecular markers identified midway through pregnancy may prove to be clinically useful in identifying women at risk for complications.

Cancer is often called a disease of DNA, since tumors develop when cells divide uncontrollably, and in many cases DNA mutations that affect the copying of DNA are to blame. Researchers today know, however, that cancers are very different from each other — almost different enough to look like a completely different health condition. In addition, as scientists learn more about the molecular roots of disease, they can classify cancers based upon molecular signatures. These signatures can aid in diagnosis, treatment, and prognosis. In addition to being different from one another the same type of cancer can be quite different in females and males. Here are a few examples.

• Between 2001 and 2010, prostate cancer was the most common cancer diagnosed among U.S. men of all races and ethnic groups.
• The most common cancer diagnosed among U.S. women was breast cancer, but lung cancer is the leading cause of death among cancers in women of all races and ethnic groups except Hispanic women, for which breast cancer is the leading killer in U.S. women.
• Some studies suggest that female cancer patients are more likely to experience inadequate pain management than male patients, but more studies are needed.
• Research comparing cell lines from women to cell lines from men reported sex differences in DNA damage to cancer-causing chemicals in tobacco smoke. For a given number of cigarettes smoked, females appear to be at higher risk of developing lung cancer than males.
• Females are less prone to liver cancer than males (humans and mice given a liver carcinogen), possibly due to estrogen's protective effect against inflammation in the liver.

For the most part, an individual has direct control over whether he or she will develop heart disease, by managing behaviors that raise or reduce the chances that heart disease will take root in their body. NIH-funded medical research that goes back decades has defined a core set of cardiovascular risk factors that individuals can manage with the help of a doctor. The risk factors include smoking, high cholesterol and triglycerides, high blood pressure, diabetes, and being overweight or obese.

Yet, even though everyone should pay attention to these risk factors that affect heart health, the risks differ between women and men in various ways that appear subtle, but can be very significant.

• In women, aspirin reduces risk of ischemic stroke, whereas in men, low-dose aspirin therapy reduces risk of heart attack.
• Cholesterol plaque in women may not build up into major artery blockages, but instead spreads evenly throughout the artery wall. This means that artery blockages can be more difficult to diagnose in women, who may not have outright symptoms but are still at high risk for heart attack.
• Cholesterol levels vary over the course of a woman's menstrual cycle.

While there are many similarities between men and women, sex can make a difference for some health risks and behaviors. For example, women are more likely to have certain mental health conditions, like depression. Men are more likely to have certain neurodevelopmental conditions, such as autism spectrum disorder. Studies have also shown sex differences in certain cognitive tasks, like the ability to recognize faces. But what underlies these differences isn’t fully understood.

Researchers have observed sex differences in the volume of certain brain regions in animals. Some studies suggest these anatomical differences are largely due to the effects of sex hormones on brain development. More recent research suggests that the activity, or “expression” of genes on the sex chromosomes plays a role in shaping these anatomical differences. Each cell in your body carries a pair of sex chromosomes, including your brain cells. Females have two X chromosomes, and males have one X and one Y.

To explore sex differences in the human brain, a team led by Drs. Siyuan Liu and Armin Raznahan at NIH’s National Institute of Mental Health (NIMH) analyzed neuroimaging data collected from two independent databanks. The Human Connectome Project involved 976 healthy adults between the ages of 22 and 35. The UK Biobank neuroimaging dataset was from 1,120 adults, ages 44 to 50. Results were published on July 20, 2020 in the Proceedings of the National Academy of Sciences.

On average, males and females showed greater volume in different areas of the cortex, the outer brain layer that controls thinking and voluntary movements. Females had greater volume in the prefrontal cortex, orbitofrontal cortex, superior temporal cortex, lateral parietal cortex, and insula. Males, on average, had greater volume in the ventral temporal and occipital regions. Each of these regions is responsible for processing different types of information.

