Women's Health

Abstract

Many of the unique health issues facing women are related to reproductive health and pregnancy. However, several conditions that affect both sexes have distinct manifestations in women including cardiovascular disease, osteoporosis, and anemia. The extent of the effect that the physiological differences between men and women have on the natural course of these diseases and the validity of applying a standard treatment to both genders has not been fully explored. Historically, medical research has largely excluded women, rendering the application of evidence-based medicine to women's health issues somewhat of a misnomer. While most research in women's health originates from developed nations, consideration must be given to women in all regions of the world. Compared to women in developed nations, women in resource-poor countries are burdened with increased morbidity and mortality from gender-related health issues. In order to globally advance women's health, the physiologic and social differences between men and women must be more clearly characterized and these differences must be taken into consideration when designing research endeavors and developing health policy.

Key Words::

• Sex differences
• life expectancy

Introduction

Why is it important that we study women's health? What are the differences between women and men that affect their health? Why hasn't more research on women been done in the past? Moving forward, what is needed to advance women's health? This review aims to address these questions and summarize the current status of women's health.

Differences between men and women that affect their health

Women have a longer life expectancy than men. Across races, across most geographic locations and throughout life, females have lower death rates. This was not always true. Female mortality exceeded male mortality during most of the history of the human species. Why? Mortality was tied closely to the enormous toll of childbirth. It was not until about 150 years ago, with the advent of the industrial revolution, that human life expectancy exceeded 40 years of age and, with dramatic improvements in midwifery that women began to outlive men. Now, in nearly all industrialized nations of the world, men live shorter lives than women and the gap is widest in high-income nations such as the US and Canada (Figure 1) [1]. Explanations for the difference in life expectancy have been classified broadly into social/ behavioral and biological differences.

Figure 1. Life expectancy at birth in the United States for all races by sex. Data from Centers for Disease Control. Accessed 26 December 2013 from: http://www.cdc.gov/nchs/data/hus/hus12.pdf#017.

Social/behavioral differences

Historically, the social and economic status of women has been lower than men in most societies, meaning women have less access to the basic necessities of life, including medical care. Their status has been rising in industrialized nations for over 50 years and women's health has benefited from this rise (hence the increased life expectancy). However, despite these gains, the socioeconomic status of women still remains markedly below men. Even in the US, women are more likely to work part-time, participate in unwaged labor and receive unequal wages, all of which affects their health, as well as their access to medical care. Life expectancy in women may increase even further as social and economic gender disparities decrease.

Behavioral differences are also evident. In most societies, men have consumed more tobacco, alcohol, and drugs than females. Hence, they are more likely to die from associated diseases such as lung cancer, tuberculosis and cirrhosis of the liver. Men are also more likely to die from injuries (Table I). Unintentional injuries, because of occupational hazards, car accidents, or war, caused 6.2 % of male deaths in the US in 2009 compared to only 3.5 % of female deaths. Likewise, suicide caused 2.4 % of deaths in males and < 1 % of deaths in women [2,3].

Table I. Leading causes of death by sex for all races in the United States 2009.

Rank	Males	%	Females	%
1	Heart disease	25.2	Heart disease	24.0
2	Cancer	24.4	Cancer	22.2
3	Unintentional injuries	6.2	Stroke	6.3
4	Chronic lower respiratory diseases	5.3	Chronic lower respiratory diseases	5.9
5	Stroke	4.3	Alzheimer's disease	4.5
6	Diabetes	2.9	Unintentional injuries	3.5
7	Suicide	2.4	Diabetes	2.8
8	Influenza & pneumonia	2.1	Influenza & pneumonia	2.3
9	Kidney disease	2.0	Kidney disease	2.0
10	Alzheimer's disease	2.0	Septicemia	1.6

Data from http://www.cdc.gov/women/lcod/ and http://www.cdc.gov/men/lcod/2009/LCODrace_ethnicity2009.pdf

Biological differences

As we level the playing field and diminish social/behavioral differences, the effect of the biological differences between men and women on the quality and quantity of life become more apparent.

