Gender approach to Non-communicable Diseases

A) Gender mainstreaming

Gender mainstreaming was defined by the Economic and Social Council of UNO as follows: Mainstreaming a gender perspective is the process of assessing the implications for women and men of any planned action, including legislation, policies or programmes, in any area and at all levels. It is a strategy for making the concerns and experiences of women as well as of men an integral part of the design, implementation, monitoring and evaluation of policies and programmes in all political, economic and societal spheres, so that women and men benefit equally, and inequality is not perpetuated. The ultimate goal of mainstreaming is to achieve gender equality. (United Nations Economic and Social Council's agreed conclusions 1997/2.)
Following those lines the WHO has developed its approach to gender in health through a series of documents (See: a) Integrating gender perspectives into the work of WHO: World Health Organization, 2002. b) Strategic action plan for the health of women in Europe. Copenhagen, World Health Organization, 2001; c) resolution AFR/RC53/r4 on Women's health: a strategy for the African Region and resolution CD46.R16 on PAHO gender equality policy; d) EB116/2005/REC/1, Summary record of the second meeting; and e) Document WHO/FCH/GWH/07.1)
At its 60th session in May 2007, the WHO Health Assembly noted with appreciation the adopted by WHO resolution WHA60.25 to gender in health . The strategy was drawn up on the basis of broad consultation throughout the Organization, with representatives from ministries of health, and with external experts, from which it emerged that gender equality and equity should be integrated into WHO’s overall strategic and operational planning, in order to bring about systemic changes across all areas of work. A plan of action for implementing the strategy continues to evolve (Document WHO/FCH/GWH/07.1).
The Millennium Declaration of United Nations Organizations include the promotion of gender equality and the empowerment of women as effective ways to combat poverty, hunger, and disease and to stimulate sustainable development (United Nations General Assembly resolution 55/2). The United Nations is strengthening gender mainstreaming through a system-wide strategy. To ensure that women and men of all ages have equal access to opportunities to achieve their full health potential and health equity, the health sector needs to recognize that they differ in terms of both sex and gender. Because of social (gender) and biological (sex) differences, women and men face different health risks, present symptoms differently, experience different responses to and from health systems, as well as treatment programs, and their health-seeking behaviour and health outcomes differ.
To fully incorporate analysis of the role of gender and sex in health and determine appropriate action, the WHO Secretariat has given itself the following principles (Strategy for integrating gender analysis and actions into the work of WHO May 2007):

• addressing gender-based discrimination is a prerequisite for health equity
• eadership and ultimate responsibility for gender mainstreaming lie at the highest policy and technical levels of the WHO
• programmes are responsible for analysing the role of gender and sex in their areas of work and for developing appropriate gender-specific responses in all strategic objectives on a continuing basis
• equal participation of women and men in decision-making at all levels of the (WH) Organization is essential in order to take account of their diverse needs
• performance management should include monitoring and evaluation of gender mainstreaming.

WHO strategic directions are chosen as follows:

• Building WHO capacity for gender analysis and planning. To help to ensure that analysis of the role of gender and sex in health and appropriate planning is integrated into WHO’s work at all levels, staff need to have a basic understanding of the subject matter.
• Bringing gender into the mainstream of WHO’s management. Incorporation of gender considerations – in the components of results-based management planning, budgeting, monitoring and evaluation – effectively influences the work of the Organization.
• Promoting use of sex-disaggregated data and gender analysis. In line with the commitment made in the Eleventh General Programme of Work (Document A59/25, paragraph 116), WHO will use sex-disaggregated data in planning and monitoring its programmes and provide support to Member States in improving the collection, analysis, and use of quantitative data on health, disaggregated by sex, age, and other relevant social stratifications.
• Establishing accountability. Accountability for the effective integration of gender perspectives into WHO programmes and operational plans will rest primarily with senior WHO staff.
• Role of the gender, women, and health network. Implementation of the strategic directions will require advocacy, information, technical support, and guidance to staff.