The team cross-referenced their anatomical findings with publicly available maps of gene expression in the brain. These maps are based on more than 1,300 postmortem tissue samples from six human donors. The spatial pattern of sex differences in cortical volume was similar to the spatial pattern of sex-chromosome gene expression in the cortex. Regions with relatively high expression of sex-chromosome genes tended to have greater cortical volume in males than females.

The researchers also compared the anatomical findings with data from more than 11,000 functional neuroimaging studies. Such studies examine brain activation during specific activities or conditions. Of 50 cognitive categories, five were associated with anatomical differences: visual object recognition, face processing, cognitive control, inhibition, and conflict. Facial processing showed the strongest association.

“Developing a clearer understanding of sex differences in human brain organization has great importance for how we think about well-established sex differences in cognition, behavior, and risk for psychiatric illness,” Raznahan says. “We were inspired by new findings on sex differences in animal models and wanted to try to close the gap between these animal data and our models of sex differences in the human brain.”

More research is needed to determine whether these anatomical distinctions play any role in sex differences in cognition and behavior.

Gender plays an important role in mental health disorders like depression, which is common but underdiagnosed. Epidemiological research shows that females are more likely than males to develop not only depression, but also eating disorders, panic disorder, and post-traumatic stress disorder. Here are some sobering facts about depression in women:

• Depression is the leading cause of disability in the United States for individuals 15-44 years of age.
• Depression is the 5th most common source of disability worldwide for women, and it is predicted to be the second leading cause of global disability by 2020.
• Some diseases, including epilepsy, Alzheimer's disease, cancer, and cardiovascular disease, can bring on depression in one sex but not the other.
• Depressed middle-aged women have almost double the risk of having a stroke.

Women and men have different health care habit and needs, both of which affect health in significant ways. Women are more likely to be the primary family caregiver, meaning their decisions affect the health of children and men in the household as well. Over the course of a woman's lifetime, due in part to reproductive health issues, she relies on the health care system more than her male peers. Recent studies have shown other specific examples of health care gender differences.

• 2012 study showed that women are more likely than men to defer seeing their doctor(s) or dentist, or fill a prescription, because they could not afford the cost.
• Women who have a heart attack are much more likely (57%) than men having a heart attack (28%) to call 9-1-1 for help. However, this 2013 study also revealed no difference in calling behavior among men and women with response to chest pain alone.

Heart attacks are a leading killer of people all over the world. Heart attacks occur when heart muscle is deprived of oxygen-rich blood. Although heart disease affects both women and men, many women remain unaware that they are at risk. Moreover, many aspects of heart disease differ between women and men. Here are some of the ways.

• Women often have early symptoms within the weeks prior to their heart attack — unusual fatigue, sleep disturbance, but not always chest pain or discomfort.
• At the time of their heart attack, women have shortness of breath, weakness, and fatigue — but not always chest pressure, pain, or tightness.
• In 2012, 56 percent of all women said they know heart disease as their number-one killer.
  • But… only 36 percent of black women and 34 percent of Hispanic women said they know heart disease as their number-one killer.
  • And… young women (25 to 34) remain least aware: only 44 percent said they know heart disease as their number-one killer.

Influenza, more commonly called the flu, is a viral infection of the nose, throat, and lungs. Flu symptoms may include muscle aches, chills, cough, fever, headache, and sore throat. Research is underway to find out why the flu virus and vaccine affect men and women differently. For example, women are more likely than men to have severe flu symptoms. Here are some facts about men and women and the flu:

• Pregnant women who get the flu are more likely than women who are not pregnant to become very ill and have to go to the hospital. For this reason, doctors recommend that most pregnant women should get a flu shot.
• Women who get a half dose of the flu vaccine produce as many antibodies as men who receive a full dose.
• Men with high levels of testosterone produce fewer antibodies in response to the flu vaccine compared with men with low testosterone.
• The immune systems of female mice respond to the flu virus with a much stronger counterattack, known as an inflammatory response, compared with male mice.
• When female mice are given estrogen, they have less inflammation and milder flu symptoms.