At the most basic level, there are differences between men and women in their very cells. Women and men have different chromosomes. Even the genes we share make proteins at different rates. Variations in imprinting cause genes inherited from the father and mother to be differentially expressed. There are also differences in the activation of signaling pathways. These observations suggest that biomarkers indicating the presence or severity of disease may need to be interpreted differently between men and women.

Female-specific differences

Women face a host of unique reproductive health problems. Despite great strides in advancing obstetrical care, pregnancy still presents significant health risks to women, even in developed countries. Approximately 350,000 women worldwide die each year from pregnancy-related causes. Almost all of these deaths occur in resource-limited settings. However, pregnancy-related deaths are not limited to under-developed countries. The number of reported pregnancy-related deaths in the US has steadily increased from 7.2 deaths per 100,000 live births in 1987 to a high of 17.8 deaths per 100,000 live births in 2009 [4]. The reason for this increase is unclear. The increase may be due to improved ways of identifying pregnancy-related deaths over time. It may also be due to the fact that many studies show an increased number of pregnant women in the US have chronic, pre-existing, health conditions such as hypertension, diabetes and chronic heart disease which may put pregnant women at increased risk of adverse outcomes. In fact, the most frequent pregnancy-related deaths in the US include cardiovascular disease, other non-cardiac diseases (such as endocrine, respiratory and gastrointestinal), infection/sepsis, hemorrhage and hypertensive disorders of pregnancy (Table II). Of women who do survive childbirth, 10–20 million each year suffer complications. The most common pregnancy complications include ectopic pregnancy, preterm labor, gestational diabetes, hyperemesis gravidarum, hypertensive states including preeclampsia, and anemia [5].

Table II. Causes of pregnancy-related death in the US, 2006–2009.

	%
Cardiovascular diseases	14.6
Infection/sepsis	14.0
Non-cardiovascular diseases, (e.g. infectious, respiratory, gastrointestinal, endocrine, hematologic)	11.9
Cardiomyopathy	11.8
Hemorrhage	11.0
Hypertensive disorders of pregnancy	9.9
Thrombotic pulmonary embolism	9.4
Cerebrovascular accidents	6.1
Amniotic fluid embolism	5.4
Anesthesia complications	0.6

From [4].

Infertility affects at least 1.5 million couples in the US according to the Centers for Disease Control and Prevention (CDC) [6]. As a result, 147,260 in vitro fertilization (IVF) procedures were performed in the US in 2010, resulting in 47,090 live births [7]. Nearly half of all infants conceived by IVF are multiple-birth deliveries which are associated with increased morbidity and mortality for both mother and infants due to increased maternal blood pressure, premature delivery, and low birth weight. It is important to note that both women seeking treatment for infertility and multiple birth pregnancies are increasing due to women waiting longer to have children.

For US women, the three most commonly diagnosed types of cancer in 2012 were: lung, breast and colorectal (Table III) [8]. Breast cancer accounted for 29 % of all new cancer cases among women. Although men have a slightly higher lifetime probability of being diagnosed with an invasive cancer than women (45 % vs 38 %) [12], because of the earlier age at diagnosis for breast cancer, women have a higher risk of developing cancer before age 60. This earlier diagnosis actually places breast cancer on the top 10 list of chronic diseases affecting women (Table III) [9], which has a huge effect on the quality of life for these women.

Table III. Ten leading causes of death by cancer, US 2012. Estimates are rounded to the nearest 10 and exclude basal and squamous cell skin cancers and in situ carcinoma except urinary bladder.

Males		%	Females		%
Lung & bronchus	87,750	29	Lung & bronchus	72,590	26
Prostate	28,170	9	Breast	39,510	14
Colon & rectum	26,470	9	Colon & rectum	25,220	9
Pancreas	18,850	6	Pancreas	18,540	7
Liver & intrahepatic bile duct	13,980	5	Ovary	15,500	6
Leukemia	13,500	4	Leukemia	10,040	4
Esophagus	12,040	4	Non-Hodgkin lymphoma	8,620	3
Urinary bladder	10,510	3	Uterine corpus	8,010	3
Non-Hodgkin lymphoma	10,320	3	Liver & intrahepatic bile duct	6,570	2
Kidney & renal pelvis	8,650	3	Brain & other nervous system	5,980	2
All sites	301,820	100	All sites	275,370	100

Data from Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012;62: 10–29 [8].