B) Short overview on the scenario in Europe

Non-communicable diseases in Europe

One of the critical problems relevant to the gender approach is found in the primary common diseases for men and women which have the largest impact. In certain diseases, such as cardiovascular diseases (myocardial infarction, stroke) and tumours, the knowledge of the differences is fairly well understood or known; however, this same depth of understanding and knowledge does not apply to the treatment and prevention of others, such as respiratory diseases. Lack of knowledge is parallel to not always certified epidemiology information. European data on mortality of the main diseases (European Cardiovascular disease 2008 http://www.ehnheart.org/content/sectionintro.asp?level0=1457) are represented in the table:

C) Cardiovascular Disease and Gender

CVD multiple risk factors
Differences between genders on the single independent risk factors of cardiovascular disease - CVD are well described. The reference values of many parameters (as blood pressure, waist circumference, HDL,) are consequently indicated (European cardiovascular disease 2008-http://www.ehnheart.org/content/sectionintro.asp?level0=1457).
Prevalence of risk factors is different in men and women. For some time the male gender was ascribed to the non modifiable risks (together familiarity/genetic and age). The modifiable risk factors taken in consideration (Lancet 2004;364: 937-52) are ApoB/ApoAI ratio, blood pressure, overweight/obesity, smoking, diabetes, bad nutrition, sedentarity, stress, social dissatisfaction. Recently air pollution was added: long term to exposure to fine particulate air pollution is associated with incidence of cardiovascular disease and death among postmenopausal women (NEJM 2007; 356:447-58). These risk factors account for more than 92% of the global CVD risk. Less is given to genetic risk. The correlation of those risk factors with CVD was shown to be marginally stronger in women than in men. These results suggest that the existence of one additional risk factor may increase the risk of cardiovascular disease more steeply in women than in men (Gend Med. 2006;3:196–205).

CVD mortality in women
Differences are described in the outcomes of those with myocardial infarction in Italian hospitals.

Hospital outcome report on CVD in Italy 2005 (www.sanita.org)

CVD mortality in U.S. women is not declining
It is the title of a document produced in 2001 (AHA Heart Disease and Stroke Statistics–2005 Update. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497). Women tend to delay seeking treatment longer than men: 18 minutes longer vs. men; time-to-treatment was 12 minutes longer (GUSTO I; Weaver WD. JAMA 1996). More than 20% of young women with multiple risk factors delayed coming to the hospital by 12 hours or more after onset of symptoms (Barron HV. Circulation 1998). Women may experience further delay in the hospital before receiving thrombolytic therapy (mean 112 minutes vs 89 minutes; p<0.01); they waited 7 minutes longer before having their first ECG (mean 26 minutes vs 19 minutes; p<0.01) (Goldberg RJ. Am Heart J 1998)

Clinical research and gender
Much clinical research in the past 20 years on the diagnosis and treatment of CHD excluded or underrepresented women. Only 20% of studies which included women published gender-specific findings. Tests and therapies used to treat coronary heart diseases - CHD in women were based on studies conducted primarily in men (Stanford-UCSF Evidence-based Practice Centre. Profile, November 2002. Agency for Healthcare Quality and Research, Rockville, MD. http://www.ahrq.gov/clinic/epc/ucsfepc.htm)

Gender bias in CVD
Cardiovascular diseases are prevalent in men until the age of 65 years; in women, CVD is prevalent after that age. Women die of CVD more often than men because of age and because of anatomical, functional, and prevalence of risk factors and suffer concomitant mobility. Beyond these differences, a greater disparity may be found in the medical treatment provided to men and women There is a gender bias in the medical approach (NEJM 1991; 325: 274-27. Arch Intern Med 1998; 158: 981-988. NEJM 2007; 356: 898-1009. Circulation 2007; 115: 833-39).
Anatomical and endothelial functional differences in vessels are described (Am Heart J 2000;139: 649-653). Aging and diabetes are increasing the differences (Hypertension 2004; 44: 67-71). Aging, hormonal fluctuations, oxidative stress, metabolic syndrome are increasing the differences between genders of the repairing activities (Circulation 2004; 109:722-725). Early menopause, gestational diabetes (as described in NEJM 2008;358:2061-3), preeclampsia, eclampsia, birth underweight, and other conditions in the young women, are predictive of higher risk of CVD at more advanced ages (J Am Coll Cardiol 2006; 47: 30S-35S).
Stroke is a condition of CVDs where gender differences are known. How much of this knowledge is utilized in the management of stroke in stroke units, or in the risk assessment and prevention in the genders ? (Lancet 2008;371:1612-23). Prehypertension is common and is associated with increased risk of myocardial infarction, stroke, heart failure, and cardiovascular death in Caucasian and non-Caucasian) postmenopausal women (Circulation. 2007;115:855-860. ). The attention to risk factors emphasizes the need for trials to evaluate the efficacy of global cardiovascular risk reduction through primary prevention. Caucasian women with stable and unstable chest pain symptoms, particularly those with angiographic CAD, had higher in-hospital mortality. Similarly, Caucasian women presenting with acute coronary syndrome (ACS) who required angiography on an emergent basis and those presenting in cardiogenic shock were particularly at risk of in-hospital death (Circulation. 2008;117:1787-1801). Cross-sectional studies suggest that prevalence of the metabolic syndrome (MetS) increases from pre-menopause to post-menopause in women, regardless of age. It is debated if the incidence of the MetS increases with progression through menopause and that this increase is explained by the progressive androgenicity of the hormonal milieu. As testosterone progressively dominates the hormonal milieu during the menopausal transition, the prevalence of MetS increases, regardless of aging. This may be a pathway by which cardiovascular disease increases during menopause (Arch Intern Med. 2008;168(14):1568-1575).