Sex-specific research analyses are especially important in orthopedics because of the substantial sex-based anatomical differences between females and males. Researchers are beginning to appreciate that structural differences of the knee joint and thigh muscles, differences in the ways male and female athletes move, and other sex differences help explain why women are often more susceptible to certain injuries than men. Here are some examples of sex-based factors that affect the health of joints:

• Females are two to three times more likely than males to develop patellofemoral pain syndrome, one of the most common causes of knee pain in teen and young-adult athletes.
• Tears of the anterior cruciate ligament (ACL), the ligament that runs through the front of the knee, are more common in females than in males.
• Temporomandibular joint and muscle disorder-type pain is 2.25 times more prevalent in women than in men
• Among people undergoing total hip replacement, women were 29 percent more likely than men to require repeat surgery within the first three years.
• Female college athletes have the highest risk of having a first-time noncontact ACL injury among female and male athletes in high school and college. (Noncontact injuries are caused by a person's own actions, such as landing after a jump or coming to an abrupt stop while running.)
• Women use their hamstring and quadriceps muscles differently from men when they are running and cutting from side to side during sports activities, and this puts greater stress on the knee.

Lupus is an autoimmune condition that causes inflammation and damage to various organs. Common symptoms include extreme fatigue, painful or swollen joints (arthritis), unexplained fever, skin rashes, hair loss, and kidney problems. Lupus develops slowly, with symptoms that come and go. The most common type, systemic lupus erythematosus, usually appears in the mid-teens, 30s or 40s. Women are more likely to get lupus than men, and African-American, Hispanic, Asian, and American Indian women have a higher lupus risk than white women. Here are examples of how lupus can differ in women and men:

• Although more women than men get lupus and a related disorder, systemic sclerosis, men are more likely to have more severe disease.
• In contrast, women are more likely than men to develop lupus-related urinary tract infections, hypothyroidism, depression, esophageal reflux, asthma, and fibromyalgia.
• Among children and adults with lupus, males are at greater risk than females for kidney injury, kidney failure, and kidney-related death.
• Researchers have found a lupus-related gene (called IRAK1) on the X chromosome, which may help explain why women get the disease more often than men.
• Sex hormones may also have a role in making women more likely to develop lupus.

As is the case with women's health, many people tend to think of men's health as it relates to the reproductive organs. However, just as in women's health, men's health is much broader. While many sex-based influences affect diseases/organs related to reproduction, such as prostate and testicular cancer, many sex-based factors influence diseases and organs unrelated to reproduction. Here are a few examples.

• Osteoporotic fractures in men over 50 are common, yet they are under-recognized and often undertreated.
• Systemic lupus erythematosus, or lupus, is often thought of as a women's disease, yet this condition affects men too. What's more, males with lupus often have more severe disease than females, and they are more likely than females to experience lupus-related kidney failure.
• White male teens and young adults are 55 percent more likely to die of melanoma, the most serious type of skin cancer, than their female peers of the same age.
• Onchocerciasis, the second leading cause of infectious blindness in the world, is more common in men, who work in contaminated rivers in the developing world. Onchocerciasis is thus an example of a gender-based health disparity, since it is caused by a behavior more common to males in certain societies, although it is treatable with antibiotics.

Osteoarthritis is a condition that accompanies aging, as the body's bones and joints suffer wear and tear with time and lots of use. It is painful, and there is no cure. What's more, osteoarthritis remains the leading cause of chronic disability in the United States, and it disproportionately affects post-menopausal women. Current treatment generally involves a mix of exercise, lifestyle modification (such as weight loss), and pain relievers. Researchers are hard at work looking for new clues about how to prevent and treat osteoarthritis. It is more common among women than men in every age group, but there are subtle differences worth knowing about.

• The severity of osteoarthritis is usually significantly worse in women than it is in men.
• In women, osteoarthritis typically affects certain joints such as the knees, hips, and/or hands.
• Before age 45, more men than women have osteoarthritis, but after age 45, the condition is more common in women.
• Black women are at greater risk than white women for developing osteoarthritis and for experiencing complications from the condition.
• Black women and black men with osteoarthritis are much less likely to undergo total knee replacement when compared to white men.