Worldwide, cervical cancer is one of the most common malignancies affecting women, primarily women of poor socioeconomic status. Infection with human papillomavirus (HPV) is a key factor in the etiology of cervical cancer and it is also associated with cancers of the vulva, vagina, anus, and oropharynx. More than 290 million women are infected with HPV, one of the most common sexually transmitted infections. Approximately 5 % of the 12.7 million new cancer cases that occurred in 2008 worldwide could be attributed to HPV infection [10]. Screening programs, including annual Pap smears, have been largely successful at identifying pre-cancerous changes of the cervix in women who have access to medical care in developed nations. The HPV vaccine is available as part of routine immunization programs in 45 countries, most of them high- and middle-income. HPV vaccination could prevent the deaths of more than 4 million women over the next decade in low- and middle-income countries, where most cases of cervical cancer occur, if 70 % vaccination coverage can be achieved.

In contrast, an effective screening test for ovarian cancer remains to be developed. While less common than cervical cancer, ovarian cancer is the fifth leading cause of death from cancer in women in the US (Table III) [8]. Ovarian cancer is more common in industrialized nations and is insidious in onset because it is usually asymptomatic until it is widespread. More than 50 % of women presenting with ovarian cancer have stage III or stage IV cancer, when it has already spread beyond the ovaries. Hence, ovarian cancer generally has a poor prognosis.

Diseases shared by men and women

Men and women suffer from many of the same diseases, but the incidence, course of disease, and hence mortality rates differ between the sexes. For instance, the sequelae of cardiovascular disease (CVD), including heart attack and stroke, are the number one cause of death in men and women the United States (Table I) and the top chronic diseases for women in the US (Table III). However, cardiovascular disease tends to occur later in life for women. The incidence of stroke in women, while lower than that in men before age 80, exceeds the incidence in males after age 80. This results in a higher lifetime risk of stroke for women than men [2,3]. CVD risk associated with diabetes is also higher in women than men, and the risk for CVD in smokers compared to nonsmokers is higher in women.

Osteoporosis is among the top ten chronic diseases in the US (Table IV) and roughly 1.5 million people suffer a bone fracture each year related to osteoporosis [11]. This disease disproportionately affects women with 16 % of women > 50 years of age diagnosed with osteoporosis of the femur, neck or lumbar spine compared to only 4 % of men [12]. This has a significant impact on mortality since ∼20 % of senior citizens who suffer a hip fracture die within a year of the fracture.

Table IV. Prevalence of the top 10 chronic diseases among women in the US.

	Prevalence (age > 18 years)^a
	%	million
Cardiovascular disease (including hypertension)	38.5	42.0
Hypertension	32.9	36.3
Intimate partner violence (lifetime)	26.4	30.2
Obesity	25.2	29.5
Smoking	17.5	20.5
Chronic obstructive pulmonary disease, COPD^b	10.7	9.0
Diabetes	7.3	8.5
Osteoporosis	17.8	7.8
Psychological distress	3.4	3.8
Breast cancer	2.1	2.5

^aThe age group for obesity (20+) and osteoporosis (50+).

^bCOPD includes both moderate obstructive lung disease and mild obstructive lung disease.

Data from [9].

Much of the difference between men and women in the prevalence of osteoporosis is due to post-menopausal loss of estrogen. Hormone replacement therapy (HRT) has been shown to reduce risk of fracture by 25–30 % [13]. For this reason HRT was common place in the 1980s and 1990s. However, the benefits of treatment were called into question when studies from the Women's Health Initiative indicated that HRT actually increased the risk of cardiovascular disease. Thus, issues such as osteoporosis prevention and identifying alternative forms of treatment are of major importance to women's health.