Cardiovascular disease in women requires increased awareness and action
In many countries on both sides of the Atlantic Ocean, women believe cancer poses the greatest health threat for them, especially the younger generation. Very few women perceived heart disease as their greatest threat (Women and Heart Disease: A Study Tracking Women’s Awareness of and Attitudes Toward Heart Disease and Stroke. Dallas, Tex: American Heart Association; 2000. http://www.americanheart.org/statistics/cvd.html). This misperception seems not to have changed in the last few years and is in contrast with the above-mentioned figures. There have been improvements in increasing the awareness of stroke symptoms. Most frequently obesity was cited as a major cause of heart disease. Physicians and health professionals report that women are aware of all of the major risk factors (diabetes, smoking, hypertension, high cholesterol, lack of physical activity, obesity); however, the question is how these factors were evaluated and which tools were provided to help women manage their risk factors on their own (Circulation 2005;111:499-510). Women often learn about risk factors in places other than the doctor’s office. The amount of women who do not know their numbers (as the levels of cholesterol, TG, glucose, Blood Pressure, Body Mass Index) is surprising. Despite American Heart Association (AHA) initiatives of more than a decade aimed at educating women about their risk of heart disease, the efforts of other organizations committed to women’s health, and the "The Heart Truth" program of the National Heart, Lung and Blood Institute, in which the American Heart Association is an active partner, most women still were not internalizing their risk from cardiovascular disease and thus were not acting to reduce it (Circulation. 2004;109:561.). Perception of risk was the primary factor associated with CVD preventive recommendations. Gender disparities in recommendations for preventive therapy were explained largely by the lower perceived risk despite similar calculated risk for women versus men. Educational interventions are needed for physicians to improve the quality of CVD preventive care and lower morbidity and mortality from CVD for men and women (Gender Med 2006 3:131-58).

D) Diabetes and gender

Even when women were included in clinical trials, investigators typically made no attempt to assess the impact of gender differences on the reported results. Existing studies, however, reveal several differences between men and women with diabetes. The prevalence of diabetes mellitus (DM) is growing fastest for older minority women. Women with diabetes, regardless of menopausal status, have a 4- to 6-fold increase in the risk of developing coronary artery disease (CAD), whereas men with diabetes have a 2- to 3-fold increase in risk. Women with diabetes have a poorer prognosis after myocardial infarction and a higher risk of death overall from cardiovascular disease than do men with diabetes. Women with type 2 DM experience more symptoms of hyperglycemia than do their male counterparts. Obesity, an important contributor to type 2 DM, is more prevalent in women. Women with diabetes have an increased risk of hypertension compared with men with diabetes. Women have a more severe type of dyslipidemia than do men (low levels of high-density lipoprotein cholesterol, small particle size of low-density lipoprotein cholesterol, and high levels of triglycerides), and these risk factors for CAD have a stronger influence in women). To assess the prevalence of self-reported prediabetes among U.S. adults and the prevalence of activities to reduce the risk for diabetes, the Center for Disease Control analyzed responses to questions regarding prediabetes asked for the first time in the 2006 National Health Interview Survey. In 2006, an estimated 4.0% of U.S. adults had self-reported prediabetes: 4.8% women and 3.2% men. (WWMR November 7, 2008 / 57(44);1203-1205).