The sensation of pain is a protective response that alerts us when we are hurt or sick. Pain can be caused by injury to a specific area of the body, or it can be caused by an illness, such as the flu, that makes the whole body ache. Pain may be dull or intense; it may be constant; or it may come and go. Sometimes the cause of the pain is unknown. Women seem to be more sensitive to pain than men. Here are some other examples of how pain is different in women and men.

• Several studies show that chronic pain is more common in women than men.
• Women experience pain from musculoskeletal, neuropathic, abdominal, and migraine-related conditions more often than men do.
• Migraines are twice as common in females as in males, and the brain is affected differently in females compared with males.
• Among individuals with depression, women are more likely to report pain complaints than men.
• In imaging tests of people with irritable bowel syndrome, brain regions that control emotions were more active in female brains, and cognitive regions were more active in male brains.
• Researchers have identified a molecular pain pathway that operates only in the spinal cords of male mice.

Women in America are dying from prescription-drug overdoses at unprecedented rates. Most of these deaths are caused by opioids, painkillers that are chemically similar to heroin and that have similar effects in the body and can be highly addictive. Examples include OxyContin, Percocet, and Vicodin. Research has shown that males and females do not respond in similar ways to opioids. Here are some facts about sex- and gender-based difference in prescription painkiller abuse.

• Overall, men are more likely to die of a prescription painkiller overdose than women; however, since 1999, the percentage increase in deaths has been greater among women (400 percent in women compared to 265 percent in men).
• For every woman who dies of a prescription painkiller overdose, 30 go to the emergency department for painkiller misuse or abuse.
• According to the Centers for Disease Control and Prevention, the majority of people, both women and men, who misused prescription pain relievers (55 percent) received them free from a friend or relative, 17 percent got them using a doctor's prescription, 4 percent bought them from a drug dealer, and a small fraction (less than a half-percent) ordered them online.
• Animal studies showed that males and females have different physiological responses to coping with opioid withdrawal, suggesting the need for gender-appropriate addiction-treatment strategies.
• Studies show that overall, women and men have similar perception of pain, but that pain perception varies significantly by trigger, such as cold, hot, pressure, ischemia, or other sensation.
• Use of opioid drugs during pregnancy can produce drug-withdrawal syndrome in newborns. The proportion of babies born with this health burden tripled from 2000 to 2009.

We spend one-third of our lives asleep: this valuable time promotes development in infants and children, cleans up waste accumulated during the body's busy waking hours, solidifies memory, and restores immune health. Sleep is regulated by the circadian clock, which in humans and many animals is controlled by the suprachiasmatic nucleus, a cluster of nerve cells in the brain. Human sleep needs vary significantly throughout life: while newborns spend 14-17 hours sleeping every day, adults need considerably less, between 7 and 9 hours. Many sex-based factors affect sleep.

• On average, women have a 6-minute shorter circadian period (24 hours) than men. Although seemingly small, this difference could contribute to different sleep needs and patterns in women and men.
• Sleep deprivation raises blood pressure more strongly in women than in men.
• A study in mice showed that disrupting circadian rhythms by changing the rodents' light-dark cycle negatively affected female animals' ability to become pregnant.
• Scientists discovered sex-based differences in the sleep patterns of fruit flies: a common animal model for biomedical research. They discovered that young (but not adult) female fruit flies slept mostly at night, whereas young males slept almost as much in the middle of the day as they did at night.
• Driving performance is impaired in women but not in men the morning after taking certain sleep medications: flurazepam (30 mg, when taken at bedtime) and zolpidem (10 mg, when taken in the middle of the night).
• Hot flashes and night sweats during perimenopause and menopause affect a woman's ability to fall asleep and stay asleep.
• Obstructive sleep apnea is more common in men than in women; however, obesity raises risk for both sexes.