Each year, approximately 500 million people worldwide acquire one of four sexually transmitted infections (STI): chlamydia, gonorrhea, syphilis and trichomoniasis [14]. An additional 2.3 million people annually acquire HIV. STIs are an important global health priority because of their devastating impact on women and infants and their inter-relationships with HIV/AIDS. Certain STIs can increase the risk of getting and transmitting HIV and alter the way HIV progresses. STIs can also cause long-term health problems, particularly in women and infants. Some of the health complications in women that arise from STIs include pelvic inflammatory disease, infertility, ectopic pregnancy, and cervical cancer (as discussed above). Mother-to-child transmission of STIs can result in stillbirth, neonatal death, low-birth-weight, prematurity, sepsis, pneumonia, neonatal conjunctivitis, and congenital deformities.

Anemia is a significant global health problem with 1 out of 4 people affected [15]. Women are disproportionally affected, with 30 % of non-pregnant women and 42 % of pregnant women defined as anemic. Anemia in women has been linked to poor pregnancy outcomes and decreased cognitive function, concentration and attention (in women and their children) [16]. Iron deficiency anemia (IDA) is the leading cause of anemia. In the US, 37 % of pregnant women have IDA and globally, 80 % of pregnant women have IDA. Why are women disproportionally affected by anemia? In adolescent girls, anemia can be linked to menstrual blood loss, the nutritional demands of growth, and dietary issues. In adult women menstrual blood loss and pregnancy affect red blood cell counts. In spite of its high prevalence and impact on global health, anemia receives little attention from the medical community which further contributes to the problem.

Women as research subjects

The atrocities of World War II and the Nuremburg trials that followed brought about new awareness of ethics in research and sensitivity to doing research on vulnerable populations. Laws were put into place in the US by the Public Health Service to make sure that research subjects, particularly those with physical, mental or social limitations were not exploited. Biomedical research was widely regarded as dangerous and of little value, so it is no surprise that women and minorities did not participate to any great extent [17]. In addition, males could be considered more attractive as study subjects because they have no menstrual cycle and hence their hormones do not fluctuate much over time so they are a more homogeneous population.

In 1977, in response to the tragic outcomes from drugs like thalidomide and Diethylstilbestrol (DES), the FDA actually banned pregnant women and women of childbearing potential from participating in early-stage clinical trials. However, the policy was interpreted very broadly and, in practice, the ban ended up being applied to all women [17]. Exclusion of women became so routine that it was seldom challenged.

During the 1980s women's rights became a national issue. People began to realize that many drugs had never been tested on women of child-bearing potential and hence physicians had no idea if they were safe and efficacious in women. In addition, it became clear that little basic research focused specifically on the health of women. In 1990, the National Institutes of Health (NIH) Office of Research on Women's Health (ORWH) was founded to address the inequities in women's health research and delivery [18].

The law banning women of child-bearing potential from participating in research studies was upheld until 1993 when Congress passed the National Institutes of Health Revitalization Act which required that all NIH-funded phase 3 clinical trials include women, unless for some reason exclusion was deemed appropriate. Since then, the number of women in studies has improved greatly and human studies committees strive to ensure equal representation in human research. There are now a number of studies, such as the NIH's Women's Health Initiative (WHI) that focus exclusively on women. The WHI is the largest disease prevention study ever conducted in the US. It was created to examine the major causes of death, disability, and frailty in older women of all races and from all socioeconomic backgrounds [18].

However, many argue that there is still disparity in biomedical research. There are a number of studies that indicate that women are still under represented in clinical trials. According to a 2006 study, women made up less than 25 % of all patients enrolled in the 46 clinical trials examined and published in 2004 [19]. In another study, women made up only 10–47 % of subjects in 19 heart-related trials [20] despite the fact that heart disease kills as many women as men each year. A survey of studies published in 2004, in nine medical journals, found that only 34 % of participants were women (24 % in drug trials), and only 13 % of these studies were analyzed by sex [21]. Interestingly, the majority of animal studies also still use male animals.