E) Visceral obesity and gender

Abdominal adiposity is significantly and positively associated with all-cause and cause-specific mortality independently from body mass index. Greater waist circumference (WC) or waist-hip ratio (WHR) are associated with increased CVD mortality even in normal-weight women. Greater abdominal adiposity is closely associated with adverse metabolic profiles such as insulin resistance, dyslipidemia, and systematic inflammation, which play essential roles in the pathogenesis of CVD and diabetes mellitus. Certain cancers such as colon cancer, breast cancer, pancreatic cancer, uterine, ovarian, and kidney cancer, are thought to be linked with adiposity (Calle EE et alii Overweight, obesity and cancer: epidemiological evidence proposed mechanisms. Nat Rev Cancer. 2004; 4: 579–591). Although maintaining a healthy weight should continue to be a cornerstone in the prevention of chronic diseases and premature death it is equally important to maintain a healthy waist size and prevent abdominal obesity (Cuilin Zhang et alii. Abdominal Obesity and the Risk of All-Cause, Cardiovascular, and Cancer Mortality Circulation. 2008;117:1658-1667). Non-marginal difference by gnder is the impact of cultural approach to nutrition in the two genders. The impact on mortality caused by cardiovascular or other chronic diseases of overall dietary patterns that reflect actual eating behaviors by gender is largely unknown. Greater adherence to the prudent pattern (high intakes of vegetables, fruit, legumes, fish, poultry, and whole grains) may reduce the risk of cardiovascular and total mortality, whereas greater adherence to the Western pattern (high intake of red meat, processed meat, refined grains, French fries, and sweets/desserts) may increase the risk among initially healthy women (Circulation. 2008;118:230-237).

F) Pharmacology and gender

The influence of gender on the effects of aspirin in preventing myocardial infarction
Gender accounts for a substantial proportion of the variability in the efficacy of aspirin in reducing MI rates across these trials, and supports the notion that women might be less responsive to aspirin than men (BMC Medicine 2007, 5:29). It is shown that 75 mg/die aspirin produce conclusive benefit in secondary prevention and in treatment in MI, stroke, and vascular disorders Men and women have apparently equal benefits using aspirin in secondary prevention after CVD events; however, women do not have equal benefits as men by using aspirin in primary prevention of CAD (Women Health Initiatives results: communicated by Julie Buring - Europrevent Congress. Paris May 2nd 2008). Aspirin treatment for primary prevention is cost-effective for men with a 10-year cardiovascular disease risk >10% and for women when the risk was >15%. In general, this occurs much later in life for women than men. Therefore, opportunities for the primary prevention of aspirin seem limited in women, and a gender-differentiated preventive strategy seems warranted (Circulation. 2008;117:2875-2883).

G) Smoking and gender

Although the rate of smoking is, for the most part, higher among males, the results of studies showed that the disease associated with smoking is higher among females. Because this risk is higher for females at both high and low levels of smoking, there may be some underlying effects that place females at a higher risk regardless of how much they are smoking. The disease outcomes included in the analyses were similar for both sexes, thus the difference in risk may not be due solely to any difference in the outcomes in each group. Rather, there are other factors involved, such as a gender difference in the relationship of smoking to specific disease exacerbation (Am J Prev Med. 2006;30:405-412 and Gend Med. 2006;3:279-291). It is more difficult to evaluate the differences in results of smoking cessation programs by gender. The prevalence of men in cessation programs is mainly linked to the higher prevalence of smoking in males than in women (about the prevalence of males and female smokers in smoking cessation programs see in Arch Intern Med. 2008;168(18):1961-1967 and Arch Intern Med. 2008;168(18):1968-1974)

H) Molecular biology and gender

Differences in the length of telomeres (repeated sequence TTAGGG at the ends of chromosomes) of the cell nucleus of men and women have been described. The telomeres are gradually eroded as life goes on, and several studies have shown that men have shorter telomeres than women (Med Hypotheses. 2004;62:151–154). Many cells die when the telomeres join to a critical length. The length of telomeres is considered a marker of biological life.
“...the replicative history of male cells might be longer than that of female cells, resulting in the exhaustion of the regeneration potential and the early onset of age-associated disease predominantly in large-bodied males” (BMJ. 2000;321:1609–1612).