Tobacco use is the leading cause of preventable disease and death in the United States and worldwide it carries a substantial health burden. Smoking is an unhealthy habit for both genders, but women and men experience different health risks, and they respond differently to techniques designed to help them quit. Here are some examples:

• Quitting smoking at any age dramatically cuts a woman's risk of death.
• Women smokers have a higher breast cancer risk.
• Women smokers who use oral contraceptives risk serious health effects such as blood clots, heart attacks, and strokes.
• Smoking affects a woman's eyes, putting her at higher risk for vision problems, such as macular degeneration and cataracts, later in life.
• There is a strong relationship between the number of cigarettes a young woman smokes per day and the probability that she will have an ischemic stroke.

Quitting smoking is one of the best decisions a woman can make toward a healthier tomorrow for herself and her family.

• While men are more sensitive than women to nicotine's effects on the body, women are more susceptible than men to smoking sensory triggers like smell and taste, as well as to social cues.
• Nicotine patches and gums don't work as well in women as they do in men.
• Quitting techniques that work better in women than in men include cognitive-behavioral therapy that focuses not only on quitting smoking but also on related issues such as controlling quitting-associated weight gain and moderating mood.

Muscle-derived stem cells, which reside in skeletal muscle tissue, are one type of adult stem cell. Hematopoietic stem cells, in bone marrow, are another. Because stem cells are not yet specialized, they can turn into other many different types of cells, such as bone, fat, and blood.

All cells, not just stem cells, have a sex. Each cell in the body is either male or female, based on its DNA content contributed by XX (female) and XY (male) chromosomes. Other factors contribute as well, such as the source (maternal or paternal) of the X chromosome, and various other biological signatures. Here are some examples of how sex affects stem cells:

• Cell sex exerts a strong effect on the regenerative capacity of muscle-derived stem cells.
• In mice, stem cells that mature to become blood cells divide faster in females than in males.
• Hormones affect growth of stem cells in the mammary gland.

A stroke is sort of like a heart attack in the brain. Strokes occur when blood flow to a part of the brain suddenly stops, starving brain cells of the oxygen they need to live. Clogged arteries can cause a so-called ischemic stroke, in which fat and cholesterol form plaques in artery walls, allowing less blood to flow through freely.

While some of the risk factors for stroke are the same in men and women — such as family history of stroke, high blood pressure or cholesterol, smoking, and being overweight — certain aspects of stroke are unique to women. Researchers have identified several sex/gender differences, such as these:

• While men have a higher risk of stroke than women in general, women are usually older when they have strokes, and they are more likely to die of strokes than men.
• Women have a poorer quality of life after a stroke than men.
• Women with a history of preeclampsia during pregnancy are 60 percent more likely to have a non-pregnancy-related stroke later in life.
• Women who suffer from migraines with visual components like flashing lights have a higher risk of having an ischemic stroke.

Made of DNA, telomeres resemble shoelace tips and serve a similar function. Telomeres are tiny pieces of DNA capping the very ends of our chromosomes. As cells divide normally throughout our lives, each DNA-containing chromosome must be copied, and the tips of stringy chromosomes are particularly vulnerable to damage, much like an actual shoestring can be physically damaged by dragging across the ground.

Thus, telomeres protect our genes by taking a hit themselves — they are known to become frayed and shorter as our cells divide many times throughout life. Scientists are learning that shorter telomeres also show up along with certain diseases, like atherosclerosis and some types of cancer. They suspect that shorter telomeres also compromise the health of cells in blood vessels, which may set the stage for clots to form, stick, and block blood flow.

As reported in a 2011 study, scientists conducting the Cardiovascular Health Study learned that certain telomere-associated molecular changes were linked with higher risk of death from cardiovascular disease in Caucasian women. These findings suggest that short telomeres might be a tool for predicting or monitoring heart disease in some women.