Finally, there is the sensitive issue of the use of pregnant women in clinical trials. The fact is that pregnant women get sick, and sick women get pregnant, so we need drugs that can be safely used in pregnant women. However, there are ethical and legal ramifications for including pregnant women in clinical trials. The end result is that medicine today remains less evidence-based for women than it is for men.

How to advance women's health in the future

Improve research

There is much to be done in the area of research. Certainly there need to be more studies on diseases that are unique to women or more serious in women or that have different risk factors in women compared to men. Sex-balanced studies are also needed, but researchers need to do more than just meet sex quotas. They need to analyze the data in a way designed to detect differences due to sex. There are ways to help expedite these necessary changes in research. Journals can insist that authors document the sex of animals used in published papers. Funding agencies should demand that researchers justify sex inequities in grant proposals and should favor studies that are more equitable when all other factors are equal. Also, health organizations should encourage more women to participate in clinical research studies. Advances have been made in these areas. As mentioned previously, the WHI is already underway examining specific risk factors and biomarkers for disease in women. Also, in 2006 the Organization for the Study of Sex Differences was founded by the Society of Women's Health Research, which also launched the journal Biology of Sex Differences.

Practice medicine that takes into account differences in sex

It is critical that ‘normal’ be properly defined. Normal growth and development for women needs to be clarified. Laboratory assay reference intervals should be established specifically for women where appropriate. Sex-specific drug dosing also needs to be outlined. It is also key that as sex differences are defined that they are translated into clinical practice.

Increase access to healthcare for women

In many parts of the world, including the US, women still lack access to healthcare. Prior to the implementation of the Affordable Care Act (ACA), it was estimated that 25 % of reproductive age women in the US were uninsured [22]. Uninsured women often forgo annual physical exams, preventative screening tests and prenatal care due to financial hardship. Ironically, US women living below the poverty line are at much higher risk of unplanned pregnancy, unplanned delivery, and electively undergoing medical or surgical abortion compared to women who reported family income of greater than twice that of the poverty line. The financial barriers to healthcare US women in poverty face are compounded by social barriers including lack of education, unreliable transportation, inflexible work schedules and inability to obtain child care.

In resource-poor countries, women's access to healthcare is further restricted. Less than half of childbirths in developing nations are attended by a trained healthcare provider (be it midwife, nurse or physician), resulting in maternal mortality that approaches one per 1,000 births in some countries. The dearth of skilled healthcare providers, appropriately outfitted medical facilities and sufficient pharmaceutical formularies leads to increased female morbidity from conditions that could be treated in developed nations including obstetrical fistulas, STIs and cervical cancer.

Promote participation of women in biomedical careers

Many of these action items are goals of the NIH's ORWH. Another goal established by the ORWH is to create pathways for women to overcome the barriers to biomedical careers. It is felt that the best way to ensure that research related to women's health remains a high priority is to increase the number of women in the fields of medicine and research and in leadership positions in federal government, universities and the private sector [18]. Women still face a glass ceiling in science careers, from salary to grant funding and laboratory space [23]. According to the US National Science Foundation, women earn approximately half the doctorates in science and engineering in the US but comprise only 21 % of full science professors and 5 % of full engineering professors. On average, they earn just 82 % of the amount male scientists make in the US and even less in Europe [23].

Conclusion

Women have a unique set of health conditions that arise from social/behavioral and biological differences. The biological differences between females and males extend from obvious phenotypic traits to subtle but significant variations at the cellular level. Women also have unique risks for developing diseases that are common to both men and women. The historical exclusion of women from clinical studies challenges the application of ‘evidence-based’ medicine in women. More recent studies including both men and women come closer to addressing the knowledge gap in women's health. However, neglecting to analyze the data in a way that can decipher differences between the sexes compromises the care we provide for both men and women. Ultimately, a careful consideration of sex differences works to everyone's benefit.

Acknowledgements

We would like to thank Melanie Yarbrough for help in editing this manuscript.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.