I) Osteoporosis and gender

Projections about increasing numbers of cases of osteoporosis in the future are well founded, since the population in general is aging and age itself is a risk factor. It is estimated that the current number of osteoporosis cases in the U.S. alone is at 10 million, with another 34 million individuals at risk of fracture due to low bone mass. Osteoporosis incidence increases with age, affecting 60 and 69; 75% between ages 70 and 79; and 87% of women older than 80 years of age (Improving and Measuring Osteoporosis Management National Pharmaceutical Council, by The Joint Commission 2008). Men are not immune to the disease, as 5% of men on Medicare in 2001 had a diagnosis of osteoporosis (Am J Manag Care. 2006;12(Suppl 7):S181-S190). Estimates are that the number of persons older than age 50 with osteoporosis will increase to 12 million by 2010 and to nearly 14 million by 2020 (Am J Med. 2006;119(4)(Suppl 1):S3-S11). One out of two women and one out of eight men will be affected by osteoporosis in their lifetime. There are several identified risk factors for the development of low bone mass. Chief among these is age itself. A recent study among 616 women, aged 60-94, found that for each year of increasing age, the fracture risk increases by 3% (Bull World Health Organ. 2003;81(11):827-830). Among women, the gradual loss of estrogen at menopause contributes significantly to this decline in bone integrity and is a principal factor in what Riggs and Melton proposed in 1983 as Type I involutional osteoporosis (N Engl J Med. 1986;314(26):1676-1686). The reduction in circulating estrogen triggers osteoclast activation and bone resorption, resulting in rapid bone loss at a rate of 1% to 5% yearly; this phase lasts from four to eight years (Am J Manag Care. 2001;7(special SP5-16) .The second phase, a more gradual bone loss, occurs 10 to 20 years after menopause and affects men as well as women. This Type II osteoporosis is marked by a rise in parathyroid hormone (PTH) levels, increase in bone turnover, and a decline in osteoblastic activity causing reduced bone formation (Am J Manag Care. 2001;7(special SP5-16) . In spite of the detailed description above, many questions remain regarding the differences between genders and consequently the necessary different medical approaches to the treatment and prevention of the osteoporosis. Women with diabetes often suffer from neuropathy and retinopathy and thus are at greater risk of falls and fractures that may result from these falls (J Clin Endocr Metab 2006;91;3404-3410). Two gene variants of key biological proteins (one close to osteoprotegerin, the other close to the LDL-receptor-related protein) found in men, increase the risk of osteoporosis and osteoporotic fracture. The combined effects of these risk alleles on fractures is similar to that of most well-replicated environmental risk factors, and they are present in more than one in five white people (Lancet 2008;371:1505-12)

J) Neurodegenerative and mental disorders and gender

Globally observed brain, psychiatric, and neurological diseases have a big impact in Europe, both socially and economically. Data of the World Health Organization (WHO) suggest that brain diseases are responsible for 35% of Europe’s total disease burden. An analysis of all health economic studies of brain diseases in Europe, published by the European Brain Council (EBC) in June 2005, estimated the total cost of brain disease in Europe in 2004 to be € 386 billion (J Neurol Neurosurg Psychiatry 2006;77(suppl_1):i1-i49).That burden is set to grow, mainly due to the fact that the European population is aging.

Major depression
It ranks second among the 10 leading causes of disability adjusted life-years (DALY) after ischemic heart disease. In the next 20 years, the number of people suffering from brain disease could grow as much as 20%. The population of Europe is aging, and the expansion of the information era, primarily through the high speed visual mode which impacts the human brain from a young age, will contribute, though not in a predictable extension, to brain disorders. Moreover the increasingly wide geographical dispersal of families, the weakening of family networks, and the changing role of women mean that patients with brain disease are not cared for in the home environment, thus shifting the cost burden to professional care services.