Vision disorders affect women disproportionately both in the United States and throughout the world. But in addition to affecting vision, eye changes can signal the presence of other conditions, especially autoimmune diseases like lupus and rheumatoid arthritis. Ocular manifestations of thyroid disease may be the first characteristic symptom that brings a woman to a physician's office to seek treatment. Here are some examples of how vision disorders affect women and men:

• Dry eye affects twice as many women than men over 50 years of age. Dry eye disease affects quality of life — interfering with routine activities such as reading, working on a computer, and driving a car.
• Cataracts that cloud the eye's lens are more likely to occur in women than in men. In developing countries, women are less likely than men to receive cataract surgery.
• Brain-imaging studies of people with migraines — intense headaches that are twice as common in women than men and that often affect vision — have reported sex-specific patterns.
• Adult women experience about 25 percent more uncorrected visual impairment due to refractive error — which impedes the ability to focus — compared to adult men.
• Worldwide, women account for two-thirds of all people with blindness or visual impairment, but more than three-quarters of these vision problems are preventable.

Vulvodynia is chronic (long-term) pain or discomfort of the vulva, which is the area outside the vagina. Vulvodynia affects women of all races and cultures. Vulvodynia is especially common among women 20 to 50 years old.

• Burning is the most common symptom, with stinging, irritation, and stabbing pain reported by many women.
• The pain or discomfort can be chronic, come and go, and involve the entire genital area or be specific to one area of the vulva.
• Researchers estimate that 9% to 18% of women between the ages of 18 and 64 may experience vulvar pain during their lifetimes.

Many terms are associated with sexual and gender identities, and terminology continues to evolve. Below are some of the terms currently used by the Division of Adolescent and School Health. This list and the definitions offered may change over time.

• Bisexual: A person who is attracted to both people of their own gender and other genders.
• Cisgender: Individuals whose current gender identity is the same as the sex they were assigned at birth.
• Gay: A person who is attracted primarily to members of the same gender. Gay is most frequently used to describe men who are attracted primarily to other men, although it can be used for men and women.
• Gender: The cultural roles, behaviors, activities, and attributes expected of people based on their sex.
• Gender Expression: How an individual chooses to present their gender to others through physical appearance and behaviors, such as style of hair or dress, voice, or movement.
• Gender Identity: An individual’s sense of their self as man, woman, transgender, or something else.
• Gender Minority: Individuals whose gender identity (man, women, other) or expression (masculine, feminine, other) is different from their sex (male, female) assigned at birth.
• Gender Nonbinary: Individuals who do not identify their gender as man or woman.  Other terms to describe this identity include genderqueer, agender, bigender, gender creative, etc.
• Gender Nonconforming: The state of one’s physical appearance or behaviors not aligning with societal expectations of their gender (a feminine boy, a masculine girl, etc.).
• Heterosexual or Straight: A man who is primarily attracted to women or a woman who is primarily attracted to men.
• Intersex: Persons with variations in physical sex characteristics, including variations in anatomy, hormones, chromosomes or other traits, that differ from expectations generally associated with male and female bodies.
• Lesbian: A woman who is primarily attracted to other women.
• LGBTQ: Acronym that refers to the lesbian, gay, bisexual, transgender, and queer/questioning community.
• Queer: An umbrella term sometimes used to refer to the entire LGBT community.
• Questioning: For some, the process of exploring and discovering one’s own sexual orientation, gender identity, or gender expression.
• Sex: An individual’s biological status as male, female, or something else.  Sex is assigned at birth and associated with physical attributes, such as anatomy and chromosomes.
• Sexual Minority: Individuals who identify as gay, lesbian, or bisexual, or who are attracted to or have sexual contact with people of the same gender.
• Sexual Orientation: Refers to a person’s sexual and emotional attraction to another person and the behavior and/or social affiliation that may result from this attraction (lesbian, gay, bisexual, etc.)
• SGM: Acronym for sexual and gender minorities.
• SGMY: Acronym for sexual and gender minority youth.
• SMY: Acronym for sexual minority youth.
• Transgender: Individuals whose current gender identity differs from the sex they were assigned at birth.