Brain and Gender
Structural and functional sex differences in the brain may be related to reproduction, sexual orientation, gender identity (i.e. the feeling of being male or female), cognition, and disease. In a number of areas of the human hypothalamus, structural and functional differences between the sexes and between homosexual and heterosexual men have been described. The mamillary body complex (MBC) in the caudal hypothalamus has been studied in postmortem brain material from the following groups: young heterosexual men, young homosexual men, aged heterosexual castrated and non-castrated men, castrated and non-castrated transsexuals, young heterosexual women, and a young virilized woman. Nuclear androgen receptor immunoreactivity (AR-ir) did not differ significantly between heterosexual and homosexual men, but was significantly stronger than that in women. A female-like pattern of AR-ir (i.e. related to nuclear staining) was observed in 26- to 53-year-old castrated male-to-female transsexuals and in old castrated and non-castrated men, 67-87 years old. In conclusion, the sexually dimorphic AR-ir in the MBC seemed to be clearly related to circulating levels of androgens and not to sexual orientation or gender identity. The functional implications of these alterations have to be discussed in relation to reproduction, cognition, and neuroprotection (The Journal of Clinical Endocrinology & Metabolism 2001;86:818-827).
Besides the well-established actions on reproductive functions, estrogens exert a variety of actions on many regions of the nervous system that influence higher cognitive function, pain mechanisms, fine motor skills, mood, and susceptibility to seizures; they also appear to have neuro-protective actions in relation to stroke damage and AD. Estrogen actions are now recognized to occur via two different intracellular estrogens receptors, ER-α and ER-β, that reside in the cell nuclei of some nerve cells, as well as by some less well-characterized mechanisms. In the hippocampus, such nerve cells are sparse in number and yet appear to exert a powerful influence on synapse formation by neurons that do not have high levels of nuclear estrogens receptors. Sex differences exist in many of the actions of estrogens in the brain, and the process of sexual differentiation appears to affect many brain regions outside of the traditional brain areas involved in reproductive functions. Furthermore, the aging brain is responsive to actions of estrogens, which have neuro-protective effects both in vivo and in vitro (Appl Physiol 2001;91:2785-2801).

Alzheimer’s disease - AD
AD the most common cause of dementia, affects 3% to 4% of the population above 65 years of age: 2.5 million with an estimated incidence approaching 0.5 million. In 2000 Alzheimer’s disease was the eighth leading cause of death for women in the United States. (National Vital Statistics Report, Vol 49, No. 11. Hyattsville (MD): National Center for Health Statistics, Centers for Disease Control and Prevention. U.S. Department of Health and Human Services; October 12, 2001 2001). There have been many observations of gender differences in normal brain structure and function. “Women’s brains are different from men’s. That’s not new. What is new is that the differences are smaller than most people believe. They are not big enough to say that one sex is smarter or better at math than the other. What is also new is that the small differences can be significant when it comes to memory, arousal, reasoning, and risk of some diseases. The latter include depression, anxiety, schizophrenia, drug abuse, Alzheimer’s, diabetes, and heart disease” (William J. Cromie Harvard News Office June 25, 2007) . Quantitative sex differences in brain aging of normal males and females have been reported in a number of magnetic resonance imaging (MRI) studies. It has been reported (Arch Neurol 1998 55(2):169-179) that, in men, reduction in brain volume was greater in the parieto-occipital regions. In a magnetic resonance spectroscopy study, phosphorus metabolism was reduced in the frontal lobes of women with AD as compared to men. A similar, though non-significant, effect was seen among normal elders (Ann Neurol 38:194-201).
Subjects with mild cognitive impairment (MCI) have been shown to have reduced hippocampal volumes relative to normal elderly control subjects. The presence of the apo-lipoprotein E ε4 (APOE*E4) allele has been associated with greater hippocampal atrophy in women than in men with AD. The APOE*E4 genotype status appears to have a greater deleterious effect on gross hippocampal pathology and memory performance in women than in men (Arch Neurol. 2005;62:953-957). Recent epidemiological and experimental data also support a role for the gonadotropin luteinizing hormone in AD (Clin. Med. Res 2007;5:177-183). Attention is devoted to the role of mitochondria in the pathogenesis of Alzheimer's disease, and to the effect of gender on the incidence of Alzheimer's disease and the pathophysiological mechanisms involved (Antioxid Redox Signa 2007;9:1677-90). It remains controversial whether men and women differ in the incidence of AD and whether there are clearly recognizable sex differences in cognition and behaviour among those afflicted. A thorough defining of these differences is important for the sake of understanding the behavioural problems of AD and for developing a more refined approach to their treatment. More research into the biological underpinnings as well as the social influences on these differences is needed (Geriatric Times, letter to November/December 2001 Vol. II Issue 6).
Hormonal changes associated with the dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis following menopause/andropause have been implicated in the pathogenesis of AD. The marked increases in serum luteinizing hormone (LH) following menopause/andropause as a physiologically relevant signal could promote Aβ secretion and deposition in the aging brain (J. Biol. Chem., 2004;279: 20539-20545). Epidemiological and experimental data also support a role for the gonadotropin LH in AD. Paralleling the female predominance for developing AD, LH levels are significantly higher in females as compared to males, and furthermore, LH levels are higher still in individuals who succumb to AD. Luteinizing hormone, which is capable of modulating cognitive behaviour, is not only present in the brain, but also has the highest receptor levels in the hippocampus, a key processor of cognition that is severely deteriorated in AD. Furthermore, examined cognitive performance in a well-characterized transgenic mouse that over-expresses LH show that these animals show decreased cognitive performance when compared to controls (Clin. Med. Res 2007;5: 177 – 183).
It is generally recognized that the prevalence of AD is higher in women, but whether incidence is increased remains a controversial issue. In a review of gender differences in the incidence of neurologic disease (Gender differences in diseases of the nervous system. In: Neurologic Disease in Women, Kaplan PW, ed. New York: Demos Medical Publishing Inc., pp433-442, 1998. ) it was reported that age-adjusted incidence was higher in women, particularly with advancing age. In a meta-analysis of AD incidence studies (Neurology 1008;51:728-733) it was found no significant sex differences overall; however, there was a trend toward higher incidence among women in the oldest age groups. It remains controversial whether men and women differ in the incidence of AD and whether there are clearly recognizable sex differences in cognition and behaviour among those afflicted. The correlation of the structural brain differences with the differences in behavioural disturbances is not clearly defined.
The gender difference in apolipoprotein E-associated risk for familial Alzheimer disease has been evaluated and may be a possible clue to the higher incidence of Alzheimer’s disease in women.
In women, ε4 heterozygotes had higher risk than those without ε4; there was no significant difference between ε4 heterozygotes and ε4 homozygotes. In men, ε4 heterozygotes had lower risk than ε4 homozygotes; there was no significant difference between ε4 heterozygotes and those without ε4 (Am J Hum Genet. 1996; 58: 803–811).
Myeloperoxidase is an enzyme associated with the plaques that appear in the brains of people affected by AD. Some versions of the gene that encode the enzyme increase the incidence of AD in women, while other versions increase the incidence in men (Neurology. 2000;55(9):1284-1290 and Exp Neurol. 1999;155:31-41). Gender differences in the neurodegenerative process of AD may add to gender differences in domain specific cognitive impairment (Archives of Women's Mental Health 2002;4:129-137).
Recognition memory for olfactory stimuli may be particularly impaired in healthy older men with the ε4 allele. In patients with AD, odour memory impairments may be less severe in women who are negative for the ε4 allele. The results offer new insight into how recognition memory is affected by gender, the ε4 allele, and the modality of the stimulus to be remembered in healthy older adults and patients with AD (Am J Geriatr Psychiatry 15:869-878, October 2007).
There is a growing body of literature on the importance of cardiovascular risk factors in the development of AD, vascular dementia, and mixed dementia (AD with cerebrovascular disease). From the scouting the MEDLINE, PubMed, and HealthSTAR databases between 1966 and January 2007 for English-language articles on the risk factors for dementia the following indications have been raised: a) the distribution and prevalence of major risk factors between the sexes and age groups are varied; b) female sex has been associated with increased risk of the development of AD; c) in women aged >75 years, rates of hypertension, hyperlipidemia, and diabetes are higher than in similarly aged men; d) midlife hypertension and hypercholesterolemia in both sexes predict a higher risk of developing AD in later life; e) diabetes is increasing in frequency to a greater extent in women than in men, and is associated with a substantial risk for cognitive impairment; f) dementia in women (probably) and in men (possibly) is influenced by obesity in middle age. It remains critical that large prospective clinical trials be designed to assess the effect of optimum management of vascular risk factors on cognitive functioning and dementia as the primary outcome, and include women and men in numbers adequate for assessment of gender effects (Gend Med. 2007;4:120-9).

L) The message
The amount of data showing differences between genders in the common (to men and women) pathologies is increasing. Some data are still controversy, and many need further research and understanding. The scenario clearly supports the need to increase the attention of basic scientists, clinicians, physicians, to gender differences affecting health and medical approaches to individuals. Gender health protection demands commitment and the efforts of all stakeholders in this field of medicine, which must be seen as a transversal discipline (or interdisciplinary) through well-established medical specialties.